Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[C:14]([C:16]1[N:20]([CH3:21])[C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:19]2[N:20]([CH3:21])[C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[CH:3][C:4]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(N)c(OC(F)(F)F)c1
Reaction time: 16 h
Yield: 71.1 %

Procedure:
4-Bromo-2-(trifluoromethoxy)aniline (1.3 g, 5.0 mmol), 5-cyano-1-methyl-1H-pyrrol-2-yl boronic acid (0.9 g, 6.0 mmol), potassium fluoride (0.96 g, 16.5 mmol), and tris(dibenzylideneacetone)dipalladium (0.12 g, 0.12 mmol) were placed in an oven dried flask under nitrogen and THF (12.5 mL) was added. Tri-t-butylphosphine (10 wt % in hexane) (0.356 mL, 0.24 mol) was added and the reaction was stirred for 16 hours. The reaction mixture was filtered through silica, rinsed with ethyl acetate, and concentrated. The crude product was pre-adsorbed onto the Celite™ reagent and purified via Isco chromatography (the Redisep® column, silica, gradient 5-30% ethyl acetate in hexane) to afford 1.0 g (71%) of 5-[4-amino-3-(trifluoromethoxy)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:6]=[CH:5][N:4]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(-c2cc(OS(=O)(=O)C(F)(F)F)nnc2-c2cccc(C(F)(F)F)c2)n1
Reactant: C1COCCN1
Product: CSc1nccc(-c2cc(N3CCOCC3)nnc2-c2cccc(C(F)(F)F)c2)n1
Temperature: 80 °C

Procedure:
Compound 74 (180 mg, 0.363 mmol) and morpholine (˜1 mL) were combined under Argon and heated to 80° C. for 2 h. Purification by flash column chromatography (hexane ethyl acetate 50:50) gave Compound 75 as an oil: 104 mg (0.240 mmol, 66%)
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:12])=[CH:8][C:9]=2[OH:11])[O:4][C@H:3]([C:13]2[CH:18]=[C:17](O)[C:16]([OH:20])=[C:15]([OH:21])[CH:14]=2)[C@@H:2]1[O:22][C:23]([C:25]1[CH:30]=[C:29]([OH:31])[C:28]([OH:32])=[C:27]([OH:33])[CH:26]=1)=[O:24].OO>CC(C)=O>[CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:12])=[CH:8][C:9]=2[OH:11])[O:4][C@H:3]([C:13]2[CH:18]=[C:18]3[C:13]([C@H:3]4[O:4][C:5]5[C:10](=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=5)[CH2:1][C@H:2]4[O:22][C:23]([C:25]4[CH:30]=[C:29]([OH:31])[C:28]([OH:32])=[C:27]([OH:33])[CH:26]=4)=[O:24])=[CH:14][C:15]([OH:21])=[C:16]([OH:20])[C:17]3=[C:16]([OH:20])[C:15](=[O:21])[CH:14]=2)[C@@H:2]1[O:22][C:23]([C:25]1[CH:26]=[C:27]([OH:33])[C:28]([OH:32])=[C:29]([OH:31])[CH:30]=1)=[O:24]
Reactant: O=C(O[C@@H]1Cc2c(O)cc(O)cc2O[C@@H]1c1cc(O)c(O)c(O)c1)c1cc(O)c(O)c(O)c1
Agent: OO
Solvent: CC(C)=O
Product: O=C(O[C@@H]1Cc2c(O)cc(O)cc2O[C@@H]1c1cc(=O)c(O)c2c(O)c(O)cc([C@H]3Oc4cc(O)cc(O)c4C[C@H]3OC(=O)c3cc(O)c(O)c(O)c3)c2c1)c1cc(O)c(O)c(O)c1
Yield: 10.6 %

Procedure:
ECG (1 g) and EGCG (1 g) were dissolved in a mixture of acetone-pH 5.0 phosphate citrate buffer (1:10, v/v, 50 mL), which contained 4 mg horseradish peroxidase. While being stirred, 2.0 ml of 3.13% H2O2 was added four times during 45 minutes. The reaction mixture was extracted by ethyl acetate (50 ml×3). After concentration, the residue was subjected to Sephadex LH 20 column eluted with acetone-water solvent system (45%). 100 mg theaflavin 3,3′-digallate was obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13](Br)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[CH:9][CH:8]=1>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([N:1]=[N+:2]=[N-:3])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C(Br)c2cccc([N+](=O)[O-])c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(N=[N+]=[N-])c2cccc([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
Sodium azide (26.1 g) was added to a solution of α-(4-methoxyphenyl)-3-nitrobenzyl bromide (25.8 g) in dimethylformamide (200 ml) in an ice bath. The mixture was stirred on the ice bath for 1 hour and then at ambient temperature for 1 hour. The dimethylformamidle was then removed by evaporation under reduced pressure. The residue was partitioned between ethyl acetate and water two times. The ethyl acetate layers were combined and washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column using a 6:1 by volume mixture of hexane and ethyl acetate as the eluant, to afford the title compound (18.6 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][S:19]([CH3:18])(=[O:20])=[O:21])=[CH:28][CH:27]=3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Product: CS(=O)(=O)Nc1ccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)cc1

