Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>N1CCCCC1.C(O)C>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:12][C:9]1[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=1[CH3:11]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)c(C)c32)c(C)c1CCC(=O)O
Yield: 55.6 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (98 mg), 91 mg 5-chloro-4-methyl-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. for 4 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 100 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([NH:18][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: NC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC2CCCC2)nc(Cl)n1

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, OR2558, 4.50 g; 21.7 mmol) in anhydrous THF (200 mL) was treated with a solution of cyclopentylamine (Aldrich, 2.36 mL; 23.9 mmol) and triethylamine (3.03 mL; 21.7 mmol) in DCM (60 mL). The reaction mixture was stirred for 1 h30. The organic solvent was removed in vacuo and the crude was redissolved in EtOAc then washed with water and brine. The organic extracts were dried over magnesium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1.Cl>N1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[CH:13][C:14]([OH:16])=[O:15]
Reactant: COc1ccc(C=O)cc1F
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(C=CC(=O)O)cc1F
Temperature: 80 °C

Procedure:
A mixture of 3-fluoro-anisaldehyde (1.5g) and malonic acid (2.08g) in 5 ml pyridine was warmed until clear solution was obtained. To this mixture piperidine (0.4ml) was added and then the content of the flask was heated at 80° C. for 1 hour. It was further refluxed for 3 hours. At the end of this period the mixture was poured into 50ml of cold water. It was then acidified by adding 5ml of concentrated hydrochloric acid. Upon addition of acid, the solid separated, which was filtered and washed with cold water. The material was dried. Yield 1.7 g. The crude material was crystallized from a mixture of tetrahydrofuran and water. m.p. 227°-230° C.
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[CH2:7][C:8]#[N:9]>N1C=CC=CC=1>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[CH:7][C:8]#[N:9]
Reactant: COc1ccccc1C(O)(CC#N)c1ccccc1OC
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1ccccc1C(=CC#N)c1ccccc1OC
Temperature: 10 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Thionyl chloride (4.5 mL) was added to a stirred suspension of beta-hydroxy-beta-(2-methoxyphenyl)-2-methoxybenzenepropanenitrile (13.45 g) in dry pyridine (70 mL) maintained at 10° C. during the addition. The reaction was stirred at room temperature for 2 hours, then was diluted with ice-water and extracted with dichloromethane. The organic extract was washed with 3N HCl (1×150 mL; 1×20 mL) and brine and then was dried (MgSO4) and evaporated. The residue was crystallized from isopropanol-hexane to provide 9.0 g of 3,3-bis(2-methoxyphenyl)-2-propenenitrile, mp 99°-100° C. Recrystallization of a portion from the same solvents afforded the analytical sample, mp 100.5°-101.5° C.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[CH3:15].[CH3:16]O>>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:16])=[O:11])=[CH:8][C:7]=1[CH3:15]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thionyl chloride (5.68 ml) was added dropwise to a solution of 4-fluoro-3-methylbenzoic acid (10 g) in MeOH (150 mL) at 0° C. over a period of 10 minutes under nitrogen. The resulting mixture was stirred at rt for 24 h. The solvent was removed and the residue diluted with EtOAc, washed with sat. NaHCO3, brine, dried, filtered and evaporated to afford the subtitle compound, 9.85 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:17]([CH3:19])[CH3:18])[C:5]2[CH2:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[OH2:20].OO.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([N:17]([CH3:19])[CH3:18])[C:5]2[CH2:10][C@H:9]([OH:20])[C@@H:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1
Reactant: O
Reactant: CN(C)c1nc(Cl)nc2c1CC=C2c1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1nc(Cl)nc2c1C[C@H](O)[C@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-chloro-N,N-dimethyl-7-phenyl-5H-cyclopenta[d]pyrimidin-4-amine (113 mg) in THF (2 mL) at rt was added borane dimethyl sulfide complex in THF (2.0 M solution, 0.41 mL), and the reaction mixture was stirred at rt for 5 h. Water (0.50 mL) was added carefully, followed by 30% H2O2 (0.50 mL) and 1 N NaOH (1 mL). 5 mL EtOAc was added, and the r×n mixture was stirred at rt for 12 h. The crude product was purified by prep. TLC eluting with 50% EtOAc/Hexanes to give the title compound as a yellowish solid (44 mg). LC-MS (M−H2O+H)+=290.05.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]/[C:5](=[CH:13]\[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([N:22]2[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]2)=[CH:16][C:15]=1[F:28])/[C:6]([O:8]C(C)(C)C)=[O:7].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Cl:1][CH2:2][CH2:3][CH2:4]/[C:5](=[CH:13]\[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([N:22]2[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]2)=[CH:16][C:15]=1[F:28])/[C:6]([OH:8])=[O:7]
Reactant: COc1cc(/C=C(\CCCCl)C(=O)OC(C)(C)C)c(F)cc1-n1cnc(C)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C(\CCCCl)C(=O)O)c(F)cc1-n1cnc(C)c1
Reaction time: 2 h

