Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42]([OH:44])=O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[NH2:55][C@:56]1([C:61]([NH:63][S:64]([C:67]2([CH3:70])[CH2:69][CH2:68]2)(=[O:66])=[O:65])=[O:62])[CH2:58][C@H:57]1[CH:59]=[CH2:60].CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:41][C@H:39]1[CH2:40][N:36]([C:34](=[O:35])[C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:28])[CH3:26])[C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C@H:37]([C:42](=[O:44])[NH:55][C@:56]2([C:61](=[O:62])[NH:63][S:64]([C:67]3([CH3:70])[CH2:69][CH2:68]3)(=[O:66])=[O:65])[CH2:58][C@H:57]2[CH:59]=[CH2:60])[CH2:38]1
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
HATU (7.60 g, 20.00 mmol) was added to a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (7.86 g, 19.05 mmol), (1R,2S)-1-amino-N-((1-methylcyclopropyl)sulfonyl)-2-vinylcyclopropanecarboxamide HCl (5.62 g, 20 mmol), and Hunig's Base (13.31 mL, 76 mmol) in DCM (110 mL). The reaction mixture was stirred at rt for 16 h. The reaction was washed with 1N HCl (3×), and then brine. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The crude material was purified by silica gel chromatography using a gradient of 20-60% Acetone in hexanes. The product fractions were collected and the solvent removed under vacuum to give tert-butyl ((2S,3R)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (9 g, 74.0% yield) as a light orange foam. MS: MS m/z 639.3 (M++1).
Reaction SMILES: [OH:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:29])[CH:20]=[CH:21]2)[CH:16]=[CH:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:4])[CH3:3].[OH-:30].[K+].OO>C(O)C.O>[O:30]1[C@H:20]2[C:19](=[O:29])[CH:18]=[C:17]3[C@:22]([CH3:23])([C@@H:21]12)[C@@H:24]1[C@H:14]([C@H:13]2[C@:27]([CH3:28])([CH2:26][CH2:25]1)[C@@H:10]([C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][C:2]([OH:1])([CH3:3])[CH3:4])[CH2:11][CH2:12]2)[CH:15]=[CH:16]3
Reactant: [OH-]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The trienone from (a) (1.3 gms) in ethanol (50 mls) was treated with 10% aqueous potassium hydroxide (0.5 ml) and 30% aqueous H2O2 (3 ml). After storage overnight at room temperature, the solution was diluted with water and the solid product collected. Recrystallization from aqueous methanol gave the title compound which after one further crystallization had melting point 162°-163°.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][CH2:9][C:10]1[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1
Reactant: COC(=O)c1sc(CO[Si](C)(C)C(C)(C)C)cc1-c1ccccc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1sc(CO)cc1-c1ccccc1

Procedure:
To a solution of 168 (6.389 g, 17.62 mmol) in 93 mL of MeOH was added concentrated HCl
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:11]=2[CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1>C1COCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:25]=3)[C:11]=2[CH2:12][S:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:39])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CSc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CS(=O)c2ccccc2)cc1
Temperature: 0 °C
Yield: 25.3 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[(phenylthio)methyl]-1H-1,2,3-triazole-4-carboxamide (145 mg, 0.344 mmol) obtained in Example 130 was dissolved in THF (3.0 ml), m-chloroperbenzoic acid (purity 65%, 110 mg, 0.412 mmol, 1.2 eq.) was added with stirring at 0° C., and the mixture was stirred for additional 1.5 hr. The reaction mixture was diluted with ethyl acetate (20 ml), washed with 5% aqueous sodium sulfite solution, 2% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography (elution solvent, ethyl acetate-hexane=1:1-5:1) on silica gel (manufactured by E. Merck, Art.7734, 10 g). The fraction obtained by elution with ethyl acetate-hexane (5:1) was concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (38 mg, 0.087 mmol, 25.3%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([PH:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH3:25].O1CCCC1>O1CCCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([PH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH3:25]
Reactant: O=[PH](c1ccc(N2CCCC2)cc1)c1ccc(N2CCCC2)cc1
Agent: B
Solvent: C1CCOC1
Product: c1cc(N2CCCC2)ccc1Pc1ccc(N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
Under a nitrogen stream, to a solution of bis[4-(pyrrolidin-1-yl)phenyl]phosphine oxide (2.50 g, 7.34 mmoL) synthesized in Example 13 in tetrahydrofuran (25 mL) was added borane-tetrahydrofuran solution (29 mL, 3.9 equivalents) at 25° C. to 30° C. over 2.4 hr. Then, silica gel (10.0 g, 22.6 equivalents) was added to the mixture, and the mixture was stirred at room temperature for 1 hr. Silica gel was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, dichloromethane) to give the title compound (0.7 g, white crystals). yield 27%. melting point 178.3° C.
Reaction SMILES: Cl.[Cl-].[NH4+].[Br:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([CH3:14])=[CH:7][C:6]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(O)C.[Fe]>[Br:4][C:5]1[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:7][C:8]([CH3:14])=[C:9]([CH:10]=1)[NH2:11]
Reactant: Cc1cc(N2CCOCC2)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: Cc1cc(N2CCOCC2)c(Br)cc1N
Temperature: 60 °C
Yield: 73.8 %

