Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[C:8]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:7]=2.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>ClCCl>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([OH:13])=[C:3]([NH:2][C:29](=[O:32])[CH2:30][CH3:31])[CH:4]=[N:5]2)=[CH:10][CH:9]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1cnc2cc(OCc3ccccc3)ccc2c1O
Yield: 96.5 %

Procedure:
To a stirred solution of 3-amino-7-benzyloxyquinolin-4-ol hydrochloride (40.4 g, 133.4 mmol), and triethylamine (2.5 eq., 33.8 g, 333.6 mmol) in dichloromethane (1000 mL) at room temperature, was slowly added propionyl chloride (1.1 eq., 13.6 g, 146.8 mmol). After 6 hours the reaction was quenched with water (250 ml). The reaction mixture was transferred to a separatory funnel and the layers were separated. The dichloromethane layer was concentrated to provide 41.5 g of N-(7-benzyloxy-4-hydroxyquinolin-3-yl)propionamide as a pale tan crystalline solid. MS (ACPI) m/z=323 (M+H)+. This material was carried on without further purification to the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].BrC1C(OC)=C(C(CBr)=CC=1)C(OC)=O.[Cl:38]C1C=C(S)C=CC=1>>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:38])[CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Sc1cccc(Cl)c1
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Agent: COC(=O)c1c(CBr)ccc(Br)c1OC
Product: COC(=O)c1c(CSc2cccc(Cl)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 73, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 3-chlorothiophenol.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].C(OCC)C>CCCCC>[CH2:9]([N:13]([CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCNCCCC
Reactant: CCOC(=O)CCBr
Solvent: CCCCC
Solvent: CCOCC
Product: CCCCN(CCCC)CCC(=O)OCC
Reaction time: 2 h

Procedure:
Ethyl 3-bromopropionate (18.0 g; 0.10 mol) was added carefully to di-n-butylamine (25.8 g; 0.20 mol), followed by stirring for 2 hours. Then diethyl ether (200 ml) and pentane (200 ml) were added. The precipitate was filtered off, the filtrate was evaporated and the residue was distilled at sub-atmospheric pressure. The yield was 7.0 g (31%).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:12])[CH2:6]2.CN1CCOCC1>CO>[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH2:12])[CH2:6]2
Reactant: NC1Cc2ccc(Br)cc2C1
Agent: Br
Solvent: CN1CCOCC1
Solvent: CO
Product: N[C@@H]1Cc2ccc(Br)cc2C1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
25 g of 5-bromo-indan-2-ylamine hydrobromide (85.32 mmol) and 9.85 ml of 4-methylmorpholin (89.59 mmol) were dissolved in 53 ml of methanol. The mixture was heated to 60° C. and a solution of 25.77 g of (1S)-(+)-campher-10-sulfonic acid (110.92 mmol) in 42 ml of methanol added within 25 minutes. The reaction mixture was stirred for 10 minutes at 60° C. and then allowed to cool down to room temperature over a 2 h time period, with stirring continuing for another 2 h. The precipitate was filtered, washed twice with 20 ml of ethyl acetate/methanol (2:1) and 20 ml of water, and finally dried at 50° C. under vacuo for 15 h to give 13.3 g of the salt.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:33][C@H:34]([CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=1)[C:35]([NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:19]([O:18][C:16]([NH:15][C@H:11]([C:12](=[O:14])[NH:33][C@@H:34]([C:35](=[O:36])[NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=1)[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2ncccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To the solution of (2S)-4-(benzyloxy)-2-{[(tert-butoxy)carbonyl]amino}-4-oxobutanoic acid VIII (430 mg, 1.33 mmol) in DCM (10 mL) was added DIPEA (0.65 mL, 3.75 mmol), (2R)-2-amino-N-(quinolin-6-yl)-4-[4-(trifluoromethyl)phenyl]butanamide VII (540 mg 1.21 mmol) and TBTU (428 mg, 1.33 mmol). The mixture was stirred at r.t. overnight. The reaction mixture was then washed with 1 M K2CO3, 1 M HCl, brine and dried over MgSO4. The residue was then purified on a silica gel column (50:1 CHCl3/methanol) to yield benzyl (3S)-3-{[(tert-butoxy)carbonyl]amino}-3-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}propanoate IX (680 mg, 1.00 mmol, 75% yield). 1H NMR (CDCl3) 1.46 (s, 9H), 1.88-2.20 (m, 2H), 2.40-2.64 (m, 1H), 2.66-2.88 (m, 1H), 2.92 (d, J=6 Hz, 1H), 3.27 (dd, J=5 Hz, J=17 Hz, 1H), 4.49-4.70 (m, 2H), 5.12 (d, J=5 Hz, 2H), 5.59 (d, J=8 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 7.22-7.42 (m, 8H), 7.53 (s, 1H), 7.57 (s, 1H), 7.72 (dd, J=2 Hz, J=9 Hz, 1H), 8.00 (d, J=9 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 8.41 (d, J=2 Hz, 1H), 8.82 (d, J=4 Hz, 1H), 8.89 (s, 1H); 19F NMR (DMSO-d6) −61.73 (s, 3F); ESIMS found for C36H37F3N4O6 m/z 679 (M+H).
Reaction SMILES: C1COCC1.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[N:10]2.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24](B(O)O)=[C:25]2[CH2:30][CH2:29][CH2:28][N:26]2[N:27]=1.C(=O)([O-])[O-].[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].CN(C=O)C.C1COCC1>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[N:10]3)=[C:25]2[CH2:30][CH2:29][CH2:28][N:26]2[N:27]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: Brc1ccc2nccnc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(-c2nn3c(c2-c2ccc4nccnc4c2)CCC3)nc1
Yield: 30.1 %

