Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][C:7]=1[O:14][CH3:15])=[O:4].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[CH2:25][NH:24][CH2:23][CH2:22]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]([CH3:16])[C:3]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:24]2[CH2:23][CH2:22][C:21]3[C:26](=[CH:27][C:28]([O:29][CH3:30])=[C:19]([O:18][CH3:17])[CH:20]=3)[CH2:25]2)=[CH:8][C:7]=1[O:14][CH3:15])=[O:4]
Reactant: COc1cc(C=O)ccc1OC(=O)N(C)C
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc2c(cc1OC)CN(Cc1ccc(OC(=O)N(C)C)c(OC)c1)CC2

Procedure:
To a solution of 4-(dimethylaminocarbonyloxy)-3-(methoxy)benzaldehyde (1.02 g) in 1,2-dichloroethane (16 ml) was added 6,7-dimethoxytetrahydroisoquinoline(0.97 g) and sodium triacetoxyborohydride (1.35 g), with stirring. The mixture was stirred at ambient temperature for 1 hr, poured onto ice/sodium carbonate solution and extracted with ethyl acetate. The extracts were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash column chromatographed (silica gel), eluting with dichloromethane, 1% and 2% methanol dichloromethane. The appropriate fractions were collected and concentrated to give 0.92 g (50.3%/o) of product. Recrystallization from ethyl acetate gave the analytical sample, mp 126-128° C.
Reaction SMILES: C(N1C2C(=CC=CC=2)C(COC(C)(C)CO)=N1)C1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:49]=[CH:48][C:29]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]([CH2:40][O:41][C:42]([CH3:47])([CH3:46])[C:43](O)=[O:44])=[N:32]2)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]([CH2:40][O:41][C:42]([CH3:47])([CH3:46])[CH2:43][OH:44])=[N:32]2)=[CH:48][CH:49]=1
Reactant: COc1ccc(Cn2nc(COC(C)(C)C(=O)O)c3ccccc32)cc1
Agent: CC(C)(CO)OCc1nn(Cc2ccccc2)c2ccccc12
Product: COc1ccc(Cn2nc(COC(C)(C)CO)c3ccccc32)cc1

Procedure:
The product was obtained with the method described for the preparation of compound 39a, using 2-{[1-(4-methoxybenzyl)-1H-indazol-3-yl]methoxy}-2-methylpropanoic acid as starting material.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:23][N:14]1[CH:13]=[C:12]([C:4]2[CH:3]=[C:2]([O:1][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:22]
Reactant: Cn1cc(-c2cc(O)cc(S(C)(=O)=O)c2)c2ccccc2c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(OCc3ccccc3)cc(S(C)(=O)=O)c2)c2ccccc2c1=O
Temperature: 80 °C
Yield: 37.6 %

Procedure:
A capped mixture of 4-(3-hydroxy-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (25 mg, 0.076 mmol), benzyl bromide (20 mg, 0.12 mmol), and Cs2CO3 (50 mg, 0.15 mmol) in DMF (600 uL) was heated to 80° C. for 3 h. The mixture was filtered and the filter cake was washed with ACN (500 uL), the filtrate was purified by prep-HPLC to afford the title compound (12 mg, 38%) as a tan solid. LCMS (M+H)+=420.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH2:33][CH2:34][CH2:35][CH3:36])=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)=[CH:11][C:10]=1[CH3:37])([CH3:7])[CH3:6])C.[Li+].[OH-]>O1CCCC1.CCOCC>[CH2:33]([C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[C:10]([CH3:37])[CH:11]=2)=[CH:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[N:19]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc(OC(C)(C)C(=O)O)c(C)c1
Yield: 92 %

