Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[O:32]1[C:36]2[CH:37]=[CH:38][C:39](B(O)O)=[CH:40][C:35]=2[CH2:34][CH2:33]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:32]1[C:36]2[CH:37]=[CH:38][C:39]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)=[CH:40][C:35]=2[CH2:34][CH2:33]1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)CCO2
Yield: 91.4 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.058 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and 2,3-dihydrobenzofuran-5-ylboronic acid (0.246 g; 1.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.184 g (91%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.CCCCCCC>[Cl:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: COc1nc(Cl)ccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(Cl)nc4OC)nccc3c2)cc1
Temperature: 80 °C
Yield: 96.8 %

Procedure:
A vial was charged with 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE ZZZZ, 97 mg, 0.220 mmol), (6-chloro-2-methoxypyridin-3-yl)boronic acid (45.3 mg, 0.242 mmol), potassium carbonate (91 mg, 0.660 mmol), and pd(ph3p)4 (12.71 mg, 0.011 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (825 μl) and water (275 μl) were added. The vial was sealed and heated to 80° C. for 45 min in a Biotage Initiator microwave reactor. LCMS showed primarily the desired product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-50% EtOAc/Heptane, then 50-100% EtOAc/Heptane) to give 1-(6-chloro-2-methoxypyridin-3-yl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (117 mg, 0.213 mmol, 97% yield) as a cream-colored foam. m/z (ESI) 548.2 (M+H)+.
Reaction SMILES: NC[CH:3]1[CH:6]([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]3=[C:9]([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][C:23]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[N:24]4)=[CH:19][CH:18]=3)[N:8]=2)[CH2:5][CH2:4]1.[CH3:33][CH2:34][N:35]([CH:39](C)C)C(C)C.CC(OC(C)=O)=[O:44]>C(Cl)Cl>[NH2:16][C:15]1[C:10]2[N:11]([C:7]([C@@H:6]3[CH2:3][C@H:4]([CH2:39][NH:35][C:34](=[O:44])[CH3:33])[CH2:5]3)=[N:8][C:9]=2[C:17]2[CH:18]=[C:19]3[C:20]([CH:21]=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:24]3)=[CH:25][CH:26]=2)[CH:12]=[CH:13][N:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)OC(C)=O
Reactant: NCC1CCC1c1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(N)nccn12
Solvent: ClCCl
Product: CC(=O)NC[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 3-[4-(aminomethyl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine (0.237 mmol, 100. mg) in DCM (6 mL) was charged with DIEA (0.475 mmol, 83 μL) and Ac2O (0.237 mmol, 22.43 μL) at −40° C. The reaction solution was warmed to rt slowly and stirred under N2 for 1.5 h. The reaction was quenched with water (3 mL), diluted with methylene chloride (20 mL), washed with water (30 mL) and brine (30 mL), and dried (Na2SO4). The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel flush column chromatography (Jones Flashmaster, 10 g/70 mL cartridge), eluting with 3% MeOH (7 N NH3) in DCM, yielding the title compound as a light yellow solid. The sample was recrystallized from DCM (minimal amount) and EtOAc. The final product was obtained as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 8.43-8.42 (m, 1H), 8.28 (dd, J=8.0 Hz, 0.4 Hz, 1H), 8.20-8.18 (m, 2H), 7.97-7.92 (m, 3H), 7.57-7.48 (m, 3H), 7.15 (d, J=4.8 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 5.19 (b, 2H), 3.78-3.70 (m, 1H), 3.38 (t, J=5.6 Hz, 2H), 2.77-2.66 (m, 3H), 2.42-2.34 (m, 2H), 1.87 (s, 3H); MS (ES+): m/z 463 (100) [MH+]; HPLC: tR=2.06 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([N:3]([C@@H:15]([CH3:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20](SC)=[CH:19][CH:18]=1)[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][O:10][C:9]1=[O:14])[CH3:2].[S:26]([O-:31])(O[O-])(=O)=[O:27].[K+].[K+].[C:34](=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH2:1]([N:3]([C@@H:15]([CH3:25])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([S:26]([CH3:34])(=[O:31])=[O:27])=[CH:21][CH:22]=1)[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][O:10][C:9]1=[O:14])[CH3:2]
