Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[C:11](=[O:12])[CH:10]=[CH:9]O[C:7]=1[CH3:13])([O:3][CH2:4][CH3:5])=[O:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:6]1[C:11](=[O:12])[CH:10]=[CH:9][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH3:13])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1c(C)occc1=O
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C)n(-c2ccccc2)ccc1=O

Procedure:
The crude 3-carboethoxy-2-methylpyr-4-one isolated from the previous reaction is dissolved in 50 ml toluene. 2.4 g of aniline and 400 mg of p-toluenesulfonic acid monohydrate are added and the mixture refluxed for one hour. Evaporation of the solvent leaves 6.3 g of crude 3-carboethoxy-N-phenyl-2-methylpyrid-4-one.
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:38][CH2:39][CH3:40])[C:26](NC(C4C=CC=CC=4)CO)=[O:27])=[CH:20][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:42].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH:11]1[C:12]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:38][CH2:39][CH3:40])[C:26]([OH:42])=[O:27])=[CH:20][CH:19]=3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: CCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)NC(CO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)O
Temperature: 90 °C
Yield: 57 %

Procedure:
A solution of [2R diastereomer, N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide (0.45 g, 0.84 mmol) obtained in example 21a in mixture of 1M sulphuric acid (17 mL) and dioxane/water (1:1, 39 mL) was heated at 90° C. for 88 h. The pH of the mixture was adjusted to 3.0 by addition of an aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate (2×25 mL) and the organic extract as washed with water (50 mL), brine (25 mL), dried (Na2SO4) and evaporated. The residue was chromatographed over silica gel using a gradient of 50-75% ethyl acetate in pet. ether to afford the title compound (0.2 g, 57%) as a white solid. mp: 77-78° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(Cl)(Cl)Cl.S(Cl)(Cl)=O.CN(C)C=O>CCCCCC.CCOCC>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([O:16][CH2:8][CH2:2][CH:3]([CH3:21])[CH3:4])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(C)CCOC(=O)C(C)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 3 h

Procedure:
1.0 G. of (5-oxo-5H-dibenzo[a,d]cyclohepten-2yl)-propionic acid is dissolved in 25 ml. of chloroform, and 1 ml. of thionyl chloride and 0.1 ml. of dimethylformamide are added thereto. The mixture is left for 3 hrs., then evaporated to dryness. The residue is dissolved in 20 ml. of benzene and evaporated to dryness. 0.5 G of the residue is dissolved in 5 ml. of acetonitrile containing 1.0 ml. of isopentylalcohol and 1.0 ml. of triethylamine. The mixture is left at room temperature for 16 hrs., then poured into water. The solution is extracted with ether and the extract washed with water, dilute hydrochloric acid, aqueous sodium carbonate, dried and evaporated to yield the crude product which is dissolved in hexane:ether (1:1), the solution passes through silica gel, and the eluant evaporated to afford isopentyl (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate [an oil; n.m.r. spectrum in deuterochloroform relative to tetramethylsilane: 0.87 (doublet CH[CH3 ]2 ; 1.57 (doublet, CHCH3) and 7.23 ppm (singlet 10H,11H); mass spectrum: 348(M+), 278, 234, 233, 205].
Reaction SMILES: [CH3:1][CH2:2][O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1.[F:16][C:17]([Si](C)(C)C)([F:19])[F:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:14]([O:13][CH:4]([O:3][CH2:2][CH3:1])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:12])[C:17]([F:19])([F:18])[F:16])=[CH:7][CH:6]=1)[CH3:15]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(C(O)C(F)(F)F)cc1
Yield: 77.9 %

