Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH2:18].[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([S:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]([OH:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: Sc1ccccc1
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: OC1CN(Cc2ccccc2)CC1Sc1ccccc1
Yield: 70.8 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a quartz round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 5 days at room temperature with irradiation by 500W Xe lamps (UXL-500D xenon lamp produced by Ushio). After evaporation of acetone under reduced pressure, continuously, 13.2 g (0.12 mol) of benzenethiol (produced by produced by Aldrich Chemical Co., Inc.) was added to the reaction mixture and stirred for 5 hours at 100° C. After completion, the reaction mixture was extracted with toluene and water. After the solvent was evaporated under reduced pressure, 20.2 g of 1-benzyl-4-phenylthio-3-pyrrolidinol (yield 70.9%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[CH:7]2.[C:12](#[N:15])[CH:13]=[CH2:14]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:14][CH2:13][C:12]#[N:15])[C:8]([CH3:11])=[CH:7]2
Reactant: Cc1cc2cccc(Cl)c2[nH]1
Reactant: C=CC#N
Solvent: C1COCCO1
Product: Cc1cc2cccc(Cl)c2n1CCC#N
Temperature: 60 °C

Procedure:
20 g of 7-chloro-2-methyl-1H-indole are mixed in 100 ml of dioxane with 3 g of triton B, 3 g of acrylonitrile are slowly added, 250 ml of dioxane are added again and then the mixture is heated at 60° C. for 2 hours. The medium is evaporated and then the residue is taken up in AcOEt. The precipitate formed being removed, the product obtained is used as is in the following stage.
Reaction SMILES: [C:1]([C:5]1[N:10]2[C:11](=[S:15])[C@H:12]([O:13][CH3:14])[C@H:9]2[S:8](=[O:17])(=[O:16])[CH:7]([CH2:18][C:19]([O:21]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:20])[C:6]=1[CH3:35])([CH3:4])([CH3:3])[CH3:2]>ClCCl.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:1]([C:5]1[N:10]2[C:11](=[S:15])[C@H:12]([O:13][CH3:14])[C@H:9]2[S:8](=[O:16])(=[O:17])[CH:7]([CH2:18][C:19]([OH:21])=[O:20])[C:6]=1[CH3:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@H]1C(=S)N2C(C(C)(C)C)=C(C)C(CC(=O)OC(c3ccccc3)c3ccccc3)S(=O)(=O)[C@H]12
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1C(=S)N2C(C(C)(C)C)=C(C)C(CC(=O)O)S(=O)(=O)[C@H]12

Procedure:
To a solution of 4-tert-butyl-7α-methoxy-3-methyl-2-(benzhydryloxycarbonylmethyl)thio-3-cephem 1,1-dioxide (see Example 16) (20 mg) in dichloromethane (0.5 ml), anisole (60 ml) and trifluoroacetic acid (0.3 ml) were added sequentially. The mixture was let stand for 3 hours at room temperature then concentrated in vacuo. Diisopropylether (10 ml) was added under stirring. The light yellow powder thus obtained was filtered and dried in vacuo (12 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl.C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:22])=[CH:5][N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ncc(Sc2cccnc2)s1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1ncc(S(=O)c2cccnc2)s1
Yield: 37.2 %

