Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C@@:11]([CH2:17][CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:17]([C@@:11]1([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:25]3[CH:24]=[C:23]([C:22]([F:36])([F:21])[F:35])[CH:28]=[CH:27][N:26]=3)[CH2:30][CH2:31]2)=[O:16])[CH2:12][CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)[CH3:18]
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Reactant: CC[C@@]1(C(=O)O)CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of (1R,3S)-3-[(tert-butoxycarbonyl)amino]-1-ethylcyclopentanecarboxylic acid (0.30 g, 1.2 mmol) and 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (0.39 g, 1.3 mmol) in DMF (10 mL) under N2 was added triethylamine (0.65 mL, 4.7 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.663 g, 1.75 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3 and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, concentrated and purified by flash column chromatography to yield the desired product (400 mg, 72.9%). MS calculated for C23H34F3N4O3: (M+H) 471.3; found 371.2 (M+H-Boc).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:6]=[C:5]([N+:14]([O-:16])=[O:15])[C:4]=1[OH:17]>Br>[N+:14]([C:5]1[CH:6]=[C:7]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:8]=[C:3]([OH:2])[C:4]=1[OH:17])([O-:16])=[O:15]
Reactant: COc1cc(-c2nnn[nH]2)cc([N+](=O)[O-])c1O
Agent: Br
Product: O=[N+]([O-])c1cc(-c2nnn[nH]2)cc(O)c1O
Reaction time: 8 h

Procedure:
4.0 g of 2-methoxy-6-nitro-4-(1H-tetrazol-5-yl)phenol are treated with 40 ml of constant-boiling hydrobromic acid, whereupon the mixture is stirred at 140° for 8 hours under a nitrogen atmosphere. After cooling, the mixture is poured on to ice. The separated precipitate is filtered under suction and recrystallized from ether. There is obtained 3-nitro-5-(1H-tetrazol-5-yl)-pyrocatechol in the form of orange crystals of m.p.>240° (dec.).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C:13]([S:16][C:17](=O)[CH3:18])([CH3:15])[CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].BrC[CH:22]1[CH2:27][CH2:26][CH2:25]C[O:23]1.C[O-].[Na+]>C(O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:12])[C:13]([CH3:15])([S:16][CH2:17][CH:18]2[CH2:25][CH2:26][CH2:27][CH2:22][O:23]2)[CH3:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCC1CCCCO1
Reactant: CC(=O)SC(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(SCC1CCCCO1)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 130 °C
Yield: 99.3 %

Procedure:
To a solution of 100 mg (0.352 mmol) of thioacetic acid S-[1-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-1-methyl-ethyl]ester (synthesized according to Method F, step 1) in ethanol (2 mL) were added 126 mg (0.704 mmol) of 2-(bromomethyl)tetrahydropyran and 76 mg (1.41 mmol) of sodium methoxide at room temperature. The reaction was heated to 130° C. for 0.5 h within a microwave (CEM Discover). The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 ml) and washed with saturated aqueous NaHCO3 solution (5 ml). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to yield 119 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(tetrahydro-pyran-2-ylmethylsulfanyl)-propionamide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1(Br)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([NH:4][CH2:3][CH2:2][OH:1])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NCCO
Reactant: BrC1CCCCCCC1
Product: OCCNC1CCCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-cyclooctyl-1,3-thiazolidine.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[CH:5][C:6]([OH:16])=[C:7]([NH:9][C:10](=O)[C:11](F)(F)F)[CH:8]=1.BrCC=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][CH2:11][CH:10]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:9][C:7]=2[CH:8]=1
Reactant: O=C(Nc1cc(F)ccc1O)C(F)(F)F
Reactant: CCOC(=O)C=CCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC1COc2ccc(F)cc2N1
Temperature: 0 °C

Procedure:
370 ml of ethanol are introduced into a 1 l reactor, with magnetic stirring, cooled to 0° C., and 3.5 g (0.146 mol) of sodium are introduced slowly, in small portions, followed by successive dropwise addition of 32.54 g (0.146 mol) of N-(5-fluoro-2-hydroxyphenyl)trifluoroacetamide and 28.18 g (0.146 mol) of 75% pure ethyl 4-bromo-2-butenoate, and the mixture is heated at 80° C. for 3 h.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].O[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: OCC1CCCNC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(OCC3CCCNC3)c2c1C

