Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)C.O1CCCC1.[Si:31]([O:48][CH2:49][C:50]1[S:54][C:53]([CH:55]=[O:56])=[N:52][N:51]=1)([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[Si:31]([O:48][CH2:49][C:50]1[S:54][C:53]([C:55](=[O:56])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:52][N:51]=1)([C:44]([CH3:45])([CH3:46])[CH3:47])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)[Si](OCc1nnc(C=O)s1)(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1nnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
To a solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.97 g) in a mixed solvent of ethanol (20 mL) and tetrahydrofuran (20 mL) were added 5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3,4-thiadiazole-2-carbaldehyde (1.51 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (139 mg) and triethylamine (281 μL), and the mixture was stirred with heating under reflux for 30 min and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.95 g, yield 59%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])=[C:11]3[CH2:22][CH2:23][CH2:24][C:10]3=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:32](Cl)([CH3:35])(=[O:34])=[O:33]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][O:15][S:32]([CH3:35])(=[O:34])=[O:33])=[C:11]3[CH2:22][CH2:23][CH2:24][C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethanol (250 mg, 0.72 mmol; example 1.4) in dry dichloromethane (5 ml) was added triethylamine (0.32 ml, 1.19 mmol) at 25° C. Mesyl chloride (0.16 ml, 0.725 mmol) was added dropwise at 0° C. The reaction mixture was allowed to stir at 25° C. for 2 h, diluted with water (5 ml), and the aqueous layer was extracted with dichloromethane (3×10 ml). The combined organic layers were washed sequentially with ice water (10 ml), 10% aqueous NaHCO3 solution (10 ml), brine (10 ml) and finally dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound as light yellow oil (250 mg, 0.58 mmol; 81%), which was sufficiently pure to be used in the next reaction step.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]([Cl:15])([Cl:14])[C:7]([C:9]1[NH:10][CH:11]=[CH:12][CH:13]=1)=[O:8]>C(OC(=O)C)(=O)C>[Cl:15][C:6]([Cl:5])([Cl:14])[C:7]([C:9]1[NH:10][CH:11]=[C:12]([N+:1]([O-:4])=[O:2])[CH:13]=1)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: O=C(c1cc([N+](=O)[O-])c[nH]1)C(Cl)(Cl)Cl
Temperature: -40 °C
Reaction time: 6 h
Yield: 55 %

Procedure:
Nitric acid (90%, 2 mL) was added dropwise over a period of 30 minutes to a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone (II) (1 g, 4.7 mmol) in acetic anhydride (10 ml), cooled to −40° C. The reaction mixture was allowed to warm up slowly to room temperature and stirred for 6 h. The solvent was evaporated under vacuum and the residue purified by flash chromatography (hexane-EtOAc 9:1) to obtain the compound of formula (III) as a yellow solid (670 mg, 55% yield). 2,2,2-Trichloro-1-(5-nitro-1H-pyrrol-2-yl)ethanone was also obtained as side product (349 mg, 29% yield).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:16]=[C:15]4B(O)O)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:35]1[CH:40]=[N:39][CH:38]=[C:37]([CH:41]2[CH2:43][CH2:42]2)[N:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH:41]1([C:37]2[N:36]=[C:35]([C:15]3[C:14]4[C:18](=[CH:19][CH:20]=[C:12]([C:10]5[S:11][C:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[N:8][N:9]=5)[CH:13]=4)[N:17]([S:21]([C:24]4[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:16]=3)[CH:40]=[N:39][CH:38]=2)[CH2:43][CH2:42]1
Reactant: Brc1cncc(C2CC2)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B(O)O)c3cc(-c4nnc(-c5ccccc5)s4)ccc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(-c5ccccc5)s4)ccc32)cc1
Temperature: 130 °C
Yield: 67.5 %