Reactant: O=S(=O)([O-])O[O-]
Reactant: O=C([O-])[O-]
Reactant: CCN(CCCCN1CCCOC1=O)[C@@H](C)Cc1ccc(SC)cc1
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(CCCCN1CCCOC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an ice cooled solution of 3-(4-{ethyl-[(S)-2-(4-methylsulfanylphenyl)-1-methylethyl]amino}butyl)-[1,3]oxazinan-2-one (0.33 g, 0.9 mmole) in methanol (10 mL) was added a solution of potassium peroxymonosulfate (Oxone®) (1.22 g, 1.98 mmole) in water (10 mL). The reaction mixture was stirred at room temperature for 5 hours. Then 1.5M sodium carbonate solution (10 mL) was added and the mixture was extracted with diethyl ether (20 mL). The organic phase was dried (magnesium sulfate) and concentrated. Purification of the residue by silica gel chromatography with 10% ethyl acetate in chloroform, gave 3-(4-{ethyl-[(S)-2-(4-methanesulfonylphenyl)-1-methylethyl]amino}butyl)-[1,3]oxazinan-2-one, 122, (0.17 g) as a colorless oil. Anal.: Calcd. for C20H33ClN2O4S: C, 55.48; H, 7.68; N, 6.47%. Found C, 52.32; H, 7.42; N, 5.97.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][N:32]=2)[C:27]([CH:34]=O)=[CH:26]1>CO.N1CCCCC1>[NH:25]1[C:33]2=[N:32][CH:31]=[CH:30][CH:29]=[C:28]2[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[CH:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0251 g, 0.0755 mmol) obtained in Example A56, Step 3 in methanol (2 mL) was added with 7-azaindole-3-carboxaldehyde (0.0116 g, 0.0793 mmol) and piperidine (5 drops), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0269 g, 77%).
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.C(N(CC)CC)C.[Br:63]C1C=CC=CC=1C(Cl)=O>ClCCl>[Br:63][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccccc1Br
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Br)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.28 g, 0.92 mmol), triethylamine (0.28 mL, 2.0 mmol) and 2-bromobenzoyl chloride (0.22 g, 1.0 mmol) in dichloromethane (10 mL) gave 2-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.45 g) as a white solid. MS m/z 488, 490 (M+1, M+3).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:15][CH2:16][OH:17])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[S:5]([N:4]([CH2:15][CH2:16][O:17][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:3][CH2:2][O:1][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN(CCOS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
Procedure 3 is illustrated with the preparation of (-)-(RR)-8a' and (+)-(RR)-8b', with (-)-(R)-6f' as a byproduct. In dry pyridine at 0°, N,N-bis-(2-hydroxyethyl)-p-toluenesulfonamide (m.p. 96°-99°) was tosylated with tosyl chloride by the standard method to give N,O,O'-tritosyldiethanolamine, m.p. 85°-87°. [Can. J. Chem. 45, 1555 (1967) gives 78°-79°].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[C:24](OCC)[C:25]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)[CH3:2].[CH2:30]([O:32]C1C=C(C=CC=1OC)C=O)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[O:32][CH3:30])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cncnc3)CC2)cc(OCC)c1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cncnc3)CC2)ccc1OC

Procedure:
In analogy to the procedure described in example 50k), pyrimidine-5-carboxylic acid piperidin-4-ylamide (example 56) was reacted with 3-ethoxy-4-methoxy-benzaldehyde, sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 371.1 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:26])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[F:26][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[C:14]([CH3:15])=[C:13]2[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(C)(=O)=O)cc1