Procedure:
According to Step 2 of Reference Example 8-17, by use of terephthalaldehyde mono(diethyl acetal) (796 μL, 4.00 mol), (trifluoromethyl)trimethylsilane (709 μL, 4.80 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 4.40 mL, 4.40 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 2.5 hours. Then, purification by silica gel column chromatography (hexane/ethyl acetate=4/1) was performed to give 1-diethoxymethyl-4-(2,2,2-trifluoro-1-hydroxyethyl)benzene (Compound CR) (1.04 g, yield: 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:30][CH3:31])=[CH:5][C:6]2[C:15]3[C:10](=[C:11]4[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][C:12]4=[N:13][CH:14]=3)[N:9]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:8](=[O:28])[C:7]=2[CH:29]=1>C(O)C.[Ni].O.NN>[NH2:20][C:19]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]3[C:10]=2[N:9]([CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[C:8](=[O:28])[C:7]2[CH:29]=[C:3]([O:2][CH3:1])[C:4]([O:30][CH3:31])=[CH:5][C:6]3=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc2c(=O)n(CCN(C)C)c3c(cnc4cccc([N+](=O)[O-])c43)c2cc1OC
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc2c(=O)n(CCN(C)C)c3c(cnc4cccc(N)c43)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound 3d (37 mg, 0.088 mmol) in ethanol (8 mL) was added 1 pinch of Raney Nickel and 5 drops of hydrazine hydrate, and the mixture was stirred at ambient temperature for 2 h. The mixture was filtered through Celite and the filtrate was evaporated. The residue was dissolved in chloroform (25 mL) and washed with brine (25 mL), dried (MgSO4), and evaporated, giving 28 mg (81%) as a yellow solid; mp 239-241° C.; 1H NMR (CDCl3) δ 1.80 (s, 6H), 2.10 (m, 2H), 4.05 (s, 3H), 4.13 (s, 3H), 4.48 (m, 3H), 5.07 (m, 1H), 6.79 (dd, 1H, J=6.3, J=2.5), 7.52 (m, 2H), 7.64 (s, 1H), 7.87 (s, 1H), 9.38 (s, 1H); 13C NMR (CDCl3) δ 45.1, 50.5, 56.3, 56.4, 57.4, 102.0, 109.1, 109.6, 111.3, 112.6, 118.7, 119.5, 127.7, 130.0, 141.0, 142.6, 144.8, 149.8, 150.0, 154.3, 164.5; HRMS calcd for C22H24O3N4H: 393.1927; found: 393.1925.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][S:27]([CH3:26])(=[O:29])=[O:28])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCc1ccccc1N)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(CCc1ccccc1NS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
A solution of N-(2-(2-aminophenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (723 mg, 2.9 mmol) and triethylamine (0.48 ml, 3.5 mmol) in dichloromethane (10 ml) was cooled to −78° C. A solution of methanesulfonyl chloride (0.22 ml, 2.9 mmol) in dichloromethane (2 ml) was added dropwise. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (50 ml) and washed with 10% aqueos sodium hydrogen sulfate solution (150 ml). The aqueous phase was extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (150 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (60 g), using ethyl acetate/heptane (1:1) as eluent, to give 870 mg of N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[CH3:39][N:40]1[C:44]([Sn](CCCC)(CCCC)CCCC)=[CH:43][N:42]=[CH:41]1>CN(C=O)C.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>[CH3:39][N:40]1[C:44]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:27][CH2:26]4)[CH:20]=[N:19][CH:18]=2)=[CH:43][N:42]=[CH:41]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cncc1-c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 183.9 %

Procedure:
A solution of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (147 mg, 0.251 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole (Synthonix, Inc., Wake Forest, N.C.; 0.099 mL, 0.327 mmol), and Pd(PPh3)4 (14.53 mg, 0.013 mmol) in DMF (2.0 mL) was heated under argon at 100° C. for 2.5 h. The reaction was cooled to RT, concentrated onto silica gel, and chromatographically purified (ISCO, 12 g silica gel column, 0-10% MeOH/DCM, 20 min, 254 nm) to provide crude (4R)-tert-butyl 4-(6-(5-(1-methyl-1H-imidazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (270.3 mg; contaminated with PPh3 and DMF) as a yellow-orange foam: MS (ESI, pos. ion) m/z: 586.2 (M+1). This material was used without further purification in the subsequent step.
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([C:11]([O:13]CC)=O)[N:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li]>>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:11]([C:9]1[N:10]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[S:7][CH:8]=1)=[O:13])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1csc(-n2ccnc2)n1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1csc(-n2ccnc2)n1

Procedure:
Prepared from ethyl 2-imidazol-1-yl-thiazole-4-carboxylate [CAS-No. 256420-32-3] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as an orange oil (12.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:18]([OH:20])=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C:18]([O:20][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCc2ccccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)OCc2ccccc2)CCc2ccccc21
Reaction time: 0.5 h

