Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]([Cl:11])=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:12])[N:7]=2)[C:3]=1[C:13]([O:15][CH3:16])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:42]([O:46][CH3:47])(=[O:45])[CH:43]=[CH2:44]>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:11][C:10]1[C:2](/[CH:44]=[CH:43]/[C:42]([O:46][CH3:47])=[O:45])=[C:3]([C:13]([O:15][CH3:16])=[O:14])[C:4]2[C:8]([CH:9]=1)=[N:7][N:6]([CH3:12])[CH:5]=2
Reactant: COC(=O)c1c(Br)c(Cl)cc2nn(C)cc12
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1c(Cl)cc2nn(C)cc2c1C(=O)OC
Temperature: 100 °C
Yield: 80.2 %

Procedure:
A suspension of methyl 5-bromo-6-chloro-2-methyl-2H-indazole-4-carboxylate (330 mg, 1.09 mmol), palladium acetate (24.5 mg, 0.109 mmol), triphenylphosphine (57.2 mg, 0.218 mmol), potassium carbonate (226 g, 1.64 mmol) and methyl acrylate (147 μL, 1.64 mmol) in N,N-dimethylformamide (11 mL) was stirred with heating at 100° C. for 1 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→60/40) to give the title compound (270 mg, yield 80%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:24][C:25]1[N:26]=[C:27]([CH3:33])[NH:28][C:29]=1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:24][C:25]1[N:26]=[C:27]([CH3:33])[NH:28][C:29]=1[C:30]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:23])=[O:31]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)(F)F)c1
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C(F)(F)F)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (27.9 mg, 0.081 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (13.0 mg, 0.081 mmol) and HATU (30.8 mg, 0.081 mmol) in DMF (1.5 ml) was added diisopropylethyl amine (0.028 ml, 0.162 mmol) and the mixture was stirred for 1 hour at rt. The mixture was purified via reverse phase HPLC and neutralized to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-2-methyl-1H-imidazole-5-carboxamide (25 mg, 0.051 mmol, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05-8.14 (m, 2H), 7.77 (s, 1H), 7.71 (s, 1H), 7.47 (d, 1H), 7.33 (t, 1H), 4.49 (d, 2H), 2.21 (s, 3H). LC-MS (ES+) m/z 486.94, [M+H].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].CCN(C(C)C)C(C)C.Cl.[CH3:25][NH:26][O:27][CH3:28]>C(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1-c1ncco1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccccc1-c1ncco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a mixture of 2-Oxazol-2-yl-benzoyl chloride (104 mg, 0.5 mmol), DIEA (0.26 mL, 1.5 mmol) in 2 ml of DCM was added N,O-dimethylhydroxylaminehydrochloride (59 mg, 0.6 mmol). The mixture was stirred at room temperature for 2 hours, washed with dilute HCl solution followed by brine. Concentration of the organic layer afforded 100 mg of N-Methoxy-N-methyl-2-oxazol-2-yl-benzamide as a sticky light yellow liquid. MS: (M+H)/z=233.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[CH:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][N:13]=1)[CH3:2].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:14][N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OS(=O)(=O)C(F)(F)F)cn1
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: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(-c2ccccc2)cn1
Yield: 86.2 %

Procedure:
Compound II (22 mg, 0.046 mmol), Pd(PPh3)4 (1.6 mg, 0.0014 mmol), phenylboronic acid (11.2 mg, 0.092 mmol) and potassium carbonate (9.5 mg, 0.07 mmol) were stirred in toluene (2 mL) at 90° C. in a sealed tube for 20 h. Then the reaction mixture was filtrated through celite and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 to 70:30) to furnish 16 mg of III in mixture with the starting material. MW: 403.52. LCMS (ES). found 404.2 [MH]+.
Reaction SMILES: C1(C2N=C(C([O-])=O)SC=2)CC1.[Li+].[CH:13]([C:16]1[N:17]=[C:18]([C:21]([Cl:23])=[O:22])[S:19][CH:20]=1)([CH3:15])[CH3:14]>>[CH:13]1([C:16]2[N:17]=[C:18]([C:21]([Cl:23])=[O:22])[S:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CC(C)c1csc(C(=O)Cl)n1
Agent: O=C([O-])c1nc(C2CC2)cs1
Agent: [Li+]
Product: O=C(Cl)c1nc(C2CC2)cs1

