Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([NH2:12])[NH:9][N:8]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[CH:21][C:16]=2[N:15]=[N:14]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[NH:12][C:10]4[N:9]([N:8]=[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[N:11]=4)[C:24](=[O:25])[CH:23]=3)=[CH:21][C:16]=2[N:15]=[N:14]1
Reactant: Nc1nc(-c2ccccn2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc(-c2ccc3[nH]nnc3c2)[nH]c2nc(-c3ccccn3)nn12
Temperature: 170 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a solution of 3-(pyridin-2-yl)-1H-1,2,4-triazol-5-amine (100 mg, 0.57 mmol) in diphenyl ether (3 ml) was added ethyl 3-(1H-1,2,3-benzotriazol-5-yl)-3-oxopropanoate (300 mg, 1.29 mmol) and 4-methylbenzene-1-sulfonic acid (5 mg, 0.02 mmol). After stirring 1 h at 170° C., the solids were collected by filtration, washed with ethyl acetate (2×10 ml), methanol (3×10 ml) and dried to give 5-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a off-white solid (36.7 mg, 18%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]([C:29](=[CH2:35])[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:10]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:35]=[C:29]([C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:28])[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Reactant: C=C(CC(=O)OC)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(=Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)C(=O)OCc1ccccc1

Procedure:
A solution of 4-bromo-1-(triisopropylsilyloxy)benzene (33.23 g, 100 mmole), methyl 3-(benzyloxycarbonyl)-3-butenoate (28.11 g, 120 mmole), Pd(OAc)2 (2.24 g, 10 mmole), P(o-tolyl)3 (6.09 g, 20 mmole), and (i-Pr)2NEt (34.8 mL, 200 mmole) in propionitrile (350 mL) was deoxygenated (3×evacuation/N2 purge cycles) then was heated to reflux. After 18 hr the mixture was concentrated, and the residue was chromatographed on silica gel (10% EtOAc/hexanes) to give a yellow oil. The oil was taken up in 5% EtOAc/hexanes (100 mL), and the solution was allowed to stand at RT. After 72 hr the mixture was filtered and the filtrate was concentrated to give crude methyl (±)-4-(4-triisopropylsilyloxyphenyl)-3-(benzyloxycarbonyl)-3-butenoate as a mixture of olefin isomers. This was used immediately in the next step.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13]([CH3:32])=[C:14]([C:28]([O:30][CH3:31])=[O:29])[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:16]=1[C:17]([O:19]C)=[O:18].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:32][C:13]1[NH:12][C:11]2[CH2:10][O:19][C:17](=[O:18])[C:16]=2[CH:15]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:14]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1C
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
In an operation carried out in a manner similar to that described in the preceding example, 1.52 grams of 80 percent pyridinium bromide perbromide (3.81 millimoles) was added in one portion to a solution of 1.00 gram (3.17 millimoles) of dimethyl 2,6-dimethyl-4-(o-tolyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.40 milliliter of pyridine in 20 milliliters of dry chloroform cooled to 0° C. The mixture was stirred for 30 minutes at 0° C., then at reflux temperature for 1.5 hours. Thereafter, the mixture was cooled, washed successively with hydrochloric acid and brine, dried, subjected to reduced pressure to remove the solvent and to obtain as residue crude methyl 2-methyl-4-(o-tolyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate product. The crude product was chromatographed on silica and eluted with 65 percent ethyl acetate--35 percent hexane to obtain 0.58 gram (61 percent yield) of white crystalline material which after recrystallizing from ethyl acetate-hexane and drying at 80° C./0.005 mm Hg for 17 hours had a melting point of 224°-225° C. and the following analyses:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]2[C:11]([O:13][C:14](=[O:15])[C:2]=12)=[O:12].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:11]([C:3]2[C:2]([C:14]([OH:13])=[O:15])=[CH:1][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[O:12])=[CH:19][CH:18]=1
Reactant: Fc1ccccc1
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(O)c1cc2ccccc2cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 113.8 %

