Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1([CH:7]([O:9][CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:21](=[O:22])[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:26][CH:25]=4)=[C:19]([CH2:38][CH2:39][CH3:40])[N:18]4[N:41]=[CH:42][N:43]=[C:17]34)[CH2:12][CH2:11]2)[CH3:8])[CH2:6][CH2:5][CH2:4]1)=[O:2].[CH3:44][Mg]Br.O1CCCC1.Cl>O1CCCC1>[C:1]([C:3]1([CH:7]([O:9][CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:21](=[O:22])[C:20]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([C:30]5[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:28][CH:29]=4)=[C:19]([CH2:38][CH2:39][CH3:40])[N:18]4[N:41]=[CH:42][N:43]=[C:17]34)[CH2:12][CH2:11]2)[CH3:8])[CH2:6][CH2:5][CH2:4]1)(=[O:2])[CH3:44]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OC(C)C3(C=O)CCC3)CC2)c2ncnn12
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OC(C)C3(C(C)=O)CCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-[(4-{4-[1-(1-formylcyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (10.35 g) in tetrahydrofuran (50 mL) was added 1 M methylmagnesium bromide-tetrahydrofuran solution (27 mL), and the mixture was stirred at room temperature for 15 hr. 1 N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the residue in acetonitrile (200 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (8.48 g), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→60/40 (volume ratio)] to give the title compound as a colorless amorphous compound (8.32 g, 79%).
Reaction SMILES: C(O[CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].Cl>CO.O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14]([CH:5]=[CH:6][CH2:7][CH:8]2[CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CCC2OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)C(CCNC(C)=O)CC=C2
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of the compound obtained in Step D (261 mg, 0.86 mmol) in a mixture of methanol/water (2/0.2 mL) at ambient temperature there is added sodium hydroxide (86 mg, 2.14 mmol). The mixture is stirred for 1 hour under reflux, and the solution is then cooled. Hydrochloric acid (2.6 mL, 2.6 mmol, 1N) is added and the mixture is stirred overnight. The aqueous phase is extracted with dichloromethane, and the organic phases are washed with saturated NaCl solution, dried over magnesium sulphate, filtered and evaporated. The title compound is obtained after purification by flash column chromatography (ethyl acetate-petroleum ether: 90-10, then ethyl acetate-methanol: 90-10) in the form of an oil in a yield of 61%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:41]=[CH:40][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[CH2:2][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:40][CH:41]=1
Reactant: Cc1oc(-c2cccs2)nc1CCl
Reactant: CCOC(=O)CCCCCC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3cccs3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
A mixture of 4-(chloromethyl)-5-methyl-2-(2-thienyl)oxazole (368 mg), ethyl E-8-(4-hydroxybenzyloxyimino)-8-phenyloctanoate (600 mg), potassium carbonate (432 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-8-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoate (762 mg, yield 95%) as a colorless oil from an ethyl acetate-hexane (1:5, v/v)-eluted fraction.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[CH:3]=1.[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O.Cl.[OH-].[Na+]>>[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][S:8][C:6]1[NH:5][C:4](=[O:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Reactant: CN(C)c1ccccc1CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)[nH]c(SCc2ccccc2N(C)C)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
A mixture containing 0.71 g (5 mmol) of 6-methyl-2-thiouracil, 0.76 g (5 mmol) of 2-dimethylaminobenzyl alcohol (J. Chem. Soc. 1954, 4127) and 5 ml of concentrated hydrochloric acid is stirred at 60° C. for 3 hours, then cooled and made alkaline by adding 5N sodium hydroxide solution under cooling by ice. The mixture is extracted 3 times with 20 ml of chloroform each. After combining the organic phase is washed with sodium carbonate solution and then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue is twice recrystallized from ethyl acetate to yield 0.59 g (43%) of the title compound, m.p.: 151°-153° C.