Procedure:
To a 20 mL microwave vial was added 5-(5-phenyl-1,3,4-thiadiazol-2-yl)-1-tosyl-1H-indol-3-ylboronic acid (245 mg, 0.515 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (14.7 mg, 0.031 mmol), Pd2(dba)3 (14.2 mg, 0.015 mmol), 2-bromo-6-cyclopropylpyrazine (118 mg, 0.593 mmol) (CombiPhos Catalysts Inc.) and potassium phosphate (328 mg, 1.55 mmol) followed by purging with argon. The solids were treated with dioxane (4.0 mL) and H2O (0.4 mL) and heated in the microwave at 130° C. for 20 min. The mixture was treated with H2O and extracted with EtOAc, dried over MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-80% EtOAc in Hex) to give 2-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-5-phenyl-1,3,4-thiadiazole (191 mg, 67%) as a light yellow amorphous solid. (ESI, pos. ion) m/z: 550.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.01 (1H, s), 8.77 (1H, s), 8.43 (1H, s), 8.17-8.22 (2H, m), 8.11-8.16 (1H, m), 8.03 (2H, dd, J=6.6, 2.8 Hz), 7.86 (2H, d, J=8.4 Hz), 7.48-7.55 (3H, m), 7.28 (2H, d, J=8.4 Hz), 2.36 (3H, s), 2.14-2.22 (1H, m), 1.29-1.34 (2H, m), 1.17-1.24 (2H, m).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:21][OH:22])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1)[CH2:21][O:22][C:24]1[CH:25]=[C:26]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1
Reactant: OCc1ccc(Oc2cncc(C(F)(F)F)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cncc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, (3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:28].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:24]=[CH:23][C:22]([C:25]([OH:28])=[O:26])=[CH:21][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formyl-N-3-pyridinylbenzamide (may be prepared as described in Example 82; 100 mg, 0.29 mmol) in acetone (10 ml) was added potassium permanganate (67.7 mg, 0.43 mmol) as a solution in 10 ml of water. The mixture was stirred at room temperature overnight. The mixture was quenched by adding 10 ml of 5% sodium sulfite solution. The solution was filtered through celite and mixed with 1 ml of acetic acid. The mixture was evaporated to a third volume, water (20 ml) was added and the mixture was filtered to yield the title compound as a white solid. This contains about 10% starting material and was used directly without further purification. 63 mg.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:26][C:12]2([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)[N:13]=[C:14]([NH:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:15][CH2:16][CH:11]2[CH2:10]1)(C(C)(C)C)(C)C.F[Si-2](F)(F)(F)(F)F.[H+].[H+]>C(#N)C.C(OCC)(=O)C>[OH:8][CH:9]1[CH2:26][C:12]2([C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)[N:13]=[C:14]([NH:17][C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:15][CH2:16][CH:11]2[CH2:10]1
Reactant: COc1cccc(-c2cccc(C34CC(O[Si](C)(C)C(C)(C)C)CC3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Agent: [H+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cccc(C34CC(O)CC3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of racemic N-((4aRS,6RS,7aSR)-6-(tert-butyldimethylsilyloxy)-7a-(3′-methoxybiphenyl-3-yl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (1.47 g, 2.31 mmol) in acetonitrile (6 mL) is added 20-25% aqueous fluorosilicic acid (2.82 g, 4.62 mmol) and the resulting mixture is stirred at room temperature for 3 h. The reaction is diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The mixture is washed with water and brine. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with a linear gradient of 10% to 60% ethyl acetate in hexanes over 40 minutes to give the title compound as a racemic mixture (0.709 g, 64%). ES/MS m/e: 459 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[CH:19][C:18]([F:30])=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([F:16])=[C:9]([NH:11][S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=1.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:30][C:18]1[CH:17]=[C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([F:16])=[C:9]([NH:11][S:12](=[O:14])(=[O:15])[NH2:13])[CH:10]=2)[C:2]([NH:1][S:34]([CH:31]2[CH2:33][CH2:32]2)(=[O:36])=[O:35])=[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[CH:19]=1
Reactant: Nc1c(Nc2ccc(I)cc2F)cc(F)cc1Oc1ccc(F)c(NS(N)(=O)=O)c1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: NS(=O)(=O)Nc1cc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)ccc1F
Temperature: 0 °C
Reaction time: 18 h
Yield: 6.2 %

Procedure:
547 mg crude N-(5-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}-2-fluorophenyl)sulfuric diamide (Intermediate 14.A) (0.993 mmol, 1. eq.) was dissolved in 8.5 mL pyridine, cooled to 0° C. and treated with 140 mg cyclopropanesulfonyl chloride (0.993 mmol, 1 eq.). The reaction mixture was stirred at rt for 18 h. Another 70 mg of cyclopropanesulfonyl chloride (0.497 mmol, 0.5 eq.) were added and stirring was continued for 24 h. The reaction mixture diluted with toluene and concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the aqueouse layer reextracted twice with ethyl acetate. The combined organic layers were washed once with half saturated brine and once with brine, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (n-hexane/ethyl acetate gradient) providing 40 mg of the desired product (6% yield).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[C:15]([O:17]C)=[O:16].COC1C=CC2C(=CC=CC=2)C=1C([O-])=O.[Na+].Cl>CO.O>[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Agent: COc1ccc2ccccc2c1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2ccccc2c1C(=O)O
Reaction time: 8 h
Yield: 95 %

