Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:21](=O)[C:22](=CN(C)C)[C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH:28][CH2:29][CH2:30][N:31]([C:33](OC(C)(C)C)=O)[NH2:32]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:33]5[N:31]([CH2:30][CH2:29][OH:28])[N:32]=[CH:21][C:22]=5[C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N(N)CCO
Reactant: CN(C)C=C1C(=O)CCc2c1sc1ncnc(Nc3ccc(F)c(Cl)c3)c21
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-8-dimethylaminomethylene-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one (10.6 g, 0.026 mol) was heated to near homogeneity in dioxane (250 mL). The heat was turned off and nitrogen was bubbled through the murky solution for ˜20 min while it cooled. The reaction flask was then evacuated and filled with nitrogen three times. In a separate flask, tert-butyl 1-(2-hydroxyethyl)hydrazinecarboxylate (13.9 g, 0.079 mol) was dissolved in toluene, concentrated in vacuo to a residue, redissolved in dioxane, and sparged with nitrogen for ˜10 minutes. The solution of tert-butyl 1-(2-hydroxyethyl)hydrazinecarboxylate was evacuated and filled with nitrogen three times and then was cannulated into the flask containing the enamine. The resulting mixture became a clear red solution upon heating in an oil bath at ˜80° C. After 6 h the reaction mixture was concentrated in vacuo to half its original volume. Xylenes (250 mL) was added and the mixture was again concentrated to half the original volume. Xylenes (250 mL) was added and the mixture was concentrated to half the original volume a final time. During the solvent swap, a yellow-orange solid precipitated. The resulting slurry was submerged in an ice-bath and TFA (200 mL) was added dropwise via an addition funnel. The slurry became a brown-red solution that was allowed to stir overnight at room temperature. Two liquid phases were present the next morning. Solvent (˜200 mL) was removed in vacuo at ˜40° C. The remaining mixture (˜300 mL) was diluted with EtOAc (500 mL) and washed twice with 500 mL portions of 1.0 N NaOH. Significant emulsions formed during the final base wash, so more EtOAc (500 mL) was added with brine (100 mL) before collecting the aqueous layer. The organic layer was then washed with brine (2×300 mL). The organic layer was filtered through a small pad of silica gel (˜1″ diameter×2″) and the pad was washed with EtOAc (750 mL). The filtrate was concentrated to a total volume of ˜200 mL, resulting in the precipitation of solid. The slurry was filtered by vacuum filtration on a Buchner funnel and the resulting solid was allowed to dry overnight on the filter. An orange solid was obtained (7.25 g, 66%, >98% regioisomeric purity by 1H-NMR). 1H NMR (DMSO-d6) δ 8.56 (s, 1H), 8.38 (s, 1H), 7.88 (m, 1H), 7.66 (s, 1H), 7.61 (m, 1H), 7.40 (t, 1H), 4.93 (t, 1H), 4.16 (t, 2H), 3.73 (dt, 2H), 3.42 (t, 2H), 3.10 (t, 2H); LCMS RT=2.76 min; [M+H]+=416.4.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:55][CH2:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58]>CN(C)C=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C(N(CC)CC)C>[NH:1]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:55][CH2:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
The Boc-Gly-Phe-Leu-OH obtained in Example 18 (2.4 g) and N-hydroxysuccinimide (656 mg) were dissolved in N,N-dimethylformamide (50 ml), cooled to 4° C., and then added with N,N′-dicyclohexylcarbodiimide (1.17 g), and stirred for 2 hours. To this solution, a N,N-dimethylformamide solution (40 ml) in which tosylate of H-Gly-OBzl (1.9 g) and triethylamine (0.79 ml) had been dissolved was added, and the mixture was allowed to react with stirring at room temperature for 16 hours. This reaction mixture was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=50:1 solution) to give the title compound (2.0 g).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](Cl)=[O:19])([CH3:14])([CH3:13])[CH3:12]>COCCOC>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:18](=[O:19])[C:17]1[CH:21]=[C:22]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:23]([OH:24])=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:16]=1)([OH:10])=[O:9]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: Nc1ccccc1C(=O)O
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccccc2C(=O)O)cc(C(C)(C)C)c1O
Temperature: 75 °C
Reaction time: 48 h
Yield: 48.1 %

