Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:16])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[CH2:18][C:19]([C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20]>ClCCl>[C:8]([O:16][CH2:18][C:19]([C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C=O)c1ccccc1C(=O)CCl
Reactant: O=C(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C=O)c1ccccc1C(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (362.8 ml) was added to a stirred mixture of benzoic acid (239.1 g) and dichloromethane (1120 ml) at 0° and the resultant solution was added dropwise over a period of 1 hour to the solution of 2'-(2-chloroacetyl)-N-methylformanilide under nitrogen whilst maintaining the temperature below 5°. The resulting solution was stirred overnight at ambient temperature, washed with water (2×1250 ml), dried over magnesium sulphate and the solvent removed by distillation at 50° to give a solid residue. Trituration with petroleum ether (b.p. 60°-80°, 1 1) gave the novel compound 2-[2-(N-methylformamido)phenyl]-2-oxoethyl benzoate, m.p. 100°-102°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:11]1([C:14]2[C:15]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:16][CH:17]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[CH:19]=2)[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:26]2[CH2:27][CH2:28][N:23]([C:15]3[C:14]([CH:11]4[CH2:12][CH2:13]4)=[CH:19][C:18]([CH:20]4[CH2:22][CH2:21]4)=[CH:17][N:16]=3)[CH2:24][CH2:25]2)=[O:10])=[N:6][CH:7]=1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: O=C(O)c1ccc(Br)cn1
Product: O=C(c1ccc(Br)cn1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 99.8 %

Procedure:
Using 5-bromo-2-picolinic acid (378 mg) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (500 mg) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (798 mg) was obtained.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:23](=[O:25])=[O:24].Cl>CCCCCC.O.O1CCCC1>[C:1]([NH:5][S:6]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:23]([OH:25])=[O:24])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1csc2ccccc12
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1c(C(=O)O)sc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-tert-Butylbenzothiophene-3-sulfonamide (13.6 g) and 400 ml of anhydrous tetrahydrofuran in admixture were cooled to 0° and 120 ml of butyl lithium in hexane (1.6 molar) was added cautiously, dropwise. After the addition was completed the mixture was stirred at room temperature for 2 hours and carbon dioxide was then passed into the system for two hours while cooling to 15°. Two hundred ml of water was then cautiously added followed by 40 ml of 12 N hydrochloric acid. The solution was then evaporated to half of its original volume, extracted with methylene chloride and the organic phase washed with water, dried over magnesium sulfate, filtered and evaporated to dryness to yield a white solid of m.p. 180° with gas evolution. Nuclear Magnetic Resonance spectroscopy showed the t-butyl absorption at 1.3 δ (singlet) and benzothiophene hydrogen absorption at 7.4-8.0 (multiplet).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4([OH:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3([OH:35])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH2:27][CH2:28]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: Cn1c(CN2CCC(C3(O)CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4(O)CCOCC4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 4-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)-tetrahydro-2H-pyran-4-ol were reacted to give 317. LCMS m/z: 547.3 (MH+)
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[N:19]=[CH:18][CH:17]=[C:16](Br)[C:13]=1[C:14]#[N:15]>CN(C=O)C>[CH2:3]([O:10][C:16]1[C:13]([C:14]#[N:15])=[C:12]([Br:11])[N:19]=[CH:18][CH:17]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1c(Br)ccnc1Br
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCc2ccccc2)ccnc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
