Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12](Cl)[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cu](C#N)[C:22]#[N:23].CN1CCCC1=O.O.N>S([O-])([O-])(=O)=O.[Cu+2].O>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([C:22]#[N:23])[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: FC(F)(F)c1ccc2c(c1)CCc1c(Cl)cccc1S2
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc2c1CCc1cc(C(F)(F)F)ccc1S2
Reaction time: 18.5 h
Yield: 14.7 %

Procedure:
The mixture of 450 mg of 2-trifluoromethyl-9-chloro-10,11-dihydrodibenzo[b,f]thiepin, 0.4 g of copper cyanide, 0.05 g of anhydrous copper sulfate and 10 ml of N-methylpyrrolidone was stirred at 180° to 210° C. for 18.5 hrs. while preventing the moisture. After cooling, to the mixture was added 2.5 ml of conc. ammonia water and 35 ml of water and the resulting mixture was filtered with the use of celite. The thus obtained solution was extracted with benzene and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 0.3 g of a brown oily substance, which was chromatographed on a silica gel, eluted with n-hexane, and there was obtained 64 mg of the desired product. This was recrystallized from n-hexane to afford 2-trifluoromethyl-9-cyano-10,11 -dihydrodibenzo[b,f]thiepin having a melting point of 113° to 114.5° C. as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:15][C:16]([O:18]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl.Cl.[NH:39]1[CH:43]=[C:42]([CH2:44][NH2:45])[N:41]=[CH:40]1.O>CN(C)C=O>[NH:39]1[CH:43]=[C:42]([CH2:44][NH:45][C:16](=[O:18])[NH:15][C@@H:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:11]([O:13][CH3:14])=[O:12])[N:41]=[CH:40]1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1c[nH]cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)NCc1c[nH]cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 226.9 %

Procedure:
1.1 g (0.37 mmol) of methyl(S)-3-(4-methoxyphenyl)-2-(4-nitrophenoxycarbonyl-amino)propanoate (cf. preparation 2-2) and 0.7 mL (0.37 mmol) of diisopropyl-ethylamine in 5 mL of dimethylformamide are added at 80° C. to a solution of 500 mg (0.37 mmol) of C-(1H-imidazol-4-yl)methylamine dihydrochloride in 15 mL of dimethylformamide. The reaction mixture is stirred for 2 hours at 80° C. The reaction is stopped by adding 30 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (eluent: 80/20 dichloromethane/methanol). 279 mg of methyl (S)-2-[3-(1H-imidazol-4-yl-methyl)-ureido]-3-(4-methoxyphenyl)propanoate in the form of a yellow oil are obtained in a yield of 63%.
Reaction SMILES: C1(=O)O[C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1C=CC=C[C:14]=1O.P(=O)(O)(O)[OH:21].Cl(O)(=O)(=O)=O>CO>[OH:21][C:9]1[CH:10]=[C:2]2[C:3]([CH2:4][CH2:14][CH2:13][NH:12]2)=[CH:7][CH:8]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=P(O)(O)O
Reactant: Nc1ccccc1O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: Oc1ccc2c(c1)NCCC2

Procedure:
and phthalic anhydride 3.0 g. were heated as described in Example 11. Another 3.0 g. of the amino-phenol and 85% phosphoric acid 8 ml. were added and the contents heated under reflux in an oil-bath at 170° for three hours. A solution of 50% aqueous perchloric acid 8 ml. in methanol 80 ml. was added to the cooled reaction, the mixture refluxed and cooled at 0° overnight. Filtration gave 5.0 g. (44%) of dark red crystals.
