Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[H-].[Na+].CCCCCC.Cl[CH2:22][C:23]1[CH:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:27][CH:28]=1>CN(C=O)C.O>[C:25]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[C:6]2[CH3:12])[CH:24]=1
Reactant: COc1cccc2[nH]c(C)cc12
Reactant: ClCc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1cc(C)n2Cc1cccc(-c2ccccc2)c1
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
805 mg (5 mmol) of 4-methoxy-2-methyl-1H-indole is reacted with 200 mg (5 mmol) of 60% NaH/mineral oil (washing with hexane before adding DMF) in 15 mL of DMF and after stirring for 0.5 hour, 1.0 g (5 mmol) of 3-(chloromethyl)biphenyl is added. The mixture is stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried (MgSO4) and after concentrating at reduced pressure, the residue is chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.25 g (76% yield) of 1-((1,1′-biphenyl)-3-ylmethyl)-2-methyl-4-methoxy-1H-indole mp, 127°-131° C.
Reaction SMILES: ClCCC[SiH3].[CH2:6]([Si:9]([CH2:17][CH:18]=[CH2:19])([CH2:14][CH:15]=[CH2:16])[CH2:10][CH2:11][CH2:12]Cl)[CH:7]=[CH2:8].[SiH4].[I-:21].[Na+]>CC(C)=O>[CH2:6]([Si:9]([CH2:17][CH:18]=[CH2:19])([CH2:14][CH:15]=[CH2:16])[CH2:10][CH2:11][CH2:12][I:21])[CH:7]=[CH2:8]
Reactant: C=CC[Si](CC=C)(CC=C)CCCCl
Reactant: [I-]
Agent: [Na+]
Agent: [SiH3]CCCCl
Agent: [SiH4]
Solvent: CC(C)=O
Product: C=CC[Si](CC=C)(CC=C)CCCI
Reaction time: 18 h

Procedure:
Triallyl 3-iodopropyl silane was prepared by the Finkelstein transhalogenation reaction from chloropropyl silane prepared in Example 6. A 250 ml flask equipped with a stir bar and a reflux condenser was charged with 20 grams (90 millimoles) of triallyl (3-chloropropyl) silane (prepared as described in Example 6) and 100 ml of acetone (available commercially as Omnisolve Reagent grade from E. Merck, Gibbstown, N.J.). The silane solution was refluxed under positive nitrogen pressure with 40 grams (270 millimoles) of sodium iodide (available commercially from Aldrich Chemical Co. of Milwaukee, Wis.) for 18 hours. After cooling, the acetone solution was decanted from the insoluble iodide salts and was concentrated on a rotary evaporator to yield triallyl 3-iodopropyl silane, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:20]([N+:21]([O-])=O)=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:24][CH2:25][CH2:26][O:27][CH3:28])[N:3]=1>[Ni].C1COCC1>[NH2:21][C:20]1[C:2]([NH2:1])=[N:3][C:4]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:5]([CH:19]=1)[C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([F:16])([F:17])[F:18])[CH2:13][CH2:14]1)=[O:7]
Reactant: COCCOc1nc(N)c([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: COCCOc1nc(N)c(N)cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
6-Amino-2-(2-methoxy-ethoxy)-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (140 mg, 0.34 mmol), THF (20 mL) and Ra—Ni (40 mg) is stirred for 2 h at rt under a hydrogen atmosphere (3.0 bar). The catalyst is removed by filtration and the mixture is concentrated to give the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([NH2:30])[CH:25]=[CH:24]2)(=[O:20])=[O:19].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[CH3:17][S:18]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([NH:30][C:14]([C:11]1[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:13][CH:12]=1)=[O:15])[CH:25]=[CH:24]2)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccc2c(ccn2N)c1
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc2c(ccn2NC(=O)c2cnc(-c3cccc(F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (0.62 mmol) in EtOAc (10 mL) is added to a stirred solution of 5-methanesulfonyl-indole-1-ylamine (0.62 mmol) and K2CO3 (3.08 mmol) in EtOAc (10 mL) and H2O (10 mL) at 0° C., and the reaction mixture is warmed to rt and stirred overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration. The solid is triturated with DCM to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-methanesulfonyl-indol-1-yl)-amide (85 mg, 34%) as a solid. MS: 411 (M+H); 1H NMR (300 MHz, CD3OD): δ 3.13 (s, 3H), 6.81 (m, H) 7.25-7.39 (m, H), 7.49-7.67 (m, 3H), 7.72-7.84 (m, H), 8.21-8.32 (m, 2H), 8.39 (d, H), 9.41 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([N:9]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[C:20]2[NH:24][N:23]=[N:22][N:21]=2)[C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>O1CCCC1>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([N:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:15][C:14]=2[C:20]2[NH:24][N:23]=[N:22][N:21]=2)[C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)N(c1cccc(C(F)(F)F)c1)c1ccc(N)cc1-c1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N(c1cccc(C(F)(F)F)c1)c1ccc(NC(=O)c2ccccc2)cc1-c1nnn[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of 3-trifluoromethylphenyl-4-amino-2-(5-tetrazolyl)phenyl urea (0.36 g, 5 1.0 mmol) in tetrahydrofuran (40 mL) was added triethylamine (0.17 mL, 1.2 mmol). The solution was cooled on an ice bath and benzoylchloride (0.14 mL, 1.2 mmol) was added. The reaction was stirred at 0° C. for another 30 min. The reaction was poured into water. The precipitate was filtered off and re-crystallised from 96% ethanol to give 0.28 g of the desired material. M.p. 271-272° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@@H:14]23)[CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][CH2:23][N:17]4[CH2:16][C@@H:15]4[CH2:24][NH:25][CH2:26][C@@H:14]34)[CH:20]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cc(N)cc(c43)[C@@H]2C1
Product: Clc1ccc(Nc2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)cc1Cl

