Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[Cl-].[C:18]([O:27][CH3:28])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O-])=[O:24].C(Cl)(=O)C(Cl)=O.C(OC)(=O)CCCCC([O-])=O>[N+](C1C=CC=CC=1)([O-])=O.C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][C:18]([O:27][CH3:28])=[O:26])[CH:11]=[CH:10]2
Reactant: COc1ccc2ccccc2c1
Reactant: COC(=O)CCCCC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)c1ccc2cc(OC)ccc2c1
Reaction time: 8 h

Procedure:
Into a solution of 6.32 g (47.4 mmol) of anhydrous aluminum chloride in 60 ml of dry nitrobenzene was added 5.03 g (31.7 mmol) of 2-methoxynaphthalene chilled with an ice bath, followed by stirring. Subsequently, under an ice bath, monomethyl adipate chloride (synthesized by adding 5.0 ml (57.3 mmol) of oxalyl chloride under an ice bath to a solution of 5.85 ml (39.5 mmol) monomethyl adipate in 50 ml of dry methylene chloride) to carry out the reaction for 6 hours, and evaporating methylene chloride and excessive oxalyl chloride under a reduced pressure) was gradually added, and the reaction was carried out at 0° C. to room temperature overnight (for 15 hours). The reaction mixture was poured into ice-water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After evaporation of the organic solvent and nitrobenzene under a reduced pressure, the desired product was obtained by silica gel chromatography. Yield: 3.82 g (40%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:40])([F:39])[C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:38])[C:17]([N:20]2[C:25](=[O:26])[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:23]([CH2:33][O:34]C(=O)C)[O:22][CH2:21]2)([CH3:19])[CH3:18])[CH:12]=[CH:13][CH:14]=1>O.CO>[F:40][C:8]([F:7])([F:39])[C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:38])[C:17]([N:20]2[C:25](=[O:26])[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:23]([CH2:33][OH:34])[O:22][CH2:21]2)([CH3:18])[CH3:19])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cccc(C(F)(F)F)c2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C(=O)Nc1cccc(C(F)(F)F)c1)N1COC(CO)=C(c2ccccc2)C1=O
Reaction time: 4 h
Yield: 42.5 %

Procedure:
A solution of potassium carbonate (0.33 g) in water was added portionwise to a stirred solution of N-(3-trifluoromethylphenyl)-2-(6-acetoxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (0.8 g) in methanol. Stirring was continued for 4 hours at room temperature, the mixture evaporated and the residue dissolved in a mixture of ether and water. The organic layer was dried (magnesium sulphate), evaporated and the residue purified by dry column chromatography eluting with ether to give N-(3-trifluoromethylphenyl)-2-(2,3-dihydro-6-hydroxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 102, 0.31 g) as a gum, NMR (CDCl3)δ 1.7(s,6H), 4.1(d,2H), 5.3(s,2H), 7.1-7.3(m,7H), 7.55(m,1H), 7.75(m,1H), 8.3(s,1H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.150 g, 0.543 mmol, US 2005/20572 A1) in DCM (4.0 mL) was added tert-butyl [2-(aminooxy)ethyl]carbamate 41 (0.143 g, 0.814 mmol, US 2005/54701 A1), 1-hydroxybenzotriazole (0.110 g, 0.814 mmol), 1-ethyl-(3-dimethylamino propyl)carbodiimide hydrochloride (0.156 g, 0.814 mmol) and DMAP (0.100 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 42 (0.21 g, 89%) as a white foam.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH:23]1[CH2:28][CH2:27][N:26](CC2C=CC=CC=2)[CH2:25][CH2:24]1)[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+]>C(O)C.Cl.[Pd]>[CH2:1]([N:3]([CH2:22][CH:23]1[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1)[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCN(CC1CCN(Cc2ccccc2)CC1)C(=O)c1cc(-c2ccccc2)nc2ccccc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Product: CCN(CC1CCNCC1)C(=O)c1cc(-c2ccccc2)nc2ccccc12
Reaction time: 5 h
Yield: 64.7 %