Procedure:
Sodium hydride (containing mineral oil at 40%, 0.68 g) was added to a solution of tert-butyl 5-chloro-2-(diethoxyphosphoryl)valerate (5.59 g) in THF (50 mL) in a nitrogen atmosphere at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. A solution of 2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (3.19 g) in THF (10 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system) to obtain tert-butyl (E)-5-chloro-2-(2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerate (5.93 g). A solution of tert-butyl (E)-5-chloro-2-(2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerate in trifluoroacetic acid (30 mL) was stirred while cooling with ice. After 2 hours, the reaction solution was concentrated under reduced pressure. Tert-butyl methyl ether was added to the resulting residue, and the resulting deposited solid was filtered to obtain 3 g of the title compound. Properties data of the compound are as follows.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:47])[CH2:10][C:11]1[CH:46]=[CH:45][CH:44]=[CH:43][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:42]=[CH:41][C:26]([O:27][CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)=[CH:25][CH:24]=2)[N:16]=1>C(Cl)Cl>[CH3:21][C:20]1[C:15]([CH2:14][CH2:13][C:12]2[CH:43]=[CH:44][CH:45]=[CH:46][C:11]=2[CH2:10][C:9]([NH2:8])=[O:47])=[N:16][C:17]([NH:22][C:23]2[CH:42]=[CH:41][C:26]([O:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:25][CH:24]=2)=[N:18][CH:19]=1
Reactant: Cc1cnc(Nc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(OC3CCNCC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.9 %

Procedure:
TFA (0.5 mL) was added to a cooled (water/ice bath 6° C.) solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenoxy)piperidine-1-carboxylate (A113) (0.050 g, 0.092 mmol) in DCM (2 mL) and the resulting mixture was stirred at room temperature for 4 hours. The volatiles were removed in vacuo then 2 M aqueous K2CO3 solution (10 mL) and water (10 mL) were added to the residue. The resulting suspension was sonicated for 1 minute, filtered and the filter cake dried to give the title compound 26 as a light pink solid (0.034 g, 83%); 1H NMR (300 MHz, d6-DMSO) δ 9.17 (s, 1H), 8.12 (s, 1H), 7.62 (d, J=8.9 Hz, 2H), 7.43 (s, 1H), 7.12-7.27 (m, 4H), 6.93 (s, 1H), 6.84 (d, J=8.9 Hz, 2H), 4.23-4.29 (m, 1H), 3.49 (s, 2H), 3.30-3.34 (m, 2H), 2.83-3.05 (m, 7H), 2.05 (s, 3H), 1.86-1.90 (m, 2H), 1.39-1.42 (m, 2H). LCMS-B: rt 4.717 min; m/z 446 [M+H]+.
Reaction SMILES: Cl.N1C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][C:17]2[C:22]([C:23](=[O:25])[CH:24]=1)=[C:21]([O:26]C)[CH:20]=[C:19]([O:28]C)[C:18]=2[C@@H:30]1[CH2:34][CH2:33][N:32]([CH3:35])[C@H:31]1[CH2:36][OH:37].C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][C:17]2[C:22]([C:23](=[O:25])[CH:24]=1)=[C:21]([OH:26])[CH:20]=[C:19]([OH:28])[C:18]=2[C@@H:30]1[CH2:34][CH2:33][N:32]([CH3:35])[C@H:31]1[CH2:36][OH:37]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@@H]1CO
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
Molten pyridine hydrochloride (4.1 g, 0.0354 mol) was added to (+)-trans-2-(2-chlorophenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one (0.4 g, 0.0009 mol) and heated at 180° C. for 1.5 h. The reaction mixture was cooled to 25° C., diluted with methanol (10 mL) and basified using sodium carbonate to pH 10. The mixture was filtered and the organic layer was concentrated. The residue was suspended in water (5 mL), stirred for 30 minutes, filtered and dried to obtain the title compound.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.Cl.[N:36]12[CH2:43][CH2:42][CH:39]([CH2:40][CH2:41]1)[CH:38]([NH2:44])[CH2:37]2.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][NH:44][CH:38]5[CH:39]6[CH2:42][CH2:43][N:36]([CH2:41][CH2:40]6)[CH2:37]5)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: NC1CN2CCC1CC2
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CNC4CN5CCC4CC5)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (100 mg) in 1,2-dichloroethane (5 mL) were added 1-azabicyclo[2.2.2]octan-3-amine dihydrochloride (100 mg) and triethylamine (150 μL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (65.0 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (30.0 mg, yield 24%) as a colorless amorphous solid. MS: 575 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:30])[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C@@H:25]3[CH2:27][C@H:26]3[CH2:28][OH:29])[CH2:20][CH2:19]2)[CH2:5]1.I[CH3:32]>CN(C)C=O.O.C(OCC)(=O)C>[CH3:32][O:29][CH2:28][C@@H:26]1[CH2:27][C@H:25]1[CH2:24][N:21]1[CH2:22][CH2:23][N:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:6]2[CH2:7][C:8]([CH3:10])([CH3:11])[CH2:9][C:4]([CH3:30])([CH3:3])[CH2:5]2)[CH2:19][CH2:20]1
Reactant: CC1(C)CC(c2ccccc2N2CCN(C[C@@H]3C[C@H]3CO)CC2)CC(C)(C)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@@H]1C[C@H]1CN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Yield: 45 %

