Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[N:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=2)=[CH:10][O:9][N:8]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:20]([C:17]2[CH:16]=[N:15][C:14]([O:13][CH2:12][C:11]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][O:9][CH:10]=3)=[CH:19][N:18]=2)=[O:22])[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: O=C(O)c1cnc(OCc2conc2-c2ccccn2)cn1
Product: O=C(NC1CC1)c1cnc(OCc2conc2-c2ccccn2)cn1
Yield: 81 %

Procedure:
As described for example 19f, 5-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (84.7 mg, 2.8 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (SiO2, heptane:ethyl acetate 7:3 to 2:8, 78 mg, 81%) which was obtained as a white solid. MS: m/e=338.3 [M+H]+.
Reaction SMILES: [O:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N:13]1([CH2:18][C:19]2[CH:20]=[CH:21][C:22](Br)=[N:23][CH:24]=2)[CH:17]=[CH:16][N:15]=[CH:14]1>>[O:1]1[C:5]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[CH:24][N:23]=2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OB(O)c1cc2ccccc2o1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1ccc2oc(-c3ccc(Cn4ccnc4)cn3)cc2c1

Procedure:
Synthesized using benzo[b]furan-2-ylboronic acid (204 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 71 mg, 0.26 mmol, 41%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.18 (s, 2H), 6.93 (s, 1H), 7.13 (s, 1H), 7.25-7.28 (m, 2H), 7.35 (dt, J=8.2, 1.2 Hz, 1H), 7.44 (d, J=0.9 Hz, 1H), 7.51 (dd, J=8.2, 2.1 Hz, 1H), 7.56 (dd, J=8.2, 0.9 Hz, 1H), 7.60 (s, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 8.56 (d, J=2.1 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 105.5, 111.5, 119.0, 119.8, 121.8, 123.3, 125.5, 128.6, 130.4, 130.8, 135.7, 137.3, 148.7, 149.4, 154.3, 155.4; MS (ESI): m/z=276.03 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:39][CH3:40])[CH2:4][C:5]1([OH:38])[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH:27]=[C:28]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:29]=2)[O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[O:12])[CH2:7][CH2:6]1)[CH3:2].[O:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]1[O:47][NH2:48].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C.O>[CH2:39]([CH:3]([CH2:1][CH3:2])[CH2:4][C:5]1([OH:38])[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](=[O:23])[NH:48][O:47][CH:42]4[CH2:43][CH2:44][CH2:45][CH2:46][O:41]4)=[CH:20][CH:19]=3)[CH:27]=[C:28]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH:29]=2)=[O:12])[CH2:7][CH2:6]1)[CH3:40]
Reactant: CCC(CC)CC1(O)CCN(C(=O)Nc2cc(Oc3ccc(F)cc3)cc(Oc3ccc(C(=O)O)cc3)c2)CC1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)CC1(O)CCN(C(=O)Nc2cc(Oc3ccc(F)cc3)cc(Oc3ccc(C(=O)NOC4CCCCO4)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.1 %

Procedure:
The compound prepared in Example 9(1) (20 mg) was dissolved in DMF (200 μL), added with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (4.2 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (19 mg) and 1-hydroxybenzotriazole monohydrate (HOBt) (15 mg) and stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate and added with water and the aqueous layer was extracted with MTBE. The organic layer was combined, washed with water, a saturated sodium hydrogen carbonate aqueous solution and a saturated ammonium chloride aqueous solution and then concentrated. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give the titled compound (19.6 mg) having the following physical properties.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:27]3[O:28][N:37]=[C:32]([CH2:33][CH2:34][O:35][CH3:36])[N:31]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (about 0.432 mmol) of the compound from Example 63A and 102 mg (0.865 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 92 mg (36% of theory)
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O>>[CH:19]1[C:18]2[C:12]3[CH:11]=[CH:10][CH:9]=[C:4]4[C:5]([O:14][C:1](=[O:13])[C:2]([C:3]=34)=[CH:21][C:17]=2[O:16][CH:20]=1)=[O:7]
Reactant: O=Cc1ccco1
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Product: O=C1OC(=O)c2cc3occc3c3cccc1c23

