Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[I-].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:18][C:17]=1[N+:42]([O-:44])=[O:43])([CH3:15])([CH3:14])[CH3:13].[Si]([O:52][C@@H:53]([CH2:56][CH:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1)CO)(C(C)(C)C)(C)C>O1CCCC1>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:53](=[O:52])[CH2:56][CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)=[CH:18][C:17]=1[N+:42]([O-:44])=[O:43])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CO)CC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CC(=O)CC2CCCCC2)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 72 %

Procedure:
8.6 ml (8.6 mmol) of a 1.0M tetrahydrofuran solution of sodium hexamethyldisilazide were added dropwise over a period of 20 minutes to a suspension of 5.04 g (8.67 mmol) of (4-t-butyl-3-nitrophenyl)methyltriphenylphosphonium iodide (prepared as described in Preparation 52) in 80 ml of tetrahydrofuran at -78° C., and the mixture was allowed to stand for 1 hour. A solution of 2.33 g (8.61 mmol) of (S)-2-t-butyldimethylsilyloxy-3-cyclohexylpropanol [prepared as described in step (iv) above] in 7 ml of tetrahydrofuran was then added all at once, and the resulting mixture was stirred for 1 hour at the same temperature. The cooling bath was then removed, and the mixture was stirred for a further 4 hours. The reaction was then stopped by adding a saturated aqueous solution of ammonium chloride, after which the reaction mixture was extracted with a 1:3 by volume mixture of ethyl acetate and hexane. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 150 g of silica gel, using a 1:19 by volume mixture of diethyl ether and hexane as the eluent, to give fractions containing small amounts of impurities. These fractions were again purified by column chromatography through 150 g of silica gel, using a 1:4 by volume mixture of methylene chloride and hexane as the eluent, to give 2.78 9 (yield 72%) of the title olefin derivative as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15].C(N(C(C)C)CC)(C)C.O1CCOCC1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[OH:5][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 34.2 %

Procedure:
Into a 25-mL RB-flask was added (R)-(+)-3-chloro-1-phenyl-1-propanol (0.426 g, 2.50 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.565 g, 2.00 mmol), diisopropylethylamine (1.29 g, 10.0 mmol), dioxane (5.0 mL) and catalytic amount of tetrabutylammonium iodide at room temperature. After stirring at 90° C. for 72 hrs, the reaction mixture was poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC plates (1:5:100=isopropylamine:methanol:ethyl acetate) to afford the desired product (0.260 g, 34.2% yield) as light-yellow solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]4([CH3:27])[O:26][C@H:25]4[C:20]=3[CH:19]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[OH:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36](=[O:43])[N:35]([CH3:44])[N:34]=1.N1C=CC=CC=1>O1CCOCC1>[NH3:34].[CH3:44][N:35]1[N:34]=[C:33]([O:32][C@H:25]2[C@@:24]([OH:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22][C:21]3[CH:30]=[CH:31][C:18]([S:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)(=[O:17])=[O:16])=[CH:19][C:20]2=3)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:43]
Reactant: Cn1nc(O)c2ccccc2c1=O
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2[C@@H]2O[C@@]21C
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cn1nc(O[C@@H]2c3cc(S(=O)(=O)c4ccc(O)cc4)ccc3OC(C)(C)[C@@]2(C)O)c2ccccc2c1=O
Product: N
Yield: 35 %
Yield: 14.9 %