Procedure:
Compound 267a was synthesized from compound 266a (3 g, 1 eq.) as a brown solid in quantitative yield, following the procedure as described for compound 214. MS (ESI, EI+): m/z=170 (MH+).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][S:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncsc1-c1ccc(F)cc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncsc3-c3ccc(F)cc3)n2)o1

Procedure:
Following general procedure B followed by either C or D, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.93 min; [M+H]+=411.03.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17]C)[CH:15]=3)[N:10]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([C:19](=[O:24])[C:20]([F:22])([F:23])[F:21])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(O)cc12
Temperature: -20 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
1-(1′-Acetyl-5-methoxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (2.74 g, 8.00 mmol) was dissolved in methylene chloride (50 mL). Thereafter, 1 M boron tribromide (40 mL, 40.0 mmol) was added to the above obtained solution at −78° C., and the thus obtained mixture was then stirred at −20° C. for 3 hours. Thereafter, the reaction solution was poured into ice water, and was then extracted with chloroform. The organic layer was washed with water and brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 1-(1′-acetyl-5-hydroxyspiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (2.39 g, 91%) in the form of a dark brown solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:23]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[C:14](=[O:16])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NCc1cccnc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1cccnc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 3-aminomethylpyridine (0.14 mL, 1.4 mmol). Purification using silica gel, eluting with 19:1 CH2Cl2 /MeOH sat'd with NH3, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 116 as a white solid (m.p. 141-146° C.).
Reaction SMILES: Cl.[F:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[N:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[CH:6]=[C:5]([CH3:19])[CH:4]=1.C(N(CC)CC)C.[O:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.ClCCCl>[F:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[N:8]([CH:13]3[CH2:18][CH2:17][N:16]([CH:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[C:5]([CH3:19])[CH:4]=1
Reactant: Cc1cc(F)c2[nH]c(=O)n(C3CCNCC3)c2c1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Fluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D5) (0.072 mmol, 21 mg) was dissolved in dichloromethane (2 ml) and triethylamine (3 eq., 0.216 mmol, 30 microliters), tetrahydro-4H-pyran-4-one (7 eq., 0.5 mmol, 47 microliters) were added and the mixture was stirred at room temperature for 10 minutes; sodium triacetoxyborohydride (7 eq., 0.5 mmol, 106 mg) was added at room temperature and the mixture was stirred at room temperature for one overnight. Reaction mixture was quenched with NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to afford the crude product. The crude obtained was dissolved in 1,2-dichloroethane (3 ml) and triethylamine (3 eq., 0.216 mmol, 30 microliters), tetrahydro-4H-pyran-4-one (7 eq., 0.5 mmol, 47 microliters) were added again and the mixture was stirred at room temperature for 10 minutes; sodium triacetoxyborohydride (7 eq., 0.5 mmol, 106 mg) was subsequently added at room temperature and the mixture was stirred at room temperature for 3 extra hours. Reaction mixture was quenched with NaHCO3 (saturated solution) and diluted with dichloromethane; the two phases were separated and the organic solvent was evaporated to afford the crude product that was purified by chromatography (methanol-NH3-dichloromethane) to afford 4-fluoro-6-methyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 10 mg, 42%, M++H=334, which was converted to the HCl salt using 1M HCl in diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:34]1>>[CH2:38]([N:35]1[CH2:36][CH2:37][CH:33]([NH:32][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)=[CH:19][CH:20]=2)[CH2:34]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NC1CCN(Cc2ccccc2)C1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-amino-1-benzylpyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z=605.96 (M+H+); retention time=0.62 minutes.
