Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)(=[O:40])=[O:39])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from {3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13o, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, 2H), 8.67 (d, 1H), 8.26 (d, 2H), 7.96 (d, 1H), 7.85 (m, 1H), 7.44 (m, 1H), 7.19-7.09 (m, 4H), 6.73 (m, 3H), 4.54 (s, 2H), 4.48 (s, 2H), 4.40 (s, 2H), 1.48 (s, 9H); MS 547 (M+1).
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][NH:9][C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)C=CC=CC=1.[CH3:23][C:24]([CH3:31])([CH3:30])[C:25](=O)[CH2:26][C:27]#[N:28].Cl>>[NH2:28][C:27]1[N:9]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)[N:8]=[C:25]([C:24]([CH3:31])([CH3:30])[CH3:23])[CH:26]=1
Reactant: O=c1ccc(NN=C(c2ccccc2)c2ccccc2)c[nH]1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2ccc(=O)[nH]c2)n1
Yield: 6.1 %

Procedure:
5-(2-(Diphenylmethylene)hydrazinyl)pyridin-2(1H)-one (950 mg, 3.29 mmol) was treated with 4,4-dimethyl-3-oxopentanenitrile (620 mg, 4.93 mmol) and 6N HCl (2.70 mL, 16.4 mmol) according to the procedure in Example 303A Step 2. Purification by flash chromatography (silica, 1-8% MeOH/DCM) afforded 5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)pyridin-2(1H)-one (46 mg, 0.20 mmol, 6%). 1H NMR (300 MHz, DMSO-d6) δ 11.65 (br s, 1H), 7.55-7.51 (m, 2H), 6.39 (d, 1H), 5.29 (s, 1H), 5.11 (s, 2H), 1.21 (s, 9H); LC-MS (ESI) m/z 233 (M+H)+.
Reaction SMILES: [NH3:1].[F:2][C:3]([F:26])([F:25])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][N:18]3[C:22](=[O:23])[CH2:21][O:20][C:19]3=[O:24])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.O1CCCC1>CO>[F:25][C:3]([F:26])([F:2])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][NH:18][C:19](=[O:24])[O:20][CH2:21][C:22]([NH2:1])=[O:23])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: N
Reactant: O=C1COC(=O)N1CCC1CCN(c2cccc(C(F)(F)F)c2)CC1
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)COC(=O)NCCC1CCN(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 24 h

Procedure:
9.3 ml (64.82 mmol) of a solution of aqueous ammonia (7N) in methanol are added to a solution of 0.77 g (2.16 mmol) of 3-(2-{1-[3-(trifluoromethyl)-phenyl]-4-piperidyl}ethyl)-1,3-oxazolidine-2,4-dione, obtained in step 3.3, in 10 ml of a 1/1 mixture of methanol and tetrahydrofuran. Stirring is continued at room temperature for 24 hours.
Reaction SMILES: [OH:1][C:2]1([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].N1C=CC=CC=1.Cl.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>>[C:26]([O:1][C:2]1([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]1=[O:8])(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(c1ccccc1)C1(O)C(=O)NC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(c1ccccc1)C1(OC(=O)C(C)(C)C)C(=O)NC(=O)NC1=O
Temperature: 75 °C

Procedure:
The amount of 5 g. of 5-hydroxy-5-(1-phenylethyl) barbituric acid, prepared following the procedure described in Belgian Pat. No. 775,117, was dissolved in a mixture of pivaloyl chloride (5 ml.) and 60 ml. pyridine. The mixture was heated at 75°C overnight, then cooled and poured into ice containing 60 ml. of concentrated hydrochloric acid. The product was extracted four times with ethyl acetate, and the combined extracts washed with saturated sodium chloride solution, sodium bicarbonate solution, dilute hydrochloric acid and sodium chloride solution. After drying over anhydrous sodium sulfate, solvent was removed by evaporation on a Buchi Rotovapor apparatus. The resulting product was purified by column chromatography (230 g. silica gel). Elution with 5% ethyl acetate in benzene solution followed by recrystallization from benzene provided 5-pivaloyloxy-5-(1-phenylethyl) barbituric acid, m.p. 205°-207°C.
Reaction SMILES: [CH2:1]([N:8]([C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][C:13]([C:26]#[N:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:30].[Na+]>S(=O)(=O)(O)O>[CH2:1]([N:8]([C:10]([CH3:29])([CH3:28])[CH2:11][CH2:12][C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:26]([NH2:27])=[O:30])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CN(Cc1ccccc1)C(C)(C)CCC(C#N)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN(Cc1ccccc1)C(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1

