Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>ClCCCl.[Fe](Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:16]2[CH:15]=[CH:14][C:13]([C:19]3([C:29]4[CH:30]=[CH:31][C:32]([C:8](=[O:9])[C:7]5[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=5)=[CH:33][CH:34]=4)[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:20]3)=[CH:18][CH:17]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCC1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: ClCCCl
Product: CCCCC1CCC(c2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)(c2ccc(C(=O)c3ccc([N+](=O)[O-])cc3)cc2)CC1
Temperature: 80 °C
Yield: 55 %

Procedure:
In a 10-liters three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 629 g (3.88 mole) of iron chloride and 1.7 liters of 1,2-dichloroethane were mixed, and 595 g (3.21 mole) of paranitrobenzoyl chloride was introduced with ice cooling to be dissolved. After warming the reaction solution to 80° C., a solution of 391 g (1.34 mole) of 1,1-diphenyl-4-butylcyclohexane in 630 milliliters of 1,2-dichloroethane was added dropwise for 3 hours and 30 minutes. After the dropwise addition was ended, the solution was stirred gently at reflux for 6 hours. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was poured on 2 liters of ice, and 1 liter of a 4N-HCl aqueous solution was added and then extracted with 1.5 liters of chloroform. The solution was washed with a 6N-HCl aqueous solution, an aqueous solution of sodium hydrogencarbonate, brine and water, and dried with magnesium sulfate. After removing off chloroform by a rotary evaporator, treating with a silica gel column and purifying by recrystallization from ethyl acetate, 435 g of 1,1-bis(4-(4-nitrobenzoyl)phenyl)-4-butylcyclohexane was obtained as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O-]CC.[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 6 h

Procedure:
To diethyl[(tert-butoxycarbonyl)amino]propanedioate (5.56 mL, 21.79 mmol) in ethanol (30 ml) was added sodium ethoxide (9.76 ml, 26.2 mmol) followed by benzyl bromide (2.59 mL, 21.79 mmol). The mixture was stirred for 6 h, and the solvent was removed in vacuo. Saturated aqueous sodium hydrogen carbonate (50 mL) was added and the mixture was extracted with ethyl acacate (3×50 mL). The combined organic fractions were washed with saturated aqueous brine (1×50 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo to afford the title compound as a colorless amorphous solid. LC/MS 366.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=[CH:5]2.C([Li])CCC.[NH:20]1[CH:24]=[C:23]([C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[N:22]=[CH:21]1.[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:14][O:13][C:7]1[C:8]([CH3:12])=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:25]([C:23]1[N:22]=[CH:21][NH:20][CH:24]=1)([OH:29])[CH:26]([CH3:28])[CH3:27])[CH:11]=[CH:10]2
Reactant: CC(C)C(=O)c1c[nH]cn1
Reactant: COc1ccc2cc(Br)ccc2c1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
6-Bromo-2-methoxy-1-methylnaphthalene (0.95 g) was dissolved in THF (15 ml). The solution was cooled to −78° C. To the reaction mixture was added dropwise a solution of n-butyllithium in hexane (1.6M, 3 ml), and the mixture was stirred for 15 min. To the mixture was added a solution of 1-(1H-imidazol-4-yl)-2-methyl-1-propanone (0.155 g) in THF (10 ml), and the temperature of the mixture was elevated to room temperature. To the reaction mixture were added aqueous solution of ammonium chloride and ethyl acetate and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The extracts were combined, dried and concentrated. The residue was purified by silica gel chromatography (eluent, dichloromethane:methanol=20:1) to give the titled compound (0.184 g) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5([C:26]#[N:27])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.C(=O)([O-])[O-:29].[K+].[K+].CS(C)=O>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5([C:26]([NH2:27])=[O:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2nccn3nc(Nc4ccc(C5(C#N)CC5)cc4)nc23)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: Cn1cc(-c2nccn3nc(Nc4ccc(C5(C(N)=O)CC5)cc4)nc23)cn1
Reaction time: 5 h