Procedure:
A solution of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (1 g), 3-(hydroxymethyl)piperidine (661 μl), triphenylphosphine (1.55 g) and azodicarboxylic acid diethyl ester (930 μl) in THF (20 ml) was stirred overnight at room temperature. A white precipitate separated out. The precipitate was filtered out and the filtrate was evaporated to dryness. The residue was separated by silica gel column chromatography developed by dichloromethane-methanol to give 3-methyl-4-(piperidin-3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester (1.1 g) as a colorless oil. FAB-MS: m/z 318 (MH+); 1H-NMR (CDCl3): δ 1.42-2.02 (4H, m), 1.43 (3H, t, J=7 Hz), 2.43 (1H, m), 2.74 (2H, m), 2.75 (3H, s), 3.34 (1H, br d, J=12 Hz), 3.49 (1H, br d, J=12 Hz), 3.96 (1H, dd, J1=9 Hz, J2=6 Hz), 4.02 (1H, dd, J1=9 Hz, J2=5 Hz), 4.43 (2H, q, J=7 Hz), 6.59 (1H, d, J=8 Hz), 7.13 (1H, d, J=8 Hz), 7.30 (1H, t, J=8 Hz).
Reaction SMILES: [NH2:1][NH2:2].C[O:4][C:5]([CH:7]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1)[CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O>C(O)(=O)C>[O:4]=[C:5]1[CH:7]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH2:18]2)[CH2:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:2][NH:1]1
Reactant: COC(=O)C(CC(=O)c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NN
Solvent: CC(=O)O
Product: O=C1NN=C(c2ccccc2)CC1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Hydrazine (3.31 mL, 104 mmol) was added to a solution of benzyl 4-[1-(methoxycarbonyl)-3-oxo-3-phenylpropyl]piperidine-1-carboxylate (2.14 g, 5.22 mmol) in acetic acid (70 mL). The reaction mixture was heated at 50° C. After 1 h, the reaction mixture was concentrated. The residue was diluted with dichloromethane, neutralized by saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate and concentrated to give the title compound. MS 392.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[OH:11]O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N+:7]=1[O-:11]
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: OO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cccc(Cl)[n+]1[O-]
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 6-chloro-2-pyridinecarboxylic acid (14.8 g, 0.093 mol, for preparation, see Delarge, II. Farmaco-Ed.Sc., 1967, 22, 1069) in trifluoroacetic acid (110 ml) was added 75 ml of 30% aqueous hydrogen peroxide solution. The mixture was heated to 60° for 2 hours, cooled to room temperature and poured onto ice water. The white precipitate was filtered and was washed well with water to yield 10.8 g (67%) of the title compound of this preparation. mp 168°-170° C. 1H NMR (CDCl3): δ 7.46 (1H, d, J=8), 7.77 (1H, dd, J=8, 8), 8.01 (1H, d, J=8).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[C:11]([C:14]1[C:15]([CH3:29])=[C:16](Br)[C:17](=[O:27])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:19]=1)(=[O:13])[CH3:12]>O.CN(C)C=O>[C:11]([C:14]1[C:15]([CH3:29])=[C:16]([S:10][C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)[C:17](=[O:27])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:19]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1nn(-c2ccc(Cl)cc2)c(=O)c(Br)c1C
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1nn(-c2ccc(Cl)cc2)c(=O)c(Sc2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 97% sodium hydroxide (51 mg) in a mixture of water (3 ml) and N,N-dimethylformamide (10 ml) was added 4-chlorothiophenol (0.19 g), followed by stirring at room temperature for 30 minutes. Then, 6-acetyl-4-bromo-2-(4-chlorophenyl)-5-methyl-3(2H)-pyridazinone (0.30 g) was added, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting crude crystals were recrystallized from ethyl acetate/hexane to obtain 6-acetyl-2-(4-chlorophenyl)-4-(4-chlorophenylthio)-5-methyl-3(2H)-pyridazinone (260 mg) (Compound No. 1-29).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14]Br)=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])=[O:4].[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K].O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14][N:30]1[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]1=[O:31])=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])=[O:4]
