Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][OH:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]=1.I[CH3:16]>CO>[CH3:16][S:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][OH:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]=1
Reactant: CI
Reactant: OCCCn1c(S)nc2ccccc21
Solvent: CO
Product: CSc1nc2ccccc2n1CCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 20.8 parts of 2-mercapto-1H-benzimidazole-1-propanol, 15.62 parts of iodomethane and 120 parts of methanol is stirred overnight at room temperature. The reaction mixture is evaporated and the residue is dissolved in 500 parts of water. The solution is filtered over hyflo and the filtrate is alkalized with solid potassium hydroxide. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated yielding 2-(methylthio)-1H-benzimidazole-1-propanol as a residue.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[NH:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1)(=O)[CH3:2].[C:13](OC(N(C)C)N(C)C)(C)(C)C.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[NH:35])=[CH:29][CH:28]=1)#[N:26].C([O-])([O-])=O.[K+].[K+].Cl>>[CH3:11][S:10][C:7]1[NH:6][C:5](=[O:12])[C:4]([C:1]2[CH:2]=[CH:13][N:36]=[C:34]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][CH:31]=3)[N:35]=2)=[CH:9][N:8]=1
Reactant: N#Cc1ccc(NC(=N)N)cc1
Reactant: CSc1ncc(C(C)=O)c(=O)[nH]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(=O)[nH]1
Temperature: 120 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
5-Acetyl-2-(methylthio)pyrimidin-4(3H)-one (33) (1.094 g, 5.94 mmol) was dissolved in 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (12.26 mL, 59.4 mmol), then the reaction mixture was heated at 120° C. for 6 hours. The reaction mixture was concentrated in vacuo, and dried over high vacuum for 1 hour. The crude intermediate was taken up in DMF (31.6 mL), then 1-(4-cyanophenyl)guanidine (2.076 g, 8.91 mmol) and K2CO3 (4.10 g, 29.7 mmol) were added. The reaction mixture was heated at 120° C. for 48 hours. Additional 1-(4-cyanophenyl)guanidine (2.076 g, 8.91 mmol) and K2CO3 (3.69 g, 26.7 mmol) were added, and the reaction mixture was stirred at 120° C. for additional 18 hours. The reaction mixture was cooled to rt, then was slowly poured into an ice-cooled 1N HCl solution while stirring vigorously. The reaction mixture was neutralized with additional 1N HCl, then the reaction mixture was allowed to stir for an additional 30 minutes. The resulting precipitate was filtered, washed multiple times with DI water, 2-propanol, then diethyl ether. The resulting crude product was dried over high vacuum for 18 hours to obtain the desired product as a red/brown solid (940 mg, 47% yield). MS (ES+): m/z=337.2 (100) [MH+]. HPLC: tR=1.35 minutes over 3 minutes. Purity: 72% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[CH:5][C:4]=1[S:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=1)(=[O:29])=[O:28])(=[O:18])=[O:17]>CC(O)=O.CCOC(C)=O.[Fe]>[NH2:36][C:33]1[CH:32]=[CH:31][C:30]([S:27]([NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][S:16]([C:4]2[CH:5]=[C:6]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:11])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:17])=[O:18])(=[O:29])=[O:28])=[CH:35][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Temperature: 100 °C
Yield: 85.9 %

