Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:19]1(=[O:25])[NH:23][C:22](=[O:24])[CH:21]=[CH:20]1>CO>[CH:5]1[C:4]2[CH2:3][C:2]3[CH:10]4[CH:18]([C:17]5[C:12]([NH:11]4)=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH:21]4[C:22](=[O:24])[NH:23][C:19](=[O:25])[CH:20]4[C:1]=3[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: C1=C(c2cc3ccccc3[nH]2)Cc2ccccc21
Reactant: O=C1C=CC(=O)N1
Solvent: CO
Product: O=C1NC(=O)C2C1C1=C(Cc3ccccc31)C1Nc3ccccc3C12
Yield: 62.3 %

Procedure:
A mixture of 2-(2-indenyl)indole (1.0 g, 4.3 mmol) and maleimide (525 mg, 5.41 mmol) in a 10 cm sealed reaction vial was heated at 180°-190° C. for 30 min. After cooling the reaction to ambient temperature, MeOH (5 mL) was added. The product was collected to give 880 mg (62%) of a white solid product with a m.p. of 254°-255° C. (MeOH). The following NMR data were obtained: 1H NMR (DMSO-d6, 300 MHz): δ3.1-3.4 (m, 2H), 3.8 (m, 2H), 3.95 (t, 1H), 4.35 (d, 1H), 6.9-7.4 (m, 7H), 7.75 (d, 1H), 11.05 (s, 1H), 11.25 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH2:40])[CH3:36]>O1CCOCC1>[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH:40][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:27])=[O:28])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1)[CH3:36]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Reactant: CCN(CC)CCN
Solvent: C1COCCO1
Product: CCN(CC)CCNc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in example 300 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol), N,N-diethyl-1,2-ethanediamine (123 mg, 1.056 mmol) in 1,4-dioxane (2 mL), the title compound was obtained as a yellow foam (30 mg, 22.47%). 1H NMR (400 MHz, DMSO-d6) ppm 1.01 (t, J=6.44 Hz, 6H), 1.65-1.83 (m, 2H), 2.01 (dd, J=12.76, 1.89 Hz, 2H), 2.58-2.73 (m, 6H), 3.27-3.41 (m, 5H), 3.42-3.58 (m, 2H), 3.93 (dt, J=9.54, 2.18 Hz, 2H), 5.78-6.17 (m, 1H), 6.60 (d, J=1.26 Hz, 1H), 6.97-7.28 (m, 3H), 7.43 (td, J=7.77, 1.64 Hz, 1H), 7.75 (s, 1H), 7.96-8.30 (m, 2H); MS (ESI): 601.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:9][NH:8][CH2:7][CH2:6]2.I[CH:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][CH:17]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)[CH3:19]
Reactant: CC(C)I
Reactant: COc1cc2c(cc1[N+](=O)[O-])CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])CN(C(C)C)CC2
Temperature: 65 °C
Yield: 89.6 %

Procedure:
6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (222 mg, 1.07 mmol) was taken in acetonitrile (5 mL), treated with 2-iodopropane (0.8 mL, 5.0 mmol) and potassium carbonate (600 mg, 4.35 mmol, Aldrich). The mixture was heated at 65° C. for 16 h, cooled, and partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated, and purified by chromatography on SiO2 (0 to 20% methanol/dichloromethane spiked with aqueous ammonia) to provide 2-(1-methylethyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydro isoquinoline (0.24 g, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 1.16 (d, J=6.4 Hz, 6 H), 2.76-2.84 (m, 2 H), 2.90-3.00 (m, 3 H), 3.70 (s, 2 H), 3.93 (s, 3 H), 6.80 (s, 1 H), 7.64 (s, 1 H); ESIMS (M+H)+=251.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][OH:12])=[N:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])=[N:2]1
Reactant: OCCc1noc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1noc2ccccc12
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution of 2-benzo[d]isoxazol-3-yl-ethanol (0.537 g, 3.29 mmol, from step (i) above ) and triethylamine (0.55 mL, 3.95 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.31 mL, 3.95 mmol) at 0° C. The reaction mixture was stirred for 1 hour and was then extracted with water (2×20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo, which afforded 818 mg (98%) of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)(O[NH2:10])=O)C=CC=CC=1.[NH2:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl:29]CCl>>[Cl-:29].[NH2:17][N+:18]1[CH:22]=[CH:21][N:20]([NH2:10])[C:19]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCCl
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: Nn1ccnc1-c1ccccc1
Product: Nn1cc[n+](N)c1-c1ccccc1
Product: [Cl-]
Reaction time: 24 h