To a suspension of NaH (1.756 g, 45.818 mmol, mineral oil 60%) in DMF (200 ml) cooled at 0° C., was added benzyl alcohol (4.542 g, 42 mmol). The resulting mixture was stirred for 5 min. Then compound D1 (10 g, 38.18 mmol) was quickly added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h. The reaction mixture was quenched with NH4Cl (aqueous sat. solution), diluted with H2O and the resulting mixture was extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 1% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D2 (9.2 g, 83%).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#N)=[CH:12][CH:11]=1.Cl.C(OCC)(=[O:21])C>C1COCC1>[F:9][C:10]1[CH:17]=[CH:16][C:13]([C:14](=[O:21])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C[Zn]Br
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Yield: 93 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 6.09 g (10 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.21 g (10 mmol) of 4-fluorobenzonitrile in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 26 hours. 15 mL of 10% hydrochloric acid was added dropwise at 20° C. or lower, and the mixture was stirred at 20˜25° C. for 1 hour, followed by dilution with ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 15 mL of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.96 g of the desired product (yield 93%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[O:45]=[C:46]1[CH2:51][CH2:50][CH2:49][CH:48]([C:52](O)=[O:53])[CH2:47]1>C(OCC)(=O)C.CN(C=O)C>[CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:52]([CH:48]2[CH2:49][CH2:50][CH2:51][C:46](=[O:45])[CH2:47]2)=[O:53])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C1CCCC(C(=O)O)C1
Reactant: CC(C)Oc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(NC(=O)C2CCCC(=O)C2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.2 %

Procedure:
4-Isopropoxyaniline (117 mg, 0.774 mmol), HATU (294 mg, 0.774 mmol) and diisopropylethylamine (0.27 mL, 1.548 mmol) were added in that order to a DMF (3 mL) solution of 3-oxo-1-cyclohexanecarboxylic acid (100 mg, 0.703 mmol), and stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction liquid, and washed with distilled water and saturated brine. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to give the intended product (194 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]2[O:14][CH2:15][C:16]([O:19][CH3:20])([O:17][CH3:18])[C@@H:9]12)=[O:7])([CH3:4])(C)C.Cl.N1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)(OCC1C=CC=CC=1)=O>C(Cl)Cl.CO>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]2[O:14][CH2:15][C:16]([O:17][CH3:18])([O:19][CH3:20])[C@@H:9]12)=[O:7])[C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccncc1
Reactant: COC1(OC)CO[C@@H]2[C@H](O)CN(C(=O)OC(C)(C)C)[C@@H]21
Agent: Cl
Agent: O=C(Cl)OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COC1(OC)CO[C@@H]2[C@H](O)CN(C(=O)OCc3ccccc3)[C@@H]21
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To a stirred solution of compound 12c (3.8 g, 13.13 mmol) in CH2Cl2 (100 mL) was added 2M HCl in MeOH (50 mL). The resulting solution was stirred overnight and then concentrated in vacuo and azeotroped with toluene (3×100 mL). The crude residue was dissolved in CH2Cl2 (100 mL) cooled to 0° C. and pyridine (1071 μL, 13.13 mmol) added followed by dropwise addition of CbzCl (1875 μL, 13.13 mmol). The reaction was stirred at room temperature for 2 hours then washed with 2 M HCl (2×50 mL), saturated NaHCO3 (2×50 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (5-100% isohexane:EtOAc) to obtain the title compound as a clear oil (2510 mg, 59%). MS M+H 324.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.Cl[C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[N:10]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:14]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc2c(Cl)nccc2[nH]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2c(C)nc3c(Cl)nccc32)nc1
Yield: 51 %

Procedure:
4-Chloro-2-methylimidazo[4,5-c]pyridine described in C.A. 79, 105515f but made by the method of Chem. Pharm. Bull, 12 (8) 866-872 (1964) (3.34 g, 20 mmol), and ethyl 6-chloronicotinate (3.71 g, 26.2 mmol) were dissolved in N,N-dimethylformamide (42 ml). Potassium carbonate (2.76 g, 20 mmol) was added and the reaction was refluxed overnight. The reaction mixture was cooled, the solvent removed under reduced pressure and the crude product purified by flash chromatography eluting with ethyl acetate. Fractions containing product were evaporated and the resulting foam triturated with ether. The solid was filtered and dried under reduced pressure yielding the title compound as a yellow solid (3.2 g, 51%).