Procedure:
Using 3,4-dichlorobromobenzene and following the procedures described in EXAMPLE 72, (±)-trans tert-butyl 2-amino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate was converted into the title compound of EXAMPLE 73 as a tan solid. 1H NMR (300 MHz, CDCl3) δ 1.25 (br s, 1H), 1.95 (m, 2H), 2.00 (m, 1H), 2.70 (m, 4H), 2.90 (t, 1H, J=9.7 Hz), 3.10-3.50 (m, 5H), 3.54 (t, 1H, J=9.7 Hz), 5.34 (br s, 1H), 6.42 (s, 1H), 6.51 (m, 1H), 6.59 (s, 1H), 6.83 (d, 1H, J=2.6 Hz), 7.16 (d, 1H, J=8.7 Hz). LRMS (ES)+: 374 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[C:21]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)(=[O:23])[CH3:22].C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CN(C)C=O>[C:21]([N:24]1[CH2:29][CH2:28][CH:27]([NH:1][C:2]2[N:11]=[CH:10][C:9]3[CH2:8][CH2:7][C:6]4[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=4[C:4]=3[N:3]=2)[CH2:26][CH2:25]1)(=[O:23])[CH3:22]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(C)=O)CC3)nc1-2
Reaction time: 18 h
Yield: 70 %

