Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[C:6]2[C:7]([N:9]([CH3:12])[C:10](=O)[C:5]=12)=O)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][C:4]1[CH:15]=[CH:14][CH:13]=[C:6]2[C:5]=1[CH2:10][N:9]([CH3:12])[CH2:7]2
Reactant: CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1Cc2cccc(N)c2C1
Yield: 96.4 %

Procedure:
A solution of 3-nitro-N-methylphthalimide (0.58 g, 2.8 mmol) in dry tetrahydrofuran (10 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.64 g, 16.8 mmol) under argon. The mixture was stirred at room temperature for 2h and then heated under gentle reflux for 2.5h. The reaction was quenched by addition of wet diethyl ether followed by a minimum amount of water. The precipithated aluminium salts were removed by filtration. The filtrate was concentrated in vacuo to give the title compound as a brown oil (400 mg) which was used directly in the next stage (Example 31).
Reaction SMILES: [C:1](=[O:11])([S:6][C:7]([CH3:10])([CH3:9])[CH3:8])[O:2][CH:3](Cl)[CH3:4].[C:12]([OH:17])(=[O:16])[CH:13]([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>CCOCC>[C:1](=[O:11])([S:6][C:7]([CH3:10])([CH3:9])[CH3:8])[O:2][CH:3]([O:17][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH3:4]
Reactant: CC(C)C(=O)O
Reactant: CC(Cl)OC(=O)SC(C)(C)C
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(OC(=O)SC(C)(C)C)OC(=O)C(C)C
Temperature: 55 °C
Yield: 90.6 %

Procedure:
Compound (3) (392 mg, 2 mmol) was dissolved in isobutyric acid (264 mg, 3 mmol) and the solution was slowly added to a pre-mixed solution of isobutyric acid (264 mg, 3 mmol) and diisopropylethylamine (387 mg, 3 mmol). The reaction mixture was heated to 55° C. for 16 h, then diluted with ether (50 mL), washed with water (2×10 mL), saturated bicarbonate solution (2×10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (8) as a colorless liquid (450 mg, 90%). The product was further purified by vacuum distillation (170° C./20 Torr). 1H NMR (CDCl3, 400 MHz): δ 1.16 (d, J=7.2 Hz, 6H), 1.47 (s, 9H), 1.48 (d, J=5.6 Hz, 3H), 2.53 (m, 1H), 6.90 (q, J=5.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:31])([F:30])[F:29])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25](O)=[O:26])=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].S(Cl)(Cl)=O>CN(C)C=O.ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:28]([F:29])([F:30])[F:31])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[C:18]([CH2:25][OH:26])=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: O=C(O)c1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: OCc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Yield: 84.8 %

Procedure:
2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoro-methyl)pyrimidine-5-carboxylic acid (2.0 g) was added to 1,2-dichloroethane (50 mL). To the resulting mixture, thionyl chloride (1.0 g), and one drop of N,N-dimethylformamide was added and the mixture was refluxed under heating for 5 hours. After removing the solvent by evaporation, the residues were dissolved in 1,4-dioxane (20 mL), and the resulting solution was added dropwise to the mixture solution comprising water (30 mL), 1,4-dioxane (30 mL), and sodium borohydride (0.4 g) under ice cooling. After the dropwise addition was completed, the solution was refluxed under heating for one hour. After cooling, the reaction solution was poured over ice water and then extracted with ethyl acetate. After cooling, the extraction was carried out by adding water and ethyl acetate to the solution. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (1.65 g, 86%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N+:15]([O-])=[CH:14][C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)([Br:22])=O>C(#N)C.O1CCOCC1>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([Br:22])[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=S(=O)(c1ccccc1)n1ccc2c[n+]([O-])ccc21
Solvent: C1COCCO1
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)nccc21
Temperature: 70 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
A 250 mL round-bottomed flask, under nitrogen, fitted with a thermometer probe and a condenser/inert gas bubbler (via a Claisen head), was charged with a solution of 1-benzenesulfonyl-1H-pyrrolo[3,2-c]pyridine 5-oxide (3.5 g, 12.8 mmol) in acetonitrile (50 mL) and dioxane (50 mL). To this solution was added dropwise phosphorus oxybromide (12 g, 40.9 mmol) and the resulting mixture was stirred at 70° C. for 18 h. The precipitate formed was removed by filtration and washed several times with dioxane. The solution was concentrated in vacuo and partitioned between DCM, water and brine. The organic layer was isolated then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PCC, 0-20% EtOAc in cyclohexane) to give the desired product (3.1 g, 72%). 1H NMR (CDCl3, 300 MHz): δ 8.23 (d, J=5.7 Hz, 1 H); 7.94-7.85 (m, 3 H); 7.67-7.59 (m, 2 H); 7.55-7.48 (m, 2 H); 6.75 (dd, J=3.7, 0.8 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])N.[CH3:10][N:11]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]1=[O:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[C:12]([N:11]([CH3:10])[C:15](=[O:16])[CH:14]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CN1C(=O)C=CC1=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CN1C(=O)C=C(c2ccc(Cl)c(Cl)c2)C1=O

