Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:16]2=[O:28])[CH2:3]1.[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH3:41])[C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:29]([O:33][C:34]([NH:36][C@@H:37]([CH3:41])[C:38]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)[C:16]3=[O:28])[CH2:3][C@H:2]2[F:1])=[CH:9][CH:10]=1)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(OC(=O)[C@H](C)NC(=O)OC(C)(C)C)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
To a solution of (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (0.03 g, 0.078 mmol, example 1) in DCM (5 mL) was added (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (0.077 g, 0.408 mmol) followed by DCC (0.049 g, 0.235 mmol) and DMAP (9.58 mg, 0.078 mmol). The reaction mixture was stirred at rt for 18 h. Water (15 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (3×15 mL) and the organic layers were combined, dried over Na2SO4, and concentrated to a crude product. The crude product was purified by preparative TLC eluting with 20% ethyl acetate in petroleum ether to provide the purified product (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)propanoate (0.032 g, 0.058 mmol, 74% yield) as off-white semi solid. LC-MS (Method A) RT=2.40 min, (M+H)+=554.2. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J=7.0 Hz, 1H), 7.44-7.32 (m, J=8.5 Hz, 2H), 7.21-7.09 (m, 4H), 7.07-6.98 (m, J=8.5 Hz, 2H), 4.62 (d, J=4.5 Hz, 1H), 4.39 (d, J=15.1 Hz, 1H), 4.30 (d, J=15.1 Hz, 1H), 4.27-4.17 (m, 1H), 3.58 (t, J=8.5 Hz, 1H), 3.50-3.40 (m, 1H), 3.22-3.07 (m, 2H), 2.81-2.64 (m, 3H), 2.39-2.31 (m, 1H), 2.29 (s, 3H), 2.17-2.04 (m, 1H), 1.93 (dd, J=12.8, 8.3 Hz, 1H), 1.78 (br. s., 1H), 1.74-1.59 (m, 1H), 1.41 (s, 9H), 1.39 (d, J=2.5 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ −180.172.
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11]Cl)[N:10]=1)(=[O:4])[CH2:2][CH3:3].[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([CH2:11][C:9]3[N:10]=[C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])[S:7][CH:8]=3)[CH2:14][CH2:15]2)=[CH:20]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CCC(=O)Nc1nc(CCl)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Reaction time: 6 h
Yield: 70.7 %

Procedure:
A mixture of 2-propionylamino-4-chloromethylthiazol (5.11 g), 3-(4-piperidyl)indole (5 g), sodium hydrogen carbonate (2.31 g) and N,N-dimethylformamide (25 ml) was heated at 102° to 103° C. with bubbling nitrogen gas and stirring for 6 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was subjected to column chromatography on silica gel and the column was eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the desired compound were combined and concentrated and ethanol was added thereto. The solution was concentrated again and the residue was triturated with diisopropyl ether to give 4-[4-(3-indolyl)piperidinomethyl]-2-propionylaminothiazole (6.50 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.[O:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:22]=[CH:37][CH:36]=[C:35]([O:34][CH3:38])[CH:23]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: COc1cccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.093 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H) 4.17 (s, 2 H) 6.84 (m, 1 H) 6.98 (m, 3 H) 7.22 (d, J=8.09 Hz, 1 H) 7.26 (d, J=5.15 Hz, 1 H) 7.56 (t, J=7.17 Hz, 1 H) 7.67 (d, J=8.09 Hz, 1 H) 7.79 (t, J=8.46 Hz, 1 H) 7.94 (d, J=7.72 Hz, 1 H) 8.22 (d, J=5.15 Hz, 1 H) 14.21 (s, 1 H) 14.84 (s, 1 H). MS (ESI−) m/z 481 (M−H)−.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:45]I>CC#N.O>[I:45][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=1
Reactant: CC(C)(C)OC(=O)n1cc(CCCO)c2ccccc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(CCCI)c2ccccc21
Reaction time: 3 h

Procedure:
To a stirring solution of tert-butyl 3-(3-hydroxypropyl)-1H-indole-1-carboxylate in MeCN were added imidazole (44 mg), PPh3 (129 mg) and iodine (124 mg) at ambient temperature. After 3 hours, water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=15:1) to give tert-butyl 3-(3-iodopropyl)-1H-indole-1-carboxylate (63 mg).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][C:9](=[O:14])[CH2:8]2)=[N:4][CH:3]=1.[NH2:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[NH2:15][C:16]1[CH:17]=[C:18]([C:2]2[S:6][C:5]([N:7]3[CH2:13][CH2:12][CH2:11][NH:10][C:9](=[O:14])[CH2:8]3)=[N:4][CH:3]=2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1
Reactant: O=C1CN(c2ncc(Br)s2)CCCN1
Reactant: Nc1cc(B(O)O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cc(-c2cnc(N3CCCNC(=O)C3)s2)cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 24.9 %

