Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:31])[C:7]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[C:8]([O:10]CC)=[O:9])C>O.C(O)C>[OH:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][C:7]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])([C:8]([OH:10])=[O:9])[C:6]([OH:31])=[O:5]
Reactant: CCOC(=O)C(CCCCC(C)(C)CO)(CCCCC(C)(C)CO)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CO)CCCCC(CCCCC(C)(C)CO)(C(=O)O)C(=O)O
Yield: 60.1 %

Procedure:
To a stirred solution of potassium hydroxide (4.83 g, 75 mmol) in water (4.2 mL) and ethanol (15 mL) was added 2,2-bis(6-hydroxy-5,5-dimethylhexyl)malonic acid diethyl ester (15.0 g). The reaction mixture was heated at reflux for 14 h. The ethanol was removed under reduced pressure and the aqueous solution was extracted with chloroform (2×50 mL). The aqueous layer was acidified with hydrochloric acid to pH 1 and extracted with diethyl ether (3×50 mL). The ethereal phases were dried over magnesium sulfate and concentrated in vacuo to yield 2,2-bis(6-hydroxy-5,5-dimethylhexyl)malonic acid (7.8 g, 82%) as a yellow solid. M.P.: 178-180° C. 1H NMR (300 MHz, CD3OD/TMS): δ (ppm): 4.86 (s br., 4 H), 3.22 (s, 4 H), 1.9-1.8 (m, 4 H), 1.36-1.10 (m, 12 H), 0.84 (s, 12 H). 13C NMR (75 MHz, CD3OD/TMS): δ (ppm): 176.0, 72.0, 58.7, 39.8, 36.0, 34.1, 26.5, 25.5, 24.5. HRMS (LSIMS, gly): Calcd. for C19H37O6 (MH+): 361.2590, found: 361.2582.
Reaction SMILES: [C:1]1([C:7]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]([CH3:10])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O.O>[N:17]([CH:9]([CH3:10])[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:8])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1OC1(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])C(O)(c1ccccc1)c1ccccc1
Yield: 69.7 %

Procedure:
A solution of 9.35 g (44.5 mmol) 2,2-diphenyl-3-methyloxirane and 9.00 g (138 mmol) NaN3 in 100 ml of 2:1 N,N-dimethylformamide-water was heated at reflux for 72 hours. The solution was concentrated and the residue was partitioned between ether and water. The ether layer was washed with NaHCO3, then water, dried over Na2SO4 and concentrated. HPLC (5% EtOAc-hexane) afforded 7.86 g (70%) of 2-azido-1,1-diphenylpropanol as a clean oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:29][NH2:30]>>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[CH2:29][NH:30][C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:15][C@@H:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:12][C@@H:11]3[CH2:13]2)[CH:17]=[N:18][CH:19]=1)=[O:23]
Reactant: NCc1cc(F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)NCc4cc(F)cc(C(F)(F)F)c4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 3-fluoro-5-trifluoromethylbenzylamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 509 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26](S(C)(=O)=O)[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].N1([C:39]([N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:40])CCNCC1>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:39]([N:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[O:40])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: O=C(N1CCCCC1)N1CCNCC1
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)N5CCCCC5)CC4)cc3c2)CC1
Yield: 95 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and piperazin-1-yl-piperidin-1-yl-methanone to afford the desired product as a light-brown foam (95%). MS (ISP): 495.5 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]1)=O>>[CH2:49]([N:46]1[CH2:47][CH2:48][N:43]([CH2:41][CH2:40][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[CH:20]3[CH2:29][CH2:28][C:27]4[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=4[CH2:21]3)=[CH:37][CH:38]=2)[CH2:44][CH2:45]1)[CH3:50]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: CCN1CCN(C(=O)CCl)CC1
Product: CCN1CCN(CCOc2ccc(CCCCNc3cc(OC)ccc3C3CCc4cc(O)ccc4C3)cc2)CC1
Yield: 52.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-(4-ethylpiperazin-1-yl)ethanone (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].C(#N)C.C1CCN2C(=NCCC2)CC1.Cl[C:27]1[C:28]([NH:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([N+:47]([O-:49])=[O:48])[CH:42]=2)(=[O:40])=[O:39])=[N:29][C:30]2[C:35]([N:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2>CO>[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH:5][C:27]1[C:28]([NH:37][S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([N+:47]([O-:49])=[O:48])[CH:42]=2)(=[O:39])=[O:40])=[N:29][C:30]2[C:35]([N:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CO
Product: COc1ccc(Cl)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 20 °C

