Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:30]2[S:34][C:33]([CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)O1.O>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.COCCOC>[N:36]1([CH2:35][C:33]2[S:34][C:30]([C:2]3[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=3)[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:31][CH:32]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CC1(C)OB(c2ccc(CN3CCCC3)s2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2ccc(CN3CCCC3)s2)c1

Procedure:
3-Bromo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 3.1, 50 mg, 0.139 mmol), 1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)pyrrolidine (0.180 mmol), (Ph3P)4Pd (8 mg, 6.94 μmol) 2 M Na2CO3 (0.104 mL, 0.208 mmol), water (0.8 mL) and DME (2.4 mL) were added to a vial, which was sealed and subjected to MW irradiation at 150° C. for 600 sec (very high absorbance). The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH (10 mL) and the combined filtrates were evaporated under reduced pressure to give the crude product was purified by preparative HPLC to afford the title compound. UPLC-MS (Condition 6) tR=1.92 min, m/z=447.4 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[CH:11]([CH3:13])[CH3:12])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:11]([C:7]1[O:8][CH:9]=[CH:10][C:6]=1[CH2:4][OH:3])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1ccoc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1occc1CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-isopropyl-furan-3-carboxylic acid ethyl ester (82) (4.0 g, 21.95 mmoles) in tetrahydrofuran (70 ml) was treated portionwise during 0.5 h with lithium aluminium hydride (0.7 g, 18.4 mmoles) under a nitrogen atmosphere. When the addition was complete the mixture was stirred at room temperature for 18 hours, then quenched by the addition of excess acetone (1 ml) and then water (1 ml). After diluting with ethyl acetate (150 ml) the grey precipitate was removed by filtration. The filtrate was evaporated and the residue dissolved in diethyl ether and dried. Evaporation of the solvent afforded (2-isopropyl-furan-3-yl)-methanol. This material was used immediately in the next step. (ii) A solution of the (2-isopropyl-furan-3-yl)-methanol from (i) in dry dichloromethane (120 ml) was treated with chloro-tri-isopropyl-silane (5.2 g, 27.0 mmoles) and imidazole (3.0 g, 44.0 mmoles) and the mixture was stirred overnight at room temperature. The reaction mixture was washed sequentially with 2M aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and brine. After drying, evaporation of the solvents afforded a colourless oil, which heated at 125° C. under reduced pressure (10 millibars). The residue was compound 83 obtained as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([C:24]([CH3:25])([CH3:26])[CH3:27])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: CC(C)(C)[Si](Oc1ccc(Br)c(C=O)c1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](Oc1ccc(Br)c(CO)c1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
The product from Step A (8.87 g, 20.2 mmol) was dissolved in methanol (50 mL) and methylene chloride (20 mL). Sodium borohydride (764 mg, 20.2 mmol) was added in portions at 0° C., and the solution was stirred for 2 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride until hydrogen evolution ceased. The resulting suspension was concentrated in vacuo and then partitioned between methylene chloride (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title product as a yellow oil which was sufficiently pure for use in the next step.
Reaction SMILES: [C:1]1([N:7]2[C:11]([N:12]3[CH2:27][CH2:26][C:14]4([CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)[CH2:13]3)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]1([N:7]2[C:11]([N:12]3[CH2:27][CH2:26][C:14]4([CH2:15][CH2:16][NH:17][CH2:18]4)[CH2:13]3)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3nnnn3-c3ccccc3)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-n2nnnc2N2CCC3(CCNC3)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl 7-(1-phenyl-1H-tetrazol-5-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (100 mg) was dissolved in 10% TFA solution in CH2Cl2 (10 mL). The reaction was stirred at room temperature for 24 hours. After removal of solvents, the residue, crude 2-(1-phenyl-1H-tetrazol-5-yl)-2,7-diazaspiro[4.4]nonane, was used in the further reactions without purification.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:15])[C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OC)(O[CH3:20])(=O)=O.[OH-].[K+]>C(O)C>[CH3:20][O:14][C:13]1[C:12]([CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(Oc2ccccc2)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cccc1Oc1ccccc1
Yield: 74.8 %

Procedure:
A mixture of 6-phenoxy-o-cresol (7.5 g) and dimethyl sulfate (14 g) and aqueous solution (30 ml) of potassium hydroxide (10.5 g) were treated in a similar manner to that of Example 14-(2). The resultant residue was pulverized with ethanol to give phenyl 2-methoxy-3-methylphenyl ether (6 g). mp 52°-53° C.