Reaction SMILES: [Na].[C:2]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14])([CH3:4])=[CH2:3].[C:15]([N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2NC1=O)([CH3:17])=C.[H-].[Na+].O1[CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O>[NH:18]1[C:22]2[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]([CH:32]2[CH2:33][CH2:34][N:5]([CH2:9][CH2:8][CH2:13][N:7]3[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[N:5]([C:2]([CH3:4])=[CH2:3])[C:6]3=[O:14])[CH2:2][CH2:31]2)=[CH:15]1
Reactant: C1CCOC1
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.5 gm of the above intermediate were dissolved in 5 ml tetrahydrofuran and added to a cooled suspension of N-isopropenyl-benzimidazolone sodium salt prepared from 0.34 gm of N-isopropenyl-benzimidazolone and 0.05 gm of sodium hydride in 5 ml of dimethylformamide. The mixture was stirred for 16 hours at room temperature and then poured on ice-water-ammonia. The crystalline product was filtered off and dried. Yield: 0.65 gm (81% of theory), m.p. 68° C., identical with the product obtained by method B in Example 6.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[Br:27][C:28]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:29]=1[CH:30]=O>O1CCCC1.O>[Br:27][C:28]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:29]=1[CH:30]=[CH2:2]
Reactant: O=Cc1cc(F)ccc1Br
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A mixture of methyltriphenylphosphonium iodide (1.195 g, 2.96 mmol) in tetrahydrofuran (25 mL) was added BuLi (1.182 mL, 2.96 mmol) at 0° C. and stirred at 0° C. for 0.5 h. It was then added 2-bromo-5-fluorobenzaldehyde (0.5 g, 2.463 mmol) and stirred at rt for 16 h. The reaction was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 5% EtOAc/hexane to obtain 1-bromo-4-fluoro-2-vinylbenzene (320 mg, 1.592 mmol, 64.6% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.56-7.48 (m, 1H), 7.33-7.23 (m, 1H), 7.09-6.96 (m, 1H), 6.89 (td, J=8.3, 3.1 Hz, 1H), 5.73 (d, J=17.4 Hz, 1H), 5.45 (d, J=11.0 Hz, 1H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C@@H:9]2[C@@H:10]3[O:12][C@H:11]3[C@H:5]1[CH2:6][C@@H:7]([O:13]C([C@@H](C1C=CC=CC=1)CO)=O)[CH2:8]2.Cl>C(O)C.C(OCC)C>[CH3:3][N:4]1[CH:9]2[CH2:8][CH:7]([OH:13])[CH2:6][CH:5]1[CH:11]1[CH:10]2[O:12]1
Reactant: CN1[C@@H]2C[C@@H](OC(=O)[C@H](CO)c3ccccc3)C[C@H]1[C@@H]1O[C@H]12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CN1C2CC(O)CC1C1OC12
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
Sodium borohydride (39.0 g, 1.03 mol) was added portionwise to a stirred suspension of scopolamine (75 g, 171 mmol) in ethanol (743 mL), at 0° C. under a nitrogen atmosphere and the reaction mixture was stirred at ambient temperature for 24 h. The mixture was then acidified with 2M hydrochloric acid in diethyl ether (600 mL) and stirred for another 24 h at ambient temperature. The reaction mixture was filtered and the resulting solid was washed with diethyl ether. The dried solid was dissolved in the minimum amount of 10% aqueous potassium carbonate solution and extracted with trichloromethane (6×150 mL). The combined organic extracts were dried (magnesium sulfate), filtered and the solvent was removed under reduced pressure to give the title compound as crystals (13.2 g, 85.5 mmol, 50%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:20]2[C@@H:29]3[C@@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][N:34](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:33][CH2:32]3)[N:21]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[CH3:9]>>[C:1]([N:34]1[CH2:35][CH2:36][CH:31]([N:22]2[N:21]=[C:20]([C:13]3[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH3:19])=[C:11]([O:10][CH2:8][CH3:9])[CH:12]=3)[C@@H:29]3[C@@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23]2=[O:30])[CH2:32][CH2:33]1)(=[O:3])[CH3:2]
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Reactant: CC(=O)OC(C)=O
Product: CCOc1ccc(C2=NN(C3CCN(C(C)=O)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from acetic anhydride and starting compound A2 as described for compound 1. Crystallised from diethyl ether. M.p. 148-150° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10](=[O:16])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:5][C:4]=1[CH3:17].[BH4-].[Na+]>>[CH3:1][N:2]([CH3:18])[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH:10]([OH:16])[CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])=[CH:5][C:4]=1[CH3:17]
Reactant: Cc1cc(C(=O)CS(C)(=O)=O)cc(C)c1N(C)C
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cc(C(O)CS(C)(=O)=O)cc(C)c1N(C)C