Procedure:
A mixture of (3S,4S)-6-(4-tert-butyldimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (0.71 g) (see Preparation 14), 1,2-dihydro-4-hydroxy-2-methyl-1-oxophthalazin (0.846 g) (see Preparation 21), pyridine (0.4 ml) and 1,4-dioxane (10 ml) was heated under reflux for 4 days. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and washed first with dilute aqueous citric acid solution and then with brine. The organic phase was dried (anhydrous magnesium sulphate), the solvent was removed and the crude product was chromatographed on silica eluting with a solvent gradient of 100:1:0.15 to 180:20:1 dichloromethane:methanol:35% aqueous ammonia solution to yield (3S,4R)-3,4-dihydro-4-(1,2-dihydro-2-methyl-1-oxophthalazin-4-yl)oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (0.12 g) as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].C[S](Cl)C.[CH3:24][S:25]([CH3:27])=O>O>[CH3:1][N:2]([CH2:24][S:25][CH3:27])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:4]
Reactant: CS(C)=O
Reactant: CNC(=O)Nc1ccc(Cl)c(Cl)c1
Agent: C[S](C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CSCN(C)C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
11 g of N-methyl-N'-(3,4-dichlorophenyl)-urea, 60 g of potassium carbonate and 50 ml of dimethylsulfur chloride were added at 10° C. to 150 ml of dimethylsulfoxide and the mixture was allowed to stand until exothermic generation of heat ceased. The reaction mixture was added to water and was extracted with ether. The ether solution was washed with water, dried and concentrated to dryness by distillation under reduced pressure. The residue was crystallized from isopropyl ether and then ethyl acetate to obtain 7.7 g of N-methyl-N-(2-thiapropyl)-N'-(3,4-dichlorophenyl)-urea melting at 103° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CCCCC=Nn1c(C(=O)OC)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCNn1c(C(=O)OC)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a mixture of 6-chloro-1-oxo-2-pentylidenamino-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (120 mg), acetic acid (76 μl) and methanol (5.0 ml) was added sodium cyano borohydride (80 mg) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with dichloromethane, and after drying, the organic layer was concentrated under reduced pressure. The residue was subjected to medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (78 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Cl)[N:22]=3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].C(O)=[O:33].O.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:33])[N:22]=3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:28]([F:29])([F:30])[F:31]
Reactant: O=CO
Reactant: O=C(c1cccc(Cl)n1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1cccc(O)n1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 2 dram vial was charged with 4-chloro-N-[5-chloro-2-(6-chloro-pyridine-2-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (65 mg, 0.127 mmol), formic acid (2.0 mL) and water (0.50 mL). The heterogeneous solution was warmed to 110° C. and stirred overnight. The following day, the resultant mixture was neutralized with saturated aqueous sodium bicarbonate, diluted with EtOAc, and the organic layer washed with saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to afford the desired hydroxypyridine: MS (ES) (M+H)+ expected 492.0, found 491.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][C:9]=2[CH3:18])=[O:5])[CH3:2].[H][H]>O1CCCC1.CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][C:9]=2[CH3:18])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])cc(C)c2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(N)cc(C)c2[nH]1

Procedure:
A mixture of 5 g 7-methyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester and 0.5 g Pd/C 10% in 200 ml tetrahydrofuran/methanol (3:1) was stirred for 5 h under a pressure of 3 bar of hydrogen. The catalyst was filtered and the mixture was evaporated under reduced pressure. The residue was purified by silica gel chromatography (SiO2; cyclohexane/ethyl acetate 75:25→50:50).
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19](F)[CH:18]=1>O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([S:4][CH:2]([CH3:3])[CH3:1])[CH:18]=1
Reactant: CC(C)S
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of propane-2-thiol (1.5 mL), potassium carbonate (3 g) and N,N-dimethylformamide (20 mL), 4-chloro-2-fluoronitrobenzene (2.5 g) was added and stirred at room temperature for 5 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 4-chloro-2-isopropylsulfanyl-1-nitrobenzene (3.30 g) as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[F:13]>C(OCC)(=O)C.C(O)(=O)C.[Fe]>[CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[F:13]
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(N)cc1F
Yield: 91.5 %

Procedure:
A mixture of N-Methyl-2-fluoro-4-nitrobenzamide (Formula 38) (0.18 g, 0.91 mmol) and iron (0.31 g, 5.60 mmol) in ethyl acetate (5 mL) and acetic acid (5 mL) was refluxed for 1 h. The solid particles were filtered off. The filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and the residue was purified with SiO2 column chromatography (dichloromethane:acetone, 95:5) to give N-Methyl-2-fluoro-4-aminobenzamide (Formula 39) (0.14 g, 92%) as an off-white solid. 1H NMR (acetone-d6) δ 2.86 (d, 3H, J=4.3), 5.50 (br s, 2H), 6.37 (dd, 1H, J=14.7 and 2.1), 6.50 (dd, 1H, J=8.6 and 2.1), 7.06 (br s, 1H), 7.68 (dd, 1H, J=8.8 and 8.8).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20]O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=S(Cl)Cl.[N-:26]=[N+:27]=[N-:28].[Na+].CCOC(C)=O>C(Cl)Cl>[N:26]([CH2:20][C:18]1[N:19]=[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[C:15]2=[N:16][CH:17]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CO)cnc32)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CN=[N+]=[N-])cnc32)cc1
Reaction time: 4 h
Yield: 84.3 %

