Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:18]2[CH:9]1[C:10]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:11]1[C:16]([CH2:17]2)=[CH:15][CH:14]=[C:13]([OH:19])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:41][OH:42]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[C@H:18]([O:42][CH3:41])[CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[C:10]1([CH2:20][CH3:21])[CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(CC)c2cc(O)ccc2CC2C1N2C(=O)OC(C)(C)C
Reactant: CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCC1(CC)c2cc(O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a slurry of 7,7-diethyl-5-hydroxy-1a,2,7,7a-tetrahydro-1-aza-cyclopropa[b]naphthalene-1-carboxylic acid tert-butyl ester (170.0 g, 535.6 mmol) and methanol (1700 mL) was added pyridinium p-toluenesulfonate (13.4 g, 53.6 mmol) and the reaction mixture was stirred at 40° C. for 4 h. The volume was reduced by rotary evaporation to ˜300 mL resulting in a thick white slurry. The product was isolated by filtration; the filter cake was washed with cold methanol (50 mL) and dried in air for 3 h to yield the title compound (150 g). The filtrate was reduced to ˜50 mL and stirred at 0° C. for 2 h, filtered, and dried to yield additional product (25 g). *In this and the following examples, the prefix trans refers to a mixture of the (2S),(2S) diastereomer and the (2R),(2R) diastereomer.
Reaction SMILES: ClC1C=CC(P(Cl)(Cl)=O)=CC=1.[NH:12]1C=NN=N1.[C:17]([O:20][C@H:21]1[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@:24]([CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH:34]([F:36])[F:35])[O:23][C@H:22]1[N:46]1[CH:51]=[CH:50][C:49](=O)[NH:48][C:47]1=[O:53])(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:20][C@H:21]1[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@:24]([CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH:34]([F:35])[F:36])[O:23][C@H:22]1[N:46]1[CH:51]=[CH:50][C:49]([NH2:12])=[N:48][C:47]1=[O:53])(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H]1[C@H](n2ccc(=O)[nH]c2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Reactant: c1nnn[nH]1
Agent: O=P(Cl)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H](n2ccc(N)nc2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 176.3 %

Procedure:
4-Chlorophenylphosphonic dichloride (0.4 g, 0.81 mmol) was added to a cooled (0° C.) solution of 1-H-tetrazole (0.056 g, 0.81 mmol) and 35 (0.113 g, 0.22 mmol) in dry pyridine (5 mL). The reaction mixture was left to stir under a nitrogen atmosphere at 20° C. for 3 h and then evaporated to dryness under reduced pressure. The residue was dissolved in dioxane and NH3.H2O (5 mL) was added. After stirring for 5 h at 20° C., the reaction mixture was evaporated to dryness under reduced pressure to afford 36 (0.2 g, crude).
Reaction SMILES: Cl[C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:22][CH:21]4[CH:19]([CH:20]4[C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:18]3)=[O:16])[CH:12]=[CH:11][C:10]=2[CH3:31])=[O:7])=[CH:4][N:3]=1.[CH:34]([NH2:37])([CH3:36])[CH3:35].C([O-])(O)=O.[Na+]>CS(C)=O>[CH:34]([NH:37][C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([N:17]3[CH2:18][CH:19]4[CH:21]([CH:20]4[C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:22]3)=[O:16])[CH:12]=[CH:11][C:10]=2[CH3:31])=[O:7])=[CH:4][N:3]=1)([CH3:36])[CH3:35]
Reactant: COc1ccc(C2C3CN(C(=O)c4ccc(C)c(NC(=O)c5ccc(Cl)nc5)c4)CC32)cc1
Reactant: CC(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C2C3CN(C(=O)c4ccc(C)c(NC(=O)c5ccc(NC(C)C)nc5)c4)CC32)cc1
Temperature: 120 °C
Yield: 36 %

Procedure:
A mixture of 6-chloro-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide (compound 118.11, 0.107 g, 0.23 mmol) and isopropylamine (1.5 mL) in DMSO (1.5 mL) was heated at 120° C. in a sealed pressure tube overnight. After cooling to room temperature, the reaction mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc (3×). The combined organic extract was dried over MgSO4, filtered and concentrated. The residue was triturated with hexane to give the title compound as a white powder (40 mg, 36% yield). MS [M+H]+: 485. 1H-NMR (DMSO-d6, 400 Hz) δ 9.63 (s, 1H), 8.69 (d, J=3 Hz, 1H), 7.95-7.90 (m, 1H), 7.55-7.51 (m, 1H), 7.39-7.30 (m, 2H), 7.10-7.03 (m, 3H), 6.84 (d, J=9.2 Hz, 2H), 6.52 (d, J=9.2 Hz, 1H), 4.17-4.07 (m, 2H), 3.85-3.77 (m, 1H), 3.74 (s, 3H), 3.65-3.51 (m, 2H), 2.30 (s, 3H), 1.87 (s, 2H), 1.69 (t, J=3.7 Hz, 1H), 1.20 (d, J=7.2 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11]>ClCCl.N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:10]([CH3:9])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(Br)cc1