Reaction SMILES: [N:1]1([CH:7]([C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][N:19]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][I:28]>CC(C)=O>[I-:28].[CH3:17][N+:14]1([CH3:27])[CH2:13][CH2:12][CH:11]([O:10][C:8](=[O:9])[CH:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][N:19]=2)[CH2:16][CH2:15]1
Reactant: CN1CCC(OC(=O)C(c2noc3ccccc23)N2CCCCC2)CC1
Reactant: CI
Solvent: CC(C)=O
Product: C[N+]1(C)CCC(OC(=O)C(c2noc3ccccc23)N2CCCCC2)CC1
Product: [I-]
Reaction time: 5 h
Yield: 78.7 %

Procedure:
A mixture of 1-methyl-4-piperidyl 2-piperidino-2-(1,2-benzisoxazol-3-yl)acetate (1 g), methyl iodide (2.5 g), and acetone (10 ml) was allowed to stand at room temperature for 5 hours. The resulting crystals were recrystallized from ethanol-methanol to give 1,1-dimethyl-4-[2-piperidino-2-(1,2-benzisoxazol-3-yl)acetoxy]piperidinium iodide (1.1 g), m.p. 176°-178° C.
Reaction SMILES: [CH2:1]([S:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:19]O>CS(O)(=O)=O>[CH2:1]([S:11]([CH2:14][CH2:15][C:16]([O:18][OH:19])=[O:17])(=[O:12])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCS(=O)(=O)CCC(=O)O
Reactant: OO
Agent: CS(=O)(=O)O
Product: CCCCCCCCCCS(=O)(=O)CCC(=O)OO
Temperature: 40 °C
Yield: 87.6 %

Procedure:
The product of Example 12 was converted to the corresponding carboxylic acid by alkaline hydrolysis followed by acidification and then to the corresponding sulfone carboxylic acid by oxidation in accordance with a procedure found in U.S. Pat. No. 3,857,875 to Brady et al. A stirred mixture of 5 g of 3-(n-decylsulfonyl)propionic acid and 50 mL of methanesulfonic acid was heated to 40±3° C. The 3-(n-decylsulfonyl)propionic acid dissolved only partially in the methanesulfonic acid at this temperature. Then 2.04 g of 90% hydrogen peroxide was added dropwise via pipette over ten minutes. Before the addition of the hydrogen peroxide was completed, the reaction mixture became thick from precipitation of a solid. After the addition of the 90% hydrogen peroxide was completed, the heating of the reaction mixture was continued at 40±3° C. until the reaction time totalled ninety minutes beginning at the start of the addition of the hydrogen peroxide. The reaction mixture was then cooled in an ice bath at 10° C. The solid was then filtered from solution using a coarse sinteredglass funnel, then transferred to a beaker containing 200 mL of ice water prepared from deionized water. The product was washed twice with ice water, filtered and dried to provide 4.63 g of the desired product (87.6% of theoretical based upon the weight of starting 3-(n-decylsulfonyl)propionic acid). The product was found to have 5.32% active oxygen. The product was stabilized with an equal weight of boric acid and put through a #30 polyethylene sieve which provided a particle size of less than 600 microns. The stabilized product contained 2.58% by weight active oxygen.