Procedure:
As described in example 14, the following compounds were prepared from dimethyl homophthalate and 2-furaldehyde:
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.[CH2:24]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[C:44]([F:46])[C:43]([O:47]C)=[CH:42][C:41]=2[F:49])[CH2:36][CH2:35]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:24]([N:34]1[CH2:35][CH2:36][N:37]([C:40]2[C:41]([F:49])=[CH:42][C:43]([OH:47])=[C:44]([F:46])[CH:45]=2)[CH2:38][CH2:39]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCN1CCN(c2cc(F)c(OC)cc2F)CC1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: CCCCCCCCCCN1CCN(c2cc(F)c(O)cc2F)CC1
Yield: 39.6 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 1-decyl-4-(2,5-difluoro-4-methoxyphenyl)piperazine (176 mg). The resulting crude product was purified on TLC (developer, chloroform: methanol=19:1) to provide 4-(4-decylpiperazin-1-yl)-2,5-difluorophenol (67 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]([CH2:10][C:11]([CH3:35])([CH3:34])[C:12](=[O:33])[CH:13]([N:27]1[CH:30](Cl)[CH2:29][C:28]1=[O:32])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])=[N+:8]=[N-:9]>C(O)(C)(C)C.O1CCCC1.C(OCC)(=O)C>[N:7]([CH2:10][C:11]([C:12]1[O:33][CH:30]2[N:27]([C:28](=[O:32])[CH2:29]2)[C:13]=1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])([CH3:35])[CH3:34])=[N+:8]=[N-:9]
Reactant: CC(C)(CN=[N+]=[N-])C(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(CN=[N+]=[N-])C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)CC2O1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 117.9 %

Procedure:
313 μl of a 0.75 M solution of potassium tert-butoxide in tert-butanol are added at -30° C. to a solution of 107 mg (0.23 mmol) of p-nitrobenzyl 5-azido-2-(4-chloro-2-oxo-1-azetidinyl)-4,4-dimethyl-3-oxopentanoate in 4.5 ml of dry tetrahydrofuran and the solution is stirred at -30° C. during the course of 30 minutes. The reaction mixture is then diluted with 20 ml of ethyl acetate, and the mixture is washed with 10 ml of water and 10 ml of NaCl solution. The aqueous phases are extracted using 10 ml of ethyl acetate and the combined organic phases are dried over MgSO4, filtered and then evaporated in vacuo. In this way, 105 mg of a yellow residue are obtained which is crystallized from methylene chloride/ diisopropyl ether. Yield 61 mg of melting point 81°-82° C. IR spectrum in CH2 --Cl2 : 2950, 2860, 2110, 1810, 1720, 1590, 1530, 1370, 1320, 1085, 1020 