Procedure:
A solution of 4-bromoaniline (1.00 g, 5.81 mmol) and methanesulfonyl chloride (1 eq) in dichloromethane (10 mL) and pyridine (5 mL) was stirred at rt for 18 h. The resultant mixture was then diluted with dichloromethane and washed with water and then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give N-(4-bromophenyl)methanesulfonamide.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=2)[CH:23]=[N:22]1.C(Cl)CCl>CN(C=O)C>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][C:12]2[C:13]([NH:18][C:30]([C:27]3[CH:28]=[C:29]4[C:24]([CH:23]=[N:22][NH:21]4)=[CH:25][CH:26]=3)=[O:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc3cn[nH]c3c2)cc1
Reaction time: 12 h
Yield: 26 %

Procedure:
To a stirring solution of N2-(4-t-butylbenzoyl)-1,2-benzenediamine (830 mg, 3.1 mmol) and 6-indazolecarboxylic acid (European Pat. Appln. Pub. No. 242 167 A2, p 43) (500 mg, 3.1 mmol) in DMF (5 mL) was added EDC (1.19 g, 6.2 mmol). After 12 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed twice with water and twice with brine. The organic phase was dried with MgSO4, filtered and concentrated in vacuo, then chromatographed over silica gel, eluting with a solvent gradient of dichloromethane through 5% methanol/dichloromethane. The product containing fractions were combined and concentrated in vacuo to give 330 mg (26%) of an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[CH3:24][C:25]1([CH3:42])[O:29][C@@H:28]([CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][O:26]1>>[CH3:24][C:25]1([CH3:42])[O:29][C@@H:28]([CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:17](=[O:18])[C:16]4[C:15]5[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=5)[NH:9][C:8]=4[C:7]([CH3:21])([CH3:22])[C:6]=3[CH:23]=2)[CH2:27][O:26]1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)O1

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and toluene-4-sulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11]C(C)(C)C)=[O:10].N1C(C)=CC=CC=1C.[Si:25](OS(C(F)(F)F)(=O)=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[Cl-].[NH4+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[O:10]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
To a methylene chloride solution (1 ml) of N-t-butoxycarbonyl-L-proline methyl ester (114.5 mg, 0.5 mmol) and 2,6-lutidine (0.116 ml, 1.0 mmol), t-butyldimethylsilyltrifluoromethane sulfonate (TBDMSOTf) (0.172 ml, 0.75 mmol) was added dropwise at room temperature in a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a saturated aqueous solution of ammonium chloride (2 ml) was added to quench the reaction and extraction with ether was conducted. The organic layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent under vacuum, the titled compound was obtained in an amount of 153 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([NH2:10])[CH:4]=1.C(=O)(O)[O-].[Na+].[Br:16][CH2:17][C:18](Br)=[O:19]>C(Cl)(Cl)Cl>[Br:16][CH2:17][C:18]([NH:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9])=[O:19]
Reactant: COc1ccc(O)c(N)c1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(O)c(NC(=O)CBr)c1
Temperature: 0 °C
Yield: 76.6 %

Procedure:
4-methoxy-2-aminophenol (3.0 g, 17.1 mmol) was dissolved in 100 mL of chloroform. 62 mL of saturated sodium bicarbonate solution was added and the new bi-phase mixture was stirred vigorously and cooled to 0° C. using an ice bath. Bromoacetylbromide (3.42 mL, 39 mmol) was added drop-wise. Fifteen minutes later the solution was removed from the ice bath and maintained at room temperature for 1.5 hours. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) indicated that all of the starting material was gone and a new peak (Rt=4.9 min) had formed. The organic layer was separated and the aqueous phase was extracted with 100 mL of chloroform. The combined organic phases were dried over Na2SO4, filtered and concentrated to give 2-bromo-N-[2-hydroxy-5-(methyloxy)phenyl]acetamide (3.42 g, 13.1 mmol, 77%) as a brown amorphous solid. MS (ES) m/e 260 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[CH:7][NH2:8])[C:5](=[O:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[CH2:16]([O:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1NOC(=O)C(F)(F)F)[CH2:17][CH3:18]>C(O)C>[CH3:1][C:2]1[C:6](=[CH:7][NH:8][C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=2[O:19][CH2:16][CH2:17][CH3:18])[C:5](=[O:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: CC1=NN(c2ccccc2)C(=O)C1=CN
Reactant: CCCOc1ccccc1NOC(=O)C(F)(F)F
Solvent: CCO
Product: CCCOc1ccccc1NC=C1C(=O)N(c2ccccc2)N=C1C

