Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:3]=[N:4][C:5]([C:9]([OH:11])=O)=[C:6]([OH:8])[N:7]=1.C(N(CC)CC)C.S(Cl)([Cl:21])=O.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(Cl)Cl>[SH:1][C:2]1[N:3]=[N:4][C:5]([C:9]([Cl:21])=[O:11])=[C:6]([OH:8])[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1nnc(S)nc1O
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cl)c1nnc(S)nc1O

Procedure:
In a similar manner to that of Example 1-4), 3-mercapto-5-hydroxy-1,2,4-triazine-6-carbonyl chloride, which was prepared from 3-mercapto-5-hydroxy-1,2,4-triazine-6-carboxylic acid (1.73 g), triethylamine (1.0 g), dimethyllformamide (30 ml) and thionyl chloride (1.19 g), was treated with a mixture of 7-(D-2-phenylglycinamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (4.0 g) and bis(trimethylsilyl) acetamide (6.4 g) in methylene chloride (40 ml). Thus obtained reaction mixture was worked up in a similar manner to that of Example 1--1) to give power (870 mg) of 7-[D-2-(3-mercapto-5-hydroxy-1,2,4-triazine-6-carboxamido)-2-phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, mp 175° to 179° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][CH:15]([NH:19][CH2:20][C@@H:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29]CC4C=CC=CC=4)=[C:25]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:24]=3)[OH:22])[CH2:14][C:13]=2[CH:42]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6](=[O:43])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH2:16][CH:15]([NH:19][CH2:20][C@H:21]([OH:22])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:24]=3)[CH2:14][C:13]=2[CH:42]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc2c(c1)CC(NC[C@H](O)c1ccc(OCc3ccccc3)c(NS(C)(=O)=O)c1)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1ccc2c(c1)CC(NC[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1)CCC2
Yield: 89.1 %

Procedure:
A mixture of 2-[8-[(2R)-2-(4-benzyloxy-3-methane-sulfonylaminophenyl)-2-hydroxyethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid tert-butyl ester (353 mg) and 10% palladium on activated carbon (50% wet, 100 mg) in methanol (5 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 3.5 hours. After filtration, the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=10:1 to 5:1) to give 2-[8-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylaminophenyl)-ethylamino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-acetic acid tert-butyl ester (268 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:15])([CH2:12][CH2:13][CH3:14])[C:4](=[O:16])[C:3]=1[C:17]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([NH:27]C(=O)OC(C)(C)C)=[CH:26][C:20]=2[S:19](=[O:36])(=[O:35])[N:18]=1.[ClH:37]>O1CCOCC1>[ClH:37].[NH2:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:3]3[C:4](=[O:16])[C:5]([CH3:15])([CH2:12][CH2:13][CH3:14])[C:6]4[C:11]([C:2]=3[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=4)=[N:18][S:19](=[O:36])(=[O:35])[C:20]=2[CH:26]=1
Reactant: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 85 %

Procedure:
A solution of Example 32A (0.488 g, 0.954 mmol) in 4M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give the title compound (0.363 g, 85%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.63 (m, 4 H) 0.88 (m, 1 H) 1.57 (m, 3 H) 2.10 (m, 2 H) 7.02 (m, 2 H) 7.45 (m, 1 H) 7.55 (m, 1 H) 7.76 (m, 2 H) 8.16 (m, 1 H) 13.56 (m, 1 H). MS (ESI−) m/z 410 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
A solution of p-hydroxybenzaldehyde (3.66 g, 30 mmole) in dry DMF (20 ml) was stirred with anhydrous potassium carbonate (12.5 g, 90 mmole) and benzylbromide (6.16 g, 36 mmole) was added. After 18 hours, the mixture was diluted with brine (75 ml) and extracted three times with ether. The extracts were combined, washed with dilute brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to afford a solid. Crystallization from ethyl ether in hexane gave 5 g of title E compound as light yellow flakes, with consistent spectral data.
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][O-:14].[Na+]>CO>[Br:8][C:7]1[C:2]([O:14][CH3:13])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc(C(F)(F)F)cc1Br
Reaction time: 16 h