Procedure:
324 mg (0.61 mmol) of 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester and 1.83 ml 1N LiOH in 3 ml terahydrofurane were stirred over night at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude product was suspended in AcOEt/heptane 1:19. The resulting crystals were filtered off providing 282 mg pure 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:11]=[C:10]2[S:12][CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=[C:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:7]=1)[CH3:2].[C:30](=O)([O:34]CC)[O:31][CH2:32][CH3:33].[H-].[Na+]>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:6]1[N:11]=[C:10]2[S:12][CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=[C:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:7]=1)[C:30]([O:31][CH2:32][CH3:33])=[O:34])[CH3:2]
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
{3-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-yl}-acetic acid ethyl ester (180 mg, 0.45 mmol) was dissolved in dry THF (10 ml) under nitrogen. Diethyl Carbonate (0.27 ml, 2.23 mmol) was added and the mixture cooled to 0° C. Sodium Hydride (36 mg, 0.89 mmol) was added and the mixture stirred at 0° C. for a further 10 min, then at room temperature for 20 min, then brought to reflux for 45 min. On cooling, the reaction was diluted with water (100 ml) and extracted with DCM (3×50 ml), the extracts combined, dried over magnesium sulphate and concentrated. The residue was purified on silica, eluting (Ethyl Acetate/DCM), 0-20%) to give 2-{3-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-yl}-malonic acid diethyl ester as a yellow solid. Yield=96 mg (45%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:6]=1[C:26]([OH:28])=[O:27])(O)=[O:2].FC1C=C2C(C=CC=C2[CH2:40][N:41]2C3C(=CC=CC=3)C3CC(=O)OC(=O)[C:42]2=3)=CC=1.CNC>>[CH3:40][N:41]([CH3:42])[C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:6]=1[C:26]([OH:28])=[O:27])=[O:2]
Reactant: O=C(O)Cc1c(C(=O)O)n(Cc2cccc3ccc(F)cc23)c2ccccc12
Reactant: O=C1Cc2c(n(Cc3cccc4ccc(F)cc34)c3ccccc23)C(=O)O1
Agent: CNC
Product: CN(C)C(=O)Cc1c(C(=O)O)n(Cc2cccc3ccc(F)cc23)c2ccccc12

Procedure:
3-Carboxymethyl-1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid (from Example 102) was converted to 9-(7-fluoro-naphthalen-1-ylmethyl)-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione as described in Example 68.1. which was converted according to Example 68.2. but using dimethyl amine to give the title compound as a white solid. MS: 403.5 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Br:1])[CH:17]=[CH2:16]
Reactant: Oc1cc(F)ccc1Br
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cc(F)ccc1Br
Yield: 100.7 %

Procedure:
Treatment of 2-bromo-5-fluorophenol (10.00 g, 0.052 mol) with potassium carbonate (29.30 g, 0.209 mol) and allyl bromide (7.60 g, 0.063 mol) generally according to the reaction procedure described for Intermediate 8 provided 12.1 g (99%) of 2-(allyloxy)-1-bromo-4-fluorobenzene as a colorless oil. Rf=0.37 (silica, ethyl acetate:hexanes 1:9); 1H NMR (DMSO-d6) δH 7.58 (dd, 1H); 7.05 (dd, 1H); 6.75 (dt, 1H); 6.02 (m, 1H); 5.43 (d, 1H); 5.27 (d, 1H); 4.65 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:57])[CH2:7][N:8]([CH2:49][C:50](=[O:56])[O:51]C(C)(C)C)[CH:9]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)[CH2:10][N:11]([CH2:20][CH2:21][N:22]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:23][C:24](=[O:30])[O:25]C(C)(C)C)[CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])(C)(C)C.Cl.CCOCC>O1CCOCC1>[C:6]([CH2:7][N:8]([CH2:49][C:50]([OH:56])=[O:51])[CH:9]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)[CH2:10][N:11]([CH2:20][CH2:21][N:22]([CH2:23][C:24]([OH:30])=[O:25])[CH2:31][C:32]([OH:34])=[O:33])[CH2:12][C:13]([OH:15])=[O:14])([OH:57])=[O:5]
Reactant: CC(C)(C)OC(=O)CN(CCN(CC(=O)OC(C)(C)C)CC(Cc1ccc([N+](=O)[O-])cc1)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(O)CN(CCN(CC(=O)O)CC(Cc1ccc([N+](=O)[O-])cc1)N(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 122.5 %

