Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[F:12][C:13]1[CH:22]=[C:17]([C:18](OC)=[O:19])[C:16]([NH2:23])=[CH:15][CH:14]=1.CC1C=C(C)C=C(C)C=1[C:27](O)=[O:28].CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18](=[O:19])[C:17]2[C:16](=[CH:15][CH:14]=[C:13]([F:12])[CH:22]=2)[NH:23][C:27]1=[O:28]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cc(F)ccc1N
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccc(F)cc2c(=O)n1-c1ccc(Cl)cc1Cl
Temperature: 180 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
17.2% by weight of 2,4-dichloronitrobenzene, 15.6% by weight of methyl 5-fluoroanthranilate, 1.5% by weight of Pd--C (5%), 1.0% by weight of 2,4,6-trimethylbenzoic acid and 0.4% by weight of 3,4,7,8-tetramethyl-1,10-phenanthroline are dissolved in 64.3% by weight of toluene and filled into an HC-4 autoclave. A pressure of 100 bar of CO is set and the temperature is increased to 180° C. After 2 hours, the autoclave is allowed to cool, and the product is filtered off together with the active carbon and recrystallized from dichlorobenzene. 51% of 3-(2,4-dichlorophenyl)-6-fluoro-2,4(1H,3H)-quinazolinedione is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([N:11]3[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]3)=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:3]1[N:2]([CH3:1])[C:6]2[C:7]([N:11]3[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]3)=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccn(-c2cccc3[nH]c(=O)n(C)c23)n1
Product: Cc1ccn(-c2cccc3nc(Cl)n(C)c23)n1
Temperature: 80 °C
Reaction time: 120 h

Procedure:
A mixture of 17 mg (0.0745 mmol) of 1-methyl-7-(3-methyl-1H-pyrazol-1-yl)-1,3-dihydro-2H-benzimidazol-2-one in 0.5 mL of phosphorus oxychloride was stirred at 80° C. for 5 days. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was neutralized by 12 N aqueous sodium hydroxide. The aqueous suspension was extracted with ethyl acetate (X2). The combined organic layer was washed with water (X1) and brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC eluting with a 30% ethylacetate/n-hexane mixture to give 2-chloro-1-methyl-7-(3-methyl-1H-pyrazol-1-yl)-1H-benzimidazole. A mixture 2-chloro-1-methyl-7-(3-methyl-1H-pyrazol-1-yl)-1H-benzimidazole obtained above, 48 mg (0.223 mmol) of 4-bromo-2-methoxy-6-methylaniline and 0.15 mL of 1-methyl-2-pyrrolidinone was stirred at 120° C. for 3 days. After cooling, the reaction mixture was neutralized by saturated aqueous sodium hydrogen carbonate. The aqueous suspension was extracted with ethyl acetate (X2). The combined organic layer was washed with water (X1) and brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC eluting with a 75% ethylacetate/n-hexane mixture to give 5.7 mg (18%) of the title compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:30]C)(=[O:29])=[O:28])=[CH:23][CH:22]=1.[CH2:32](OC(=O)C)C>C(#N)C>[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1.[OH:17][C:12]1[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]2[O:6][C:5]([CH2:4][CH2:3][S+:2]([CH3:32])[CH3:1])([CH3:19])[CH2:10][CH2:9][C:8]=2[C:11]=1[CH3:18]
Reactant: CSCCC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: CCOC(C)=O
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC[S+](C)C)O2
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 87 %

Procedure:
A solution of 2.90 g of 3,4-dihydro-2-(2-methylthioethyl)-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol and 2.12 g (10% excess) of methyl 4-methylbenzenesulfonate in 30 ml of acetonitrile is refluxed for 48 hours. On cooling and addition of ethylacetate, the product crystallizes and is recrystallized from the same solvent pair, 4.19 g (87% yield), m.p. 156°-158° C., identified by elemental analysis, IR, UV and 1H and 13C NMR spectra.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:27])=[C:15]([CH:18]=[CH:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>C(OC(C)C)(C)C>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH:18]=[CH:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnc3)CS[C@H]12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(C=Cc3cccnc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of benzhydryl 7-phenylacetamido-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (cis-trans mixture)(5.9 g), anisole (6 ml) and trifluoroacetic acid (20 ml) was stirred at ambient temperature for 30 minutes. The reaction mixture was added to di-iso-propylether (300 ml). The precipitate was collected by filtration, washed with di-iso-propylether to give 7-phenylacetamido-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid trifluoroacetate (cis-trans mixture) (2.5 g).