Procedure:
45.0 g (227 mmols) of 2,3-naphthalenedicarboxylic anhydride are suspended in 200 ml (2.1 mols) of fluorobenzene, and in the course of 5 minutes, with vigorous stirring, 75.5 g (565 mmols) of powdered aluminium chloride are added (exothermic reaction up to about 32° C.). The dark-red suspension is refluxed and stirred for 6 hours, and the solution is then allowed to cool to room temperature; it is subsequently poured onto about 500 g of ice, and is stirred until completion of hydrolysis. Excess fluorobenzene is evaporated off, and the product obtained is suspended in water. The suspension is filtered off, the filtrate is afterwards washed and the product is dried. There are obtained 76 g of crude 2-(4-fluorobenzoyl)-naphthalene-3-carboxylic acid. The crude product is stirred up with 2 liters of 10% sodium carbonate solution; the resulting solution is then acidified with hydrochloric acid, and the white precipitate is filtered off and dried. The yield is 54.2 g (81% of theory) of 2-(4-fluorobenzoyl)-naphthalene-3-carboxylic acid. MS: (M+ =294; M+ --COOH=249, M+ --COO=250, M+ --C6H4F=199); IR spectrum (KBr): OH about 3300 cm-1 ; C=O double bands 1695/1705 cm-1.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH2:11])=[N-]>CCOCC>[CH:1]1([C:6]([O:8][CH3:11])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C1CCCC1
Solvent: CCOCC
Product: COC(=O)C1CCCC1
Temperature: 0 °C
Yield: 85.2 %

Procedure:
To an ice-cooled and stirred solution of cyclopentanecarboxylic acid (8.0 g, 0.070 mol) in 30 ml of ether was slowly added an excess solution of diazomethane in ether. After concentration of ether, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl cyclopentanecarboxylate (7.65 g, 0.053 mol, yield 85.2%, b.p. 82°-83° C./62 mmHg), which was assigned the structure by the following data.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([O:19][CH2:25][CH3:26])=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1oc2cccc-2cc1-c1ccccc1

Procedure:
A solution of 40 g., of 3-phenyl-7-benzofuranacetic acid in 400 ml. of ethanol and 40 ml. of sulfuric acid is heated under reflux for four hours. The solution is partially concentrated under reduced pressure, poured onto ice and extracted with ether. The ether is washed, dried and concentrated and the residue distilled to give ethyl 3-phenyl-7-benzofuranacetate, b.p. 187°-189°/0.12 mm.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[S:15][C:16]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:9][CH2:8]2)=[N:4][N:3]=1.C(N(CC)CC)C.Cl[S:37]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])(=[O:39])=[O:38]>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[S:15][C:16]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([S:37]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])(=[O:39])=[O:38])[CH2:27][CH:28]=5)[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:9][CH2:8]2)=[N:4][N:3]=1
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: Cc1nnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(c5nnc(C)s5)CC4)sc3c2)CC1
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
To a solution of 2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (95 mg, 0.230 mmol) and triethylamine (0.065 mL, 0.459 mmol) in CH2Cl2 (2 mL) at 0° C. was added methyl 3-(chlorosulfonyl)propanoate (64 mg, 0.345 mmol). The reaction mixture was stirred at this temperature for 15 min, then at rt for 2 h. The reaction mixture was quenched with sat. aq. NaHCO3 (2 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 70% EtOAc) to afford methyl 3-(4-(2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)propanoate (80 mg, 0.142 mmol, 62% yield) as a yellow solid. LCMS (m/z)=564 (M+H)+.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>CCO>[N:15](=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[OH:16]
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of 4-oxo-4-phenylbutyric acid (1.0 g, 5.3 mmol) in 50 mL of EtOH was added hydroxylamine hydrochloride (742 mg, 11 mmol) and sodium acetate (1.8 g, 21 mmol). The reaction flask was heated at 80° C. for 4 h and was then cooled to room temperature. Addition of water and filtration of the resultant precipitate afforded, after recrystallization (10:1 chloroform:hexane), 620 mg (60%) of the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]3[N:15]=2)[CH:8]=1.[Cl-].[NH4+:36]>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([NH2:36])=[O:24])=[C:16]3[N:15]=2)[CH:8]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCN3CCOCC3)nc12
Reactant: [NH4+]
Agent: Cl
Agent: [Cl-]
Product: NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCN3CCOCC3)nc12
Yield: 91 %

