Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:29]([O:31][CH3:32])=[O:30]>O1CCCC1>[CH3:32][O:31][C:29](=[O:30])[N:14]([CH2:13][CH2:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=1[Br:1])[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(CCC)NCCc1ccc(C(F)(F)F)cc1Br
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(CCC)N(CCc1ccc(C(F)(F)F)cc1Br)C(=O)OC

Procedure:
770 mg of N-[2-(2-bromo-4-trifluoromethylphenyl)ethyl]heptan-4-amine in solution in 15 cm3 of anhydrous tetrahydrofuran and 500 mg of potassium carbonate are stirred under an inert atmosphere at a temperature in the vicinity of 5° C. 0.19 cm3 of methyl chloroformate is introduced over 5 minutes into the reaction mixture. The reaction mixture is brought to reflux over 15 h, the insoluble material is separated by filtration and the filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual oil is purified by filtration through a silica pellet using a mixture of 10% ethyl acetate and 90% cyclohexane as eluent. The organic phase is then concentrated to dryness using a rotary evaporator under reduced pressure (5 kPa) in order to result in 666 mg of methyl[2-(2-bromo-4-trifluoromethylphenyl)ethyl](1-propylbutyl)carbamate in the form of a colorless oil.
Reaction SMILES: [N:1]1([C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]C2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH2:6][CH2:5]1)(=[O:32])=[O:31]
Reactant: CCOC(=O)C1(N2CCNCC2)CCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)CC1
Yield: 63 %

Procedure:
Ethyl 1-(piperazin-1-yl)cyclobutanecarboxylate (0.20 mmol) was dissolved in CH2Cl2 (1 ml). Triethylamine (0.30 ml, 2.2 mmol), followed by 2-chlorobenzenesulfonyl chloride (64 mg, 0.30 mmol), was added at room temperature. The orange-colored solution was stirred at room temperature for 18 h before saturated NaHCO3 solution was added. The mixture was extracted twice with EtOAc. Combined organic layers were washed once with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 25% EtOAc/hexanes) to give ethyl 1-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)cyclopropanecarboxylate (47 mg, 63% 2 steps) as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm: 0.85 (m, 2 H), 1.23 (t, J=7.5 Hz, 3 H), 1.23 (m, 2 H), 2.98 (bs, 4 H), 3.14 (bs, 4 H), 4.09 (q, J=7.2 Hz, 2 H), 7.37 (t, J=7.3 Hz, 1 H), 7.42-7.53 (m, 2 H), 8.00 (d, J=7.8 Hz, 1 H), 13C NMR (100 MHz, CHLOROFORM-D) δ ppm 14.3, 19.1, 45.7, 46.7, 48.8, 60.5, 126.9, 132.1, 132.2, 132.3, 133.6, 136.0, 173.8; ESI-MS: m/z 373.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H]2OC(OCC)[O:18][C@@H:14]2[C@@H:13](CO)[CH2:12]1.[CH3:24][O:25][C:26]([O:29][CH3:30])([CH3:28])[CH3:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:24]2[O:25][C:26]([CH3:28])([CH3:27])[O:29][C@@H:30]2[C@@H:13]([CH2:14][OH:18])[CH2:12]1
Reactant: COC(C)(C)OC
Reactant: CCOC1O[C@@H]2[C@@H](CO)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The above crude ((3aR,4R,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2-ethoxytetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol was taken up in 2,2-dimethoxypropane (214 mL, 1740 mmol) and treated with p-toluenesulfonic acid monohydrate (13.2 g, 69.5 mmol) to afford a brown oil partially suspended in a cloudy solution, which was stirred at rt for 1 h 20 min; HPLC/LC MS indicated complete conversion to the desired product. The reaction was quenched by the careful addition of sodium bicarbonate (8.76 g, 104 mmol) and a minimal amount of water. The volatiles were removed in vacuo and the remaining aqueous layer was diluted with water (100 mL) and extracted with CH2Cl2 (3×400 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford a brown oil. Purification by column chromatography (7×16 cm silica; 0-5% MeOH/CH2Cl2) afforded the title compound (8.30 g, 74% over 3 steps) as a yellow foam: MS (ESI+) for C14H17ClN4O3 m/z 325.1 (M+H)+; MS (ESI−) for C14H17ClN4O3 m/z 369.0 (M+HCO2)−; HPLC purity >95 area %.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]1)=O>>[CH:34]([N:8]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][CH:46]([CH3:49])[CH2:45][CH2:44]2)=[CH:38][CH:37]=1)[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:20]2[CH:21]=[C:22]([OH:27])[CH:23]=[CH:24][C:19]=2[CH2:18]1)([CH3:35])[CH3:36]
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCC(C)CC3)cc2)C(C)C)c1
Yield: 66.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (21 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23](O)[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:9]=1)([CH3:4])[CH3:3].CS([Cl:35])(=O)=O>C(Cl)Cl.O>[Cl:35][CH:23]([C:10]1[CH:9]=[C:8]([CH2:7][O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:30])[CH3:29])[CH:13]=[CH:12][C:11]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)C(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(Cl)C(C)(C)C)c1
Reaction time: 22 h
Yield: 43.4 %