Reaction SMILES: CS(O[C@H:6]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH2:7][CH2:8][C@H:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[O:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>CN1C(=O)CCC1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([C@H:9]2[CH2:8][CH2:7][C@H:6]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[N:43]2[C:42]2[CH:41]=[CH:40][C:39]([N:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)=[CH:45][CH:44]=2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: CS(=O)(=O)O[C@@H](CC[C@H](OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc([C@H]2CC[C@H](c3ccc([N+](=O)[O-])cc3)N2c2ccc(N3CCOCC3)cc2)cc1

Procedure:
The product from Example 38A and 4-morpholinoaniline were processed using the method described in Example 1D using NMP for the solvent to afford the title compound. MS (ESI) m/z 475 (M+H)+.
Reaction SMILES: COC([C:5]1[C:6]([C:17]2[CH:25]=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)(C#N)[C:7]2[C:12]([C:13]=1N)=[CH:11][CH:10]=[CH:9][CH:8]=2)=O.S(=O)(=O)(O)[OH:27].[C:31]([OH:34])(=[O:33])C>>[O:21]1[C:20]2[CH:24]=[CH:25][C:17]([C:6]3([C:31]([OH:34])=[O:33])[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:13](=[O:27])[CH2:5]3)=[CH:18][C:19]=2[O:23][CH2:22]1
Reactant: COC(=O)C1=C(N)c2ccccc2C1(C#N)c1ccc2c(c1)OCO2
Reactant: CC(=O)O
Reactant: O=S(=O)(O)O
Product: O=C1CC(C(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 3-amino-1-benzo[1,3]dioxol-5-yl-1-cyano-1H-indene-2-carboxylic acid methyl ester (10 g) and acetic acid, (30 mL) were heated to 100° C.; 60% aqueous sulfuric acid (20 mL) was added with stirring during 30 min. The mixture was heated to 110° C. for 6 h, cooled to rt, extracted with toluene (50+10 mL), washed with water (3×100 mL), extracted with 0.1 M aqueous sodium hydroxide (100+20 mL), acidified with concentrated hydrochloric acid, extracted with toluene (25+10 mL), and filtrated through activated carbon. Removal of the toluene gave 80% of 1-(benzo[1,3]dioxol-5-yl)-3-oxo-indan-1-carboxylic acid. The acid was subsequently decarboxylated by heating to 100° C. in N-methylpyrrolidone (15 mL) for 1 h. After cooling, the solution was poured into water (40 mL) with efficient stirring. Filtration, washing with water (5×20 mL), dissolution in ethyl acetate (40 mL), filtration through activated carbon and removal of the ethyl acetate gave 80% of 3-(benzo[1,3]dioxol-5-yl)-indan-1-one.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:38][CH2:39][C@H:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[OH:41]>>[OH:41][C@@H:40]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:39][NH:38][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20]([F:19])([F:36])[F:37])=[CH:32][CH:31]=1)=[O:7])=[O:18]
Reactant: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Reactant: NC[C@@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3C(F)(F)F)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, and (1S)-2-amino-1-phenylethanol, the title compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=526.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[C:27]([Cl:29])[CH:28]=1.Cl.O1CCOCC1>CC(O)C.O1CCOCC1>[ClH:1].[Cl:29][C:27]1[CH:26]=[C:25]([OH:30])[CH:24]=[C:23]([NH:22][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1cc(O)cc(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Temperature: 80 °C
