Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=3)[N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:10]=2)[CH:6]=[N:5]1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9]([C:7]3[CH:6]=[N:5][N:4]([CH2:3][CH2:2][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[CH:8]=3)=[CH:10][N:11]2[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:16][CH:15]=1
Reactant: C1CNCCN1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CCBr)c2)c2ccc(F)cc21
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CCN3CCNCC3)c2)c2ccc(F)cc21
Yield: 68.2 %

Procedure:
Following the general method as outlined in Example 28, starting from 3-(1-(2-bromoethyl)-1H-pyrazol-4-yl)-6-fluoro-1-(phenylsulfonyl)-1H-indole (Intermediate 22; 100 mg; 0.22 mmol) and piperazine (38 mg; 0.44 mmol), 68 mg (68%) of the title compound was obtained as a yellow solid after purification by preparative TLC (DCM/MeOH=10/1).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:30])=[CH:23][CH:24]=1
Reactant: NCCCSc1ccncc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 78.9 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 846 mg (4.96 mmol) of 4-anisoyl chloride under ice-cooling with stirring and the mixture was stirred for at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with ether and dried to obtain 990 mg of the desired compound (78.9%, colorless powder), mp: 121.0°-122.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=1.C1C(=O)N([Cl:40])C(=O)C1>>[Cl:40][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@H:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Yield: 8.3 %

Procedure:
Following General Procedure H, (R)-tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate (300 mg, 0.67 mmol) was reacted with NCS (110 mg, 0.87 mmol) to afford the desired product (27 mg, 11%) as a yellow solid: ESI MS m/z 485 [C25H25ClN2O4S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13](O)=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([Cl:25])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1c(-c2ccccc2)nc2ccccc2c1C(=O)Cl

Procedure:
3-Methyloxy-2-phenylquinoline-4-carboxylic acid (200 mg, 0.72 mmol) [J. Med. Chem. 1999, 42, 1053-1065] was suspended in CH2Cl2 (5 mL) at 0° C. and oxalyl chloride (62 μL, 0.72 mmol) was added with stirring. After stirring at 0° C. for 1 h the cooling bath was removed and the solution allowed to stir at room temperature for 18 h. After this time the solvent was evaporated and the crude acid chloride used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([C:30](=[O:32])[CH3:31])[CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Product: CCOC(=O)c1c(CN(C)C(C)=O)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-methylaminomethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 86.1.) was reacted with acetyl chloride as described in Example 77.1. to give 3-[(acetyl-methyl-amino)-methyl]-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a pale yellow solid. MS: 403.5 ([M−H]−).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1.BrBr.C([O:17]CC)C>CS(C)=O>[ClH:1].[ClH:1].[NH2:12][C:9]1[NH:8][C:7](=[CH:6][CH2:5][CH2:4][NH2:3])[C:11](=[O:17])[N:10]=1
Reactant: NCCCc1c[nH]c(N)n1
Reactant: CCOCC
Agent: BrBr
Agent: Cl
Solvent: CS(C)=O
Product: NCCC=C1NC(N)=NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-amino-propyl)-1H-imidazol-2-ylamine 16 (0.200 g, 0.930 mmol) was dissolved in anhydrous dimethyl sulfoxide (6 mL). Bromine (0.047 mL, 0.930 mmol) was added drop-wise and the solution was stirred at room temperature for 1 h. Diethyl ether (7 mL) was added and the organics were then decanted. The residue was purified by column chromatography (MeOH sat. with NH3) to yield the desired product as its free base. Addition of concentrated hydrochloric acid to a methanol solution (8 mL) of the free base followed by evaporation under reduced pressure afforded the target compound ((Z)-isomer exclusively) (0.141 g, 67%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 12.10 (br s, 1H), 9.20 (br s, 2H), 8.18 (br s, 2H), 5.92 (t, 1H, J=7.8 Hz), 2.96 (m, 2H), 2.66 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 164.13, 156.63, 130.88, 113.70, 37.57, 24.94; HRMS (FAB) calcd for C6H10N4O (MH+) 155.0933. Found 155.0943.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:24])[CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:24])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
The solution of 4.0 g of N-(4-nitro-o-tolyl)-4-carboxyphthalimide in 200 ml of ethyl acetate is hydrogenated over 1.0 g of platinum oxide at 2.5 atm. and about 40° for 50 minutes. The suspension obtained is evaporated, the residue taken up in 50 ml of dimethylformamide, the mixture filtered, the filtrate evaporated and the residue triturated with 100 ml of ethanol, to yield the N-(4-amino-o-tolyl)-4-carboxyphthalimide melting at 280°. Analogously the N-(4-amino-o-tolyl)-4-carbomethoxyphthalimide is prepared, melting after recrystallization from ethyl acetate-diethyl ether at 161°-162°.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12]([N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:15]1[C:24](=[O:34])[NH:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])=[O:13])[CH:9]([CH3:11])[CH3:10])(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:24]([C@@H:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][N:14]1[C:12](=[O:13])[C@@H:8]([NH2:7])[CH:9]([CH3:11])[CH3:10])=[O:34]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](N)C(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {(S)-1-[(S)-1-(2-chloro-6-fluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-methyl-propyl}-carbamic acid tert-butyl ester (47 mg, 93.3 μmol, Eq: 1.00) in CH2Cl2 (3 mL) was added TFA (1 mL) dropwise. The reaction was stirred at RT for 1 h. The mixture was evaporated to provide (S)-2-((S)-2-amino-3-methyl-butyryl)-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2-chloro-6-fluoro-phenyl)-amide trifluoroacetate which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5](B(O)O)[C:4]=2[CH:3]=[CH:2]1.Br[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1/[C:16](=[CH:24]/[C:25]1[NH:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[C:17](=[O:23])[NH:18]2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH:1]1[C:9]2[C:4](=[C:5]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3/[C:16](=[CH:24]/[C:25]3[NH:26][CH:27]=[CH:28][C:29]=3[O:30][CH3:31])/[C:17](=[O:23])[NH:18]4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc4[nH]ccc34)c21
Temperature: 90 °C
Yield: 38.1 %