Procedure:
A 162 g portion of 3,4-dichloroaniline was reacted with 111 g of N-methylmaleimide as described in Example 6, giving 112 g of 2-(3,4-dichlorophenyl)-N-methylmaleimide.
Reaction SMILES: O.NN.C1(=O)[N:8]([C@@H:9]2[C:15](=[O:16])[NH:14][C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][CH2:10]2)C(=O)C2=CC=CC=C12.C(N(CC)CC)C.[C:32]1([C:38]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)Cl)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO>[C:32]1([C:38]([NH:8][C@@H:9]2[C:15](=[O:16])[NH:14][C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][CH2:10]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1(C)CCC[C@H](N2C(=O)c3ccccc3C2=O)C(=O)N1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(C)CCC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1
Reaction time: 72 h

Procedure:
Hydrazine monohydrate (4.59 ml., 94.6 mmol.) was added to a solution of (S)-hexahydro-6-phthalimido-2,2-dimethyl-2H-azepine-7-one [prepared as described in Example 66(e), 19.98 g., 68.76 mmol.]in methanol (250 ml.) at room temperature under argon. The resulting mixture was stirred for 72 hours then filtered to remove the white precipitate. The volatiles were evaporated and the residue was dissolved in methylene chloride (560 ml.) and filtered to remove additional precipitate. To this filtrate was added triethylamine (13.3 ml., 96.21 mmol.) followed by triphenylchloromethane (20.65 g., 74.07 mmol.) and the resulting mixture was stirred for 1.5 hours. Additional triphenylchloromethane (958 mg., 3.44 mmol.) was added and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, filtered and concentrated to give a pale yellow foam. Following a crystallization from ethyl acetate and hexanes, 7.47 g. of title product was obtained as off-white crystals. The mother liquor was concentrated and crystallized from ethyl acetate and pentane to give a second crop (8.02 g.) of title product. The mother liquor was concentrated and the residue was flash chromatographed (E Merck silica gel) eluting with 4.5:5.5 ethyl acetate/hexanes to give 6.0 g of title compound as a white foam. The combined yield of title product was 21.49 g.; m.p. 139°-140° C.; [α]D =+43.4° (c=0.37, methylene chloride). TLC (2:3 hexane:ethyl acetate) Rf =0.63.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.O1CCCC1>[Si:17]([O:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)Cc1ccc(CO)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CC(=O)O)s1
Reaction time: 0.33 h
Yield: 24 %

Procedure:
To a solution of 2-[5-(hydroxymethyl)-2-thienyl]acetic acid (500 mg, 2.91 mmol) and imidazole (415 mg, 6.11 mmol) was added tert-butyldimethylsilyl chloride (916 mg, 6.11 mmol) portionwise over 20 minutes. The resultant solution was stirred at room temperature for one hour, tetrahydrofuran (10 mL) was then added and the reaction mixture cooled in an ice-bath. A solution of potassium carbonate (500 mg, 3.62 mmol) in water (10 mL) was added and the reaction mixture stirred for 20 minutes. The reaction solution was diluted with ethyl acetate (30 mL) and washed with brine (2×30 mL). The organic phase was dried over magnesium sulfate, filtered and concentration in vacuo. The residue was purified by silica gel chromatography, eluting with 0-50% ethyl acetate in iso-hexane to give the title compound as a yellow oil (200 mg, 24%) which was used in the next step without further purification.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][CH:30]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][C:34]=2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].NN>C1COCC1.CO>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][CH:30]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][C:34]=2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cn1ncc(-c2ccccc2)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ncc(-c2ccccc2)c1-c1csc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)c1
Reaction time: 12 h

Procedure:
To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (crude from part a) in THF-MeOH (1:1, 10 mL) was added hydrazine (384 uL, 12 mmol). After 12 h, the solution was filtered and the filtrate was concentrated, dry loaded onto silica and purified via column chromatography (2% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:14][CH:13]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccn1Cc1ccc(Cl)cc1

