Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([O:22][CH3:23])=[O:21])[CH:10]=2)=[CH:5][CH:4]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([N:13]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([O:22][CH3:23])=[O:21])=[N:12]1)(=[O:26])[CH3:25]
Reactant: COC(=O)c1ccccc1-c1cc(-c2ccc(OC)cc2)[nH]n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1-c1cc(-c2ccc(OC)cc2)n(C(C)=O)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g of 5-(4-methoxyphenyl)-3-(2-carbomethoxyphenyl)pyrazole, 3.5 g of acetic anhydride, and 25 ml of pyridine was allowed to stir overnight at 25°. The mixture was poured into 100 ml of ice water, and the product was extracted with benzene. Recrystallization from hexane-ethyl acetate (2:1) gave 1-acetyl-3-(2-carbomethoxyphenyl)-5-(4-methoxyphenyl)pyrazole, mp 119°-121°.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([CH2:20]O)=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[N:16]=2)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].C(N(S(F)(F)[F:33])CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([CH2:20][F:33])=[C:18]([C:22]([F:24])([F:25])[F:23])[N:17]([CH3:26])[N:16]=2)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)OC(=O)c1cc(-c2nn(C)c(C(F)(F)F)c2CO)c(F)cc1Cl
Solvent: ClCCl
Product: CC(C)OC(=O)c1cc(-c2nn(C)c(C(F)(F)F)c2CF)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.5 g 2-chloro-4-fluoro-5-[4-(hydroxymethyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzoic acid, 1-methylethyl ester in 50 ml methylene chloride was added 5 mL of diethyl aminosulfurtrifluoride and the solution stirred overnight at room temperature. The reaction mixture was poured onto ice water and the organic layer washed with brine, dried over anhydrous magnesium sulfate, filtered and the concd in vacuo to give 2-chloro-4-fluoro-5-[4-(fluoromethyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzoic acid, 1-methylethyl ester as a tan solid: mp 74° C.; 1HNMR (CDCl3) δ 8.02 (d, 1H, J=8.0), 7.30 (d, 1H, J=9.6), 5.29 (d, 2H, J=48.0), 5.26 (m, 1H, J=6.0), 4.09 (s, 3H), 1.37 (d, 6H, J=6.4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[CH2:10].[Cu][C:12]#[N:13].Cl>CN(C)C=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[C:3]([CH:9]=[CH2:10])[CH:4]=1
Reactant: N#C[Cu]
Reactant: C=Cc1cc(F)ccc1Br
Agent: Cl
Solvent: CN(C)C=O
Product: C=Cc1cc(F)ccc1C#N
Temperature: 200 °C
Yield: 60.5 %

Procedure:
4.0 g 1-Bromo-4-fluoro-2-vinyl-benzene and 1.87 g copper (I) cyanide were dissolved in 16 ml dimethylformamide and heated under microwave irradiation at 200° C. for 25 minutes. The cooled reaction mixture was poured into 200 ml 1 M HCl and extracted five times with portions of 60 ml ethyl acetate. The combined organic layers were washed with 100 ml 1 N HCl, dried over MgSO4, then the solvent was removed in vacuo and the resulting residue purified on silica gel with the eluent heptane=>n-heptane:ethyl acetate=6:1 to obtain 1.77 g 4-Fluoro-2-vinyl-benzonitrile as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:7][C:6]([N:15]([CH3:24])[C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[CH2:16]([N:15]([CH3:24])[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:8][C:3]([N:2]([CH3:31])[CH3:1])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][CH2:5]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)C1(c2ccccc2)CCC(c2ccccc2)(N(C)C(=O)c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(c2ccccc2)(N(C)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The title compound from step 1 (160 mg, 0.387 mmol) was dissolved in abs. THF (15 mL) and mixed with LiAlH4 (29 mg, 0.775 mmol) in argon. The batch was boiled for 7 h with reflux and then cooled to room temperature. THF (5 mL) and H2O (5 mL) were added to the batch with ice cooling and subsequently stirred for 30 min. The batch was filtered over a fritted glass filter with diatomaceous earth and subsequently rinsed with dichloromethane (50 mL). The combined filtrates were concentrated to low volume in vacuum.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([NH:17]C(=O)OCC1C=CC=CC=1)[CH:12]=3)(=[O:3])[NH2:2]>O1CCCC1.CO.[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]3[C:7]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]=3[NH:10]2)=[CH:15][CH:14]=1
Reactant: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(NC(=O)OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Yield: 90.1 %

Procedure:
A mixture of benzyl 1-carbamoyl-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indol-7-ylcarbamate (210 mg, 0.416 mmol) and 10% Pd/C (45 mg, 0.042 mmol) in tetrahydrofuran (5 mL) and methanol (15 mL) was stirred under H2, provided with a H2 balloon, at rt for 1 hr. The catalyst was removed by suction filtration through CELITE®. The filtrate was concentrated under vacuum. The residue was diluted with CH2Cl2 (100 mL), washed with brine (30 mL), and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product, 7-amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (132 mg, 0.375 mmol, 90% yield), as a tan solid. LCMS (M+H)+=321.10.
Reaction SMILES: [OH:1][CH:2]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:36][CH2:35][C:9]2([N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][N:11]([CH2:20][C:21]3[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=3)[C:24]([O:26]C(C)(C)C)=[O:25])[C:10]2=[O:34])[CH2:8][CH2:7]1>Cl.O1CCOCC1>[OH:1][CH:2]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][C:9]2([N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][N:11]([CH2:20][C:21]3[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=3)[C:24]([OH:26])=[O:25])[C:10]2=[O:34])[CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(O)c4ccccc4)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(O)c4ccccc4)CC3)C2=O)c1
Yield: 44.3 %