Procedure:
To a flask containing compound 4a (50 mg, 0.0618 mmol) at 0-5° C. was added dropwise 4M HCl (g) in 1,4-dioxane (3 mL) over 10 min. The resulting mixture was gradually warmed to room temperature and continuously stirred for 40 h. Ether (20 mL) was added to the reaction mixture which was then stirred for 10 min. The resulting precipitate was filtered and washed with ether. The solid product was quickly dissolved in deionized water. The aqueous solution was concentrated in vacuo to provide 5a (40 mg, 100%) as an off-white solid. 1H NMR (D2O, 300 MHz) δ 2.63-2.82 (m, 1H), 2.96-3.40 (m, 7H), 3.40-4.05 (m, 11H), 7.39 (d, J=8.1 Hz, 2H), 8.09 (d, J=7.8 Hz, 2H); 13C NMR (D2O, 300 MHz) δ 32.7 (t), 50.2 (t), 50.7 (t), 52.5 (t), 54.0 (t), 54.9 (t), 55.3 (t), 61.1 (d), 124.1 (d), 130.3 (d), 144.5 (s), 146.8 (s), 170.4 (s), 170.9 (s), 173.5 (s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[O:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C)CCN>O1CCOCC1.[Cu](I)I>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([N:20]3[CH2:21][CH2:22][O:18][C:19]3=[O:23])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: O=C1NCCO1
Agent: I[Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1OCCN1c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Yield: 34.3 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine (150 mg), 2-oxazolidinone (103 mg), potassium phosphate tribasic (250 mg), copper iodide (7 mg), 4 μL of N,N-dimethylethylenediamine in 2 mL of 1,4-dioxane was heated to 100° C. for 15 hr. The reaction mixture was evaporated and the residue was diluted with ethyl acetate (50 mL), washed with brine (30 mL), dried over MgSO4, filtered and evaporated. The crude product was purified on reverse phase HPLC to give 46 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl) oxazolidin-2-one.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:33]=2)[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH2:23][OH:24])[N:20]=[C:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:33]=2)[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH:23]=[O:24])[N:20]=[C:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(CO)nc3-c3ccccc3Cl)c(Cl)c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C=O)nc3-c3ccccc3Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.3 %