Procedure:
Iron powder (320 mg, 5.8 mmol) was stirred in ethanol (12 mL) with 1 N HCl solution (0.6 mL, 0.6 mmol) and heated at 60° C. for 2 hours. 5 N aqueous Ammonium chloride solution (1.0 mL, 5.0 mmol) and 4-(2-bromo-5-methyl-4-nitrophenyl)morpholine (350 mg, 1.2 mmol) were added and the mixture was heated at 60° C. for 30 minutes. The mixture was filtered through celite and the collected solids were washed with ethanol. The combined filtrates were evaporated to give the desired compound (0.24 g, 75%). LCMS for C11H16BrN2O (M+H)+: m/z=271.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([C:13]2[C:14](Cl)=[N:15][CH:16]=[CH:17][CH:18]=2)=O)=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:22][N:21]=2)=[CH:9][NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]cc1C(=O)c1cccnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]cc1-c1n[nH]c2ncccc12
Temperature: 80 °C
Yield: 16.3 %

Procedure:
A mixture of 4-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-carboxylic acid ethyl ester (170 mg, 0.6 mmol) and hydrazine hydrate (0.8 g) in ethanol (10 mL) was heated at 80° C. for 24 hours. The reaction was concentrated, the residue was recrystallized to give 25 mg (16%) of the titled compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[C:13]=3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:30]([O:34][C:35](=[O:56])[N:36]([C:48]1[CH:53]=[CH:52][C:51]([CH:54]=[O:55])=[CH:50][N:49]=1)[CH2:37][C:38]1[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=1)([CH3:33])([CH3:32])[CH3:31].Cl>O1CCCC1>[C:30]([O:34][C:35](=[O:56])[N:36]([C:48]1[CH:53]=[CH:52][C:51]([CH:54]([C:12]2[C:13]3[C:18]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[N:17][CH:16]=[N:15][C:14]=3[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:55])=[CH:50][N:49]=1)[CH2:37][C:38]1[CH:39]=[N:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2c(C3CCCC3)ncnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1ccc(C=O)cn1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncnc(C4CCCC4)c23)cn1
Temperature: 0 °C

Procedure:
To 7-benzenesulfonyl-4-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (50, 0.119 g, 0.262 mmol) in 1.8 mL of tetrahydrofuran at −20° C. under nitrogen, isopropylmagnesium chloride (0.144 mL, 2.0 M in tetrahydrofuran, 0.289 mmol) was added and the reaction stirred and allowed to warm to 0° C. over 1 hour. The reaction was cooled to −15° C. and (5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (51, 0.120 g, 0.315 mmol) in 0.53 mL of tetrahydrofuran was added. The reaction was poured into 0.1 N aqueous hydrochloric acid and extracted with ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Mg].II.BrC1SC2C=CC=CC=2C=1.CON(C)[C:27](=[O:31])[CH2:28][CH2:29][CH3:30]>O1CCCC1>[S:6]1[CH:7]=[CH:8][C:4]2[CH:3]=[C:2]([C:27](=[O:31])[CH2:28][CH2:29][CH3:30])[CH:10]=[CH:9][C:5]1=2
Reactant: CCCC(=O)N(C)OC
Reactant: Brc1ccc2sccc2c1
Agent: Brc1cc2ccccc2s1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A few drops of a solution of 5-bromobenzo[b]thiophene (0.93 g; prepared in a manner similar to that described in Example 21) in tetrahydrofuran (10 ml) was added under nitrogen to a mixture of magnesium turnings (0.1 g), tetrahydrofuran (2 ml) and a few small crystals of iodine, heat was applied to initiate the reaction, then the remainder of the bromobenzo[b]thiophene solution was added at reflux temperature over 10 minutes. When the addition was complete, the mixture was heated under reflux for 45 minutes, then a solution of N-methoxy-N-methylbutyramide (0.6 g) in tetrahydrofuran (10 ml) was added. The mixture was heated under reflux for 1 hour, cooled to ambient temperature, then quenched by the addition of 2M hydrochloric acid (15 ml). Ethyl acetate (25 ml) was added, the mixture was stirred at ambient temperature for 45 minutes, the organic layer was separated, then further product was isolated from the aqueous layer by extraction into ethyl acetate (20 ml). The combined ethyl acetate solutions were washed with water (2×10 ml) and saturated aqueous sodium chloride solution (10 ml), then they were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using petroleum ether (b.p. 60-80° C.) followed by a 95:5 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluants. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-5-yl)butan-1-one (0.1 g) as a yellow oil which was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[C:38](C1C=CC(B(O)O)=CC=1)#[N:39]>>[NH2:37][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:38]#[N:39])=[CH:7][CH:6]=2)=[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:34])([F:33])[F:35])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[N:12]=[CH:11][N:10]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-cyanophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=522, obsd.=522).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH3:5].Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2>>[Br:1][C:2]1[CH:8]=[C:9]2[C:5](=[CH:4][CH:3]=1)[N:12]([CH2:13][CH2:14][CH2:15][CH3:7])[CH:11]=[CH:10]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CCCCBr
Product: CCCCn1ccc2cc(Br)ccc21

