Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N+:9]=2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Cl:18])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cccc(C)[n+]2[O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cccc(CCl)n2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-methylphenyl)-6-methylpyridine-N-oxide (2.8 g) in 1.0 ml of chloroform was added simultaneously phosphorus oxychloride (1.48 ml) in 10 ml of chloroform and triethylamine (2.22 ml) in 10 ml of chloroform, over a period of 15 minutes. An exothermic reaction took place initially, and then the mixture was refluxed for a further 30 minutes. The mixture was then cooled, washed with ice-water, the solvent evaporated under reduced pressure, and the residue flash-chromatographed on silica gel, eluting with 33% methylene chloride in heptane, to yield 1 g of 2-(4- methylphenyl)-6-chloromethylpyridine, m.p. 94° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH:17]([C:19]([O:21]C)=[O:20])[CH2:16][CH2:15][N:14]1[C:23]([O:25][CH3:26])=[O:24].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16][CH2:15][N:14]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(OC(F)(F)F)cc2F)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(OC(F)(F)F)cc1F
Yield: 98.8 %

Procedure:
Dimethyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1,4-dicarboxylate (5.35 g, 14.10 mmol) was dissolved in acetonitrile (100 mL) and water (2.000 mL), then lithium bromide (9.80 g, 112.84 mmol) was added. Triethylamine (7.82 mL, 56.42 mmol) was added and the resulting suspension was heated under reflux for 7 h. MTBE (350 mL) and water (180 mL) were added, the phases separated and the organic layer was extracted with water. The combined aqueous layers were acidified with 3.8 M HCl and extracted with EtOAc. The combined organic layers were dried with Na2SO4 and evaporated. 2-(2-Fluoro-4-(trifluoromethoxy)phenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (5.09 g, 99%) was yielded as a colorless solid. MS m/z 364 (M−H)−
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[C:30](OCC)(=[O:32])C>CO>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([O:32][CH3:30])=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc(OC)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromopyrazine-2-carboxylate (500 mg, 1.16 mmol; example A-10, step 1) in MeOH (10 ml) was added sodium methoxide (30%; 280 μl, 1.5 mmol) at room temperature and stirring was continued at r.t. for 2 h. The reaction mixture was poured into ethyl acetate (75 ml) and extracted with potassium hydrogen sulfate (10%). The organic phase was washed with water and brine and the aqueous layers were back-extracted with ethyl acetate. The organic layers were dried and evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as colorless solid (320 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].C[O:17][P:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=2[O:19]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([P:18]1(=[O:17])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=2[O:19]1)=[O:7]
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)cc(OC)c1OC
Temperature: 115 °C

Procedure:
35.6 g (0.154 mol) of 3,4,5-trimethoxybenzoyl chloride were warmed to 100° C. under a nitrogen atmosphere. 35.5 g (0.154 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were then added dropwise while stirring, and the temperature was increased to 115° C. When the reaction was complete, 70 ml of toluene were added at 90° C., and the mixture was then cooled further. After crystallization, 44 g (70% of theory) of the abovementioned compound of melting point 147° to 149° C. were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[C@@H:10]([NH:24]C(OC(C)(C)C)=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33].CCOCC>C(OCC)(=O)C>[ClH:33].[CH2:1]([O:8][C:9](=[O:32])[C@@H:10]([NH2:24])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of (S)-2-(t-butoxycarbonylamino)-3-(biphenyl-4-yl)-propionic acid benzyl ester (3.95 g, 9.15 mmol) in ethyl acetate (40 mL) under nitrogen is cooled to 0° and treated with hydrochloric acid gas (4 g). A precipitate appears and the mixture is warmed to room temperature and stirred for 1 hour. Ether (25 mL) is added and the solid is filtered off and briefly dried under high vacuum for 1 hour. (S)-2-amino-3-(biphenyl-4-yl)-propionic acid benzyl ester hydrochloride is obtained as white solid, [α]D =-21.14 (c 0.92, MeOH).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:3]1.C[Si]([NH-])(C)C.[Na+].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[CH:26][C:27]=1[Cl:28]>C(Cl)(Cl)Cl.C1COCC1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([N:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)[CH2:10][CH2:11]2)=[S:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CN1CCCC(CN2CCNCC2)C1
Agent: C[Si](C)(C)[NH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1CCCC(CN2CCN(C(=S)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[(1-methylpiperidin-3-yl)methyl]piperazine (400 mg) in chloroform (10 ml) was added a 2M solution of sodium(trimethylsilyl)amide in THF (2.2 ml). The resulting solution was stirred at room temperature for 10 minutes. 3,4-Dichlorophenylisothiocyanate (0.44 ml) was added and mixture stirred at room temperature for 1 hour. The reaction was quench with water (1 ml) then concentrated in vacuo before being separated between ethyl acetate (100 ml) and saturated sodium bicarbonate solution (100 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, filtered then concentrated in vacuo onto silica gel (1.0 g). The resulting powder was purified by column chromatography on silica gel (50 g) using a gradient of 100% dichloromethane through to 10% methanolic ammonia in dichloromethane to give the title compound (726 mg).
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH:12]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:25][CH2:24]3)[C:15](=[O:16])[NH:14][CH2:13]2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCC2c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCC(c2ccc(F)cc2)C12CCNCC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
A solution of 4-(4-fluoro-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (46.0 g, 132 mmol) in DCM (260 mL) containing TFA (150 mL, 1.32 mol) was stirred vigorously at 0° C. for 15 min. The reaction mixture was then poured into NaOH (3 N, 200 mL) and the product extracted with DCM (3×100 mL). The combined organic extracts were then washed with water (100 mL) and brine (100 mL) and then dried over sodium sulfate. Filtration and evaporation afforded the title compound (22.14 g, 68%) as a white solid after trituration from ethyl acetate. MS: m/e=249.2 (M+H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[NH2:12])([CH3:3])[CH3:2].CO[C:15]1C(OC)=C[C:18]2[NH:19][C:20](CCCNC)=N[C:17]=2[CH:16]=1>>[CH:1]([O:4][C:5]1[C:6]2[N:12]=[C:15]([CH2:16][CH2:17][CH2:18][NH:19][CH3:20])[NH:11][C:7]=2[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Reactant: CC(C)Oc1cccc(N)c1N
Product: CNCCCc1nc2c(OC(C)C)cccc2[nH]1