Procedure:
A mixture of 7.6 g of 2-chloro-3-bromo-5-(trifluoromethyl)pyridine, 6.2 ml of 25 percent sodium methoxide in methanol (0.027 mol), and 20 ml of anhydrous methanol was prepared and allowed to react at ambient temperature with stirring for 16 hours. The mixture was then poured onto ice and the resulting mixture extracted with ether. The ether extract was extracted with water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure and the residue was purified by distillation under reduced pressure to obtain 4.1 g (65 percent of theory) of the title compound as a colorless oil boiling at 86°-88° C. at 21 mm pressure and having a refractive index at 19° C. of 1.4816. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[Br-:50].[NH2:51][CH2:52][CH2:53][CH2:54][CH2:55][N+:56]([CH2:59][CH2:60][NH:61][C:62]([C:64]1[C:69]([NH2:70])=[N:68][C:67]([NH2:71])=[C:66]([Cl:72])[N:65]=1)=[O:63])([CH3:58])[CH3:57]>CN(C=O)C>[Br-:50].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH:51][CH2:52][CH2:53][CH2:54][CH2:55][N+:56]([CH2:59][CH2:60][NH:61][C:62]([C:64]2[C:69]([NH2:70])=[N:68][C:67]([NH2:71])=[C:66]([Cl:72])[N:65]=2)=[O:63])([CH3:58])[CH3:57])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](C)(CCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[N+](C)(CCCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-Benzyloxyphenyl acetic acid (0.013 g, 0.30 mmol) in DMF (1.5 mL) is added HATU (0.12 g, 0.3 mmol), N-methylmorpholine (0.13 mL, 1.2 mmol) and (4-amino-butyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate N) (0.1 g, 0.30 mmol). The solution is stirred at RT for 2 h. The solvent is removed in vacuo and the residue is purified by reverse phase chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% TFA) to yield the title compound. M+ 535. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (1H, t), 8.05 (1H, t), 7.25 (2H, br), 7.42-7.32 (5H, m), 7.17 (2H, d), 7.09 (2H, br), 6.92 (2H, d), 5.06 (2H, s), 3.61-3.53 (2H, m), 3.39-3.33 (4H, m), 3.32 (2H, s), 3.10-3.03 (2H, m), 3.02 (6H, s), 1.61-1.49 (2H, m), 1.44-1.33 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[CH3:35][S:36][CH2:37][CH2:38]O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:38][CH2:37][S:36][CH3:35])[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Reactant: CSCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCSC)cc5C)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (280 mg) and 2-(methylthio)-ethanol (54 μL) in toluene (8 mL) are successively added 1,1′-(azodicarbonyl)-dipiperidine (240 mg) and tributylphosphine (240 mL). The mixture is stirred for 12 hours at room temperature, partitioned between saturated aqueous NaHCO3 solution and dichloromethane and stirred for 30 minutes. The phases are separated and the organic phase is dried (MgSO4). The solvents are evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→70:30) to give the title compound. Yield: 235 mg; LC (method 4): tR=1.97 min; Mass spectrum (ESI+): m/z=537 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=2)[N:15]=1)=[O:13].[C:25]([O:29][C:30]([N:32]1[C@H:37]([C:38]([OH:40])=[O:39])[CH2:36][C@@H:35]2[C@H:33]1[CH2:34]2)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C.C([O-])(O)=O.[Na+]>[C@@H:33]12[CH2:34][C@@H:35]1[CH2:36][C@@H:37]([C:38]([O:40][CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:24])[CH:20]=3)[N:15]=1)=[O:13])=[O:39])[N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
DIPEA (0.21 mL, 1.2 mmol) was added to a solution of 2-bromo-1-(6-bromoquinolin-2-yl)ethanone (268 mg, 0.815 mmol)) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (204 mg, 0.896 mmol) in acetonitrile (8 mL) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with sat. aq. NaHCO3 (5 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by flash silica gel chromatography (used DCM as loading solvent, eluted with Et2O/hexanes, gradient from 10% to 30% Et2O) to yield (1R,3S,5R)-3-(2-(6-bromoquinolin-2-yl)-2-oxoethyl) 2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (332 mg) as white solid. LC-MS retention time 4.283 min; m/z 476.88 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:41]([O:43][C:44](=[O:50])[CH2:45][CH2:46][N:47]=[C:48]=[O:49])[CH3:42]>>[CH2:41]([O:43][C:44](=[O:50])[CH2:45][CH2:46][NH:47][C:48]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=4)[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)=[O:49])[CH3:42]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCOC(=O)CCN=C=O
Product: CCOC(=O)CCNC(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 3-isocyanato-propionic acid ethyl ester (244 μl) instead of isocyanato-acetic acid ethyl ester, in the same manner as Example 1-D-29 in Step A, a crude product of the desired compound was obtained (114 mg, quant.).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[Cl:25].[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[Cl:25][C:3]1[C:2]([C:31]2[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[N:7][C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(Cl)c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2Cl)cn1
Temperature: 120 °C
Yield: 51.1 %