Procedure:
4-(5-Bromo-1,3-thiazol-2-yl)-1,4-diazepan-2-one (Step 5 of Intermediate XX, 1.96 g, 7.10 mmol), (3-amino-5-nitrophenyl)boronic acid (1.291 g, 7.10 mmol), tetrakis-(triphenylphosphine)palladium(0) (0.410 g, 0.355 mmol), 1,2-dimethoxyethane (42 mL) and 2M aqueous sodium carbonate (10.65 mL, 21.29 mmol) were successively introduced in a high pressure reaction vessel. The headspace was flushed with nitrogen, the vessel capped and the mixture was stirred at 100° C. for 18 h. The reaction was then cooled to room temperature and 25% aqueous ammonium acetate was added. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification via CombiFlash (ethanol/ethyl acetate) afforded 590 mg (1.77 mmol, 25% yield) of 4-[5-(3-amino-5-nitrophenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one as a yellow solid. MS APCI: [M+H]+ m/z 334.1.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1.Cl[CH2:34][C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=2[CH:50]=1>>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:34][C:35]2[CH:36]=[CH:37][C:38]3[O:43][CH2:42][C:41](=[O:44])[N:40]([CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:39]=3[CH:50]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccccc3F)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccccc4F)cc3)cc21

Procedure:
Analogously to Method D, 1.08 g of tert-butyl 4-{4-[3-(2-fluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.720 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as an opaque oil. Rf=0.30 (1:1 EtOAc-heptane); Rt=5.89.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[F:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][NH:57][C:58](=[O:61])[O:59][CH3:60])=[C:51]([OH:62])[CH:50]=1>>[F:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][NH:57][C:58]([O:59][CH3:60])=[O:61])=[C:51]([CH:50]=1)[O:62][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COC(=O)NCCc1ccc(F)cc1O
Product: COC(=O)NCCc1ccc(F)cc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method G, 0.40 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.26 g of methyl N-[2-(4-fluoro-2-hydroxyphenyl)ethyl]carbamate are reacted. The title compound is obtained as a yellow oil. Rf=0.42 (1:1 EtOAc-heptane); Rt=5.93.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[CH2:16]([N:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23](=[O:30])[C:22]1=[O:31])[CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1.ClCCl>[OH:30][C:23]1([C:7]2[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=2)[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:22]1=[O:31]
Reactant: CCCCCN1C(=O)C(=O)c2cccnc21
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol in THF (40.0 mL) was added a solution of iso-propyl magnesium chloride (7.90 mL, 15.9 mmol, 2.0 M in THF) dropwise at 0° C. over 5 min. The reaction mixture was stirred for 30 min upon which time colorless precipitate formed. After the solvent was removed under reduced pressure, the residue was dissolved in anhydrous dichloromethane (40.0 mL) and cooled to 0° C. followed by the addition of a solution of 1-pentyl-1H-pyrrolo[2,3-b]pyridine-2,3-dione (1.84 g, 8.44 mmol) in dichloromethane (10.0 mL). The reaction mixture was stirred at ambient temperature for 16 h and quenched with saturated ammonium chloride solution (30.0 mL). The organic layer was separated and washed with water (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from ethyl acetate and ether to afford the title compound (2.20 g, 73%) as a beige solid: 1H NMR (300 MHz, CDCl3) δ 8.29 (dd, 1H), 7.74 (dd, 1H), 7.08 (dd, 1H), 6.60 (s, 1H), 6.24 (s, 1H), 5.87 (dd, 2H), 3.78 (d, 2H), 1.77-1.67 (m, 2H), 1.33-1.28 (m, 4H), 0.85 (d, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.9, 157.7, 148.9, 147.3, 147.2, 139.7, 131.1, 127.7, 119.3, 118.3, 107.1, 101.1, 97.8, 74.6, 40.7, 29.0, 27.0, 22.3, 14.4; MS (ES+) m/z 357 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24].CN1CCOCC1>CO>[F:21][C:22]([F:26])([F:25])[CH2:23][NH:24][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: NCC(F)(F)F
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCC(F)(F)F)cc2s1
Yield: 9.4 %

