Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]([CH3:18])[NH:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[NH4+:20]>>[S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]([CH3:18])[NH:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:20]
Reactant: [NH4+]
Reactant: CC1NC(=O)NN=C1c1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Product: CC1NC(=O)NN=C1c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-(4-chlorosulfonylphenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (4.27 g) and concentrated ammonium hydroxide (30 ml) was stirred at room temperature for 30 minutes and then at 50° C. for 1 hour, and concentrated under reduced pressure. To the residue was added water and the mixture was stirred with ice-cooling for 10 minutes. The crystals which formed were recovered by filtration, washed with water and recrystallized from aqueous ethanol to give 6-(4-sulfamoylphenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.91 g).
Reaction SMILES: [CH:1]1([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]C)=[O:27])[CH:20]=4)[NH:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=4)[NH:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)C3CCC3)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(NC(=O)C2CCC2)cc1
Yield: 37.7 %

Procedure:
To a mixture of methyl 2-(4-(cyclobutanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (42 mg, 0.21 mmol) in methanol (3 mL) and water (1.5 mL) was treated with a solution of sodium hydroxide (133 mg, 2.63 mmol) in water (1.5 mL). The resultant mixture was heated to reflux until the completion of the reaction (monitored by thin layer chromatography). The methanol was removed under vacuum. The residue was acidified with 2M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 30 mg of 2-(4-(cyclobutanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid Yield: 84%. MS (ESI+APCI) M+1=379.2.
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[N:19]([C:22]1[CH:39]=[CH:38][C:25]([CH2:26][O:27][C:28]([N:30]2[C@H:34]([C:35]([OH:37])=O)[CH2:33][S:32][CH2:31]2)=[O:29])=[CH:24][CH:23]=1)=[N+:20]=[N-:21].[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55]([NH:57][C@@H:58]([CH2:62][CH2:63][CH2:64][CH2:65][NH2:66])[C:59]([OH:61])=[O:60])=[O:56])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(O)=O>[CH:49]1[C:50]2[CH:51]([CH2:53][O:54][C:55]([NH:57][C@@H:58]([CH2:62][CH2:63][CH2:64][CH2:65][NH:66][C:35]([C@@H:34]3[CH2:33][S:32][CH2:31][N:30]3[C:28]([O:27][CH2:26][C:25]3[CH:24]=[CH:23][C:22]([N:19]=[N+:20]=[N-:21])=[CH:39][CH:38]=3)=[O:29])=[O:37])[C:59]([OH:61])=[O:60])=[O:56])[C:52]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:45]=2[CH:46]=[CH:47][CH:48]=1
Reactant: [N-]=[N+]=Nc1ccc(COC(=O)N2CSC[C@H]2C(=O)O)cc1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(COC(=O)N2CSC[C@H]2C(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
4-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (2.85 g, 10.3 mmol) was added to a solution of (R)-3-(((4-azidobenzyl)oxy)carbonyl)thiazolidine-4-carboxylic acid (Acbz-Thz-OH) (Compound SP610) (3.17 g, 10.3 mmol) in dimethylformamide (DMF) (17.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. A solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-aminohexanoic acid (Fmoc-Lys-OH) hydrochloride (4.16 g, 10.3 mmol) and diisopropylethylamine (DIPEA) (2.69 ml, 15.4 mmol) in dimethylformamide (DMF) (17 ml) was added to the reaction solution at room temperature, and the mixture was stirred at the same temperature for 4 hours. Formic acid (1.9 ml) was added to the reaction solution, and the mixture was purified by reverse-phase silica gel chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-((R)-3-(((4-azidobenzyl)oxy) carbonyl) thiazolidine-4-carboxamido)hexanoic acid (Fmoc-Lys(Acbz-Thz)-OH) (Compound SP611) (3.48 g, 51%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][P:17]([O:23][CH2:24][CH:25]=[CH2:26])([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])=[CH:11][C:7]=1[C:8](O)=[O:9])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:30])=O.CN(C)C=O>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][P:17]([O:23][CH2:24][CH:25]=[CH2:26])([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])=[CH:11][C:7]=1[C:8]([Cl:30])=[O:9])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOP(=O)(OCC=C)OCc1ccc(COC(C)=O)c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCOP(=O)(OCC=C)OCc1ccc(COC(C)=O)c(C(=O)Cl)c1
Temperature: 0 °C

