Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:28][C:23]1[CH:22]=[C:21]([C:9]2([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:20])=[CH:17][C:11]=3[O:10]2)[CH:26]=[C:25]([Cl:27])[CH:24]=1
Reactant: O=C(O)c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2
Reactant: C1CCNCC1
Product: O=C(c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2)N1CCCCC1

Procedure:
This compound was prepared from 2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid and piperidine according to Example 269f; waxy solid, MS: m/e=([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[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].[C:31]1([CH3:40])[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH: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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:34]2[CH:35]=[CH:36][C:31]([CH3:40])=[CH:32][CH:33]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: CCN(c1cc(-c2ccc(C)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 73.2 %

Procedure:
To a stirred solution 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (200 mg, 0.42 mmol) and p-tolyl boronic acid (86 mg, 0.63 mmol) in dioxane (3 mL), aqueous 2M Na2CO3 solution (0.75 mL, 1.51 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (48 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (150 mg, 73%). LCMS: 488.20 (M+1)+; HPLC: 99.33% (@ 254 nm) (Rt; 5.393; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H), 7.51 (d, 2H, J=8 Hz), 7.37 (s, 1H), 7.25 (d, 2H, J=8 Hz), 7.19 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.81-3.83 (m, 2H), 3.22-3.27 (m, 2H), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.55 (m, 2H), 0.82 (t, 3H, J=6.8 Hz).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([CH:7]1[O:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=2[N:9]([CH:26]([CH3:28])[CH3:27])[C:8]1=[O:29])[OH:6])C.[OH-].[Na+].Cl>C(O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:10]2[N:9]([CH:26]([CH3:28])[CH3:27])[C:8](=[O:29])[CH:7]([CH:5]([OH:6])[C:4]([OH:30])=[O:3])[O:13][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:11]=2[CH:21]=1
Reactant: CCOC(=O)C(O)C1OC(c2ccccc2Cl)c2cc(Cl)ccc2N(C(C)C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N1C(=O)C(C(O)C(=O)O)OC(c2ccccc2Cl)c2cc(Cl)ccc21
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
In ethanol (8 ml) was dissolved (3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid ethyl ester (0.3 g) obtained in Example 1. To the solution was added 1N sodium hydroxide (2 ml), and the mixture was left standing for 20 minutes at room temperature. To the resultant mixture was added 1N hydrochloric acid (50 ml) to make the solution acid, followed by extraction with ethyl acetate (50 ml). The extract solution was washed with water, dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure to give (3RS,5SR,αSR)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid (0.26 g) as prisms, m.p. 245°-247° C. (decomp.).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].O>O1CCCC1>[Cl:8][C:7]1[C:2]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:3][C:4]([C:11]#[N:12])=[C:5]([C:9]#[N:10])[N:6]=1
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: CC(C)(C)N
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nc(C#N)c(C#N)nc1Cl
Reaction time: 2 h
Yield: 76.4 %

Procedure:
5.0 g (0.025 mol) of 2,3-dichloro-5,6-dicyanopyrazine was dissolved in 50 ml of dry tetrahydrofuran, and 25 ml of a dry tetrahydrofuran solution containing 3.7 g (0.050 mol) of tert-butylamine was dropwise added thereto at a temperature of from -15°to 0° C. After completion of the dropwise addition, the mixture was stirred for 2 hours, and the reaction solution was poured into 500 ml of water. The precipitated solid was collected by filtration and recrystallized from toluene to obtain 4.5 g of slightly yellow crystals (yield: 76.4%, melting point: 174°-176° C.).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]2([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:23]([F:29])[CH:24]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(F)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(F)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 88 %

Procedure:
In a manner similar to the method described in Example 1d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 65b (1 g, 2.1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 88%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](O)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.N>CN(C)C=O.O>[Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:24])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Reaction time: 0.5 h
Yield: 676.3 %