Procedure:
A solution of 4-(N-benzyl-N-methylamino)-1-cyano-1,1-diphenyl-4-methylpentane (1.0 g--see Preparation 12) in 90% sulphuric acid (10 ml) was heated at 90° for 1 hour. The mixture was poured onto ice (100 g), basified to a pH of about 12 by the addition of 40% aqueous sodium hydroxide and extracted with dichloromethane (2×100 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.6 g.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[OH:37][C:35]([CH3:38])([CH3:36])[CH2:34][N:31]1[CH:32]=[CH:33][C:29]([NH:28][C:9](=[O:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:7][C@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[N:30]1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
(R)-3-((R)-3-Oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (prepared in Example 118, 90 mg, 0.30 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 160 μL, 0.32 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (3 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 47 mg, 0.30 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (3 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 100% ethyl acetate) to afford (R)—N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (84 mg) which still contained impurities. This material was then cleaned up by using reverse phase HPLC. The purified material was then concentrated in vacuo then dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and then brine, dried over sodium sulfate and concentrated in vacuo to afford pure (R)—N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (53 mg, 40%) as a white foam: [α]29589=−67.5° (c=0.12, methanol); ES-HRMS m/e calcd for C22H26N3O3F3 (M+H)+ 438.1999, observed 438.1999; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.50 (m, 1H, CH), 1.73-2.30 (m, 8H, 4×CH2), 3.87 (s, 2H, NCH2), 3.95 (m, 1H, ArCHCO), 4.64 (s, 1H, OH), 6.46 (d, J=2.2 Hz, 1H, Ar), 7.50 (d, J=2.2 Hz, 1H, Ar), 7.60 (m, 2H, Ar), 7.69 (brd, 1H, Ar), 7.73 (brs, 1H, Ar), 10.79 (s, 1H, NH).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:12][C:7]=2[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5][CH2:4][C:3]1=[O:25]>CO>[CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:11]=[CH:12][C:7]=2[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5][CH2:4][C:3]1=[O:25]
Reactant: COC(=O)/C=C/c1ccc2c(c1)N(C)C(=O)CN=C2c1ccccc1
Solvent: CO
Product: COC(=O)CCc1ccc2c(c1)N(C)C(=O)CN=C2c1ccccc1
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Title compound 358 (410 mg, 1.23 mmol) was dissolved in methanol (30 mL) and Pd(C) (250 mg) was added. The reaction mixture was stirred under hydrogen atmosphere for 2 hours. The catalyst was filtered off and the filtrate was evaporated to afford title compound 360 (370 mg, 90%) as a clear oil. 1H NMR (DMSO-d6) δ (ppm): 7.65-7.61 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.28-7.22 (m, 4H), 4.51 (d, J=10.6 Hz, 1H), 3.69 (d, J=10.8 Hz, 1H), 3.56 (s, 3H), 3.29 (s, 3H), 2.88 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.5 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.[I:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[NH:14][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([I:22])[CH:24]=1
Reactant: NC(c1ccccn1)c1ccccn1
Reactant: O=C(Cl)c1cccc(I)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(c1ccccn1)c1ccccn1)c1cccc(I)c1
Reaction time: 1 h
Yield: 39 %

Procedure:
1.5 g of C,C-dipyridin-2-yl-methylamine are suspended in 50 ml of methylene chloride and 1.15 ml of triethylamine and treated dropwise at 0° with a solution of 3-iodo-benzoyl chloride. After 1 hr. at 0° the reddish suspension is concentrated, the residue is poured into water and extracted three times with methylene chloride. Chromatography on silica gel with methylene chloride/methanol 9:1 yields 1.31 g of brownish N-(di-pyridin-2-yl-methyl)-3-iodo-benzamide. Yield: 39%. Mass spectrum: peaks inter alia at m/e: 415 (M+, 8%), 320 (44%), 231 (36%), 184 (100%).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=O)=O)[CH:8]=2)[NH:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])(=O)C.[Na+]>[Zn].C(O)(=O)C>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][C:16](=[O:18])[CH3:17])[CH:8]=2)[NH:3]1
Reactant: O=c1ccc2cc(S(=O)(=O)Cl)ccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(=O)Sc1ccc2[nH]c(=O)ccc2c1
Yield: 65 %