Procedure:
2-(Acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoic acid (475.5 mg, 1.24 mmol) obtained from Example 1-(11) was dissolved in tetrahydrofuran (5 ml), and the solution was cooled to 0° C., then oxalyl chloride (189.2 mg, 1.49 mmol) and N,N-dimethylformamide (15 μl) were added thereto with stirring. The mixture was warmed to room temperature and then stirred for 40 minutes. The solvent was distilled off under reduced pressure to give the crude 2-(acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoyl chloride.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=1.[OH-].[Na+].Cl.C(O)C>CN(C)C=O>[O:18]=[C:15]1[NH:14][CH:13]=[C:12]([CH2:11][NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:19])=[O:2])[CH:17]=[CH:16]1
Reactant: COC(=O)c1ccccc1NCc1ccc(=O)[nH]c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1NCc1ccc(=O)[nH]c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
3.5 g (12.7 mmol) of 2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic acid-methyl ester is mixed in 15 ml of dimethylformamide with 30 ml of 6N sodium hydroxide solution and stirred for 1.5 hours at room temperature. While being cooled with ice, it is then mixed with about 50 ml of 4N hydrochloric acid, the precipitation is suctioned off, and it is washed with water. 3.1 g, which is taken up in 29.3 ml of 1N sodium hydroxide solution and 142 ml of ethanol, is obtained, and it is heated for 1.5 hours to a bath temperature of 120° C. The ethanol is then drawn off in a vacuum, it is made acidic with 2N hydrochloric acid, and the precipitated product is suctioned off and dried well. 2.9 g (93.5% of theory) of 2-[(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-amino]-benzoic acid is obtained.
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>CO>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[C:7]3=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]3[CH:5]([CH3:16])[CH2:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC1CCC(Br)c2ncc(C(=O)O)c(=O)n21
Solvent: CO
Product: CC1CC=C(Nc2ccc(Br)cc2)c2ncc(C(=O)O)c(=O)n21
Temperature: 25 °C
Yield: 64.6 %

Procedure:
2.0 g. (6.97 mmoles) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 1.72 g. of p-bromo-aniline are added to 20 cm3 methanol. The mixture is heated under stirring until a solution is obtained. The solution is cooled to room temperature and stirred for 2-3 days. The precipitated crystals are filtered and washed with methanol. 1.7 g. (64.6%) of 9-[(4-bromo-phenyl)-amino]-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained which melts at 202°-204° C. after recrystallization from methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[C:16]([O-])(=[O:18])C.[Na+]>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:16]([C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1)=[O:18]
Reactant: CC(=O)[O-]
Reactant: C[C@H](NC(=O)C1CC1)c1ccc(Br)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NC(=O)C1CC1)c1ccc(C=O)cc1
Temperature: 100 °C

Procedure:
To 5.0 g (19 mmol) (S)-cyclopropanecarboxylic acid [1-(4-bromo-phenyl)-ethyl]-amide (WO 2012/01107) in 40 mL MeOH are added 125 mg (0.600 mmol) palladium-(II)-acetate, 620 mg (1.10 mmol) 1,1′-bis(diphenylphosphino)-ferrocene and 4.6 g (56 mmol) sodium acetate. The mixture is stirred at 100° C. and 5 bar CO atmosphere over night. After that time, the mixture is filtered over celite and the filtrate is concentrated by evaporation. The residue is purified by column chromatography (silica gel; gradient hexane/EtOAc 1:0→1:4) to yield the desired product.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[Cl-].[OH:15][NH3+:16].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[N:16][OH:15]
Reactant: Cc1ccc(C(=O)C(F)(F)F)cc1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=NO)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
49.5 g (0.263 mol) of 2,2,2-trifluoro-1-(4-methylphenyl)-ethanone are dissolved in 250 ml of ethanol at 80° C. To the solution are added dropwise 19.2 g (0.276 mol) of hydroxylammonium chloride and 36.7 g (0.447 mol) of sodium acetate dissolved in 125 ml of water. The reaction mixture is refluxed for 3.5 hours. The mixture is poured into ice water, affording a white solid. The filtration yields 39.2 g of 2,2,2-trifluoro-1-(4-methylphenyl)-ethanone oxime as a white solid, mp. 54-68° C. The crude product is used in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:19]=[O:20].[Cl-].[NH4+]>C(#N)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]=[O:20])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(I)c1
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1ccc(I)cc1O
Yield: 160.1 %