Procedure:
To a solution of the 2-methoxy-N-[2-(4-nitrobenzenesulfonylamino)phenyl]-5-trifluoromethanesulfonylbenzenesulfonamide (1 mmol) in AcOH (5 mL), iron powder (300 mg) was added and the resulting reaction mixture was heated at 100° C. for 30 min. The reaction mixture was filtered through a short pad of Celite and the pad was washed with methanol (50 mL) and dichloromethane (25 mL). The filtrate was concentrated under vacuum. The residue obtained was dissolved in EtOAc (50 mL) and washed with 1% aqueous KOH solution (25 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was removed to dryness in vacuo to give 486 mg of crude N-[2-(4-aminobenzenesulfonylamino) -phenyl]-2-methoxy-5-trifluoro methanesulfonyl-benzenesulfonamide. LC: Tr 1.09 min; MS: 566.7 (M+1)+.
Reaction SMILES: [OH:1][C:2]1([C:15]([F:18])([F:17])[F:16])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[F:18][C:15]([F:16])([F:17])[C:2]1([OH:1])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(C(F)(F)F)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate (0.07 g, 0.26 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 30 minutes. Concentration and drying afforded 4-(trifluoromethyl)piperidin-4-ol (0.044 g, 100%). MS (EI) for C6H10F3NO: 269 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]2[N:7]3[CH2:18][CH2:19][NH:20][C:21](=[O:22])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:26]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]2[N:7]3[CH2:18][CH2:19][N:20]([CH3:26])[C:21](=[O:22])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: O=C1NCCn2c1cc1cc(F)cc(-c3ccc(F)cc3)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c(cc3cc(F)cc(-c4ccc(F)cc4)c32)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a stirred solution of 8-fluoro-6-(4-fluoro-phenyl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 18) (0.05 g, 0.17 mmol) in DMF (1.1 ml) was added at room temperature sodium hydride (8.78 mg, 0.2 mmol), and the mixture was allowed to stir at room temperature for 30 min. Afterwards iodomethane (23.8 mg, 10.5 μl, 0.17 mmol) was added and the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was poured into ice/water (30 ml) and extracted with ethyl acetate (2×25 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4) and evaporated. The crude product (50 mg) was further purified by flash chromatography on silica gel [dichloromethane-dichloromethane/MeOH 9:1 (0-50%)] to yield the title compound as a white solid (21 mg, 40%), MS (ISP) m/z=313.4 [(M+H)+], mp 212° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:19]([NH2:20])=[N:18][C:12]3[N:13]=[C:14]([NH2:17])[N:15]=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[NH2:17][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)[C:19]([NH:20][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:18][C:12]=2[N:13]=1
Reactant: Cc1cc(C)cc(-c2cc3cnc(N)nc3nc2N)c1
Reactant: CC(C)(C)N=C=O
Product: Cc1cc(C)cc(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c1

Procedure:
The title compound was prepared from 0.3 g of 6-(3,5-dimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 94 and 0.14 mL of tert-butyl isocyanate according to Example 2. The product is purified by MPLC eluting with 1:1 CHCl3 :EtOAc; mp 180-182° C., CIMS (1% ammonia in methane): m/z (relative intensity) 365 (MH+ +1, 16), 366 (MH+ +2, 3), 84 (100).
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1)([CH3:8])[CH3:7].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](Cl)=[O:26])=[CH:19][CH:18]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:25](=[O:26])[CH2:24][CH:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[CH3:1])([CH3:8])[CH3:7]
Reactant: COc1ccc(CCC(=O)Cl)cc1
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(C)CC(=O)N2C(=O)OC[C@@H]2C(C)C)cc1
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
18.19 ml (29.1 mmoles) of butyllithium (as a 1.6M hexane solution) were added dropwise at -78° C. and under an atmosphere of nitrogen to a solution of 3.13 g (24.2 mmoles) of 4(S)-isopropyl-2-oxazolidinone in 50 ml of anhydrous tetrahydrofuran, and then the mixture was stirred for 30 minutes. At the end of this time, a solution of 5.43 g (29.1 mmoles) of 3-(4-methoxyphenyl)propionyl chloride in 20 ml of anhydrous tetrahydrofuran was added dropwise to the resulting mixture over the course of 10 minutes. The mixture was then stirred for a further 1 hour, after which a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by medium pressure silica gel column chromatography (using a 1:3 by volume mixture of ethyl acetate and hexane as eluent), followed by recrystallization from diisopropyl ether, to give 5.63 g (yield 80%) of the title compound as white crystals, melting at 62.0°-63.5° C.
Reaction SMILES: Br[CH:2]([C:11]([C:13]1[S:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[O:12])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])=[O:20].[Na+].CO>C(OCC)(=O)C>[Cl:18][C:15]1[S:14][C:13]([C:11](=[O:12])[CH:2]([OH:20])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCCC(Br)C(=O)c1ccc(Cl)s1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CCCC(O)C(=O)c1ccc(Cl)s1