Procedure:
1-{4-[8-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamino]-phenyl}-cyclopropanecarbonitrile is dissolved in methanol before potassiumcarbonate (5 eq.), DMSO (3.5 eq) and hydrogeneperoxide (30% solution, 5.eq) are added. The mixture is stirred for 5 h and monitored via LCMS MS. DMSO (3.5 eq) and hydrogeneperoxide (30% solution, 5.eq) ares added and the mixture iss stirred at rt for 16 h. The mixture is concentrated and the crude material purified via column chromatographie. LCMS purity (Method D): 100%, Rt: 1.70 min, observed [M+H]=375.1;
Reaction SMILES: COS(O)(=O)=O.COCOC.C(=O)(OC)OC.C[C:19]([O:21][CH2:22][C:23]1[CH2:32][S:31][C@@H:26]2[C@H:27]([NH2:30])[C:28](=[O:29])[N:25]2[C:24]=1[C:33]([OH:35])=[O:34])=O>CO>[NH2:30][CH:27]1[C:28](=[O:29])[N:25]2[C:24]([C:33]([OH:35])=[O:34])=[C:23]([CH2:22][O:21][CH3:19])[CH2:32][S:31][C@H:26]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COS(=O)(=O)O
Solvent: COCOC
Solvent: COC(=O)OC
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 10 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
20.28 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 2), 1.77 g of methanol and 2.30 g of methylal (prepared as described in Preparation 5) were added to 30 ml of dimethyl carbonate. The mixture was cooled to 10° C., and 2.74 g of 7-ACA were added thereto, followed by stirring at 10° C. for 1 hour. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2 to give 2.01 g (yield 82%) of the desired compound at a high purity.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[NH2:23][CH:24]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CO>[C:33]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:34]=[CH:35][C:30]([CH:24]([NH:23][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:31][CH:32]=1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)CC(N)c1ccc(-c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)CC(Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2,4-dinitrofluorobenzene (247 mg, 847 μmol) in methanol (2 mL) was added N,N-diisopropylethylamine (147 μL, 844 μmol) and methyl 3-amino-3-(1,1′-biphenyl)-4-ylpropanoate (158 mg, 849 μmol). The solution was stirred at room temperature for 72 hours, then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of petroleum ether and dichloromethane (1:1 to 0:1), to afford the title compound, [LCMS (Method B, Mobile Phase I) RT=3.81 min, MH+ 422].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:13][N:14]2[C:22]3[C:17](=[N:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)OCC[O:9]1>CO.Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:9])[CH2:13][N:14]1[C:22]2[C:17](=[N:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: COc1ccc2c(ccn2CC2(c3ccccc3Br)OCCO2)n1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(ccn2CC(=O)c2ccccc2Br)n1

Procedure:
A solution containing 1.60 g (4.1 mmol) of the compound obtained in Step A in 10 ml of methanol and 20 ml of 18% hydrochloric acid is refluxed for 4 hours. After returning to room temperature and removal of the methanol by evaporation, the mixture is neutralised with a saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 8:2) to yield the title compound in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[NH4+:10].[OH-]>O.[O-]S([O-])(=O)=O.[Cu+2].O>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([NH2:10])[CH:3]=[N:4][CH:5]=1
Reactant: COc1cncc(Br)c1
Reactant: [NH4+]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Solvent: O
Product: COc1cncc(N)c1
Temperature: 120 °C

Procedure:
A solution of 3-bromo-5-methoxypyridine (5.2 g, 27.5 mmol) and CuSO4.H2O (1.37 g, 5.5 mmol) in NH4OH (5 mL) was placed in a sealed tube and heated at 120° C. for 10 hours. The reaction mixture was then cooled to room temperature, diluted with H2O (40 mL), and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound that was used in the next step with no further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH:22]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]>ClCCl.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:31]([C@H:28]1[CH2:29][CH2:30][C@H:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]1)=[O:32]
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Reactant: CC(C)[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](C(C)C)CC1
Temperature: 2.5 °C
Reaction time: 14 h