Procedure:
(i.b) 43.8 g of O-diphenylphosphinylhydroxylamine are added to 30.1 g of 1-amino-2-phenylimidazole in 2000 ml of dichloromethane. After stirring at room temperature for 3 days an additional 21.9 g of O-diphenylphosphinylhydroxylamine are added. After one day, the mixture is filtered and the filter material is washed four times with 150 ml of dichloromethane each time. The residue is placed on a column loaded with 700 ml of ion-exchanger Amberlite IRA 400 (chloride), whereupon elution is carried out with water. The eluate is evaporated and the residue is treated with ethanol and evaporated. After drying in a high vacuum over potassium hydroxide, there is obtained 1,3-diamino-2-phenylimidazolium chloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21].O>CN(C=O)C.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:20]([CH3:22])[CH3:21])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(O)cc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl 3,5-dihydroxybenzoate (0.1 mol) in DMF (180 mL) was added powdered potassium carbonate (0.2 mol) and 2-iodopropane (0.1 mol), and the resulting mixture stirred at ambient temperature for 16 hours. The reaction mixture was poured into water (1000 mL) and the mixture extracted with ether. The extracts were combined and washed sequentially with water (twice) and brine; the solution was dried (MgSO4), filtered and evaporated in vacuo to give the crude product as a pale yellow oil (12.6 g). This was treated with toluene (40 mL) and allowed to stand overnight. The insoluble material (starting phenol) was removed by filtration, and the filtrate evaporated in vacuo. The resulting oil was chromatographed (2×90 g Biotage silica cartridges), eluting with hexane containing ethyl acetate (10% increasing to 15% v/v). The title compound was obtained as an oil (25% yield), which was identical by tlc to a sample prepared by a similar procedure. 1H NMR δ (d6-DMSO): 1.2 (d, 6H), 3.8 (s, 3H), 4.5-4.6 (hept, 1H), 6.55 (m, 1H), 7.85 (m, 1H), 7.95 (m, 1H), 9.8 (s, 1H)
Reaction SMILES: C(C1CCCC1=[O:11])CCCC.[OH-:12].[Li+].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:15][CH3:16]>>[OH:12][OH:11].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:15][CH3:16]
Reactant: CCCCCC1CCCC1=O
Reactant: [OH-]
Agent: [Li+]
Solvent: CCOC(=O)CC
Product: OO
Temperature: 100 °C
Yield: 70 %

Procedure:
In a three-necked 250 ml flask equipped with a magnetic stirrer and a reflux condenser were introduced 31 g of 2-pentyl cyclopentanone (0.2 mole), 31 g of anhydrous ethyl propionate, and 0.048 g (1 mol %) of anhydrous lithium hydroxide. The mixture was brought to reflux at ca. 100° C. Then 57.5 g (0.22 mole) of an anhydrous 13% w/w hydrogen peroxide solution in ethyl propionate, obtained from extraction of a 70% aqueous H2O2 solution by ethyl propionate, were slowly added over 4 h in the reactor while maintaining the reflux 2 h after the end of the introduction. The reaction mixture was then washed with 10% water to remove the non converted H202, and finally distilled to recover the solvent.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:21][C:22]1[C:27]([F:28])=[C:26]([O:29][CH2:30][CH3:31])[CH:25]=[CH:24][C:23]=1O.C1(N=C=NC2CCCCC2)CCCCC1.O>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]([O:20][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH3:31])=[C:27]([F:28])[C:22]=3[F:21])=[O:19])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC(=O)O)CC2)CC1
Reactant: CCOc1ccc(O)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC(=O)Oc3ccc(OCC)c(F)c3F)CC2)CC1
Reaction time: 0.5 h