Procedure:
To 0.140 mol of 1-[(tert-butyloxycarbonyl)amino]-1-indancarboxylic acid there are added 750 ml of dimethylformamide and then 0.147 mol of caesium carbonate. Stirring is then carried out for 2 hours 30 minutes at ambient temperature and there is then poured in, dropwise, over ½ hour, 0.145 mol of benzyl bromide dissolved in 150 ml of dimethyl-formamide, and stirring is carried out for 20 hours at ambient temperature.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[CH3:20])#[N:14].[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>C1COCC1.CN1CCCN(C)C1=O>[C:13]([C:15]1[S:16][C:17]([Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:18][C:19]=1[CH3:20])#[N:14]
Reactant: Cc1ccsc1C#N
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Product: Cc1cc([Si](C)(C)C)sc1C#N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.45M in hexanes, 51.9 ml) was added dropwise to a stirred solution of diisopropylamine (11.7ml, 83.0 mmol) in dry THF (150 ml) at -5-0° C. and the solution stirred for 30 min. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (13.6 ml, 0.11 mmol) was added, the mixture was cooled to -78° C. and a solution of 2-cyano-3-methylthiophene (9.27 g, 75.4 mmol) in THF (20 ml) added dropwise, followed by trimethylsilylchloride (19.1 ml) after 30 sec. The mixture was warmed to room temperature over 30 min., evaporated, taken up in diethyl ether, the solids filtered off and the filtrate evaporated to afford a yellow oil. This was purified by flash chromatography on untreated neutral alumina, eluting with 1% diethyl ether in hexane, to give 2-cyano-3-methyl-5-trimethylsilylthiophene as a clear oil (6.52 g). M+ 195; 360 MHz 1H n.m.r. (CDCl3) 7.02 (1H, s), 2.43 (3H, s), 0.33 (9H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]([CH2:11][CH3:12])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][NH2:6].[C:14](O)(=[O:17])[CH:15]=[CH2:16]>C1C=CC(NC2C=CC(NC3C=CC=CC=3)=CC=2)=CC=1>[CH3:13][N:2]([CH3:1])[CH2:3][C:4]([CH2:11][CH3:12])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][NH:6][C:14](=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)O
Reactant: CCCCC(CC)(CN)CN(C)C
Agent: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Product: C=CC(=O)NCC(CC)(CCCC)CN(C)C
Yield: 54.6 %

Procedure:
Proceeding as in Example 1, 173.5 g 3-dimethylamino-2-ethyl-2-butylpropylamine; 67 g acrylic acid; 2 g N,N'-diphenyl-p-phenylenediamine; and 2 g calcium tert-butylate were mixed. 122 g (55%) N-(3-dimethylamino-2-ethyl-2-butylpropyl)-acrylamide, boiling point 129° C. at 66.5 Pa, was isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36].C(OCC)(=O)C>ClCCl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]2[C:18]([CH3:19])([CH3:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)=[CH:3][C:2]=1[NH:1][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(N)c1)N2
Reactant: CC(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(NC(=O)C(C)C)c1)N2
Yield: 109.1 %

Procedure:
To a solution of methyl 2-(3-amino-4-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (182 mg, 0.53 mmol) in dichloromethane (5 mL) was added N,N-diisopropyle thylamine (136 mg, 1.06 mmol) with ice cooling, followed by the addition of isobutyryl chloride (84 mg, 0.8 mmol) in dichloromethane (2 mL) via syringe. The resultant mixture was stirred at room temperature overnight. Thin layer chromatography (petroleum ether: ethyl acetate=10:1) showed the reaction was complete. The mixture was separated by Preparative Thin layer chromatography to afford 240 mg of methyl 2-(4-chloro-3-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate, which was used in next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5]>C(OC(=O)CCC)(=O)CCC>[C:2]([O:6][CH:2]([CH3:1])[CH2:3][CH2:4][CH3:5])(=[O:6])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)O
Agent: CCCC(=O)OC(=O)CCC
Product: CCCC(=O)OC(C)CCC
Yield: 57 %

Procedure:
Butyric anhydride (400 ml, Aldrich) was added to 2-pentanol (176 g, 2.0 mol, Aldrich) over a 1.5 hour period at 100-120° C. The mixture was heated to 160° for 4 hours. The reaction mixture was then cooled, washed with hot water, washed with aqueous sodium carbonate to remove butyric anhydride, dried over sodium sulfate, and then concentrated. Fractional distillation of the crude residue under vacuum provided 1-methylbutyl butyrate (107-110°/115-120 mm Hg, 57% yield), the structure of which was confirmed by mass spectroscopy, nuclear magnetic resonance spectroscopy, and infra red spectroscopy (not shown).
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].C1(C)C=CC=CC=1.[S:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])(=[O:21])[NH2:20].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:7][C:6]1[C:2]([C:26]2[CH:27]=[CH:28][C:23]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:24][CH:25]=2)=[C:3]([C:8]([O:10][CH3:11])=[O:9])[S:4][CH:5]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1scc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1scc(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 105 °C
Reaction time: 15 h
Yield: 74.4 %

Procedure:
To a stirred suspension of methyl 3-bromo-4-methylthiophene-2-carboxylate (compound 7a, 9.0 g, 38.0 mmol) in ethanol:toluene (100:30 ml) in sealed tube, (4-sulfamoylphenyl) boronic acid (8.46 g, 42.0 mmol) and potassium carbonate (10.57 g, 76.0 mmol) were added under a nitrogen atmosphere at room temperature (about 25° C.). Nitrogen gas was purged to this suspension for further minute at room temperature (about 25° C.) and tetrakis(triphenyl phosphine)palladium(0) (2.21 g, 1.9 mmol) was added at 25° C. and sealed tube was closed. The reaction mixture was stirred at 105° C. for 15 hr and the progress of the reaction was monitored by TLC. Reaction mixture was filtered and washed with ethyl acetate (2×100 ml). Organic layer was concentrated under reduced pressure to obtain crude product as semi-solid (11.2 g); which was purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (20% ethyl ester as trans esterified product was observed) (8.8 g, 70.70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].[OH-].[K+].I[CH2:15][CH3:16]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[O:10][CH2:15][CH3:16])[CH:5]=[O:6]
Reactant: CCI
Reactant: O=Cc1cc(F)c(O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(F)cc(C=O)cc1Cl