Reaction SMILES: [CH2:1]([C@@H:8]([C@@H:13]([OH:15])[CH3:14])C(NN)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:17]([O-])=O.[Na+].CCCCCC.C([O:30][CH2:31]C)(=O)C>O>[CH2:1]([C@H:8]1[C@H:13]([CH3:14])[O:15][C:31](=[O:30])[NH:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: CCOC(C)=O
Reactant: C[C@H](O)[C@H](Cc1ccccc1)C(=O)NN
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: C[C@@H]1OC(=O)N[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
5.5 ml of water was added to 0.50 g (2.40 mmol) of (2S,3S)-2-benzyl-3-hydroxybutanohydrazide (optical purity: >99.9%e.e.; anti/syn>99/1), and the mixture was cooled to 0° C. A 0.30 g (2.88 mmol) of 35% HCl was added thereto dropwise. After the addition, then an aqueous solution of 0.20 g (2.88 mmol) of sodium nitrite dissolved in 1.0 ml of water was further added thereto dropwise slowly. After the reaction mixture was stirred for 1 hour at that temperature, the thus prepared reaction mixture was added to 10 ml of warm water (50° C.) dropwise over 0.5 hour. After the addition, the mixture was further stirred for 1 hour, cooled to room temperature, and then extracted thrice with a 10 ml portion of toluene. The extracted toluene was then concentrated to give 0.33 g of a crude product. The crude product was subjected to column chromatography (hexane/ethyl acetate=1/1 by volume) to obtain 0.25 g (52%) of the title compound. Melting point: 115.5° C. Optical purity: >99.9%e.e. anti/syn>99/1
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]2[CH2:15][O:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-][CH2:17][CH3:18].[Na+].CC[OH:22]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:22])[CH2:15][O:14][CH2:17][CH3:18])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[O-]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H]2CO2)C1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)—(R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (440 mg, 2.1 mmol) was added to 2M of sodium ethoxide in EtOH (2.1 mL, 4.1 mmol; prepared from EtOH and NaH). The resulting solution was placed in a microwave reactor for 10 minutes at 100° C., then cooled to room temperature. DCM (5 mL) was added, followed by washing with saturated aqueous NaCl (5 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (0-100% ether/Hexanes) to give the title compound as a clear oil (400 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][C:16]2[CH:26]=[CH:25][C:19](C(OCC)=O)=[CH:18][CH:17]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[C:10]=2[CH:11]=1.[CH2:27]1COCC1.C=O.[BH3-]C#N.[Na+].[C:38]([O:41][CH2:42][CH3:43])(=[O:40])C>O.C(O)(=O)C>[CH3:27][C:18]1[CH:19]=[CH:25][C:26]([C:38]([O:41][CH2:42][CH3:43])=[O:40])=[C:16]([NH:15][C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:9]([CH3:12])=[CH:8][CH2:7][C:6]([CH3:13])([CH3:14])[C:5]=3[CH:4]=2)[CH:17]=1
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Reactant: CCOC(C)=O
Reactant: C1CCOC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(C)cc1Nc1cc2c(cc1C)C(C)=CCC2(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
Following the previously described General Procedure D to a solution of ethyl 4-(3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 39, 0.10 g, 0.27 mmol) and 6 mL of THF was added an aqueous solution of formaldehyde 37% (0.20 mL, 2.7 mmol), followed by NaBH3CN (0.05 g, 0.82 mmol) and glacial acetic acid (5 mL). The resulting reaction mixture was stirred at room temperature for 24 h, then treated with water and ethyl acetate. The layers were separated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with NaHCO3 1 N, brine, and dried over MgSO4, and filtered. The solvent was removed, and the residue was purified by flash column (hexane:ethyl acetate=4:1) to give 0.050 g (50%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]1[CH2:12][C:11]2[CH:13]=[C:14](Br)[CH:15]=[N:16][C:10]=2[NH:9][C:8](=[O:18])[CH2:7]1)[CH3:2].[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH:21]=[CH2:22].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:25]([O:24][C:20](=[O:23])/[CH:21]=[CH:22]/[C:14]1[CH:15]=[N:16][C:10]2[NH:9][C:8](=[O:18])[CH2:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH2:12][C:11]=2[CH:13]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)CN1CC(=O)Nc2ncc(Br)cc2C1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CC(=O)Nc2ncc(/C=C/C(=O)OC(C)(C)C)cc2C1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A suspension of (7-Bromo-2-oxo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-4-yl)acetic acid ethyl ester (6.18 g, 17.4 mmol) in propionitrile (70 mL) and DMF (17 mL) was de-oxygenated with Ar for 30 min. The mixture was treated with tert-butyl acrylate (10.2 mL, 69.6 mmol) and (i-Pr)2EtN (6.4 mL, 37 mmol) and was then de-oxygenated with Ar for 10 min. Pd(OAc)2 (0.39 g, 1.7 mmol) and P(o-tol)3 (1.06 mg, 3.48 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. After heating to reflux for 14 h, the mixture