Procedure:
To a stirred solution of 69.16A (0.200 g, 0.46 mmol) in DCM (5.00 mL) at 0° C. was added TEA (0.077 mL, 0.55 mmol), followed by methanesulfonyl chloride (0.043 mL, 0.55 mmol). The reaction was then stirred for 22 hours, diluted with water, and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-10% EtOAc in hexanes) to yield 69.16B as a colorless oil (0.090 g, 43% yield) and a further product 69.16C as a clear oil (0.050 g, 21% yield).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[Cl:6][Si:7](Cl)([Cl:9])[Cl:8]>>[CH2:1]([O:5][Si:7]([Cl:9])([Cl:8])[Cl:6])[CH2:2][CH2:3][CH3:4]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: CCCCO
Product: CCCCO[Si](Cl)(Cl)Cl

Procedure:
On the other hand, 14.8 g (0.2 moles) of n-butanol was used in place of methanol as used in Example 3(b) and was reacted with 34.0 g of tetrachlorosilane in the same manner as in Example 3(b). There was thus obtained a solution of n-butoxytrichlorosilane.
Reaction SMILES: [NH4+].[OH-].ClC(Cl)(Cl)[C:5]([C:7]1[N:8]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][CH:11]=1)=[O:6].C[N:25](C)C=O.C(OCC)(=O)C>O>[C:5]([C:7]1[N:8]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][CH:11]=1)(=[O:6])[NH2:25]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc(-n2cccc2C(=O)C(Cl)(Cl)Cl)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-n2cccc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
28% Ammonia aqueous solution (0.4 ml) was added to a mixture of methyl 3-(2-trichloroacetylpyrrol-1-yl)benzoate (1.0 g) and N,N-dimethylformamide (2 ml), and the mixture was stirred for 1.5 hours at ambient temperature. The mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 3-(2-carbamoylpyrrol-1-yl)benzoate (0.61 g).
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[CH2:16][S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18]>>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:20](/[S:17]([CH2:16][C:15]2[CH:23]=[CH:24][CH:25]=[C:13]([C:12]([F:27])([F:11])[F:26])[CH:14]=2)(=[O:19])=[O:18])\[C:21]#[N:22])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCS(=O)(=O)Cc1cccc(C(F)(F)F)c1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and 3-trifluoromethylbenzylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-nitrothien-5-yl)-2-[3-(trifluoromethyl)benzylsulfonyl]acrylonitrile
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH:3]=O.[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].N1CCCCC1>C(O)(=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH3:5])[CH:3]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)C=O
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=CC(C)C)C(=O)OCC
Yield: 90.4 %