Procedure:
Add THF (2.2 mL) to 6-bromo-quinoxaline (Yamamoto, T. et al., J. Am. Chem. Soc. 1996, 118, 3930-3936; 219 mg, 1.05 mmol) and purge the solution with nitrogen for 10 min. Add tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.087 mmol) and bis(1,2-bis(diphenylphosphino)ethane)palladium(0) (78 mg, 0.087 mmol), purge the reaction with nitrogen for 2 min, and stir the reaction at room temperature for 20 min. Add (2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 200 mg, 0.87 mmol) in 1:1 DMF/THF (2 mL each) and stir for 10 min. Add 2.0M aqueous potassium carbonate (1.04 mL, 2.1 mmol) and heat the reaction to 65° C. Add additional tris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.087 mmol) after 1 h and 3 h. Stir the reaction at 65° C. for 18 h, filter through Celite® with methanol/chloroform, and concentrate in vacuo. Purify by flash column chromatography followed by reverse-phase preparative HPLC. Concentrate the pure fractions from the preparative HPLC in vacuo, take up in methanol, treat with MP-carbonate beads, filter, and concentrate in vacuo to provide the title compound (82 mg, 30%) as a clear, colorless oil. MS ESI+ m/e 314 (M+1). 1H NMR (CDCl3) δ 8.86 (m, 3H), 8.11 (m, 1H), 8.05 (m, 2H), 7.79 (m, 2H), 7.47 (m, 1H), 4.33 (m, 2H), 3.11 (m, 2H), 2.72 (m, 2H). HPLC: 98.5%, Rt=13.61 min. TLC (SiO2): Rf0.3 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C:22]([S:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([S:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@H:23]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C:22]([S:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([S:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:21]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1CC(Sc2ccccc2)(Sc2ccccc2)[C@H](n2ccc(=O)[nH]c2=O)O1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CC(C)(C)[Si](OC[C@@H]1CC(Sc2ccccc2)(Sc2ccccc2)[C@@H](n2ccc(=O)[nH]c2=O)O1)(c1ccccc1)c1ccccc1

Procedure:
To a solution prepared by dissolving 7 mg (0.10 mmol) of 1-[5-O-(t-butyldiphenylsilyl)-2,3-dideoxy-2,2-di(phenylthio)-β-D-glycero-pentofuranosyl]uracil prepared in step (3) in 10 ml of anhydrous benzene, 150 μl (0.57 mmol) of hydrogenated tributyl tin and 10 mg of azobisisobutylonitrile were added, followed by subjecting the resultant solution to a reflux under heating for 48 hours under an argon gas atmosphere. After completion of the reaction, a low boiling point substances were removed by distillation under a reduced pressure so as to obtain a residue.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[C:25]([C:26]#[N:27])=[CH:24][NH:23][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[N:10]=2)[CH2:3][CH2:2]1.C([O-])([O-])=[O:29].[K+].[K+].OO>CS(C)=O>[CH:1]1([NH:4][C:5]2[C:6]3[C:25]([C:26]([NH2:27])=[O:29])=[CH:24][NH:23][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[N:10]=2)[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c[nH]c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc(NC3CC3)c12
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1c[nH]c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc(NC3CC3)c12
Yield: 22.3 %