Procedure:
Ethyl 1H-imidazole-2-carboxylate (4 g, 28.5 mmol), p-chlorobenzylchloride (4.38 mL, 34.3 mmol), and sodium carbonate (3.63 g, 34.3 mmol), was dissolved in DMF (8 mL). The solution was stirred at rt for 24 h, at which time water was added and material was extracted with EtOAc. The organic phase was collected, dried over magnesium sulfate, and decanted. Purification accomplished via silica gel flash chromatography (150 g silica, 10% EtOAc/Hexanes to 80% EtOAc/Hexanes.) The title compound was obtained as a clear, yellow-tinted oil. (Yield: 7.28 g, 27.5 mmol, 96%) 1H NMR (400 MHz, CDCl3) 7.25, 7.15, 7.10-7.00, 5.55, 4.34, 1.36
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29]C4C=CC([N+]([O-])=O)=CC=4)=O)[CH2:23][CH2:22]3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C(O)C>[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([NH:1][NH2:2])=[O:29])[CH2:23][CH2:22]3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:6]
Reactant: NN
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)Oc4ccc([N+](=O)[O-])cc4)CC3)cn2)cc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)NN)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Hydrazine (0.140 mL, 4.45 mmol) was added to a mixture of 4-nitrophenyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (456 mg, 0.89 mmol) in ethanol (30 mL) at ambient temperature. The mixture was stirred at ambient temperature overnight. The mixture was charged with additional ethanol (30 mL) and hydrazine (5 mL, 159 mmol), stirred at reflux until homogeneous (15 min), then at ambient temperature overnight. The mixture was concentrated to dryness, charged with 4:1 EtOH:CH2Cl2 and MP-Carbonate (8 g). The mixture was stirred at ambient temperature for 2 h, filtered, washed with 4:1 EtOH:CH2Cl2, and the filtrate was concentrated to give 352 mg (98%) of 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarbohydrazide as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.43 (d, 1H, J=2.9 Hz), 8.28 (d, 2H, J=8.6 Hz), 8.06 (d, 1H, J=8.9 Hz), 7.99 (d, 2H, J=8.6 Hz), 7.61 (bs, 1H), 7.54 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.03-3.92 (m, 4H), 3.84 (d, 2H, J=3.2 Hz), 3.25 (s, 3H), 2.74-2.64 (m, 2H), 2.05-1.88 (m, 1H), 1.79-1.67 (m, 2H), 1.23-1.09 (m, 2H); LRMS (ESI), m/z 405 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28]C(=O)C.[Br:32]C1C=C2C(=CC=1)NC=C2CC(O)=O.ClC1C=C(C=C(Cl)C=1N)CN>>[NH2:28][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([CH2:8][NH:9][C:10]([NH:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Br:32])[CH:21]=3)[NH:16][CH:15]=2)=[NH:26])=[CH:5][C:4]=1[Cl:27]
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: NCc1cc(Cl)c(N)c(Cl)c1
Product: N=C(NCc1cc(Cl)c(N)c(Cl)c1)NC(=O)Cc1c[nH]c2ccc(Br)cc12

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-bromo-1H-indol-3-yl)acetic acid in step 17 (A) and 3,5-Dichloro-4-aminobenzylamine (preparation A) in step 17 (B), the title compound was prepared. MS (ESI) (M+H)+=467.90/469.86/471.83 1H-NMR (500 MHz, CD3OD) δ 7.71 (s, 1 H), 7.32 (m, 2 H), 7.16-7.28 (m, 3 H), 4.35 (s, 2 H), 3.93 (s, 2 H).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].[CH2:28]([S:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CN(C)C=O.ClCCl>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:34][CH2:33][CH2:32][CH2:31][S:30][CH2:28][CH3:29])=[C:3]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Reactant: CCSCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCSCCCNc1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 2.75 h
Yield: 86 %

