Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14](O)=[CH:15][C:16](=[O:18])[CH3:17])[CH:3]=1.[H][H]>C(O)(=O)C.[Pd]>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:3]=1
Reactant: COc1ccc2cc(C(O)=CC(C)=O)cc(F)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2cc(CCC(C)=O)cc(F)c2c1
Yield: 49.3 %

Procedure:
4-(4-Fluoro-6-methoxy-2-naphthyl)-4-hydroxy-but-3-en-2-one (3 g) was hydrogenated at atmospheric pressure and room temperature in glacial acetic acid (150 ml) using 10% palladium on carbon (0.5 g) catalyst. When hydrogen uptake had ceased the catalyst was removed by filtration and the filtrate concentrated. The residue was taken up in ether and the resulting solution washed with sodium bicarbonate solution, then water, dried (MgSO4) and concentrated in vacuo to give a low melting solid which was recrystallised from ether to give colourless crystals (1.40 g) m.p. 69°-70° C. 'H Nmr (CDCl3)δ: 6.81-7.71 (m, 5H), 3.89 (s, 3H), 2.88-2.99 (m, 4H), 2.12 (s, 3H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.N1CCCCC1>C(OC(C)C)(=O)C>[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: O=Cc1ccccc1F
Solvent: CC(=O)OC(C)C
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1ccccc1F
Yield: 28.3 %

Procedure:
Malononitrile (3.303 g, 50 mmol), 2-fluorobenzaldehyde (6.205 g, 50 mmol), 1 g of molecular sieves, and 500 mg of a resin bound piperidine (described in Tetrahedron Lett., 1999, 40, 7031-33) were placed in a vessel which was irradiated in a 300 W single mode microwave for 15 seconds. The reaction mixture was taken up in iso-propyl acetate, filtered, evaporated, taken up in dichloromethane, filtered through a pad of Magnasol, evaporated, and recrystallized from ethanol to yield 2.435 g of the title material as a crystalline solid,
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)#[N:2].[N:11]([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2)=[C:12]=[O:13]>C(OCC)C>[CH:19]1[C:20]2[C:15](=[C:14]([NH:11][C:12](=[O:13])[O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: N#Cc1ccc(CO)cc1
Reactant: O=C=Nc1cccc2cnccc12
Solvent: CCOCC
Product: N#Cc1ccc(COC(=O)Nc2cccc3cnccc23)cc1
Reaction time: 2 h
Yield: 44 %

Procedure:
4-Cyanobenzyl alcohol (150 mg, 1.13 mmol) in diethyl ether (10 mL) was treated with the product from Example 61A as an ethereal solution. The mixture was stirred for 2 hours, filtered, and the filter cake was washed with diethyl ether to provide the title compound as an off-white solid (150 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.32 (d, J=1.0 Hz, 1H), 8.52 (d, J=6.1 Hz, 1H), 7.88-7.99 (m, 5H), 7.65-7.70 (m, 3H), 5.31 (s, 2H); MS (ESI+) m/z 304 (M+H)+.
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]([C:19]([OH:21])=O)=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.S(Cl)(Cl)=O.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([NH:39][C:19]([C:14]1[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]2[C:4](=[O:22])[C:3]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]3[C:1]2=[O:27])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:21])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Solvent: O=S(Cl)Cl
Product: O=C(NCc1ccccc1)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O

Procedure:
From 2′-phthalimidomethylbiphenyl-2carboxylic acid (precursor 2), after conversion into the acid chloride using thionyl chloride and reaction with benzylamine, 2′-phthalimidomethylbiphenyl-2-carboxylic acid benzylamide was obtained. 1.2 g (2.7 mmol) of the product were dissolved in 55 ml of methanol and treated with 1.35 ml of hydrazine hydrate. After stirring at 40° C. for 1 h, the reaction mixture was concentrated and the residue was taken up in methylene chloride. After filtering off the 2,3-dihydro-phthalazine-1,4-dione formed, the mother liquor was concentrated and the residue was purified by flash chromatography using methylene chloride/methanol 30:1. 0.49 g of 2′-aminomethylbiphenyl-2-carboxylic acid benzylamide was obtained.