Procedure:
A mixture of ethyl 5-bromo-6-(5-chloro-2-thienyl)-6-oxohexanoate (64.4 g), sodium formate (60.0 g) and methanol (150 ml) was stirred with heating under reflux for 16 hours. The reaction mixture was diluted with ethyl acetate (500 ml) and washed with water (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 6-(5-chloro-2-thienyl)-5-hydroxy-6-oxohexanoate was obtained as a yellow oil (21.6 g, 41%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]3[N:19]=[CH:20][N:21]([CH3:22])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:23]([F:26])([F:25])[F:24].C(Br)(Br)(Br)[Br:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:28][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]3[N:19]=[CH:20][N:21]([CH3:22])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:23]([F:26])([F:25])[F:24]
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(CCCO)c(C(F)(F)F)c3)cc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cnc2c(C#N)nc(-c3ccc(CCCBr)c(C(F)(F)F)c3)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
6-[4-(3-Hydroxypropyl)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.3 g) was gently heated in THF (36 ml) until all dissolved and then cooled to 0° C. in an ice bath. Carbon tetrabromide (2.4 g) was added followed by triphenylphosphine (1.9 g). The mixture was stirred at 0° C. for 15 minutes and then at room temperature for 20 minutes until the cloudy suspension became a clear solution. The reaction mixture was diluted with DCM (100 ml) and washed with water (100 ml×2). Organic layer was dried over sodium sulphate and solvent was evaporated under reduced pressure. The residue was then columned (100 g SiO2 column, 1:1 EtOAc/Heptane to EtOAc gradient) to afford 6-(4-(3-bromopropyl)-3-(trifluoromethyl)-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.2 g) as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].Cl[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C(O)C>O>[CH2:18]([S:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([OH:7])=[O:6])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: O=C(O)c1cc(S)cc(C(F)(F)F)c1
Reactant: O=C(CCl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(SCC(=O)c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.33 g. (6 m moles) of 3-mercapto-5-trifluoromethylbenzoic acid, 12 ml. of 1N sodium hydroxide solution and 930 mg. (6 m moles) of α-chloroacetophenone in 20 ml. of ethanol is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, extracted with ether and the resulting aqueous phase acidified with 12N hydrochloric acid. The light yellow oil which separates gradually crystallizes and is filtered, 1.8 g., m.p. 135°-150° C. A sample is sublimed at 165° C. and 0.05 mm pressure, m.p. 153°-155° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[CH3:25])[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[N:15]1[CH2:16][CH2:17][N:12]([C:10]([C:5]2[CH:4]=[CH:3][C:2]([N:29]3[CH2:30][CH2:31][N:27]([CH3:26])[C:28]3=[O:32])=[CH:9][C:6]=2[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]1
Reactant: CN1CCNC1=O
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3C#N)CC2)c(C)c1
Yield: 83.7 %

Procedure:
Using 5-bromo-2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]benzonitrile (398 mg) described in Preparation Example 188 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (349 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[N:19]1([C:30](=[O:31])[C:29]2[NH:28][CH:27]=[N:26][C:25]=2[N:23]([CH3:24])[C:21]1=[O:22])[CH3:20].C(=O)([O-])[O-].[K+].[K+].[CH3:38][N:39]1[C:48](=[O:49])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][C:46]=2[CH3:50])[N:41]=[C:40]1[SH:51]>CN(C=O)C>[CH3:38][N:39]1[C:48](=[O:49])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][C:46]=2[CH3:50])[N:41]=[C:40]1[S:51][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([C:7](=[O:8])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:28]3[C:29]4[C:30](=[O:31])[N:19]([CH3:20])[C:21](=[O:22])[N:23]([CH3:24])[C:25]=4[N:26]=[CH:27]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(Cn5cnc6c5c(=O)n(C)c(=O)n6C)cc4)cc3)n(C)c(=O)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A solution of 4,4'-bis(bromomethyl)benzophenone (1.75 g), theophylline (900 mg) and potassium carbonate (828 mg) in DMF (40 ml) was stirred at 40° C. for 1 hour. Then, 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.03 g) was added and the mixture was stirred at 60° C. for 1 hour. This reaction mixture was concentrated, the residue was dissolved in ethyl acetate, and the solution was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to provide the title compound as colorless solid (787 mg).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=O)(=O)OC.O.[NH2:31][NH2:32]>>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]1[CH:19]=[C:4]2[C:3]([C@:2]3([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]2[CH2:6][CH2:7]3)=[N:32][N:31]=1
Reactant: COc1ccccc1C(=O)CP(=O)(OC)OC
Reactant: NN
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Solvent: O
Product: COc1ccccc1-c1cc2c(nn1)[C@@]1(C)CC[C@@H]2C1(C)C

Procedure:
yellow solid. MS (EI): 294.3 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(2-Methoxy-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:36][CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=1[O:32][CH3:31])=[O:29]
Reactant: COc1ccccc1CN
Reactant: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)NCC2
Reactant: O=C(Br)CBr
Product: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1OC)CC2

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxy-benzyl-amine
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40](Cl)=[O:41]>ClCCl>[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:8]2)=[CH:21][CH:22]=1)=[O:41]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1nn(Cc2ccc(N)cc2)c2ncccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ncccc12
Yield: 66.6 %