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.[CH3:13][C:14]([CH3:16])=O.[BH3-]C#N.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>CO>[CH:14]([N:9]1[CH2:8][CH2:7][C:6]2([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]2)[CH2:11][CH2:10]1)([CH3:16])[CH3:13]
Reactant: O=C1COC2(CCNCC2)CN1
Reactant: CC(C)=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCC2(CC1)CNC(=O)CO2
Temperature: 50 °C

Procedure:
1-Oxa-4,9-diaza-spiro[5.5]undecan-3-one was dissolved in MeOH and treated with acetone (6 equivalents) and NaCNBH3 (4 equivalents). To the reaction mixture was added acetic acid (3 equivalents). The reaction was heated at 50° C. for 6 hours and then cooled to room temperature. The reaction was then poured into an aqueous NaHCO3 solution and extracted with EtOAc (3×). The fractions were dried over MgSO4 and concentrated to provide the title compound as a yellow oil that was purified by chromatography (10% MeOH/CH2Cl2). LC/MS (m/z) 213.1 (MH+), Rt=1.38 minutes.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@H:16]([NH2:22])[CH2:15]2.[OH-].[Na+]>S(Cl)(Cl)=O.C(Cl)Cl.C(OCC)(=O)C>[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@H:16]([NH:22][C:11]([C:10]1[CH:9]=[N:8][N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=13)=[O:13])[CH2:15]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: Cc1cccc2c(C(=O)O)cnn12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: Cc1cccc2c(C(=O)N[C@@H]3CN4CCC3CC4)cnn12
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A solution of 880 mg (5 mmol) of 7-methyl-3-pyrazolo[1,5-a]pyridinecarboxylic acid in 10 ml of thionyl chloride was heated under reflux for 30 minutes. Thionyl chloride was distilled off under reduced pressure and the residue was dissolved in 30 ml of methylene chloride. The resultant solution was added dropwise under ice cooling to a solution of 644 mg (5.1 mmol) of (S)-(-)-1-azabicyclo[2.2.2]octan-3-amine, which had been prepared in accordance with the procedure disclosed in Japanese Patent Application Laid-Open No. 196583/1988, in 30 ml of methylene chloride. The resultant mixture was stirred for 30 minutes under ice cooling and for additional 40 minutes at room temperature. 2N aq. NaOH solution was added to the reaction mixture and, after the mixture so obtained was stirred for 10 minutes, the organic layer was collected. Further, the water layer was extracted with methylene chloride and the extract was dried over anhydrous potassium carbonate. Methylene chloride was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column (chloroform:methanol=10:1, 5:1). An oily substance thus obtained was dissolved in ethyl acetate. The solvent was distilled off under reduced pressure, and crystals thus obtained were washed with ether, whereby 1.2 g (4.2 mmol) of the title compound were obtained as white crystals (yield: 84.5%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:12]([CH:13]2[O:17]CCO2)=[C:11]([F:18])[C:10](CCC)=[CH:9][CH:8]=1.[B:22]([O:27]C)([O:25]C)OC.C1C[O:32][CH2:31][CH2:30]1>>[F:18][C:11]1[C:12]([CH:13]=[O:17])=[C:7]([B:22]([OH:25])[OH:27])[CH:8]=[CH:9][C:10]=1[O:32][CH2:31][CH3:30]
Reactant: COB(OC)OC
Reactant: CCCc1ccc(Br)c(C2OCCO2)c1F
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CCOc1ccc(B(O)O)c(C=O)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Under a nitrogen atmosphere, n-BuLi (141.1 mL, 232.8 mmol) was slowly added dropwise, at −70° C. or lower, to a THF (500 mL) solution of compound (78) (61.2 g, 213.0 mmol). The reaction mixture was agitated at −70° C. or lower for 1 hour, and then trimethyl borate (33.0 g, 317 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 400 mL of 2N hydrochloric acid aqueous solution, and extracted with 200 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was washed with heptane, and thus (3-fluoro-2-formyl-4-ethoxyphenyl)boronic acid (79) (38.1 g, yield 86.0%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:4]([O:21][CH3:22])[CH:3]=1.I[CH2:24]C>>[ClH:8].[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:4]([O:21][CH2:22][CH3:24])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCCCN1CCCCC1
Reactant: CCI
Product: CCOc1cc(N)c(Cl)cc1C(=O)CCCCN1CCCCC1
Product: Cl

Procedure:
Proceeding as in Example 12, Step (a), but replacing 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{1-[2-(methylsulfonyl)aminoeth yl]piperidin-4-yl}propan-1-one with 1-[4-amino-5-chloro-2-methoxyphenyl]-5-(piperidin-1-yl)pentan-1-one, and then as in Example 12, Step (b), but replacing 3,5-dimethoxybenzyl chloride with iodoethane, gave 1-[4-amino-5-chloro-2-ethoxyphenyl]-5-(piperidin-1-yl)-pentan-1-one hydrochloride, m.p. 230°-231° C.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][N:2]=1.C([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)=C.N1C=CC=[CH:25][CH:24]=1>>[CH:24]([C:16]1[CH:15]=[CH:14][CH:22]=[CH:21][C:17]=1[C:18]([N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[N:2]1)=[O:19])=[CH2:25]
Reactant: O=c1[nH]nnc2ccccc12
Reactant: c1ccncc1
Reactant: C=Cc1ccc(C(=O)Cl)cc1