Procedure:
A solution of 8.6g (0.063 mole) of anthranilic acid in 50 ml of 1,2-dimethoxyethane was added to a suspension of 8.0g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 150 ml of 1,2-dimethoxyethane. The reaction mixture was heated at approximately 75° C. for 30 minutes after which time it was stirred for 48 hours at room temperature. The reaction mixture was then filtered, and the filtrate was evaporated to give the crude product as an oil. This oil was triturated with a mixture of ethanol and water to give a solid which was recrystallized twice from a mixture of ethanol and water to give 5.3 g of white crystalline N-(2-carboxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 202°-203° C. Analysis: Calculated for C22H27NO4 ; %C, 71.5; %H, 7.4; %N, 3.8; Found: %C, 71.4; %H, 7.5; %N, 3.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](O)=[O:7].S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([Cl:17])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Yield: 99.6 %

Procedure:
A heterogeneous mixture comprising 3-methoxy-4-nitrobenzoic acid (15.42 g, 78.2 mmol) and thionyl chloride (70 mL, 391 mmol) was heated at reflux for one hour. The excess thionyl chloride was removed by distillation and the residue was concentrated in vacuo to provide 3-methoxy-4-nitrobenzoyl chloride (16.8 g, 99% yield) as a light yellow solid; MS (PB-PCI) C8H6CINO4 m/e calc 215.59; found 216 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)=[O:18])=[CH:23][CH:22]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCc1cc(-c2ccc(C(=O)O)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(=O)NCc3ccc(C(F)(F)F)cc3)s2)c(C)[nH]c1=O
Yield: 75 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-carboxylic acid and 4-trifluoromethyl-benzylamine to afford the title compound (75% yield). LC/MS: RT 3.15 min; m/e 421 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 4-chloro phenyl isocyanate (0.041 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 49 as a colorless solid (0.052 g, 42%). LCMS m/z (%)=463 (M+H+79Br, 35Cl, 41), 465 M+H+ (81Br35Cl 88), 467 H+ (81 Br 37Cl, 21), 1H NMR (400 MHz, acetone-d6) δ: 8.30 (bs, 1H), 8.24 (bs, 1H), 7.685 (d, J=2.66 Hz, 1H), 7.577 (d, J=1.92 Hz, 2H), 7.74 (d, J=2.65, 1H), 7.292 (d, J=1.9 Hz, 2H), 7.280 (d, J=1.6 Hz, 1H), 7.135 (d, J=9.01 Hz, 1H), 4.256 (m, 1H), 3.811 (s, 3H), 1.447 (d, J=6.61 Hz, 3H), 1.288 (d, J=6.61 Hz, 3H).
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1.O>O1CCOCC1>[CH:5]([NH:8][C:11](=[O:10])[C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[N:14][CH:13]=1)([CH3:7])[CH3:6]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ccc(C(=O)NC(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.25 mL, 2.0 mmol) was added dropwise (exothermic) to a solution of isopropylamine (210 μL, 2.0 mmol) in dioxane (6 mL) and the resulting mixture was stirred at room temperature for 1 h. Then 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (200 mg, 0.62 mmol) was added. The resulting mixture was then heated at 90° C. for 2 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:4) afforded the title compound (170 mg, 78%) which was obtained as a white solid after trituration from diisopropylether/ethyl acetate. MS: m/e=348.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].[CH:28](Br)([CH3:30])[CH3:29].O>CN(C)C=O>[CH:28]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20])([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1sc(-c2ccc(O)c([N+](=O)[O-])c2)nc1C
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-c2ccc(OC(C)C)c([N+](=O)[O-])c2)nc1C
Temperature: 70 °C
Yield: 75.7 %