Procedure:
Sodium hydride (60%, oily) (31 mg, 0.78 mmol) was suspended in dimethylformamide (3 mL), and the suspension was stirred at room temperature under a nitrogen atmosphere. To the suspension was added a solution of trans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanol (60 mg, 0.156 mmol) produced in Example (91a) in dimethylformamide (3 mL), and the mixture was stirred for 30 minutes under the same conditions. The reaction mixture was cooled in ice water, and then iodomethane (0.015 mL, 0.241 mmol) was added. The reaction mixture was then stirred for 3 hours and 30 minutes while increasing the temperature to room temperature. The reaction mixture was cooled at an external temperature of 0° C., and water was carefully added while blowing nitrogen. Then, ethyl acetate and water were added thereto and extraction was performed with ethyl acetate. The separated organic layer was washed twice with water and then once with brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 28 mg of trans-1-(2-methoxymethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][C:17]1[CH:28]=[CH:27][C:20]([CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][C:17]2[CH:28]=[CH:27][C:20]([CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: COC(=O)C=Cc1ccc(CBr)cc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccc(C=CC(=O)OC)cc2)ccc(C(C)=O)c1O
Yield: 53.2 %

Procedure:
A mixture of 1.0 g (5.15 g) of 2,4-dihydroxy-3-propylacetophenone, 1.58 g (6.18 mmol) of methyl 4-bromomethylcinnamate and 0.85 g (6.18 mmol) of anhydrous potassium carbonate in 20 ml of acetone was stirred at reflux for 18 hours. Ether extraction gave 1.01 g of the title compound as a light yellow powder mp 121°-125° C.
Reaction SMILES: ClC(Cl)(Cl)C(C1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=4[CH3:32])=[CH:22][CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=O.[OH-:36].[Na+].Cl.C[C:40]([CH3:42])=[O:41]>>[CH3:32][C:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C:26]=1[C:23]1[CH:22]=[CH:21][C:20]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:42]([C:40]([OH:36])=[O:41])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:33])=[CH:25][CH:24]=1
Reactant: CC(C)=O
Reactant: CC1=C(c2ccc(C(=O)N3Cc4ccc(C(=O)C(Cl)(Cl)Cl)n4Cc4ccccc43)cc2)CCCC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC1=C(c2ccc(C(=O)N3Cc4ccc(C(=O)O)n4Cc4ccccc43)cc2)CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
2,2,2-Trichloro-1-{10-[4-(2-methyl-cyclohex-1-en-1-yl)-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}-ethanone of Step E (1 g, 1.67 mmol) was dissolved in acetone (11.1 mL) followed by the addition of 2.5 N aqueous sodium hydroxide (1.2 mL, 3.01 mmol). After stirring at room temperature for six hours, the reaction mixture was neutralized with 2 N hydrochloric acid and extracted with diethyl ether. The organic phase was extracted with 1 N sodium hydroxide, the combined basic extracts were acidified with 2 N hydrochloric acid and extracted with diethyl ether. The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by HPLC (Primesphere 5 C-18, solvent gradient of 65 to 90% acetonitrile in 1% aqueous trifluoroacetic acid) to afford (97%) the title compound (0.805 g) as a white solid. m.p. 171° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4](/[CH:10]=[CH:11]/[CH2:12][CH:13]([OH:15])[CH3:14])[CH2:3]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:15][CH:13]([CH2:12]/[CH:11]=[CH:10]/[C:4]2[CH2:3][N:2]([CH3:1])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=2)[CH3:14])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC1=CN(C)CC(/C=C/CC(C)O)=C1
Solvent: c1ccncc1
Product: COC1=CN(C)CC(/C=C/CC(C)OS(=O)(=O)c2ccc(C)cc2)=C1