Procedure:
To a suspension of 5.187 g (19 mmol) of ethyl 8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in dry dimethylformamide (120 mL), were added 1-acetyl-4-piperidone (4.7 mL, 38 mmol), CF3COOH (10 mL, 128 mmol) and NaBH(OAc)3 (8.862 g, 42 mmol). After 18 hours, NaOH 0.33N (800 mL, 264 mmol) was added dropwise to the mixture. The precipitate was filtered, washed with water and dried in oven to dryness to give 5.3 g (70% yield) of the title compound.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][N:12]([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)(C)(C)C>C1COCC1.CCO>[ClH:1].[ClH:1].[NH2:9][CH2:10][CH2:11][N:12]([CH3:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CN(C)CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CN(C)CCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (10 ml) was added to a solution of ethyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)(methyl)amino)acetate (intermediate 83, 3.05 g, 11.13 mmol) in THF (20 ml) and EtOH (100 ml) at room temperature. After stirring 1 h at room temperature the reaction mixture was evaporated, ethanol (20 ml) added, evaporated, further ethanol (50 ml) added and then stirred at 60° C. for 70 min. The cooled reaction mixture was then evaporated to give the title compound as a pale-yellow glass. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, br, 3H), 4.19 (q, 2H), 4.26-4.15 (m, 2H), 3.44 (s, br, 2H), 3.21 (s, br, 2H), 2.88 (s, 3H), 1.21 (t, 3H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([C:21]([N:15]2[CH2:16][CH2:17][C:12]([NH:11][C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:19])([CH3:18])[CH2:13][CH2:14]2)=[O:22])=[CH:24][CH:25]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCC(C)(NC(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dichloromethane (3 mL) at room temperature was added methyl 4-chlorocarbonylbenzoate (0.125 g, 0.62 mmol) and triethylamine (0.17 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 3 hours, aqueous ammonium chloride was added, and the mixture was extracted with dichloromethane (2×). The combined organic layers were washed with 10% KHSO4, sat. NaHCO3, brine, dried (MgSO4), and concentrated under reduced pressure to provide the titled compound. MS (CI) m/z 411 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.07 (d, 2H), 7.46 (d, 2H), 7.33 (m, 5H), 5.06 (s, 2H), 4.63 (m, 1H—NH), 4.18-4.13 (m, 2H), 3.95 (s, 3H), 3.36 (m, 2H), 2.09 (m, 2H), 1.78-1.42 (m, 2H), 1.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[CH3:20])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C.Cl>ClCCl>[CH2:25]([O:24][C:22]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:6](=[CH:12]/[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[CH3:20])/[C:7]1=[O:11])=[O:23])[CH3:26]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(F)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=O)/C(=C\c2cc(F)ccc2C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-1,3-dihydro-indol-2-one prepared in example 145a (0.20 g, 0.71 mmol) in dichloromethane (3 mL) at 0° C. was added ethyl chloroformate (0.10 mL, 1.1 mmol), followed by the addition of triethylamine (0.14 g, 1.4 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. The mixture was then poured into aqueous HCl solution (1 N). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over Na2SO4, and concentrated to give E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid. The crude product was purified by chromatography to obtain 75 mg yellow solid (Yield 1.7 g, 30%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH2:23]([N:25]([CH2:29][CH3:30])[C:26](Cl)=[S:27])[CH3:24]>O>[N:7]1[C:8]2[C:3](=[C:2]([O:1][C:26](=[S:27])[N:25]([CH2:29][CH3:30])[CH2:23][CH3:24])[CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:5][CH:6]=1
Reactant: CCN(CC)C(=S)Cl
Reactant: Oc1cccc2nccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=S)Oc1cccc2nccnc12
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A mixture of 5-hydroxyquinoxaline (2.13 g, 14.6 mmol), finely ground K2CO3 (4.0 g, 29 mmol), and DMF (50 mL) was stirred at 23° C. for 1 h. Solid diethylthiocarbamoyl chloride (2.43 g, 16.1 mmol) was then added. The resulting mixture was stirred for 2 h, then was diluted with water (150 mL) and extracted with Et2O (2×100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), then dried and concentrated to a viscous orange oil, which was used without purification (3.63 g, 95%). MS (ESI+): mass calcd. for C13H15N3OS, 261.1; m/z found, 262 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.85-8.65 (m, 2H), 7.96 (dd, J=8.5, 1.1, 1H), 7.71 (t, J=7.9, 1H), 7.46 (dd, J=7.6, 1.2, 1H), 3.87 (q, J=7.1, 2H), 3.78 (q, J=7.1, 2H), 1.38 (t, J=7.1, 3H), 1.28 (t, J=7.1, 3H). 13C NMR (125 MHz, CDCl3): 186.6, 149.4, 144.9, 144.5, 143.4, 137.0, 128.9, 127.0, 123.1, 48.2, 44.5, 13.1, 11.5.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][CH2:10][C:11](O)=[O:12])=[C:4]([N+:14]([O-])=O)[CH:3]=1.BrC1C=C([N+]([O-])=O)C(F)=CC=1NCC(O)=O.O.O.[Sn](Cl)Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:9][CH2:10][C:11](=[O:12])[NH:14]2)=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CNc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C(O)CNc1cc(F)c([N+](=O)[O-])cc1Br
Solvent: O
Solvent: CCO
Product: O=C1CNc2cc(F)c(Br)cc2N1
Temperature: 25 °C