Procedure:
A mixture of 69.80 g of 2-methylpropanal, 77.30 g of diethyl malonate, 2.06 g of benzoic acid, 2.47 cm3 of piperidine and 100 cm3 of toluene is stirred at reflux for 15 hours. After cooling, 100 cm3 of toluene are added. The solution is washed in succession twice with 100 cm3 of distilled water, twice with 100 cm3 of 1M hydrochloric acid and 100 cm3 of saturated aqueous sodium carbonate solution. The organic phase is dried over anhydrous sodium sulphate and concentrated. The residue obtained is distilled under reduced pressure (117° C./10 torr) to obtain 93.44 g of the expected product in the form of a colourless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]4[O:7][C:3]([CH2:2][NH:1][S:28]([CH3:27])(=[O:30])=[O:29])=[N:4][N:5]=4)=[CH:13][CH:12]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNS(C)(=O)=O)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-[5-Aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) was mixed with methanesulphonyl chloride (0.02 ml) and pyridine (0.034 ml) in DCm (3 ml) and the reaction stirred at room temperature for 18 hours. The reaction was washed with water (4×4 ml) and then hydrochloric acid (2N, 5 ml). The organic phase was reduced to dryness under vacuum and the residue purified by HPLC to give after evaporation of the solvents N-cyclopropyl-6-methyl-4′-5-{[(methylsulfonyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([NH:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:24][C:25]([C:27]2[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])=[CH:4][CH2:3]1.IC.[C:37]([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:17]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH3:37])([CH3:15])[CH3:16])[CH:11]=[CH:10][C:9]=2[NH:24][C:25]([C:27]2[NH:28][CH:29]=[C:30]([C:32]#[N:33])[N:31]=2)=[O:26])=[CH:4][CH2:3]1
Reactant: O=C([O-])O
Reactant: CC1(C)CC=C(c2cc(C(C)(C)NCCS(C)(=O)=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(CCS(C)(=O)=O)C(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.1 %

Procedure:
A mixture of 4-cyano-1H-imidazole-2-carboxylic acid {2-(4,4-dimethyl-cyclohex-1-enyl)-4-[1-(2-methanesulfonyl-ethylamino)-1-methyl-ethyl]-phenyl}-amide (as prepared in Example 18, 8.0 mg, 0.017 mmol), iodomethane (25 μL, 0.40 mmol) and solid NaHCO3 (25 mg, 0.30 mmol) in 1.0 mL of THF was stirred at RT for 6 h. The solvent was removed by evaporation and the residue was purified by silica gel chromatography (0-2% MeOH/DCM) to afford the title compound (5.0 mg, 61%) as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 11.90 (s, 1H), 9.63 (s, 1H), 8.31 (d, 1H, J=8.6 Hz), 7.75 (s, 1H), 7.41 (dd, 1H, J=8.6, 2.3 Hz), 7.28 (d, 1H, J=2.3 Hz), 5.77 (m, 1H), 3.11 (t, 2H, J=7.1 Hz), 2.87 (s, 3H), 2.84 (t, 2H, J=6.0 Hz), 2.29 (m, 2H), 2.24 (s, 3H), 2.11 (m, 2H), 1.60 (t, 2H, J=6.3 Hz), 1.40 (s, 6H), 1.11 (s, 6H). Mass spectrum (ESI-neg, m/z): Calcd. for C26H35N5O3S, 496.3 (M−H). found 496.1.
Reaction SMILES: [NH3:1].Cl[C:3]1[C:8]([CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=2[CH:19]([CH3:21])[CH3:20])=[CH:7][N:6]=[C:5]([S:22][CH3:23])[N:4]=1>CCO>[Cl:16][C:14]1[C:13]([O:17][CH3:18])=[CH:12][C:11]([CH:19]([CH3:21])[CH3:20])=[C:10]([CH:15]=1)[CH2:9][C:8]1[C:3]([NH2:1])=[N:4][C:5]([S:22][CH3:23])=[N:6][CH:7]=1
Reactant: COc1cc(C(C)C)c(Cc2cnc(SC)nc2Cl)cc1Cl
Reactant: N
Solvent: CCO
Product: COc1cc(C(C)C)c(Cc2cnc(SC)nc2N)cc1Cl
Temperature: 85 °C
Yield: 92 %

Procedure:
To 25 ml of saturated NH3 in EtOH was added 4-Chloro-5-(5-chloro-2-isopropyl-4-methoxy-benzyl)-2-methylsulfanyl-pyrimidine (0.580 g, 1.6 mmol). The solution was warmed to 85° C. in a sealed reaction vessel. After 3 days the solution was cooled, concentrated in vacuo and suspended in CH2Cl2. The precipitate was filtered and the mother liquor was concentrated in vacuo. Purification via flash chromatography (7:3 hexane/ethyl acetate) afforded 5-(5-chloro-2-isopropyl-4-methoxy-benzyl)-2-methylsulfanyl-pyrimidin-4-ylamine (0.504 g, 92%) as a white solid.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][N:9]=1
Reactant: BrC1CCCC1
Reactant: Oc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ccc(OC2CCCC2)cn1
Reaction time: 2 h

