Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C:10]([CH3:15])([CH3:14])[CH2:9]1)=O)(C)(C)C.[CH:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH2:17]>CO>[CH3:21][S:18]([CH2:16][CH2:17][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:14])[CH3:15])(=[O:20])=[O:19]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: C=CS(C)(=O)=O
Solvent: CO
Product: CC1(C)CNCCN1CCS(C)(=O)=O
Temperature: 65 °C
Reaction time: 96 h

Procedure:
A mixture of 3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.33 mmol) and methyl vinyl sulfone (510 μL, 619 mg, 5.83 mmol) in MeOH (15 mL) was heated to 65° C. for 5.5 h then stirred at room temperature for 96 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-3%) affording 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine as a white waxy solid (550 mg, 74%). 1H NMR (CDCl3, 300 MHz): δ 3.47-3.40 (m, 2 H); 3.15 (s, 2 H); 3.09 (t, J=6.4 Hz, 2 H); 3.03 (s, 3 H); 2.89 (t, J=6.4 Hz, 2 H); 2.58-2.50 (m, 2 H); 1.45 (s, 9 H); 1.04 (s, 6 H).
Reaction SMILES: [C:1]1([C:7]([CH3:18])([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:8][CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C)(C)C.N.[H][H]>[Ru].[Pd].O>[C:1]1([C:7]([CH3:18])([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CC(CCCC#N)(CCCC#N)c1ccccc1
Agent: [Pd]
Agent: [Ru]
Agent: N
Solvent: O
Solvent: CC(C)(C)O
Product: CC(CCCCN)(CCCCN)c1ccccc1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
A one liter autoclave was charged with 50 g 0.21 mol of a dinitrile consisting essentially of 5-phenyl-5-methylnonanedinitrile. Also charged to the reactor was 300 mL 237 g t-butyl alcohol, 25 mL water, 5 g of 5 percent by weight ruthenium on alumina, and 2 g of 5 percent by weight palladium on alumina. The reactor was flushed with nitrogen and charged with 70 g 4.1 mol of ammonia. The reactor was pressured to 1200 psig with hydrogen and heated with stirring at 170° C. for two hours. Hydrogen uptake indicated only reduction of nitrile groups to amino groups had taken place thus producing the aralkylenediamine, 5-phenyl-5-methyl-1,9-nonanediamine.
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:10]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[N:19]=[C:18]([S:25][CH3:26])[N:17]=3)=[CH:14][CH:15]=2)=[CH:9][C:8]([C:27]([F:30])([F:29])[F:28])=[C:7]([C:31]#[N:32])[C:6]1=[O:33].[OH2:39].[OH2:40].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2].C1C=C(C([O-])=O)C(C(O[O-])=O)=CC=1.[Mg+2]>ClCCl.CO>[F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:10]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[N:19]=[C:18]([S:25]([CH3:26])(=[O:40])=[O:39])[N:17]=3)=[CH:14][CH:15]=2)=[CH:9][C:8]([C:27]([F:29])([F:30])[F:28])=[C:7]([C:31]#[N:32])[C:6]1=[O:33]
Reactant: O
Reactant: CCOc1cc(-c2ccc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)s2)nc(SC)n1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: CCOc1cc(-c2ccc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)s2)nc(S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
1-(2,4-Difluoro-benzyl)-6-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydropyridine-3-carbonitrile (49 mg, 0.087 mmol) was dissolved in a mixture of dichloromethane (2 mL) and methanol (0.4 mL). To this solution was added magnesium monoperoxyphthalate hexahydrate, MMPP, (108 mg, 0.218 mmol, 80% tech.) and the mixture was stirred at ambient temperature for overnight. After this period the reaction mixture was combined with dichloromethene (20 mL) and was washed with 1M NaHCO3 (2×10 mL), and brine (10 mL). The resulting organic layer was separated and dried over anhydrous Na2SO4 and evaporated in vacuo to yield crude product. The crude product was purified using flash silica chromatography (25-50% EtOAc/Hexane) to yield 1-(2,4-difluorobenzyl)-6-[5-(6-ethoxy-2-methanesulfonyl-pyrimidin-4-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (42 mg, 80%) as a yellow solid. 1H-NMR (CDCl3): δ 7.72 (m, 1 H), 7.14 (m, 1 H), 7.13 (m, 1 H), 7.07 (s, 1 H), 6.88 (m, 1 H), 6.78 (m, 1 H), 6.63 (s, 1 H), 5.40 (s, 2 H), 4.61 (q, J=7.1 Hz, 2 H), 3.36 (s, 3 H), 1.46 (t, J=7.1 Hz, 3 H). MS(ES+): 597.2 (M+H).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[S:23]([CH2:26][C@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])(=[O:25])=[O:24]>C(Cl)Cl>[C:9]1([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[NH:1][S:23]([CH2:26][C@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])(=[O:25])=[O:24])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@@H](C)CS(=O)(=O)Cl
