Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])([OH:4])(=[O:3])=[O:2].[Na].[OH-].[Na+:10].[OH:11][CH2:12][CH:13]([CH2:15]O)[OH:14].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[OH:14][CH:13]([CH2:12][OH:11])[CH2:15][O:7][CH2:6][CH2:5][S:1]([O-:4])(=[O:3])=[O:2].[Na+:10]
Reactant: O=S(=O)(O)CCO
Reactant: OCC(O)CO
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCOCC(O)CO
Temperature: 200 °C

Procedure:
To a 500 ml, three neck, round bottom flask equipped with a magnetic stirring bar, modified Claisen head, condenser (set for distillation), thermometer, and temperature controller (Therm-O-Watch™, I2R) is added isethionic acid, sodium salt (Aldrich, 50.0 g, 0.338 mol), sodium hydroxide (2.7 g, 0.0675 mol), and glycerin (Baker, 310.9 g, 3.38 mol). The solution is heated at 190° C. under argon overnight as water distills from the reaction mixture. A 13C-NMR(DMSO-d6) shows that the reaction is complete by the virtual disappearance of the isethionate peaks at ~53.5 ppm and ~57.4 ppm, and the emergence of product peaks at ~51.4 ppm (--CH2SO3Na) and ~67.5 ppm (CH2CH2SO3Na). The solution is cooled to ~100° C. and neutralized to pH 7 with methanesulfonic acid (Aldrich). The desired, neat material is obtained by adding 0.8 mol % of potassium phosphate, monobasic as buffer and heating on a Kugelrohr apparatus (Aldrich) at 200° C. for ~3 hrs. at ~1 mm Hg to afford 77 g of yellow waxy solid. As an alternative, not all of the glycerin is removed before use in making the oligomers. The use of glycerin solutions of SEG can be a convenient way of handling this sulfonated monomer.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2C(OC(C)(C)C)=O)=[O:8])=[CH:3][CH:2]=1.Cl.CCN(C(C)C)C(C)C.[CH3:32][N:33]1[CH:37]=[C:36]([S:38](Cl)(=[O:40])=[O:39])[N:35]=[CH:34]1>O1CCOCC1>[CH3:32][N:33]1[CH:37]=[C:36]([S:38]([N:12]2[CH2:13][CH2:14][CH:9]([C:7]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][N:5]=3)=[O:8])[CH2:10][CH2:11]2)(=[O:40])=[O:39])[N:35]=[CH:34]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1cnc(S(=O)(=O)N2CCC(C(=O)c3ccccn3)CC2)c1
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 6 (950 mg, 3.27 mmol) in 1,4-dioxane (5 mL) was added 4 N HCl in dioxane (10 mL) and stirred for 1 h. The solvent was removed under vacuum. The residue was dissolved in CH2Cl2 (10 mL), added DIPEA (1.94 mL, 10.8 mmol) and 1-methylimidazole-4-sulfonyl chloride (589 mg, 3.27 mmol). The reaction was stirred for 18 h at room temperature. The reaction mixture was washed with 2 N NaOH (10 mL), dried over MgSO4 and concentrated under vacuum to afford 7 as a light orange oil (920 mg, 84%); 1H-nmr (400 MHz, CDCl3) δ 8.63 (d, J=5.0 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.85 (td, J=8.0, 1.5 Hz, 1H), 7.50 (s, 1H), 7.48 (dd, J=8.0, 1.5 Hz, 1H), 7.44 (s, 1H), 4.00-3.82 (m, 3H), 3.77 (s, 3H), 2.86 (t, J=11.0 Hz, 2H), 2.04-1.96 (m, 2H), 1.91-1.78 (m, 2H); m/z 335.1 [M+H].