Procedure:
To a −78° C. solution of oxalyl chloride (0.20 mL, 2.33 mmol) in 5 mL dichloromethane was added DMSO dropwise followed by (1-(3-chloro-3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-chlorophenyl)-1H-imidazol-4-yl)methanol (735 mg, 1.55 mmol) in 5 mL of dichloromethane. Triethylamine (1.3 mL, 9.30 mmol) was then added at −78° C. and the reaction was stirred 12 h and warmed to room temperature. The reaction was diluted with 50 mL ethyl acetate, washed with water 1×50 mL, brine, and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography using hexanes:ethyl acetate as eluents to afford 1-(3-chloro-3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-chlorophenyl)-1H-imidazole-4-carbaldehyde (338 mgs, 47%) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 9.90 (s, 1H), 8.56 (s, 1H), 8.22-8.21 (m, 1H), 8.12-8.09 (m, 2H), 7.97-7.94 (m, 1H), 7.84 (dd, J=8.33 Hz, J=2.04 Hz, 1H), 7.75 (t, J=7.82 Hz, 1H), 7.67-7.65 (m, 1H), 7.58-7.56 (m, 1H), 7.50-7.43 (m, 2H), 7.40-7.36 (m, 1H), 3.30 (s, 3H); MS (ES) 471.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Oc3ccc(C(F)(F)F)cc3)nccc12
Yield: 100.1 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-6, step-1 using 1-chloro-5-nitroisoquinoline (Step-1, Intermediate-1, 500 mg, 2.39 mmol), 4-(trifluoromethyl)phenol (776 mg, 4.79 mmol) and K2CO3 (989 mg, 7.17 mmol) in CH3CN (5 mL) to afford 800 mg of the title product. MS (m/z): 335.09 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](I)[CH3:8].[Br:10][C:11]1[CH:12]=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:14]([O:18][CH2:19][O:20][CH3:21])=[C:15]([OH:17])[CH:16]=1.C(OCC)(=O)C>C(#N)C>[Br:10][C:11]1[CH:16]=[C:15]([O:17][CH2:7][CH3:8])[C:14]([O:18][CH2:19][O:20][CH3:21])=[C:13]([C:22]([CH3:23])([CH3:24])[CH3:25])[CH:12]=1
Reactant: COCOc1c(O)cc(Br)cc1C(C)(C)C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1cc(Br)cc(C(C)(C)C)c1OCOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
Cesium carbonate (10.05 g, 30.9 mmol) and EtI (2.58 ml, 32.2 mmol) were added to a solution of the 5-bromo-3-(tert-butyl)-2-(methoxymethoxy)phenol (7.76 g, 26.8 mmol) in acetonitrile and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added and the reaction mixture was washed with water and brine in that order. The organic layer was dried over anhydrous magnesium sulfate and then the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (6.5 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31]/[CH:32]=[CH:33]/[C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34](=[O:35])/[CH:33]=[CH:32]/[CH2:31][N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]3)/[S:21][C:20]1=[O:22]
Reactant: COC(=O)/C=C/CBr
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COC(=O)/C=C/CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(2E)-4-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]but-2-enoic acid methyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and methyl 4-bromocrotonate following General Procedure S.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[C:17]([O:23]C(C)(C)C)[CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[C:17]([OH:23])[CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(SCc2ccc(C(C)(C)C)cc2)oc2cccc(OC(C)(C)C)c2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(SCc2ccc(C(C)(C)C)cc2)oc2cccc(O)c2c1=O

Procedure:
A 50 mL round bottomed flask is charged with 2-(4-tertbutylbenzylmercapto)-3-methyl-5-tertbutoxy chromen-4-one (10 g, 24.3 mmol). To this is then added anhydrous trifluoroacetic acid (15 mL) and the reaction mixture is stirred for 8 hours at 0° C. Dichloromethane is then added to the flask and the mixture poured into a separatory funnel. It is then washed with water and then with brine and dried over sodium sulfate and filtered. The filtrate is then concentrated in vacuo and the residue obtained is purified by silica gel flash chromatography (ethyl acetate:hexanes) to obtain the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:25])[C:18]([O:21][C:22](=[O:24])[CH3:23])([CH3:20])[CH3:19].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(OCC)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:33](=[O:35])[CH3:34])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:25])[C:18]([O:21][C:22](=[O:24])[CH3:23])([CH3:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC(C)(C)C(=O)Nc1ccc(Sc2ccc(N)cc2)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Sc2ccc(NC(=O)C(C)(C)OC(C)=O)c(Cl)c2)cc1
Temperature: 2.5 °C