Procedure:
To a mixture of 2-amino-5-(3-pyridylthio)thiazole (3.0 g) in a mixture of dichloromethane (100 ml) and chloroform (100 ml) was added dropwise the solution of 3-chloroperbenzoic acid (3.4 g) in dichloromethane (50 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 3 hours. The reaction mixture was washed with aqueous sodium bicarbonate and the aqueous layer was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was recrystallized from ethanol to give 2-amino-5-(3-pyridylsulfinyl)thiazole (1.2 g, yield: 37.2%). mp: 178°-179° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([C@@H:36]2[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[N:37]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:33]([OH:35])=O)=[C:28]([F:50])[CH:27]=1.Cl.Cl.[CH3:53][C@H:54]1[C:62]2[C:61]([N:63]3[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]3)=[N:60][CH:59]=[N:58][C:57]=2[C@H:56]([OH:69])[CH2:55]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([C@H:36]2[N:37]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[C:38]([CH3:41])([CH3:42])[CH2:39][CH2:40]2)[C:33]([N:66]2[CH2:67][CH2:68][N:63]([C:61]3[C:62]4[C@H:54]([CH3:53])[CH2:55][C@@H:56]([OH:69])[C:57]=4[N:58]=[CH:59][N:60]=3)[CH2:64][CH2:65]2)=[O:35])=[C:28]([F:50])[CH:27]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@H](C(=O)O)c2ccc(Br)cc2F)CCC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
HATU (0.149 g, 0.391 mmol) was added to a solution of (R)-2-(4-bromo-2-fluorophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.168 g, 0.391 mmol; prepared analogously to that described in Example B), (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.1 g, 0.326 mmol; see Example 3, Step 12), and N-ethyl-N-isopropylpropan-2-amine (0.171 mL, 0.977 mmol) in DCM (8 mL), and the reaction mixture was stirred overnight at room temperature. The reaction was then quenched with H2O. The reaction was washed with H2O (3×30 mL). The organic layer was dried with MgSO4, filtered and concentrated. Purification by flash chromatography yielded (S)-tert-butyl 5-((S)-1-(4-bromo-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.0334 g, 0.0517 mmol, 15.9% yield). LCMS (APCI+) 646.4, 648.5 m/z [M+H]+; Retention time=4.25 minutes.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=[N:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(#N)C>[O:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:20](=[O:21])[O:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)[CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=[N:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc(-c2ncno2)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2ncno2)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(1,2,4-oxadiazol-5-yl)phenyl amine (0.97 g, 0.006 mol, prepared in sequence by the procedures described in Lin et al. J. Org. Chem., 1979, 44, 4160 and Lin et al., J. Org. Chem., 1979, 44, 4160) in acetonitrile (25 mL) and pyridine (0.97 mL, 0.95 g, 0.012 mol) under argon at 0° C. was treated with p-nitrophenyl chloroformate (1.21 g, 0.006 mol) and was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and an effort was made to partition the remaining oil between ethyl acetate and 10% citric acid, resulting in separation of a solid, insoluble in either phase. The solid was collected and triturated with anhydrous ether and dried in vacuo to yield 1.54 g of [3-(1,2,4-oxadiazol-5-yl)]phenylcarbamic acid, 4-nitrophenyl ester, m.p. 195°-197° C. TLC, silica gel, EtOAc/MeOH (20:1), Rf =0.75; M.S. (M+H)+ at 327, M.W. 326. This compound contained minor impurities and was used without further purification.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([C@@H:10]([NH:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1[C:36](O)=[O:37].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1[C:36]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([C@@H:10]([NH:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:37]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a solution of N-{(1S)-1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-2,2-dimethylpropyl}-1H-indole-2-carboxamide (120 mg, 0.34 mmol) in CH2Cl2 (4 mL) was added 1H-indole-2-carboxylic acid (55 mg, 0.34 mmol), EDC (78 mg, 0.41 mmol), HOBt (9 mg, 0.07 mmol) and NMM (102 mg, 0.93 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was diluted with CH2Cl2 (5 mL) and washed with sat. NaHCO3 (10 mL), 1N HCl (10 mL), sat. NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to yield the crude product. The material was purified by HPLC (YMC C18 5.0 uM 250*20 mm) and then recrystallized from water, dried by lyophilization to afford 64 mg of the title compound: LCMS (m/z): 498.4 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 0.98-1.16 (9H, m), 1.83-2.07 (3H, m), 3.52-3.96 (4H, m), 4.65-5.20 (3H, m), 6.62-6.98 (3H, m), 7.06-7.18 (2H, m), 7.21-7.45 (3H, m), 7.53-7.68 (2H, m), 9.42-9.73 (2H, m).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([C:11](=O)[CH3:12])[CH:9]=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+].O>CO>[OH:1][B:2]1[C:6]2[CH:7]=[C:8](/[C:11](=[N:16]/[OH:17])/[CH3:12])[CH:9]=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1
Reactant: CC(=O)c1ccc2c(c1)B(O)OC2(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C/C(=N\O)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]-oxaborol-6-yl)ethanone (190 mg, 0.93 mmol), NH2OH HCl (77 mg, 1.12 mmol) and NaOAc (114 mg, 1.4 mmol) in MeOH (15 mL) was heated to 65° C. and stirred for 3 h. Water was added and the mixture was extracted with DCM. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give (E)-1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ethanone oxime as a white solid. It was used in the next step without further purification. MS: m/z=220.1 (M+1, ESI+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[C:22](=[O:23])[NH:21][N:20]=[C:19]1[CH2:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30](OC(C)(C)C)=[O:31])[CH2:26]1.[CH3:37][C:38]1(C(O)=O)[CH2:40][CH2:39]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[C:19]([CH2:24][C@@H:25]2[CH2:29][CH2:28][N:27]([C:30]([C:38]3([CH3:37])[CH2:40][CH2:39]3)=[O:31])[CH2:26]2)=[N:20][NH:21][C:22]1=[O:23]
Reactant: CC1(C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2F)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1(C(=O)N2CC[C@@H](Cc3n[nH]c(=O)n3-c3ccc(-c4ccc5cccnc5c4)cc3F)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
Into a 50 mL round bottom flask was placed 1,1-dimethylethyl (3S)-3-({4-[2-fluoro-4-(7-quinolinyl)phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate (0.082 mmol). Added was 4N HCL in dioxane (1.0 mL). The solution was stirred at room temperature for 1 h and then was concentrated in vacuo. The solid was taken up in N,N-dimethylformamide (1 mL). Added to flask was 1-methylcyclopropanecarboxylic acid (0.100 mmol), 1-hydroxybenzotriazole (0.196 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.183 mmol), and N,N-diisopropylethylamine (0.286 mmol). The flask was capped and stirred at room temperature for 1 h. Purification of the crude material was performed by injecting the solution directly onto a reverse phase HPLC (10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA). The desired fractions were combined and concentrated in vacuo. The recovered material was taken up in 1 mL dichloromethane and 1 mL acetonitrile. A 6 mL tube packed with PL-HCO3 (Stratospheres Solid Phase Extraction macroporous resin for Acid Removal, Varian Industries) was pretreated with 2 mL of dichloromethane. The product solution was added to the top of the resin via pipette and was allowed to freely pass through the column via gravity. The column was rinsed with dichloromethane (2 mL) and acetonitrile (2 mL). The recovered filtrate was concentrated in vacuo to afford the title compound (23 mg, 59%). MS(ES)+ m/e 472.2 [M+H]+.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[O:23])[CH3:22])C.[S:24]([O-:28])([O-])(=[O:26])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:24]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[O:23])[CH3:22])(=[O:28])=[O:26])[CH3:11]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1ccccc1C(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccccc1C(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
8.41 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 3.0 g of 2′-ethylsulfanylacetophenone and 40 ml of chloroform under ice cooling, and the mixture was stirred at room temperature for 4 hours. A 10% aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was filtered. The filtrate was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to obtain 3.5 g of 2′-ethylsulfonylacetophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11].[Br:18]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:18])=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH:10][CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(Cc1ccccc1N)c1sccc1C
Solvent: CN(C)C=O
Product: CNC(Cc1cc(Br)ccc1N)c1sccc1C
Reaction time: 8 h