Reaction SMILES: [NH:1]1[CH:7]([CH2:8][C:9]([OH:11])=O)[C:5](=[O:6])[NH:4][C:2]1=[O:3].C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:38])[CH2:36][NH2:37])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>CN1C(=O)CCC1>[O:3]=[C:2]1[NH:1][CH:7]([CH2:8][C:9]([NH:37][CH2:36][CH:35]([C:32]2[CH:33]=[CH:34][C:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)=[CH:30][CH:31]=2)[CH3:38])=[O:11])[C:5](=[O:6])[NH:4]1
Reactant: O=C(O)CC1NC(=O)NC1=O
Reactant: CC(CN)c1ccc(-c2ccc(F)cc2)cc1
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CC(CNC(=O)CC1NC(=O)NC1=O)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
600μL of a 0.15M solution in NMP of 5-hydantoin acetic acid was mixed with 98 mg of polystyrene-bound caibodiimide resin (loading 1.28 mmol/g). 340 μL of a 0.3M solution of HOBT in NMP was added to the mixture and vortexed for 10 minutes before 200 μL of a 0.3M solution in NMP of 2-(4′-fluoro-biphenyl-4-yl)-propylamine was added. The reaction mixture was vortexed overnight at room temperature in a sealed vessel. Resin was removed by filtration and the solution was evaporated to dryness. The product was purified on semi prep-HPLC C18-column (H2O:CH3CN, 0.1% TFA buffer, gradient 10% to 95% CH3CN, 10 min).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22](=[O:24])[CH3:23])([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OC)(=[O:30])[C:26]([O:28]C)=[O:27].[H-].[Na+].Cl>C(COC)OC.C1COCC1>[ClH:21].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22](=[O:24])[CH2:23][C:25](=[O:30])[C:26]([OH:28])=[O:27])([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)C1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: O=C(O)C(=O)CC(=O)C1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of N-Benzyl-4-Acetyl-4-(4-Chlorobenzyl)-piperidine (600 mg, 1.75 mmol) and dimethyl oxalate (310 mg, 2.63 mmol) in dimethoxyethane (20 mL) was treated with sodium hydride (105 mg of a 60% dispersion in mineral oil, 2.63 mmol) and heated to reflux for 3 hours. The reaction was then cooled to room temperature, poured into 1 N aqueous HCl (200 mL) and extracted with ethyl ether (1×50 mL). The ether extract was discarded. The pH of the aqueous phase was adjusted to pH 8 and extracted with ethyl acetate (3×200 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The crude ester thus obtained was dissolved in THF (5 mL) and 3 N HCl (20 mL) and heated to reflux for 1 hour. The reaction was then cooled to room temperature, and concentrated at reduced pressure. The residue was triturated with tetrahydrofuran and the solid collected by filtration and crystallized from isopropanol to give 200 mg of the title compound. mp. 189°-181° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][N:21]([CH3:32])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]3[CH:26]=[CH:27][C:22]([N:21]([CH3:32])[CH3:20])=[CH:23][CH:24]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: CN(C)c1ccc(CC(=O)Nn2nc(-c3ccc(Cl)cc3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 86A and 2-[4-(dimethylamino)phenyl]acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.42 (m, 1H), 7.93-8.04 (m, 2H), 7.71-7.74 (m, 1H), 7.58-7.69 (m, 4H), 7.41-7.43 (m, 2H), 7.23-7.25 (m, 2H), 3.68-3.69 (bs, 2H), 3.06 (s, 6H); MS (APCI+) M/Z 433 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:27])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)=[O:2].S([CH2:38][N+:39]#[C-:40])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[O:2]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[C:10](=[O:27])[N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:14]=2)=[CH:40][N:39]=[CH:38]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=c1c(-c2ccccc2-c2cnco2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
13 mg of 3-(2-formylphenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of methanol. To the mixture were added 11 mg of tosylmethylisocyanide and 8 mg of potassium carbonate, followed by heating under reflux overnight. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. It was filtered through NH silica gel and silica gel, and the filtrate was evaporated. The resulting precipitates were washed with ether and dried, to give 9 mg of the title compound.