Reaction SMILES: C1([C@H]([N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=3)[CH2:10]2)C)C=CC=CC=1.C([O-])=O.[NH4+].O1CCCC1.CO>[Pd].O>[NH:9]1[CH2:14][CH2:13][O:12][C@@H:11]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=2)[CH2:10]1
Reactant: CC(=O)Nc1ccc([C@H]2CN([C@H](C)c3ccccc3)CCO2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc([C@H]2CNCCO2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 131.2 %

Procedure:
To a solution of N-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)acetamide (6.47 g, 20 mmol) and ammonium formate (6.3 g, 100 mmol) in mixture of tetrahydrofuran (136 ml), methanol (270 ml) and water (70 ml) was added 10% palladium on carbon (wet, 270 mg) and the solution was stirred at 95° C. for 3 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give N-(4-((2S)-morpholin-2-yl)phenyl)acetamide (5.78 g, quant.) as an yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)=[CH:4][CH:3]=1.[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.CI.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH:13]([CH3:25])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)=[CH:4][CH:3]=1
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a solution of 6-(4-chlorophenyl)-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (100 mg, 0.31 mmol) in THF was added LiHMDS (0.17 mL, 0.33 mmol) at −78° C. The mixture was stirred at the same temperature for 1 h, and then CH3I (84.00 mg, 0.59 mmol) was added. The mixture was stirred at −78° C. for 2 h, then warmed to room temperature, and maintained at room temperature for 2 h. NH4Cl aqueous (15 mL) was added, and then extracted with DCM (10 mL*3). The product was purified by column chromatography (silica-gel, DCM:MEOH=30:1) to give 6-(4-chlorophenyl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (40.0 mg, 38%). LRMS (M+H+) m/z: calcd 338.09. found 338.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1)=[O:4].C(OO)(=O)C1C(=CC=CC=1)C(O)=[O:36].[Mg]>CCO.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])[CH:11]1[CH2:16][CH2:15][S:14](=[O:36])[CH2:13][CH2:12]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCSCC1
Reactant: O=C(O)c1ccccc1C(=O)OO
Agent: [Mg]
Solvent: CCO
Solvent: O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCS(=O)CC1
Reaction time: 24 h

Procedure:
To a stirred solution of 3-[(trans-4-methyl-cyclohexanecarbonyl)-(tetrahydro-thiopyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (57 mg, 0.124 mmol) in EtOH (1.2 mL) from step 2 was added magnesium monoperoxyphthalic acid (29.6 mg, 0.06 mmol) in one portion, stirred for 24 h. Reaction mixture was diluted with water, extracted with EtOAc. The combined organic solution was washed with brine, dried, and concentrated. Purification of the residue on Preparative TLC using 5% MeOH-DCM gave 3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-oxo-tetrahydro-thiopyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (30 mg, 51%). NMR 1H (CDCl3, 400 MHz, For major isomer): 7.66-7.6 (m, 2H), 7.5-7.4 (m, 3H), 7.09 (s, 1H), 4.84-4.76 (t, 1H), 3.85 (s, 3H), 3.4-1.2 (m), 0.772 (d, J=6.6, 3H), 0.74-0.56 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[CH:24]=O.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:24]([C:23]3[CH:26]=[CH:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:29][C:22]=3[CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Cc1cc(N2CCOCC2)ccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1cc(N2CCOCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 34.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 2-Methyl-4-morpholin-4-yl-benzaldehyde (38.4 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to produce 28.37 mg (35%) of the title compound. (300 MHz, DMSO-d6) 12.83 (s, 1H), 7.91 (s, 1H), 7.72 (m, 2H), 7.21 (s, 1H), 7.00 (d, J=9 Hz, 1H), 6.90 (s, 2H), 6.33 (s, 1H), 6.26 (s, 1H), 5.18 (t, J=17 Hz, 9 Hz, 1H), 3.75 (s, 4H), 3.22 (s, 4H), 2.86 (s, 1H), 2.75 (s, 1H), 2.59 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz). MS=479 (M+H), HPLC: 2.42 min. (G Method)
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1[O:18][CH3:19].C[O:21][B:22](OC)[O:23]C.Cl>O1CCCC1.O>[CH3:19][O:18][C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:12][C:7]=1[B:22]([OH:23])[OH:21]
Reactant: COB(OC)OC
