Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C)(C)C.Cl[S:7]([N:10]=C=O)(=[O:9])=[O:8].C(OC(NS(Cl)(=O)=O)=O)(C)(C)C.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[N:39]=[CH:40][C:41]([NH2:44])=[N:42][CH:43]=2)=[C:34]([F:45])[CH:33]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[NH:25][S:7]([NH2:10])(=[O:9])=[O:8])=[CH:33][C:34]=2[F:45])=[N:39][CH:40]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1cnc(-c2ccc(-c3ccccc3N)cc2F)cn1
Agent: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1cnc(-c2ccc(-c3ccccc3NS(N)(=O)=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
To a solution of tert-butanol (13 mg, 0.18 mmol) in DCM (5 mL) was added chlorosulfonylisocyanate (25 mg, 0.18 mmol) at 0° Celsius. The resulting solution containing N-(tert-butoxycarbonyl)sulfamoyl chloride was added to a reaction flask containing 5-(2′-amino-3-fluorobiphenyl-4-yl)pyrazin-2-amine (50 mg, 0.18 mmol) and triethylamine (36 mg, 0.36 mmol) in anhydrous DCM (10 mL) at 0° Celsius. The mixture was warmed to rt, stirred 2 hours, then concentrated to dryness, re-dissolved in TFA/DCM (5 mL/5 mL), stirred at rt for 1 hour, and concentrated to dryness. The residue was diluted with water (10 mL) and saturated NaHCO3(aq) (10 mL), extracted with DCM (10 mL×3) and the combined organic extracts washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by HPLC to give the title compound (10 mg, 16%). MS (ESI): mass calcd. for C16H14FN5O2S, 359.09; m/z found, 360.0 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.33 (s, 1H), 8.04 (d, J=1.3, 1H), 7.91 (m, 1H), 7.63 (d, J=7.8, 1H), 7.44-7.22 (m, 4H), 7.24 (m, 1H), 7.05 (s, 2H), 6.70 (s, 2H).
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:17]=2)[C:13]#[N:14])=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.O.N>CO.C1COCC1.[Ni]>[N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH2:13][NH2:14])[CH:15]=[C:16]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:17]=2)=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: COCCOc1cc(C#N)cc(-c2cn3ncccc3n2)c1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cc(CN)cc(-c2cn3ncccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.2 %

Procedure:
3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)benzonitrile (6 mmol) in 40 ml MeOH and 30 ml THF was added Raney-Ni (0.6mmol) and 1 ml ammonia hydrate solution and stirred at room temperature for 4 h. Raney-Ni was removed and the filtrate was concentrated to yield (3-(imidazo[1,2-b]pyridazin-2-yl)-5-(2-methoxyethoxy)phenyl)methanamine (70.2%).
Reaction SMILES: [C:1]([C:3]([C:12]#[N:13])=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)#[N:2].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=1[S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=1[S:23]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[C:3]([C:12]#[N:13])[C:1]#[N:2])=[CH:6][CH:7]=1)(=[O:25])=[O:24]
Reactant: N#CC(C#N)=Cc1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Solvent: c1ccncc1
Product: N#CC(C#N)=Cc1ccc(OS(=O)(=O)c2cc(Cl)c(Cl)cc2Cl)cc1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
1.7 g of 4-(2,2'-dicyanovinyl)phenol and 2.7 g of 2,4,5-trichlorobenzenesulfonyl chloride were dissolved in 10 ml of pyridine and reacted at 80° C. for 30 minutes. Crystals were precipitated by cooling to the room temperature and adding water, filtered and recrystallized from toluene to obtain 3.5 g of 4-(2,2'-dicyanovinyl)phenyl 2,4,5-trichlorobenzenesulfonate as white crystals. Melting point=165-166° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:19]=[CH:20][CH:21]=1>>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[S:11]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:17]=1)(=[O:13])=[O:12]
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccccc12
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2ccccc12
Yield: 34 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 11) (25 mg, 0.10 mmol) and 5-(3-amino-phenyl)tetrazole (33 mg, 0.20 mmol). The title compound was obtained in 34% yield (13.3 mg). MS (ESI+) calcd for C16H13N5O2S2 371.051066, found 371.049276.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:19]3[CH2:26][CH:27]([NH2:31])[CH:28]([CH3:30])[CH3:29])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[C:32]([O-:35])(=O)[CH3:33].[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[CH2:20][N:19]3[CH2:26][C@@H:27]([NH:31][C:16]([CH:18]3[CH2:33][CH2:32][O:35][CH2:23]3)=[O:17])[CH:28]([CH3:29])[CH3:30])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC(=O)[O-]
Reactant: CC(C)C(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: [NH4+]
Product: CC(C)[C@@H](CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12)NC(=O)C1CCOC1