Procedure:
D-Phenylalanine methyl ester hydrochloride (10 g, 0.046 mol) was suspended in a solution of triethylamine (33 mL) in dichloromethane (50 mL). The mixture was cooled to 0-5° C. and trans-4-isopropylcyclohexane carboxylic acid (7.9 g, 0.046 mol) was added. A solution of propane phosphonic acid anhydride (46.4 mL, 0.046 mol) in ethyl acetate was added dropwise over a period of 30 minutes, maintaining the temperature at 0-5°. The resulting mixture was stirred for 14 hours at ambient temperature. The reaction mixture was washed with 1.5 N HCl, 5% sodium bicarbonate solution and brine. The organic layer was concentrated to yield 12.5 g of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25]O)=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:27]([F:28])([F:29])[F:30])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[C:18]([CH2:25][N:35]4[C:31](=[O:41])[C:32]5[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:34]4=[O:36])=[CH:17][N:16]=3)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: OCc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Reaction time: 3 h
Yield: 84.7 %

Procedure:
{2-({2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)pyrimidin-5-yl}methanol (Reference document: WO 2010/043315) (2.20 g), phthalimide (0.72 g) and triphenylphosphine (1.40 g) were dissolved in tetrahydrofuran (50 ml), and to the solution was added diethyl azodicarboxylate (40% toluene solution, 2.43 ml) at room temperature. After stirring the reaction solution for 3 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound (2.35 g).
Reaction SMILES: CC1C=C([CH2+]=NC(C(O)=O)C(C)C)C=CC=1.[NH2:17][CH:18]([C:22]([OH:24])=[O:23])[CH:19]([CH3:21])[CH3:20].C(=O)([O-])O.[Na+].[CH3:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38]=[O:39])[CH:34]=[CH:35][CH:36]=1>>[CH3:30][C:31]1[CH:32]=[C:33]([NH:37][C:38]([NH:17][CH:18]([C:22]([OH:24])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:39])[CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)C(N)C(=O)O
Reactant: Cc1cccc(N=C=O)c1
Agent: Cc1cccc([CH2+]=NC(C(=O)O)C(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cccc(NC(=O)NC(C(=O)O)C(C)C)c1

Procedure:
(RS)-N-(3-Methylphenylcarbamo-yl)valine may be prepared in a manner similar to that described in Example 35 for the preparation of (RS)-N-(3-methylphenylcarbamoyl)phenylglycine, but starting with (RS)-valine (4.7 g), sodium hydrogen carbonate (3.36 g) and 3-methylphenyl isocyanate (5.14 cc). (RS)-N-(3-Methylphenylcarbamoyl)valine (6.6 g), m.p. 170° C., is thereby obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]2)=[O:16])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([CH:15]([OH:16])[C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:18]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2c(F)cccc2C(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2c(F)cccc2C(O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Reaction time: 2 h
Yield: 139.3 %

Procedure:
To a solution of (R)-tert-butyl 3-(6-fluoro-3′-methylbiphenylcarbonyl)piperidine-1-carboxylate (3.5 g, 6.29 mmol) in MeOH (50 mL) was added NaBH4 (0.95 g, 25 mmol) in portions at rt. After addition, the mixture was stirred for 2 h. Tlc showed the starting material had disappeared. The solvent was removed in vacuo to leave a residue which was partitioned between water and EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated to give (3R)-tert-butyl 3-((6-fluoro-3′-methylbiphenyl-2-yl)(hydroxy)methyl)piperidine-1-carboxylate (3.5 g, 100%), which was used in the next step without purification.
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5]1>C(O)(C(F)(F)F)=O.[Pd]>[N:11]1[C:12]2[CH:4]([NH2:3])[CH2:5][CH2:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CON=C1CCc2cccnc21
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: NC1CCc2cccnc21
Reaction time: 14 h