Procedure:
the title compound (11 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 2,2,2-trifluoroethylamine (48 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 392.4 (M+1, 100%). Yield=9%.
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=3)[C:20]=1[S:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:15])[CH2:10]2>CO>[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)[C:20]=1[S:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:15])[CH2:10]2
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2SC2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2SC2CCCC2)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
2M aqueous sodium hydroxide (1.694 mL, 3.39 mmol) was added in one portion to methyl 4-[4-(2-adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoate (Intermediate #90) (325 mg, 0.68 mmol) in methanol (10 mL). The resulting mixture was stirred at 20° C. for 18 hours. The reaction mixture was concentrated and diluted with water (50 mL), and washed with ether (20 mL). The aqueous solution was adjusted to pH 3 with 2M HCl and extracted with EtOAc (2×25 mL), and the combined extracts washed sequentially with water (2×20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 4-[4-(2-adamantylcarbamoyl)-5-cyclopentylsulfanyl-pyrazol-1-yl]benzoic acid (307 mg, 97%).
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([C:9]2([NH:15]C=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4]1>CO>[ClH:1].[NH2:15][C:9]1([C:6]2[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=CNC1(c2ccc(=O)[nH]c2)CCCCC1
Agent: Cl
Solvent: CO
Product: NC1(c2ccc(=O)[nH]c2)CCCCC1
Yield: 14.4 %

Procedure:
A solution of N-[1-(1,6-dihydro-6-oxo-3-pyridinyl)cyclohexyl]formamide hydrochloride (43.0 g) in 700 ml of methanol was heated at reflux for 17 hours, and then cooled and concentrated. The residual o il was triturated with methanol affording 13.1 g of a white powder. Recrystallization from methanol gave 5.5 g of crystals, m.p. 233°-234° C.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@@H:12]([OH:15])[CH2:13][OH:14])=[C:10]([CH3:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([Sn](=O)CCCC)CCC.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].CCN(CC)CC>C(Cl)Cl>[CH3:34][C:33]1[CH:35]=[CH:36][C:30]([S:27]([O:14][CH2:13][C@@H:12]([C:11]2[C:2]([Br:1])=[C:3]3[C:8](=[CH:9][C:10]=2[CH3:16])[N:7]=[CH:6][CH:5]=[CH:4]3)[OH:15])(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: Cc1cc2ncccc2c(Br)c1[C@@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)c2c(C)cc3ncccc3c2Br)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of (R)-1-(5-bromo-7-methylquinolin-6-yl)ethane-1,2-diol (197 mg, 0.70 mmol) in CH2Cl2 (97 mL), dibutyltinoxide (3.3 mg, 0.01 mmol), TsCl (150 mg, 0.79 mmol), and Et3N (0.12 mL, 0.83 mmol) were added at 0° C. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated aqueous NH4Cl, and then diluted with CH2Cl2. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 5 to 100% ethyl acetate/hexanes) to give (R)-2-(5-bromo-7-methylquinolin-6-yl)-2-hydroxyethyl 4-methylbenzenesulfonate. LCMS-ESI+ (m/z): [M+H]+ calc'd for C19H19BrNO4S: 436.02; Found: 436.1.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH:4]1[C:9]([OH:11])=[O:10].[CH3:12]O>>[CH3:12][O:10][C:9]([C@H:4]1[C@@H:3]([OH:2])[CH2:8][CH2:7][CH2:6][NH:5]1)=[O:11]
Reactant: CO
Reactant: O=C(O)C1NCCCC1O
Agent: Cl
Product: COC(=O)[C@@H]1NCCC[C@@H]1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Hydrogen chloride gas was bubbled through a suspension of 3-hydroxy-piperidine-2-carboxylic acid (0.54 g, 0.370 mol) in MeOH (100 mL) cooled to 0° C. for 10 min. The resulting clear solution was stirred at rt for 4 h, then evaporated carefully under reduced pressure (white precipitates formed during the concentration). The resulting white solid was dried overnight under vacuum to afford 0.86 g of the title compound as an off-white powder.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1.[CH3:29][O:30][CH2:31][CH2:32][C:33](O)=[O:34]>>[CH3:29][O:30][CH2:31][CH2:32][C:33]([NH:25][C@H:22]1[CH2:21][CH2:20][C@H:19]([CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:9]3[C:8]4[CH:26]=[CH:27][O:28][C:7]=4[CH:6]=[C:5]([CH3:4])[N:10]=3)[CH2:16][CH2:15]2)[CH2:24][CH2:23]1)=[O:34]
Reactant: COCCC(=O)O
Reactant: Cc1cc2occc2c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nc(C)cc4occc34)CC2)CC1