Procedure:
The title compound was prepared from 1-bromobutane (11 mL, 101 mmol) and 5-bromoindole (20 g, 101 mmol) in substantially the same manner, as described in Step 1 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 252. 1HNMR (300 MHz, DMSO-d6): δ 7.71 (d, 1H, J=1.9 Hz), 7.46 (d, 1H, J=8.7 Hz), 7.42 (d, 1H, J=3.1 Hz), 7.22 (dd, 1H, J=6.7 Hz and J=2.0 Hz), 6.40 (d, 1H, J=3.1 Hz), 4.15 (t, 2H, J=7.0 Hz), 1.70 (q, 2H, J=7.0 Hz), 1.19 (h, 2H, J=7.47 Hz), and 0.85 ppm (t, 3H, J=7.47 Hz).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([NH:16][C:17]([NH2:19])=[N:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:5][CH:4]=[C:3]([C:20]([NH:22][C@@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:2]=1.[Na+:32].[Na+].[OH2:34]>CCO>[CH:5]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([N:16]=[C:17]([NH2:19])[NH:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:1][CH:2]=[C:3]([C:20]([NH:22][C@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:4]=1.[OH2:34].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[OH2:15].[Na+:32].[Na+:32]
Reactant: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@H](CCC(=O)[O-])C(=O)[O-])cc3)c2c(=O)[nH]1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1

Procedure:
To a suspension of Pemetrexed Disodium Form A in EtOH was added water until a mixture of EtOH containing 25% water (v/v) was obtained. The resulting suspension was stirred at 20° C. to 30° C. until conversion was complete according to PXRD. Pemetrexed Disodium Heptahydrate was isolated by filtration, washed with EtOH and dried in vacuo at 200 mbar at 20° C. to 30° C. until water content of the dried product was 20.1% to 22.1%.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:19]2[CH2:20][CH2:21][N:22](CC3C=CC=CC=3)[CH2:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Yield: 69.8 %

Procedure:
To the solution of 5-Phenyl-3-[1-(phenylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1H-indole-7-carboxamide (2.66 g, 6.5 mmol) in ethanol (150 mL) and acetic acid (3 mL) was added Pd(OH)2 (20% by weight on carbon) (0.8 g,) at ambient temperature. The solution was stirred under 1 atm of hydrogen for 2 days. The reaction mixture was then filtered through Celite, neutralized with 5% sodium hydroxide solution, and extracted with ethyl acetate. The solvent was removed under reduced pressure to yield the desired product (1.45 g, 70%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl.P([O-])([O-])([O-])=O>CN(C=O)C>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NS(=O)(=O)c1cccc(CO)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(CO)c1
Reaction time: 0.25 h

Procedure:
A solution of 3(hydroxymethyl)benzenesulfonamide (670 mg) in DMF (20 ml) under nitrogen was treated with sodium hydride (315 mg, 60% in oil) and the mixture was stirred at 20° for 15 min. The mixture was then treated with 2-(trimethylsilyl)ethoxymethyl chloride (1.27 ml) and the mixture was stirred at 20° for 1 h. Phosphate buffer solution (50 ml, pH6.5) was added and the mixture was extracted with EtOAc. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel (40 mm diameter column). Elution with EtOAc-cyclohexane (3:7) gave the title compound (985 mg). LCMS RT=3.84 min.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([CH:9]2[CH:14]=[CH:13][N:12](C(OCC(Cl)(Cl)Cl)=O)[CH:11]=[CH:10]2)[S:5][CH2:4][C:3]1=[O:23]>C(O)=O.[Zn]>[CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[S:5][CH2:4][C:3]1=[O:23]
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SCC(=O)N1C
Agent: [Zn]
Solvent: O=CO
Product: CC1=C(c2ccncc2)SCC(=O)N1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.3 %