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](C)CS(=O)(=O)NC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 1 g aminodiphenylmethane, 2 mL triethylamine in 20 mL CH2Cl2. The reaction was cooled to 0° C. and 1 g of methyl 3-chlorosulfonyl-2(R)-methylpropionate was slowly added. The reaction was stirred 1 hour then concentrated in vacuo. The residue was partioned between ethyl acetate and water. The organic phase was washed with brine, dried, and concentrated in vacuo. Trituration from Et2O/hexanes gave 1.15 g of methyl 3-[N-(diphenylmethyl) aminosulfonyl]-2(R)-methylpropionate as a white solid. HRMS (M+Li): calcd. 354.1351, obs 354.1569.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[C:4](/[C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)=[N:5]\[O:6][CH2:7][CH2:8][CH3:9].[Cl:17][CH2:18][C:19](Cl)=[O:20]>>[CH3:1][O:2][C:3](=[O:16])/[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:19](=[O:20])[CH2:18][Cl:17])[S:13][CH:14]=1)=[N:5]\[O:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C(Cl)CCl
Reactant: CCCO/N=C(\C(=O)OC)c1csc(N)n1
Product: CCCO/N=C(\C(=O)OC)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a solution of 5.0 g of 2-(2-amino-4-thiazolyl)-(Z)-2-(n-propoxyimino)acetic acid methyl ester in 35 ml of N,N-dimethylacetamido is added dropwise under ice-cooling and stirring 3.25 g of chloroacetyl chloride in the course of 10 minutes. The mixture is stirred for one hour at room temperature, then poured into 200 ml of ice-water, whereupon an oily product separates out, which is left standing to crystallize. The crystals are collected by filtration, washed with water and dried to yield 6.35 g (96.7%) of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(n-propoxyimino)-acetic acid methyl ester, m.p. 100° C.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[F:31][C:32]([F:47])([F:46])[S:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>O1CCCC1.O>[C:1]1([C:7]2[N:11]([S:42]([C:39]3[CH:38]=[CH:37][C:36]([S:33]([C:32]([F:47])([F:31])[F:46])(=[O:35])=[O:34])=[CH:41][CH:40]=3)(=[O:44])=[O:43])[CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(S(=O)(=O)C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 60 mg) was added, and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (0.30 mL) was added and the mixture was further stirred at the same temperature for 15 min. 4-[(Trifluoromethyl)sulfonyl]benzenesulfonyl chloride (432 mg) was added and the reaction mixture was stirred at room temperature for 30 min. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and 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=9:1→4:1) to give 5-phenyl-1-({4-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrole-3-carbaldehyde (191 mg) as an orange solid. The obtained 5-phenyl-1-({4-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrole-3-carbaldehyde (191 mg) was subjected to a similar operation as in the synthesis of Example 179 to give the title compound as a solid (yield 86 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][CH3:18])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[N:30]1([C:35]2[CH:40]=[C:39]([CH2:41][NH2:42])[CH:38]=[C:37]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=3)[N:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:17][CH3:18])[C:12](=[CH2:16])[C:13]([NH:42][CH2:41][C:39]2[CH:38]=[C:37]([C:43]3[CH:44]=[CH:45][C:46]([C:49]([F:52])([F:50])[F:51])=[CH:47][CH:48]=3)[N:36]=[C:35]([N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[CH:40]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
Acid 4D (289.74 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.15 ml) and [2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27A (1.1 equiv., 353.47 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:petroleum ether) afforded 140 mg of a pale yellow solid. Yield=23.6% 1HNMR (DMSO, 200 MHz) δ 1.09 (3H, t), 1.91 (4H, m), 3.38 (6H, m), 4.40 (2H, d), 5.17 (1H, s), 6.11 (1H, d), 6.34 (1H, s), 7.19 (1H, s), 7.78 (6H, m), 8.28 (2H, d), 8.80 (1H, bt) [M+1] 593.9 (C28H28ClF3N4O3S requires 593.06).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([OH:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([O:25][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:14][CH:13]=2)=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(O)ccc2c1=O