Procedure:
Cyclopentyl bromide (690.3 mg, 4.63 mmol), 2-chloro-5-hydroxypyridine (500 mg, 3.86 mmol) and cesium carbonate (1.51 g, 4.63 mmol) were stirred in 30 ml of DMF at room temperature for 3 h. The reactants had not yet completely reacted. 50% of each of cyclopentyl bromide and cesium carbonate were added, and stirring was continued for 2 h. The reaction mixture was concentrated in vacuo, and the residue was taken up in ethyl acetate and water. The organic phase was separated off and concentrated. Yield: 737 mg (97%), M+H+: 198.08.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[C:4]([CH2:17][C:18]([CH3:20])=O)[C:3]1=[O:21].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.Cl.C([BH3-])#N.[Na+]>CO>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[C:4]([CH2:17][CH:18]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH3:20])[C:3]1=[O:21]
Reactant: COc1cccc(C2=C(CC(C)=O)C(=O)N(C)CCC2)c1
Reactant: C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C2=C(CC(C)N3CCCCC3)C(=O)N(C)CCC2)c1

Procedure:
The solution of 8.0 g of 1-methyl-3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, 14.2 g of piperidine, 6.4 ml of 5 N methanolic hydrogen chloride and 1.91 g of sodium cyanoborohydride in 100 ml of methanol is refluxed overnight. An additional portion of 1.91 g of sodium cyanoborohydride is added and refluxing continued for another day. The solution is cooled, acidified with a 35 ml of concentrated hydrochloric acid and evaporated. The residue is diluted with 100 ml of water, the aqueous solution washed with benzene, filtered, basified with 65 ml 3 N aqueous sodium hydroxide and extracted with diethyl ether. The extract is dried, evaporated and the residue crystallized from petroleum ether and recrystallized from hexane, to yield the 1-methyl-3-(2-piperidinopropyl)-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 101°-103°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([F:26])([F:25])[F:24])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[S:18][C:13]2[CH2:14][O:15][CH:16]([CH3:17])[C:12]=2[C:11]=1[C:19](O)=[O:20])=[O:8].Cl.[F:28][C:29]1([F:33])[CH2:32][NH:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([F:26])([F:24])[F:25])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[S:18][C:13]2[CH2:14][O:15][CH:16]([CH3:17])[C:12]=2[C:11]=1[C:19]([N:31]1[CH2:32][C:29]([F:33])([F:28])[CH2:30]1)=[O:20])=[O:8]
Reactant: CC1OCc2sc(NC(=O)c3cc(Cl)ccc3C(F)(F)F)c(C(=O)O)c21
Reactant: FC1(F)CNC1
Agent: Cl
Product: CC1OCc2sc(NC(=O)c3cc(Cl)ccc3C(F)(F)F)c(C(=O)N3CC(F)(F)C3)c21

Procedure:
The title compound was prepared from the product of Example 53A and commercially available 3,3-difluoroazetidine hydrochloride by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.30 (d, J=6.4 Hz, 3H), 4.30-4.53 (m, 4H), 4.89-5.01 (m, 2H), 5.18-5.27 (m, 1H), 7.82-7.95 (m, 3H), 11.60 (br s, 1H). MS (ESI+) m/z 481 (M+H)+. Anal. calcd. for C19H14ClF5N2O3S: C, 47.46; H, 2.93; N, 5.83. Found: C, 47.38; H, 2.52; N, 5.72.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1)[CH3:17]
Reactant: CCOC(CBr)OCC
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(CN1CCC(C(=O)c2ccc(F)cc2)CC1)OCC
Yield: 25 %