Procedure:
19.8 g (56.9 mmol) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 100 ml of N,N-dimethylformamide, treated at room temperature with 10.1 g (62.6 mmol) of 1,1'-carbonyldiimidazole and stirred at 70° for 30 minutes. 50 ml of 25% ammonia were added dropwise at 25°-30°. The reaction mixture was diluted with 50 ml of water and cooled to 0°, and the crystallizate was filtered off under suction and dried. There were obtained 133.6 g (69%) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide of m.p. 314°-317°.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10].[CH3:11][C:12]1[C:13]([OH:19])=[N:14][C:15]([SH:18])=[N:16][CH:17]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:9])[C:3]=1[CH2:2][S:18][C:15]1[N:14]=[C:13]([OH:19])[C:12]([CH3:11])=[CH:17][N:16]=1
Reactant: Cc1cnc(S)nc1O
Reactant: Clc1cncc(Cl)c1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cnc(SCc2c(Cl)cncc2Cl)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a mixture of 4-(bromomethyl)-3,5-dichloropyridine (1.0 g, 4.15 mmol) and 5-methyl-2-sulfanylpyrimidin-4-ol (0.38 g, 2.69 mmol) in anhydrous ethanol (25 mL) at 0° C. was added triethylamine (1.67 g, 16.6 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, water was added, and the mixture was sonicated and then filtered. The solid was washed with water and hexane to provide 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-5-methylpyrimidin-4-ol (0.817 g, 65% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.90 (s, 3H), 4.66 (s, 2H), 7.99 (s 1H), 8.66 (s, 2H); M+ 302.5.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25]C(C2C3C(=CC=CC=3)NC=2)=O)[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[Cl:1])=[O:13])[CH2:20][CH2:19]1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN1CCC(CNC(=O)c2c[nH]c3ccccc23)CC1
Reactant: O=C(O)c1c(Cl)[nH]c2ccccc12
Product: CCCCN1CCC(CNC(=O)c2c(Cl)[nH]c3ccccc23)CC1

Procedure:
2-Chloroindole-3-carboxylic acid (L. Marchetti and A Andreani, Ann. Chim. (Rome), 1973, 63, 681) was converted to its acid chloride and reacted with N-(1-n butyl-4-piperidyl)methylamine (D1) using the procedure of Description 1b to afford N-[(1-n butyl-4-piperidyl)methyl]2-chloroindole-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][CH:22]=O)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]>>[F:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][CH:22]2[NH:10][CH2:9][CH2:8][N:3]3[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]23)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(CCC=O)cc1F
Reactant: Cc1cn(CCN)c(C)n1
Product: COc1ccc(CCC2NCCn3c(C)nc(C)c32)cc1F

