Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:49])=[C:11]([CH:17]([C:19]2[N:20]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[OH:18])[CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH2:15]([C:13]1[CH:12]=[C:11]([CH:17]([OH:18])[C:19]2[N:20]([C:30]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[C:10]([F:49])=[C:9]([OH:8])[CH:14]=1)[CH3:16]
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(O)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of intermediate 448.1 (1.74 g, 2.60 mmol) in 10 mL THF at rt, was added TBAF (1M in THF, 2.60 mL, 2.60 mmol). The mixture was stirred at rt for 30 min, then was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was triturated with hexanes (10 mL) to afford after filtration 1.32 g of intermediate 448.2 as a white solid. LCMS (2 min gradient) RT=1.81 min, 555.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[O:14][CH:11](OC)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:29]1[C:34](=[O:35])[C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][NH:31][C:30]1=[O:40])(C)C.C(O)C>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([CH2:16][OH:17])[O:14][C@@H:11]([N:31]2[CH:32]=[C:33]([C:36]([F:38])([F:39])[F:37])[C:34](=[O:35])[NH:29][C:30]2=[O:40])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)n1c(=O)[nH]cc(C(F)(F)F)c1=O
Reactant: COC1C[C@H](OCc2ccccc2)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Solvent: CCO
Solvent: ClCCl
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1C(F)(F)F
Temperature: 5 °C

Procedure:
To a stirred mixture of 3.5 g (0.01 mole) of methyl 3-O-benzyl-5-O-(t-butyldimethylsilyl)-2-deoxyribofuranoside and 3.4 g (0.01 mole) of Bis-(trimethylsilyl-5-trifluoromethyluracil in 30 ml of methylene chloride at <5° C. was added a solution of 2.9 g (0.011 mole) of stannic chloride in 5 ml of methylene chloride at ca. 0.25 ml/min. The clear yellow solution was stirred for an additional one and one-half hours at 5° C. during which time the color darkened and a fine precipitate formed. Anhydrous ethanol (11 ml) was then added to the mixture. After warming to ambient temperature, the mixture was filtered removing only a small amount of a solid material. The solvent was then removed under vacuum. The dark residual oil was triturated (3×50 ml) with hexane. The residue was taken up in 100 ml of ethyl acetate, washed with 100 ml of cold saturated sodium bicarbonate solution forming an emulsion. This was vacuum filtered and the filtrate layers separated. The organic phase was washed (2×100 ml) with DI water, dried (Na2SO4), filtered, and the solvent removed under vacuum affording 1.0 g of a thick yellow oil. This material was chromatographed on 75 cc of silica gel eluting with ethyl acetate/hexane (1:1). From early eluting fractions, 150 mg (0.39 mmole, 3.9%) of crude beta-anomer of the title product was obtained with 200 mg (0.52 mmole, 5.2%) of the alpha-anomer being found in later eluting fractions. The products were identified by thin layer chromatography and 1H NMR analysis.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:25](=[O:26])[N:12]2[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[NH2:20])[CH2:15][S:16][C@H:11]12)=[O:8].[N+](=[CH2:29])=[N-]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:25](=[O:26])[N:12]2[C:13]([C:22]([O:24][CH3:29])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[NH2:20])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: C=[N+]=[N-]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: CCO
Product: COC(=O)C1=C(COC(N)=O)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12

Procedure:
7-(2-(2-Thienyl)acetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (50 milligrams) in ethanol was reacted with excess diazomethane. After five minutes the excess diazomethane was evaporated and the desired methyl ester crystallized with ethanol, then with chloroform, and with acetone. Nine milligrams of the desired 7-(2-(2-thienyl)acetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, methyl ester were obtained, m.p., 212°-214° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[C:5]=2[O:6][C:7]=1[CH3:8].[C:24](=O)([O-])[O-:25].[K+].[K+].O>CO>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:14]([NH:13][C:9]1[C:5]2[O:6][C:7]([O:25][CH3:24])([CH3:8])[C:3](=[CH2:2])[C:4]=2[CH:12]=[CH:11][CH:10]=1)=[O:23]
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=C1c2cccc(NC(=O)c3c(Cl)cccc3Cl)c2OC1(C)OC
Yield: 25.3 %