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]2[NH:14][C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=2)=[CH:4][CH:3]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[CH:25]=[CH:24][C:23](=[O:26])[N:14]3[C:13]4[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=4[NH:11][C:10]=23)=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1ccc(Br)cc1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1ccc(Br)cc1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 500 mg (1.57 mmol) of 1-(4-Bromophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXVI), 169.2 mg (3.13 mmol) of sodium methylate and 131.7 mg (1.57 mmol) methyl propiolate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([CH3:25])[CH2:13]1.C(N(CC)CC)C>[Pt].CO.C(Cl)Cl>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:14]([CH3:25])[CH2:13]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2Cl)CCN1C(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N)cc2Cl)CCN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
A mixture of 1,1-dimethylethyl (2S)-4-[(2-chloro-4-nitrophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D103) (0.199 g, 0.538 mmol), triethylamine (0.75 mL, 5.38 mmol) and 5% Pt/C catalyst (0.134 g) in MeOH (5 mL) was hydrogenated at room temperature and atmospheric pressure for 3 h. The catalyst was removed by filtration and the filtrate was concentrated to give a colourless oil which was dissolved in DCM. The DCM solution was washed with water (×2) and brine, then dried and concentrated to give the crude product. Purification by column chromatography eluting with 10-40% EtOAc/pentane gave the title compound as a colourless oil (0.125 g). δH (CDCl3, 400 MHz) 7.19 (1H, d), 6.69 (1H, d), 6.54 (1H, dd), 4.18 (1H, br.s), 3.79 (1H, d), 3.70 (2H, br.s), 3.45 (2H, m), 3.07 (1H, td), 2.74 (1H, m), 2.60 (1H, m), 2.19 (1H, dd), 2.03 (1H, m), 1.45 (9H, s), 1.22 (3H, d). MS (ES): MH+ 340/342.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:21])[S:13][C@@H:12]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:11]2[C@H:10]1[C:18]([OH:20])=[O:19].C[Si](C)(C)Cl.[C:27]1([O:33][C:34](=[O:45])[CH:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36](O)=[O:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)(O)[O-].[Na+:50]>C(Cl)Cl>[Na+:50].[O:33]([C:34]([CH:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36]([NH:17][CH:14]1[C:15](=[O:16])[N:11]2[CH:10]([C:18]([O-:20])=[O:19])[C:9]([CH3:21])([CH3:8])[S:13][C@H:12]12)=[O:37])=[O:45])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: O=C(O)C(C(=O)Oc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccccc3)c3ccccc3)C(=O)N2C1C(=O)[O-]
Temperature: 35 °C
Reaction time: 1 h