Procedure:
3-Chloro-5-fluoro-4-hydroxybenzaldehyde (1.0 gram, 5.7 mmol) in THF (40 mL) was heated at reflux for 17 hours with KOH (534 mg, 9.5 mmol, 1.7 eq) in water (5 mL) and iodoethane (1 mL, 2.2 eq). The reaction was then transferred to a separatory funnel with water and extracted with methylene chloride (thrice, 150 mL each). The combined organic layers were washed with 10% aqueous HCl (40 mL), dried (MgSO4), and concentrated to a viscous orange liquid to yield 1.13 g of 3-chloro-4-ethoxy-5-fluorobenzaldehyde. 1H-NMR (500 MHz, CDCl3): 9.84 (d, J=1.9 Hz, 1H), 7.71 (t, J=1.6 Hz, 1H), 7.53 (dd, J=1.9, 10.7 Hz, 1H), 4.37-4.32 (m, 2H), 1.47-1.40 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].I[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([C:21]3[CH:25]=[C:24]([CH3:26])[N:23]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:22]=3)[O:18][N:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C.[Cu]I.C(OCC)(=O)C>[CH3:26][C:24]1[N:23]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:22]=[C:21]([C:19]2[O:18][N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:11][CH:12]=3)[N:20]=2)[CH:25]=1
Reactant: OCC(F)(F)F
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(I)cc4)no3)cc2C)cc1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(OCC(F)(F)F)cc4)no3)cc2C)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
A solution of 2,2,2-trifluoroethanol (175 mg, 1.75 mmol) in DMF (2 ml) was added to sodium hydride (117 mg of a 60% suspension in mineral oil, 2.94 mmol). The mixture was stirred at 50° C. for 15 minutes. Then, 3-(4-iodophenyl)-5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazole (Example 13, 200 mg, 0.44 mmol) and copper(I) iodide (167 mg, 0.88 mmol) were added and the reaction mixture was stirred at 110° C. for one hour. The reaction mixture was cooled and water (100 mL) and ethyl acetate (100 mL) was added. The layers were separated and the organic layer was washed with water and brine and then dried with magnesium sulfate. The solvent was evaporated and the residue was purified, first using preparative HPLC and then via flash chromatography (silica, gradient elution from cyclohexane/ethyl acetate 10:1 to 3:1) to afford the title compound as a white solid (33 mg, 18%): 1H NMR (400 MHz, CDCl3) 8.19 (d, 2H), 7.13 (d, 2H), 7.07 (d, 2H), 7.03 (d, 2H), 6.78 (s, 1H), 5.42 (s, 2H), 4.42 (quart, 2H), 2.32 (s, 3H), 2.26 (s, 3H); ES-MS m/z 429 (MH)+, HPLC RT (Method D) 3.19 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][N:11]=[C:10]([C:19]([OH:21])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[CH:12][N:11]=[C:10]([C:19]([NH:31][CH2:30][C:28]3[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=3)=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC2CC2)cn1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cc(-c2ccc(Cl)cc2)c(OCC2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(cyclopropylmethyloxy)-pyridine-2-carboxylic acid (example H) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 453.0924 (M+H)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:12]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15].[CH3:22][S:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C1COCC1>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([S:23][CH3:22])=[CH:25][CH:26]=2)[N:20]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CSc1ccc(N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(Nc2nc(Cl)ccc2C(N)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
A 1 M THF solution of LiHMDS (6.06 mL, 6.06 mmol) was added dropwise to a mixture of 2,6-dichloronicotinamide (331 mg, 1.733 mmol) and 4-(methylthio)aniline (289 mg, 2.079 mmol) in THF (20 mL) at 0° C. The resulting brown solution was stirred at 0° C. for 5 min, at room temperature for 30 min, quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3×25 mL). The combined extracts were washed with brine (5 mL), dried (MgSO4), and concentrated. Silica gel chromatography, eluting with 30-70% EtOAc in hexanes, gave the desired product as tan solid (376 mg, 74% yield). LCMS: (M+H)+=293.9. 1H NMR (400 MHz, chloroform-d) δ ppm 10.74 (1H, s), 7.54-7.73 (3H, m), 7.20-7.36 (2H, m), 6.68 (1H, d, J=8.03 Hz), 5.84 (2H, br. s.), 2.48 (3H, s).