Procedure:
A mixture of 3-chloromethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (20 mg) and potassium carbonate (7.5 mg) in methanol was refluxed for 1 hour. The mixture was cooled and poured into water. The separated oil was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by preparative TLC to give 7-(2,6-dichlorobenzoylamino)-2,3-dihydro-2-methoxy-2-methyl-3-methylenebenzo[b]furan (5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:16][C:15](=[O:17])[NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:16][C:15](=[O:17])[N:14]([CH3:20])[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CCNC(=O)O2)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2CCN(C)C(=O)O2)cc1OC
Temperature: 25 °C

Procedure:
To a solution of the 6-(3,4-dimethoxyphenyl)-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (1.20 g, 5.06 mM) produced in Example 1 in dried N,N-dimethylformamide (30 ml) were added sodium hydride (60%) (0.41 g, 10.12 mM) and methyl iodide (1.44 g, 10.12 mM). The solution was then stirred at room temperature for one night. The reaction solution was carefully poured into ice water, then extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to obtain a residue as a brown oil. The residue was purified by flash chromatography (SiO2; eluted by 0.5% methanol/chloroform) to obtain the above-described compound 0.28 g (yield 22.3%) as a colorless solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]=O)=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:33]([S:35][CH2:36][CH2:37][NH2:38])[CH3:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH2:31][NH:38][CH2:37][CH2:36][S:35][CH2:33][CH3:34])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=Cc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: CCSCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCSCCNCc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carbaldehyde (0.31 g), 2-(ethylsulfanyl)ethanamine (0.14 g), acetic acid (1 drop) and tetrahydrofuran (2 mL) was stirred overnight at 50° C. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was m washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was dissolved in methanol (4 mL), and sodium borohydride (28 mg) was added at 0° C. The reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (0.37 g, quantitatively) was obtained as a yellow oil from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). MS: 471 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]([Br:24])(Br)Br.[F:25][C:26]1[CH:27]=[C:28]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35](=[O:42])[O:34][C:33]=2CO)[CH:29]=[CH:30][CH:31]=1>C(Cl)Cl.CO>[Br:24][CH2:21][C:33]1[O:34][C:35](=[O:42])[C:36]2[C:41]([C:32]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2
Reactant: BrC(Br)(Br)Br
Reactant: O=c1oc(CO)c(-c2cccc(F)c2)c2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=c1oc(CBr)c(-c2cccc(F)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Triphenylphosphine (265 mg, 1.01 mmol) and perbromomethane (335 mg, 1.010 mmol) were added to a solution of 4-(3-fluorophenyl)-3-(hydroxymethyl)-1H-isochromen-1-one (intermediate B3, 210 mg, 0.777 mmol) in DCM (6.5 ml) and the mixture was stirred overnight at RT. Further triphenylphosphine (265 mg, 1.010 mmol) and perbromomethane (335 mg, 1.01 mmol) were then added and left on stirring at RT for 6 hrs. The reaction was then diluted with MeOH (1 ml) and straightforward purified on 50 g Biotage silica cartridge eluting with a gradient of Hexane and EtOAc to give the title compound (154 mg, 59.5%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([CH:17]=[CH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:25])[C:7]=2[N:6]=[CH:5]1>CO>[CH3:1][CH:2]([CH3:26])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:25])[C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)Cn1cnc2c(N)nc3cc(C=Cc4ccccc4)ccc3c21
Solvent: CO
Product: CC(C)Cn1cnc2c(N)nc3cc(CCc4ccccc4)ccc3c21

Procedure:
A modification of the method described in Example 123 was used to reduce 1-(2-methylpropyl)-7-styryl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.5 mmol). The reaction was carried out in methanol (100 mL) for seven days. The crude product was purified by flash column chromatography on silica gel (eluting with 90:10 chloroform:CMA) followed by recrystallization from acetonitrile to provide 1-(2-methylpropyl)-7-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, mp 172-173° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:45])[O:14][CH2:15][C@@H:16]([N:31]([CH3:44])[C:32]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[Cl:43])=[O:33])[CH2:17][CH2:18][CH2:19][N:20]1C(=O)C3C(=CC=CC=3)C1=O)=[CH:5]2.NN>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:45])[O:14][CH2:15][C@@H:16]([N:31]([CH3:44])[C:32]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[Cl:43])=[O:33])[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:5]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN1C(=O)c2ccccc2C1=O)COC(=O)Nc1cc2cc(F)ccc2cn1
Agent: NN
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(1,3-dioxoisoindolin-2-yl)pentyl 6-fluoroisoquinolin-3-ylcarbamate (400 mg, 0.64 mmol) in MeOH (10.0 mL) was added NH2NH2 (1.0 mL). The reaction mixture was stirred at RT for 2 h. The mixture was concentrated and re-dissolved in MeOH. The mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (305 mg, quant.). LRMS (M+H+) m/z 506.2.
Reaction SMILES: Br.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C@H:8]2[CH2:13][CH2:12][C@@H:11]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[CH2:10][C@H:9]2[CH2:19][CH3:20])[C:4]1=[O:21].C(N(CC)CC)C.Cl[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=2)[N:33]=[CH:32][N:31]=1>CCO>[CH2:19]([C@@H:9]1[CH2:10][C@H:11]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[CH2:12][CH2:13][C@@H:8]1[N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:42])([F:43])[F:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[C:4]1=[O:21])[CH3:20]
Reactant: CC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 80 °C