Procedure:
56 ml. (0.4 moles) of triethylamine are added to a suspension of 42 g. (0.2 moles) of 6-APA in 600 ml. of methylene chloride. Subsequently 430 g. (0.4 moles, 50 ml.) of trimethyl chlorosilane are added to the obtained solution at 10° C., and the mixture is stirred for 60 minutes. Thereafter the mixture is heated to 35° C., 104 g. (0.2 moles) of phenylmalonic acid phenylester pnetachlorophenyl ester are added, and subsequently 28 ml. (0.2 moles) of triethylamine are introduced dropwise into the mixture. The reaction mixture is stirred at room temperature for 3 hours, thereafter it is neutralized to pH=7 with 200 ml. of 8% aqueous sodium bicarbonate solution.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.[CH2:10]([CH:13]1[CH2:17][NH:16]C(=O)[CH2:14]1)[CH2:11][CH3:12].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:6][O:7][C:9]1[CH2:14][CH:13]([CH2:10][CH2:11][CH3:12])[CH2:17][N:16]=1
Reactant: C[O+](C)C
Reactant: CCCC1CNC(=O)C1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCC1CN=C(OC)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67.3 %

Procedure:
Trimethyloxonium tetrafluoroborate (715 mg, 4.83 mmol) was added to a solution of 4-propyl-2-pyrrolidinone (410 mg, 3.22 mmol) in methylene chloride (8 ml) and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture to render it weekly basic and then it was extracted with ethyl acetate. After washing the organic layer with brine and drying over anhydrous magnesium sulfate, the organic layer was subjected to distillation under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (306 mg) as a light yellow oil. 1H-NMR (CDCl3) δ(ppm) 0.90 (3H, t, J=7.2 Hz), 1.21-1.50 (4H, m), 2.13 (1H, dd, J=16.4 Hz, 16.8 Hz), 2.34-2.48 (1H, m), 2.57 (1H, dd, J=16.4 Hz, 9.2 Hz), 3.24 (1H, dd, J=13.6 Hz, 6.0 Hz), 3.71-3.90 (4H, m)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:19]([Sn](CCCC)(CCCC)C#C)[CH2:20]CC.[F-].[Cs+].ClCCl>O1CCOCC1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:19]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[CH:20]
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Br)cc(-c2ccc(C)cn2)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C#Cc1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a degassed solution of methyl 3-bromo-5-(5-methylpyridin-2-yl)benzoate (200 mg, 0.653 mmol) in dioxane (3 mL) was added tributyl(ethynyl)tin (247 mg, 0.784 mmol), cesium fluoride (198 mg, 1.31 mmol) and bis(tri-t-butylphosphine) palladium (16.7 mg, 0.033 mmol) and the mixture heated to 70° C. After 2 h, the reaction was cooled to ambient temperature and dichloromethane (50 mL was added). The organic layer was washed with 30 mL of saturated aqueous sodium bicarbonate (2×), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) to give the title compound (145 mg). MS 252.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[S:42]([NH2:45])(=[O:44])=[O:43].[C:46](Br)(=[O:48])[CH3:47]>>[C:46]([NH:45][S:42]([C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:11][CH2:12][C:13]([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:43])=[O:44])(=[O:48])[CH3:47]
Reactant: CC(=O)Br
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Product: CC(=O)NS(=O)(=O)c1cc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)ccc1Cl

Procedure:
N-acetyl-2-chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene-sulfonamide (21.8 mg, quant.) was obtained as amorphous solid from 2-chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide and acetyl bromide following the procedure outlined in example 476. 1H NMR (300 MHz, DMSO-d6) 87.85-7.50 (m, 3H), 7.49 (d, J=8.5 Hz, 1H), 7.41-7.35 (m, 5H), 7.25-7.21 (m, 1H), 7.15-7.09 (m, 2H), 4.54 (br, 1H), 3.96 (br, 1H), 3.42-3.29 (m, 5H), 3.06-3.03 (m, 1H), 2.45-2.36 (m, 5H), 2.17-2.07 (m, 2H), 1.98-1.75 (m, 10H), 1.71-1.70 (m, 3H), 1.63-1.61 (m, 2H). HRMS m/z (M+H)+ calcd: 688.2724, obsd: 688.2745.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: Fc1cccc(CCl)c1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3-fluorobenzyl chloride gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:20]([O-])=O)[C:5]2[O:10][CH:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1.S1C=CC=C1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]2[O:10][CH:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: O=[N+]([O-])c1cc(F)cc2c1OC(COC1CCCCO1)CC2
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: Nc1cc(F)cc2c1OC(COC1CCCCO1)CC2
Yield: 98.3 %