Procedure:
N-Ethyl-N-[(1-benzylpiperidin-4-yl)-methyl]-2-phenylquinoline-4-carboxamide (9.6 g) is heated in ethanol (200 ml) until it has dissolved. After cooling, this solution is treated with a 4.5N ethanolic solution of hydrogen chloride (9.2 ml), 10% strength palladium-on-charcoal (2.9 g) as a catalyst and, finally, sodium acetate (1.7 g). The mixture is hydrogenated at 60° C., with stirring, under a hydrogen pressure equal to normal pressure (1 bar), for 5 hours. After 5 hours (at which time the amount of hydrogen absorbed is 470 ml), the catalyst is removed by filtration, the ethanol is evaporated off by distillation under reduced pressure, the residue is taken up in water (200 ml) and the mixture is brought to pH 10 by the addition of a concentrated solution of sodium hydroxide and extracted with ether (3×100 ml). The organic phase is washed with water (3×50 ml), dried over magnesium sulphate and evaporated under reduced pressure. N-ethyl-N-[(piperidin-4-yl)methyl]-2-phenylquinoline-4-carboxamide (5 g) is isolated in this way; it is dissolved in acetone and converted to the monohydrochloride by the addition of a solution of hydrogen chloride in ether. This monohydrochloride melts at 219° C.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[CH2:23]([C:25]1[C:29]([N+:30]([O-:32])=[O:31])=[C:28]([C:33]([NH2:35])=[O:34])[NH:27][N:26]=1)[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[CH:10]([N:8]1[CH2:9][CH:6]([N:26]2[C:25]([CH2:23][CH3:24])=[C:29]([N+:30]([O-:32])=[O:31])[C:28]([C:33]([NH2:35])=[O:34])=[N:27]2)[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 75 °C

Procedure:
1-Benzhydryl-3-azetidinyl methanesulfonate (8.03 g, 25.3 mmol, prepared according to the procedure in J. Org. Chem. 1991, 56, 6729-30) was added to a mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (4.64 g, 25.3 mmol, prepared using procedure in WO9849166) and cesium carbonate (8.24 g, 25.3 mmol) in MeCN (170 ml). The mixture was heated to 75° C. for 2 h and concentrated in vacuo. Water (200 ml) and EtOAc (200 ml) were added, and the mixture shaken. The insoluble solid at the interface was filtered off and dried to afford the title compound of preparation 52. The two layers of the filtrate were separated and the organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated with EtOAc (50 ml) and the resultant solid was filtered off, washed with hot DCM/MeOH (90:10, 50 ml) and dried to afford more of the title compound of preparation 52. The liquors and washings were combined and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH, 98:2-95:5) to afford the title compound of preparation 51 plus a further small quantity of the title compound of preparation 52. The identity of the regioisomers was confirmed by nOe studies.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH:12]=[C:13]([CH3:21])[CH2:14][O:15][CH2:16][P:17](=[O:20])([OH:19])[OH:18])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2.[C:26]1(O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:26]1([O:20][P:17]([CH2:16][O:15][CH2:14][C:13]([CH3:21])=[CH:12][CH2:11][C:10]2[C:2]([OH:1])=[C:3]3[C:7](=[C:8]([CH3:24])[C:9]=2[O:22][CH3:23])[CH2:6][O:5][C:4]3=[O:25])(=[O:19])[OH:18])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Oc1ccccc1
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)COCP(=O)(O)O)C(=O)OC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1c(C)c2c(c(O)c1CC=C(C)COCP(=O)(O)Oc1ccccc1)C(=O)OC2
Temperature: 25 °C
Yield: 31.7 %

Procedure:
To a solution of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid (49 mg, 0.13 mmol) in DMF (0.4 mL) and phenol (62 mg, 0.65 mmol) was added dicyclohexyl carbodiimide (107 mg, 0.52 mmol) and DMAP (8 mg, 0.065 mmol) in DMF (0.6 mL), slowly at 0° C. The reaction was allowed to warm to room temperature and heated to 140° C. for 10 hours. After cooling to room temperature the mixture was filtered and extracted with aqueous 1N NaOH solution. The aqueous layer was acidified with aqueous 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by RP HPLC to provide 18.5 mg of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid monophenyl ester, as a pale yellow solid and 4.1 mg of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid diphenyl ester (minor product) also as a pale yellow solid. Major product: 1H NMR (300 MHz, CD3OD) δ 1.82 (s, 3H), 2.16 (s, 3H), 3.46 (d, 2H, J=7 Hz), 3.70 (d, 2H, J=8 Hz), 3.77 (s, 3H), 3.96 (s, 2H), 5.25 (s, 2H), 5.52 (t, 1H, J=8 Hz), 7.10-7.21 (m, 3H), 7.30 (t, 2H, J=8 Hz) ppm; 31P (121.4 MHz, CD3OD) δ 17.3 ppm; MS (m/z) 449.0 [M+H]+, 471.2 [M+Na]+. Minor product: 1H NMR (300 MHz, CD3OD) δ 1.82 (s, 3H), 2.15 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.77 (s, 3H), 3.98-4.06 (m, 4H), 5.25 (s, 2H), 5.50-5.61 (m, 1H), 7.10-7.25 (m, 6H), 7.30-7.41 (m, 4H) ppm; 31P (121.4 MHz, CD3OD) δ 16.3 ppm; MS (m/z) 525.2 [M+H]+, 547.2 [M+Na]+.
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N+:11]=[N-:12].[NH:24]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:25]([C:31]([OH:33])=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][NH2:30].C(=O)(O)[O-].[Na+].S(=O)(=O)(O)[O-].[K+]>O1CCOCC1.C(OCC)(=O)C.O>[N:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][O:2][C:1]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]([NH:24][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:31]([OH:33])=[O:32])=[O:23])=[N+:11]=[N-:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Reactant: [N-]=[N+]=Nc1ccccc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)O
Temperature: 25 °C
Reaction time: 22 h
Yield: 85.5 %