Procedure:
A sample of the bis-HBr salt of (S)-3-amino-1-((1S,2R,4R)-2-ethyl-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (147 mg) was dissolved in EtOH (5 mL) and the resulting solution was charged with triethylamine (0.55 mL) and 4-chloro-6-trifluoromethylquinazoline (183 mg) before being heated at 80° C. for 14 h. The reaction was cooled and concentrated under reduced pressure, and the residue was partitioned between diethyl ether and water. The organic phase was extracted twice with water. The combined aqueous extracts were lyophilized and the resultant powder was purified by RP-HPLC to afford (S)-1-((1S,2R,4R)-2-ethyl-4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one. MS found: (M+H)+=478.4.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1(O)[CH2:14][CH2:13][CH2:12]1.CCN(S(F)(F)[F:24])CC>ClCCl>[F:24][C:11]1([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C:2]([F:17])([F:16])[F:1])[CH2:14][CH2:13][CH2:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2cnccc2OCC(F)(F)F)CCC1
Solvent: ClCCl
Product: FC(F)(F)COc1ccncc1C1(F)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 1-[4-(2,2,2-Trifluoro-ethoxy)-pyridin-3-yl]-cyclobutanol (example 108b, 1.7 g, 6.88 mmol) in dry dichloromethane (25.0 ml) under an argon atmosphere cooled down to 0° C. was added DAST (1.36 ml, 10.3 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. The reaction was quenched by addition of a 2M aqueous solution of sodium carbonate and the bi-phasic mixture was stirred for 20 minutes. The bi-phasic mixture was transferred into a separatory funnel and the organic phase was collected. The organic phase was dried over sodium sulfate and evaporated down to dryness to yield the title compound (1.68 g, 98%); MS (ESI, m/z): 250.4 (M+H+). The crude material was used without any purification for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([CH3:25])[CH2:19][C:20]([O:22]CC)=[O:21])=[C:8]2[CH3:26])=[CH:4][CH:3]=1.[OH-].[K+].O>CCO>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([CH3:25])[CH2:19][C:20]([OH:22])=[O:21])=[C:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)c(C(C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 60 °C
Yield: 75 %