Procedure:
In a 3-L three-neck flask equipped with a stirrer, a thermometer and a dropping funnel, 32.0 g (114.9 mmol) of 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propionic acid and 20.0 g (114.9 mmol) of 2,3-difluoro-4-ethoxyphenol were dissolved in 1000 ml of dichloromethane at room temperature under nitrogen atmosphere, and 15.4 g (126.4 mmol) of 4-dimethylaminopyridine was added thereto. The solution was stirred for 30 minutes thereafter, and then 26.1 g (126.4 mmol) of dicyclohexylcarbodiimide was dissolved in 400 ml of dichloromethane to prepare a solution, which was added dropwise to the reaction mixture at room temperature. After dropwise adding, the solution was stirred at room temperature for 14 hours. 500 ml of water was added to the reaction solution, insoluble materials were filtered, and then the filtrate was washed with 300 ml of 3M hydrochloric acid, 300 ml of water, 300 ml of a saturated aqueous sodium hydrogencarbonate solution and 600 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled off from the reaction solution under reduce pressure to obtain 56.4 g of a concentrated substance, which was then purified by means of a silica gel column chromatography with a mixed solvent of heptane/ethyl acetate (7/3) used as a developing solvent to obtain 51.4 g of 2,3-difluoro-4-ethoxyphenyl 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propionate as colorless crystals.
Reaction SMILES: [NH:1]([C:22]([O:24]CC1C=CC=CC=1)=O)[CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:32]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:33](C(O)=O)[CH2:34][CH2:35][C:36](=[O:38])[NH2:37].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CO.CN(C=O)C>[NH:32]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:33]([C:22]([NH:1][CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4])=[O:24])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37]
Reactant: CN(C(=O)CNC(=O)OCc1ccccc1)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(N)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C(=O)CNC(=O)[C@@H](CCC(N)=O)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=O
Reaction time: 15 h

Procedure:
0.85 g of Z-Gly-MePhe-NHNHCONH2 is subjected to catalytic reduction in methanol, dissolved in 10 ml of DMF, and after ice-cooling, 0.50 g of BOC-(D)-Gln-OH, 0.40 g of HONB and 0.45 g of DCC are added. The mixture is stirred for 15 hours, the precipitated DCU filtered off and the solvent distilled off. The residue is dissolved in n-butanol, washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and dried over anhydrous sodium sulfate. The solvent is distilled off, treated with ether and filtered to obtain a powder. Yield 0.82 g; m.p. 124°-128° C.; [α]D24 -36.5° (c=1.0, DMF); Rf1 0.11.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.[C-:26]#[N:27].[Na+].O>CS(C)=O>[C:26]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)#[N:27]
Reactant: [C-]#N
Reactant: BrCCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
2-(7-Bromoheptyl)-4,5-diphenyloxazole (13.8 g) in dimethylsulphoxide (80 ml) was added over 45 minutes to a mixture of sodium cyanide (1.87 g) in dimethylsulphoxide (80 ml). The reaction was stirred at 50° C. for 2 h, cooled and poured into water (500 ml). The aqueous was extracted with diethyl ether (4×250 ml). The ether extracts were combined, washed with water (250 ml), dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a hexane: dichloromethane gradient gave 2-(7-cyanoheptyl)-4,5-diphenyloxazole (4.89 g, 41%) as an oil. Found: C, 80.20; H, 7.02; N, 8.13%; C23H24N2O requires: C, 80.31; H, 7.18; n, 8.16%;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[CH:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:11][CH2:10][CH2:9][C:8]=2[C:7]=1[N+:27]([O-])=O)[CH3:2].C(OC(=O)NC1C([N+]([O-])=O)=CC2C(NC3C=CC(C(F)(F)F)=CC=3)CCCC=2C=1)C>CO.[Ni]>[CH2:1]([O:3][C:4](=[O:30])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[CH:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=3)[CH2:11][CH2:10][CH2:9][C:8]=2[C:7]=1[NH2:27])[CH3:2]
Reactant: CCOC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCCC2Nc1ccc(C(F)(F)F)cc1
Agent: [Ni]
Agent: CCOC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(Nc1ccc(C(F)(F)F)cc1)CCC2
Solvent: CO
Product: CCOC(=O)Nc1ccc2c(c1N)CCCC2Nc1ccc(C(F)(F)F)cc1
Reaction time: 4 h