Procedure:
A stirred solution of 5.02 g of 2-amino-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine and 79 ml of dimethylformamide was treated with a solution of 4.71 g N-bromosuccinimide in 55 ml of dimethylformamide. The solution was stirred for 8 h with the exclusion of moisture and then concentrated to an oil on a rotary evaporator (70° C.) under high vacuum. The oil was diluted with distilled water (100 ml) and basified with a 10% sodium hydroxide solution (25 ml). The basic solution was extracted with dichloromethane (3×100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Thin layer chromatography (silica gel, methanol eluent) indicated a 2-component mixture.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-].[Li+:9].C[C:11](C)=[O:12]>CO>[C:4]([O:12][CH3:11])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O-:6])=[O:7].[Li+:9]
Reactant: CC(C)=O
Reactant: O=C1C=CC(=O)O1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)/C=C\C(=O)[O-]

Procedure:
Twenty grams of maleic anhydride is dissolved in 200 mls methanol, 4.8 grams (0.2 moles) lithium hydroxide is added. The mixture is stirred until all the lithium hydroxide dissolves (at this point the pH reads 7.0). To the solution is added acetone and the solid is filtered and dried. 23 grams product is obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][C:20]#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.[N:36](=[CH:44]CCl)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Cl>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][CH2:44][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: ClCC=NCCCCCCCl
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCCCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-(hexamethyleneimino)ethylchloride
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[N:10]=[CH:9][NH:8][C:7]2=O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38].[C:42]([C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47])#[CH:43]>C(O)(C)C>[ClH:38].[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[N:10]=[CH:9][N:8]=[C:7]2[NH:47][C:46]1[CH:48]=[CH:49][CH:50]=[C:44]([C:42]#[CH:43])[CH:45]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: C#Cc1cccc(N)c1
Reactant: CCOc1cc2nc[nH]c(=O)c2cc1OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(OCC)c(OCC)cc23)c1
Product: Cl