Procedure:
Prepared from 3-isopropoxy-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C@H:10]([CH3:11])[CH2:9][C@H:8]([CH2:12][CH2:13][C:14](=O)[CH3:15])[C:7]1=[O:17])[CH3:2].[NH2:19][C:20]1[C:25]([CH:26]=O)=[CH:24][CH:23]=[CH:22][N:21]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C@H:10]([CH3:11])[CH2:9][C@H:8]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:26][C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[C:7]1=[O:17])[CH3:2]
Reactant: Nc1ncccc1C=O
Reactant: CCOC(=O)CN1C(=O)[C@@H](CCC(C)=O)C[C@H]1C
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)CN1C(=O)[C@@H](CCc2ccc3cccnc3n2)C[C@H]1C

Procedure:
A mixture of 11-9 (220 mg, 0.8619 mmol), 1-4, 2-amino-3-formylpyridine (137 mg, 1.12 mmol) and proline (99 mg, 0.8619 mmol) in absolute ethanol (5 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) to give 11-10 as a yellow oil.
Reaction SMILES: O.[F-].[K+].[Si]([C:8]([F:11])([F:10])[F:9])(C)(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:24]2[C:32]3[C:27](=[C:28]([N:33]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)([CH2:22][CH3:23])[C:20]#[CH:21])=[CH:15][CH:14]=1>CN(C=O)C.[Cu]I>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:24]2[C:32]3[C:27](=[C:28]([N:33]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)([C:22]#[C:23][C:8]([F:11])([F:10])[F:9])[CH2:20][CH3:21])=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C#CC(CC)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C#CC(F)(F)F)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A three-neck round-bottom flask was charged with CuI (38 mg, 0.2 mmol), Phen.H2O (40 mg, 0.2 mmol), KF (58 mg, 1.0 mmol) and stirring bar. The flask was dried at 130° C. in vacuo for 3 h. After cooling to RT, the flask was backfilled with air and TMSCF3 (142 mg, 1.0 mmol), DMF (2 mL) was added. Then the flask was heated to 130° C. for 30 min. A solution of N-(1-(3-(4-chlorophenyl)pent-1-yn-3-yl)-1H-indol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl) methanesulfonamide (102 mg, 0.2 mmol, enantiomer A) in DMF (1 mL) was slowly added to the mixture at 130° C. over 1 h. The resulting mixture was stirred for another 1 h at 130° C. The crude product was purified by Combiflash (mobile phase: CH3CN/water (0.08% of NH4HCO3)) to give the title compound. LC/MS m/z=606.7 [M+Na]+.
Reaction SMILES: [Li+].[OH-].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:25][C@H:26]([NH:37][C:38](=[O:51])[C@@H:39]([NH:41][C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH3:40])[C:27]([O:29]CC2C=CC=CC=2)=[O:28])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O.CO>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:25][C@H:26]([NH:37][C:38](=[O:51])[C@@H:39]([NH:41][C:42](=[O:50])[CH2:43][N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)[CH3:40])[C:27]([OH:29])=[O:28])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O

