Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:52](=[O:53])[C:51]4[CH:54]=[C:55]([Cl:69])[C:56]5[N:57]=[CH:58][N:59](COCC[Si](C)(C)C)[C:60]=5[C:50]=4[O:49][C:48]=3[C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(OC(=O)NC1(C2C=CC(C3C(=O)C4C=C(Cl)C5N(CCCC[Si](C)(C)C)C=NC=5C=4OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.CO>C(Cl)Cl>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:52](=[O:53])[C:51]4[CH:54]=[C:55]([Cl:69])[C:56]5[N:57]=[CH:58][NH:59][C:60]=5[C:50]=4[O:49][C:48]=3[C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(cc(Cl)c5ncn(COCC[Si](C)(C)C)c54)c3=O)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(cc(Cl)c5c4ncn5CCCC[Si](C)(C)C)c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: CO
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(cc(Cl)c5nc[nH]c54)c3=O)cc2)CCC1
Yield: 48 %

Procedure:
Following the procedure for 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, a mixture of (1-{4-[4-chloro-6-oxo-8-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,6-dihydro-chromeno[7,8-d]imidazol-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester and (1-{4-[4-chloro-6-oxo-8-phenyl-3-(4-trimethylsilanyl-butyl)-3,6-dihydro-chromeno[7,8-d]imidazol-7-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (46 mg, 0.07 mmol) were reacted to give crude product. This residue was subjected to flash chromatography [SiO2, gradient 0 to 15% MeOH (2 M NH3) in DCM] to furnish the title compound as a white solid (15 mg, 48%). LCMS (Method E): RT=2.96 min, [M+H]*=442/444. 1H NMR (400 MHz, DMSO-d6): 8.33 (s, 1H), 7.87 (s, 1H), 7.45-7.41 (m, 2H), 7.39-7.35 (m, 2H), 7.32-7.27 (m, 1H), 7.22-7.16 (m, 4H), 2.59-2.50 (m, 2H), 2.31-2.22 (m, 2H), 2.12-2.00 (m, 1H), 1.80-1.69 (m, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[CH:29][C:30]([F:39])=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[CH:28]=[CH:29][C:30]([F:39])=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:32]=3)[CH2:25][CH2:26]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)ccc1F

Procedure:
Example 56 was prepared from diphenylacetyl chloride and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CD3OD,) δ 7.80–7.64 (m, 1H), 7.37–7.09 (m, 12H), 7.08–6.98 (m, 1H), 6.98–6.88 (br, 1H), 4.90 (s, 1H), 3.47–3.33 (m, 2H), 3.33–3.18 (m, 2H), 3.01–2.81 (m, 4H), 2.81–2.69 (m, 1H), 2.69–2.54 (m, 1H), 2.10–1.66 (m, 6H), 1.10 (d, 6H, J=6.4 Hz); ESMS m/e: 516.4 (M+H)+. Anal. Calc. For (HCl salt) C32H39ClFN3O2.0.16CHCl3: C, 67.68; H, 6.92; N, 7.36. Found: C, 67.43; H, 6.85; N, 7.17.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:15]3[CH2:21][CH2:20][N:19]([C:22]4[N:27]=[C:26]([C:28]([O:30]C)=[O:29])[CH:25]=[C:24]([CH3:32])[N:23]=4)[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[C:15]3[CH2:21][CH2:20][N:19]([C:22]4[N:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[C:24]([CH3:32])[N:23]=4)[CH2:18][C:16]=3[N:17]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2nc(C)cc(C(=O)OC)n2)C3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2nc(C)cc(C(=O)O)n2)C3)cc1
Yield: 39 %