Procedure:
2-Azidobenzyl (4-nitrophenyl) carbonate (414 mg, 1.317 mmol) was added to a suspension of Boc-Lys-OH (Compound tk39) (295 mg, 1.198 mmol) and sodium bicarbonate (252 mg, 2.99 mmol) in 1,4-dioxane (3 mL)-water (2 mL). The reaction mixture was stirred at room temperature for 22 hours and then cooled in an ice bath and diluted with ethyl acetate and water, and a saturated aqueous potassium bisulfate solution (0.7 mL) was added to the resulting mixture. The mixture was extracted with ethyl acetate (×2), and the organic phase was washed with water (10 mL×2) and brine (10 mL) and dried over sodium sulfate. Following concentration under reduced pressure, the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoic acid (Compound tk40) (431.5 mg, 85%).
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][O:65][C:66]2[CH:73]=[CH:72][C:69]([CH:70]=[O:71])=[CH:68][CH:67]=2)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:74][O:75][C:76]1[CH:81]=[CH:80][C:79]([Mg]Br)=[CH:78][CH:77]=1>C1COCC1>[CH3:74][O:75][C:76]1[CH:81]=[CH:80][C:79]([CH:70]([C:69]2[CH:68]=[CH:67][C:66]([O:65][CH2:64][CH:22]3[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]3)=[CH:73][CH:72]=2)[OH:71])=[CH:78][CH:77]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C=O)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C(O)c3ccc(OC)cc3)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
4-(3,4,5-Tris-octadecyloxy-cyclohexylmethoxy)-benzaldehyde (130 mg, 127 μmol) was dissolved in dehydrated THF (2 mL), 4-methoxy-phenyl-magnesiumbromide (350 μmol) was added, and the mixture was stirred at 40° C. for 1.5 hr. After evaporation of the solvent, 1N hydrochloric acid (5 mL) was added to the residue to allow crystallization. The crystals were filtered, and thoroughly washed with hydrochloric acid, water and methanol in this order to give (4-methoxy-phenyl)-[4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-phenyl]-methanol (110 mg, 97.2 μmol, 96%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH2:20]O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH2:20][O:22]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccncc1C1(O)CCN(Cc2ccccc2)CC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(CN2CCC3(CC2)OCc2ccncc23)cc1
Yield: 123.6 %

Procedure:
To a solution of 0.46 g (1.5 mmol) 1′-benzyl-4-hydroxymethyl-2′,3′,5′,6′-tetrahydro-1′H-[3,4′]bipyridinyl-4′-ol and 0.45 ml (3.2 mmol) triethylamine in 15 ml dry tetrahydrofuran at were added 0.11 ml (1.5 mmol) methane sulfonyl chloride room temperature. The reaction mixture was heated at reflux for 1 h and then quenched with water. The aqueous layer was basified with aqueous 1 M sodium hydroxide and extracted with three portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash-chromatography (aminopropyl-modified silica gel) gave the title compound (0.52 g, 57%) as a light yellow amorphous solid.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:10][CH:9]([CH2:11][OH:12])[CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].Cl.NC1C(CC2C=CC(Cl)=C(Cl)C=2)C2C=C(CN[S:36]([CH2:39]CC)(=[O:38])=[O:37])C=CC=2CC1>>[CH2:1]([S:4]([N:7]1[CH2:8][CH:9]([CH2:11][O:12][S:36]([CH3:39])(=[O:38])=[O:37])[CH2:10]1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N)CC2
Reactant: CCCS(=O)(=O)N1CC(CO)C1
Agent: Cl
Product: CCCS(=O)(=O)N1CC(COS(C)(=O)=O)C1