Reactant: COc1ccc(OC(F)(F)F)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6M in hexanes, 3.8 mL, 6 mmol) was added dropwise to a cooled (−78° C.) solution of 2-bromo-1-methoxy-4-(trifluoromethoxy)benzene (Description 16, 1.5 g, 5.5 mmol) in tetrahydrofuran (prefiltered through alumina, 18 mL) [internal temperature <−70° C.]. The mixture was stirred at −78° C. for 15 min., then trimethylborate (2 mL, 17.6 mmol) was added dropwise [internal temperature <−70° C.]. The mixture was stirred at −78° C. for 30 min., then hydrochloric acid (1M, 6 mL) was added. The mixture was warmed to room temperature and stirred for 30 min. Water (25 mL) was added and the mixture was extracted with ethyl acetate (2×40 mL). The combined organic fractions were washed with water (20 mL) and brine (20 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried in vacuo at 40° C. to give the title compound as an off white solid (366 mg, 28%). 1H NMR (360 MHz, CDCl3) δ3.93 (3H, s), 5.84 (2H, s), 6.90 (1H, d, J 9.0 Hz), 7.29 (1H, m) and 7.70 (1H, J 2.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22][CH2:23]O)[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:23][CH2:22][CH2:21][CH2:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCCCc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OCCCCc2cccnc2)cc1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.14 g), 3-pyridinebutanol (1.04 g), triphenylphosphine (2.07 g), and tetrahydrofuran (25 mL) was stirred at 0° C. while adding dropwise a solution of diethyl azodicarboxylate (1.37 g) in tetrahydrofuran (10 mL). The mixture was stirred for 2 hours at 0° C. and evaporated to dryness. The material was purified by HPLC (hexane-acetone; 2:1) to provide 1.4 g of alpha-oxo-4-[4-(3-pyridinyl)butoxy]benzeneacetic acid methyl ester (4:1) molar hydrate as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([Br:17])[CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].Cl[CH2:19][C:20]#[N:21]>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:19][C:20]#[N:21])[C:10]2[C:15]([CH:16]=1)=[C:14]([Br:17])[CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2c(Br)cccc2[nH]1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Br)cccc2n1CC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
Sodiumhydride (4.0 g, 92 mmol) was suspended in dimethylformamide (20 mL) and a solution of 4-bromo-1H-Indole-2-carboxylic acid ethyl ester (16.4 g, 61 mmol) in dimethylformamide (70 mL) was added. The mixture was stirred for 1 h at room temperature and after cooling to 0° C. chloroacetonitrile (7.7 mL, 122 mmol) was added. After 1 h at room temperature the mixture was added to an ice/water mixture (800 mL) and extracted with ethylacetate. The organic phases were pooled washed with brine, dried with MgSO4 and the solvent was removed in vacuo. Chromatography on silica gel (ethyl acetate/n-hexane 4:1) yielded 4-bromo-1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (13.4 g, 71%) as a colorless solid, MS: m/e=306.0 (M+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25](Br)[CH:24]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O(C1C=C(CC(NCC2C=C(C3C=CC=CC=3C(F)(F)F)C=CC=2)(O)C(F)(F)F)C=CC=1)C1C=CC=CC=1>CCO.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.O.CN(C=O)C.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:24]=[C:25]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]([F:42])([F:41])[F:30])[CH:26]=[CH:27][CH:28]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: OC(CN(Cc1cccc(Br)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
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: OC(Cc1cccc(Oc2ccccc2)c1)(NCc1cccc(-c2ccccc2C(F)(F)F)c1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: OC(CN(Cc1cccc(-c2ccccc2C(F)(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F

Procedure:
To a toluene (8 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol (0.51 g, 1.1 mmol) from EX-595B was added 2-(tri-fluoromethyl)phenylboronic acid (0.33 g, 1.7 mmol) and DMF (3 mL). To the resulting solution was added K2CO3 (0.31 g, 2.2 mmol) and Pd(PPh3)4 (0.060 g, 0.05 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.32 g (55%) of the desired 3-[(3-phenoxyphenyl)[[(2′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]methyl]amino]-1,1,1-tri-fluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H23NO2F6.0.8 EtOH C, 64.67; H, 4.93; N, 2.46. Found: C, 64.53; H, 4.69; N, 2.49. HRMS calcd. 532.1711 [M+H]+, found: 532.1708. 1H NMR (C6D6) δ 1.72 (d, 1H), 3.17 (dd, 1H), 3.46 (dd, 1H), 3.72 (m, 1H), 4.23 (s, 2H), 6.33 (dd, 1H), 6.43 (dd, 1H), 6.52 (t, 1H), 6.82 (m, 2H), 6.9-7.1 (m, 11H), 7.43 (d, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[O:8][C:9]2[C:15]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]3=[O:28])=[C:14]([F:29])[CH:13]=[C:12]([Cl:30])[C:10]=2[N:11]=1)(=[O:5])[CH3:4].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>O1CCCC1>[C:3]([N:6]([C:7]1[O:8][C:9]2[C:15]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[N:18]([CH3:27])[C:17]3=[O:28])=[C:14]([F:29])[CH:13]=[C:12]([Cl:30])[C:10]=2[N:11]=1)[S:32]([CH3:31])(=[O:34])=[O:33])(=[O:5])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(c1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1)S(C)(=O)=O