Procedure:
To a solution of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (35.8 g, 118 mmol) in DCM (600 mL) was added SOCl2 (21.5 mL, 295 mmol). After about 4 h at ambient temperature, additional SOCl2 (8.60 mL, 118 mmol) was added. After about 16 h, the reaction was concentrated under reduced pressure and washed with saturated aqueous NaHCO3 (1000 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in DCM (600 mL) and re-subjected to SOCl2 (21.51 mL, 295 mmol). After about 16 h at ambient temperature, the reaction was concentrated under reduced pressure followed by the addition of DCM (500 mL) and saturated aqueous NaHCO3 (500 mL). The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. To the resulting residue was added DMF (500 mL) followed by NaN3 (38.3 g, 589 mmol). After about 16 h, at ambient temperature EtOAc (500 mL) was added and the organic solution was washed with water:brine (1:1, 2000 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (500 mL). The combined organic layers were washed with brine (3×1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide 2-(azidomethyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (32.65 g, 82% yield) as a tan solid: LC/MS (Table 2, Method a) Rt=2.31 min; MS m/z: 329 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[S:4][NH:3]1.[N+](=[CH2:16])=[N-]>C(O)(C)C.CCOCC>[CH3:16][O:12][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[C:2](=[O:1])[NH:3][S:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: O=C(O)c1ccc2c(=O)[nH]sc2c1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(=O)[nH]sc2c1
Reaction time: 0.17 h

Procedure:
A solution of 19.5 g (0.1 mole) of 3-oxo-1,2-benzisothiazoline-6-carboxylic acid in 40 ml of isopropanol is treated with an excess of a solution of diazomethane in ether added at 0° C. with stirring over a period of 10 minutes. The reaction mixture is evaporated to dryness and the 3-oxo-1,2-benzisothiazoline-6-carboxylic acid methyl ester is obtained as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:39]([NH:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH3:30])[CH:33]=3)=[O:40])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: COc1cccc(N=C=O)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
A suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and triethylamine (0.3 g, 2.6 mmol) in THF (30 mL) was cooled to 5° C. 3-Methoxyphenyl isocyanate (0.4 g, 2.6 mmol) was added, and the mixture was stirred at room temperature 5 hours. The mixture was concentrated, and the residue was dissolved in CH2Cl2 (80 mL). The CH2Cl2 solution was washed with 1N HCl (40 mL), water (40 mL), and brine (40 mL), and dried (MgSO4). Solvent was removed, and the solid was slurried with ethanol (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3 dihydro-1H-isoindol-4-ylmethyl]-3-(3-methoxy-phenyl)-urea (0.7 g, 80%) as a white solid: mp 160-162° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H), 2.50-2.65 (m, 2H), 2.85-2.99 (m, 1H), 3.69 (s, 3H, OCH3), 4.69 (d, J=5.2 Hz, 2H, CH2), 5.14-5.20 (dd, J=4.6 and 12.1 Hz, 1H, CH), 6.49 (d, J=7.9 Hz, 1H, Ar), 6.76-6.86 (m, 2H, Ar), 7.08-7.14 (m, 2H), 7.76-7.85 (m, 3H, Ar), 8.81 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.94, 38.72, 48.87, 54.82, 103.44, 106.70, 110.05, 121.86, 127.19, 129.36, 131.61, 133.62, 134.72, 140.23, 141.51, 155.15, 159.62, 167.01, 167.60, 169.82, 172.76; Anal. calcd. for C22H20N4O6: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.18; H, 4.42; N, 12.63.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1.Cl[C:29]1[CH:37]=[CH:36][C:32]([C:33](N)=[O:34])=[CH:31][N:30]=1.C(N(C(C)C)CC)(C)C.C([OH:51])CCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([C:29]5[CH:37]=[CH:36][C:32]([C:33]([OH:51])=[O:34])=[CH:31][N:30]=5)[CH2:24][CH2:25]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1
Reactant: CCCCO
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCNCC1
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(N2CCC(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)CC2)nc1
Temperature: 110 °C