Procedure:
A solution of LiOH (279 mg, 6.6 mmol) in water (6 mL) was added to a solution of (S)-benzyl 3-(3,4-bis(benzyloxy)phenyl)-2-((S)-2-(2-morpholinoacetamido) propanamido)propanoate (1.1 g, 1.66 mmol) in MeOH (30 mL) at 0° C. with stirring. The reaction mixture was stirred for 3 h and then acidified with 2 N aqueous HCl to pH=3. The resulting mixture was concentrated and the residue was carried forward without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[O:10])=[C:4]([F:20])[CH:3]=1.[CH2:21]([O:23][C:24]1[C:25]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[N:26][CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:27]=[N:26][C:25]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=3)=[C:24]([O:23][CH2:21][CH3:22])[CH:29]=2)=[CH:3][C:4]=1[F:20]
Reactant: O=C(Cc1ccc(Br)cc1F)Nc1cc(F)ccc1F
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(F)ccc3F)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-N-(2,5-difluorophenyl)acetamide (40 mg, 0.116 mmol), 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (44.8 mg, 0.116 mmol) and Cs2CO3 (114 mg, 0.349 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added PdCl2(dppf) (8.51 mg, 0.012 mmol) in one charge. Then the mixture was stirred at 110° C. in a microwave for 30 min. After LCMS analysis showed the starting material had disappeared, the mixture was filtered. The filtrate was concentrated and evaporated to dryness to give crude product which was dissolved in DCM and washed with H2O and brine. Then the crude product was purified by preparative TLC to give N-(2,5-difluorophenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (45.0 mg, 0.054 mmol, 46.1% yield). 1H NMR: (400 MHz, CD3OD) δ 7.96 (d, J=2.0 Hz, 1H), 7.88 (d, J=9.6 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.36-7.44 (m, 5H), 7.18 (m, 1H), 6.91 (d, J=8.6 Hz, 2H), 6.87 (br. s., 1H), 5.37 (s, 2H), 4.15-4.13 (m, 2H), 3.88 (s, 2H), 3.79 (s, 3H), 1.43 (t, J=7.0 Hz, 3H); ES-LCMS: m/z 403.0 (M−120+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[SH2:10]>N1C=CC=CC=1>[N:1]1[S:10][C:8]([NH2:9])=[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]=12
Reactant: N#Cc1cccnc1N
Reactant: S
Solvent: c1ccncc1
Product: Nc1snc2ncccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-amino-3-cyanopyridine (1.00 g, 8.40 mmol) in pyridine (8 mL) and TEA (0.8 mL) in a sealed tube, H2S gas was bubbled through for 5 min. It was then stirred at room temperature for 20 h. The mixture was concentrated in vacuo to dryness. The residue was dissolved in MeOH (10 mL). To the solution, aq. H2O2 (30%, 3 mL) was added. The mixture was then stirred at room temperature for 5 h, during which time, solids precipitated out. The solids were collected by filtration, dried on vacuum to give isothiazolo[3,4-b]pyridin-3-amine (860 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]([CH3:13])[CH:7]=[C:6]2[C:14]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH:15]=1.[H-].[Na+].Br[CH2:36][CH2:37][CH2:38][Cl:39]>CN(C)C=O.ClCCl.O.C(OC(C)C)(C)C>[Cl:39][CH2:38][CH2:37][CH2:36][O:12][C:11]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3[N:22]([S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)(=[O:25])=[O:24])[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[CH:15]=3)=[CH:7][N:8]2[CH3:13])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1O
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCCCl
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-methoxy-1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-6-ol (0.45 g; 1.006 mmol) in solution in dimethylformamide (5 ml) is placed in a 50 ml round-bottomed flask rendered inert with argon, and sodium hydride (0.06 g; 2.01 mmol) is then added. The reaction mixture becomes dark in color and 1-bromo-3-chloropropane (0.199 ml, 2.01 mmol) is added. The reaction mixture is agitated for 30 minutes at 20° C. The reaction mixture is diluted with dichloromethane (50 ml) and water (100 ml), separated by settling out, and extracted with dichloromethane (2×50 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure, resulting in an oil. The oil is taken up in diisopropyl ether (10 ml) and then triturated, discarding crystals. After filtration, washing with diisopropyl ether and drying under reduced pressure, 2-[6-(3-chloropropoxy)-5-methoxy-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is isolated in the form of ochre-colored crystals (0.415 g; 79%), the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[C:6](=[C:8]1[S:12]C(=S)N[C:9]1=[O:14])[CH3:7])([OH:3])=O.[OH-:19].[Na+].Cl>>[CH3:7][C:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[C:1](=[O:3])[S:12][C:8]=1[C:9]([OH:19])=[O:14]
Reactant: CC(=C1SC(=S)NC1=O)c1ccccc1C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1c(C(=O)O)sc(=O)c2ccccc12