Reaction SMILES: [C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[O:20])[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:31]([O:33]C(C)(C)C)=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([N:9]1[C:13]2([CH2:14][CH2:15][CH:16]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=3)=[O:20])[CH2:17][CH2:18]2)[S:12][CH2:11][C@H:10]1[C:31]([OH:33])=[O:32])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NC(=O)C2CCC3(CC2)SC[C@@H](C(=O)OC(C)(C)C)N3C(=O)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(NC(=O)C2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.4 %

Procedure:
In 7 ml of methylene chloride was dissolved 0.35 g of tert-butyl (3R)-4-benzoyl-8-[(4-isopropylanilino)-carbonyl]-1-thia-4-azaspiro[4.5]-decane-3-carboxylate. After adding 1.8 ml of trifluoroacetic acid at 0-5° C., the resulting mixture was stirred at ambient temperature for 6 hours. After distilling off the solvent under reduced pressure, the residue was several times subjected to an azeotropic distillation treatment together with toluene and then purified by column chromatography [eluent: chloroform:ethanol=20:1]. The residue was treated with ethyl ether, and the deposited crystal was collected by filtration to obtain 0.12 g of (3R)-4-benzoyl-8-[(4-isopropylanilino)carbonyl]-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid as a colorless crystalline product.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15](OC)[O:16]C)=[CH:11][CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15]=[O:16])=[CH:11][CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(Cc1c(C(C)(C)C)[nH]c2cc([N+](=O)[O-])ccc12)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1[nH]c2cc([N+](=O)[O-])ccc2c1CC=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.6 %

Procedure:
To a solution of 2-tert-butyl-3-(2,2-dimethoxy-ethyl)-6-nitro-1H-indole (0.80 g, 2.6 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (5 mL, 50%) at 0° C. and the resulting solution was stirred at room temperature for 6 h. Saturated sodium bicarbonate was added until pH>7. The aqueous layer was extracted with methylene chloride several times. The combined organic layers were dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified via silica gel column chromatography to give the title compound (0.62 g, 91%). LCMS (m/z): 261.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10]N=N[C:7]=2[CH:11]=1.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:19](=[N:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:20][C:7]=2[CH:11]=1
Reactant: S=C=Nc1ccccc1
Reactant: COc1ccc2snnc2c1
Product: COc1ccc2sc(=Nc3ccccc3)sc2c1

Procedure:
A solution of 5-methoxy-1,2,3-benzothiadiazole (5 g) in 50 ml of phenyl isothiocyanate is heated at 220° C under an inert atmosphere until the evolution of nitrogen ceases (about two hours). The excess phenyl isothiocyanate is removed in vacuo. The resultant residue is chromatographed on silica gel (500 ml) eluting with pentane/dichloromethane (4:1). Fractions containing the desired product (Rf =0.2, silica gel, benzene) are combined and concentrated in vacuo. The resultant solid is recrystallized from pentane to yield 2.8 g of the title compound, melting point 58°-60° C.
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8](=[O:42])[C:9]2[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([C:16]3[C:17]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[CH:18][C:19]4[O:23][C:22]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[C:21]([C:31](=[O:34])[NH:32][CH3:33])[C:20]=4[CH:35]=3)[N:10]=2)=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:53](Cl)([O:55]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:8](=[O:42])[C:9]3[N:10]=[C:11]([C:16]4[C:17]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:38])=[O:39])=[CH:18][C:19]5[O:23][C:22]([C:24]6[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=6)=[C:21]([C:31]([NH:32][CH3:33])=[O:34])[C:20]=5[CH:35]=4)[CH:12]=[CH:13][C:14]=3[O:15][C:53]2=[O:55])=[CH:43][CH:44]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(C(=O)NCc4ccc(F)cc4)n3)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4oc(=O)n(Cc5ccc(F)cc5)c(=O)c4n3)cc12
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of N-(4-fluorobenzyl)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-hydroxypicolinamide (30 mg, 0.05 mmol) and Et3N (11 mg, 0.10 mmol) in CH2Cl2 (5 mL) was stirred at RT under N2 atmosphere, and then triphosgene (18 mg, 0.06 mmol) was added portionwise. The mixture was stirred at RT for 4 h. The solvent was removed by rotary evaporator. After purified by prep-TLC (DCM:MeOH=60:1), 5-(3-(4-fluorobenzyl)-2,4-dioxo-3,4-dihydro-2H-pyrido[2,3-e][1,3]oxazin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide was obtained. (15 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 7.97˜8.05 (m, 2H), 7.92 (m, 2H), 7.72 (d, J=8.4 Hz, 1H), 7.52˜7.63 (m, 3H), 7.19 (t, J=8.4 Hz, 2H), 7.01 (t, J=8.4 Hz, 2H), 6.14 (d, J=4.4 Hz, 1H), 5.20 (s, 2H), 3.24 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.95 (s, 3H). MS (M+H)+: 647.