Procedure:
Prepare a solution with 0.585 kg of 2-chloro-5-methoxyaniline-HCl, 3.5 volumes of acetonitrile and 0.46 kg of DBU. (solution A) Mix 1 kg of N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide and 5.5 volumes of acetonitrile. Heat to reflux. Add solution A and 1 volume of acetonitrile onto the reaction mixture. After completion of the reaction at reflux, cool down at 20° C., dilute with 10 volumes of methanol and filter. Wash the cake 3 times with 5 volumes of methanol and dry it under vacuum.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)=[N:8]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Yield: 96.1 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (150 mg) obtained in Step C of Example 12, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (145 mg), tetrakis(triphenylphosphine)palladium(0) (47.4 mg) and 2M aqueous sodium carbonate solution (1.03 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (147 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[C:3]1=[O:16].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:48][C:49]1[C:54]([C:55]([F:58])([F:57])[F:56])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:59][NH2:60]>ClCCl>[Cl:48][C:49]1[C:54]([C:55]([F:57])([F:58])[F:56])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:59][NH:60][C:7]([CH:6]1[CH2:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[C:3](=[O:16])[N:2]1[CH3:1])=[O:9]
Reactant: CN1C(=O)N(c2cncnc2)CC1C(=O)O
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)N(c2cncnc2)CC1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.8 %

Procedure:
A solution of 3-methyl-2-oxo-1-(5-pyrimidinyl)-4-imidazolidinecarboxylic acid (0.6 mmol) in dichloromethane (6 ml) was treated with N-ethyl morpholine (0.460 ml, 3.60 mmol), 1-hydroxybenzotriazole hydrate (110 mg, 0.720 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg, 0.720 mmol) and the mixture was stirred at room temperature for 10 minutes. A solution of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (126 mg, 0.600 mmol) in dichloromethane (1 ml) was added and the reaction stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane and the solution was washed with 3N citric acid, water, saturated sodium bicarbonate solution and brine, dried and evaporated. The residue was purified by mass-directed automated HPLC to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-2-oxo-1-(5-pyrimidinyl)-4-imidazolidinecarboxamide (54 mg, 22%). LC/MS [M+H]+=414, retention time 2.37 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:12]C.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: COc1ccc2[nH]c(C)nc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nc2c(Cl)c(O)ccc2[nH]1

Procedure:
Under a nitrogen atmosphere 1.50 g (7.63 mmol) 4-chloro-5-methoxy-2-methyl-1H-benzo[d]imidazole and 11.20 g (0.10 mol) pyridine hydrochloride were stirred for 15 min at a bath temperature of 180° C. The reaction mixture was poured onto water while hot. The substance was extracted with ethyl acetate and washed with water. The organic phase was separated off, dried and evaporated down i.vac. The residue was stirred with DIPE and ethyl acetate, suction filtered and dried.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CC1CCN(Cc2ccccc2)CC1)N1CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC1CCN(C(=O)CC2CCN(Cc3ccccc3)CC2)CC1
Temperature: 66 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a mixture of 4.75 g (0.015 mol) of 1-(1-benzyl-4-piperidylacetyl)-4-hydroxypiperidine [1], 51 g of toluene, 1.68 g (0.017 mol) of triethylamine, 1.87 g (0.016 mol) of mesyl chloride was added dropwise at a temperature in the range of 0 to 10° C. and the reaction was allowed to proceed for 2 hours at the temperature in the range. Thereafter, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium chloride. The resultant organic layer was dried with anhydrous magnesium sulfate and concentrated under a reduced pressure. To the concentrated residue, 7 g of 2-propanol and 43 g of diisopropyl ether were added and the temperature of the mixture was increased. The mixture was stirred for 0.3 hours at a reflux temperature of 66° C. Thereafter the mixture was cooled to room temperature and subjected to filtration. The resultant wet crystal was dried under a reduced pressure, whereby 5.01 g of the title compound in the state of white powder was obtained (the yield was 84.7%).
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Product: CC(C)(C)OC(=O)NCCNc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and (2-aminoethyl)-carbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH:6]([CH3:8])[NH2:7])[CH3:3].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:10]([NH:7][CH:6]([CH3:8])[C:5]([O:4][CH2:2][CH3:3])=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(C)N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a mixture of DL-alanine ethyl ester hydrochloride (913 mg, 5.9 mmol) in DCE (15 mL) was added TEA (1.2 mL, 8.8 mmol) followed by benzaldehyde (0.538 mL), 5.3 mmol) and Na(OAc)3BH (2.0 g, 9.4 mmol). The mixture was stirred at room temperature overnight and then quenched with saturated aqueous NaHCO3 solution. The layers were separated and the aqueous layer extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 eluting EtOAc/Hex afforded the desired compound as a colorless liquid (798 mg, 73%). MS (ESI) mass calcd. C12H17NO2, 207.1. m/z found 208.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.39-7.23 (m, 5H), 4.23-4.16 (m, 2H), 3.83-3.65 (m, 2H), 3.37 (q, J=7.0 Hz, 1H), 1.34-1.27 (m, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[C:24]5[CH:25]=[CH:26][CH:27]=[C:18]([C:19]=45)[S:17]3(=[O:29])=[O:28])[CH2:9][CH2:8]2)[C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[NH:3]1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[H-].[Na+]>CN(C)C=O.O1CCCC1>[C:34]([N:3]1[C:4]2[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=2[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[C:24]5[CH:25]=[CH:26][CH:27]=[C:18]([C:19]=45)[S:17]3(=[O:29])=[O:28])[CH2:11][CH2:12]2)[C:2]1=[O:1])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(CCCN2c3cccc4cccc(c34)S2(=O)=O)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)n1c(=O)n(C2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 15 h
Yield: 51.5 %