Reactant: COC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Oc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
To a solution of tert-butyl[6-hydroxy-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.42 g, 1 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (48 mg, 1.2 mmol) (60% in oil). The resulting mixture was stirred at 0° C. for 10 min. To the mixture was added methyl 2-bromoisobutyrate (0.22 g, 1.2 mmol), and the mixture was stirred at room temperature for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoate (0.31 g, 59.6%) as crystals.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH:36]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=[C:32]1[C:30]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[C:19]([NH:18][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([F:8])=[CH:10][CH:11]=2)[CH:31]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1NC(=O)c1ccc(F)cc1
Reaction time: 5 h

Procedure:
0.054 mL of triethylamine and 0.035 mL of 4-fluorobenzoyl chloride were added to 3.5 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-(benzofuran-2-yl)benzoate at room temperature sequentially and stirred at the same temperature for 5 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 4-(benzofuran-2-yl)-2-(4-fluorobenzamido)benzoate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][SH:4].[NH2:5][C:6]1[CH:11]=[N:10][C:9](Br)=[CH:8][N:7]=1>CN(C)C=O.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>[NH2:5][C:6]1[N:7]=[CH:8][C:9]([S:4][CH2:3][CH2:2][OH:1])=[N:10][CH:11]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OCCS
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cnc(SCCO)cn1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
According to the method described in WO2004/052869, 2-hydroxy-1-ethanethiol (0.93 mL) and tetrakis(triphenylphosphine)palladium (3.39 g) were added to a solution of 2-amino-5-bromopyrazine (1.00 g, 5.75 mmol) in N,N-dimethylformamide (15.1 mL), and the mixture was heated and stirred at 120° C. in a sealed tube for about 3 hours. After cooling, the reaction mixture was diluted with water and extracted with a mixed solution (dichloromethane:ethanol=5:1) (100 mL×6). The organic layer was dried over anhydrous sodium sulfate and then filtrated, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate, and then ethyl acetate:methanol=10:1) and was recrystallized (using chloroform) to give the title compound as yellow needle crystals (470 mg, yield: 44%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][C:28]([C:30]5[N:35]=[CH:34][CH:33]=[CH:32][N:31]=5)=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:42][NH2:43]>O1CCOCC1>[NH:42]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][C:28]([C:30]5[N:35]=[CH:34][CH:33]=[CH:32][N:31]=5)=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2)[NH2:43]
Reactant: NN
Reactant: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ncccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Solvent: C1COCCO1
Product: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ncccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
To a stirred solution of 11-2 (0.4 g, 0.7 mMol) in anhydrous 1,4-dioxane (3 mL) was added hydrazine (0.45 mL, 14.5 mMol). The solution was heated to 100° C. in a microwave reactor for 5 minutes. The solvent was removed in vacuo and was dried azeotropically with toluene three times to yield 11-3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([Cl:18])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Nitrophenyl)propanoic acid prepared in Example DD (12.5 g, 64 mmol) was suspended in CH2Cl2 (300 mL) and treated with oxalyl chloride (7.4 mL, 85 mmol) and DMF (5 drops). The solution was stirred overnight at room temperature. The solution was concentrated, and the residue was dissolved in CH2Cl2 and re-concentrated. The crude product was used as is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O)=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:26].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][CH2:16][CH2:17][NH2:18])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:26]
Reactant: COC(=O)CC1Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2NC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC1Cc2ccc(OCCN)cc2NC1=O
Reaction time: 18 h
Yield: 100.4 %

Procedure:
[7-(2-tert-Butoxycarbonylamino-ethoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester (2.5 g, 6.6 mmol) and trifluoroacetic acid (5.1 mL, 66 mmol) were combined in methylene chloride (25 mL) at 25° C. After 18 h, the solution was concentrated in vacuo to give the title compound as a tan solid (2.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@H:50]([NH2:52])[CH3:51])[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C.CCOC(C)=O>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@H:50]([NH:52][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:51])[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)c1ccc(OC[C@@H](C)N)c(OC)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC[C@@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a stirred solution of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (459 mg, 0.96 mmol) and ethyl (R)-3-methoxy-4-(2-aminopropoxy)benzoate (242 mg, 0.96 mmol) in DMF (5 mL) was added Et3 N (200 μl, 1.43 mmol), and the resulting mixture was stirred for 2 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 360 mg (69%) ethyl (R)-3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a colorless crystalline solid. 1H-NMR (CDCl3) δ 1.23–1.28 (m, 3 H), 1.38–1.41 (t, 3 H, J=7.3 Hz), 2.32 (s, 3 H), 3.50–4.13 (m, total 11 H), 4.36 (q, 2 H, J=7.3 Hz), 6.65–8.13 (series of m, total 12 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][O:20]2)=[C:15]([OH:22])[CH:14]=1)(=[O:12])=[O:11].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:21][OH:20])=[C:15]([OH:22])[CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)c(O)c2)c(C)c1
Reactant: C1COCCN1
Solvent: CCO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(CO)N3CCOCC3)c(O)c2)c(C)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a stirred solution of N-(2,4-dimethylphenyl)-3-hydroxy-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (60 mg, 0.160 mmol) in ethanol (1 mL) at 25° C. was added morpholine (30.6 mg, 0.352 mmol) and the reaction mixture stirring at 50° C. for 12 hours. The reaction mixture was then concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give a single regioisomer of the desired product, 11.2 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 463 (M+H).
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][O:21][CH3:22].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccccc1
Yield: 61 %

Procedure:
Using the general method of Example 242, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with benzenesulfonyl chloride (993 mg, 5,62 mmol) to provide 1.37 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}benzenesulfonamide as a white powder, m.p. 149-151° C. Analysis: Calculated for C22H25N5O3S: % C, 60.12; % H, 5.73; % N, 15.93; Found: % C, 60.40; % H, 5.82; % N, 15.85.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:25])([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2].[CH2:27]([SH:31])[CH2:28][CH2:29][SH:30].B(F)(F)F.CCOCC>ClCCl>[CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:25])([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:22])[CH3:21])[S:31][CH2:27][CH2:28][CH2:29][S:30]1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC(C)(C)C(=O)OCC
Reactant: SCCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)CCCCC1(CCCCC(C)(C)C(=O)OCC)SCCCS1
Reaction time: 3 h
Yield: 80.4 %

Procedure:
Under N2 atmosphere, to a solution of 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid diethyl ester (1.0 g, 2.70 mmol) and 1,3-propanedithiol (361 mg, 361 L, 3.24 mmol) in dichloromethane (20 mL; dried with Aluminum oxide, activated, neutral, Brockman I) was added boron trifluoride diethyl etherate (100 L) at rt. The reaction mixture was stirred for 3 h, diluted with dichloromethane (100 mL), and extracted with 5% NaOH solution (100 mL) and water (75 mL). The organic phase was dried over MgSO4, concentrated in vacuo, and dried in high vacuo to furnish 6-[2-(5-ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoic acid ethyl ester (1.0 g, 80%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): (ppm): 4.11 (q, 4H, J=7.1), 2.79 (t, 4H, J=5.6), 1.94 (m, 2H), 1.84 (m, 4H), 1.54 (m, 4H), 1.39 (m, 4H), 1.24 (t, 6H, J=7.1), 1.30-1.20 (m, 4H), 1.16 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): (ppm): 178.08, 60.33, 53.32, 42.27, 40.69, 38.28, 26.14, 25.67, 25.28, 24.71, 14.41. HRMS (LSIMS, nba): Calcd. for C24H45S2O4 (MH4): 461.2759, found 461.2774.