Procedure:
A solution of 4-indoleboronic acid (64 mg, 0.40 mmol) (from Step A above), (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.31 mmol) (Starting Material 7), and sodium carbonate (35 mg, 0.33 mmol) in 3 mL DME and 1 mL water was degassed for 15 min. by bubbling argon through the solution. Dichlorobis(triphenylphosphine)palladium (II) (13 mg) (Aldrich) was then added and the reaction was heated at 90° C. for 2 days. The reaction was then poured into 100 mL water and the product was extracted with ethyl acetate (4×50 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified via flash column chromatography (1% CH3OH in CHCl3) to yield 42 mg (38%) orange powder.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([NH2:19])(=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOCC>C(O)C>[C:12]1([C:11]2[S:18][CH:2]=[C:3]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CC(=O)CBr
Reactant: NC(=S)c1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)Cc1csc(-c2ccccc2)n1

Procedure:
Ethyl γ-bromoacetoacetate [2.62 g, 0.9-1.0 mole, described by A. Burger and G. E. Ullyot, J. Org. Chem., 12, 346 (1947)]is added in one portion to a suspension of thiobenzamide [117.5 g, 0.857 mole, described by A. Silberg et al., Ber., 94, 2887 (1961)] in ethanol. The clear solution is refluxed on a steam bath for 2 hr, cooled and slowly added with stirring to ether (3500 ml). The white crystalline precipitate is collected, washed with ether and partitioned between water and ether. Sodium bicarbonate is added in portions until the mixture is alkaline. The mixture is extracted with ether, the ether solution is washed with saturated sodium chloride solution, dried, and evaporated to give ethyl 2-phenylthiazole-4-acetate (VII; R1 = H, R9 = CH2CH3), γmaxCHCl3 1725 cm-1.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[S:3](OC1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)(=[O:5])=[O:4].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:36]([OH:46])=[C:37]([CH3:45])[CH:38]=[C:39]3[C:44]=2[N:43]=[CH:42][CH:41]=[CH:40]3)=[CH:31][CH:30]=1>>[F:1][C:2]([F:27])([F:26])[S:3]([O:46][C:36]1[C:35]([C:32]2[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][CH:33]=2)=[C:44]2[C:39]([CH:40]=[CH:41][CH:42]=[N:43]2)=[CH:38][C:37]=1[CH3:45])(=[O:5])=[O:4]
Reactant: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1O
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(OS(=O)(=O)C(F)(F)F)c(Cl)cc2n1
Product: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1OS(=O)(=O)C(F)(F)F