Procedure:
To a solution of 5-bromo-1(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonylpyrazole (5.0 g, 9.7 mmol) in 1,4-dioxane (20 ml) and N,N-dimethylformamide (20 ml) was added 3-ethylthiopropylamine (2.306 g, 19.3 mmol) and potassium carbonate (2.7 g, 19.3 mmol). The resulting mixture was stirred at 20° C. for 2.75 hours, left to stand overnight, then poured into a mixture of water and dichloromethane. The organic phase was washed with water, dried (sodium sulfate), evaporated and chromatographed on silica gel, eluting with heptane-ethyl acetate (4:1) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-(3-ethylthiopropylamino)-4-trifluoromethylsulfonylpyrazole as a yellow solid (Compound number 1-14, 4.79 g, 86% yield), mp 80° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:7]2.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C=O.O>[C:19]1([S:25]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=3)[CH:7]=[C:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1ccc2[nH]c(-c3ccccc3)cc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (in oil, minimum 55%, 801 mg) in N,N-dimethylformamide (30 mL) was added dropwise a solution of 5-bromo-2-phenylindole (3.33 g) in N,N-dimethylformamide (30 mL) under cooling with ice and under an argon atmosphere, and the mixture was stirred at room temperature for one hour and a half. Then benzenesulfonyl chloride (1.88 mL) was added dropwise and the stirring was continued for additional 17 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.87 g).
Reaction SMILES: C(OC([N:11]1[CH2:17][C:16]2[CH:18]=[C:19]([O:25][CH3:26])[C:20]([N+:22]([O-])=O)=[CH:21][C:15]=2[NH:14][C:13](=[O:27])[CH2:12]1)=O)C1C=CC=CC=1>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:22][C:20]1[C:19]([O:25][CH3:26])=[CH:18][C:16]2[CH2:17][NH:11][CH2:12][C:13](=[O:27])[NH:14][C:15]=2[CH:21]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2c(cc1N)NC(=O)CNC2
Reaction time: 18 h
Yield: 58.9 %

Procedure:
A solution of 7-methoxy-8-nitro-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester (380 mg, 1.0 mmol) in ethyl acetate (50 mL) and ethanol (50 mL) was treated with 10% Pd on carbon (50 mg) and placed on a Paar shaker under an atmosphere of hydrogen gas (50 psi). After 18 hours LCMS indicated completion of reaction. The mixture was filtered and concentrated to give 8-amino-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (122 mg, 53%) as a tan solid, used without further purification; 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 6.64 (s, 1H), 6.33 (s, 1H), 4.72 (s, 2H), 3.72 (s, 3H), 3.67 (s, 2H), 3.19 (s, 2H); MS (m/e) 208 (M+1); mp 196° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)#[CH:32]>>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:27])([CH3:29])[CH3:28]
Reactant: C#CC1CCCC1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Product: Cc1cc2ccc(C#CC3CCCC3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(cyclopentylethynyl)-3-methylnaphthalen-2-yl)acetic acid (74) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using ethynylcyclopentane.
Reaction SMILES: [Li+].[OH-].[CH2:3]1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[C:41](F)[CH:40]=3)=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1.Cl>C(Cl)Cl.O.CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[C:41]([CH3:3])[CH:40]=3)=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(F)c(F)c3)cc2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1cc(-c2ccc(NCc3ccc(Cl)cc3-c3ccc(C(=O)NCCC(=O)O)nc3)cc2)ccc1F
Temperature: 25 °C

Procedure:
A 1M aqueous solution of LiOH (2.0 mL, 2.0 mmol) was added to a THF (2.0 mL) and MeOH (0.5 mL) solution of ethyl 3-(5-(5-chloro-2-(((3′,4′-difluoro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (32 mg, 0.06 mmol) and the resulting mixture was stirred at room temperature. After 1 h the resulting mixture was neutralized with 2M aqueous HCl, diluted with DCM and water and the layers were separated. The aqueous layer was extracted with DCM and the combined extracts were dried (Na2SO4), and concentrated. The product was dissolved in Et2O (5-7 mL) and then added to heptane (25 mL). The resulting mixture was contracted slowly to about half volume (15 mL). The solid was collected by filtration, washed with heptane (3 mL×2) and dried in vacuo to yield the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[O:17][CH3:18])(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:9]([O:17][CH3:18])[CH:10]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCOC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1OCCOC(C)=O
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A suspension of 2-(2-methoxy-4-nitrophenoxy)ethyl acetate (1.5 g, 5.9 mmol) and Pd/C (Aldrich, 10%, 0.2 g) in ethyl acetate (19 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 2 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give acetic acid 2-(4-amino-2-methoxy-phenoxy)-ethyl ester as a light brown oil (1.32 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH2:44][O:45][CH2:46][CH:47]=2)=[CH:38][C:37]=1[CH3:48].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[O:45]1[CH2:46][CH:47]=[C:43]([C:39]2[CH:38]=[C:37]([CH3:48])[C:36]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[C:10]4[C:6]=3[CH2:7][CH2:8][C@H:9]4[O:11][C:12]3[CH:25]=[CH:24][C:15]4[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=4[CH:13]=3)=[C:41]([CH3:42])[CH:40]=2)[CH2:44]1
Reactant: Cc1cc(C2=CCOC2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C6=CCOC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydro-benzofuran-3-yl)acetate and 3-(4-bromo-3,5-dimethylphenyl)-2,5-dihydrofuran following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.26 min; Mass spectrum (ESI+): m/z=515 [M+H]+.