Procedure:
3-methyl-4arninomethylene-1-phenyl-4,5-dihydro-pyrazol-5-one (2 g) and 2-propoxyanilino-trifluoroacetic acid salt (1.6 g) are refluxed 1.5 hours in ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 20 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd (PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The reaction was heated at 100° C. for 4 h. After cooling, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure to afford crude product. Purification by column chromatography over silica gel afforded the title compound (0.02 g, 20%).
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][CH2:11][N:12]1[C:17]2[CH2:18][CH2:19][S:20][CH2:21][C:16]=2[C:15](=[O:22])[NH:14][C:13]1=[O:23])C1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:27]>C(#N)C>[O:23]=[C:13]1[N:12]([CH2:11][CH2:10][CH2:9][N:8]([CH3:1])[C:26](=[O:27])[O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])[C:17]2[CH2:18][CH2:19][S:20][CH2:21][C:16]=2[C:15](=[O:22])[NH:14]1
Reactant: CN(CCCn1c2c(c(=O)[nH]c1=O)CSCC2)Cc1ccccc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CN(CCCn1c2c(c(=O)[nH]c1=O)CSCC2)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of 11.5 g (33.29 mmol) of 1-{3-[benzyl(methyl)amino]propyl}-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-d]pyrimidine-2,4-(3H)-dione in 200 ml of acetonitrile is treated with 7.92 g (36.63 mmol) of 2,2,2-trichloroethyl chloroformate, and the mixture is stirred at room temperature for 30 minutes. The solvent is then removed under reduced pressure and the residue is purified by column chromatography (silica gel, cyclohexane/ethyl acetate 1:1). This gives 9.4 g (63% yield) of a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][C:7]([OH:16])=[CH:6][C:5]2=1.Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.[I-].[K+]>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]=[CH:11][C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][C:7]([O:16][CH2:18][CH:19]1[CH2:21][CH2:20]1)=[CH:8][CH:9]=3
Reactant: BrCC1CC1
Reactant: Oc1ccc2ccc3ccc(Br)cc3c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Brc1ccc2ccc3ccc(OCC4CC4)cc3c2c1
Yield: 86.9 %

Procedure:
A mixture of 6-bromophenanthren-3-ol (0.823 g, 3.02 mmol) from Step 1 above, (bromomethyl)cyclopropane (0.5 mL, 5.4 mmol), potassium carbonate (2.5 g, 18 mmol) and potassium iodide (5 mg) in acetone (50 mL) was heated at reflux for 3 days. Water was then added and the reaction mixture extracted with ethyl acetate The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography on silica (100% hexanes) to provide 3-bromo-6-(cyclopropylmethoxy)phenanthrene (0.859 g, 87%).
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])(C)(C)C.FC(CC(O)=O)(F)F.C(OCC)(=O)C>ClCCl>[Cl:29][C:24]1[CH:23]=[C:22]([C:16]2([C:18]([F:20])([F:19])[F:21])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:31])=[O:5])=[C:8]([CH3:30])[CH:9]=3)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Agent: O=C(O)CC(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (Example I19) (74.14 g) in dichloromethane (750 ml) was added trifluoromethyl acetic acid (“TFA”) (148 ml). The reaction mixture was stirred at ambient temperature for 16 hours. Ethyl acetate was added and the mixture was washed with water, dried over sodium sulfate and concentrated. The residue was crystallized from ethyl acetate and heptane to give 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (55.0 g). 1H-NMR (CDCl3, 400 MHz): 8.12 (d, 1H), 7.65-7.45 (m, 5H), 4.15 (d, 1H), 3.75 (d, 1H), 2.75 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([N:11](F)[N:12](F)F)=[O:10])[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:22]CC(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([Cl:22])[C:9]([NH:11][NH2:12])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: O=C(Cc1cccc(Cl)n1)N(F)N(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: NNC(=O)C(Cl)c1cccc(Cl)n1
Reaction time: 1 h