Procedure:
The desired compound was prepared following Method E from Intermediate 61 and the appropriate acid. 1H-NMR (300 MHz, methyl-d3 alcohol-d): δ 0.87 (m, 6H), 1.25 (d, 3H), 1.37 (d, 3H), 1.81 (m, 1H), 2.10-2.47 (m, 4H), 2.93 (m, 2H), 3.10 (m, 1H), 3.26 (m, 1H), 3.80 (m, 1H), 3.86-4.07 (m, 6H), 7.86 (d, 1H), 8.10 (m, 2H), 8.32 (d, 1H), 8.89 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.73 min. MS (M+H+): 542.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][CH2:6][CH2:5]2.[O-:19][C:20]#[N:21].[Na+]>C(O)(=O)C.O>[C:12]1([C:11]2[NH:21][C:20](=[O:19])[NH:1][C:2]3[C:10]=2[CH:9]=[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1)CCC2
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(-c2ccccc2)c2cc3cccc3cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of 5-amino-6-benzoylindane (160 mg, 0.68 mmol) in 6 mL of acetic acid and 0.6 mL of water was added sodium cyanate (53 mg, 0.81 mmol) and the solution was stirred at rt for 3 h. Water was then added to produce a suspension which was filtered and washed with water. The resulting solid was dried under vacuum to give the title compound (139 mg, 79%). 1H NMR (CDCl3): 13.25 (bs, 1H), 7.80 (d, 2H), 7.70 (s, 1H), 7.60 (m, 4H), 3.05 (t, 2H), 2.95 (t, 2H), 2.15 (p, 2H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][C:12]=1[F:20].[CH:21]1([C@H:24]([NH2:26])[CH3:25])[CH2:23][CH2:22]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(Cl)Cl.C([O-])(O)=O.[Na+]>>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:26][C@@H:24]([CH:21]2[CH2:23][CH2:22]2)[CH3:25])=[O:17])=[CH:13][C:12]=1[F:20]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: C[C@@H](N)C1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1ccc(Br)c(F)c1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
N,N-Diisopropylethylamine (0.92 mL, 5.3 mmol) was added to a mixture of 4-bromo-3-fluorobenzoic acid (0.58 g, 2.6 mmol), (1R)-1-cyclopropylethanamine (0.27 mL, 2.9 mmol, Alfa Aesar: Cat. #H26902) and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (1.3 g, 2.9 mmol) in methylene chloride (5.8 mL, 91 mmol). The reaction mixture was stirred at room temperature for 30 minutes, worked up with aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-10%) to afford the desired product (0.71 g, 94%). LCMS (M+H)+: m/z=286.0/288.0.
Reaction SMILES: [CH2:1]([P:8]([CH2:11][CH:12]([C:25]([O:27]CC1C=CC=CC=1)=[O:26])[CH2:13][CH2:14][C:15]([O:17]CC1C=CC=CC=1)=[O:16])(=[O:10])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.[Pd]>[CH2:1]([P:8]([CH2:11][CH:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:25]([OH:27])=[O:26])([OH:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC(CP(=O)(O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: O=C(O)CCC(CP(=O)(O)Cc1ccccc1)C(=O)O
Yield: 56.6 %

Procedure:
Benzyl [2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (0.5 g, 1.0 mmol) in 20 mL of water containing 120 mg of 10% Pd/C was hydrogenated at 40 psi for 6 hours. Filtration through a Celite pad followed by evaporation on high vacuum gave 0.17 g (57%) of 2-[(benzylhydroxyphosphinyl)methyl]-pentanedioic acid (4, R=CH2Ph) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>CO.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Br)c(C(=O)O)c1
Yield: 91.2 %