Yield: 98.8 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (3.24 g, 9.95 mmol) was dissolved in 2-propanol (40 mL). 3-Amino-5-chlorophenol (1.50 g, 10.4 mmol) from Example 64A and a 4 M solution of gaseous hydrogen chloride in dioxane (124 μL, 0.50 mmol) were added, and the mixture was heated to 80° C. for 20 h. Subsequently, further hydrogen chloride in dioxane (5.0 mL, 20 mmol) was added, and the mixture was heated for additional 3 h. The resulting precipitate was collected by suction filtration to yield 3.63 g (99%) of the title compound.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[NH2:15][C:16]1[S:20][C:19]2[C:21]3[C:26]([CH2:27][C:18]=2[C:17]=1[C:28]([NH2:30])=[O:29])=[CH:25][CH:24]=[CH:23][CH:22]=3.O>ClCCl>[C:10]([OH:12])([C:9]([F:14])([F:13])[F:8])=[O:11].[NH:15]([C:16]1[S:20][C:19]2[C:21]3[C:26]([CH2:27][C:18]=2[C:17]=1[C:28]([NH2:30])=[O:29])=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:6]([NH2:5])=[O:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Nc1sc2c(c1C(N)=O)Cc1ccccc1-2
Reaction time: 0.5 h
Yield: 255.9 %

Procedure:
Chlorosulfonyl isocyanate (0.025 g, 0.17 mL) was added dropwise to a stirred solution of 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide trifluoroacetate (0.040 g, 0.17 mmol) in dry dichloromethane (2 mL). The resulting reaction mixture was stirred under nitrogen for 30 min. Water (0.5 mL) was then added to the reaction mixture and the reaction mixture was allowed to stir an additional 10 minutes before the solvent was removed under vacuo. The residue was then purified on Gilson preparative HPLC (YMC HPLC column 50×20 mm I.D., s-5 μm, 120 A; gradient elution, 0.1% TFA in acetonitrile: 0.1% aqueous TFA, 10:90 to 90:10, 10 min) to give title compound as brown solid (0.020 g, 0.435 mmol, 43.5% yield). ESMS m/z: 274 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].S(Cl)([Cl:16])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:16][C:3]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1(Cl)CCCCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
First, ethyl 1-chloro-2-oxocyclohexanecarboxylate was prepared from ethyl 2-oxocyclohexanecarboxylate referring to the process described in Organic Synthesis volume 4, page 162. 17 g (0.1 mol) of ethyl 2-oxocyclohexanecarboxylate was dissolved in 50 ml of carbon tetrachloride, and to the solution was added dropwise 14.8 g (0.11 mol) of sulfuryl chloride dissolved in 15 ml of carbon tetrachloride at 0° C. After stirring at room temperature for 2 hours, the reaction solution was poured into 100 ml of ice water, the mixture was extracted three times with 50 ml each of carbon tetrachloride, and the extract was washed twice with 75 ml each of saturated aqueous sodium bicarbonate and once with 75 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled away to obtain 18 g (yield: 88%) of ethyl 1-chloro-2-oxocyclohexanecarboxylate. 1.22 ml (2 mmol) of dimethyl sulfide borane was dissolved in 40 ml of tetrahydrofuran, and 2.5 g (12 mmol) of ethyl 1-chloro-2-oxocyclohexanecarboxylate was added dropwise at -5° C. to 0° C. After stirring at 0° C. for 1 hour, the solvent was distilled away under reduced pressure and the reaction solution was poured into 50 ml of ice water. The mixture was extracted three times with 50 ml each of ethyl acetate, and the resulting organic layer was washed once with 75 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled away to obtain 2.2 g of a stereoisomer mixture of ethyl 1-chloro-2-hydroxy-1-cyclohexanecarboxylate.