Reactant: COC(=O)c1cc2cc(CBr)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cc(CN3C(=O)c4ccccc4C3=O)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
1-BOC-5-bromomethyl-7-nitro-indole-2-carboxylic acid methyl ester (4.9 g, 11.4 mmol) prepared in Step B of Preparation 37 was dissolved in N,N-dimethylformamide (50 mL). Potassium phthalimide (2.7 g, 14.8 mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. Water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography to give the title compound (3.6 g, Yield 66%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[O:16]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:16][CH:15]([C:3]1[C:2]([CH3:1])=[C:11]([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[OH:13])[C:14]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Cc1cc(O)c2ccccc2c1C
Reactant: CCOC(=O)C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(O)c1c(C)c(C)c2ccccc2c1O
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3,4-dimethylnaphthalen-1-ol (3.18 g, 18.46 mmol) in dichloromethane (180 mL) at −40° C. was added a 1M solution of titanium tetrachloride in dichloromethane (18.46 mL, 18.46 mmol) over 10 minutes. In a separate flask, ethyl glyoxalate (2.26 g, 22.16 mmol) was heated at 100° C. for 45 minutes. The colorless oil was dissolved in dichloromethane (20 mL) and added to the reaction mixture over 10 minutes. The reaction mixture was stirred at −40° C. for 1.5 hours, then warmed to −25° C. over 30 minutes. The reaction mixture was quenched with acetic acid (5.8 mL). Acetonitrile (30 mL) was added and the reaction mixture was stirred for 5 minutes. The cold bath was removed and water (59 mL) was added and stirred for 15 minutes. The mixture was diluted with water and brine and extracted with dichloromethane (3×). The combined organic layer was dried (MgSO4), filtered, concentrated and purified twice by flash column chromatography (silica gel, 0 to 25% ethyl acetate/hexanes) to give ethyl 2-hydroxy-2-(1-hydroxy-3,4-dimethylnaphthalen-2-yl)acetate. LCMS-ESI− (m/z): [M−H]− calcd for C16H17O4: 273.31. Found: 272.8.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([O:14][CH3:15])[C:6]=1[O:16][CH3:17])#[N:2].[Cl-].[NH4+]>C(O)C.C(Cl)Cl.[Fe]>[C:1]([CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([O:14][CH3:15])[C:6]=1[O:16][CH3:17])[NH2:11])#[N:2]
Reactant: COc1cc([N+](=O)[O-])cc(OCC#N)c1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(N)cc(OCC#N)c1OC
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A solution of 1.4 g of 1-cyanomethoxy-2,3-dimethoxy-5-nitrobenzene in 75 mL ethanol with 1.65 g of iron and 1.65 g of ammonium chloride was refluxed for 4 h, cooled to RT, diluted with DCM, filtered, extracted with DCM and the combined organic were dried with sodium sulfate and evaporated to give 1 g 82% of the desired product 3-cyanomethoxy-4,5-dimethoxyaniline, MS (m/e): 209 (MH+).
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1.C([O:20][C:21]([C:23]([NH:29][C:30]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:31])([CH3:28])[CH2:24][CH2:25][O:26][CH3:27])=O)C>C1(C)C=CC=CC=1.ClCCl>[CH3:27][O:26][CH2:25][CH2:24][C:23]([NH:29][C:30]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:31])([CH3:28])[C:21](=[O:20])[NH:17][C:14]1[CH:15]=[CH:16][C:9]2[CH2:8][CH2:7][N:6]([CH3:5])[CH2:12][CH2:11][C:10]=2[CH:13]=1
Reactant: CCOC(=O)C(C)(CCOC)NC(=O)c1ccc(Cl)s1
Reactant: CN1CCc2ccc(N)cc2CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COCCC(C)(NC(=O)c1ccc(Cl)s1)C(=O)Nc1ccc2c(c1)CCN(C)CC2
Reaction time: 0.25 h