Reaction time: 15 h
Yield: 87.3 %

Procedure:
To a solution of [6-fluoro-4-(4-methansulfonyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (77.7 mg, 0.2 mmol) in THF (10 mL) was added a solution of lithium hydroxide monohydrate (83.92 mg, 2.0 mmol) in water (2 mL) at room temperature. The resulting clear solution was stirred for 15 hours. The reaction mixture was concentrated to remove THF. The residue was diluted with water (˜30 mL) to obtain a clear solution. The basic aqueous layer was acidified with 1.0 N hydrochloric acid. The precipitated solids were collected by filtration and washed with water and hexanes. After drying in air, [6-fluoro-4-(4-methansulfonyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid (65 mg, 87%) was isolated as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (br. s, 1 H), 8.11 (d, J=8.2 Hz, 2 H), 8.02 (dd, J=9.0, 6.0 Hz, 1 H), 7.92 (s, 1 H), 7.54 (d, J=8.2 Hz, 2 H), 7.39 (td, J=9.0, 2.3 Hz, 1 H), 6.71 (dd, J=11.3, 2.3 Hz, 1 H), 3.86 (s, 2 H), 3.35 (s, 3 H), 2.08 (s, 3 H). HRMS calcd. for C20H18FO4S [(M+H)+] 373.0905, obsd. 373.0904.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[CH:7]=[C:6]([CH3:12])[N:5]=2.C(N(CC)C(C)C)(C)C.[Cl:31][CH2:32][C:33](Cl)=[O:34].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH3:1][C:2]1[N:3]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][C:33](=[O:34])[CH2:32][Cl:31])[CH:7]=[C:6]([CH3:12])[N:5]=2
Reactant: Cc1cc(C)c(-n2c(C)nc3c(N)cc(C)nc32)c(C)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(-n2c(C)nc3c(NC(=O)CCl)cc(C)nc32)c(C)c1
Temperature: 25 °C

Procedure:
Treat a solution of 2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridine-7-ylamine (0.8 g, 2.85 mmol), and N,N-diisopropylethylamine, (0.54 mL, 3.13 mmol) in 1,2-dichloroethane (10 mL) with chloroacetyl chloride (0.25 mL, 3.13 mmol). Heat the solution to reflux for 5 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter and concentrate. Purify by preparative TLC (5% MeOH in CH2Cl2) to obtain the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C([C:20](CC)([C:24]([O-:26])=[O:25])[C:21]([O-:23])=O)C.[CH2:29](O)[CH3:30]>>[CH2:29]([O:26][C:24]([C:20]1[C:21](=[O:23])[NH:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)=[O:25])[CH3:30]
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: CCO
Reactant: COc1ccc(C(=O)c2ccccc2)c(N)c1
Product: CCOC(=O)c1c(-c2ccccc2)c2ccc(OC)cc2[nH]c1=O
Temperature: 160 °C
Yield: 90.2 %

Procedure:
A mixture of 2-amino-4-methoxybenzophenone (20 g, 88 mmol), diethylmalonate (26.7 ml, 176 mmol), 1,8-diazabicyclo[5,2,0]-undeca-7-en (DBU) (0.66 ml, 4.4 mmol) was stirred with heat at 160° C. for 2 hours. The reaction mixture was cooled by air. To the cooled mixture was added ethanol (30 ml) to obtain a precipitated crystal by filtration. The crystal obtained was washed with ethanol to give 25.7 g (yield: 90.2%) of the title compound.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].NC1C([Cl:13])=CC(C(=O)CCC2CCNCC2)=C(OC)C=1.[NH2:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34](=[O:43])[CH2:35][CH2:36][CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[C:29]2[O:44][CH2:45][CH2:46][O:47][C:28]=12>>[ClH:13].[NH2:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34](=[O:43])[CH2:35][CH2:36][CH:37]2[CH2:42][CH2:41][N:40]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:39][CH2:38]2)=[C:29]2[O:44][CH2:45][CH2:46][O:47][C:28]=12
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Reactant: CCCCI
Reactant: Nc1c(Cl)cc(C(=O)CCC2CCNCC2)c2c1OCCO2