Procedure:
50% Aqueous sodium hydroxide was added to a solution of this methyl 2-methoxynaphthoate in methanol (400 mL). The mixture was refluxed, and water (300 mL) was added at a rate which kept the forming sodium 2-methoxynaphthoate in solution. After the water was added, the reaction was refluxed an additional 3 hours, then allowed to stand at room temperature overnight. The resulting solid mass was acidified with concentrated HCl, then was diluted with water (1 liter) and the product collected by filtration. Vacuum drying gave 50.96 g of 2-methoxy-1-naphthoic acid, a 95% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Mg].BrC(Br)C.[C:14](Cl)(=[O:18])[C:15]([Cl:17])=[O:16]>C1COCC1.CCOCC>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14](=[O:18])[C:15]([Cl:17])=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1Br
Agent: CC(Br)Br
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)C(=O)Cl
Reaction time: 1 h
Yield: 95.8 %

Procedure:
In a stream of argon gas, 2-bromotoluene (8.55 g, 0.05 mol) in dry THF (60 ml) was dropwise added to a mixture of magnesium (2.43 g, 0.1 mol) and dibromoethane (0.1 ml) in dry THF (10 ml) at 50° to 60° C. for 13 minutes. The reaction mixture was stirred at 60° to 65° C. for 1 hour, diluted with dry THF (30 ml) and cooled below 20° C. This mixture was dropwise added to oxalyl chloride (7.62 g, 0.06 mol) in dry ether (150 ml) below -50° C. over 8 minutes, followed by stirring at -75° C. for 1 hour, and filtered in a stream of argon gas at room temperature. The filtrate was concentrated under reduced pressure at room temperature. The precipitated crystals were filtered in a stream of argon gas and washed with dry ether. The filtrate and the wash liquid were combined together and the solvent was distilled off under reduced pressure to give crude 2-(2-methylphenyl)glyoxyloyl chloride (8.75 g; yield, 95.8%) as a pale brown oil.
Reaction SMILES: [S:1]([NH2:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].N1C=CC=CC=1.[CH3:18][O:19][CH2:20][C:21](Cl)=[O:22].O>O1CCOCC1>[CH3:18][O:19][CH2:20][C:21]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([S:1](=[O:10])(=[O:2])[NH2:11])=[CH:8][CH:7]=1)=[O:22]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COCC(=O)Nc1ccc(S(N)(=O)=O)cc1
Reaction time: 2 h

Procedure:
10 g (0.06 mol) of sulfanilamide are suspended in 150 ml of dioxane and 4.6 g (60 mmol) of pyridine are added. 6.3 g (60 mmol) of methoxyacetyl chloride are then added at 0° C., and stirring is continued for 2 hours at room temperature. The mixture is stirred into 200 ml of water, and the precipitate which separates out is filtered off with suction and dried;
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[C:14]1[CH:18]=[CH:17][S:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].IC1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C.O>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[C:2](=[O:1])[CH:11]=1
Reactant: Cc1cc(O)nc2ccccc12
Reactant: Brc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Ic1ccccc1
Product: Cc1cc(=O)n(-c2ccsc2)c2ccccc12

Procedure:
A mixture of 0.8 g of 2-hydroxy-4-methylquinoline, 1.22 g of 3-bromothiophene, 0.69 g of potassium carbonate and 1.9 g of iodobenzene in 10 mL of DMF is heated to reflux for 16 hours. The reaction is worked up with water and ethyl acetate and the desired product is isolated by column chromatography.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([C:10]1[N:11]=[C:12]([CH3:16])[O:13][C:14]=1[CH3:15])(=[O:9])[CH3:8]>>[CH3:16][C:12]1[O:13][C:14]([CH3:15])=[C:10]([C:7]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)([OH:9])[CH3:8])[N:11]=1
Reactant: CC(=O)c1nc(C)oc1C
Reactant: Brc1ccsc1
Product: Cc1nc(C(C)(O)c2ccsc2)c(C)o1