Procedure:
Prepared by the method described in Example 76, Step F, using ((R)-5-(2-(5-fluoro-2-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid hydrochloride and ammonium chloride to yield the title compound as a white solid (42.2 mg, 91% yield). MS (apci) m/z=455.1 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[NH:14]1[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]1>CC(C)=O>[NH2:11][C:6]1[N:5]=[C:4]([S:12][CH3:13])[N:3]=[C:2]([N:14]2[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=S1CCNCC1
Reactant: CSc1nc(N)c([N+](=O)[O-])c(Cl)n1
Solvent: CC(C)=O
Product: CSc1nc(N)c([N+](=O)[O-])c(N2CCS(=O)CC2)n1
Yield: 78.2 %

Procedure:
3.08 gm (0.014 mol) of 4-chloro-6-amino-2-methylthio-5-nitro-pyrimidine were dissolved in 50 ml of acetone, and a solution of 3.2 gm (0.027 mol) of thiomorpholine-1-oxide in 20 ml of acetone was added dropwise at room temperature, while stirring. After stirring the mixture for 1.5 hours more, ice was added to the reaction mixture, and the yellow precipitate formed thereby was suction-filtered off and recrystallized from ethanol. Yield: 78.2% of theory; m.p. 239°-242°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:26][CH3:27])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.O.NN>[Ni].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:26][CH3:27])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccc(N)cc12
Yield: 65.4 %

Procedure:
N1-(pyrid-3-yl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (500 mg) (from step 1) was reduced using raney nickel (150 mg) (30% w/w aqueous suspension) in methanol (10 ml) in the presence of hydrazine hydrate (0.32 ml) under gentle reflux for 4 h. The reaction mixture was flitered through celite and the filterate was concentrated in vaccuo. The residue was triturated with water, to obtain a solid which was filtered dried to give the product as white solid (300 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:11]1([C@H:17]([NH2:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OC(C)C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:9])[CH2:10][NH:19][C@@H:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:18])=[CH:4][CH:3]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Brc1ccc([C@H]2CO2)cc1
Solvent: CC(C)OC(C)C
Product: C[C@@H](NC[C@@H](O)c1ccc(Br)cc1)c1ccccc1
Temperature: 80 °C
Yield: 64.4 %

Procedure:
A mixture of (2S)-2-(4-bromophenyl)oxirane (55.0 g) and (R)-1-phenylethylamine (98.2 g, 810 mmol) was heated at 80° C. for 6 hours. Addition of isopropyl ether (200 ml) to the residue after distillation of excess phenethylamine and successive filtration yielded (1S)-1-(4-bromophenyl)-2-((1R)-1-phenylethylamino) ethanol (57.0 g) as white crystals. Further crystallization was performed by the concentration of the filtrate in vacuo and cooling the residue in refrigerator. Filtration of the crystal with isopropyl ether (30 ml) yielded additional title compound (5.60 g) as crystals (72.4% yield, 3 steps).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[NH:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[NH:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CNC(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c1CNC(=O)c1c(Cl)cccc1-2

Procedure:
A mixture of 9 g (29.4 mmol) of ethyl 7-chloro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 1.434 g (35.9 mmol) of sodium hydroxide, 30 ml of ethanol and 15 ml of water is heated to boiling under reflux for 70 minutes. The mixture is then diluted with 80 ml of water, filtered, the filtrate is neutralized by the addition of 8.9 ml (35.9 mmol) of 4N hydrochloric acid and the ethanol is distilled off in vacuo. The residue is subsequently cooled to about 0°, the product is filtered off under suction, rinsed with water and dried at 80°-90° in a high vacuum. There is obtained 7-chloro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of decomposition point 289°.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:45]2[CH:46]=[CH:47][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:43][CH:44]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(C)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 80.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (500 mg, 0.93 mmol), 4-methylsulfonyl phenylboronic acid (560 mg, 2.8 mmol) and dichlorobis(triphenylphosphine)palladium (II) (65 mg, 0.093 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 1.40 mL, 2.8 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (silica gel from QingDao, 200-300 mesh, 35% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methyl-1H-pyrrolo[2,3-b]pyridine (390 mg, 81%) as a white solid: LC/MS m/e calcd for C28H28N2O4S2 [M+H]+ 521.67, observed 520.7.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[C:3]=1[CH2:10][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cccc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cccc(Cl)c1CBr
Yield: 46 %