Product: CCCCN1CCC(CCC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Product: Cl

Procedure:
Proceeding as in Example 10, but replacing 1-bromopropane with iodobutane and 1-(4-amino-5-chloro-2-methoxyphenyl)-3-(piperidin-4-yl)propan-1-one with 1-(4-amino-5-chloro-2,3-ethylenedioxyphenyl)-3-(piperidin-4-yl)propan-1-one, gave 1-(4-amino-5-chloro-2,3-ethylenedioxyphenyl)-3-[1-(but-1-yl)-piperidin-4-yl]propan-1-one hydrochloride, m.p. 265°-267° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:24]([Li])CCC.[C:29]([O:33][C:34]([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42](C=O)[CH:43]=2)[CH:38]=[C:37]1[C:47]1[CH:52]=[C:51]([C:53]2[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=2)[N:50]=[N:49][C:48]=1[O:59][CH3:60])=[O:35])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([O:33][C:34]([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH:24]=[CH:4][O:3][CH3:2])[CH:43]=2)[CH:38]=[C:37]1[C:47]1[CH:52]=[C:51]([C:53]2[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=2)[N:50]=[N:49][C:48]=1[O:59][CH3:60])=[O:35])([CH3:31])([CH3:30])[CH3:32]
Reactant: [Li]CCCC
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(C=O)cc2n1C(=O)OC(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC=Cc1ccc2cc(-c3cc(-c4ccncc4)nnc3OC)n(C(=O)OC(C)(C)C)c2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.23 g Methoxymethyltriphenylphoshonium chloride is suspended in 10 mL THF and cooled to −78° C. 2.20 mL butyllithium (1.6 M in hexanes) is added dropwise and the resulting mixture is stirred for 30 min at −78° C. and then warmed in an ice bath to 0° C. After addition of a solution of 734 mg 6-formyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester (see above) in 5 mL THF the reaction mixture is heated to reflux for 5 hours. After cooling to rt, the reaction mixture is diluted with heptanes, washed with water, dried (MgSO4) and concentrated in vacuo. The resulting 280 mg crude enol ether is directly used in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH+:9]([O-:25])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[NH+]([O-])CCc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
tert-Butyl 2-(4-pyridyl)ethylcarbamate (6.9 g, 31 mmol) and 3-chloroperbenzoic acid (77%, 9.1 g, 40 mmol) were dissolved in ethyl acetate (100 ml), and the mixture was stirred at room temperature for 3 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:3, v/v) were collected and concentrated to give the titled compound (7.4 g, 99%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][CH:12]([CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:11][CH:12]([CH3:33])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=3)[N:21]=2)=[CH:18][CH:19]=1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(C=O)cc3)no2)cc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of 9.8 mL (112.4 mmol) of oxalyl chloride in 300 mL of dichloromethane was treated with 12 mL (168.6 mmol) of DMSO at −78° C. To the reaction mixture, 16.5 g of 4-(5-(4-(2-methylpropyl)phenyl)-1,2,4-oxadiazol-3-yl)phenylmethanol (from Step B) was added followed by 78 mL (450 mmol) of N,N-diisopropylethylamine at −78° C. The reaction mixture was allowed to warm to rt over 1 h. Dichloromethane was removed under reduced pressure and the residue was partitioned between ethyl acetate and 0.5 N KHSO4 solution. The organic layer was washed with 1 N HCl solution, saturated NaHCO3 and water and then was concentrated to dryness. The crude product was recrystallized from hexanes to afford 11.9 g of the title compound: 1H NMR (400 Mhz) δ 0.97 (d, J=6.7, 6H), 1.97 (m, 1H), 2.61 (d, J=7.0, 2H), 7.37 (d, J=8.0, 2H), 8.06 (d, J=8.2, 2H), 8.16 (d, J=8.2, 2H), 8.39 (d, J=8.0, 2H), 10.14 (s, 1H); ESI-MS 307 (M+1H); LC-1: 4.5 min.