Procedure:
N-(6-Bromo-5-chloropyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (259 mg, 0.600 mmol) was dissolved in 6 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. 6-Methoxypyridin-3-ylboronic acid (138 mg, 0.900 mmol), 0.6 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 34.7 mg, 0.0300 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The crude product was evaporated to dryness and then purified on 40 g of silica gel utilizing a gradient of 0-100% ethyl acetate in hexanes to yield N-(3-chloro-6′-methoxy-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane carboxamide (141 mg, 51%) as a colorless oil. ESI-MS m/z calc. 459.1. found; 459.9 (M+1)+ Retention time 2.26 minutes.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:35]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:36])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: NCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)N1CCOCC1
Product: Nc1nc2ccccc2c2c1nc(CCCOc1ccccc1)n2CCCNC(=O)N1CCOCC1
Yield: 69.3 %

Procedure:
Using the general method of Example 150, 1-(3-aminopropyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 5.32 mmol) was reacted with 4-morpholinecarbonyl chloride (880 mg, 5.86 mmol) to provide 1.8 g of N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide as a light yellow crystalline solid, m.p. 198.8-199.9° C. Analysis: Calculated for C27H32N6O3: % C, 66.37; % H, 6.60; % N, 17.20. Found: % C, 66.31; % H, 6.70; % N, 17.40.
Reaction SMILES: [NH2:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:21](Cl)(=O)[CH:22]([CH3:24])[CH3:23]>>[CH3:21][CH:22]([C:24]1[O:20][C:19]2[C:2]([N:1]=1)=[CH:3][C:4]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=1[CH:18]=2)[CH3:23]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Product: CC(C)c1nc2cc3c(cc2o1)CCNCC3

Procedure:
The title compound was prepared as described in General Procedure 2 from 1,1-dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate and isobutyryl chloride.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]C(C)=O)=[CH:7][CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>O1CCCC1>[CH2:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CC(=O)Nc1ccc(OC(C)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCNc1ccc(O)cc1
Yield: 61.9 %

Procedure:
Five g of this 4-acetoxyacetanilide (0.0259 moles) was dissolved in 200 ml of dry tetrahydrofuran (THF). To this mixture was added slowly, over one-half hour, 1.97 g (0.0518 moles) of lithium aluminum hydride. After the addition of this reagent, the reaction was refluxed for three hours, cooled, and saturated ammonium chloride solution was slowly added. The resultant mixture was filtered, evaporated to dryness and the remaining oil was dissolved in dilute HCl. This solution was extracted with chloroform several times. The remaining aqueous phase was made basic with sodium carbonate to achieve approximately pH 10 and extracted once again with chloroform. The chloroform solution was dried over anhydrus magnesium sulfate and evaporated to dryness. This acid/base extraction procedure was repeated several time to yield 2.2 g of p-ethylaminophenol, as an oil which solidified upon standing.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:23]([CH:30](C(OCC)=O)[C:31]([O:33]CC)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=2)[C:7]([CH2:10][CH:30]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:31]([OH:33])=[O:32])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Product: CCCCc1ncc(CC(Cc2ccccc2)C(=O)O)n1Cc1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared following the procedure of Example 21 using 2-n-butyl-1-[(4-carbomethoxyphenyl)methyl]-1H-imidazol-5-carboxaldehyde and diethyl benzylmalonate; mp 120°-124° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].C(OC(=O)C)C>O1CCOCC1.C(O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH:21]=[C:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[N:5]3)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Brc1ccc2nccnc2c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3nccnc3c2)CC1
Temperature: 160 °C