Reaction SMILES: Cl.[CH:2]([C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])[CH3:3].C[Al](C)C.C1(C)C=CC=CC=1.C[O:25][C:26](=O)[CH2:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[S:34][CH:35]=[CH:36][N:37]=1>ClCCCl>[NH2:12][C:7]1[CH:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[N:10]=[CH:9][C:8]=1[NH:11][C:26](=[O:25])[CH2:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[S:34][CH:35]=[CH:36][N:37]=1
Reactant: COC(=O)Cn1ccnc1-c1nccs1
Reactant: CC(C)c1cc(N)c(N)cn1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CC(C)c1cc(N)c(NC(=O)Cn2ccnc2-c2nccs2)cn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 6-isopropyl-pyridine-3,4-diamine hydrochloride (265 mg, 1.41 mmol) in 1,2-dichloroethane (10 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (2.12 mL, 4.24 mmol). The mixture is stirred at room temperature for 45 min and then treated with a solution of (2-thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester (252 mg, 1.13 mmol) in 1,2-dichloroethane (2 mL) via cannula, followed by a 1 mL rinse. The reaction mixture is then stirred at reflux for 20 h. After cooling, the reaction mixture is diluted with some MeOH (˜2 mL), followed by some water and then saturated aq NaHCO3. The resulting mixture is stirred vigorously for 15 min. The mixture is then extracted thrice with CHCl3 containing some (˜5) MeOH. The combined extracts are dried over Na2SO4 and concentrated. The crude residue is then triturated with CHCl3, and the resulting mixture filtered. The solid is washed with a small amount of CHCl3 and dried, affording N-(4-amino-6-isopropyl-pyridin-3-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide as an off-white solid. 1H NMR (DMSO-d6, 300 MHz) δ 9.52 (s, 1H), 7.86 (s, 1H), 7.85 (d, J=3.3 Hz, 1H), 7.75 (d, J=3.6 Hz, 1H)/, 7.39 (s, 1H), 7.04 (d, J=0.9 Hz, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 5.38 (s, 2H), 2.74 (sept, J=6.9 Hz, 1H), 1.13 (d, J=6.9 Hz, 6H) ppm. The filtrate is concentrated and further purified by flash chromatography on silica gel. Elution with 20:1 CHCl3-MeOH followed by 15:1 CHCl3-MeOH affords 6-isopropyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-1H-imidazo[4,5-c]pyridine (160 mg, 44%). 1H NMR (CDCl3, 300 MHz) δ 12.23 (br, 1H), 8.97 (br, 1H), 7.94 (d, J=2.7 Hz, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.23 (br, 1H), 7.20 (d, J=0.9 Hz, 1H), 7.04 (s, 1H), 5.82 (s, 2H), 3.14 (sept, J=6.9 Hz, 1H), 1.30 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1.[CH3:20][S:21]SC.CCOCC>C1COCC1>[Cl:6][C:7]1[C:8]([S:21][CH3:20])=[C:9]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CSSC
Reactant: CC1(C)COC(c2cccc(Cl)c2)=N1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1c(Cl)cccc1C1=NC(C)(C)CO1
Temperature: -65 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
n-Butyllithium (2.5M in hexane, 4.2 ml) was added to a solution of 2-(3-chlorophenyl)-4,4-dimethyloxazoline (2 g) in THF while maintaining the temperature below -45° C. The mixture was stirred at -65° C. for 3 hours. Dimethyl disulphide (1.0 g) was added and the mixture was stirred at -65° C. for 2.5 hours and allowed to warm to room temperature. Ether was added and the mixture was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-(3-chloro-2-methylsulphenylphenyl)-4,4-dimethyloxazoline (2.35 g) as a yellow oil NMR (CDCl3) 2.0(s,6H) 3.0(s,3H) 4.65(s,2H) 7.5-8.1(m,3H).