Procedure:
0.60 ml of a 2M solution of trimethylaluminium in toluene are added to a mixture of 130 mg (0.738 mmol) 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in dichloromethane and stirred for 15 min. Then the mixture is added to 233 mg (0.729 mmol) 5-chloro-thiophene-2-carboxylic acid-N-(1-ethoxycarbonyl-3-methoxy-1-methyl-propyl)-amide and stirred for 3 days. Then it is poured onto ice water/2 N NaOH, extracted several times with ethyl acetate and dried with sodium sulphate. The crude product is purified by chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[O:29][CH3:30]>O1CCCC1>[CH3:30][O:29][C:28]([NH:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1)=[O:31]
Reactant: COC(=O)Cl
Reactant: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Temperature: -10 °C
Yield: 49.1 %

Procedure:
A well stirred mixture of a solution of benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (464 mg, 1.74 mmol) and triethylamine (0.49 mL, 3.47 mmol) in tetrahydrofuran was cooled to −10° C. and treated drop wise with methyl carbonochloridate (0.15 mL, 1.92 mmol). The reaction mixture was stirred at room temperature for 30 minutes followed by removal of volatiles under vacuum. The residue was dissolved in ethyl acetate and organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to yield benzyl 4-[(methoxycarbonyl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (278 mg, 49.13%).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](Cl)=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([CH:37]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[CH:27]=1>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:38])=[C:20]([O:21][C:22]3[CH:23]=[CH:24][C:25]4[N:26]([N:28]=[C:29]([NH:31][C:32]([CH:34]5[CH2:36][CH2:35]5)=[O:33])[N:30]=4)[CH:27]=3)[CH:37]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in 1-methylpyrrolidin-2-one (7.0 mL) was added N-[6-(5-amino-2-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.619 mmol), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained oil was triturated with toluene and diisopropyl ether to give the title compound (256 mg, 84%) as a colorless powder.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([N:10]=[S:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:25][B-:26]([F:29])([F:28])[F:27].[CH3:30][O+](C)C>C(Cl)Cl>[F:25][B-:26]([F:29])([F:28])[F:27].[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([S:7]([N:10]([S+:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:30])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: C[O+](C)C
Reactant: Cc1ccc(S(=O)(=O)N=S(c2ccccc2)c2ccccc2)cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(C)[S+](c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
10.65 g (0.03 mol) of N-p-toluenesulfonyldiphenylsulfilimine were dissolved in 40 ml of dry methylene chloride, and 4.44 g (0.03 mol) of trimethyloxonium tetrafluoroborate were added. After stirring overnight and concentrating, the reaction product formed a crystalline precipitate. Drying under reduced pressure left 11.45 g of the salt (IV). Analysis and properties are indicated in Table 1.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCC1c1ccccc1

Procedure:
The title compound, pale pink solid, m.p. 119° C. and MS: m/e=321 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-phenyl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>O.CCOC(C)=O>[NH:11]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[CH:8]=[N:12]1
Reactant: O=Cc1cccnc1Cl
Reactant: NN
Solvent: CCOC(C)=O
Solvent: O
Product: c1cnc2[nH]ncc2c1
Temperature: 25 °C

Procedure:
A solution of 2-chloropyridine-3-carbaldehyde (20 g, 141 mmol) and hydrazine monohydrate (60% in water, 113 g, 2.1 mol) in 140 mL water was heated at 100° C. for 72 hours. The reaction mixture was cooled to room temperature and diluted with 200 mL of EtOAc. The aqueous layer was separated and extracted with EtOAc (3×). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give a light orange solid which was crystallized from hexanes to give the title compound as an off-white solid. 1H NMR (400 MHz, CH3CN-d3): δ 11.56 (s, 1H); 8.51 (dd, J=4.52, 1.56 Hz, 1H); 8.17 (dd, J=8.05, 1.58 Hz, 1H); 8.05 (s, 1H); 7.17 (dd, J=8.05, 4.51 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].O>CN(C)C=O>[O:19]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=3)[CH:10]=2)[N:15]1[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (291 mg, 1.0 mmol) in anhydrous N,N-dimethylformamide (2.5 ml) was added potassium carbonate (276 mg, 2.0 mmol), and the mixture stirred at room temperature for 5 minutes in a 5 ml Personal Chemistry microwave reaction vial. To the above mixture was added tert-butyl 2-bromoacetate (390 mg, 2.0 mmol), the vial was sealed, and subjected to microwave irradiation at 120° C. for 5 min, and then at 140° C. for 40 min until most of the 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one was converted. The reaction mixture was cooled, poured into water (40 mL), extracted with ethyl acetate (2×40 mL), the combined organic phase was washed with water (40 mL), 2N sodium carbonate (10 mL), brine (40 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude product was dissolved in a mixture of N,N-dimethylformamide-methanol (1 and 2 mL respectively), subjected to reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford tert-butyl 2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate (247 mg, 0.61 mmol, 61%). LCMS mz 350.0 (M−56+H), 428.0 (M+Na), anal HPLC>98% in purity, 1H NMR (400 MHz; CDCl3) δ 7.67 (m, 4H); 7.40-7.50 (m, 2H); 6.86 (d, J=8.6 Hz, 1H); 4.63 (s, 2H); 3.04 (t, J=7.4 Hz, 2H); 2.76 (t, J=7.4 Hz, 2H), 1.48 (s, 9H).