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][OH:16])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:16][CH2:15][C:11]1([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: OCC1(O)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: OCC1(O)CCNCC1

Procedure:
A suspension of 26.0 g (117 mmol) 1-benzyl-4-hydroxymethyl-piperidin-4-ol and 5.0 g 10% Pd/C in 500 mL MeOH was hydrogenated at 50° C. and 3 bar hydrogen pressure until the theoretical hydrogen uptake had occurred (4 h). The catalyst was filtered off and washed with MeOH. After the solvent had been eliminated the residue was reacted further without purification.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31](=[O:33])[NH2:32])[CH:20]=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:31]([NH2:32])=[O:33])[CH:20]=[C:19]1[CH3:34])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: C=CCON([C@H]1CN[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 20, 2.16 g, 4.35 mmol) in DCM (20 mL) at room temperature was added zinc bromide (0.700 mL, 13.05 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated to afford the desired product (1.450 g, 84%) as a yellow foam.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:7]=1[CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:5])=[O:4])[CH3:2]>CO.CCOC(C)=O.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[C:7]([CH:18]=1)[CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCS(=O)(=O)c1ccc(N)cc1CN(C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 3A (2.2 g, 6.14 mmol) in MeOH (50 ml) and EtOAc (50.0 ml) was added 10% Pd on carbon (0.653 g, 0.614 mmol) and the mixture was stirred under a hydrogen balloon for 2 h. Pd/C was removed by filtration. The filtrate was concentrated to give 3B that was used for next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.75 (d, J=8.35 Hz, 1H) 6.58-6.67 (m, 1H) 6.52 (s, 1H) 4.78 (s, 2H) 3.04-3.13 (m, 2H) 2.94 (s, 3H) 1.45 (d, J=39.11 Hz, 9H) 1.26 (t, J=7.47 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:10](=[O:12])[CH3:11])=[C:3]([OH:9])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)Nc1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a suspension of 2-amino-5-chlorophenol (1.01 g, 7.0 mmol) in methanol (10 mL) was added acetic anhydride (1.08 g, 10.55 mmol) and the reaction mixture was stirred at room temperature for 30 min. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (hexane:ethyl acetate 5:2) to give the subtitled compound (1.19 g).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH:12]([C:15]1[C:20]([CH2:21][OH:22])=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:18]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:17]([CH:35]([CH3:37])[CH3:36])[N:16]=1)([CH3:14])[CH3:13]>C(Cl)Cl>[CH:12]([C:15]1[C:20]([CH:21]=[O:22])=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:18]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:17]([CH:35]([CH3:36])[CH3:37])[N:16]=1)([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.18 g (0.139 mol) of neutral Al2O3 and 29.96 g (0.13 mol) of pyridinium chlorochromate (PCC) are added to a solution of 25.0 g (0.0695 mol) of the compound from Example IX in 500 ml CH2Cl2 and the mixture is stirred for 1 h at room temperature. It is drawn off by suction over silica gel and subsequently washed with CH2Cl2, and the filtrate is concentrated in a vacuum, whereby the product precipitates out.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1.P1(Cl)(=O)OC2C=CC=CC=2O1.[C:19]1([CH:25]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[O:26][C:27]([CH:29]([N:63]2[C:67](=[O:68])[C:66]3=[CH:69][CH:70]=[CH:71][CH:72]=[C:65]3[C:64]2=[O:73])[CH2:30][CH2:31][CH2:32][C:33]([NH:35][C@@H:36]2[C:61](=[O:62])[N:38]3[C:39]([C:45]([O:47][CH:48]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:46])=[C:40]([CH2:43]O)[CH2:41][S:42][C@H:37]23)=[O:34])=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(Cl)Cl>[C:19]1([CH:25]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[O:26][C:27]([CH:29]([N:63]2[C:67](=[O:68])[C:66]3=[CH:69][CH:70]=[CH:71][CH:72]=[C:65]3[C:64]2=[O:73])[CH2:30][CH2:31][CH2:32][C:33]([NH:35][C@@H:36]2[C:61](=[O:62])[N:38]3[C:39]([C:45]([O:47][CH:48]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)=[O:46])=[C:40]([CH2:43][S:1][C:2]4[N:6]([CH3:7])[N:5]=[N:4][N:3]=4)[CH2:41][S:42][C@H:37]23)=[O:34])=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cn1nnnc1S
Reactant: O=C(CCCC(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)c2ccccc2C1=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Agent: O=P1(Cl)Oc2ccccc2O1
Solvent: ClCCl
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)CCCC(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
In 5 ml of methylene chloride was dissolved 0.195 g of 5-mercapto-1-methyl-1H-tetrazole and the solution was cooled to -10° C. Then, a solution of 0.268 g of o-phenylene phosphorochloridate in 5 ml of methylene chloride was added and, under cooling at -20° to -25° C., a solution of 1.170 g of diphenylmethyl 7β-(5-diphenylmethyloxycarbonyl-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylate in 8 ml of methylene chloride was added dropwise. The mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added 10 ml of water and, then, the mixture was allowed to stand at room temperature for phase separation. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated and poured into 80 ml of ether. The powdery precipitate was collected by filtration and subjected to silica gel column chromatography (silica gel: 30 g, column height: 36 cm), elution being carried out with ethyl acetate-n-hexane (4:1). The fractions were checked by TLC (developing solvent: the same as the above eluent) and the fractions (Rf : about 0.71) containing the desired product were collected and concentrated. To the concentrate was added ether to give diphenylmethyl 7β-(5-diphenylmethyloxycarbonyl-5-phthalimidovaleramido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[O:23]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:31]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.28 mmol) in acetonitrile (20 ml) were added 3-phenoxybenzoic acid (274 mg, 1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (368 mg, 1.92 mmol) and 1-hydroxy-1H-benzotriazole (196 mg, 1.28 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (400 mg, 61%).