Procedure:
5,6-Dihydro-[1]pyrindin-7-one O-methyl-oxime (4.1 g, 25.28 mmol) and Pd/C (150 mg) were mixed in TFA and then resulting reaction mixture was hydrogenated under 50 psi for 14 hours. Filtration via celite and concentration afforded the desired title amine. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 1.89-2.02 (m, 1H), 2.46-2.58 (m, 1H), 2.89-3.01 (m, 2H), 4.62-4.73 (m, 1H), 7.30-7.37 (m, 1H), 7.77 (d, J=7.62 Hz, 1H), 8.35-8.50 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]([CH:32]=[O:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][Mg]Cl>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]([CH:32]([OH:33])[CH3:34])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Cl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2cc(C=O)c3ccccc3c2)n1
Solvent: C1CCOC1
Product: CC(O)c1cc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc(Cl)c2Cl)cc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To this aldehyde (150 mg, 0.312 mmol) in THF (5 mL) at 0° C. was added dropwise MeMgCl (0.37 mL, 82 mg, 1.09 mmol). The mixture was stirred at 0° C. for 1 h and then warmed to RT and stirred for 7 h. The mixture was treated with an additional batch of MeMgCl (0.2 mL, 0.6 mmol), stirred overnight at RT, treated with additional MeMgCl (0.3 mL, 0.9 mmol) and then quenched with H2O (25 mL) and diluted with EtOAc (25 mL) and 5% citric acid (10 mL). The organic phase was separated, washed with brine dried (Na2SO4), filtered, concentrated and purified to yield 1-(3-t-butyl-1-(4-(1-hydroxyethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (65 mg, 42% yield). 1H-NMR (300 MHz, DMSO-d6): δ 1.31 (s, 9H), 1.49 (d, J=6.2 Hz, 3H), 5.47-5.48 (m, 1H), 5.53-5.54 (m, 1H), 6.45 (s, 1H), 7.28-7.31 (m, 2H), 7.57-7.60 (m, 2H), 7.83 (s, 1H), 7.94 (s, 1H), 8.02-8.18 (m, 3H), 8.78 (s, 1H), 9.31 (s, 1H); MS (ESI) m/z: 499.0 (M+H+).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.OCCOCN1C=C(C=C)C(=O)NC1=O.[N-]=[N+]=[N-].[Na+].[OH:28][CH2:29][CH2:30][O:31][CH2:32][N:33]1[CH:40]=[C:39]([CH:41]([N:44]=[N+:45]=[N-:46])[CH2:42]Br)[C:37](=[O:38])[NH:36][C:34]1=[O:35]>COCCOC.O>[OH:28][CH2:29][CH2:30][O:31][CH2:32][N:33]1[CH:40]=[C:39]([CH:41]([N:44]=[N+:45]=[N-:46])[CH2:42][Cl:1])[C:37](=[O:38])[NH:36][C:34]1=[O:35]
Reactant: [N-]=[N+]=NC(CBr)c1cn(COCCO)c(=O)[nH]c1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: C=Cc1cn(COCCO)c(=O)[nH]c1=O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: [N-]=[N+]=NC(CCl)c1cn(COCCO)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
N-Chlorosuccinimide (NCS, 88 mg, 0.65 mmol) was added slowly to a precooled (−5° C.) suspension prepared by mixing a solution of 1 (116 mg, 0.55 mmol) in 1,2-dimethoxyethane (20 ml) with a solution of sodium azide (143 mg, 2.2 mmol) in water (0.35 ml). The reaction was stirred for 3 h at 0° C. Completion of the reaction, as described for the isolation of 2a, gave a residue which was purified by silica gel column chromatography. Elution with chloroform:methanol (97:3, v/v) as eluent yielded 2b as a syrup (56 mg, 35%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1>>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[O:27][CH:31]=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: c1ccoc1
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)c3ccco3)c2)c1

Procedure:
This compound was prepared by method C using compound 12b and furan.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:8]=2[CH:26]([NH:28][C:29]2[N:37]=[CH:36][N:35]=[C:34]3[C:30]=2[N:31]=[CH:32][NH:33]3)[CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:26]([NH:28][C:29]2[N:37]=[CH:36][N:35]=[C:34]3[C:30]=2[N:31]=[CH:32][NH:33]3)[CH3:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C(C)Nc3ncnc4[nH]cnc34)c(-c3ccccc3)c3ccccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(Nc1ncnc2[nH]cnc12)c1[nH]c2ccccc2c1-c1ccccc1
Temperature: 70 °C
Reaction time: 72 h
Yield: 59.6 %