Reaction SMILES: [C:1]([C:3](=[C:9](SC)[S:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Cl.[NH2:15][NH2:16].C([O-])(=O)C.[Na+]>C(O)C>[NH2:2][C:1]1[NH:16][N:15]=[C:9]([S:10][CH3:11])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: NN
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(SC)n[nH]c1N
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of ethyl 2-cyano-3,3-bis(methylthio)-acrylate (40 g), hydrazine hydrochloride (12.6 g) and sodium acetate (22.6 g) in ethanol was stirred at 90° C. for 2 hour. After cooling to room temperature, the reaction mixture was concentrated in vacuo, and to the residue were added water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo, and to the residue was added ethyl acetate and hexane. The precipitates were collected by filtration and dried to give 5-amino-4-ethoxycarbonyl-3-methylthio-1H-pyrazole (17.4 g, yield: 47%) as a colorless solid.
Reaction SMILES: [C:1]12([CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][O:19][C:20]4=O)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[C:1]12([CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][N:32]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[C:20]4=[O:19])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c(=O)occc12
Reactant: NCc1ccc(F)cc1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c(=O)n(Cc3ccc(F)cc3)ccc12
Temperature: 145 °C
Yield: 75.3 %

Procedure:
A mixture of 2-adamantan-1-yl-N-(1-oxo-1H-isochromen-5-yl)-acetamide (0.3 g, 0.89 mmol) and 4-fluorobenzylamine 0.668 g (5.33 mmol) in an 8 mL sealed vial was heated at 145° C. for 48 h. The reaction vessel was cooled to room temperature. The crude product was purified by prep. HPLC to yield 2-adamantan-1-yl-N-[2-(4-fluoro-benzyl)-1-oxo-1,2-dihydro-isoquinolin-5-yl]-acetamide (0.298 g, 0.67 mmol, 75%) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:26]=[C:27]([S:29]([CH3:31])=[O:30])[N:28]=2)[C:21]([NH:23][O:24][CH3:25])=[O:22])[CH2:14][CH2:13]1)=[O:10].C1C=C(Cl)C=C(C(OO)=[O:40])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:19]=[C:20]([CH:26]=[C:27]([S:29]([CH3:31])(=[O:40])=[O:30])[N:28]=2)[C:21]([NH:23][O:24][CH3:25])=[O:22])[CH2:16][CH2:17]1)=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(S(C)=O)c1
Solvent: ClCCl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.8 %

Procedure:
2-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-N-methoxy-6-(methylsulfinyl)isonicotinamide (Example 152) (90 mg, 0.185 mmol) was dissolved in anhydrous DCM (5 ml). mCPBA (32 mg, 0185 mmol) was added and the mixture was stirred at room temperature for 12 h. The crude mixture was diluted and washed with 10% sodium thiosulfate, water, brine and dried over sodium sulfate and concentrated in vacuo. The brown oil was purified by flash chromatography eluting with acetonitrile/water (0.1% TFA) to give the title compound (11 mg).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:25][N:26]([CH3:36])[S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:25][N:26]([CH3:36])[S:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:16][C:13]2[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])=[N:15][CH:14]=2)[CH2:32][CH2:31]1)(=[O:28])=[O:29]
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CN(C)S(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 42.1 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (84 mg, 0.25 mmol), piperazine-1-sulfonic acid dimethyl amide hydrochloride (115 mg, 0.50 mmol) and sodium triacetoxyborohydride (70 mg, 0.33 mmol) to afford 54 mg (42%) of the desired product after purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][C:32]([OH:36])([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=3)=[CH:4][CH:3]=2)[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: Brc1ccc(-c2ccc3ccccc3c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(-c3ccc4ccccc4c3)cc2)CCCN(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