Procedure:
To a solution of 3-iodophenol (3.00 g, 13.6 mmol) in acetonitrile (50 mL) was added magnesium chloride (3.89 g, 40.9 mmol), triethylamine (7.6 mL, 55 mmol), and paraformaldehyde (1.64 g, 55 mmol). The reaction mixture was refluxed overnight, then neutralized with saturated aqueous ammonium chloride. The resultant red precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. The precipitate was dissolved in methanol and added to the combined organic extracts, which were then dried over magnesium sulfate. The solvent was removed under reduced pressure to provide an orange solid (5.4 g) as the crude product. This material was used in the subsequent step without further purification.
Reaction SMILES: CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:41](=[O:44])[CH2:42][Br:43])=[C:34]2[C:39]=1[NH:38][C:37](=[O:40])[CH:36]=[CH:35]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C@@H:41]([OH:44])[CH2:42][Br:43])=[C:34]2[C:39]=1[NH:38][C:37](=[O:40])[CH:36]=[CH:35]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A solution of [(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c] [1,3,2]-oxazaborole] (1M, 424 μL) in THF (2 ml) was added to borane dimethylsulfide complex (2M, 212.7 μl) in THF (15 ml) and stirred at 0° C. for 10 min. The reaction mixture was cooled to −10° C. and treated with a solution of 8-benzyloxy-5-bromoacetylcarbostyril (EP 147719A2) (791 mg) in THF (16 ml) over 20 min. Further borane dimethylsulfide complex (1.28 ml) was added over 4 h at 0° C. The reaction mixture was stirred for a further hour at 0° C. prior to quenching with methanol and 1N HCl(aq). The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried and concentrated in vacuo. The residue was triturated with hexane-ethyl acetate to afford the title compound (700 mg). Rf (EtOAc) 0.47
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:14]([CH2:18][OH:19])[CH2:15][CH:16]=[CH2:17])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:14]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH:16]=[CH2:17])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: CS(=O)(=O)Cl
Reactant: C=CC[C@H](CO)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@H](COS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.8 %

Procedure:
Methanesulphonyl chloride (3.55 g) was added dropwise to an ice-cooled solution of 4(S)-(3,4-dichlorophenyl)-5-hydroxypent-1-ene (6.0 g) (see Preparation 91) and triethylamine (3.48 g) in dichloromethane (100 ml) and the mixture stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure and the residue partitioned between diethyl ether and water. The two phases were separated and the aqueous layer firrter extracted with diethyl ether. The organic pahses were then combined and washed sequentially with water, dilute aqueous citric acid solution, brine, saturated aqueous sodium hydrogen carbonate solution and brine before drying over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave 4(S)-(3,4-dichlorophenyl)-5-(methanesulphonyloxy)pent-1-ene (8.25 g) as an oil.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][C:16]([Br:26])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.C1COCC1.[OH-].[Na+]>O>[Br:26][C:16]1[CH:17]=[C:18]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=1
Reactant: O=C(NC(=S)Nc1ncc(Br)cc1Oc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A 2 L flask was charged with 1-benzoyl-3-(5-bromo-3-phenoxypyridin-2-yl)thiourea (94.3 g, 220 mmol) and THF (900 mL). 2M NaOH (330 mL, 660 mmol) was added and the reaction was heated at reflux overnight. The reaction was cooled to ambient temperature and 300 mL water was added slowly and then the THF was removed in vacuo to afford an aqueous slurry which was filtered, washed with water and dried to give 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (66.35 g, 93% yield) as a light tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][Zn]C.C1(C)C=CC=CC=1>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:37])[N:7]=2)=[C:9]([C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: C[Zn]C
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.269 mmol) and dimethyl zinc in toluene (0.269 mL, 0.539 mmol), the title compound was obtained as a yellow solid (105 mg, 72% yield). MS (ESI): 537 [M+H]+.
Reaction SMILES: C([N:8]([C@H:16]([C@H:18]([OH:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:17])CC1C=CC=CC=1)C1C=CC=CC=1>CO>[NH2:8][C@H:16]([C@H:18]([OH:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:17]
Reactant: CCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Solvent: CO
Product: CCCCCCCCCCC[C@@H](O)[C@H](C)N
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of N,N-dibenzylamine 29 (182 mg, 0.44 mmol) in MeOH (4.5 mL) at room temperature, Pd(OH)2—C (20% wt, 24 mg, 0.04 mmol) was added. The mixture was purged with a stream of dry Ar, and then H2. The reaction was stirred overnight under a H2 atmosphere (1 atm). The catalyst was filtered off through a 0.45 μm teflon filter in polypropylene housing, washing the filter with MeOH (30 mL) and the solvent was evaporated in vacuo. The crude was purified by column chromatography on silica (90:10 CH2Cl2/MeOH to 100% MeOH) to obtain aminoalcohol 30 as a white solid (87 mg, 85% yield).
Reaction SMILES: [CH2:1]([CH:8]([C:26]([N:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([C:34]2[N:38]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:37]3[CH:44]=[CH:45][CH:46]=[CH:47][C:36]=3[N:35]=2)[CH2:29]1)=[O:27])[C@H:9]([NH:18]C(=O)OC(C)(C)C)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[NH2:18][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:26]([N:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([C:34]2[N:38]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:37]3[CH:44]=[CH:45][CH:46]=[CH:47][C:36]=3[N:35]=2)[CH2:29]1)=[O:27]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C(Cc3ccccc3)[C@@H](Cc3ccc(Cl)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: ClCCl
Product: COCCCn1c([C@@H]2CCCN(C(=O)[C@H](Cc3ccccc3)C(N)Cc3ccc(Cl)cc3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.4 %