Procedure:
6,7-Diethoxyquinazolin-4-one (120 mg, 0.512 mmol), triphenylphosphine (295 mg, 1.126 mmol) and 3 mL of carbon tetrachloride were refluxed for 16 hours. The reaction mixture was concentrated in vacuo to a residue which was diluted with 3 mL of isopropyl alcohol and 3-ethynylaniline (66 mg, 0.563 mmol) and refluxed for 3 hours. The cooled reaction mixture was filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 140 mg (75%); mp 269°-270° C.
Reaction SMILES: [C:1]1([CH3:36])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH:20]([C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH2:21][S:22]([C:24]3[NH:28][N:27]=[CH:26][N:25]=3)=[O:23])=[N:8]2)=[CH:3][CH:2]=1.OO.C(O)(=[O:41])C.CO>CN(C)C=O>[C:1]1([CH3:36])[CH:2]=[CH:3][C:4]([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH:20]([C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH2:21][S:22]([C:24]3[NH:28][N:27]=[CH:26][N:25]=3)(=[O:41])=[O:23])=[N:8]2)=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(-c2cc(CC(CS(=O)c3ncn[nH]3)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Agent: OO
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(CC(CS(=O)(=O)c3ncn[nH]3)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Temperature: 50 °C
Yield: 95 %

Procedure:
To a flask was added 5-[3-(1,5-di-p-tolyl-1H-pyrazol-3-yl)-2-m-tolyl-propane-1-sulfinyl]-1H-[1,2,4]triazole (Example 136; 25 mg, 0.05 mmol), hydrogen peroxide (0.15 mL, 30% solution in water) and acetic acid (0.1 ml). The mixture was heated at 50° C. for 24 h and then cooled. Methanol (0.5 mL) and N,N-dimethylformamide (0.5 mL) were added to dissolve the resulting precipitate. This solution was then purified directly by reversed-phase chromatography yielding the title compound (24 mg, 95%). HPLC: Rt=2.97 (Method B). MS (ESI): mass calculated for C29H29N5O2S, 511.20; m/z found, 512.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 14.87 (br s, 1H), 8.72 (s, 1H), 7.18 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.08 (d, J=7.0 Hz, 1H), 7.07-7.04 (m, 3H), 7.01-6.99 (m, 3H), 6.95 (d, J=7.4 Hz, 1H), 6.15 (s, 1H), 3.91 (d, J=6.6 Hz, 2H), 3.52-3.49 (m, 1H), 3.08 (dd, J=14.7, 7.6 Hz, 1H), 2.91 (dd, J=14.5, 7.4 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20]>CN(C)C=O.N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20]
Reactant: N#Cc1c(CBr)cccc1[N+](=O)[O-]
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1c(COc2cccc(Cl)c2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
3-Chlorophenol (0.27 g, 2.07 mmol) and potassium carbonate were added to a cooled (0° C.) and stirred solution of 2-bromomethyl-6-nitrobenzonitrile [W. T. Ashton and J. B. Hynes, J. Med. Chem, 16, 1233 (1973)] (0.5 g, 2.07 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried. Purification by silica gel chromatography (1:1 dichloromethane in hexanes) yielded 185 mg of 2-(3-chlorophenoxymethyl)-6-nitrobenzonitrile.
Reaction SMILES: CO[C:3](=[O:30])[NH:4][C:5]1[NH:6][C:7]2[CH:13]=[C:12]([O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[CH:10][C:8]=2[N:9]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.N12CCCN=C1CCCCC2>CN1CCCC1=O.O1CCCC1>[CH:31]1([NH:34][C:3](=[O:30])[NH:4][C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([O:14][S:15]([C:18]4[CH:19]=[CH:20][C:21]([NH:24][CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:22][CH:23]=4)(=[O:16])=[O:17])=[CH:13][C:7]=3[N:6]=2)[CH2:33][CH2:32]1
Reactant: NC1CC1
Reactant: COC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)cc2[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2cc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)ccc2[nH]1)NC1CC1
Temperature: 60 °C

Procedure:
10 mg of methyl-5-(4-cyclopentylaminophenylsulfonyloxy)benzimidazole-2-carbamate (example 19) were combined with 25 μl cyclopropylamine and 10 μl 1,8-diazabicyclo[5.4.0]undec-7-ene in 2 ml N-methylpyrrolidone/tetrahydrofuran (0.8/1.2) in a 24 well Inox plate for high pressure reaction. The reaction mixture was put under a 10 Bars argon pressure and then heated to 60° C. for 40 hours, and then cooled to room temperature. Compounds were put in an assay tube, tetrahydrofuran was evaporated under reduced pressure and compound in N-methylpyrrolidone was directly purified by LC/MS trigged purification yielding 8.7 mg title compound. (LC/MS analysis: retention time=3.66 min., mass spectrum: 456.36, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)C(C)(C)c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (2.0 g, 9.97 mmol), tert-butyl 4-amino-1-piperidinecarboxylate (2.396 g, 11.96 mmol), DIEA (2.61 ml, 14.95 mmol), and hatu (4.17 g, 10.97 mmol) in DMF (30 mL) was stirred at RT overnight. The reaction mixture was then heated to 55° C. for 4 h, cooled, and H2O was added, the light brown solid was collected, dried and used in the next step (3.1 g, 81%). MS (M+1): 383.1