Procedure:
A mixture of 2-bromo-5-nitrobenzoic acid (1.10 g, 4.06 mmol) (Aldrich, 38, 184-5), activated Pd-C (43.62 mg, 0.41 mmol)(Aldrich, 20, 569-9) in methanol (30 ml) was hydrogenated for 4 hr under 30 psi of hydrogen pressure. After the mixture was filtered, the filtrate was concentrated to give 0.80 g (91.2% yield) of 5-amino-2-bromobenzoic acid as a pale yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[CH:22]=[CH:23][CH2:24][OH:25])=O)C1C=CC=CC=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>O1CCCC1.O>[OH:25][CH2:24][CH:23]=[CH:22][C@H:18]1[CH2:19][CH2:20][CH2:21][N:17]1[CH3:15]
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCC[C@@H]1C=CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a stirred solution of lithium aluminum hydride (0.73 g, 19.24 mmol, 2.2 equivalents) in anhydrous tetrahydrofuran (20 mL) at 0° C. was added dropwise a solution of (R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene (2.30 g, 8.80 mmol) in anhydrous tetrahydrofuran (20 mL). The resulting reaction mixture was heated at reflux under nitrogen for 3.5 hours. The resulting mixture was then cooled, and sodium sulfate decahydrate (10 g) was added slowly with caution. This mixture was stirred at room temperature under nitrogen for 1 hour, and then ethyl acetate (100 mL) and water (1 mL) was added. The resulting mixture was stirred at room temperature under nitrogen overnight. The mixture was then filtered through Celite®, and the filtrate was evaporated under reduced pressure. Column chromatography of the residual oil using silica gel (approximately 200 g) and elution with methylene chloride/methanol/ammonium hydroxide (9:1:0.1) afforded the title compound (1.13 g, 8.00 mmol, 91%) as a clear, colorless liquid: 13C NMR (CDCl3) δ 132.6, 132.5, 69.0, 62.7, 56.6, 40.2, 31.8, 22.1; Anal. calcd for C8H18NO·0.175 H8NO [ammonium hydroxide]: C, 64.21; H, 10.88; N, 11.34. Found: C, 65.01; H, 10.71; N, 10.81.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]([OH:11])=[O:10].[BH4-].[Na+].Cl>[OH-].[Na+]>[O:11]1[CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[CH2:8][C:9]1=[O:10]
Reactant: O=C(O)CC1CCCCC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: O=C1CC2CCCCC2O1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
2-Oxocyclohexylacetic acid (31.2 g, 200 mmol) is dissolved in 125 ml of 0.2 N aqueous sodium hydroxide solution and, at room temperature, added dropwise to a solution of sodium borohydride (18.9 g, 500 mmol) in 150 ml of 0.2 N aqueous sodium hydroxide solution. The mixture is stirred for 20 h and then cooled to 0° C. and carefully acidified with 6 N HCl. The strongly acidic solution is then heated at 100° C. for 30 min and subsequently stirred overnight. The cold mixture is then extracted with MTBE, and the combined ether phases are washed with 5% strength sodium carbonate solution and sat. NaCl solution, dried over magnesium sulphate, filtered and concentrated. Purification is carried out by distillation (b.p.: 75° C./0.01 mm). Yield: 22.9 g (81.7%). MS (CI): m/e=141 [M+H+]
Reaction SMILES: C1(=O)[N:5]([C:6]2[N:11]=[C:10]([NH:12][C:13](=[O:33])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH:9]=[CH:8][CH:7]=2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][C:6]1[N:11]=[C:10]([NH:12][C:13](=[O:33])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:21](=[O:32])[C:22]2[CH:23]=[CH:24][C:25]([C:28]([CH3:29])([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(N3C(=O)c4ccccc4C3=O)n2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(N)n2)cc1
Yield: 29.8 %