Procedure:
A solution of a mixture of N-(4'-bromo-5'-fluoro-2'-nitrophenyl)glycine and N-(2'-bromo-5'-fluoro-4'-nitrophenyl)glycine (0.150 g, 0.512 mmol, as prepared above) and tin (II) chloride dihydrate (0.346 g, 1.53 mmol, Aldrich, used as received) in ethanol (3.0 mL) was refluxed for 30 min. It was then cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with water (10 mL) and basified with saturated NaHCO3 (3.0 mL) to pH ~8. The resulting white suspension was extracted with ethyl acetate (30 mL). The ethyl acetate was dried over anhydrous Na2SO4 and removed under vacuum to yield 0.050 g of crude product, which was purified by precipitation from ethanol:water (1:1) to give 30 mg (24%) of the pure (1H NMR) title compound as a light yellow powder; m.p. 172° C. (decomposed); 1H NMR (DMSO-d6): δ3.73 (s, 2H), 6.37 (s, 1H), 6.551 (d, 1H, J=10.2 Hz), 6.825 (d, 1H, J=6.6 Hz), 10.303 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24]C)[CH:21]=[C:20]([Cl:26])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:18][CH2:17][C:16]3[C:12](=[CH:13][NH:14][N:15]=3)[CH2:11]2)[C:6]1=[O:19].B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:26][C:20]1[CH:21]=[C:22]([OH:24])[CH:23]=[C:2]([Cl:1])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:18][CH2:17][C:16]3[C:12](=[CH:13][NH:14][N:15]=3)[CH2:11]2)[C:6]1=[O:19]
Reactant: COc1cc(Cl)c(CC2CCN(C3CCc4n[nH]cc4C3)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C1C(Cc2c(Cl)cc(O)cc2Cl)CCN1C1CCc2n[nH]cc2C1
Temperature: 0 °C
Reaction time: 28 h
Yield: 74 %

Procedure:
Dissolve 3-(2,6-Dichloro-4-methoxy-benzyl)-1-(4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-2-one (Example 1) (15.0 g, 38 mmol) in methylene chloride (1.5 L) and cool to 0° C. Treat with boron tribromide (19.9 mL, 190 mmol) dropwise over 30 minutes and allow reaction mixture to warm to room temperature. Stir for 28 h at room temperature, re-cool in an ice-bath, add methanol (38 mL) carefully over 15 minutes to the stirred reaction mixture. Remove organic solvents by rotary evaporator, and dissolve the residue in 4:1 chloroform/isopropyl alcohol (600 mL) and water (100 mL). Neutralize to pH 7 using 5 N NaOH, separate, reserve the organics and extract the aqueous layer with two portions of chloroform/isopropyl alcohol. Dry the combined organics over sodium sulfate, filter and evaporate to a solid and vacuum dry at 90° C. to yield 10.7 g (75%) of the titled compound. MS (m/z): 380 (m+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.CS(O)(=O)=O>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl>[CH:13]1([NH:12][C:4]2[CH:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([N:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)=[CH:31][CH:30]=3)[N:7]=[CH:6][C:5]=2[CH2:8][C:9]([NH2:11])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: NC(=O)Cc1cnc(Cl)cc1NC1CCCCC1
Agent: CS(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NC1CCCCC1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To 60 mg of 6-chloro-4-(cyclohexylamino)pyridine-3-carboxyamide (the compound of Example 339) suspended in 0.5 mL of diphenyl ether, 84 mg of 4-morpholinoaniline and 23 mg of methanesulfonic acid were added, and stirred at 180° C. for 30 minutes. After cooling, the reaction mixture was dissolved in chloroform, washed with saturated sodium bicarbonate in water, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=40:1 to 20:1) to obtain 77 mg (82%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:20]([NH2:22])=O>CN(C=O)C.C(O)=O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:4]2[NH:3][C:2]3[N:1]=[CH:20][N:22]=[C:7]([OH:8])[C:6]=3[CH:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2cccc(OC)c2)[nH]c1N
Solvent: CN(C)C=O
Solvent: O=CO
Product: COc1cccc(-c2cc3c(O)ncnc3[nH]2)c1

Procedure:
Under a protective gas, 7.19 g (29 mmol) of 2-amino-3-ethoxycarbonyl-5-(3-methoxy-phenyl)-1H-pyrrole in 59 ml of formamide, 29.5 ml of DMF and 14.7 ml of formic acid are heated at 150° C. overnight. Working-up analogously to Step 8.2 yields the title compound; TLC-Rf =0.3 (hexane/ethyl acetate [1:1]).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[S:16]([O-:19])([OH:18])=[O:17].[Na+:20].C(O)C>O>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=[C:2]([S:16]([O-:19])(=[O:18])=[O:17])[CH:7]=1.[Na+:20]
Reactant: O=S([O-])O
Reactant: FC(F)(F)c1cc(Cl)nc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)n1
Yield: 66.5 %