Procedure:
4-(5-Chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 was reacted with N-methylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine via General Procedure A to give crude 4-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)-N-methylsulfonylbenzenamine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 125 after purification by reverse HPLC. MS (Q1) 485 (M+)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:31])[NH:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[C:32]1([C@H:38]([NH:40][C:41]([NH2:43])=[O:42])[CH3:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:6]1[C:5]2[C:9](=[O:31])[NH:10][N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=[C:2]([NH:43][C:41]([NH:40][C@@H:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:39])=[O:42])[N:7]=1
Reactant: Cc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
6-Chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3 (2H)-one (Intermediate 4B; 300 mg, 0.704 mmol), (R)-1-(1-phenylethyl)urea (139 mg, 0.845 mmol), palladium(II) acetate (31.6 mg, 0.141 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (122 mg, 0.211 mmol), and cesium carbonate (574 mg, 1.761 mmol) were taken up in dioxane (10.0 mL) in a 25 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) then the reaction mixture was heated to 80° C. for 24 h. The reaction mixture was diluted with DCM, filtered through celite, and the filtrate was washed with water then brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (20-80% EtOAc/Hexanes) to give (R)-1-(4-methyl-3-oxo-1-trityl-2,3-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C35H31N5O2 [M+1]+ 554. found 554.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:2]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:16])[CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCCCCc1cccnc1
Solvent: ClC(Cl)Cl
Product: ClCCCCCCc1cccnc1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
A solution of 22 g of 6-(3-pyridyl)hexanol in 100 ml of chloroform was cooled in an ice bath and treated with a solution of 21.9 g of thionyl chloride in 50 ml of chloroform. The reaction mixture was allowed to warm to room temperature over 1 hour, was heated to a bath temperature of 60° C. for 1 hour and was concentrated. The residue was taken up in chloroform, washed with saturated potassium carbonate, dried, and evaporated. The residue was distilled to give 20.5 g (84%) of 6-(3-pyridyl)hexylchloride, bp 180°-190° C./0.15 mm.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]2[CH2:17][N:12]3[CH2:13][CH2:14][NH:15][CH2:16][C@@H:11]3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@H:8]2[CH2:17][N:12]3[CH2:13][CH2:14][N:15]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)[CH2:16][C@@H:11]3[CH2:10][CH2:9]2)=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCN3C[C@H](COc4ccc(F)cc4)CC[C@H]3C2)cc1
Temperature: 95 °C
Yield: 84.3 %

Procedure:
A mixture of 0.500 g (1.89 mmol) of (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 8), 0.400 g (2.84 mmol) of 4-fluoronitrobenzene and 0.401 g (3.78 mmol) of sodium carbonate in 15 mL of DMSO was heated at 95° C. for 16 h. The mixture was cooled to room temperature, acidified with 1M HCl, washed with ethyl ether (3×), basified with conc. ammonium hydroxide and extracted with ethyl acetate (3×). The combined organic layers were washed with water and brine, dried (magnesium sulfate), filtered and evaporated to give 0.614 g of (7R,9aS)-7-(4-fluorophenoxy)methyl-2-(4-nitrophenyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [OH-].[K+].CS(C)=O.[CH3:7][N:8]([CH3:17])[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([OH:16])=[CH:11][N:10]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH3:17][N:8]([CH3:7])[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][N:10]=1
Reactant: Cc1nc(N(C)C)ncc1O
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(N(C)C)ncc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
Potassium hydroxide (85%, 2.64 g, 40 mmol) was powdered and added to 20 ml of DMSO at room temperature. 2-Dimethylamino-4-methyl-5-hydroxypyrimidine (1.53 g, 10 mmol) was added and the reaction mixture stirred for 5 minutes at room temperature. Benzylbromide (1.2 ml, 10 mmol) was added and the reaction mixture after stirring for a half hour at room temperature was poured into 50 ml of water. The reaction mixture was extracted four times with 50 ml hexane portions. The combined hexane extracts were dried over Na2SO4, filtered, and evaporated. Recrystallization of the formed solid from hexane yielded 1.8 g (75% yield) of the title compound as pale yellow crystals, m.p. 73° to 74° C.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:17])=[S:12])=[CH:6][CH:5]=1>[OH-].[Li+].CO>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])=[S:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCNC(=O)CCNC(=S)Nc1ccc(C=NN)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NN=Cc1ccc(NC(=S)NCCC(=O)NCCC(=O)O)cc1