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH:19]([CH3:21])[CH3:20])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])[CH:19]([CH3:21])[CH3:20])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCCBr
Reactant: CC(C)[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](C(C)C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 14 (447 mg, 1.59 mmol) and 1-bromopentadecane (1.16 g, 4.0 mmol), alcohol 68 was obtained as a colorless oil (340 mg, 43% yield).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:29])[C@@H:16]2[CH2:20][C@@H:19](O)[CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]([N:57]1[C:62](=[O:63])[C:61]([CH3:64])=[CH:60][NH:59][C:58]1=[O:65])(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]1([CH:7]([O:14][C:15](=[O:29])[C@@H:16]2[CH2:20][C@H:19]([N:59]3[CH:60]=[C:61]([CH3:64])[C:62](=[O:63])[N:57]([C:49](=[O:56])[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:58]3=[O:65])[CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: Cc1c[nH]c(=O)n(C(=O)c2ccccc2)c1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@@H](C(=O)OC(c3ccccc3)c3ccccc3)N(C(=O)OC(C)(C)C)C2)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: -15 °C

Procedure:
N-Boc-trans-4-hydroxy-Lroline diphenylmethyl ester (2a) (0.425 g, 1.07 mmol), triphenylphosphine (0.290 g, 1.10 mmol) and N3-benzoylthymine (0.250 g, 1.09 mmol) were dissolved in dry THF (10 ml) and the solution was cooled to −15° C. DEAD (180 μL, 1.10 mmol) was then added dropwise with stirring. The reaction mixture was stirred under argon at room temperature overnight. The solvent was evaporated and the residue was chromatographed on silica gel using dichloromethane-acetone 20:1 as eluant to give N-tert-butoxycarbony-cis-4-(N3-benzoylthymin-1-yl)-L-proline diphenylmethyl ester (3a) (Rf 0.56), which was recrystallised from ethanol to give a white fluffy solid (0.310 g, 51%), m.p. 183-185° C., (Found C, 68.9; H, 5.5; N, 6.7%; C35H35N3O7 requires C, 69.0; H, 5.8; N, 6.9%), δH (200 MHz; CDCl3) 1.30 and 1.49 (9H, 2xbr s, Boc rotamers), 1.82 (3H, br s, thymine CH3), 2.05 and 2.85 [2H, br m, CH2(3′)], 3.65 (1H, br m) and 4.02 (1H, dd, J=12.0, 8.0 Hz)[CH2(5′)], 4.54 [1H, br m, CH(2′)], 5.26 [1H, br m, CH(4′)], 6.94 (1H, s, CHPh2), 7.12 and 7.18 [1H, 2xbr s, CH(6) rotamers], 7.30-7.42 (10H, br m, phenyl CH), 7.50 (2H, t, J=7.9 Hz, benzoyl m-CH), 7.67 (1H, t, J=7.0 Hz, benzoyl p-CH), 7.92 (2H, d, J=7.0 Hz, benzoyl o-CH); δC (50.28 MHz; CDCl3) 12.3 (thymine CH3), 27.9 and 28.2 (Boc CH3 rotamers), 34.9 and 35.3 [CH2(3′) rotamers], 49.3 and 49.4 [CH2(5′) rotamers], 52.1 and 52.5 [CH(4′) rotamers], 57.5 [CH2(2′)], 78.1 and 78.4 (CHPh2 rotamers), 81.3 (Boc C), 111.7 [C(5)], 126.9-130.6 (aromatic CH), 131.6 (benzoyl C), 135.3 (benzoyl p-CH), 136.0 and 136.2 [CH(6) rotamers], 139.4 (phenyl C), 150.1 [C(2)], 153.6 (Boc CO), 162.6 [C(4)], 169.1 (benzoyl CO), 171.6 (ester CO); m/z (FAB+) 632 (M+Na+, 10%), 610 (M+H+, 39), 554 ([M−C4H8+H]+, 27), 506 ([M−PhCO+H]+, 18), 338 ([M-PhCO-Ph2CH+, 20), 266 (31), 231 (BzT+H+, 52), 167 (Ph2CH+, 100), 105 (PhCO+, 24), 57 (C4H9+, 28); νmax (KBr)/cm31 1 1751, 1694 and 1659 (C═O); [α]D≅−17.2 (c=1.0, DMF).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[CH:24][C:25]([C:27]([OH:29])=O)=[CH:26][C:17]=4[C:16]=3[N:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:31]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:36][CH2:37][CH2:38][NH:39][C:27]([C:25]2[CH:24]=[CH:23][C:18]3[NH:19][C:20](=[O:22])[CH2:21][C:15]4[CH:14]=[N:13][C:12]([NH:11][C:5]5[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:30][C:16]=4[C:17]=3[CH:26]=2)=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)O)ccc2NC(=O)C3)cc1OC
Reactant: NCCCN1CCCC1
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)NCCCN4CCCC4)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described in Method N, 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic acid (I-43) and 3-(pyrrolidin-1-yl)propan-1-amine were converted to I-77 (6%) after purification by C-18 RP LC-MS chromatography. HRMS Calcd. for C28H32N6O4: 517.2563, Found 517.2552.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C@@H:7]([CH3:12])[CH2:6][C@H:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.C(N(CC)CC)C.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[Cl-].[NH4+]>ClCCl>[CH:28]1([C:34]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=3)[C@H:5]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:6][C@@H:7]2[CH3:12])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C[C@H]1C[C@@H](Nc2ccc(F)cc2)c2cc(F)ccc2N1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1C[C@@H](Nc2ccc(F)cc2)c2cc(F)ccc2N1C(=O)C1CCCCC1