Procedure:
A stirred solution of 2.00 g. (7.17 mM) of the carboxylic acid of Example 13 in 15 ml. of 15% sodium hydroxide is refluxed for 0.75 hour, cooled, and poured into dilute hydrochloric acid, whereupon a precipitate forms. The solid is collected and recrystallized from ethyl acetate-hexane to give a tan solid. This solid is heated briefly to 245°, cooled, and the residue recrystallized from ethyl acetatehexane to give 4-methyl-1-oxo-1H-2-benzothiopyran-3-carboxylic acid as tan crystals, m.p. 247°-248°.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].O>CC(C)=O>[C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: C=CC(=O)Cl
Solvent: CC(C)=O
Solvent: O
Product: C=CC(=O)Nc1cccc(C(=O)OCC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
Propenoyl chloride (668 mg, 600 ul, 7.4 mMole) was added dropwise to an ice-cold solution of ethyl 3-aminobenzoate (2.0 gm, 12 mMole) in 10 ml of acetone. The solution was stirred for 30 minutes on ice and then for 30 minutes at room temperature. 50 ml of water was added and the yellowish oil was separated by decantation. It was washed with water and then dissolved in 15 ml of diethl ether. This solution was washed with 10% (w/v) sodium bicarbonate, water and then dried over anhydrous sodium carbonate. The ether was evaporated and a white creamy product was crystallized from ethanol. The overall yield was 37%, and the melting point of the product was 93° C. to 94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[OH-].[Na+].[Br-].C([NH3+])(C)(C)C>CC(=O)CC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)COCCCl
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CC(C)(C)[NH3+]
Agent: [Br-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 150 °C
Yield: 64.9 %

Procedure:
A suspension of 1-((4-chlorophenyl)phenylmethyl)piperazine (260 g, 0.9 mol), tert-butyl 2-(2-chloroethoxy)acetate (195 g, 1.0 mol), sodium hydroxide (106 g, 1 mol) and tert-butyl-ammonium bromide (“TABB”, 3.22 g, 0.01 mol, NOTE-TABB is a catalyst for this reaction) is dissolved in 2-butanone (“MEK”, 300 mL) heated to 150° C. and the water of reaction azeotroped over a period of about 4 hours. Heating is stopped and to the reaction mixture is added MEK (500 mL) added. The mixture is cooled to ambient, filtered and the solvent removed from the resulting solution by distillation under reduced pressure. The residue is dissolved in methyl tert-butylether (800 mL), washed with water (2×200 mL), saturated sodium chloride (2×100 mL) and the solvent removed under reduced pressure. The residue is treated with hexanes (1.8 mL) to afford tert-butyl (RS) 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate as a white crystalline powder (260 g, 96% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]#[N:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1.C(Cl)Cl.C1COCC1>[C:20]([C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([CH:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:3][CH2:2][O:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:12]=2)[NH:16][CH:15]=1)#[N:21]
Reactant: N#Cc1c[nH]c2ccc(C(CCO)c3ccccc3)cc12
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)OCCC(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 5-(3-hydroxy-1-phenyl-propyl)-1H-indole-3-carbonitrile LXV (600 mg, 2.17 mmol) in THF/DCM (1/1, 12 ml) was added dropwise MsCl (168 μl, 2.17 mmol). The mixture was stirred at 0° C. for 10 min and TEA (360 μl, 2.58 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 2 hours, diluted with THF (6 ml), stirred at 0° C. for additional 2 hours, poured into an ice/water mixture, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated affording the methanesulfonic acid 3-(3-cyano-1H-indol-5-yl)-3-phenyl-propyl ester as a yellow oil. A solution of this mesylate in MeNH2 (33% in EtOH, 10 ml) was heated in a sealed tube at 100° C. for 1 hour. The mixture was concentrated, and the residue was partitioned between a saturated solution of NaHCO3 and DCM. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified via flash chromatography (DCM/MeOH/NH4OH) affording 5-(3-methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile LXVI as a white solid (156 mg). MS (M+H)=290.