Procedure:
200 mg of Ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate prepared in (1) was dissolved in 3 ml of N,N-dimethylformamide, 540 mg of anhydrous potassium carbonate and 440 mg of isopropyl bromide were added thereto, and the mixture was heated at 70° C. for 18 hours. After the reaction mixture was cooled, 20 ml of water was added thereto. The mixture was extracted twice with 30 ml of ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and the solvent was removed by distillation. The resulting crystal was recrystallized from ethanol to give 172 mg of ethyl 2-(4-isopropoxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate. This product was hydrolyzed by a conventional process, and the resulting crystal was recrystallized from a 80% aqueous ethanol solution to give 135 mg of 2-(4-isopropoxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylic acid (yield:
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25])[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][C:23]1[C:24](=[O:25])[O:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:27]=1[OH:28])[CH3:15]
Reactant: CCc1ccccc1SC(C(=O)O)C(=O)O
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: CCc1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (4.17 g, 21.72 mmol) and diethyl ester of [(2-ethylphenyl)thio]propanedioic acid (1.5 g, 10.86 mmol). m.p. 190-192° C.; 1H NMR (400 MHz, DMSO-d6) δ1.25 (t, 3H), 2.78 (q, 2H), 6.89 (s, 1H), 6.92 (m, 1H), 7.08 (m, 2H), 7.2 (m, 1H), 7.58 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15]O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:18].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[Br:18][CH2:15][C:13]1[C:14]2[C:5]([CH:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2
Reactant: BrP(Br)Br
Reactant: OCc1c2ccccc2cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: BrCc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
To a stirring suspension of 9-anthracenemethanol (2.0 g, 9.6 mmol) at 0° C. in toluene (100 ml) was added PBr3 (1.2 mL, 12.51 mmol) and the suspension was stirred at 0° C. for 1 h. The reaction mixture was then brought up to room temperature and let to stir for further 1 h. The mixture turned into a yellow solution. K2CO3 (10 mL) was added to quench the reaction. Toluene was evaporated off in-vacuo. The residue was taken up in EtOAc and washed with saturated aqueous K2CO3, water and brine and dried (MgSO4). The solvent was evaporated off in-vacuo and the crude residue was purified by flash chromatography, eluting with hexane:EtOAc (2:1) to give 47 (1.4 g, 54%) as yellow solid. H1 NMR (500 MHz, CDCl3): δ=8.45 (1H, s, Ar-10H), 8.27 (2H, d, Ar-1, 8H), 8.00 (2H, d, Ar-4, 6H), 7.62 (2H, d, Ar-2, 7H), 7.48 (2H, d, Ar-3, H), 5.50 (2H, s, CH2).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].[NH2:16]C(N)=O>O>[NH2:16][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15]
Reactant: NC(N)=O
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Solvent: O
Product: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Temperature: 150 °C
Yield: 92.5 %

Procedure:
A mixture of 5-chloro-6-nitroisoindoline-1,3-dione (28.0 g, 0.123 mol) and urea (73.8 g, 1.23 mol) was stirred and heated to 150° C. under argon for 6 h. After cooled to rt, the solid was suspended in hot water (100 mL, 80° C.), filtered, washed with hot water (3×50 mL) and dried under vacuum to give a yellow solid product, 23.56 g, 92.5% yield.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[CH:9]1)(C)(C)C.[C:29]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:29][N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:28])[CH:9]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:26])=[O:27]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Cn1cc(C2NS(=O)(=O)c3ccccc32)c2ccccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(c2cn(CC(=O)O)c3ccccc23)c2ccccc2S1(=O)=O