Procedure:
Ethyl β-[[3-[[[4(aminoiminomethyl)phenyl]amino]thiocarbonyl]aminopropanoyl]amino]propanoate (65 mg; 0.18 mmoles) was treated in 1N lithium hydroxide/methanol (20 ml; 1:1) for 10 min. Methanol was evaporated and the pH of the remaining mixture was adjusted to 5 with 50% acetic acid. The mixture was then purified by HPLC using a linear gradient of acetonitrile/water/0.05% trifluoro-acetic acid (0-20% acetonitrile in 30 min). Yield: 51 mg (85%). FAB-MS: MH+ =338.0. Elemental analysis: C14H19N5O3S.CF3COO
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([Sn](C)(C)C)=[CH:3][CH:2]=1.Br[C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[C:15]([C:14]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:13]=1[C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)#[N:16]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Br
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To a solution of p-tolyltrimethyltin (389 mg, 1.525 mmol) in dry toluene (5 mL) under N2 was added 2-bromo-5-nitro-benzonitrile (276 mg, 1.22 mmol) and Pd(PPh3)4 (176 mg; 10 mol %). The reaction was stirred at reflux under N2 for 24 hours and then cooled to room temperature. The mixture was diluted with EtOAc and the solid was removed by filtration through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on a silica column eluting with Hex/EtOAc (10:1) to afford 214 mg (74%) of the titled compound as a slightly yellow solid.
Reaction SMILES: CC(C)([O-])C.[CH:6]1([C@H:9]([OH:31])[C:10]([N:12]2[CH2:16][C:15]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])=[CH:14][C@H:13]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:11])[CH2:8][CH2:7]1.C(N(CC)CC)C.[P:39](Cl)([O:43]C)([O:41]C)=[O:40]>ClCCl>[P:39]([OH:43])([OH:41])([O:31][C@@H:9]([CH:6]1[CH2:8][CH2:7]1)[C:10]([N:12]1[CH2:16][C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:14][C@H:13]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:11])=[O:40]
Reactant: COP(=O)(Cl)OC
Reactant: O=C([C@@H](O)C1CC1)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Agent: CC(C)(C)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C([C@@H](OP(=O)(O)O)C1CC1)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reaction time: 2 h

Procedure:
Titianium(IV) tert-butoxide (0.022 mL, 0.065 mmol, 0.100 equiv) was added to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanol (6-2,230 mg, 0.647 mmol, 1 equiv) in dichloromethane (5 mL) at 23° C. followed by triethylamine (0.271 mL, 1.94 mmol, 3.00 equiv) and dimethyl chlorophosphate (0.140 mL, 1.29 mmol, 2.00 equiv). The resulting mixture was stirred for 2 h, then partitioned between saturated sodium bicarbonate solution (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The residue was dissolved in dimethyl sulfide (0.5 mL) and to the resulting solution was added methanesulfonic acid (1 mL). The resulting mixture was stirred for 10 min, then diluted with acetonitrile (3 mL). Purification by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) provided (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl dihydrogen phosphate (10-1) as a white solid. 1H NMR (500 MHz, CDCl3) major rotamer: δ 7.42-7.04 (m, 8H), 6.46 (s, 1H), 5.95 (m, 1H), 5.14 (br d, 1H, J=14 Hz), 5.04 (br d, 1H, J=14 Hz), 4.46 (t, 1H, J=8.2 Hz), 1.32 (m, 1H), 0.62 (m, 4H). LRMS m/z (M+H) 436.4 found, 436.1 required.
Reaction SMILES: [Cl-].[Zn+2:2].[Cl-].[CH2:4]([N:6]([CH2:11][CH3:12])[CH2:7][CH2:8][CH2:9]Cl)[CH3:5]>O1CCCC1>[CH2:4]([N:6]([CH2:11][CH3:12])[CH2:7][CH2:8][CH2:9][Zn:2][CH2:9][CH2:8][CH2:7][N:6]([CH2:11][CH3:12])[CH2:4][CH3:5])[CH3:5]
Reactant: [Zn+2]
Reactant: CCN(CC)CCCCl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCN(CC)CCC[Zn]CCCN(CC)CC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6.8 g (0.05 mol) of zinc chloride in 100 ml of tetrahydrofuran are added at room temperature to a Grignard reagent prepared from 4.9 g (0.2 mol) of Mg and 19.4 g (0.16 mol) of 3-diethylaminopropyl chloride in 100 ml of tetrahydrofuran. When the reaction has ended, the mixture is stirred at room temperature for 24 hours and filtered, the solvent is removed and the residue is distilled in vacuo. Bis(3-diethylaminopropyl)zinc is obtained as a colourless liquid having a boiling point of 103° C./0.1 mbar.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([CH3:38])([O:10][C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:37][CH2:36][CH2:35][C@H:21]1[C:22]([NH:24][CH:25]([CH:32]([CH3:34])[CH3:33])[CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])=[O:23])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:9].CCN(CC)CC>ClCl.C(Cl)Cl.CS(C)=O>[CH3:9][C:8]([CH3:7])([O:10][C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:37][CH2:36][CH2:35][C@H:21]1[C:22]([NH:24][CH:25]([CH:32]([CH3:33])[CH3:34])[C:26](=[O:31])[C:27]([F:28])([F:29])[F:30])=[O:23])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:38]
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(O)C(F)(F)F
Agent: ClCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 96.1 %