Procedure:
A suspension of 12 g. of 4'-(dimethylamino)-3',5'-dimethyl-2-(methylsulfonyl)-acetophenone and 6.6 g. of sodium borohydride in 300 ml. of alcohol was stirred at room temperature for 20 hours, resulting in a solution. After the addition of 300 ml. of water, the alcohol was removed under vacuum. The crystals formed were removed by filtration with suction, washed with water and dried, whereby there was obtained 4-(dimethylamino)-3,5-dimethyl-α-[(methylsulfonyl)-methyl]-benzyl alcohol having a melting point of 133°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(OCC)(=O)C.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: CCOC(C)=O
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.78 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), Ethyl acetate(300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml ethyl acetate. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>98%, trans<2%, dehalogenation product<0.1%, yield 0.78 to 0.80%].
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:3].[Br:13]Br>C(Cl)(Cl)Cl>[CH:8]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([C:2]([CH2:1][Br:13])=[O:3])[CH:9]=1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1cccc([N+](=O)[O-])c1

Procedure:
60 g. of 3-nitroacetophenone in 250 ml. of chloroform is treated with 58.2 g. of bromine in 50 ml. of chloroform. The solvent is evaporated and the product separated by filtration and recrystallized from benzene to provide α-bromo-3-nitroacetophenone, m.p. 91°-94° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1/[CH:4]=[N:5]/[S@:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7].[CH3:20][Mg]Br.C1COCC1>ClCCl>[F:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][C:3]=1[CH:4]([NH:5][S@:6]([C:8]([CH3:11])([CH3:9])[CH3:10])=[O:7])[CH3:20]
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@](=O)/N=C/c1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(N[S@@](=O)C(C)(C)C)c1cc(C(F)(F)F)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of (S,E)-N-(2-fluoro-5-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (single enantiomer) (150 mg, 0.51 mmol, Step-1) in dichloromethane (5 mL) is added dropwise a solution of methylmagnesium bromide in THF (0.99 M, 2.57 mL, 2.54 mmol) at −78° C. The resulting mixture is stirred at −78° C. for 2 hours and at room temperature for 1 hour. The reaction is quenched by saturated aqueous ammonium chloride solution (50 mL), and the aqueous phase is extracted with EtOAc (50 mL×2). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (3:1-1:1) to give 63 mg (40% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:40][O:41][CH2:42][C:43]1[CH:63]=[C:62]([Cl:64])[C:46]2[O:47][C:48]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[O:49][C:45]=2[C:44]=1[Cl:65]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:40]/[O:41][CH2:42][C:43]2[CH:63]=[C:62]([Cl:64])[C:46]3[O:47][C:48]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:49][C:45]=3[C:44]=2[Cl:65])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCc1cc(Cl)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCc4cc(Cl)c5c(c4Cl)OC(c4ccccc4)(c4ccccc4)O5)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)NO)nc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 104 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (52 mg) (0.088 mmol) and 47 mg (0.11 mmol) of 5-[(aminooxy)methyl]-4,7-dichloro-2,2-diphenyl-1,3-benzodioxol are dissolved in 1 ml of absolute dimethylacetamide. After stirring at room temperature for 20 hours the solvent is removed in a high vacuum at room temperature and the residue is crystallized by the addition of diethyl ether. The product is filtered off and washed in succession with diethyl ether and water. After drying in a high vacuum at room temperature there are obtained 88 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(4,7-dichloro-2,2-diphenyl-1,3-benzodioxol-5-yl)methoxy]imino]acetamido]-3-[[[2-(hydroxycarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:13]([CH3:16])([O-:15])=[O:14]>>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[CH:16][N+:13]([O-:15])=[O:14])[C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C=O)c1OC
Reactant: C[N+](=O)[O-]
Product: COc1cccc(C=C[N+](=O)[O-])c1OC

Procedure:
In close analogy to the procedure described above, 2,3-Dimethoxy-benzaldehyde is reacted with nitromethane to provide the title compound.