Procedure:
A mixture of 2-chloro-4,6-bis(trifluoromethyl)pyridine (2.50 g, 10 mmol), sodium hydrogen sulfite (4.2 g, 40 mmol), ethanol (40 ml) and water (40 ml) was heated under reflux for 96.5 hours. The reaction mixture was evaporated to dryness under reduced pressure. To the residue, conc. hydrochloric acid was added and the mixture was again evaporated to dryness. The residued was extracted with methanol, and a methanol phase was filtered. The filtrate was evaporated to dryness under reduced pressure to obtain sodium 4,6-bis(trifluoromethyl)pyridine-2-sulfonate (2.11 g). Yield, 66%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:7][C:8]1[CH:15]=[C:13]([I:14])[C:12]([O:16][C:17]2[CH:24]=[C:22]([I:23])[C:21]([OH:25])=[C:19]([I:20])[CH:18]=2)=[C:10]([I:11])[CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH3:34][N:35]1[CH2:41][C:40](=[O:42])[O:39][C:37](=[O:38])[CH2:36]1>CN(C)C=O.O1CCCC1>[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:7][C:8]1[CH:9]=[C:10]([I:11])[C:12]([O:16][C:17]2[CH:18]=[C:19]([I:20])[C:21]([OH:25])=[C:22]([I:23])[CH:24]=2)=[C:13]([I:14])[CH:15]=1)[NH:6][C:40](=[O:42])[CH2:41][N:35]([CH3:34])[CH2:36][C:37]([OH:39])=[O:38]
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reactant: CN1CC(=O)OC(=O)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)CN(C)CC(=O)O
Reaction time: 0.17 h
Yield: 103.4 %

Procedure:
In 15 ml of dimethylformamide (DMF), 2 g of thyroxine methyl ester hydrochloride was dissolved and 500 μl of triethylamine was added to the resulting solution. After 10 minutes passed, a solution of 0.55 g of N-methyliminodiacetic acid anhydride in 5 ml of tetrahydrofuran (THF) was added to the mixture. After completion of the reacton, the reaction mixture was condensed using a rotary evaporator and the residue was dissolved in 50 ml of THF. Further, 150 ml of ethyl acetate was added to the solution. After stirring the mixture by shaking, the ethyl acetate layer was taken out and washed three times with distilled water and then once with a saturated aqueous sodium chloride solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the supernatant was condensed using a rotary evaporator. To the residue, 20 ml of THF was added and then a small quantity of n-hexane was added to form precipitates. The precipitates were subjected to suction filtration to obtain white crystals. The crystals were dried in a dessicator under reduced pressure to obtain 2.3 g of white crystals. The yield was 69%.
Reaction SMILES: C([N:4]1[C:13]2[C:8](=[CH:9][C:10](N)=[CH:11][CH:12]=2)[C:7]([CH3:16])([CH3:15])[CH2:6][C:5]1=[O:17])(C)C.CC(C)=CC(Cl)=O.NC1C=CC=CC=1>>[CH3:15][C:7]([CH3:16])=[CH:6][C:5]([NH:4][C:13]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:17]
Reactant: CC(C)N1C(=O)CC(C)(C)c2cc(N)ccc21
Agent: CC(C)=CC(=O)Cl
Solvent: Nc1ccccc1
Product: CC(C)=CC(=O)Nc1ccccc1

Procedure:
Reaction Scheme 4 illustrates the synthesis of N-isopropyl 4,4-dimethyl-2-oxo-6-aminoquinoline (Compound 34), which is used in accordance with Reaction Scheme 1 to synthesize exemplary Compound 8 of the present invention. Thus, 3,3-dimethylacryloyl chloride (Compound 35, available from Aldrich) is reacted with aniline (Compound 36) to yield N-3,3-dimethylacryloyl aniline (Compound 37). Compound 37 is ring closed under Friedel Crafts conditions to yield 4,4-dimethyl-2-oxoquinoline (Compound 38) which is thereafter alkylated with iso-propyl iodide to give N-isopropyl 4,4-dimethyl-2-oxoquinoline (Compound 39). Nitration of Compound 39 yields N-isopropyl 4,4-dimethyl-2-oxo-6-nitroquinoline Compound 40, which is reduced with hydrogen on palladium to give Compound 34.