Procedure:
A solution containing 6-bromo-quinoxaline (417 mg, 2.0 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (600 mg, 1.94 mmol), tetrakis [triphenylphosphine] palladium (108 mg, 0.1 mmol) and sodium carbonate (2 M solution, 3 mL) in 5 mL of dioxane/ethanol/water (7:3:1) was heated at 160° C. using microwave reactor for 15 minutes. After the reaction, ethylacetate was added and the mixture was filtered, washed with water. After concentration under vacuum, the product was purified using column chromatography (5% methanol in dichloromethane)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[C:25]1([CH3:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1CCCCC1>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH:28]1[CH:29]=[C:30]2[CH:1]=[CH:2][C:7]([OH:8])=[C:31]([C:19]3[C:20]4[C:15](=[CH:11][CH:5]=[CH:6][CH:10]=4)[CH:16]=[CH:17][C:18]=3[OH:22])[C:25]2=[CH:26][CH:27]=1
Reactant: Cc1ccccc1
Agent: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Solvent: C1CCCCC1
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Temperature: 52.5 °C

Procedure:
S-1,1′-bi-2-naphthol (124 gm) was added to a solution of omeprazole (100 gm) in a mixture of toluene and cyclohexane (2000 ml, 4:1) at room temperature. The reaction mixture was heated to 50 to 55° C. and maintained for 1 hour at 50 to 55° C. The solution was cooled to room temperature and filtered, washed with a mixture of toluene and cyclohexane (200 ml, 4:1). The solid was dried at 45 to 50° C. under vacuum for 4 hours to obtain 80 gm of esomeprazole-S-BINOL complex.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32](=[O:48])[CH2:33][C:34]1[CH:35]=[C:36]([C:40]2[CH:45]=[CH:44][C:43]([CH:46]=O)=[CH:42][CH:41]=2)[CH:37]=[CH:38][CH:39]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:46][C:43]3[CH:44]=[CH:45][C:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([CH2:33][C:32]([OH:48])=[O:31])[CH:35]=4)=[CH:41][CH:42]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1cccc(-c2ccc(C=O)cc2)c1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)Cc1cccc(-c2ccc(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and (4′-formylbiphenyl-3-yl)-acetic acid methyl ester. MS (ESI) m/z 615.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].Br.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22]Br)[CH:15]=1>C(O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCCc1cccnc1
Agent: Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCc1cccnc1)C(=O)OCC

Procedure:
To a solution of 48 mL (0.37 mole) of diethyl malonate in 960 mL ethanol is added 14.03 g (0.61 mole) sodium metal and the mixture is stirred until all of the metal dissolved. The solution is heated to reflux and a solution of 80.04 g (0.28 mole) of 3-(3-pyridyl)-propyl bromide hydrobromide in 960 mL ethanol is added rapidly and the mixture is maintained at reflux for 10 hours. The reaction mixture is evaporated and the residue is taken up in 400 mL of 1N aqueous hydrochloric acid and washed with 400 mL hexane. The aqueous phase is adjusted to pH 8 using solid sodium bicarbonate. The mixture is then extracted with methylene chloride (3×200 mL). Combined organic extracts are dried (MgSO4), filtered and evaporated to dryness to give diethyl [3-(3-pyridyl)-propyl]-malonate as an oil.