Reaction time: 16 h
Yield: 17 %

Procedure:
88 mg of cis-6-fluoro-4-[(4-fluorophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 3 mL of dichloromethane, and 117 mg of triethylamine and 168 mg of cyclohexanecarbonyl chloride were added to the solution under ice cooling. The mixture was stirred for 16 hours under ice cooling. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction liquid, and the mixture was extracted with dichloromethane. Subsequently, the extraction product was dehydrated over anhydrous magnesium sulfate, and then was concentrated under reduced pressure. The resulting residue was subjected to recrystallization using chloroform, and thus 21 mg (17%) of the title compound was obtained as a colorless flake-shaped crystal.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[N:23]1([C:29]([N:31]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[CH2:34][CH:33]([C:47]([NH:49][CH2:50][C:51](=O)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=O)[CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCOCC1>[N:23]1([C:29]([N:31]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[CH2:34][CH:33]([C:47]3[S:10][C:51]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:50][N:49]=3)[CH2:32]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(CNC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1)c1ccccc1
Solvent: C1COCCO1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2ncc(-c3ccccc3)s2)C1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
600 mg (1.484 mmol) of Lawesson reagent were added to a solution of 300 mg (about 0.371 mmol) of the compound from Example 106A in 5 ml of dioxane. The reaction mixture was stirred at 50° C. for 5 h and, without any further purification, was purified by preparative HPLC. Yield: 5 mg (3% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[N:12][C:13](Cl)=[N:14][CH:15]=1>>[Br:9][C:10]1[CH:11]=[N:12][C:13]([O:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:14][CH:15]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Oc1ccc(Cl)nc1
Product: Clc1ccc(Oc2ncc(Br)cn2)cn1

Procedure:
6-Chloropyridin-3-ol (670 mg, 5.17 mmol) and 5-bromo-2-chloropyrimidine (1.0 g, 5.17 mmol) were reacted in analogy to example 2c. Yield: 1.02 g (69%), M+H+: 285.95.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH2:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:28][CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)CCCN
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Product: CN(C)CCCNc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cn1
Yield: 44 %

Procedure:
Following the procedure described above in Example 34, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile was reacted with N1,N1-dimethylpropane-1,3-diamine. The crude product was purified by flash column chromatography (15% methanol in methylene chloride) to give a yellow solid (0.040 g, 44%). 1H NMR (400 MHz, chloroform-D) δ ppm 1.8 (m, 2 H) 2.3 (s, 6 H) 2.4 (t, J=6.4 Hz, 2 H) 3.2 (t, J=6.6 Hz, 2 H) 3.5 (s, 1 H) 6.3 (s, 1 H) 7.1 (m, 2 H) 7.2 (t, J=8.6 Hz, 1 H) 7.3 (dd, J=6.3, 2.8 Hz, 1 H) 8.4 (s, 1 H) 9.0 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH:14]([CH3:16])[CH3:15].Cl.[CH3:19][O:20][NH2:21]>C(O)C>[CH:14]([C:13]1[N:21]([O:20][CH3:19])[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1)([CH3:16])[CH3:15]
Reactant: CON
Reactant: CC(C)C(=O)Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCO
Product: COn1c(C(C)C)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of N-(4-chloroquinolin-3-yl)-2-methylpropanamide (6.0 g, 24 mmol), O-methylhydroxylamine hydrochloride (2.5 g, 0.030 mol), and ethanol (75 mL) was heated at reflux for five hours, allowed to cool to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and the solution was washed with saturated aqueous sodium carbonate (2×50 mL) dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 4.9 g of 2-isopropyl-1-methoxy-1H-imidazo[4,5-c]quinoline as a dark oil.