Procedure:
Prepared by standard procedure from [1-(propane-1-sulfonyl)-azetidin-3-yl]-methanol and methan-1-sulfonyl chloride (e.g. example 40)
Reaction SMILES: [N:1]([C:4]1[C:13]([Cl:14])=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[Cl:23])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)=[N+]=[N-].CCOC(C)=O>C(Cl)Cl.CC(O)=O.[Zn]>[NH2:1][C:4]1[C:13]([Cl:14])=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[Cl:23])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1
Reactant: COC(=O)c1cnc(N=[N+]=[N-])c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of methyl 6-azido-4-(4-bromo-2-chlorophenylamino)-5-chloronicotinate (316 mg, 0.76 mmol) in a mixture of DCM (6 ml) and AcOH (2 ml) was added Zn dust (255 mg, 3.9 mmol) in small portions. After complete addition it was furthers stirred at room temperature for 30 min. Then, the mixture was poured into EtOAc (30 ml), washed with H2O, saturated sodium bicarbonate solution and brine. The organic fractions were dried with Na2SO4 and the solvents were removed and the product was dried in oil-pump vacuo (246 mg, 83%). Rf (CHCl3/MeOH 30:1)=0.3. 1H-NMR (500 MHz, DMSO-D6): δ=9.17 (s, 1H), 8.45 (s, 1H), 7.70-7.70 (d, 1H), 7.38-7.36 (dd, 1H), 7.1 (s, 1H, br), 6.68-6.67 (d, 1H), 3.76 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:53][O:54][CH2:55][CH2:56][NH2:57]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.CO.O>[CH3:53][O:54][CH2:55][CH2:56][NH:57][C:27](=[O:29])[CH2:26][CH:23]1[S:22][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:20][CH:19]=3)=[N:25][CH2:24]1
Reactant: COCCN
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)ccc3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.5 %

Procedure:
To a solution of [2-(5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (80 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg), and 2-methoxyethylamine (52 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 10:90:0, volume ratio), and crystallized from acetonitrile to give the title compound (101 mg, yield 60%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:24])=[C:4]([C:9]2[C:10](=O)[NH:11][N:12]=[C:13]([CH3:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:5]([F:8])=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:22])=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9]=1[C:4]1[C:5]([F:8])=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:24]
Reactant: Cc1n[nH]c(=O)c(-c2c(F)ccc(Cl)c2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2c(F)ccc(Cl)c2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
1.33 g of 4-(3-chloro-2,6-difluorophenyl)-5-(4-chlorophenyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 1.33 g of 3-chloro-4-(3-chloro-2,6-difluorophenyl)-5-(4-chlorophenyl)-6-methylpyridazine (hereinafter, referred to as compound (x) of the present invention).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1>ClCCl>[NH:12]1[C:16]2=[N+:17]([O-:9])[CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: ClCCl
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 3-chloroperbenzoic acid (224.3 g) in dichloromethane (1500 mL) was cooled to 0° C. To this a solution of 1H-pyrrolo[2,3-b]pyridine (59.1 g) in dichloromethane (500 mL) was added dropwise over 30 minutes. The reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated, diluted with methanol (1500 mL) and treated with 10% potassium carbonate in water (300 mL). The slurry was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on neutral alumina with 20% methanol in dichloromethane to give the title compound as a tan solid (47.0 g). MS: 135 (MH+). 1HNMR (CDCl3): δ 13.1 (s, 1H), 8.2 (d,1H), 7.65 (d, 1H), 7.4 (d, 1H), 7.0 (m, 1H), 6.55 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([C:15]#[N:16])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:8])[N:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[C:3]([C:15]#[N:16])=[N:4][C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[C:6]([CH3:8])[N:7]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: Cc1nc(Cl)c(C#N)nc1-c1ccccc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c(C#N)nc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 75a-c, 1-phenyl-1,2-propanedione and 2-aminomalonamide were heated in an aqueous solution to give 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide. Then, the 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide was treated with triethylamine and phosphorus pentachloride in phosphorus oxychloride at reflux to give 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile. The 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile was finally treated with 1-(4-fluorophenyl)piperazine and N-ethyldiiso-propyl-amine in N,N-dimethylformamide at room temperature to yield the 4-(4-fluoro-phenyl)-6′-methyl-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-carbonitrile as yellow solid; m.p. 117-120° C.; MS: 374 (M+H)+.