Procedure:
4-(4-Fluorobenzoyl)piperidine (207 mg, 1.0 mmol) was dissolved in methylene chloride (5 ml) to which were subsequently added bromoacetoaldehyde diethylacetal (305 mg, 1.5 mmol) and triethylamine (0.5 ml). After 12 hours of heating under reflux, the solvent was removed by evaporation, and the resulting residue was purified by subjecting it to a silica gel column chromatography (ether) to obtain 81 mg (25.0%) of the title compound in the form of orange oil.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][C:21](=[CH:24][C:25](O)=[O:26])[CH2:20][CH2:19]3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.[CH3:60][NH:61][O:62][CH3:63]>ClCCl>[CH3:63][O:62][N:61]([CH3:60])[C:25](=[O:26])[CH:24]=[C:21]1[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:28])([F:29])[F:2])[CH:5]=3)[CH2:15][CH2:14]2)[CH2:19][CH2:20]1
Reactant: CNOC
Reactant: O=C(O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To a solution of 200 mg (0.46 mmol) of (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetic acid, hydrochloride in 5 mL of dichloromethane stabilized on amylene are successively added 63 mg (0.46 mmol) of 1-hydroxybenzotriazole, 88 mg (0.46 mmol) of 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride and 140 mg (1.4 mmol) of triethylamine. The mixture is stirred for 15 minutes then 45 mg (0.46 mmol) of N,O-dimethylhydroxylamine hydrochloride are added. The mixture is stirred overnight at room temperature, then evaporated under reduced pressure. The residue is dissolved in ethyl acetate and washed twice with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified over 10 g of silica gel (eluant dichloromethane/methanol 98/2) to give 143 mg (71%) of N-methoxy-N-methyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetamide as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[C:12]=[O:13]>>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:11][C:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[N:2]1[C:12]([NH:11][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[O:13])=[O:13]
Reactant: Cc1ccccc1CN=C=O
Reactant: Oc1n[nH]c2ccccc12
Product: Cc1ccccc1CNC(=O)n1c(=O)c2ccccc2n1C(=O)NCc1ccccc1C

Procedure:
In analogy to example 11, 300 mg (2.24 mmol) of 1H-indazol-3-ol were reacted with 395.5 mg (2.69 mmol) of 1-isocyanatomethyl-2-methylbenzene. Yield: 177 mg (18%), M+H+: 429.26.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]1([O:23][CH3:24])[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18]>>[CH3:24][O:23][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[O:18][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1O
Reactant: Brc1cccc(NCc2cccnc2)c1
Product: COc1ccccc1Oc1cccc(NCc2cccnc2)c1

Procedure:
Using the method of Example 342 using N-(3-bromophenyl)pyridin-3-ylmethylamine and guaiacol (Aldrich) and purifying via preparative HPLC eluting with 1:1 DCM/ethyl acetate gave N-(3-(2-Methoxyphenoxy)phenyl) pyrid-3-ylmethylamine. Anal Calcd for C19H18N2O2.0.5H2O: C, 72.36; H, 6.07; N, 8.88. Found: C, 72.43; H, 5.80; N, 8.96. MS found 307.2 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH:13]2[CH:8]([CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[CH:12]2)[C:7]([C:19]2[CH:27]=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=2)=[N:6]1)=[O:4].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH:13]2[CH:8]([CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[CH:12]2)[CH:7]([C:19]2[CH:27]=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=2)[NH:6]1)=[O:4]
Reactant: COC(=O)C1CC2C=C(OC)C(OC)=CC2C(c2ccc3c(c2)OCO3)=N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CC2C=C(OC)C(OC)=CC2C(c2ccc3c(c2)OCO3)N1
Yield: 54.1 %

Procedure:
A solution of Intermediate 6 (1.5 g, 4.06 mmol) in MeOH (60 mL) was cooled to 0° C. and stirred under a nitrogen blanket. Sodium borohydride (154 mg) was added, and the resulting mixture was stirred for 2 hours. The reaction mixture then was concentrated in vacuo, during which time a white solid precipitated. The solid was triturated with MeOH (20 mL), collected by filtration, and dried to give 0.82 g (54%) of Intermediate 7: TLC Rf (90:10:1 CH2Cl2/EtOAc/MeOH)=0.33; 1H NMR (300 MHz, CDCl) δ: 6.84 (dd, J=7.8 Hz, J=1.6 Hz, 1H), 6.76-6.79 (m, 2H), 6.62 (s, 1H), 6.21 (s, 1H), 5.95 (dd, J=3.4 Hz, J=1.1 Hz, 2H), 5.02 (bs 1H), 3.82-3.86 (m, 1H), 3.86 (s, 3H), 3.78 (s, 3H) 3.64 (s, 3H), 3.01-3.14 (m, 2H), 2.41 (bs, NH); MS (API) m/z 372 (M+H).