Procedure:
The experiment is carried out as in Example 44, starting with 2-{3-[4-(2-oxo-1-benzimidazolinyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.6 g) in dimethylformamide (20 cc) and benzoyl chloride (1.4 g) in tetrahydrofuran (20 cc) and sodium hydride (0.48 g) as a 50% dispersion in vaseline oil. The mixture is stirred for 15 hours at a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a dichloromethanemethanol (90-10 vol) mixture as eluant, and then recrystallization from a boiling acetone/ethanol (90-10 vol) mixture (60 cc), 2-{3-[4-(3-benzoyl-2-oxo-1-benzimidazolinyl)piperidino]propyl}naphto [1,8-cd]isothiazole 1,1-dioxide (2.9 g) is obtained, m.p. 133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][OH:31].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:30][OH:31])[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(CO)c1ccccc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CC(CO)c2ccccc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 7 h
Yield: 65.6 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 3-(methylamino)-2-phenylpropan-1-ol (DE 1261862 19680229 CAN 69:35694) (74 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (86 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#[N:2].[OH:21]O.[OH-].[Na+].Cl>C(O)C.O1CCCC1.ClCCl>[S:17]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:3]([CH:4]=1)[C:1]([NH2:2])=[O:21])(=[O:19])(=[O:18])[NH2:20]
Reactant: OO
Reactant: N#Cc1cc(S(N)(=O)=O)ccc1OCC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)c1cc(S(N)(=O)=O)ccc1OCC1CCOCC1
Temperature: 35 °C

Procedure:
To a solution of EXAMPLE 38A (0.455 g) in ethanol (3 mL) and tetrahydrofuran (1 mL) was added hydrogen peroxide (30% in water, 2 mL) followed by 1 N aqueous NaOH (1.024 ml) and heated to 35° C. for 3 hours. The reaction was poured into dichloromethane (50 mL) and 1N aqueous HCl (25 mL). The aqueous layer was extracted with dichloromethane (3×50 mL). The precipitate contained in the combined organic layers was collected by filtration to give the title compound.
Reaction SMILES: [OH:1][CH:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:14](C1C=CC=CC=1Br)([CH3:16])[CH3:15]>>[OH:1][CH:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)c1ccccc1Br
Reactant: OC(c1ccccc1)c1ccco1
Product: CC(C)c1ccccc1C(O)c1ccco1

Procedure:
(±) 2-(α-Hydroxy-2-isopropylbenzyl)furan (b.p. 110° C./0.15 mm.Hg) was prepared by the procedure hereinbefore described in (i) for the preparation of (±) 2-α-hydroxybenzylfuran but replacing the bromobenzene by 2-isopropylbromobenzene (described by Crawford and Stuart, J.C.S., 1952, 4445).
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].[CH:25]1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=C[CH:26]=1.C1(C)C(C)=CC=CC=1.C([Sn](CCCC)(CCCC)CCCC)=C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[NH2:1][C:2]1[N:23]=[C:22]([CH:25]=[CH2:26])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 130 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a mixture of 2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (30 mg, 0.083 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.017 mmol) and xylene (1.5 mL) was added vinyl(tri-butyl)tin (0.073 mL, 0.25 mmol), and the solution was stirred at 130° C. for 3 hours. After cooling, water and ethyl acetate were added to the reaction solution for extraction, which was then washed with brine. The solvent was evaporated in vacuo, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=2:1), and the title compound (19 mg, 0.054 mmol, 65%) was obtained as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8]2.C(N(CC)CC)C.[C:24]1([C:29](Cl)=[O:30])[S:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH3:1][N:2]([C:29]([C:24]1[S:28][CH:27]=[CH:26][CH:25]=1)=[O:30])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cccc(NC)c2[nH]1
Reactant: O=C(Cl)c1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cccc(N(C)C(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of ethyl 7-(methylamino)-1H-indole-2-carboxylate (54 mg) in tetrahydrofuran (3 mL) were added triethylamine (42 μL) and 2-thenoylchloride (44 mg), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:3) to give colorless crystals (71 mg, yield 87%). melting point 193° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=O)[NH:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([Cl:24])=[N:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cccc(Cl)c1-c1nc(Cl)n(-c2ccc(Br)cc2)n1

Procedure:
To 2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-1, 0.100 g, 0.271 mmol) was added POCl3. The reaction mass was refluxed for 48 h. The reaction mass was quenched in water, basified with NaHCO3 and extracted with ethyl acetate and concentrated. The obtained crude product was purified with column chromatography on silica gel eluting with 0.5% EA:DCM to afford 0.110 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.44 (t, J=9.3 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.60-7.68 (m, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.85 (d, J=8.7 Hz, 2H). MS (m/z): 388.22 (M+H)+.