Procedure:
To an ice bath cooled, stirred mixture of impure 2-Oxo-1,2-dihydro-quinoline-6-sulfonyl chloride (20 g, ˜82 mmol), acetic acid (240 cm3) and acetic anhydride (80 cm3) was added sodium acetate (24 g) in three equal sized batches. Then Zinc (20 g) was added in small batches (exothermic reaction). After one hour the ice bath was removed and the reaction was left stirring at room temperature for five days then concentrated in vacuo then triturated with water (˜200 cm3). The solid that was formed was filtered off and dried in vacua to yield Thioacetic acid S-(2-oxo-1,2-dihydro-quinolin-6-yl) ester as a dry grey solid (11.7 g, ˜65%); δH (300 MHz; D6 DMSO) 2.42 (3H, s, COCH3), 6.51–6.57 (1H, m, Ar—H), 7.32–7.37 (1H, m, Ar—H), 7.43–7.48 (1H, m, Ar—H), 7.72 (1H, s, Ar—H), 7.88–7.92 (1H, m, Ar—H) and 11.95 (1H, br s, N—H); LCMS retention time ˜3.03 min, m/z (FIAPOS) 220 [(M+H)+, 100%].
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.[C:12](OCCCC)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C1(C)C=CC=CC=1>[C:12]([O:10][C@H:3]1[C@H:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][C@@H:1]([CH3:11])[CH2:2]1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: CCCCOC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 23 °C
Yield: 114.5 %

Procedure:
A solution of (-)-menthol (23.0 g, 147 mmol, 1 equiv) and 1-butyl acetoacetate (20.0 ml, 121 mmol, 0.80 equiv) in toluene (50 mL) was heated at reflux for 12 h, then was cooled to 23° C. Volatiles were removed in vacuo and toluene (20 mL) and 1-butyl acetoacetate (12.2 mL, 73.5 mmol, 0.50 equiv) were added to the residue. The resulting solution was heated at reflux for 12 h, then was cooled to 23° C. The cooled reaction mixture was concentrated in vacuo and the residue was purified by distillation under reduced pressure (bp 90° C., 30 mmHg) to afford (1R,3R,4S)-p-menth-3-yl acetoacetate (1) as a low-melting solid (33.3 g, 94%). ##STR14##
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].[H][H].[CH:10]([Si:13](Cl)([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])([CH3:12])[CH3:11]>CN(C=O)C>[CH:10]([Si:13]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)([CH3:12])[CH3:11]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: [H][H]
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 30.1 %

Procedure:
Pyrrole (1.0 mL, 0.96 g, 15 mmol) was added dropwise at 0° C. to a stirred suspension of sodium hydride (0.758 g of 50% dispersion in mineral oil, 16 mmol) in anhydrous DMF (20 mL). When hydrogen evolution (foaming) had ceased, triisopropylsilyl chloride (3.1 mL, 2.8 g, 15 mmol) was added dropwise and stirring at 0° C. was then continued for 0.75 h. The reaction mixture was partitioned between ether and water, and the ether phase was washed with water, dried oversodium sulfate, and evaporated in vacuum. Purification by column chromatography on silica gel (hexane/ethyl acetate=10:1) gave an oil (1.01 g, 30.2% yield); 1H NMR (CDCl3) δ 1.09 (d, 18 H, Me), 1.45 (sept, 3 H, CH), 6.31 (t, 2H, H-3.4), 6.80 (t, 2H, H-2.5). MS (M+H) m/z 224.
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)=[CH:11][CH:10]=1)=[O:6])([CH3:4])[CH3:3].[CH3:22][Mg]Br>C(Cl)Cl>[CH3:4][C:2]([S:5]([NH:7][C@H:8]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)=[CH:13][CH:14]=1)[CH3:22])=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(Oc2cncnc2)cc1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@H](NS(=O)C(C)(C)C)c1ccc(Oc2cncnc2)cc1
Temperature: -20 °C

Procedure:
A solution of (R,E)-2-methyl-N-(4-(pyrimidin-5-yloxy)benzylidene)propane-2-sulfinamide (830 mg, 2.74 mmol) in DCM (6.72 mL) was cooled to −40° C. To the solution was added methylmagnesium bromide (3M in diethylether; 1.81 mL) dropwise over 10 min. Additional DCM (5 mL) were added to retain stirring. The yellow suspension was stirred at −40° C. for ˜30 min while warming to −20° C. The mixture was cooled to −40° C. and additional methylmagnesium bromide (3M in diethylether; 1.8 mL) was added. The suspension was stirred for ˜3 hour while slowly warming to −20° C. The mixture was cooled to ˜−40° C., and additional methylmagnesium bromide (3M in diethylether; 0.4 mL) was added. The suspension was stirred for 30 min and allowed to warm to −10° C. The mixture was quenched slowly over 10 min with saturated aqueous NH4Cl solution (10 mL). The mixture was diluted with saturated aqueous NH4Cl solution (30 mL) and water (15 mL). The separated aqueous phase was extract with DCM (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered off and concentrated under reduced pressure. The residue was purified by column chouromatography [SiO2, 40 g, heptane/ethyl acetate followed by 5% MeOH in EtOAc] providing 2-methyl-N—((S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethyl)propane-2-sulfinamide (55 mg; purity ˜87%) as an off-white solid. LCMS m/z 320.0 (M+H)+, Rt 0.69 min.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[CH2:14]3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[NH:15]1[CH2:16][CH2:17][CH2:18][CH:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)[CH2:14]1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(C3CCCN(C(=O)OCc4ccccc4)C3)oc12
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCCNC3)oc12
Yield: 241.6 %