Procedure:
methyl 2-(2-(4-(3-ethylureido)-phenyl)-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-6-methylpyrimidine-4-carboxylate (yc) (0.25 mmol) in a mixed solvent of NaOH (10%, 5 mL) and MeOH (5 mL) were stirred at room temperature overnight. The mixture was neutralized with diluted HCl to pH=6 and extracted with ethyl acetate thrice. The combined organic phases were dried over Na2SO4 and concentrated to give 50.6 mg of 2-(2-(4-(3-ethyl-ureido)phenyl)-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-6-methylpyrimidine-4-carboxylic acid (yd): 1H NMR (D6-DMSO, 400 MHz) δ 8.18 (d, J=8.8, 2H), 7.51 (d, J=8.0, 2H), 6.91 (s, 1H), 4.84 (s, 2H), 3.96 (m, 2H), 3.69 (s, 4H), 3.41 (s, 4H), 3.09 (t, J=7.2, 2H), 2.67 (s, 2H), 2.32 (s, 3H), 1.04 (t, J=7.2, 2H); LC-MS: m/z=+519 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([OH:7])=[O:6].CN(CCN(C)C)C.[Li]CCCC.[CH3:25][O:26]C=O.Cl>CC1CCCO1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[C:10]=1[CH:25]=[O:26])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: COC=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CC1CCCO1
Product: O=Cc1c(F)cc(C(=O)O)cc1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
To a solution of 3,5-difluorobenzoic acid (291 g, 1.84 mol) in 2-methyltetrahydrofuran (4.35 L) was added TMEDA (604 mL, 4.03 mol) at room temperature. The resulting solution was cooled to −78° C. Afterward, n-BuLi (2.5 M in hexane) (1.77 L, 4.43 mol) was added drop-wise, during which the temperature of the mixture remained at less than −65° C. The mixture was then stirred at −78° C. for 1.5 hr. Anhydrous MeOCHO (239 mL, 3.88 mol) was added dropwise at a rate that allowed the temperature to be maintained at less than −65° C. The resulting solution was allowed to warm at room temperature, and then maintained a room temperature while being stirred for 18 hr. The mixture was then cooled to 0-5° C., and excess base was quenched with 6M aqueous HCl (2.2 L, 13.2 mol). The phases were then separated, and the aqueous layer was extracted 3 times with 2-methyltetrahydrofuran (3×500 mL). The combined organic phases were washed with saturated brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was dissolved in ethyl acetate (350 mL) at reflux, and cooled to room temperature. Hexanes (480 mL) were then added, and the resulting mixture was further cooled to −15° C. The solid was collected by filtration, rinsed with hexanes, and dried under mechanical vacuum to form the title compound (122 g, 35%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.63-7.70 (m, 2H), 10.23 (s, 1H); MS m/z 187.17 [M+H]+ (ESI).
Reaction SMILES: [CH2:1]([Sn:5]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:27]I.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:27][N:11]([CH:8]1[CH2:9][CH2:10][C:6]([Sn:5]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:7]1)[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CC(NC(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCC[Sn](CCCC)(CCCC)C1=CC(N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 24 h
Yield: 96.1 %

Procedure:
Tert-butyl (3-tri-n-butylstannylcyclopent-2-enyl)carbamate (2.0 g, 4.24 mmol) was dissolved in N,N-dimethylformamide (40 ml), and at 0° C., methyl iodide (527 μl, 8.47 mmol) and then sodium hydride (55%, w/w), (277 mg, 6.35 mmol) were added. With gradually warming from 0° C. up to room temperature, this was stirred for 24 hours. At 0° C., aqueous saturated ammonium chloride solution was added to the solution, followed by stirring at the same temperature for 30 minutes. The solution was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=99:1, v/v) to obtain a colorless oil (1.982 g, 96%).
Reaction SMILES: [Cl:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](O)[CH:4]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:5]1[CH:4]=[C:3]([C:2]([Cl:1])([F:20])[F:19])[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1c(Cl)cc(C(F)(F)Cl)nc1C(F)(F)F
Yield: 85.6 %

Procedure:
This compound was prepared as described in Example 19: 75 g (0.235 mol) of product of Example 5, 50.29 g (55 ml, 0.469 mol) of 2,6-lutidine and 252.66 g (214 ml, 2.3 mol) of phosphorus oxychloride were reacted affording 68 g of a black oil. Crude was purified by kugelrohr distillation at 200 Pa, pot temperature 110° C., to give 48 g (60%) of product as a yellow oil; nD25 1.4466.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([N:30](S(C)(=O)=O)[S:31]([CH3:34])(=[O:33])=[O:32])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cc1nc(Cl)ccc1N(S(C)(=O)=O)S(C)(=O)=O
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1NS(C)(=O)=O