Reaction SMILES: [C:1]([C@:3]([CH3:26])([C@H:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[C:4](O)=[O:5])#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1>C1COCC1.CN(C=O)C.CN(C1C=CN=CC=1)C.ClCCl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:43]2[CH2:44][CH2:45][N:46]([C:4](=[O:5])[C@:3]([C@H:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][CH:9]=3)([CH3:26])[C:1]#[N:2])[CH2:47][CH2:48]2)[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1
Reactant: COc1ccccc1[C@H](c1cccc2ccccc12)[C@@](C)(C#N)C(=O)O
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)cc(N2CCN(C(=O)[C@](C)(C#N)[C@H](c3ccccc3OC)c3cccc4ccccc34)CC2)c1
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A solution of (S,S)2-cyano-3-(2-methoxy-phenyl)-2-methyl-3-naphthalen-1-yl-propionic acid (0.45 g, 1.30 mmol) in THF (150 mL) is treated with DMF (2 drops). Oxalyl chloride (0.16 mL, 1.84 mmol) is added dropwise in order to control gas evolution; when the gas evolution stopped the solution is heated to reflux for 5 minutes. The solution is cooled, the THF is evaporated in vacuo and the solid is dissolved in dry toluene (15 mL) and evaporated to a solid. This procedure is repeated twice. The acid chloride is dissolved in dichloromethane (10 mL) this is added to a solution of 1-(3,5-dimethoxy-phenyl)-piperazine (305 mg, 1.36 mmol) and a crystal of DMAP in dichloromethane (15 mL). This is followed by the dropwise addition of TEA (0.6 mL, 4.27 mmol). The reaction is stirred overnight. The reaction mixture is diluted with dichloromethane (50 mL), washed with aqueous HCl (10 mL 0.5 N) then saturated NaHCO3 (10 mL) and brine (10 mL). The sample is dried over NaSO4, filtered and concentrated in vacuo. Chromatography on silica gel using 30% ethyl acetate/hexanes provided 510 mg the title compound as a white solid. Recrystallization from ethyl acetate/hexanes yielded colorless needles. mp 186-188° C.; [α]D25=−153.91° (1%, CHCl3);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=[S:24]>C(#N)C>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]1[S:24][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:25]=1
Reactant: NC(=S)c1ccccc1Cl
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CC#N
Product: CSc1ccc(-c2sc(-c3ccccc3Cl)nc2-c2ccc(F)cc2)cc1
Temperature: 80 °C
Yield: 49.9 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethanone (2.03 g, 5.98 mmol) (Example 1, Step 3) in acetonitrile (60mL) in a 125 mL round bottom flask was added 2-chlorothiobenzamide (1.08 g, 6.28 mmol) and the suspension heated to 80° C. for 4 hours. The reaction was cooled to room temperature and the suspension filtered through a fritted funnel. The solid was recrystallized from hot acetonitrile (50 mL) and methanol (150 mL) yielding 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylthiophenyl)thiazole as a tan solid (1.23 g, 50 %): mp 133°-134° C. 1H NMR (CDCl3) 300 mHz δ8.37 (d, J=6.17 Hz, 1H), 7.60 (dd, J=8.68, 5.28, 2H) 7.51 (d, J=9.44 Hz, 1H), 7.32-7.42 (m, 2H), 7.32 (d, J=8.68 Hz, 2H), 7.21 (d, J=8.68 Hz, 2H), 7.02 (t, J=8.68, 2H), 2.51 (s, 3H). MS (EI): m/z 412 (MH+).