Procedure:
To a solution of 4,5-dimethyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4dihydro-4-pyridinyl]-2H-1,4-thiazin-3-one (0.38 g) in formic acid (5 ml), zinc powder (1.9 g) was added and the reaction mixture was stirred at room temperature for 2 hours. Zinc powder was removed by filtration and formic acid was removed under reduced pressure. The residue was dissolved in water and neutralized with 1N aqueous sodium hydroxide. The precipitates were extracted with ethyl acetate (50 ml×6 times). The combined extracts were dried over anhydrous magnesium sulfate and ethyl acetate was removed under reduced pressure to give an oily product. The oily product was purified by silica gel column chromatography (Wakogel C-200 particles size 100-200 mesh, chloroform/methanol=20/1) to give 4,5-dimethyl-6-(4-pyridinyl)-2H-1,4-thiazin-3-one (30 mg, yield 14.3%) as a light yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F-].[Cs+]>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].O1CCOCC1>[C:10]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
In the drybox, 9.6 mg (0.058 mmol) of (Me3C)2PH(O) from Experiment 2, 13.3 mg (0.0145 mmol) of Pd2 (dba)3 and 3.0 mL of 1,4-dioxane were loaded into a reactor (20 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature overnight. Next, 143.0 mg (1.0 mm) of 4-chloroanisole, 182.9 mg (1.5 mm) of PhB(OH)2 and 456 mg (3.0 mmol) of CsF were added into the reactor. The resulting mixture was refluxed for 24 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 179 mg (97% yield) of 4-phenylanisole. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ 7.45 (m, 4H), 7.32 (m, 2H), 7.21 (m, 1H), 6.88 (d, J=8.72 Hz, 2H), 3.74 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ 159.2, 140.8, 133.8, 128.7, 128.1, 126.7, 126.6, 114.2, 55.3 ppm.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[S:7][CH:8]=[CH:9][C:4]=2[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(O[K])(C)(C)C.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>C1COCC1>[CH3:1][C:2]1[N:6]([S:31]([C:28]2[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=2)(=[O:33])=[O:32])[C:5]2[S:7][CH:8]=[CH:9][C:4]=2[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2sccc12
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)c2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate (0.059 g, 0.282 mmol) in THF at about 0° C. was added tBuOK (0.044 g, 0.395 mmol), followed by the 4-(methylsulfonyl)-benzene-1-sulfonyl chloride (0.086 g, 0.338 mmol). The reaction mixture was stirred at ambient temperature for about 1 h to give the crude title compound, which was used without further purification. LC/MS (Table 1, Method b) Rt=2.25 min; MS m/z 428 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH:14]3[CH2:19][CH2:18][CH:17]=[C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15]3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCC(CN2CC=C(c3ccccc3)CC2)C1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)CCN(CC2CCC=C(c3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[(3,6-dihydro-4-phenyl-1(2H) -pyridinyl)methyl]cyclohexanone (Example A) (5.9 g) in 400 mL of tetrahydrofuran is added a solution of phenylmagnesium bromide (9.13 mL, 3.0M in diethyl ether), dropwise under nitrogen, at 0° C. The mixture is stirred at room temperature for 1 hour, then cooled in an ice bath and quenched with 250 mL of 10% aqueous hydrochloric acid solution. The solvent is evaporated in vacuo and the residue partitioned into chloroform/5% aqueous ammonium hydroxide solution. The organic extract is dried over magnesium sulfate and filtered. The filtrate is treated with trifluoroacetic acid (4.2 mL) and stirred overnight at room temperature. The solvent is evaporated in vacuo, and the residue is partitioned into ethyl acetate/5% aqueous ammonium hydroxide solution. The organic extract is dried over magnesium sulfate, filtered, and concentrated. The crude product is purified by medium pressure chromatography to give 3.9 g of (±)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine; mp 90°-95° C. as an off-white solid (Example 1) and 2.7 g of (±)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-2-cyclohexen-1-yl) methyl]pyridine; mp 124°-126° C. as a tan solid (Example 1a).