Procedure:
To a stirred solution N-(6-phthalimidopyridin-2-yl)-2-[(4-tert-butylbenzoyl)amino]benzamide (230 mg, 0.44 mmol) in ethanol (15 mL) was added hydrazine hydrate (0.22 g, 4.4 mmol). After refluxing the mixture for 30 min, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate, washed twice with saturated aqueous sodium bicarbonate solution, twice with saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in a minimal amount of chloroform and chromatographed (silica gel, eluting with a gradient of chloroform to 2% methanol/98% chloroform. The appropriate fractions were combined and concentrated In vacuo to give 51 mg (30%) of the title compound as a white solid.
Reaction SMILES: C(O)(=O)/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7]C)[CH:5]=1.[OH-].[K+].[CH3:17]C1NC=CN=1>CN(C)C=O>[CH:3]([C:4]1[CH:5]=[C:6]([OH:7])[C:9]([O:10][CH3:17])=[CH:11][CH:12]=1)=[CH2:2]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: Cc1ncc[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C=Cc1ccc(OC)c(O)c1
Yield: 64 %

Procedure:
A mixture of Ferulic acid (0.0083 mol), KOH (10%, 3 ml), methylimidazole (1 mL) and dimethylformamide (10 ml) were taken in a 100 ml round bottom flask fitted with reflux condenser. The flask was placed inside the microwave oven and irradiated (150 W, 150° C.) for 12 minutes. The cooled mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with dil HCl, water, saturated sodium bicarbonate, brine and then organic layer dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain liquid which was purified on silica gel column chromatography using mixture of hexane and ethyl acetate (9:1 to 6:4), provided sweet and pleasant smelling viscous liquid. 64% yield; 1H NMR (CDCl3) δ 6.90 (3H, m), 6.70 (1H, dd, J=10.90 Hz and J=17.36 Hz), 5.79 (1H, s), 5.59 (1H, d, J=17.36 Hz), 5.11 (1H, d, J=10.90 Hz), 3.83 (3H, s); 13C NMR (CDCl3) δ 146.7, 145.7, 136.7, 130.3, 120.1, 114.5, 111.4, 108.1, 55.9.
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[CH:17]=[C:16]([C:18](O)=[O:19])[S:15][C:6]=3[N:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[N:8]=2)[CH2:3][CH2:2]1.Cl.[NH:22]1[C:26]([C:27]2[CH:28]=[C:29]3[C:39](=[CH:40][CH:41]=2)[O:38][C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][C:30]3=[O:42])=[N:25][N:24]=[N:23]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>O.CN(C=O)C>[CH:1]1([C:4]2[C:5]3[CH:17]=[C:16]([C:18]([N:35]4[CH2:36][CH2:37][C:32]5([CH2:31][C:30](=[O:42])[C:29]6[C:39](=[CH:40][CH:41]=[C:27]([C:26]7[NH:25][N:24]=[N:23][N:22]=7)[CH:28]=6)[O:38]5)[CH2:33][CH2:34]4)=[O:19])[S:15][C:6]=3[N:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc2c(C3CC3)nn(-c3ccccn3)c2s1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC2(CCN(C(=O)c3cc4c(C5CC5)nn(-c5ccccn5)c4s3)CC2)Oc2ccc(-c3nnn[nH]3)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
DMF (5 mL) and TEA (0.2 mL) were added to 3-cyclopropyl-1-pyridin-2-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (143 mg), 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (177 mg), EDCI (119 mg) and HOBT (90 mg), heated at 80° C. and stirred for 2 hours. This was cooled to room temperature, iced water was added to it, and its pH was adjusted at 2.5 with 1 N HCl added thereto. The formed crystal was taken out through filtration, washed with water, washed with Et2O and dried in vacuum at 70° C. to obtain the title compound as a pale brown powder. 1H-NMR (400 MHz, DMSO-d6) δ: 8.54-8.51 (1H, br m), 8.43 (1H, d, J=2.2 Hz), 8.25 (1H, dd, J=8.3, 2.2 Hz), 8.03-7.97 (1H, m), 7.88 (1H, d, J=8.3 Hz), 7.51 (1H, s), 7.36-7.27 (2H, m), 4.24-4.14 (2H, br m), 3.4-3.6 (2H, br m), 3.00 (2H, s), 2.31-2.22 (1H, m), 2.10-2.02 (2H, br m), 1.93-1.81 (2H, br m), 1.11-1.04 (4H, m). MS [M+H]+=553.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C@H:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCCI
Reactant: CCCCCCC[C@@H](O)CC(=O)OC(C)(C)C
Product: CCCCCCC[C@@H](O)[C@@H](CCCCCC)C(=O)OC(C)(C)C