Procedure:
A mixture of benzyl 3-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate (200 mg, 0.27 mmol), 10% Pd/C (40 mg) in methanol (30 ml) was stirred at room temperature over 1 atm hydrogen for 2 hr. Then the mixture was filtered and evaporated, 160 mg of 2-(piperidin-3-yl)benzo[d]oxazole-7-carboxamide as a solid was obtained. Yield 24%. LC-MS (ESI) m/z: 246 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[CH3:27][C:28]1[NH:32][N:31]=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:29]4[C:28]([CH3:27])=[N:32][NH:31][CH:30]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: Cc1[nH]ncc1B1OC(C)(C)C(C)(C)O1
Product: Cc1n[nH]cc1-c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following the procedure in Example 93, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was coupled with 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give 318. MS (ESI) 450.1
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[NH:11][C:10]1=[O:19].[F:28][C@@H:29]1[CH2:33][NH:32][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])[C:9]2([N:32]1[CH2:33][C@@H:29]([F:28])[CH2:30][C@H:31]1[C:34]([O:36][CH3:37])=[O:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COC(=O)[C@@H]1C[C@H](F)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](F)CN1C1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21
Reaction time: 13 h
Yield: 109.9 %

Procedure:
2.79 g of triethylamine was added under ice cooling and a nitrogen atmosphere to a 50 mL chloroform solution of 1.70 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 1.03 g of the compound obtained in step 4-1, after which the reaction mixture was raised to room temperature and stirred for 13 hours at the same temperature. The reaction solution was stirred while a 50 mL saturated sodium hydrogencarbonate aqueous solution was added, and the reaction mixture was stirred for 15 minutes. After liquid separation, the aqueous layer thus obtained was extracted with chloroform. The combined organic layer was washed with saturated brine and dried with magnesium sulfate, after which the drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 2.54 g of residue (yellow, amorphous). The residue thus obtained purified by column chromatography (silica gel 60, mobile phase: ethyl acetate), and stirred and washed in diisopropyl ether to obtain 1.98 g of a diastereoisomer mixture of the titled compound (pale green, amorphous).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: COc1ccc(C(CN)N2CCOCC2)cc1
Product: COc1ccc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCOCC2)cc1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[C:22]3[C:17](=[CH:18][C:19]([OH:43])=[C:20]([O:41][CH3:42])[CH:21]=3)[C:16]2=[O:44])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N([CH2:50][CH3:51])CC)C.[C:52](=[O:55])([O-])O.[Na+]>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:52]([O:43][C:19]1[CH:18]=[C:17]2[C:22]([C:23]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)=[C:24]([C:25]([O:27][CH3:28])=[O:26])[N:15]([C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:10][CH:11]=3)[C:16]2=[O:44])=[CH:21][C:20]=1[O:41][CH3:42])(=[O:55])[C:51]1[CH:50]=[CH:11][CH:10]=[CH:9][CH:14]=1
Reactant: CCN(CC)CC
Reactant: O=C([O-])O
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC(=O)c3ccccc3)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound obtained in Example 5 (200 mg) is dissolved in dimethylformamide (10 ml), and thereto are added benzochloride (40 μl), triethylamine (48 μl) and 4-dimethylaminopyridine (5 mg), and the mixture is stirred at room temperature overnight. After the reaction is complete, to the mixture is added a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. The extract is washed, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=1:1) to give 7-benzoyloxy-2-[4-(tert-butoxycarbonylamino)phenyl]-6-methoxy-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone as listed in Table 20.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6](F)[CH:7]=1.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1cc(F)cc(Cl)c1
Reactant: OCc1ccccc1
Product: O=C(O)Cc1cc(Cl)cc(OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 185, Step 1, using the following starting materials: 3-chloro-5-fluorophenylacetic acid and benzyl alcohol.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([Cl:10])=[C:8](Cl)[CH:7]=[CH:6][N:5]=1.[F:12][CH:13]([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:24])[CH2:22][CH3:23])=[CH:17][CH:16]=1>>[Cl:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][CH:6]=[CH:7][C:8]=1[NH:24][CH:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:13]([F:12])[F:25])=[CH:16][CH:17]=1)[CH2:22][CH3:23]
Reactant: COCc1nccc(Cl)c1Cl
Reactant: CCC(N)c1ccc(OC(F)F)cc1
Product: CCC(Nc1ccnc(COC)c1Cl)c1ccc(OC(F)F)cc1

Procedure:
was prepared analogously to Example 84 using 2-methoxymethyl-3,4-dichloropyridine and 1-(4-difluoromethoxyphenyl)-propylamine.