was allowed to cool and then concentrated in vacuo. The resulting residue was diluted with CH2Cl2 and filtered through Celite. The orange filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (200 mL) and washed with H2O (100 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with H2O (2×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3) and again by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave the title compound (2.55 g, 39%) as an off-white solid: MS (ESI) m/e 376 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([O:21][CH2:22][C:23]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cn(C(=O)COCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of indole-3-carboxaldehyde (2 g, 13.8 mmol) in THF (70 mL) at 5° C., was added NaH (60% in mineral oil, 551 mg, 13.8 mmol) under nitrogen atmosphere. The mixture was stirred at 5° C. for 30 min before dropwise addition of benzyloxyacetyl chloride (2.6 mL, 16.53 mmol) over 20 min maintaining the internal temperature between 5° C. and 10° C. The resulting dark solution was further stirred at RT for 1 h. As the reaction was not completed benzyloxyacetyl chloride (1 mL, 6.44 mmol, 0.5 eq) and NaH (60% in mineral oil, 551 mg, 13.8 mmol) were added and the mixture was further stirred at RT for 3 days. The reaction mixture was concentrated, and the residue taken up in CH2Cl2 and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 4-1) corresponding to the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.61; MS (LC/MS): 294.1 [M+H]+, 316.1 [M+Na]+; tR (HPLC conditions a): 3.87 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>O1CCCC1>[CH3:16][O:17][CH2:18][C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Product: COCC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 44.3 %

Procedure:
6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 3.9 g (35.9 millimoles) of methoxyacetyl chloride in 150 ml of absolute tetrahydrofuran were refluxed for 2 hours, while stirring. The product was filtered off under suction at 10° C., washed with water and recrystallized from dimethylformamide/water. 3.6 g (44%) of 6-[p-(methoxyacetylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained as colorless crystals. Mp.: 212° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=[C:3]1[CH2:16][C:17]([OH:19])=[O:18].[Na].CN1C(C(C2C=CC(C)=CC=2)=O)=CC=C1CC#N.C([SH:41])C.Cl>>[CH2:16]([C:3]1[N:2]([CH3:1])[C:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1)[CH3:17].[S:41]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:16][C:17]([O-:19])=[O:18]
Reactant: Cc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1
Reactant: CCS
Agent: Cc1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Agent: Cl
Agent: [Na]
Product: CCc1ccc(C(=O)c2ccc(C)cc2)n1C
Product: O=C([O-])Cc1cccs1

Procedure:
A process of preparing sodium 1-methyl-5-(p-toluoyl)- pyrrole-2-acetic acid which comprises reacting 1-methyl-5- (p-toluoyl)pyrrole-2-acetonitrile with ethyl mercaptan in the presence of hydrogen chloride in an anhydrous aprotic organic solvent under an inert atmosphere at or below 10° C. to yield ethyl 1-methyl-5-(p-toluoyl)pyrrole-2-thiolacetate and then hydrolyzing said thiolacetate by treatment with aqueous sodium hydroxide.
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].CC(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: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: CC(C)O
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.8 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), IPA (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (50 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 IPA. 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>95%, trans<5%, dehalogenation product<0.1%, yield 0.80 to 0.82%].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[CH:13]([C:16]1[N:21]=[C:20]([NH2:22])[CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:22][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:13]([CH3:15])[CH3:14])[N:21]=2)[CH:7]=1
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Reactant: CC(C)c1cccc(N)n1
Solvent: CC#N
Product: COC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)C)n1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A stirred solution of methyl 4,6-dichloropyridazine-3-carboxylate (255 mg, 1.23 mmol) and 6-isopropylpyridin-2-amine (252 mg, 1.85 mmol) in acetonitrile (8.0 mL) was heated at 140° C. for 21 h. After cooling to room temperature the reaction mixture was concentrated in vacuo, then the residue purified by chromatography (silica, 20-45 μm, 80 g, Thomson, 0 to 10% acetone in dichloromethane, 20 min) to give methyl 6-chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxylate (113 mg, 30%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.64 (br. s., 1H) 9.39 (s, 1H) 7.63 (t, J=7.83 Hz, 1H) 6.94 (d, J=7.58 Hz, 1H) 6.78 (d, J=8.08 Hz, 1H) 4.12 (s, 3H) 3.01-3.19 (m, 1H) 1.31-1.42 (m, 6H). LCMS (EI/CI) m/z: 307 [M+H].