Procedure:
To a solution of a mixture of [1-nitro-5-(4-trifluoromethyl-phenylamino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-carbamic acid ethyl ester and [3-Nitro-5-(4-trifluoromethyl-phenylamino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-carbamic acid ethyl ester (500 mg) in 20 ml of methanol was added a catalytic amount of Raney Ni. The resulting mixture was hydrogenated under regular pressure at room temperature for 4 hours. The reaction mixture was filtered through celite and washed with methanol. The filtrate was evaporated to dryness in vacuo and the residue was separated by preparative HPLC to give two products as white solids in a quantitative yield.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N:10]2[C@H:14]([CH3:15])[CH2:13][C@@:12]([OH:17])([CH3:16])[C@@H:11]2[CH3:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:19][O-:20].[Na+].O>CS(C)=O>[OH:17][C@@:12]1([CH3:16])[CH2:13][C@@H:14]([CH3:15])[N:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:20][CH3:19])[CH:9]=2)[C@H:11]1[CH3:18]
Reactant: C[C@@H]1C[C@](C)(O)[C@H](C)N1c1ccc(C#N)c(F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2[C@H](C)C[C@](C)(O)[C@@H]2C)ccc1C#N
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 50.3 %

Procedure:
To a solution (5 mL) of 2-fluoro-4-[(2S,3S,5R)-3-hydroxy-2,3,5-trimethylpyrrolidin-1-yl]benzonitrile (47.6 mg) in DMSO was added sodium methoxide (35 mg) and the mixture was stirred at 100° C. for 3.5 hr. Sodium methoxide (130 mg) was added, and the mixture was stirred at 100° C. for 4.5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→2/3) to give the title compound as a colorless solid (yield: 25.1 mg, yield: 50%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][O:7][C:8]=1[CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([OH:3])=[O:2].N1C=CC=CC=1.[C:28](O)([CH3:31])([CH3:30])[CH3:29].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:28]([O:2][C:1]([C:4]1[N:5]=[CH:6][O:7][C:8]=1[CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:3])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C(NCCc1ocnc1C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ncoc1CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2.9 g of 4-carboxy-5-{2-(benzyloxycarbonylamino)ethyl}oxazole, 4.9 g of pyridine, 6 ml of tert-butyl alcohol and 50 ml of chloroform was added dropwise 1.84 g of phosphoryl chloride at -10° C., and the mixture was stirred at the same temperature for 1 hour and further at room temperature overnight. The mixture was washed and dried, and then the solvent was removed. The residue was purified by silica gel chromatography to obtain 2.85 g of 4-tert-butoxycarbonyl-5-{2-(benzyloxycarbonylamino)ethyl}oxazole as a colorless oily product.
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]([O:16]C)=[O:15])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].O[Li].O>CO.C1COCC1.O>[CH3:1][N:2]([CH2:13][C:14]([OH:16])=[O:15])[S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: COC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Reaction time: 3 h