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.CS(O)(=O)=O>O>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: CS(=O)(=O)O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 2 h

Procedure:
9α-Hydroxyandrostenedione (280 mg.; 302 mg. of 92.7% purity) is added to a solution of water (3 ml.) and methanesulfonic acid (1 ml.) and stirred at 22° for 2 hours. Additional methanesulfonic acid (1 ml.) is added and stirred for 6 hours with heating to 68°. The reaction mixture is quenched by addition of water (20 ml.) and benzene (20 ml.). Work-up gives androsta-4,9(11)-diene-3,17-dione, 147 mg. (55.7% chemical yield); m.p. 186°-194°. GC (Example 1) shows an androsta-4,9(11)-diene-3,17-dione/androsta-4,8-diene-3,17-dione ratio of greater than 99 to 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.C(S([C:28]1[N:33]=[C:32]([N:34]2[C:42]3[C:37](=[C:38]([O:43][CH2:44][CH2:45][CH2:46][S:47]([NH2:50])(=[O:49])=[O:48])[CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35]2)[CH:31]=[CH:30][N:29]=1)=O)CCC.O>CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:28]2[N:33]=[C:32]([N:34]3[C:42]4[C:37](=[C:38]([O:43][CH2:44][CH2:45][CH2:46][S:47](=[O:48])(=[O:49])[NH2:50])[CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35]3)[CH:31]=[CH:30][N:29]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CCCCS(=O)c1nccc(-n2ccc3c(OCCCS(N)(=O)=O)cccc32)n1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(N)(=O)=O)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Aminocyclohexane carboxylic acid ethyl ester (588.4 mg, 3.44 mmol) was dissolved in NMP (5 mL) and treated with DIEA (0.993 mL, 5.7 mmol) and the reaction mixture allowed to stir at RT for 5 min. 3-[1-(2-Butylsulfinyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-propane-1-sulfonic acid amide (500 mg, 1.14 mmol) was then added, and the reaction mixture heated to 120° C. for 1 h. The reaction was then allowed to cool to RT, water was added, the mixture was sonicated, filtered, and the solid dried in vacuo to yield 4-{4-[4-(3-sulfamoyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (Compound 318).
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9]([C:11]1[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH2:20][CH2:19]2)[CH:12]=1)=[O:10].[Br:32][C:33]1[CH:34]=[C:35](C(OC2C(F)=C(F)C(F)=C(F)C=2F)=O)[NH:36][C:37]=1[CH3:38].C(N(CC)C(C)C)(C)C.Cl.NC1CCN(C2C=C(C=C(Cl)N=2)C(N)=O)CC1>CC(N(C)C)=O>[Br:32][C:33]1[CH:34]=[C:35]([C:25]([NH:24][CH:21]2[CH2:20][CH2:19][N:18]([C:13]3[CH:12]=[C:11]([CH:16]=[C:15]([Cl:17])[N:14]=3)[C:9]([NH2:8])=[O:10])[CH2:23][CH2:22]2)=[O:31])[NH:36][C:37]=1[CH3:38]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=O)cc(Cl)n2)CC1
Reactant: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Agent: Cl
Agent: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.5 %

Procedure:
4 N HCl/dioxane solution (10 ml) was added to tert-butyl 1-[4-(aminocarbonyl)-6-chloropyridin-2-yl]piperidin-4-ylcarbamate (Intermediate 16, 100 mg, 0.282 mmol). The mixture was stirred at room temperature for 90 minutes. The solvent was removed in vacuo and the anhydrous diethylether (25 ml) was added. The solvent was removed in vacuo and light brown solid that resulted was dried under vacuum for several hours. LCMS indicated a pure product 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride salt (MS M+H:255). Pentafluorophenyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 17) (104 mg, 0.282 mmol), and N,N-diisopropyl ethylamine (98 μl, 0.564 mmol) were added to 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride salt (82 mg, 0.282 mmol) in anhydrous DMA (4 ml). The mixture was stirred at room temperature 18 h and was filtered and purified by semi-preparative HPLC using CH3CN/H2O (0.1% TFA) to give the title compound (28 mg).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1)[CH3:3].C(O[C:14](=[O:16])[CH3:15])(=O)C.C(O)(=O)C.[C:21]1([CH3:27])[CH:26]=C[CH:24]=[CH:23][CH:22]=1>>[CH3:1][CH:2]([C:4]1[N:5]=[C:6]([CH:9]=[CH:27][C:21]2[CH:26]=[C:15]([CH:24]=[CH:23][CH:22]=2)[CH:14]=[O:16])[S:7][CH:8]=1)[CH3:3]