Procedure:
The title compounds were prepared in one pot as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and N-(6-chloro-2-methylpyridin-3-yl)-N(methylsulfonyl)methanesulfonamide (143 mg, 0.48 mmol) as starting materials. Mono and bis methylsulfonyl compounds were separated by column chromatography.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)#[N:2].[OH-:23].[Na+].OO>CCO.O.[Na+].[Cl-]>[NH2:2][C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C#N)CC1
Reactant: [OH-]
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(N)=O)CC1
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[(2-cyanophenyl)amino]-1-piperidinecarboxylate (D17) (355 mg, 1.18 mmol) in EtOH (6 ml) at 40° C. was added 2M NaOH solution (2.6 ml) followed by a mixture of hydrogen peroxide solution (27% w/w, 3.7 ml) in water (2.9 ml) and the reaction stirred for 2 h. Further hydrogen peroxide solution (27% w/w, 3.7 ml) in water (2.9 ml) was added and the reaction stirred at 40° C. for 1.5 h. Another portion of hydrogen peroxide solution (27% w/w, 7.4 ml) in water (5.8 ml) was added and stirring and heating were continued overnight. The reaction mixture was diluted with saturated aqueous NaCl solution (4 ml) and extracted with tBuOH (5 ml). The organic extract was diluted with EtOAc (15 ml), dried (MgSO4) and concentrated. Column chromatography eluting with 0-100% EtOAc/petroleum ether gave the title compound (150 mg). δH (CDCl3, 250 MHz) 7.96 (1H, br d), 7.40 (1H, m), 7.31 (1H, m), 6.71 (1H, d), 6.57 (1H, t), 5.80 (2H, br s), 3.93 (2H, m), 3.53 (1H, m), 3.06 (2H, m), 1.99 (2H, m), 1.50 (2H, m), 1.47 (9H, s). MS (ES): MH+ 320.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.[Br:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][N:13]1[C:14](=[O:16])[C:15]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=3)[C:8]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=3)=[N:9][C:10]=2[N:11]([CH3:18])[C:12]1=[O:17]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCOCCBr)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 62.3 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (120 mg, 0.26 mmol, intermediate 9) in DMF (3 mL) was added 1-bromo-2-(2-bromoethoxy)ethane (77 mg, 0.33 mmol), potassium carbonate (71 mg, 0.51 mmol). The reaction was heated at 60° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give crude product (100 mg, 70% of purity by HPLC), which was used without purification. LCMS retention time 2.054 min; LCMS MH+ 617
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>[O-2].[O-2].[Mn+4].C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(O)c3c(C)noc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1nc2ccc(C(=O)c3c(C)noc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(3,5-dimethylisoxazol-4-yl)methanol (1.4 g, 2.94 mmol, Intermediate 63: step a) was added THF (75 mL) followed by manganese dioxide (1.1 g, 12.6 mmol). The reaction mixture was heated to reflux for 2 hours, and then the contents were filtered through Celite® and rinsed with additional THF. The effluent was concentrated to provide the title compound as a white amorphous solid which was used without further purification.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]([CH3:25])([CH3:24])[CH2:10]1>CC(C)=O>[CH:18]1([O:17][N:12]2[C:11]([CH3:24])([CH3:25])[CH2:10][CH:9]([NH:8][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:14][C:13]2([CH3:16])[CH3:15])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C1CCC(=O)O1
Reactant: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1
Solvent: CC(C)=O
Product: CC1(C)CC(NC(=O)CCC(=O)O)CC(C)(C)N1OC1CCCCC1
Temperature: 25 °C

Procedure:
A solution of 1.0 gram (10.0 mmol) of succinic anhydride in 25 ml of acetone is added to a solution of 2.64 gram (10.0 mmol) of 4-amino-1-cyclohexyloxy-2,2,6,6tetramethylpiperidine (as prepared in Example 6B) in 10 ml of acetone. The reaction mixture is stirred for sixteen hours at room temperature and then concentrated to form a white solid. Purification by flash chromatography (silica gel; 9:1 ethyl acetate:ethanol) and recrystallization from heptane:ethyl acetate affords the title compound as a white solid melting at 136°-138 ° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:5][C:6]=1[CH:7]([O:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][NH:16]2)=[CH:12][CH:11]=1)[CH3:8].[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30].[H-].[Na+]>CN(C=O)C>[C:29]([O:33][C:34](=[O:37])[CH2:35][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([O:9][CH:7]([C:6]3[S:5][C:4]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[N:3][C:2]=3[CH3:1])[CH3:8])[CH:18]=2)[CH:14]=[CH:15]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Oc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 1 b], [rac]-6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-1H-indole was reacted with bromo-acetic acid tert-butyl ester in the presence of sodium hydride in DMF to yield [rac]-(6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless gum.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([F:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:29][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][CH:13]([CH2:12][NH:31][CH3:30])[O:14][C:15]=2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Product: CNCC1Cc2ccc(F)c(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.12 g, 40%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 0.92 mmol) and methylamine (0.55 g, 17.7 mmol). mp 170-173° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH2:4][CH:5]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][C:6]2=[CH2:13].[H][H]>C(O)(=O)C.C=C>[CH3:1][C:2]1[CH2:3][CH2:4][CH:5]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][CH:6]2[CH3:13]
Reactant: [H][H]
Reactant: C=C1CC(=O)CCC2=C(C)CCC12
Agent: C=C
Solvent: CC(=O)O
Product: CC1=C2CCC(=O)CC(C)C2CC1