Procedure:
A solution of 4-(cyclopropylamino)-2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (30 mg, 0.083 mmol), K2CO3 (100 mg, 0.724 mmol) and H2O2 (50% aq., 0.500 mL) in DMSO (1 mL) was heated at 100° C. for 5 min. Gas evolved violently. After cooling down, the mixture was purified by HPLC to give the titled compound (7 mg). MS 378.4 (M+H); UV 200.4, 241.8, 295.8 nm.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C:10](=[O:11])[C@H:9]([NH:7][CH3:6])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N1CCc2ccccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 46.3 %

Procedure:
N-((1R)-2-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamic acid tert-butyl ester (6.12 g, 13.8 mmol) was dissolved in dichloromethane (40 ml). The solution was cooled to 0° C. Trifluoroacetic acid (40 ml) was added. The reaction mixture was stirred for 90 min at 0° C. Dichloromethane (110 ml) and a saturated aqueous solution of sodium hydrogen carbonate (150 ml) were added successively. Solid sodium hydrogen carbonate was added until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×60 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (130 g), using dichloromethane/methanol/25% aqueous ammonia 100:10:1 as eluent, to give 2.20 g of (2R)-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(methylamino)-3-(2-naphthyl)-1-propanone.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([S:8](=[O:17])(=[O:16])[NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:7])[CH3:6])C.[NH2:19][NH2:20]>C(O)C>[CH:10]1([NH:9][S:8]([C:5]([C:4]([NH:19][NH2:20])=[O:3])([CH3:7])[CH3:6])(=[O:17])=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)NC1CCCCC1
Reactant: NN
Solvent: CCO
Product: CC(C)(C(=O)NN)S(=O)(=O)NC1CCCCC1
Reaction time: 12 h

Procedure:
Using a method similar to that described by S. Paik and E. H. White (Tetrahedron, 1996, 52, 5303), 2-cyclohexylsulfamoyl-2-methylpropionic acid ethyl ester DF1 (which is prepared by the method of A. De Blic et al. (Synthesis, 1982, 281)) in ethanol is treated with 1.2 equivalent of 95% hydrazine under N2 and the mixture is allowed to stand at RT for 12 h. The reaction mixture is concentrated to give the title compound DF2 which is used directly in Step 2.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7](=[O:22])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[N:10][CH:9]=1>C(OCC)C.O1CCCC1.C(OCC)(=O)C>[C:16]1([C:15]#[C:14][C:12]2[CH:13]=[C:8]([C:7](=[O:22])[CH3:1])[CH:9]=[N:10][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)c1cncc(C#Cc2ccccc2)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Add a 3.0 M solution of methylmagnesium bromide (1.25 mL, 3.8 mmol) in diethyl ether dropwise to a cooled solution of N-methoxy-N-methyl-5-phenylethynyl -nicotinamide, (prepared as described in PREPARATION 2), (1.00 g, 3.7 mmol) in tetrahydrofuran (8.0 mL) at 0° C. Warm to room temperature, stir overnight and dilute with ethyl acetate. Wash with an aqueous saturated solution of ammonium chloride, dry (magnesium chloride), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 10:90 to 30:70 tetrahydrofuran:hexanes, to give the title compound as a white solid (0.70 g, 84%).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][S:8][C:9]1[N:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)C.[OH-].[Na+]>C(O)C>[C:26]1([N:10]2[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:13]=[C:9]2[S:8][CH2:7][CH2:6][CH2:5][C:4]([OH:32])=[O:3])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CCCSc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCSc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
80 g of 4-(1.4.5-triphenylimidazol-2-yl mercapto)-butyric acid ethyl ester are dissolved in 700 cc. of ethanol at 80° C. 22 g of sodium hydroxide dissolved in 200 cc. of ethanol are added thereto and the mixture is stirred for 3 hours at 80° C. The solvent is distilled off, the residue is washed with ether and acidified with dilute hydrochloric acid. The resulting acid is triturated in chloroform, the chloroform solution is washed with water, dried over sodium sulfate and the solvent is distilled off.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)=[N:6][N:7]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([C:5]2[C:4]([C:1]([NH2:2])=[O:3])=[C:8]3[CH2:9][NH:10][C:11]4([CH2:14][CH2:13]4)[CH2:12][N:7]3[N:6]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2CC12CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CNC1(CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of Intermediate 350G (0.29 g, 0.689 mmol) in DCM (5 mL) was added TFA (3 mL) and the resulting solution was stirred at RT for 2 h. The volatiles were removed under reduced pressure. The residue was basified with a 10% aqueous solution of NaHCO3 and extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 350H as a yellow solid (0.2 g, 85%). MS(ES): m/z=321 [M+H]+; 1H NMR (300 MHz, chloroform-d) δ ppm 7.71 (dd, J=7.2, 2.3 Hz, 1H), 7.51 (ddd, J=8.3, 4.5, 2.3 Hz, 1H), 7.33-7.11 (m, 1H), 5.33 (br. s., 2H), 4.40 (s, 2H), 4.03 (s, 2H), 1.02-0.88 (m, 2H), 0.80-0.59 (m, 2H).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cc4ccccc4o3)sc2n1
Temperature: 100 °C
Yield: 10 %