Procedure:
To a refluxing solution of 3-chloro-2-methylbenzonitrile (2.0 g, 13.2 mmol) in 20 mL of CCl4 was added 2.6 g (14.4 mmol, 1.1 eq) of N-bromosuccinimide and 0.2 g of AIBN. The solution was refluxed for 3 hours and then cooled, diluted with 500 mL of CH2Cl2 and washed with 200 mL of H2O and 200 mL of brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resultant oil was flash chromatographed with 5:1 hexane/ethyl acetate to yield the titled compound (1.4 g, 46%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[CH3:18][C:19]1[N:20]=[CH:21][S:22][C:23]=1[CH:24]=O>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:24][C:23]3[S:22][CH:21]=[N:20][C:19]=3[CH3:18])[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: Cc1ncsc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1ncsc1C=Nc1[nH]nc(Nc2cccc(Cl)c2)c1C(N)=O

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was suspended in EtOH and 4-methyl-5-thiazolecarboxaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain B62 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([C:23](OC)=[O:24])=[CH:18][CH:19]=3)[CH2:14]2)(=[O:12])=[O:11])=[C:5]([CH3:27])[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([CH2:23][OH:24])=[CH:18][CH:19]=3)[CH2:14]2)(=[O:11])=[O:12])=[C:5]([CH3:27])[CH:4]=1
Reactant: COC(=O)c1ccc2c(c1)CN(S(=O)(=O)c1c(C)cc(OC)cc1C)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(CO)cc3C2)c(C)c1
Reaction time: 1 h

Procedure:
A solution of methyl 2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (3.85 mmol, 1 equiv.) in THF (10 ml) was added dropwise to a cold suspension of LAH (7.7 mmol, 2 equiv.) in THF (30 ml), and the resulting mixture was stirred for 1 h. THF/water was added to the reaction mixture, and filtration over Celite was carried out. The filtrate was concentrated and the yellow oil so obtained was used in the following stage without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH2:30])=[O:29])[CH2:24]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C@H:23]([F:22])[CH2:24][C@H:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@@H]1C[C@@H](F)CN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)[C@@H]1C[C@@H](F)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Yield: 48.5 %

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 25 mg, 87.9 μmol) was reacted with (2S,4R)-4-fluoropyrrolidine-2-carboxamide hydrochloride (CAN 796884-06-5, 17.8 mg, 106 μmol) to obtain the title compound (17 mg, 49%) as white solid; MS (EI): m/e=399.4 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:20]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:20])=[CH:23][CH:24]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)Oc4ccc(F)cc4)cc3c2C1
Yield: 39.8 %

Procedure:
Beginning with 6.0 mg (0.026 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 4.8 mg (0.0273 mMol) 4-fluorophenyl chloroformate, 3.8 mg (40%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[F-:12].[Cs+].[F-].[K+].C1S(=O)(=O)CCC1>>[F:12][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: [F-]
Agent: [Cs+]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1
Yield: 10.3 %

Procedure:
1,500 parts of 3-chloro-4-fluoronitrobenzene, 25 parts of cesium fluoride and 1,000 parts of potassium fluoride are heated in 1,500 parts of tetramethylenesulfone for 16 hours at 230° C. The mixture is worked up as described in Example 1(a). 139 parts (10.3% of theory) of 3,4-difluoronitrobenzene of boiling point 54° C./1 mm Hg are obtained.