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(3-fluoro-4-methoxy-phenyl)-propionaldehyde. LC-MS: tR=0.57 min.; [M+H]+=304 g/mol.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:7][OH:8])[CH2:5][CH2:4]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][C:18]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>O1CCCC1>[CH:3]1([CH:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:7][O:8][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[C:18]([O:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:19]=2)[CH2:5][CH2:4]1
Reactant: OCC(c1ccc(Cl)cc1)C1CC1
Reactant: Fc1ccc(CCl)cc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(COCC(c2ccc(Cl)cc2)C2CC2)cc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A stirred suspension of 0.1 gram (0.0044 mole) of sodium hydride in 5 mL of tetrahydrofuran was cooled to 0° C., and a solution of 0.8 gram (0.0041 mole) of 2-cyclopropyl-2-(4-chlorophenyl)ethanol in 2.5 mL of tetrahydrofuran was added via syringe during a two minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 30 minutes and then was heated to 55° C. where it stirred for 1.5 hours. The reaction mixture was cooled to ambient temperature, and a solution of 1.0 gram (0.0043 mole) of (4-fluoro-3-phenoxyphenyl)methyl chloride in 2.5 mL of tetrahydrofuran was added via syringe. Upon completion of addition, the reaction mixture stirred at ambient temperature for 20 hours and then was warmed to 60° C. where it stirred for 30 minutes. The reaction mixture was cooled, and 15 mL of water was added. The aqueous layer was removed and extracted with three 25 mL portions of hexanes. The organic materials were combined and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residual oil. The oil was purified by rotating disk thin layer chromatography using 5-10% ethyl acetate in hexanes for elution. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.65 gram of (4-fluoro3-phenoxyphenyl)methyl 2-cyclopropyl-2-(4-chlorophenyl)ethyl ether. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[C:18]([NH2:20])=[O:19])=[C:5]([F:34])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:41]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[C:5]([F:34])=[CH:4][C:3]([C:1]([NH2:2])=[O:41])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-c4ccncc4)cc3)C(N)=O)c(F)cc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-c4ccncc4)cc3)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-(4-(pyridin-4-yl)phenyl)propanamide (12 mg, 0.025 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (6 mg). MS 491.1 (M+H); UV 216.8, 278.0, 312.5 nm.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]([N:9]1[C:13]([OH:14])=[C:12]([C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:17]=2[CH3:34])[CH:11]=[N:10]1)([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:8][C:6]([N:9]1[C:13]([O:14][C:1](=[O:3])[CH3:2])=[C:12]([C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:17]=2[CH3:34])[CH:11]=[N:10]1)([CH3:5])[CH3:7]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C(C)(C)C)c3O)c2C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C(C)(C)C)c3OC(C)=O)c2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.25 mL of acetyl chloride in 3 mL of dry dichloromethane was added slowly under nitrogen at 0° C. with stirring to a solution of 1.5 g (3.4 mmol) of 1-(1,1-dimethylethyl)-5-hydroxy-4-(2-methyl-4-methylsulfonyl-3-(4-methoxyphenyl)benzoyl)pyrazole and 0.52 mL of triethylamine in about 20 mL of dry dichloromethane. The mixture was allowed to warm to ambient temperature and stir for 2 hours and was then diluted with dichloromethane. The resulting solution was extracted with saturated aqueous sodium bicarbonate solution and with water, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residual yellow oil was chromatographed on silica gel eluting with a 50:50 mixture of ethyl acetate and hexane. The product fractions were combined and concentrated by evaporation under reduced pressure to obtain 1.03 g (62 percent of theory) of the title compound as a white powder melting at 160-163° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[F:10][C:11]([F:51])([F:50])[C:12]1[CH:13]=[C:14]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([C:27]([C:29]2[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])=[N:31][O:32][C:33]=2[CH:34]=O)=[O:28])[N:18]=[N:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:50][C:11]([F:10])([F:51])[C:12]1[CH:13]=[C:14]([CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=1)[CH2:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([C:27]([C:29]2[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])=[N:31][O:32][C:33]=2[CH2:34][NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[O:28])[N:18]=[N:17]1
Reactant: O=Cc1onc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Reactant: NCCN1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1)c1c(-c2ccccc2Cl)noc1CNCCN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Add 4-(2-aminoethyl)-morpholine (129 mg, 0.992 mmol) to a solution of 4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-3-(2-chloro-phenyl)-isoxazole-5-carbaldehyde (150 mg, 0.248 mmol) in 1,2-dichloroethane (2.5 mL). Then add NaBH(OAc)3 (157 mg, 0.744 mmol) and allow the mixture to stir at RT. After 3 h., quench the reaction with water and extract with EtOAc (2×50 mL). Dry the organic layer over MgSO4, filter, and concentrate in vacuo. Purify the residue by flash chromatography on silica gel to provide the title compound (61% yield) as a brown oil. MS (ES) 720.1 (M++1); TLC Rf=0.1 (EtOAc).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][CH2:13][CH2:14][NH:15][CH3:16])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Br[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][N:15]([CH2:14][CH2:13][NH:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11])[CH3:16]
Reactant: CNCCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCN(C)CCNC(=O)c1nc(Cl)c(N)nc1N
Yield: 63.4 %

Procedure:
A mixture of 2.44 g (10.0 mmol) of 3,5-diamino-6-chloro-N-(2-methylaminoethyl)pyrazine-2-carboxamide, 1.67 g (10.0 mmol) of methyl 3-bromopropionate and 1.38 g (10.0 mmol) of potassium carbonate was stirred in 20 ml of DMF for 18 hours at ambient temperature. Water (100 ml) was added and the solid was filtered and air dried. Crystallization from ethanol provided 2.1 g (6.34 mmol, 63%) of N-[2-[[(3,5-diamino-6-chloropyrazinyl)carbonyl]amino]ethyl]-N-methyl-beta-alanine methyl ester as white crystals; mp 136.5°-137° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[S:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:21]Br.O>ClCCl.[Fe]>[Br:21][C:16]1[C:17]([CH3:19])=[CH:18][C:13]2[S:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:14]=2[C:15]=1[CH3:20]
Reactant: Cc1cc(C)c2c(c1)SCC2c1ccc(C(C)C)cc1
Reactant: BrBr
Agent: [Fe]
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(c(C)c1Br)C(c1ccc(C(C)C)cc1)CS2
Reaction time: 1 h
Yield: 80 %