Procedure:
To solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (100 mg, 0.232 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added 1-benzofuran-2-ylboronic acid (56.3 mg, 0.347 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol) and potassium carbonate (112 mg, 0.811 mmol) and the reaction mixture heated at 100° C. using a microwave reactor for 30 min. The mixture was then filtered through celite, washing with DCM (20 mL×2) and the filtrate dried (phase separation cartridge) and concentrated. The residue was then purified by MDAP (acidic conditions), followed by MDAP (basic conditions) to afford the title compound (10.89 mg). LCMS (A) m/z: 469 [M+1]+, Rt 1.42 min (acidic).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]=[CH:17][C:16]=2[CH2:26][OH:27])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]=[CH:17][C:16]=2[CH:26]=[O:27])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a solution of (4-(4-benzylphenylamino)-6-chloroquinolin-3-yl)methanol (800 mg, 2.1 mmol) in CH2Cl2 (9 mL) was added 4-Methylmorpholine N-oxide (377 mg, 3.2 mmol) and tetrapropylammonium perruthenate at room temperature and stirred for overnight. The reaction mixture was filtered and concentrated. The crude product was used without further purification. MS m/z: 373.28 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:33]=[C:32]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: CC(=O)c1cccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1
Yield: 22.4 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 3-acetylphenylboronic acid (available from Combi-Blocks Inc.; 66 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 3′-acetyl-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (21 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.96 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.55-7.71 (m, 3H), 2.63 (s, 3H).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].O>C(Cl)Cl>[OH:4][C:5]1[CH:6]=[C:7]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C)c1cccc(OCOC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(3-(methoxymethoxy)phenyl)propanoate (4.17 g, 17.5 mmol) in methylene chloride (80 mL) was added trifluoroacetic acid (40 mL) at 0° C. The mixture was stirred for 1 hr at 0° C. and then slowly added solid sodium bicarbonate (60 g) and water (250 mL) at 0° C. The mixture was extracted with methylene chloride. The organic layer was dried with MgSO4. The organic layer was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=4/1.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[I:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.O>[O:16]1[C:15]2([CH2:14][CH2:13][CH:12]([N:25]3[CH:24]=[C:23]([I:22])[CH:27]=[N:26]3)[CH2:21][CH2:20]2)[O:19][CH2:18][CH2:17]1
Reactant: Ic1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cnn(C2CCC3(CC2)OCCO3)c1

Procedure:
A mixture of 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (prepared according to U.S. Pat. No. 4,360,531) (2.0 g, 6.4 mmol), 4-iodopyrazole (1.36 g, 7.0 mmol), K2CO3 (1.06 g, 7.7 mmol), and 18-crown-6 (0.2 g, 0.7 mmol) in DMF (5 mL) was heated under nitrogen at 50° C. for 16 h. Water (50 mL) was added to the reaction mixture, which was then extracted with EtOAc (3×40 mL). The combined EtOAc extracts were washed with water (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc/CH2Cl2 (1:9) to give the title compound. 1H NMR (CDCl3, 400 MHz): δ=1.67-1.76 (m, 2 H), 1.84-1.91 (m, 2 H), 1.99-2.17 (m, 4 H), 3.95-3.99 (m, 4 H), 4.18-4.27 (m, 1 H). MS (ES+): m/z=334.96 (100) [MH+]. HPLC: tR=3.26 min (polar—5 min, ZQ3).