Procedure:
The target compound (1.80 g, 33%) was obtained in the same manner as in Production Example C-1, except that the (R)-3-hydroxydecanoic acid t-butyl ester (4.00 g, 16.4 mmol) obtained in Production Example B-5 and 1-iodohexane (5.20 g, 24.5 mmol) were used.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[S:17][CH:18]=[C:19]([Br:25])[C:20]=1[C:21]([O:23][CH3:24])=[O:22]>>[Br:25][C:19]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:16]([NH:15][C:12](=[O:14])[CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][CH:2]=[N:1]3)[S:17][CH:18]=1
Reactant: O=C(O)Cc1cccc2ncccc12
Reactant: COC(=O)c1c(Br)csc1N
Product: COC(=O)c1c(Br)csc1NC(=O)Cc1cccc2ncccc12

Procedure:
Methyl 4-bromo-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate was prepared from 2-(quinolin-5-yl)acetic acid (427 mg, 2.18 mmol) and methyl 2-amino-4-bromothiophene-3-carboxylate (514 mg, 2.18 mmol) according to protocol A. Retention time (min)=1.660, method [1], MS(ESI) 405.0 (M+H).
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[Br:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1>>[Br:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=3[CH3:26])=[O:17])[C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1
Reactant: O=c1cc(OCc2ccc(Br)cn2)cc[nH]1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccc(Br)cn2)cc1=O
Yield: 98 %

Procedure:
4-(5-Bromo-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared following preparation 1c employing 4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17]1([NH2:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClC1C2N(C(C)=NN=2)C2C(N=1)=CC=CC=2.C1(N)CCCC1>>[CH2:15]([C:12]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([NH:23][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:3]2=[N:14][N:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH3:16]
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Reactant: Nc1ccccc1
Agent: Cc1nnc2c(Cl)nc3ccccc3n12
Agent: NC1CCCC1
Product: CCc1nnc2c(Nc3ccccc3)nc3ccccc3n12

Procedure:
The title compound was prepared essentially as described in Example 2 substituting 4-chloro-1-ethyl [1,2,4]triazolo[4,3-a]quinoxaline and benzenamine for 4-chloro-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline and cyclopentanamine respectively; mp 172°-174° C.
Reaction SMILES: [C:1]([O:11][CH2:12][CH:13]=[CH2:14])(=[O:10])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].CCC(OO)=[O:18].C1C=CC=CC=1>>[C:4]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O:11][CH2:12][CH:13]1[O:18][CH2:14]1)=[O:10]
Reactant: CCC(=O)OO
Reactant: C=CCOC(=O)/C=C\C(=O)OCC=C
Solvent: c1ccccc1
Product: C=CCOC(=O)/C=C\C(=O)OCC1CO1

Procedure:
9.8 kg (50 mol) of diallyl maleate were reacted with 28.9 kg of a 21.8% strength solution of perpropionic acid in benzene (70 mol) at a reaction temperature of 60° C. in a manner analogous to that described in Example 1. After a reaction time of 8.5 hours, the percarboxylic acid conversion was 97.2%. The conversion of diallyl maleate was 88.3%. Allyl glycidyl maleate was formed with a selectivity of 45.8% and diglycidyl maleate was formed with a selectivity of 44.7%, in each case based on the diallyl maleate reacted.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1.O>CC(N(C)C)=O>[Cl:31][C:32]1[CH:33]=[C:34]([S:38]([N:19]2[CH2:18][CH:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])[N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:20]2=[O:28])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(Cl)c4)C(=O)N3c3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (0.050 g) in dimethylacetamide (1 ml) under an argon atmosphere was added sodium hydride (55% in mineral oil, 6.3 mg) at 0° C. The mixture was stirred at 0° C. for 30 min. 3-Chlorobenzenesulfonyl chloride was added. The mixture was stirred at 0° C. for 30 min and at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and concentrated. The product was purified by chromatography ((SiO2, cyclohexane=>cyclohexane/ethyl acetate 1:2) to give (RS)-1-(3-chloro-benzenesulfonyl)-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-3-phenyl-imidazolidin-2-one (0.049 g) as a colorless solid. MS: 552.7 ([M+H]+)