Reaction SMILES: [CH2:1]([S:9]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:11]1([NH:17][S:18]([C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([S:9][N:17]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[S:18]([C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)(=[O:19])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCSCl
Reactant: O=S(=O)(NC1CCCCC1)c1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCSN(C1CCCCC1)S(=O)(=O)c1nc2ccccc2s1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The resulting orange-red n-octyl chlorosulfide solution is added dropwise to a stirred solution of 77.5 grams of N-cyclohexyl benzothiazole-2-sulfonamide (0.26 mole) and 28 grams triethylamine (0.28 mole) in 300 ml anhydrous dimethylformamide at about 13°-17° C. over 80 minutes. After 90 minutes of stirring, the reaction mixture is poured into 2 liters of ice water. A muddy solid is obtained upon decanting the water. The solid is washed in 200 ml n-hexane and filtered by suction. 105 grams of light brownish white crystal is obtained.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:23]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[C:16]([Cl:37])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[Cl:37][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:23]([N:24]2[CH2:25][CH2:26][C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([OH:30])[CH2:28][CH2:29]2)=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.036 g, 0.18 mmol), 1-[7-(1-aminoethyl)-5-chloroquinolin-8-yl]-4-phenylpiperidin-4-ol (0.035 g, 0.092 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.18 mmol) in ethanol (0.32 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the product as the free base. LCMS calculated for C27H27ClN7O (M+H)+: m/z=500.2; Found: 500.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=1B(O)O.C(=O)([O-])O.[Na+].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.O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[C:29]([O:33][CH3:34])=[CH:30][CH:31]=[CH:32][C:27]=2[F:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: COc1cccc(F)c1B(O)O
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: O
Solvent: COCCOC
Product: COc1cccc(F)c1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-6-methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (176 mg) were added to a mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 100° C. for 20 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 100 mg, 21%).
Reaction SMILES: N1C=CN=C1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10](=[O:24])[N:11]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]2)[N:12]=1.[H-].[Na+].[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][O:36][C:32]=2[C:31]([C:37](N2C=CN=C2)=[O:38])=[CH:30][C:29]=1[Cl:44]>C1COCC1>[NH2:27][C:28]1[C:33]2[CH2:34][CH2:35][O:36][C:32]=2[C:31]([C:37]([O:23][CH2:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][N:11]3[C:10](=[O:24])[CH:9]=[CH:8][C:7]([Cl:6])=[N:12]3)[CH2:17][CH2:18]2)=[O:38])=[CH:30][C:29]=1[Cl:44]
Reactant: O=c1ccc(Cl)nn1CCCN1CCC(CO)CC1
Reactant: Nc1c(Cl)cc(C(=O)n2ccnc2)c2c1CCO2
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(=O)OCC2CCN(CCCn3nc(Cl)ccc3=O)CC2)c2c1CCO2
Yield: 42.6 %

Procedure:
1H-imidazole (2.72 g) was added to a solution of 6-chloro-2-[3-[4-(hydroxymethyl)-1-piperidinyl]propyl]-3(2H)-pyridazinone (2.62 g) in THF (100 ml). NaH (60%, 0.4 g) was added, under nitrogen atmosphere. The mixture was stirred for minutes. 1-[(4-Amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]-1H-imidazole (2.64 g) was added and the resulting reaction mixture was stirred for 15 minutes at room temperature. The solvent was evaporated. The residue was partitioned between water and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane/(CH3OH/NH3)50/45/5). The desired fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE with a drop of ACN. The precipitate was filtered off, washed and dried, yielding 1.88 g (39%) of [1-[3-(3-chloro-6-oxo-1 (6H)-pyridazinyl)propyl]-4-piperidinyl]methyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate (compound 21, mp: 137 ° C.) In a similar way, [1-[3-(3-methyl-6-oxo-1(6H)-pyridazinyl)propyl]-4-piperidinyl]-methyl 7-amino-6-chloro-1,3-benzodioxole-4-carboxylate (compound 22) was also prepared.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](O)(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH2:13]>>[C:1]1([N:7]2[C:10](=[O:18])[C:11]3[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:13][C:8]2=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ccccc1C(=O)O