Procedure:
A mixture of 3.0 g. of 2-chloro-6-hydrazinopyridine (prepared in Example 1), 1.7 g. of pyridine and 35 ml. of methylene chloride is treated with 2.5 g. of chloroacetyl chloride according to the procedure of Example 2. The reaction mixture is stirred for one hour, then is filtered and washed with methylene chloride to collect 2.3 g. of colorless solid. The solid is recrystallized from tetrahydrofuran-hexane to give the product of the Example m.p. 176°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>>[CH2:24]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[CH3:19])=[N:8]1)[CH:23]=[CH2:22]
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc(-c2ccc(OC)cc2C)c2cccc(Cl)c21
Yield: 62.7 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and allyl bromide (0.07 mL, 0.7 mmol) to give the title compound (0.102 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.C([Li])CCC.[Cl:21][Si:22](Cl)([Cl:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)C.CCCCCC>[Cl:21][Si:22]([Cl:29])([C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cl[Si](Cl)(Cl)c1ccccc1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(C)(C)C)cc([Si](Cl)(Cl)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
Under a nitrogen atmosphere, to a diethyl ether solution (106 mL) of 1-bromo-3,5-di-tert-butylbenzene (10.60 g, 39.37 mmol), a 1.65 M hexane solution of n-butyllithium (23.86 mL, 39.37 mmol) was added dropwise at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature for 3 hours. The resultant mixture was added dropwise to a diethyl ether solution (106 mL) of trichlorophenylsilane (24.99 g, 118.12 mmol) at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, hexane wad added to the residue, and insoluble materials were removed by filtration. The solvent was removed from the filtrate under reduced pressure. Trichlorophenylsilane was removed by heating to 100° C. under reduced pressure to obtain dichloro(3,5-di-tert-butylphenyl)(phenyl)silane (11.77 g, yield 81.8%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[F:14][C:15]([F:30])([F:29])[C:16]1[CH:17]=[C:18]([N:26]=[C:27]=[O:28])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1>C(OCC)(=O)C>[F:14][C:15]([F:29])([F:30])[C:16]1[CH:17]=[C:18]([NH:26][C:27]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=3)[N:6]=2)=[O:28])[CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Nc1nc(-c2ccc(Cl)cc2)cs1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
To a stirred solution of 2-amino-4-(4-chlorophenyl)thiazole (0.647 g, 3.07 mmol) in ethyl acetate (50 mL) was added 3,5-bis(trifluoromethyl)phenyl isocyanate (0.53 mL, 3.1 mmol). The mixture was refluxed for 16 hours, cooled to room temperature, and washed with 10% aqueous hydrochloric acid solution, water and brine. The mixture was dried (magnesium sulfate), filtered, and concentrated to provide a white solid. Flash chromatography over silica (hexanes/ethyl acetate) provided 0.850 g (59%) of the product as a white solid: 1H NMR (NMR (DMSO-d6) δ9.62 (br s, 1H), 8.18-8.17 (m, 2H), 7.92-7.88 (m, 2H), 7.72-7.66 (m, 2H), 7.49-7.46 (m, 2H) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:17]([C:19]1[CH:20]=[C:21]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:22]=[CH:23][C:24]=1F)#[N:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[C:17]([C:19]1[CH:20]=[C:21]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:22]=[CH:23][C:24]=1[N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)#[N:18]
Reactant: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)Cc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)OC(C)(C)C)ccc32)c(C#N)c1
Temperature: 95 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
tert-Butyl 1H-indole-5carboxylate (0.800 g, 3.68 mmol), methyl 2-(3-cyano-4-fluorophenyl)acetate (0.593 g, 3.07 mmol), and potassium carbonate (0.509 g, 3.68 mmol) were combined in 15 mL of DMSO and the reaction mixture was stirred at 95° C. for 24 hours. Reaction was diluted with ethyl acetate washed twice with water, dried over magnesium sulfate and concentrated. Silica gel chromatography eluting with a gradient of 5% ethyl acetate/hexanes to 60% ethyl acetate/hexanes gave tert-butyl 1-(2-cyano-4-(2-methoxy-2-oxoethyl)phenyl)-1H-indole-5-carboxylate (0.380 g, 0.973 mmol, 32%). MS (APCI)=390.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9]C(=O)C(F)(F)F)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.CO.C([O-])([O-])=O.[K+].[K+]>O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: O=C(Nc1cc(F)c(Br)cc1[N+](=O)[O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To N-(4-bromo-5-fluoro-2-nitrophenyl)-2,2,2-trifluoroacetamide (3.5 g, 10.5 mmol) was added CH3OH (30 mL) followed by 1.0 M K2CO3 (10.5 mL, 10.5 mmol), and the solution was stirred for 30 minutes (Charifson, P. S.; et al. J. Med. Chem. 2008, 51, 5243-5263). The solution was diluted with H2O and stirred for 1 hour. The resulting orange solid was collected by filtration and dried in a vacuum oven to give the title compound (2.1 g, 8.8 mmol, 84%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)=[O:4]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Add dropwise trimethylacetyl chloride (3.3 mL, 27 mmol) to a mixture of 4-aminobenzonitrile (2.92 g, 24.7 mmol) and triethylamine (3.8 mL, 27 mmol) in anhydrous DCM (25 mL) at 0° C. Stir the mixture to room temperature overnight. Partition the reaction mixture between DCM (500 mL) and water (250 mL) and extract the aqueous phase with DCM (250 mL). Wash the combined organic extracts with water (3×250 mL), dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (5 g, 100%). MS (ES+) m/z: 203.2 (M+H)+.