Procedure:
Compound 4D was prepared following the procedure used to prepare compound 1F of example 1, except that 8-(4-chloro-phenyl)-6-methylquinolin-7-ol (4C) was used instead of compound 1E. LCMS-ESI+ (m/z): 402.0, 403.9 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/c1ccc(C(C)(C)C)c([N+](=O)[O-])c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(/C=C/CO)cc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
A solution of 9.24 g (33.4 mmol) of 2-t-butyl-5-[(E)-2-ethoxycarbonyl-ethenyl]-1-nitrobenzene [prepared as described in step (ii) above] in 200 ml of tetrahydrofuran was cooled to -70° C. in a dry ice-acetone bath, and 100 ml (100 mmol) of a 1M solution of diisobutylaluminum hydride in tetrahydrofuran were added dropwise thereto over a period of 45 minutes. The resulting mixture was then stirred for a further 30 minutes. At the end of this time, the reaction temperature was allowed to rise to 0° C., and the reaction was quenched by adding dropwise a mixture of 4 ml of methanol and 20 ml of tetrahydrofuran. The reaction mixture was then poured into 2N aqueous hydrochloric acid-ice, after which it was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 300 g of silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 7.06 g (yield 90%) of the title compound as an oily substance.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[C:10]1([NH:16][CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[F:9][C:2]([F:1])([F:8])[C:3]([NH:19][CH2:18][CH2:17][NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCNc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCNc1ccccc1)C(F)(F)F
Temperature: 25 °C
Yield: 114.4 %

Procedure:
Ethyl trifluoroacetate [383-63-1] (5.5 mL, 46.1 mmol) was added to a stirred, 0° C., solution of N1-phenylethane-1,2-diamine [1664-40-0] (5.0 mL, 38.4 mmol) in THF (125 mL) and was allowed to stir and warm to ambient temperature under N2 blanket over 17 h then was partitioned between brine and ethyl acetate. The extract was dried (MgSO4) and evaporated to provide 10.2 g of clear dark yellow liquid. LRMS (ESI) m/z 232.9 [(M+H)]+, calc'd for C10H11F3N2O: 232.21.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:13]([O:17][C:18](=[O:22])[CH:19](Br)[CH3:20])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[N:6]=[CH:5][N:4]([CH:19]([CH3:20])[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22])[N:3]=1
Reactant: Cc1nc[nH]n1
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ncn(C(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of 3-methyl-1H-1,2,4-triazole (7.3 g, 88 mmol) in DMF (75 mL) was added K2CO3 (60.7 g, 439 mmol) and 2-bromopropionic acid tert-butyl ester (14.6 mL, 88 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc (500 mL), washed with water (×3) then brine. Dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane (20 to 100%) to give 13 g of crude product as a 3:1 mixture of regioisomers. The mixture was purified by Chiralcel OD with a gradient from 4% to 30% IPA/Heptane. Then the first two peaks were separated with Chiracel OD column isocratically eluting with 4% IPA/Heptane. The second peak was collected as the desired single stereoisomer (R or S) (2-(3-methyl-1H-1,2,4-triazol-1-yl)propanoic acid tert-butyl ester) (3.5 g, 19%). 1H-NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 4.90 (q, J=7 Hz, 1H), 2.35 (s, 3H), 1.72 (d, J=7 Hz, 3H), 1.40 (s, 9H). ESI-MS calculated for C10H17N3O2: Exact Mass: 211.13. Found 156.05 (-tBu).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Cu]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2](=[O:1])[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]=1
Reactant: Ic1ccccc1
Reactant: Cc1ccc(O)nc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(=O)n(-c2ccccc2)c1
Temperature: 185 °C
Yield: 55.4 %

Procedure:
A finely pulverized mixture of 2-hydroxy-5-methylpyridine (0.500 g, 4.58 mmol), anhydrous potassium carbonate (0.693 g, 6.41 mmol), copper powder (0.006 g, 0.09 mmol) and iodobenzene (1.68 g, 8.26 mmol) was heated at 180-190° C. for 7 hours. The mixture was cooled, and standard extractive workup was performed to afford a brown residue which was triturated with petroleum ether and recrystallized from hot water to yield the title compound as a white solid (0.470 g, 56%). m.p. 105-107° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.50 (s, 3H), 6.43 (d, J=9.3 Hz, 1H), 7.36-7.53 (m, 7H); IR (KBr) ν 3045, 1675, 1611, 1531, 1270 cm−1; MS 186 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[Br:13]Br>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Br:13])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrBr
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Solvent: ClCCl
Product: Cc1cc(Br)c(O)c(C(C)(C)C)c1
Reaction time: 0.33 h