Procedure:
tert-Butyl (R)-3-benzyl-1-(4-chlorophenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (131B) (0.25 mmole, 165 mg) in DCM (10 mL) was added TEA (2 mL). The reaction solution was stirred at rt for 1 hr and then concentrated in vacuo. The residue was purified by preparative LC/MS (25-30% CH3CN in H2O) to afford (R)-3-amino-2-benzyl-4-(4-chlorophenyl)-1-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)butan-1-one (240) (0.016 mmole, 9 mg, two-step yield: 6.4%). ESI-MS: m/z 560.4 (M+H)+. ESI-MS: m/z 560.4 (M+H)+. 1H NMR (400 MHz, MeOD) δ ppm 1.49-1.74 (m, 1H) 1.82-1.95 (m, 1H) 2.01-2.33 (m, 3H) 2.50-2.95 (m, 3H) 2.95-3.09 (m, 2H) 3.11-3.23 (m, 1H) 3.24 (s, 3H) 3.44-3.59 (m, 2H) 3.62-3.95 (m, 2H) 4.62-4.86 (m, 4H) 5.88-6.10 (m, 2H) 7.18 (d, 0.1=6.25 Hz, 2H) 7.23-7.32 (m, 2H) 7.38 (d, J=2.40 Hz, 5H) 7.57-7.76 (m, 3H) 7.99-8.07 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:17][C@H:18]([C:20]([O:22]C(C)(C)C)=[O:21])[CH3:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C@@H:6]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)N[C@@H](C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add cold trifluoroacetic acid (600 ml) (ice bath) to N-[1(S)-ethoxycarbonyl-2-(4-nitrophenyl)ethyl]-(S)-alanine, t-butyl ester (25.5 g) and stir the resulting mixture at room temperature under a nitrogen atmosphere for 4 hours. Concentrate the solution in vacuo to give a viscous oil. Triturate the viscous oil with hexane (3 l) and then ether to yield N-[1(S)-ethoxycarbonyl-2-(4-nitrophenyl)ethyl]-(S)-alanine.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][O:10][C:11]1[C:12](=[O:21])[CH:13]=[C:14]([CH3:20])[C:15](=[O:19])[C:16]=1[O:17][CH3:18]>O.C(OCC)C>[CH3:20][C:14]1[C:15]([OH:19])=[C:16]([O:17][CH3:18])[C:11]([O:10][CH3:9])=[C:12]([OH:21])[CH:13]=1
Reactant: COC1=C(OC)C(=O)C(C)=CC1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1c(O)cc(C)c(O)c1OC
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
A solution of sodium dithionite (95.4 g, 0.548 mols) in water (330 ml) was added to a solution of 2,3-dimethoxy-5-methyl-1,4-benzoquinone (50 g, 0.274 mols) in diethyl ether (330 ml), and shaken for 15 minutes. The ether layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated in vacuo. The resulting crystals were washed with hexane to obtain 2,3-dimethoxy-5-methyl-1,4-hydroquinone (46.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[S:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=2)=[CH:4][CH:3]=1.[OH:44]OS([O-])=O.[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[S:29]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=2)=[O:44])=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(SCc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(S(=O)Cc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylthio)-1H-purine-2,6(3H,7H)-dione (60 mg, 0.108 mmol, example 129, step 2) in THF (4 mL) and water (2 mL) was added Oxone (73 mg, 0.119 mmol) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The mixture was quenched with aqueous sodium thiosulfate, partitioned between DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product. This crude material was purified by silica gel chromatography eluting with petroleum/ethyl acetate (1:0 to 1:1) to give 7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-8-(3-(trifluoromethoxy)benzylsulfinyl)-1H-purine-2,6(3H,7H)-dione (60 mg, 97.6%) as yellow oil. LCMS retention time 1.499 min; LCMS MH+-THP 571.