Product: C=Cc1ccccc1C(=O)n1nnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of benzo-1,2,3-triazin-4-one (3.8835 g) in dry pyridine (40 mL) was stirred, and to this solution was added, over a period of 30 seconds, freshly prepared 4-vinylbenzoyl chloride (4.3945 g, prepared as described in Hirao et al., Macromolecules, 21, 561 (1988)). The resultant reaction mixture was stirred at room temperature for 1.5 hours, then poured into an ice/water mixture (300 mL). The colorless precipitate which formed was filtered off, washed with water on the frit and dried. The dried product was then dissolved in methylene chloride (75 mL) and the resultant solution was washed with water, dried over anhydrous magnesium sulfate and passed through a short column of silica gel. The solution was then concentrated on a rotary evaporator to give the desired 3-(vinylbenzoyl)benzotriazinone product as a colorless solid (6.12 g) having melting point 120° C. The identity of the product was confirmed by proton nuclear magnetic resonance (NMR) and infra-red spectroscopy, the spectra being as follows:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]O)[O:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])(=O)=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13][Cl:19])[O:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(CO)CN1Cc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1OC(CCl)CN1Cc1ccccc1
Yield: 80.6 %

Procedure:
A solution of 20 g (0.1 mole) of 3-benzyl-5-hydroxymethyl-2-oxazolidinone and 24 g (0.2 mole) of sulfonyl chloride in chloroform was refluxed for 3 hr. The reaction mixture was dried over anhydrous sodium sulfate, concentrated and subjected to distillation to give 18.2 g (81%) liquid, b.p. 176°-178° C. at 0.1 mm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:36][C:37]([NH2:39])=[O:38].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([O:26][CH2:36][C:37]([NH2:39])=[O:38])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)CI
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(O)ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(OCC(N)=O)ccc2c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
To a solution of tert-butyl[4-(4-chlorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.45 g, 1 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (48 mg, 1.2 mmol) (60% in oil) at 0° C., and the mixture was stirred at 0° C. for 10 min. To the obtained mixture was added 2-iodoacetamide (0.22 g, 1.2 mmol) and the mixture was stirred at 0° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(2-amino-2-oxoethoxy)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.27 g, 52.9%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-phenylpiperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=448.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]([CH:22]([CH3:24])[CH3:23])[C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(OCC)C.[N-:30]=[C:31]=[O:32].[O:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[CH:35]=[CH:34]1.C(N(CC)CC)C>C(Cl)Cl>[O:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[CH:35]=[C:34]1[NH:30][C:31]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH:17][C@@H:18]([C:19]([OH:21])=[O:20])[CH:22]([CH3:24])[CH3:23])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)=[O:32]
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1)C(=O)O
Reactant: c1ccc2occc2c1
Reactant: [N-]=C=O
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3cc4ccccc4o3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid (314 mg, 0.9 mmol) dissolved in methylene chloride (10 mL) and diethyl ether (20 mL) was added with benzofuran isocyanate (143 mg, 0.9 mmol, 1 equiv) and triethyl amine (363 mg, 3.6 mmol, 4 equiv). The mixture was stirred at room temperature overnight. Solid precipitated from reaction mixture was collected by filtration followed by column chromatography (silica gel, 5% MeOH/CH2Cl2). 76 mg of white solid was obtained in 16% yield.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-])=O)[C:3]=1[Cl:17].O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:14][C:4]1[C:3]([Cl:17])=[C:2]([Br:1])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2
Reactant: O=c1[nH]c2cc(Br)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)c(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A suspension of 7-bromo-6-chloro-5-nitro-1,4-dihydro-2,3-quinoxalinedione (50 mg, 0.16 mmol) and tin (II) chloride dihydrate (176 mg, 0.780 mmol, Aldrich, used as received) in ethanol (5 mL) was refluxed for 7 h. It was then cooled to r.t. and poured into ice (10 g). The suspension was then basified with 10% aq. NaHCO3 (25 mL) to pH 8-8.5 (pH paper) and extracted with ethyl acetate (50 mL). The ethyl acetate extract was washed with water and brine, dried over Na2SO4 and evaporated to give a solid which was dried under high vacuum to furnish 28 mg (62%) of pure title compound as a brown powder, m.p. >350° C.; 1H NMR (DMSO-d6) δ 5.888 (br s, 2H), 6.075 (s, 1H), 11.286 (s, 1H), 11.827 (s, 1H).