Procedure:
A mixture of {1-[3-phenyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]ethyl}-(9H-purin-6-yl)amine from Example 21 (200 mg, 0.393 mmol) and 2M KOH (0.8 mL) in MeOH (4 mL) was stirred at 70° C. for 72 h. Volatiles were removed under reduced pressure and the resulting residue was diluted with water. The pH of the solution was adjusted to 1 by addition of 1M HCl and then to 8 by addition of a saturated solution of NaHCO3. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a gradient 10-98% 0.1% HCO2H in acetonitrile/water) and then by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 116 as a white solid (83 mg, 60%). LCMS: RT 3.98 min [M+H]+ 355.0. 1H NMR (DMSO, 400 MHz): δ 11.29 (1H, s), 8.21-8.09 (2H, m), 7.71-7.55 (3H, m), 7.52-7.42 (5H, m), 7.32 (1H, t, J=7.39 Hz), 7.13 (1H, t, J=7.93 Hz), 7.02 (1H, t, J=7.93 Hz), 5.96 (1H, s), 1.62 (3H, d, J=6.93 Hz)
Reaction SMILES: C(C1C=C2C(=CC=1)NC(=O)C2)(=O)C.C(C1C=C2C(=CC=1)NC(=O)C2)(=O)CC.C1(C(C2C=C3C(=CC=2)NC(=O)C3)=O)SC=CC=1.C1SC=CC=1C(C1C=C2C(=CC=1)NC(=O)C2)=O.CC1C(C(=O)C)=CC=C2C=1CC(=O)N2.ClC1C(C(=O)C)=CC=C2C=1CC(=O)N2.C[C:91]1[CH:92]=[C:93]([C:101](=[O:108])[C:102]2[CH:107]=[CH:106][CH:105]=[CH:104][CH:103]=2)[CH:94]=[C:95]2[C:99]=1[NH:98][C:97](=[O:100])[CH2:96]2>>[C:101]([C:93]1[CH:94]=[C:95]2[C:99](=[CH:91][CH:92]=1)[NH:98][C:97](=[O:100])[CH2:96]2)(=[O:108])[C:102]1[CH:103]=[CH:104][CH:105]=[CH:106][CH:107]=1
Reactant: Cc1cc(C(=O)c2ccccc2)cc2c1NC(=O)C2
Agent: CC(=O)c1ccc2c(c1)CC(=O)N2
Agent: CC(=O)c1ccc2c(c1C)CC(=O)N2
Agent: CC(=O)c1ccc2c(c1Cl)CC(=O)N2
Product: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1

Procedure:
Using a similar procedure and starting with the requisite reagents, 5-acetyloxindole, 5-propionyloxindole, 5-(2-thenoyl)oxindole, 5-(3-thenoyl)oxindole, 4-methyl-5-acetyloxindole, 4-chloro-5-acetyloxindole and 7-methyl-5-benzoyloxindole are prepared.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([NH2:19])[C:16]([C:20]#[N:21])=[C:15](Cl)[N:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:25]([NH2:28])([CH3:27])[CH3:26]>CN(C)C(=O)C.C(#N)C>[NH2:19][C:17]1[C:16]([C:20]#[N:21])=[C:15]([NH:28][CH:25]([CH3:27])[CH3:26])[N:14]=[C:13]([C:11]([NH:10][CH2:9][C:8]2[CH:23]=[CH:24][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:12])[CH:18]=1
Reactant: CC(C)N
Reactant: CS(=O)(=O)c1ccc(CNC(=O)c2cc(N)c(C#N)c(Cl)n2)cc1
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CC(C)Nc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cc(N)c1C#N
Yield: 20.6 %

Procedure:
A mixture of Example 181F (36 mg, 0.1 mmol), isopropylamine (85 μL, 1.0 mmol) in N,N-dimethylacetamide (500 μL) was heated at 190° C. for 80 minutes in a microwave reactor. The crude mixture was diluted with 1 mL acetonitrile and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate), followed by second purification via silica gel chromatography, eluting with hexane/ethyl acetate (1:1 to 100% ethyl acetate) to provide the titled compound (8 mg, 21% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.02 (t, J=6.4 Hz, 1H), 7.88 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 6.89 (bs, 2H), 6.69 (s, 1H), 6.15 (d, J=8.1, 1H), 4.58-4.46 (m, 3H), 3.17 (s, 3H), 1.16 (t, J=6.8 Hz, 6H). MS (m/e) 388 (M+H)+.