Procedure:
Starting with 3-bromothiophene and 4-acetyl-2,5dimethyloxazole and following the general method of Example 4 the title compound was prepared. M.p. 83°-84° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:19]([O:30][C@@H:31]3[O:57][C@H:56]([CH2:58][O:59]C(=O)C(C)(C)C)[C@@H:48]([O:49]C(=O)C(C)(C)C)[C@H:40]([O:41]C(=O)C(C)(C)C)[C@H:32]3[O:33]C(=O)C(C)(C)C)=[N:20][N:21]([CH2:26][CH2:27][CH2:28][OH:29])[C:22]=2[CH:23]([CH3:25])[CH3:24])=[C:13]([CH3:66])[CH:12]=1)(=[O:3])[NH2:2].C[O-].[Na+]>CO>[C:1]([CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:19]([O:30][C@@H:31]3[O:57][C@H:56]([CH2:58][OH:59])[C@@H:48]([OH:49])[C@H:40]([OH:41])[C@H:32]3[OH:33])=[N:20][N:21]([CH2:26][CH2:27][CH2:28][OH:29])[C:22]=2[CH:23]([CH3:25])[CH3:24])=[C:13]([CH3:66])[CH:12]=1)(=[O:3])[NH2:2]
Reactant: Cc1cc(OCCCNCCC(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn(CCCO)c1C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(OCCCNCCC(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn(CCCO)c1C(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a solution of 4-[(4-{3-[2-(carbamoyl)ethylamino]-propoxy}-2-methylphenyl)methyl]-1-(3-hydroxypropyl)-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.3 g) in methanol (6 mL) was added sodium methoxide (28% methanol solution, 0.25 mL), and the mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (0.16 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2].[OH-].[Na+].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[CH3:26].Cl>CCO.O>[OH:17][C:18]1[CH:25]=[CH:24][C:21](/[CH:22]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=2[CH3:14])=[O:3])=[CH:20][C:19]=1[CH3:26]
Reactant: Cc1cc(C=O)ccc1O
Reactant: CC(=O)Nc1ccc(C(C)=O)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)/C=C/c2ccc(O)c(C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of N-(4-acetyl-3-methylphenyl)acetamide (1.3 g, 7.0 mmol) and NaOH (1.4 g, 36 mmol) in 25 mL of absolute EtOH was added 4-hydroxy-3-methylbenzaldehyde (1.0 g, 7.3 mmol). The reaction mixture was stirred at room temperature for 18 hr. 5 mL of water was added and the reaction mixture was acidified with concentrated HCl to pH 5-6. The aqueous layer was extracted with two 25 mL portions of EOAc, and the layers were separated. The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The resulting product was submitted to the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.O>CN(C)C=O>[S:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[CH2:25][N:4]1[C:5](=[O:16])[C:6]2[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:17]
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: BrCc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3ccccc3s1)c(=O)n2C
Yield: 90 %

Procedure:
By utilizing the well known method, 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1a (327 mg, 1 mmol) was dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (221 mg, 1.6 mmol) and 2-bromomethyl-1,3-benzothiazole (228 mg, 1 mmol) were added to give a reaction mixture. The reaction mixture was reacted overnight at room temperature and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was poured into water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 2b (400 mg, yellow solid), yield: 90%.
Reaction SMILES: [Br-].[CH2:2]([Zn+])[CH:3]([CH3:5])[CH3:4].Br[C:8]1[CH:9]=[C:10]([C@:15]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([F:34])[CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:12][C:13]=1[F:14]>CN1C(=O)CCC1.C1COCC1.CCOC(C)=O>[F:14][C:13]1[CH:12]=[CH:11][C:10]([C@:15]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([F:34])[CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][C:8]=1[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(Br)c1
Reactant: CC(C)C[Zn+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)Cc1cc([C@](N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Temperature: 75 °C
Yield: 18 %

Procedure:
To a solution of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(H) dichloride (8 mg, 0.01 mmol) in NMP (0.5 mL) was added isobutylzinc(II) bromide in THF (0.5 M, 0.7 mL, 0.35 mmol) followed by (S)-1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine, prepared as described Procedure 62, 5 and 6, (50 mg, 0.11 mmol) in anhydrous THF. The reaction mixture was heated at 75° C. overnight. The reaction mixture was diluted with EtOAc and the organic layer was washed with sat. NH4Cl, dried over Na2SO4 and concentrated to yield (R)-1-(4-fluoro-3-isobutylphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine. LCMS: RT=3.62 min [M−NH2] 417 (Waters Sunfire-S5-C18 4.6×50 mm, eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).