Procedure:
To a solution of 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-piperidin-4-ylmethyl-piperazin-2-one (20 mg, 0.047 mmol) in n-butanol (0.5 mL) is added 6-chloronicotinamide (15 mg, 0.094 mmole) and diisopropylethylamine (0.016 mL, 0.094 mmole) and heated at 110° C. 16 h. The reaction is concentrated and purified by column chromatography (silica, 20% methanol/dichloromethane) to provide 4-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid. 1H NMR (300 MHz, CD3OD) δ 8.59 (d, 1H), 8.11-7.92 (m, 3H), 7.54 (dd, 1H), 6.72 (d, 1H), 4.27 (d, 1H), 3.92 (s, 2H), 3.57-3.47 (m, 4H), 3.25 (d, 2H), 2.79-2.71 (dt, 2H), 1.96-1.80 (m, 1H), 1.50 (d, 2H), 1.29-1.06 (m, 2H); MS (Ion spray) 549 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:20])=[N:4][N:5]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13]C=2Cl)[C:6]=1[C:7]([NH:9][CH3:10])=[O:8].[C:21]([Cl:24])(Cl)=O.[O:25]1CCC[CH2:26]1>>[CH3:20][C:3]1[C:2]2[NH:1][C:26](=[O:25])[N:9]([CH3:10])[C:7](=[O:8])[C:6]=2[N:5]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:21]=2[Cl:24])[N:4]=1
Reactant: C1CCOC1
Reactant: CNC(=O)c1c(N)c(C)nn1-c1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(Cl)Cl
Product: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2c(=O)n(C)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4 amino-N,3-dimethyl-1-(2,4,6-trichlorophenyl)-1H-pyrazole-5-carboxamide (20 mg, 0.0600 mmol) in tetrahydrofuran (1 ml) was added phosgene (20% solution in tetrahydrofuran, 0.048 ml) and the mixture was stirred at room temperature for 2 h. The solvent was evaporated under vacuum to give the title compound, which was used for the next step without further purification.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:9]=[C:10]([C@:14]2([CH3:30])[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[CH2:16][C@@H:15]2[CH3:29])[CH:11]=[CH:12][CH:13]=1)=[O:7].Cl>O.O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]([C@:14]2([CH3:30])[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[CH2:16][C@@H:15]2[CH3:29])[CH:11]=[CH:12][CH:13]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cccc([C@]2(C)CCN(C(=O)OCC[Si](C)(C)C)C[C@@H]2C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(C(=O)OCC[Si](C)(C)C)CC[C@@]1(C)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 97.2 %

Procedure:
A solution of lithium hydroxide monohydrate (2.75 g, 0.065 mol, 6 eq) in water (20 mL) was added drop wise to a cold (0° C.) solution of (6) (4.28 g, 0.0109 mol, 1 eq) in tetrahydrofuran (40 mL). The mixture was allowed to warm to room temperature and stirring was continued for 5 days. A 1N aqueous HCl solution (100 mL) was added to the mixture which was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL) and dried over sodium sulfate. Evaporation of the solvent afforded the desired compound (4.0 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>N1C=CC=CC=1>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NS(C)(=O)=O)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
4-{5-[2-Amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 150 mg, 0.326 mmol) was dissolved in pyridine (4 mL) and methanesulfonyl chloride (50 μL, 0.652 mmol) was added. The reaction mixture was stirred at RT for 18 hrs then at 60° C. for 3 hrs. A further quantity of methanesulfonyl chloride (50 μL) was added and the mixture was heated at 60° C. overnight. The reaction mixture was allowed to cool then water was added and the mixture was extracted with EtOAc. The organic extract was washed with 1 M HCl followed by water and then saturated brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography eluting with a gradient of 0-50% EtOAc in cyclohexane to give the title compound as a tan solid (85 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:27](=[O:29])[CH3:28])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)NCc2ccccc2)c2c1oc1ccc(N)cc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCc2ccccc2)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N1-benzyl-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (80 mg, 0.23 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF (10 ml) containing pyridine (1.0 eq) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 2 h. The reaction mixture was filterd and the filterarte was concentrated. The residue was triturated with ethanol to obtain 63 mg of N1-benzyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 264–265° C.