Procedure:
Methyl ester 6 (2.60 g, 10.1 mmol) was dissolved in a 3:1:1 mixture of MeOH-THF—H2O. LiOH.H2O (0.53 g, 12.6 mmol) was added at room temperature and the reaction allowed to stir for 3 h. All solvents were evaporated, apart from water. The remaining aqueous solvent was diluted further and thoroughly washed with ethyl acetate. The aqueous basic aqueous layer was then acidified to pH 2 with 1 M HCl and the product extracted with ethyl acetate. The organic layers were then combined and dried over Na2SO4, filtered and concentrated to afford the title compound. (2.33 g, 95%): δH (400 MHz, CDCl3) 2.43 (s, 3H, CH3), 2.87 (s, 3H, CH3), 3.99 (s, 2H, CH2), 7.32 (d, J=8.0 Hz, 2H, CH), 7.69 (d, J=8.0 Hz, 2H, CH); δC (100 MHz, CDCl3) 21.4, 35.7, 50.6, 127.3, 129.6, 134.8, 143.7, 173.5; LRMS (ES+) calcd for [C10H13NO4S+H] 244.06. found 244.07 [M+H].
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:26]=[CH:25][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[SiH4].C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:21]([N:20]([CH2:23][CH3:24])[C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:49]3[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=3)=[CH:26][CH:25]=2)[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCN(CC)C(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Agent: [SiH4]
Solvent: O=CO
Product: CCN(CC)C(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 24.2 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N,N-diethyl-1-piperidinecarboxamide formate (0.37 g, 1.01 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane silane (0.367 g, 0.909 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.159 g, 0.22 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:44])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][CH:16]=3)[C:10]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:9]2)[CH:7]=1.[C:45](Cl)(=[O:49])[CH2:46][CH2:47][CH3:48]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:40]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:38])(=[O:39])[NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])[CH:3]=[CH:4][C:5]=2[Cl:44])[N:9]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCC(=O)Cl
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)CCC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 100 mg (0.154 mmole) of 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 60), 18.8 mg (0.154 mmole) of 4-(dimethylamino)pyridine (DMAP), 80 μL (82 mg, 0.77 mmole) of butyryl chloride, and 1 mL of pyridine was stirred at room temperature overnight. Work-up of the reaction as in Example 57 provided a 65% yield of the title compound as a white solid, mp >130° C., homogeneous by TLC (9:1 MeOH-CH2Cl2), mass spectrum (FAB) m/e 758 (M+K)+.
Reaction SMILES: [NH2:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].ClCCl.N1C=CC=CC=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](Cl)=[O:32]>C(OCC)(=O)C>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([NH:1][C:31](=[O:32])[CH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[F:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:7]
Reactant: CCOC(=O)C(N)c1ccccn1
Reactant: O=C(Cl)Cc1ccccc1F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C(NC(=O)Cc1ccccc1F)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.50 g (12.1 mmol) of ethyl amino(pyridin-2-yl)acetate [G. van Zyl et al., J. Org. Chem. 1961, 26, 3373] are introduced into 20 ml of dichloromethane and, after addition of 4.9 ml (60.3 mmol) of pyridine, cooled to 0° C. A solution of 1.86 g (12.1 mmol) of (2-fluorophenyl)acetyl chloride is then slowly added, and the mixture is stirred at 0° C. for 30 min and then at RT for 2 h. It is diluted with ethyl acetate, washed with sodium bicarbonate solution and dried over sodium sulfate. The crude product is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1). 2.9 g (76% of theory) of the desired product are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[NH:4][N:3]=1.[Cl:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24][N:3]3[C:2]([CH3:1])=[C:10]4[C:5]([CH:6]=[N:7][N:8]([CH3:12])[C:9]4=[O:11])=[N:4]3)=[CH:22][CH:21]=2)=[O:19])=[CH:28][CH:29]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1n[nH]c2cnn(C)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c2c(=O)n(C)ncc2nn1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (2 ml) was dissolved 3,5-dimethyl-1H-pyrazolo [3,4-d]pyridazin-4(5H)-one (94 mg) followed by addition of 4-(4-chlorobenzoyl)benzyl bromide (279 mg) and potassium carbonate (124 mg), and the mixture was stirred at room temperature for 15 hours. This reaction mixture was extracted with ethyl acetate and the organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=1:4), washed with the following solvent, and dried. As the washing solvent, n-hexanediethyl ether was used for 1-[4-(4-chlorobenzoyl) benzyl]-3,5-dimethyl-1H-pyrazolo[3,4-d]pyridazin-4(5H)-one and diethyl ether for 2-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-2H-pyrazolo [3,4-d]pyridazin-4(5H)-one.