Reaction time: 1 h

Procedure:
A stirred suspension of 2.0 grams (51 mmole) of 60% sodium hydride (in mineral oil) in 25 mL of tetrahydrofuran is cooled in an ice bath. To this is added a solution of 10.2 grams (25.5 mmole) of 3-(2-acetylamino-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione in 25 mL of tetrahydrofuran. Upon completion of the addition 2.9 grams (25.3 mmole) of methanesulfonyl chloride is added. The reaction mixture is heated to reflux, where it stirs for one hour and then concentrated under reduced pressure, yielding 3-[2-(N-acetyl-N-methylsulfonylamino)-4-chloro-6-fluorobenzoxazol-7-yl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C1CNC(=O)C1.[Br:18][Br-]Br>C1COCC1>[CH:4]([C:2]([CH2:1][Br:18])=[O:3])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)C=Cc1ccccc1
Agent: O=C1CCCN1
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)CBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.8 %

Procedure:
To a solution of styryl methyl ketone (5.0 g, 34.2 mmol) in dry THF (80 mL) at room temperature under nitrogen is slowly added a solution of pyrrolidone hydrotribromide (20.3 g, 40.9 mmol) in dry THF (120 mL) in 1 hr. The mixture is continued to stir at room temperature for 24 hrs. Excess pyrrolidone hydrotribromide is removed by filtration. The filtrate is concentrated to dryness. The resulting residue is dissolved in Et2O, washed with brine and dried (Na2SO4). Removal of the solvents affords a crude product, which is chromatographed on silica gel eluting with Et2O-hexanes (1:6) to give bromomethyl styryl ketone (5.91 g, 77%) as colorless crystals (from Et2O), 1H NMR (400 MHz, CDCl3) d 7.70 (1H, d, J=16.0 Hz, β-CH═), 7.58 (2H, m, Ph), 7.43 (3H, m, Ph), 6.95 (1H, d, J=16.0 Hz, a-CH═), 4.11 (2H, s, CH2Br); 13C NMR (100 MHz, CDCl3) d 191.1 (s, C═O), 145.4 (d, β-CH═), 134.0 (s, Ph), 131.2 (d, Ph), 129.1 (2C, d, Ph), 128.7 (2C, d, Ph), 122.3 (d, a-CH═), 33.3 (t, CH2Br).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([CH3:19])=[C:17]3[C:12]([C:13]([NH:21][CH3:22])=N[N:15]=[C:16]3[CH3:20])=[C:11]2[CH3:23])=[CH:6][CH:5]=1)[CH3:2].CNN.C[OH:28]>CC(O)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([CH3:19])=[C:17]3[C:12]([C:13](=[O:28])[N:21]([CH3:22])[N:15]=[C:16]3[CH3:20])=[C:11]2[CH3:23])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CO
Reactant: CCOc1ccc(-n2c(C)c3c(C)nnc(NC)c3c2C)cc1
Agent: CNN
Solvent: CC(=O)O
Product: CCOc1ccc(-n2c(C)c3c(C)nn(C)c(=O)c3c2C)cc1
Temperature: 70 °C

Procedure:
A solution of ethyl-4-acetyl-1-(4-ethoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (prepared as in EXAMPLE 85) (70 mg, 0.20 mmol) and MeOH (5 mL) in a resealable reaction vessel was mixed with methylhydrazine (0.032 mL, 0.60 mmol) and AcOH (˜3 drops). The vessel was sealed and heated at 70° C. for 12 h. The resulting slurry was allowed to cool to rt and poured into ice water (50 mL). The resulting white solid was filtered and dried under vacuum for 8 h to give 6-(4-ethoxyphenyl)-2,4,5,7-tetramethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one: 1H NMR (CDCl3, 500 MHz) δ 7.00-7.26 (m, 4H), 4.10 (q, 2H), 3.71 (s, 3H), 2.49 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H), 1.48 (t, 3H); MS (ESI) 312 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1>CN(C)C=O>[CH:17]1([CH2:20][N:14]2[CH2:15][CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:10][CH2:11][CH2:12][C:13]2=[O:16])[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: O=C1CCCC(c2ccccc2)CN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCC(c2ccccc2)CN1CC1CC1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.793 g, 19.8 mmol) was added to a solution of 6-phenylazepan-2-one (2.50 g, 13.2 mmol) and cyclopropylmethyl bromide (1.92 mL, 19.8 mmol) in N,N-dimethylformamide (30 mL) at 0° C. and then warmed to ambient temperature. After 18 h the mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water (3×) and saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) gave the title compound (2.33 g). MS 244 (M+1).