Procedure:
The title compound, white solid (100 mg, 78%), MS (ISP) m/z=429.4 [(M+H)+], mp 158° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate D) (136 mg, 0.3 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5](Br)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH:24]([CH3:29])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([OH:28])([C:5]2[C:6]3[O:10][CH:9]=[CH:8][C:7]=3[CH:11]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)[CH:24]([CH3:29])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: FC(F)(F)c1cc(Br)c2occc2c1
Product: CC1CN(Cc2ccccc2)CCC1(O)c1cc(C(F)(F)F)cc2ccoc12
Yield: 43.3 %

Procedure:
Beginning with 1.1 gm (4.15 mMol) 5-trifluoromethyl-7-bromobenzofuran and 0.93 gm (4.57 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 0.70 gm (43%) of the desired compound were recovered as a yellow solid essentially as described in EXAMPLE 3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][C@@H:22]([C:24]3[CH:35]=[CH:34][C:27]4[O:28][C:29]([CH3:33])([CH3:32])[O:30][CH2:31][C:26]=4[CH:25]=3)[O:21][C:20]2=[O:36])[CH:5]=[CH:6][CH:7]=1.[N+:37]([C:40]1[CH:41]=[C:42]([N:46]=[C:47]=[O:48])[CH:43]=[CH:44][CH:45]=1)([O-:39])=[O:38].C(O)(C)C>ClCCl>[CH3:33][C:29]1([CH3:32])[O:28][C:27]2[CH:34]=[CH:35][C:24]([C@H:22]3[O:21][C:20](=[O:36])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][C:4]4[CH:3]=[C:2]([NH:1][C:47]([NH:46][C:42]5[CH:43]=[CH:44][CH:45]=[C:40]([N+:37]([O-:39])=[O:38])[CH:41]=5)=[O:48])[CH:7]=[CH:6][CH:5]=4)[CH2:23]3)=[CH:25][C:26]=2[CH2:31][O:30]1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc([N+](=O)[O-])c5)c4)C(=O)O3)ccc2O1
Reaction time: 4 h
Yield: 85 %

Procedure:
A solution of (5R)-3-{6-[2-{(3-aminophenyl)methoxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.00 g) in anhydrous dichloromethane (15 ml) was treated under nitrogen at 200 with 3-nitrophenyl isocyanate (0.43 g) and the mixture stirred for 4 h. Isopropanol (20 ml) was added and the mixture stirred for 17 h before the solvent was removed in vacuo to give a residue that was purified by Biotage. Elution with dichloromethane-EtOH-ammonia (325:8:1) followed by solvent evaporation in vacuo gave the title compound (1.13 g). LCMS RT=3.85 min, ES+ve 663 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=2)[C:21]([O:23][CH3:24])=[O:22])=[C:3]([CH2:10][CH2:11][CH3:12])[CH:4]=1
Reactant: CCCc1cc(CO)ccc1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(CO)ccc1OC(C(=O)OC)c1ccccc1
Yield: 82.6 %

Procedure:
To a solution of 0.484 g (2.91 mmol) of the product of Step F dissolved in 12 mL of acetone were added 0.667 g (2.91 mmol) of methyl 2-bromophenylacetate, 0.804 g (5.82 mmol) of anhydrous K2CO3 and the mixture was stirred and heated at reflux for 5 hours. The mixture was then cooled, filtered and evaporated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 0.756 g (83%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](Cl)=[O:15])[CH:5]=[CH:4][C:3]1=2.[CH3:18][C:19]1[CH:28]=[CH:27][C:22]([C:23](=[N:25]O)[NH2:24])=[CH:21][CH:20]=1.B(F)(F)F>O1CCOCC1>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[O:15][N:25]=[C:23]([C:22]4[CH:27]=[CH:28][C:19]([CH3:18])=[CH:20][CH:21]=4)[N:24]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: Cc1ccc(C(N)=NO)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Agent: FB(F)F
Solvent: C1COCCO1
Product: Cc1ccc(-c2noc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)cc1
Reaction time: 4 h
Yield: 30.8 %

Procedure:
8.0 g (30 millimoles) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl chloride and 4.5 g (30 millimoles) of 4-methylbenzamidoxime in 250 ml of dioxane were refluxed for 1 hour. 1 ml of boron trifluoride dietherate were added and refluxing was continued for a further 4 hours. The mixture was allowed to cool, poured onto ice/water and extracted with methylene chloride. The organic phase was washed several times with water, dried over magnesium sulfate and evaporated down. The oily residue was purified by column chromatography (silica gel; n-heptane +0.5% of ethyl acetate), and the crude product obtained from the first fractions was recrystallized from methanol to give 3.2 g of the title compound of melting point 106°-109° C.