Procedure:
The manner in which certain aryl substituted olefinic amine compounds possessing a branched side chain are provided can vary. Using one synthetic approach, a compound such as (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine can be synthesized by coupling a halo-substituted pyridine, 5-bromo-3-methoxypyridine with an olefin containing a secondary alcohol functionality, 4-penten-2-ol, under Heck reaction conditions; and the resulting pyridyl alcohol intermediate can be converted to its p-toluenesulfonate ester, followed by treatment with methylamine. Typically, the types of procedures set forth in W. C. Frank et al., J. Org. Chem. 43:2947 (1978) and N. J. Malek et al., J. Org. Chem. 47:5395 (1982) involving a palladium-catalyzed coupling of an olefin and an aromatic halide are used. The required halo-substituted pyridine, 5-bromo-3-methoxypyridine is synthesized using methodology similar to that described by H. J. den Hertog et al., Recl. Trav. Chim. Pays-Bas 74:1171 (1955), namely by heating 3,5-dibromopyridine with 2.5 molar equivalents of sodium methoxide in dry methanol in the presence of copper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glass tube at 150° C. for 14 hours to produce 5-bromo-3-methoxypyridine. The resulting 5-bromo-3-methoxypyridine, previously described by D. L. Comins, et al., J. Org. Chem. 55:69 (1990), can be coupled with 4-penten-2-ol in acetonitrile-triethylamine (1.1:1, v/v) using a catalyst consisting of 1 mole % palladium(II) acetate and 4 mole % tri-o-tolylphosphine. The reaction is carried out by heating the components in a sealed glass tube at 140° C. for 14 hours to yield (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2 -ol. The resulting alcohol is treated with 2 molar equivalents of p-toluenesulfonyl chloride in dry pyridine at 0° C. to produce (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-ol p-toluenesulfonate. The tosylate intermediate is treated with 120-molar equivalents of methylamine as a 40% aqueous solution, containing a small amount of ethanol as a co-solvent to produce (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:14]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)[CH:13]=2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].O1CCCC1.CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:14]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)[CH:13]=2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-c2ccc(SCC(C)C)c(-n3cnnn3)c2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(SCC(C)C)c(-n3cnnn3)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
A reaction mixture solution prepared by suspending 155.2 mg of ethyl 2-[4-fluoro-3-nitrophenyl]-4-methyl-1,3-thiazole-5-carboxylate and 244.4 mg of cesium carbonate in 1.5 mL of N,N-dimethylformamide and adding 49.6 mg of 2-methylpropylthiol was heated under stirring at 80° C. for 5 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, 3 mL of water was added and extraction was performed using ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a crude product of ethyl 2-[4-(2-methylpropylthio)-3-nitropheny]-4-methyl-1,3-thiazole-5-carboxylate. (2) The crude product of ethyl 2-[4-(2-methylpropylthio)-3-nitropheny]-4-methyl-1,3-thiazole-5-carboxylate obtained above was reduced using palladium carbon under a hydrogen atmosphere to obtain ethyl 2-[3-amino-4-(2-methylpropylthio)phenyl]-4-methyl-1,3-thiazole-5-carboxylate. (3) A reaction mixture solution prepared by suspending ethyl 2-[3-amino-4-(2-methylpropylthio)phenyl]-4-methyl-1,3-thiazole-5-carboxylate obtained above in 2.0 mL of acetic acid and adding 65 mg of sodium azide and 148 mg of triethyl ortho formate was heated at 70° C. for 5 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, water was added and extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduce pressure, followed by purifying by a conventional method to obtain 123 mg of ethyl 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate. (4) A reaction mixture solution prepared by adding 123 mg of ethyl 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate to 2 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 0.5 mL of 2 M sodium hydroxide aqueous solution was stirred at room temperature for 3 hours. After the addition of 0.5 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using ethyl acetate. The organic phase was concentrated, followed by purifying by a conventional method to obtain 67.9 mg of 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylic acid.