Reaction SMILES: [CH:1]1[C:17]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18]C(C)([O-])C.[K+].COS(OC)(=O)=O.[OH-].[Na+]>C(Cl)Cl.C1COCC1>[CH3:18][N:9]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:17]=3[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: CC(C)(C)[O-]
Reactant: c1ccc2c(c1)ccc1[nH]c3ccccc3c12
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: Cn1c2ccccc2c2c3ccccc3ccc21
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser and N2 inlet line with bubbler was added 7H-benzo[c]carbazole (H. G. Pars Pharmaceutical Laboratories, Inc., 6.6 g, 30.4 mmol) and dry THF (250 mL). To the flask was added in one portion potassium t-butoxide (Aldrich, 4.2 g, 37.4 mmol). Dimethylsulfate (Aldrich, 7.56 g, 60.0 mmol, 5.9 mL) was added dropwise to the solution and the mixture stirred for 15 min. TLC (SiO2 /PhCH3) showed the reaction to be complete. The reaction mixture was then poured into a 1N NaOH solution (2L) and stirred. The white solid which formed was collected by filtration, washed with H2O (3×500 mL), sucked semidry, dissolved in PhCH3 (300 mL) and eluted through a plug of SiO2 (5×5 cm) using PhCH3 as the eluting solvent. Appropriate fractions were combined and the solvent removed to give a crude white product. This material was dissolved in CH2Cl2 (400 mL), filtered and diluted to 1 L with hexane. The mixture was concentrated to 500 mL by rotary evaporation. A white solid formed which was filtered, washed with pentane and dried in a vacuum to give 5.0 g of 7-methyl-7H-benzo[c]carbazole, mp 116°-118°, (C,H,N). A further 1.06 g of product was obtained on standing and further concentration of the filtrate to give a combined yield of 87.3%.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14].C(N(CC)CC)C>C1COCC1>[CH3:13][C:9]1[C:8]2[O:14][CH2:2][C:3](=[O:4])[NH:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(N)c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc2c1OCC(=O)N2
Reaction time: 24 h
Yield: 78.4 %

Procedure:
A solution of chloroacetyl chloride (0.71 mL, 8.94 mmol) in THF (5 mL) was added dropwise to a solution/suspension of 2-amino-6-methylphenol (1 g, 8.13 mmol) and triethylamine (1.24 mL, 8.94 mmol) in THF (50 mL) which had been pre-cooled in an ice-water bath. After stirring for 5 minutes a further portion of triethylamine (1.24 mL, 8.94 mmol) was added. The mixture was stirred and warmed to r. t. After 24 h the reaction was allowed to stand overnight. The mixture was concentrated in vacuo and the residue was partitioned between water (100 mL) and EtOAc (50 mL). Brine (20 mL) was added to the aqueous phase, and this was further extracted with EtOAc (50 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo, and purified by column chromatography (SiO2, 20-100% EtOAc/heptane) to give an orange-brown solid (1.04 g), which was dissolved in THF (10 mL) and triethylamine (2 mL), and the mixture left to stand for 3 days. The mixture was concentrated in vacuo and purified by column chromatography (SiO2, 10-50% EtOAc/heptane) to give a cream solid (0.6 g). This was dissolved in DCM (40 mL), and the solution was washed with aqueous NaOH (2M, 10 mL). The organic fraction was dried (MgSO4) and concentrated in vacuo to give the title compound (0.29 g, 22%) as a beige solid. LCMS (ES+) 164 (M+H)+, RT 2.61 minutes (Method 1).