Procedure:
To a suspension of the ester from Step 4 (5.13 g, 11.5 mmol) in 50 mL of EtOH was added 8N KOH (5 mL, 40 mmol) and 5 mL water. The mixture was heated to 60° C. for 1 h, then cooled and concentrated. The residue was partitioned between 1M HCl and EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated. Crystallization from CH2Cl2/ hexanes gave 3.59 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=3)[CH2:10][CH2:9][C:8]([C:22]([O:24][CH3:25])=[O:23])=[CH:7][C:6]=2[CH:26]=1.B([O-])([O-])O[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:39]([O:38][CH2:37][CH2:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([C:12]4[CH:13]=[CH:14][C:15]([S:18](=[O:20])(=[O:21])[NH2:19])=[CH:16][CH:17]=4)[CH2:10][CH2:9][C:8]([C:22]([O:24][CH3:25])=[O:23])=[CH:7][C:6]=3[CH:26]=2)=[CH:34][CH:33]=1)[CH2:40][CH2:41][CH3:42]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(c2ccc(S(N)(=O)=O)cc2)CC1
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A mixture of methyl 7-bromo-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g), 4-(2-butoxyethoxy)phenyl borate (0.22 g), 1M potassium carbonate solution (3 ml), ethanol (5 ml) and toluene (50 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed under argon atmosphere for 3 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:23])=[CH:17][C:9]1=2
Reactant: NC1CCCCC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NC1CCCCC1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with cyclohexylamine as in General Procedure 10 to give the title compound. LCMS: m/z=529.01 (M+H+); retention time=0.96 minutes.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[N:3][C:2]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=3.[Cl:19][CH2:20][C:21](Cl)=[O:22]>CN(C)C=O>[Cl:19][CH2:20][C:21]([N:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH:1]=[C:2]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:3]=[C:4]2[CH2:13]1)=[O:22]
Reactant: CCOC(=O)c1cn2c(n1)CNc1ccccc1-2
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(n1)CN(C(=O)CCl)c1ccccc1-2
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of 2 g of ethyl 4,5-dihydroimidazo[1,2-a]quinoxaline-2-carboxylate in 20 ml of dry dimethylformamide was treated with 2 ml of chloroacetyl chloride and the mixture was stirred overnight. A white solid settled out and was filtered off and crystallized from ethanol to obtain 2.27 g (86% yield) of ethyl 4,5-dihydro-5-chloroacetylimidazo[1,2-a]quinoxaline-2-carboxylate melting at 178°-83° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[N:23]=[C:22]3[CH3:30])=[CH:17][CH:16]=2)=[N:5][C:6]2[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:7]=2[N:8]=1.[C:31](OC)(=[O:34])[C:32]#[CH:33]>C(O)CCC>[CH3:13][C:11]1[C:10]([CH3:14])=[CH:9][C:7]2[N:8]3[CH:33]=[CH:32][C:31](=[O:34])[N:1]=[C:2]3[CH2:3][C:4]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:29]5[CH:28]=[CH:27][N:26]=[CH:25][C:24]=5[N:23]=[C:22]4[CH3:30])=[CH:19][CH:20]=3)=[N:5][C:6]=2[CH:12]=1
Reactant: C#CC(=O)OC
Reactant: Cc1cc2c(cc1C)N=C(c1ccc(-n3c(C)nc4cnccc43)cc1)CC(N)=N2
Solvent: CCCCO
Product: Cc1cc2c(cc1C)-n1ccc(=O)nc1CC(c1ccc(-n3c(C)nc4cnccc43)cc1)=N2
Yield: 10.3 %

Procedure:
A solution of 2-amino-7,8-dimethyl-4-[4-(2-methylimidazo-[4,5-c]pyrid-1-yl)phenyl]-3H-[1,5]benzodiazepine (Example 44) (395 mg, 1.0 mmol) and methyl propiolate (168 mg, 2.0 mmol) in n-butanol (4 ml) was heated at reflux for 16 hours under nitrogen. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (eluting with ethyl acetate:methanol: diethylamine=100:10:5). Fractions containing product were concentrated, and the residue was treated with dichloromethane, leaving some insoluble tarry material. The dichloromethane solution was decanted, concentrated, and the resulting brown solid triturated with hexane to give the title compound (46 mg, 10%), m.p. 192°-194° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C>[O:3]=[C:4]1[N:9]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(F)(F)F)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
Sodium hydride (840 mg, 24.5 mmol) was gradually added to a solution of tert-butyl 3-oxopiperazine-1-carboxylate (4.1 g, 20.4 mmol) in DMF (30 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 30 minutes. A solution of 4-trifluoromethylbenzyl chloride (5 g, 20.9 mmol) in DMF (5 ml) was added dropwise to the mixture while cooling in an ice-bath, which was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate twice. The extract was washed with water twice and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride) to afford tert-butyl 3-oxo-4-(4-trifluoromethylbenzyl)piperazine-1-carboxylate (6.7 g, yield 91%) as a colorless crystalline powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH3:18][C:19]1([CH3:29])[CH:24]2[CH2:25][CH2:26][CH:20]1[C:21](=O)[O:22][C:23]2=[O:27]>>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[C:23](=[O:27])[CH:24]3[C:19]([CH3:18])([CH3:29])[CH:20]([CH2:26][CH2:25]3)[C:21]2=[O:22])[CH2:11][CH2:10]1
Reactant: CC1(C)C2CCC1C(=O)OC2=O
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Product: CC1(C)C2CCC1C(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Yield: 30.3 %

Procedure:
Following substantially the procedure of Example 1, 0.54 g (2.34 mmol) of 1-(4-aminobutyl)-4-(2-pyrimidinyl) piperazine was reacted with 0.36 g (2.14 mmol) of 8,8-dimethyl-3-oxabicyclo[3.2.1]octan-2,4-dione. The product was chromatographed on silica gel, eluting with dichloromethane/methanol (96:4), to give 0.25 g (32% yield) of the title compound.