2-(4-Bromophenyl)naphthalene (9.29 g, 32.8 mmol) is placed in a round bottom flask under argon and dissolved in anhydrous THF (150 mL). The solution is cooled to -78° C. in a dry ice/acetone bath with stirring. A solution of n-butyl lithium (2.0M, 18.0 ml) is added dropwise and after fifteen minutes 1-benzyl-3-piperidone (8.14 g, 36.08 mmol) in 20 mL of THF is added dropwise with vigorous stirring. After 30 minutes the solution is allowed to warm to room temperature and quenched with saturated ammonium chloride (10 ml). The mixture is diluted with ethyl acetate (500 ml), washed with water and brine. The organic layer is dried over MgSO4 and concentrated on a rotovap. The crude material is purified by silica gel flash column chromatography using 30% ethyl acetate in hexane as the eluant to yield 6.91 g (48%) of 1-benzyl-3-hydroxy-3(4-naphth-2-yl-phenyl)piperidine as a white solid.
Reaction SMILES: [Si:1]([O:18][C@H:19]1[CH2:24][C@H:23]2[CH2:25][C@@H:20]1[CH2:21][C:22]2=[O:26])([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.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[Si:1]([O:18][C@H:19]1[CH2:24][C@H:23]2[CH2:25][C@@H:20]1[CH2:21][C@H:22]2[OH:26])([C:14]([CH3:17])([CH3:15])[CH3:16])([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
Reactant: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1CC2=O)(c1ccccc1)c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1C[C@H]2O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of (1R,4R,5S)-5-(tert-butyldiphenylsilyloxy)bicyclo[2.2.1]heptan-2-one (5.75 g, 15.8 mmol) in THF (15.0 mL) was added dropwise to L-Selectride (1.0 M solution in THF, 31.5 ml, 31.5 mmol) at −78° C. under nitrogen. The resulting mixture was stirred at −78° C. for 3 h, then quenched with tris-HCl (1M, PH 7.0 at 25° C.). The mixture was warmed to ambient temp. and partitioned between EtOAc and Tris-HCl. The combined organic portions were washed with brine, and conc. in vacuo. The residue was dissolved in MeOH (60 mL), stirred with NaOH (pellets, 3.2 g) at 60° C. overnight. After cooling to ambient temp., the solvent was removed in vacuo. The residue was partitioned between diethyl ether and water. The combined organic portions were washed with brine, dried with Na2SO4, filtered, and conc. in vacuo. The crude product was purified by flash column chromatography (0 to 30% of EtOAc in hexanes) to yield the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][C@H:9]1[C:14](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]2[C:32](=[O:33])[NH:34][C:14]([C@@H:9]3[CH2:10][CH:11]=[CH:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:25][C:26]=2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC=CC[C@H]1C(=O)O
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=CC[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To a mixture of (2S)-1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-2-carboxylic acid (1.16 g), triethylamine (1.42 mL) and tetrahydrofuran (12 mL) was added 2-methylpropyl chlorocarbonate (0.662 mL) with stirring at room temperature. After 1 hr, 3-amino-5-bromothiophene-2-carboxamide (752 mg) produced in Example 1, step D, was added, and the mixture was stirred in a microwave reactor at 100° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (10 mL), 2M aqueous sodium hydroxide solution (10.2 mL) was added, and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was ice-cooled, and 6M hydrochloric acid (3.33 mL) was added dropwise. The reaction mixture was poured into brine, and extracted with 3:1 ethyl acetate/tetrahydrofuran mixture. The extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (851 mg) as a white solid. The optical purity was 51.1% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK IC (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 1 mL/min, column temperature: 30° C., detection 220 nm).