Procedure:
The intermediate from example 1, step d (33 mg, 0.08 mmol) was dissolved in DMF (1 mL) and treated with K2CO3 (28 mg, 0.2 mmol) followed by methyl iodide. The reaction was heated to 70°-80° C. for 1 h. The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was washed several times with water then concentrated to dryness. The crude residue was then treated with TFA (2 mL) for 2 h. The reaction was concentrated and purified by preparative LCMS to give the title compound. 1H NMR (DMSO-d6) δ 8.22-8.20 (m, 1H), 7.88-7.85 (m, 2H), 7.81 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.40-7.35 (m, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 5.94 (s, 1H), 4.80 (s, 2H), 2.88 (s, 3H); MS: ESI (negative): 355 (M−H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:14]2=[N:15][CH:16]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:1]1([C:11]2[CH:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:21])=[O:22])[C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)cnc32)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(-c4ccccc4)cnc32)cc1

Procedure:
A mixture of phenyl boronic acid (1.74 g), 5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [5 g, Reference Example 9(d)], (tetrakis)tripyhenylphosphine palladium[0] (0.49 g) and saturated aqueous sodium bicarbonate solution (133 mL) and dimethylformamide (266 mL), under nitrogen, was heated at reflux temperature overnight. The reaction mixture was filtered through Hyflo and then evaporated. The residue was partitioned between ethyl acetate (50 mL) and water (25 mL) and the aqueous layer was extracted with ethyl acetate (25 mL). The combined organic phases were washed with water (25 mL), then with brine (20 mL), then dried over magnesium sulfate and then evaporated. The residue subjected to chromatography on silica eluting with a mixture of pentane and ether (1;1, v/v) to give the title compound as a white solid, mp. 151–152° C. MS: 335 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]2)[C:6]2[CH:24]=[C:25]([O:28][C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:27][C:5]=2[O:4][CH2:3]1.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:16][CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][N:7]2[C:6]3[CH:24]=[C:25]([O:28][C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:27][C:5]=3[O:4][CH2:3][C:2]2=[O:1])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(OC(F)(F)F)cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3ccc(OC(F)(F)F)cc32)CC1

Procedure:
tert-Butyl (1-{2-[3-oxo-6-(trifluoromethoxy)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)carbamate (Intermediate 62) (790 mg, 1.72 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6]C(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[C:51]([C:56](O)=[O:57])=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN>C1COCC1>[CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6][C:56]([C:51]1[C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:57]
Reactant: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: O=C(O)c1ccccc1-c1ccccc1CSCCOc1ccccc1
Agent: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccccc1-c1ccccc1CSCCOc1ccccc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (3-dimethylamino-propyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.7 g, 1.92 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.32 g, 1.96 mmol, 1.02 eq.) and 3-(dimethylamino)propylamine (0.30 g, 2.30 mmol, 1.2 eq.). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]([F:46])([F:45])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:14][N:15]([C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1)[C@H:16]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]2[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:25]([CH3:27])=[CH:26][C:17]1=2>C(O)(=O)C>[F:46][C:10]([F:45])([F:9])[C:11]1[CH:12]=[C:13]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:14][N:15]([C@H:16]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]2[C:23]([Br:1])=[C:24]([C:28]([F:29])([F:30])[F:31])[C:25]([CH3:27])=[CH:26][C:17]1=2)[C:32]1[N:33]=[N:34][N:35]([CH3:37])[N:36]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Cc1cc2c(c(Br)c1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
Add N-bromosuccinimide (1.10 g, 6.19 mmol) in one portion to a solution of (S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine (2.85 g, 5.16 mmol) (Example 3, Step 18) in acetic acid (25 mL) at room temperature. Stir for 2 hours. Evaporate the solvent under reduced pressure. Partition the residue between ethyl acetate (250 mL) and aqueous Na2CO3 (250 mL). Separate the layers, dry over Na2SO4, filter and concentrate. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-30%), to provide the title compound as an off-white solid (2.99 g, 92%). MS (ES+): 631, 633 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[F:19][C:18]([F:20])([F:21])[CH2:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:31])=[O:30])=[CH:9][CH:10]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:37]2[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Product: O=C(O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 552.2 [M−H]−.