Procedure:
2-t-Butyl-4-methylphenol (10 g, 60.8 mmol) is dissolved in CH2Cl2 (300 mL). Bromine (3.1 mL, 60.8 mmol) is added dropwise to the solution. After 20 minutes, the crude mixture is washed with H2O, dried over MgSO4, filtered and rotovapped to give yellow oil: 12.6 g, 85%. 1H NMR (CDCl3) δ: 1.402 (s, 9H, t-Bu), 2.267 (s, 3H, CH3), 5.640 (s, 1H, OH), 7.017 (s, 1H, Ar), 7.167 (s, 1H, Ar).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH2:11]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:12]1[O:14][CH2:13]1.Cl>>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:13][CH:12]([OH:14])[CH2:11][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22]
Reactant: COCCOCCOCC1CO1
Reactant: COCCOCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COCCOCCOCC(O)COCCOCCOC
Temperature: 70 °C
Yield: 74.9 %

Procedure:
44.0 g (1.1 mol) of NaOH pellets were added to 360 g (3.0 mol) of diethyleneglycol monomethyl ether, and 176 g (1.0 mol) of 2-(2-methoxyethoxy)ethyl glycidyl ether was gradually dropwise added while stirring at 70° C. After the completion of dropwise addition, the mixture was stirred for about one hour and then stood for cooling at room temperature. Then, the mixture was neutralized with hydrochloric acid, a precipitated salt was filtered off and the liquid was condensed. The liquid was purified by vacuum distillation to give 222 g of 1,3-bis[2-(2-methoxyethoxy)ethoxy]-2-propanol (yield: 75%). The distillation temperature was from 171 to 175° C./0.8 mmHg.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH:31]([CH3:33])[CH3:32])[CH3:15])=[CH:8][C:7]=1[CH3:34].[OH-].[Na+].Cl>O1CCCC1.C(OCC)C>[CH:31]([C:17]1[N:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=2)[S:20][C:16]=1[CH:14]([CH3:15])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]([CH3:34])[CH:8]=1)([CH3:32])[CH3:33]
Reactant: COC(=O)CCc1ccc(OCC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(OCC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)ccc1CCC(=O)O
Temperature: 25 °C

Procedure:
3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionic acid methyl ester (239 mg, 0.4725 mmol) is dissolved in tetrahydrofuran (1 mL) and 5N NaOH (1 mL) is added. The mixture is heated to reflux until the conversion is complete. Upon complete conversion, the reaction is cooled to room temperature and 5N HCl (1 mL) is added. The mixture is diluted with diethyl ether and extracted with 1N HCl. The organic layer is washed with water and brine, then dried over anhydrous sodium sulfate. Concentration of the solvent reveals the pure 3-(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-propionic acid in near quantitative yield (221 mg, 0.4489 mmol).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](=[O:14])[CH3:13]>>[C:1]1([N:7]2[C:11]([CH:12]([OH:14])[CH3:13])=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC=O
Reactant: c1ccc(-n2cccn2)cc1
Product: CC(O)c1ccnn1-c1ccccc1
Yield: 54 %

Procedure:
This compound was prepared from 1-phenyl-1H-pyrazole and acetaldehyde using the method described in example 10B and isolated as a yellow oil in 54% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9](=[S:25])[NH:8][C:7]=2[N:26]=1.C(=O)([O-])O.[Na+].I[CH2:33][CH2:34][CH3:35].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=3)[C:9]([S:25][CH2:33][CH2:34][CH3:35])=[N:8][C:7]=2[N:26]=1
Reactant: CCCI
Reactant: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 7-methoxy-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (153 mg), 1M aqueous sodium hydrogen carbonate solution (439 μl), 1-iodopropane (117 μl) and N,N-dimethylformamide (3 ml) was stirred at 80° C. for 10 min. The reaction mixture was allowed to be cooled, and water (20 ml) was added thereto. The white precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran (10 ml). The solution was diluted with ethyl acetate (20 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of ethyl acetate/heptane to give the title compound (114 mg) as cotton-like needle crystals.