Procedure:
A mixture of intermediate 15-b (0.47 mol) in methanol (600 ml) was hydrogenated with palladium on activated carbon, palladium content 10% (5 g) as a catalyst in the presence of a 4% thiophene solution (3 ml). After uptake of H2 (3 equiv), the catalyst was filtered off and the filtrate was evaporated, yielding 130 g (98.3%) of (±)-6-fluoro-3,4-dihydro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran-8-amine (interm. 16-b).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19]Cl)=[CH:7]2.[N-:21]=[N+]=[N-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][NH2:21])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8-chloro-3-(chloromethyl)-2-phenoxyquinoline (1 eq) in DMSO (0.25 M) was added NaN3 (3 eq) at rt and the mixture was stirred for 4 h at rt. The mixture was diluted with water, extracted with EtOAc (2 times) and the combined organic layers were washed with water (2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH and treated with 10% Pd—C (5 wt %) and the mixture was then stirred under H2 balloon over night. The mixture was filtered through a Celite™ pad followed by removal of solvents to give (8-chloro-2-phenoxyquinolin-3-yl)methanamine.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.OC(C(F)(F)F)=O.[N:21]1([C@@H:26]2[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]2)[CH:25]=[N:24][CH:23]=[N:22]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:32][C@H:29]2[CH2:28][CH2:27][C@@H:26]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)[CH2:31][CH2:30]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: N[C@H]1CC[C@@H](n2cncn2)CC1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@@H](n2cncn2)CC1
Temperature: 90 °C
Yield: 20.2 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.10 g, 0.46 mmol), cis-4-(1H-1,2,4-triazol-1-yl)cyclohexanamine TFA salt (0.10 g, 0.60 mmol) and N,N-diisopropylethylamine (0.40 mL, 2.3 mmol) in isopropyl alcohol (1.0 mL) was heated at 90° C. for 2 h. The resulting mixture was concentrated and purified on silica gel (eluting with 0 to 10% EtOAc in dichloromethane) to give the desired product (32 mg, 20%). LCMS calculated for C15H17N6O2S (M+H)+: m/z=345.1. Found: 345.0.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[OH:1][C:2]1([C:9]2[S:13][C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)c1ncc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: C[Si](C)(C)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(2-trimethylsilanyl-thiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([C@@H:6]([CH3:10])[C:7](O)=[O:8])[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.S(Cl)([Cl:19])=O>ClC1C=CC=CC=1>[C:1]1(=[O:16])[N:5]([C@@H:6]([CH3:10])[C:7]([Cl:19])=[O:8])[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Solvent: Clc1ccccc1
Product: C[C@@H](C(=O)Cl)N1C(=O)c2ccccc2C1=O
Temperature: 85 °C
Reaction time: 12 h

Procedure:
To a mixture of (S)-2-phthalimidopropionic acid (25.0 g) and chlorobenzene (25 mL), thionyl chloride (9.9 mL) was added and the resulting mixture was stirred at 85° C. (external temperature) for 12 hours. (S)-2-phthalimidopropionyl chloride was obtained by removing the solvent in vacuo. To a mixture of alminium chloride (16.7 g) and chlorobenzene (150 mL), anisole (18.6 mL) was added and this mixture was stirred at 60–65° C. (internal temperature). To this mixture, the solution of (S)-2-phthalimidopropionyl chloride, mentioned above, in chlorobenzene (30 mL) was added dropwise over 20 minutes, and the resulting mixture was stirred at 60–65° C. (internal temperature) for 12 hours. After the temperature of the reaction mixture was raised to 70–75° C. (internal temperature), aluminium chloride (45.6 g) was added to this mixture, and then stirred at same temperature for 3 hours. The mixture was cooled to 50° C. (internal temperature) and ethyl acetate (50 mL) was added dropwise. The resulting mixture was added to a mixture of water (250 g), ethanol (25 mL) and ethyl acetate (100 mL) at 30–45° C. (internal temperature), and stirred at same temperature for 30 minutes. Organic layer was separated from the reaction mixture, the organic layer was washed with brine, sodium bicarbonate solution, brine, 1 mol/L hydrochloric acid and brine, and dried over anhydrous sodium sulfate. After removing the solvent in vacuo, the resulting residue was recrystallized from toluene to obtain (S)-2-[2-(4-hydroxyphenyl)-1-methyl-2-oxoethyl]-isoindol-1,3-dione (18.1 g, 53.6% yield, optical purity 99.9% e.e.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[N+:11]([O-])=O.C(Cl)Cl.[H][H]>[Pd].CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[NH2:11]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc2cn[nH]c2cc1F
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc2cn[nH]c2cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To the product of Step (c) (530 mg, 2.93 mmol, 1 equiv) and 10% Pd/C (200 mg) was added CH2Cl2 (10 mL) and MeOH (40 mL). The atmosphere was replaced with hydrogen gas and the solution was stirred at room temperature and atmospheric pressure for 2 hours. The reaction mixture was filtered through a plug of celite and rinsed with MeOH and CH2Cl2. The residue was purified by flash chromatography (linear gradient, 40→70% EtOAc/hexanes) affording 330 mg (75%) of the title compound as a pale purple solid. MS (ES+) m/e 152 [M+H].