Reactant: Cc1ccccc1
Reactant: Cc1nc(C(C)C)cs1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(C)c1csc(C=Cc2cccc(C=O)c2)n1

Procedure:
4-(1-Methylethyl)-2-methylthiazole (546 mg, EP 0219436 p. 19) and isophthaladehyde (570 mg, 1.1 equiv.) are heated at reflux in acetic anhydride (1.1 mL, 3 equiv.) 16 hours. The reaction mixture is cooled and the acetic acid and anhydride are co-evaporated with toluene. The title compound is purified by flash chromatography on silica using EtOAc:hexane 10:90.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1)=[C:20]=[O:21]>C1COCC1.C(Cl)Cl>[NH2:17][C:16]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)=[O:21])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)ccnc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(-c3ccnc4c3c(N)nn4C)cc2)c1
Yield: 46.2 %

Procedure:
A solution of Example 40 (87 mg, 0.36 mml) and 1-isocyanato-3-methylbenzene (0.046 mL, 0.36 mmol) in THF (3 mL), CH2Cl2 (3 mL) was stirred at room temperature for 5 h. The resulting precipitate was filtered off and purified via HPLC on an Agilent Zorbax Stablebond C-18 (7 micron particle size) preparative column using a solvent gradient of 20% to 100% acetonitrile in 0.1% aqueous TFA at a flow rate of 15 ml/min over 50 min, to give the 62 mg of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 3.83 (s, 3H) 6.81 (d, J=7.46 Hz, 1H) 6.92 (d, J=4.75 Hz, 1H) 7.17 (t, J=7.80 Hz, 1H) 7.26 (d, J=8.48 Hz, 1H) 7.32 (s, 1H) 7.53 (d, J=8.81 Hz, 2H) 7.65 (d, J=8.82 Hz, 2H) 8.40 (d, J=4.75 Hz, 1H) 8.67 (s, 1H) 8.90 (s, 1H). MS (ESI(+)) m/e 373 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].[NH2:23][C:24]1[CH:28]=[CH:27][NH:26][N:25]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:23][C:24]3=[CH:28][CH:27]=[N:26][N:25]23)=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Nc1cc[nH]n1
Product: CC1(C)CCC2=C(C1=O)C(c1ccc(Cl)c([N+](=O)[O-])c1)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 4-chloro-3-nitrobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)[CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH2:9][CH2:10]1)(=[O:26])=[O:25]
Reactant: Cc1ccnc(N2CCC(CO)CC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccnc(N2CCC(COS(C)(=O)=O)CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1-(4-Methylpyridin-2-yl)piperidin-4-yl)methanol (0.970 mmol, 0.2 g) and triethylamine (2.91 mmol, 0.404 mL, 0.294 g) were stirred in DCM at 0° C. Methanesulfonyl chloride (1.454 mmol, 0.113 mL, 0.167 g) was added dropwise and the reaction allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was washed with water, dried over Na2SO4 and concentrated in vacuo to afford (1-(4-methylpyridin-2-yl)piperidin-4-yl)methyl methanesulfonate. (0.234 g)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([Br:11])=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:17]=[N+:18]=[O:19]>C(#N)C.[Cl-].[Na+].O>[NH2:1][C:2]1[C:3]([N+:18]([O-:19])=[O:17])=[CH:4][C:5]([Br:11])=[C:6]([F:10])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(N)ccc(Br)c1F
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1c(N)c([N+](=O)[O-])cc(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a cooled (0° C.) solution of 6-amino-3-bromo-2-fluoro-benzonitrile (8.0 g, 37 mmol) in acetonitrile (40 mL) under nitrogen was added dropwise a solution of nitronium tetrafluoroborate in acetonitrile. The reaction mixture and stirred for 16 h at RT. The reaction mixture was treated with brine and extracted with ethyl acetate. The organic fraction was washed with water followed by brine and dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (10 to 20% ethyl acetate:hexanes) afforded 5.0 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.6 (d, J=6.9 Hz, 1H), 6.8-7.1 (br. s, 2H).