Product: O=c1c2ccccc2[nH]c(=S)n1-c1ccccc1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Phenyl isothiocyanate (28.3 g) was added to anthranilic acid (28.7 g) in absolute alcohol (250 ml) and heated at reflux for 4.5 hours. The mixture was cooled to room temperature and the solid removed by filtration to give 32.5 g of 3-phenyl-2,3-dihydro-2-thioxoquinazolin-4(1H)-one, mp 287°-291° C. Sulphuryl chloride (5.4 ml) was added dropwise at room temperature to a suspension of this product (32.5 g) in chloroform (250 ml). The mixture was heated at reflux for 4 hours. When cool, it was poured into water (400 ml), filtered and the solid washed with dichloromethane. The organic layer was separated from the filtrate, dried and concentrated in vacuo. The residue was extracted with ether, filtered and the filtrate concentrated in vacuo to give an oil which solidified on standing. This was recrystallised from cyclohexane to give crude 2-chloro-3-phenylquinazolin-4(3H)-one, mp 102°-5° C. (shown to be 90% pure by high pressure liquid phase chromatography (hplc). A mixture of this product (3.85 g), imidazole (1.02 g) and potassium carbonate (2.07 g) in acetonitrile (60 ml) was heated at reflux for 4 hours. The mixture was cooled to room temperature, and concentrated in vacuo. The residue was chromatographed on silica using light petroleum (bp 60°-80° C.)/ethyl acetate (1:1) as eluant. The resulting solid was recrystallised from cyclohexane to give 0.8 g of 3-phenyl-2-(imidazol-1-yl)-quinazolin-4(3H)-one, mp 163°-5° C. (Compound 1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[N:9][N:10]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[CH:3]=1.C(O)=O.C(N(CC)CC)C.[OH-].[Na+]>>[CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[N:8]=[N:9][N:10]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[CH2:3]1
Reactant: Cc1cc2c(cn1)nnn2-c1cnccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC1Cc2c(nnn2-c2cnccn2)CN1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
To a solution of 6-methyl-1-(pyrazin-2-yl)-1H-[1,2,3]triazolo[4,5-c]pyridine (245 mg, 1.15 mmol) in formic acid (0.70 mL, 18.5 mmol) was added dropwise triethylamine (1.28 mL, 9.24 mmol). The resulting mixture was heated to 140° C. for 24 h. The reaction was cooled and 1M NaOH was added until the pH was 7-9. The water layer was extracted with CH2Cl2 three times. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated. The residue was dissolved in 3:1 isopropanol/concentrated HCl (4 mL) and stirred at 50° C. for 16 h. The reaction was cooled and 1M NaOH was added until pH 12 was reached. The water layer was extracted with 1:4 isopropanol/CH2Cl2 three times. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated to a yellow solid (230 mg, 92%). MS (ESI) mass calcd. C10H12N6, 216.11. m/z found, 217.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.51-9.47 (m, 1H), 8.64-8.60 (m, 1H), 8.49-8.46 (m, 1H), 4.26-4.08 (m, 2H), 3.37-3.28 (m, 1H), 3.14-3.04 (m, 1H), 2.85-2.74 (m, 1H), 2.23-2.02 (br s, 1H), 1.36 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].CS(O[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=1)(=O)=O>C1COCC1.CN(C=O)C>[Br:21][C:19]1[CH:18]=[N:17][CH:16]=[C:15]([CH2:14][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:20]=1
Reactant: OCC(F)(F)F
Reactant: CS(=O)(=O)OCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: FC(F)(F)COCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
2,2,2-Trifluoroethanol (0.434 g, 4.34 mmol) was added to a suspension of NaH (0.198 g, 4.96 mmol) in THF (10 mL). When gas evolution had ceased, a solution of (5-bromopyridin-3-yl)methyl methanesulfonate (see WO2007/076247; 1.10 g, 4.13 mmol) in DMF was added. The resulting mixture was stirred for 2 h at r.t. and then the volatile solvent was evaporated. The remaining solution was diluted with water and extracted with EtOAc (3×30 mL). The combined extracts were dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica using gradient elution with EtOAc in heptane to give 227 mg of the title compound (20% yield). 1H NMR (500 MHz, CDCl3) δ ppm 3.92 (q, 2 H), 4.70 (s, 2 H), 7.87 (m, 1 H), 8.50 (m, 1 H), 8.66 (d, 1 H); MS (EI) m/z 269 M+.