Procedure:
N-[2-Chloro-4-(4-aminophenylsulphanyl)phenyl]-2-acetoxy-2-methylpropanamide (Method 22) (0.50 g) was dissolved in DCM (10 ml) and cooled to 0-5° C. in an ice bath. Triethylamine (0.46 ml) was added followed by dropwise addition of acetyl chloride (0.1 ml) and the mixture was allowed to warm to ambient temperature over 2 hours. Ethyl acetate (20 ml) was added and the solution was washed with water (2×10 ml) and brine then dried. Volatile material was removed by evaporation and the residue was purified by flash chromatography eluting with 40-80% ethyl acetate/hexane to give the title compound (0.470 g) as a solid. NMR (CDCl3): 1.8 (s, 6H), 2.2 (d, 6H), 7.2-7.3 (m, 5H), 7.5 (d, 2H), 8.3 (d, 1H), 8.4 (s, 1H); MS (ESP−): 419; EA: found: C, 56.7; H, 5.0; N, 6.0%; C20H21ClN2O4S.0.4 EtOAc requires C, 56.9; H, 5.3; N, 6.1%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:8].O1CCCC1.[CH2:27]([Mg]Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C(#N)C.O.FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH2:27]([C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:8])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(NCc1cccc(Br)c1)c1ccc2ncccc2c1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1cccc(Cc2ccccc2)c1)c1ccc2ncccc2c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a mixture of quinoline-6-carboxylic acid 3-bromobenzylamide described in Preparation Example E+-8 (8.0 mg, 0.023 mmol), dichloro(1,1′-bis(diphenylphosphino)ferrocene)nickel(II) (3.2 mg, 0.0047 mmol) and tetrahydrofuran (1 mL) was added benzylmagnesium chloride (1.1M tetrahydrofuran solution, 0.088 mL, 0.094 mmol) at room temperature, and the solution was stirred for 30 minutes at 50° C. After cooling, water and ethyl acetate were added for extraction, the solution was washed with brine, the solvent was then evaporated in vacuo. The residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt of the title compound (2.1 mg, 0.0045 mmol, 19%) was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=O)=[CH:5][CH:4]=1.[NH2:13][C@H:14](CO)[CH:15]([CH3:17])[CH3:16]>ClC1C=CC=CC=1>[CH:15]([C@H:14]1[CH2:10][O:9][C:7]([C:6]2[CH:11]=[CH:12][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[N:13]1)([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CC(C)[C@H](N)CO
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(c2ccc(CO)cc2)=N1
Yield: 66 %

Procedure:
Under an argon atmosphere, a mixture of methyl 4-hydroxymethylbenzoate (1.5 mmol), (L)-valinol (1.8 mmol), Zn4(OCOCF3)6O (0.15 mmol) and chlorobenzene (2.5 mL) was heated under reflux for 12 hours. From the resulting solution, the solvent was removed using an evaporator, and the residues were purified by silica gel column chromatography to give (S)-4-isopropyl-2-(4-hydroxymethylphenyl)-1,3-oxazoline in 66% yield. The compound was identified by comparison with physical property data of the known compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)C(=C1SCCCS1)[CH2:6][CH2:5]2.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:19]([C:18]([OH:21])=[O:20])[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCC2=C1SCCCS1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)C1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 86 %

Procedure:
To a mixture of 2-(5-bromo-indan-1-ylidene)-[1,3]dithiane (2.02 g, 6.45 mmol) in acetic acid (34 ml) was added 37% HCl (11 ml). After the addition, the brown mixture was heated to reflux for 3 h; then, the reaction mixture was allowed to cool to room temperature and was concentrated to dryness, using toluene as co-evaporating solvent to remove acetic acid and water. This process was repeated four times. The remaining brown oil was purified by chromatography (silica gel; CH2Cl2/EtOAc 100:0-0:100) to obtain the title compound as light brown solid (1.335 g, 86%). MS: 238.6 [M−H]−.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[C:18]([F:31])[C:17]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[F:15][C:16]1[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[C:18]([F:31])[CH:19]=[CH:20][C:21]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccn3)c2F)OC1(C)C
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)c(F)c1-c1ccccn1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2-[2,6-difluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine as described in Example 1 to give 3-[2,4-difluoro-3-(pyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a pale yellow solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 7.55 (1H, dd, J 9 and 9), 7.62-7.68 (2H, m), 7.86-7.96 (2H, m), 8.14 (1H, ddd, J 8, 8 and 2), 8.38 (1H, s), 8.84 (1H, d, J 5), 9.30 (1H, dd, J 7 and 3); m/z (ES+) 377 (M++H).