Procedure:
To a mixture of 3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene synthesized in Reference Example 212 (4.45 g, 15.8 mmol) and iron powder (59 mg, 1.05 mmol) in dichloromethane (20 mL) was added bromine (0.81 mL, 15.8 mmol) at 0° C., and the mixture was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The extract was washed with a saturated sodium hydrogen carbonate solution and water, was dried over magnesium sulfate, was filtered and then was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to obtain 4.6 g (yield 80%) of the title compound. Melting point: 98-100° C. (hexane-ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]([CH3:20])([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35][CH2:36]O>>[CH3:20][C:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:36][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:28][C:24]=2[CH3:23])=[CH:22][CH:21]=1)([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: CCOC(=O)C(C)(Cc1ccccc1)Oc1ccc(O)cc1
Product: CCOC(=O)C(C)(Cc1ccccc1)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
Mitsunobu coupling of 2-(4-hydroxyphenoxy)-2-methyl-3-phenylpropionic acid, ethyl ester and 2-(5-methyl-2-phenyloxazol-4-yl)ethanol [Hulin, et al., J. Med. Chem. (1992) 35(10), 1853-64] in the manner described in Example 2, Step A. 1H NMR (300 MHz, CDCl3) δ 7.89-7.93 (m, 2H), 7.33-7.41 (m, 3H), 7.19-7.23 (m, 5H), 6.74 (d, 2H), 6.70 (d, 2H), 4.17 (q, 2H), 4.13 (t, 2H), 3.24 (d, 1H), 3.09 (d, 1H), 2.91 (t, 2H), 2.32 (s, 3H), 1.25 (s, 3H), 1.21 (t, 3H); MS(EI): 486 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[NH:17][CH:16]=[C:15]([CH:18]=[O:19])[CH:14]=1)(=[O:6])=[O:5].C1OCCOCCOCCOCCOC1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:36]=1>>[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:17]([S:41]([C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)(=[O:43])=[O:42])[CH:16]=[C:15]([CH:18]=[O:19])[CH:14]=1)(=[O:6])=[O:5]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CS(=O)(=O)c1ccccc1-c1cc(C=O)c[nH]1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)c1ccccc1-c1cc(C=O)cn1S(=O)(=O)c1cccnc1

Procedure:
By a similar operation as in Reference Example 154 and using sodium hydride (60% in oil, 40 mg), 5-[2-(methylsulfonyl)phenyl]-1H-pyrrole-3-carbaldehyde (88.9 mg), 15-crown-5 (94.4 mg) and pyridin-3-ylsulfonyl chloride (69.7 mg), the title compound was obtained as a colorless amorphous form (yield 72.0 mg, 52%).
Reaction SMILES: [Br:1][C:2](Br)=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C1COCC1.[Cl-].[NH4+]>CO.[Zn]>[Br:1][CH:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)Br)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
tert-Butyl 4-(dibromomethylene)piperidine-1-carboxylate (64 g, 0.18 mol) was dissolved in methanol (438 mL) and THF (220 mL) and the solution was cooled to 0° C. Ammonium chloride (77.14 g, 1.44 mol) was added and the reaction was stirred for 30 min. Zinc dust (47.13 g, 0.72 mol) was added and the reaction mixture was stirred at RT for 2.5 h. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel chromatography using 230-400 mesh silica gel (2% ethyl acetate in hexane) to give the title compound (33 g). 1H NMR (500 MHz, CDCl3): δ 5.99 (s, 1H), 3.40 (m, 4H), 2.38 (m, 2H), 2.23 (m, 2H), 1.47 (s, 9H).