Procedure:
528 mg of 1-methyl-4 -methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene were hydrogenated in 20 ml of ethylene acetate with the aid of 200 mg of palladium-on-calcium carbonate (5%). After hydrogen uptake was completed the mixture was filtered off from the catalyst, the filtrate concentrated under reduced pressure and distilled. There was obtained pure 1,4-dimethyl-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene, b.p.0.06 60°; IR(film):νmax = 1700, 1450, 1378, 1250, 1190 cm-1. The compound was a woody, earthy, camphorous odour.
Reaction SMILES: [N:1]1C=CC=CC=1C(C)C=O.[CH:11]1([C:17](=[O:29])[C:18]([CH3:28])([C:22]2C=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][CH:20]=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:17](=[O:29])[C:18]([CH3:28])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:1]=2)[CH2:19][CH:20]=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C=O)c1ccccn1
Reactant: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Product: CC(CC=O)(C(=O)C1CCCCC1)c1ccccn1

Procedure:
Scheme VI, steps A-D: 4-Cyclohexyl-3-methyl-4-oxo-3-(2-pyridyl)butyraldehyde is prepared from 2-(2-pyridyl)-propanaldehyde in a manner analogous to the procedure described in example 7 for the preparation of 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12](=[O:22])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH2:6][CH2:5]1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[Na+].[I-]>CC(N(C)C)=O>[Cl:21][C:17]1[CH:16]=[C:15](/[CH:14]=[CH:13]/[C:12]([N:7]2[CH2:8][CH2:9][C:10](=[O:11])[N:4]([CH2:3][CH2:2][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH2:5][CH2:6]2)=[O:22])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCCl)CC1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCN2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.2 %

Procedure:
A solution of 0.085 g (0.25 mmol) of 4-(2-chloro-ethyl)-1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one in 1.3 ml of DMA was treated with 0.04 ml (0.50 mmol) of morpholine and stirred for 8 h at RT, a crystal of NaI was added and stirring was continued for 40 h. The reaction was extracted with aqueous saturated NaHCO3/EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4), concentrated and evaporated. Purification by catridges, Si-Amine, 70 ml, 20 g (EtOAc) gave 0.008 g (8%) of the title compound as off-white viscous oil. MS: 392.0 (MH+, Cl).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]3[CH2:20][O:19][CH2:18]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C.[Cl-].[NH4+]>[Fe].O>[O:19]1[CH2:20][CH:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[CH2:18]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(CC3COC3)CC2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(N2CCN(CC3COC3)CC2)cc1
Temperature: 80 °C

Procedure:
To a round-bottomed flask equipped with a stirring bar, were added 1-(4-nitrophenyl)-4-(oxetan-3-ylmethyl)piperazine XXIX (3.20 g, 11.54 mmol), ethanol (60 mL) and water (60 mL). Following the addition of iron (4.51 g, 80.77 mmol) and ammonium chloride (4.32 g, 80.77 mmol), the reaction mixture was heated at 80° C. for 1 h, then filtered through Celite and washed with DCM (5 mL×5). The resulting filtrate was extracted with DCM (20 mL×3). The combined organic extracts were washed with water (20 mL×2), brine (20 mL×1), dried over Na2SO4, and concentrated in vacuo. The desired 4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)aniline XXX was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7](Br)=[CH:8][N:9]=1)[C:5]#[N:6].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([C:7]([C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][C:16]=2[Cl:18])=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: N#Cc1cc(N)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N#Cc1cc(N)ncc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of 2-amino-5-bromo-isonicotinonitrile (1.0 g, 5.1 mmol, prepared according to Example 3, Step 2.1), 2,4-dichloro-benzeneboronic acid (1.45 g, 7.6 mmol), Pd(PPh3)4 (292 mg, 0.25 mmol) and Na2CO3 (2.0 M solution in water, 8.8 mL) in DME (10 mL) was refluxed for 2 h under an inert atmosphere of argon. The reaction mixture was cooled to RT, diluted in AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7) to yield the title compound (880 mg, 3.3 mmol, 66%). MS: 264 [M+1]+; HPLC: AtRet=1.73; TLC: RF 0.31 (hexane/DCM/TBME 1:1:2).