Procedure:
To a stirred solution of oxalyl chloride (0.31 mL, 3.56 mmol) in CH2 Cl2 (30 mL) cooled to -60° C. is added DMSO (0.51 mL, 7.12 mmol) dropwise. After 6 min, a solution of 49 (1.11 g, 2.37 mmol) in a mixture of CH2Cl2 (5 mL) and DMSO (3 mL) is slowly added and, 20 min later, Et3N (1.99 mL, 14.25 mmol) is added. The reaction mixture is allowed to warm to room temperature, diluted with CH2 Cl2 (100 mL) and washed with 0.5N aqueous HCl (2×150 mL), and half-saturated aqueous NaHCO3 (2×100 mL) followed by brine (75 mL). Drying (MgSO4) and concentration gives 50 (1.06 g, 96%, mixture of two diastereomers, ratio≈1:1) as a white foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COCCN
Reactant: CCOc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Product: CCOc1cc(NCCOC)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 37 %

Procedure:
The same reaction procedure as in Example 16 was performed, except that the compound obtained in Example 116 was used in place of the compound obtained in Example 15, and methoxyethylamine was used in place of N-methylpiperazine. In this manner, 55 mg (37%) of the captioned compound was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3][CH3:4].[NH4+].[Cl-]>CO.[Zn]>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[CH:14][C:15]([NH2:16])=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=1
Reactant: CCCCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CCCCOc1cc(C(=O)OC)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A solution of methyl 3-butoxy-4-nitrobenzoate (2.5 g, 9.9 mmol) in methanol (100 mL) was added an aqueous solution (50 mL) of NH4Cl (5.3 g, 99 mmol), followed by activated zinc (Aldrich, 6.5 g, 99 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a short pad of celite. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 4-amino-3-butoxy-benzoic acid methyl ester as a yellow solid (1.8 g, 82%).
Reaction SMILES: C1C(C#N)=CC2C(CCCCN3CCN(C4C=CC5OC(C(N)=O)=CC=5C=4)CC3)=CNC=2C=1.[OH:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:48]#[N:49])[CH:46]=2)[NH:41][CH:40]=1>CS(C)=O>[O:34]=[CH:35][CH2:36][CH2:37][CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:48]#[N:49])[CH:46]=2)[NH:41][CH:40]=1
Reactant: N#Cc1ccc2[nH]cc(CCCCO)c2c1
Agent: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(N)=O)cc5c4)CC3)c2c1
Solvent: CS(C)=O
Product: N#Cc1ccc2[nH]cc(CCCC=O)c2c1

Procedure:
According to another synthetic process described in US'916 patent, vilazodone is prepared by reacting 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile with sulfur trioxide/pyridine complex in dimethylsulfoxide to produce a reaction mass, followed by customary work up and then concentrating the resulting mass to produce an oily residue. The resulting residue is then chromatographed on silica gel using a mixture of dichloromethane and methyl tert-butyl ether to produce 3-(4-oxobutyl)-1H-indole-5-carbonitrile. The oxobutyl compound is reacted with 5-(1-piperazinyl)benzofuran-2-carboxamide in the presence of sodium cyanoborohydride to produce vilazodone free base, which is further treated with aqueous hydrochloric acid to produce vilazodone hydrochloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:2]1.C([Li])CCC.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>C1COCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[OH:24])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1cc(CCN2CCCC2)cs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1sccc1CCN1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
A solution of 1-(2-(thiophen-3-yl)ethyl)pyrrolidine (1.0 g, 5.5 mmol) in THF (11.0 mL) was cooled to −78° C. in a dry-ice acetone bath before dropwise addition of n-butyllithium solution (2.5 M in hexanes, 2.4 mL, 6.0 mmol). The reaction mixture was stirred at −78° C. for 1 h and then neat p-fluorobenzaldehyde (0.65 mL, 6.1 mmol) was added dropwise via syringe. The mixture was allowed to warm to room temperature over 16 h and subsequently diluted with saturated aqueous NaHCO3 and EtOAc. The organic layer was separated, washed with brine, and dried over Na2SO4. The residue remaining after solvent removal in vacuo was purified by flash chromatography to afford the desired alkylation product as a white solid (353 mg, 1.16 mmol, 21% yield). MS (M+H)+ 306.