Procedure:
Methyl 2-[1-(4-aminobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]acetate (58 mg, 0.20 mmol) and triethylamine (41 mg, 0.41 mmol) were dissolved in 15 mL dichloromethane. In an ice bath, 2-naphthoyl chloride (38 mg, 0.20 mmol) was added. Upon completion of addition, it was moved to react at room temperature for 1 hour. It was rotate evaporated to dryness to remove the solvent, and chromatographed on a column (PE:EA=15:1) to obtain a white oil 60 mg, at a yield of 65%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][N:24]([CH3:34])[CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][N:24]([CH3:34])[CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][N:31]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=2[F:1])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:6])[CH2:30][CH2:29]1
Reactant: CN(C)CCOC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Reaction time: 1 h
Yield: 28.7 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), N,N-dimethyl-2-(piperidin-4-yloxy)ethanamine (85) (0.116 g, 0.67 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (0.087 g, 28.7% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.62-1.51 (1H, m), 1.84-1.66 (3H, m), 1.95-1.89 (1H, m), 2.28 (6H, s), 2.52 (2H, t), 3.15-3.01 (1H, m), 3.48-3.40 (1H, m), 3.62-3.51 (3H, m), 4.07-3.98 (1H, m), 4.27 (2H, s), 7.01 (1H, t), 7.32-7.25 (2H, m), 7.77-7.70 (3H, m), 8.47-8.45 (1H, m), 10.62 (1H, s); m/z (LC-MS, ESI+), RT=1.67 (M+H 452).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:16]([C:17]([NH2:19])=[O:18])[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:8](=[O:9])[CH2:7][C:5]=2[CH:6]=1.[BH4-].[Na+]>>[CH:1]1[CH:2]=[CH:3][C:4]2[N:16]([C:17]([NH2:19])=[O:18])[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@@H:8]([OH:9])[CH2:7][C:5]=2[CH:6]=1
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Product: NC(=O)N1c2ccccc2C[C@H](O)c2ccccc21
Temperature: 57.5 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of phenyl boronic acid (48.5 gm), D-(−)-tartaric acid (59.4 gm), calcium hydride (33.2 gm) in acetonitrile (750 mL) was heated to about 80-85° C. for about 1 hr. The reaction mass was cooled to about 25-30° C. (‘Solution X’). A solution of oxcarbazepine (50 gm) in acetonitrile (250 mL) was prepared separately. ‘Solution X’ obtained above was added to the solution of oxcarbazepine followed by stirring the reaction mass for about 2 hrs. To the resulting solution sodium borohydride (59.4 gm) was added at about 30-35° C. The reaction mass was stirred at the same temperature for about 8-10 hrs followed by distillation of solvent. To the resulting residue water (1000 mL) was added. The pH of the resulting solution was adjusted to about 12-13 by adding NaOH solution. The reaction mass was heated to about 55-60° C. followed by stirring at the same temperature for about 1 hr. consequently, cooled the reaction mass to about 20-25° C. The reaction mass was stirred at the same temperature for about 4 hrs. The reaction mass was again cooled to about 10-15° C. and stirred for about 3 hrs. The resulting solid (35 gm) was filtered, washed and dried to obtain the title compound (Yield: 70%; HPLC purity: 99.5%; Chiral purity: 96.4%; d0.9 114.3 μm, d0.5 53.1 μm, d0.1 22 μm).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[C:10]2[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:20]([CH3:22])=[CH:21][C:9]1=2.N1C=CC=CC=1.[C:48](Cl)(=[O:50])[CH3:49]>ClCCl>[F:37][C:36]([F:39])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:40])([F:1])[F:41])[CH:35]=1)[CH2:6][N:7]([C:27]1[N:28]=[N:29][N:30]([CH3:32])[N:31]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17][C:48](=[O:50])[CH3:49])[C:10]2[CH:18]=[C:19]([C:23]([F:24])([F:25])[F:26])[C:20]([CH3:22])=[CH:21][C:9]1=2
Reactant: CC(=O)Cl
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CCO)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCN1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-ethanol (Example 130, Step 2) (0.12 mmol) in dichloromethane (5 mL), add pyridine (0.47 mmol) followed by acetyl chloride (0.47 mmol). After stirring at room temperature for 14 h, quench the reaction with water (5 mL) and dilute with dichloromethane (5 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×5 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (5-40%), to afford the title compound as a colorless foam. MS (ES+): 639 (M+H).