Procedure:
A solution tert-butyl 3-((8-(4-hydroxy-4-phenylbutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (300 mg, 0.527 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 5 h. The mixture was concentrated in vacuo and purified using preparative high performance liquid chromatography to afford the acetate salt of the title compound as a white solid (120 mg, 44.4%); 1H NMR (400 MHz, DMSO-d6): δ 1.38-1.52 (m, 2H); 1.60 (d, 2H, J=13.2 Hz); 1.84-1.94 (m, 2H); 2.41 (t, 2H, J=7.2 and 7.6 Hz); 2.53-2.59 (m, 2H); 2.69-2.75 (m, 4H); 4.58 (s, 2H); 4.61 (s, 2H); 5.84 (t, 1H, J=6.8 and 6.4 Hz); 6.74 (t, 1H, J=7.6 and 7.2 Hz); 6.81 (s, 1H); 6.83 (s, 1H); 7.16-7.20 (m, 2H); 7.31-7.38 (m, 5H); 7.48-754 (m, 2H); 7.86-7.88 (m, 2H); 8.30 (S, 1H); 12.8 (bs, 1H); MS for C31H35N3O4 m/z 514.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[F:18][C:19]1[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]2[C:20]=1[C:21]([CH:31]=O)=[CH:22][NH:23]2.[BH4-].[Na+]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([NH:1][CH2:31][C:21]3[C:20]4[C:24](=[C:25]([F:30])[C:26]([F:29])=[C:27]([F:28])[C:19]=4[F:18])[NH:23][CH:22]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1c[nH]c2c(F)c(F)c(F)c(F)c12
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1c[nH]c2c(F)c(F)c(F)c(F)c12

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was then suspended in EtOH (4 mL) and 4,5,6,7-tetrafluoro-1H-indole-3-carbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr. Resulting imine was suspended in 5 mL MeOH and sodium borohydride (3 eq.) was added. HPLC confirmed reaction was complete (absence of imine). After completion (1 hr), precipitate was filtered to obtain D22 as a light yellow powder as product. Product was washed with deionized water to remove excess sodium borohydride.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[C:28]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:29]=[CH:30][C:31]=1[Cl:32].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:37][CH2:38][N:33]([C:28]3[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=3)[CH2:34][CH2:35]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3,4-Dichlorophenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.40 (d, 1H), 7.16 (s, 1H), 6.95 (d, 1H), 5.37 (s, 2H), 3.59 (m, 4H), 3.31 (m, 2H), 3.21 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=455.0, found=455.0.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cccc(I)c1
Solvent: C1CCOC1
Product: OCCCc1cccc(I)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To an ice cooled solution of 3-(3-iodophenyl)propionic acid (8.0 g, 29.7 mmol) in THF (30 mL) was added 1.0 M BH3 in THF (40 mL, 40 mmol). The mixture was stirred at 0° C. for 1 hour, then quenched by careful addition of 1:1 THF:H2O (10 mL). The mixture was concentrated in vacuo, the residue taken up in diethyl ether (100 mL), washed with water (1×100 mL, 1×50 mL), and brine (1×25 mL), dried over MgSO4, filtered, and concentrated to an oil. The oil was purified via silica gel chromatography, eluting with 40% ethyl acetate in hexanes to provide the titled compound (6.3 g, 81%). 1H NMR (300 MHz, d6-DMSO) δ 7.58 (d, 1H, J=1.4 Hz), 7.53 (ddd, 1H J=1.0, 1.7, 6.1 Hz), 7.22 (dd, 1H, J=1.7, 6.4 Hz), 7.08 (t, 1H, J=7.6 Hz), 4.47 (t, 1H, J=5.1 Hz), 3.38 (dt, 2H, J=5.1, 6.3 Hz), 2.57 (t, 2H, J=7.8 Hz), 1.68 (m, 2H); MS (ESI) m/z 279 (M+NH4).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](OCC2C=CC=CC=2)=O)[CH:4]2[CH2:18][CH2:19][N:20]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH:3]12.Br.C(O)(=O)C.C(Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH:3]2[N:20]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:19][CH2:18][CH:4]12)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC1CCN(C(=O)OCc2ccccc2)C2CCN(c3ncnc4[nH]ccc34)C12
Reactant: BrCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CC1CCN(Cc2ccccc2)C2CCN(c3ncnc4[nH]ccc34)C12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product of Example 20 (40 mg, 0.102 mmol), was added HBr in acetic acid (1.5 mL, 0.102 mmol) and the reaction was stirred at room temperature for 2 hours before being concentrated in vacuo and azeotroped with heptanes (×2) and MeOH/heptanes (×1). The residue was taken up in methanol and passed through a Varian StratoSpheres™ SPE PL-HCO3 MP SPE resin. The solution was concentrated in vacuo and taken back up in MeOH (0.10 mL) and an additional amount of benzyl bromide (12.2 mg, 0.0714 mmol) was added and the reaction was stirred at 40° C. for 16 hours. The reaction was concentrated in vacuo and purified by mass triggered reverse phase HPLC. Lyophilization of the desired fractions gave the title product (TFA salt) as a white solid. LRMS calc'd for C21H26N5 [M+H]+, 348; found 348. Jak1 activity: ++.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10].Br[CH2:28][CH2:29][CH2:30][O:31][CH3:32]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCOC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
To a pre-cooled THF solution (200 ml) under an argon atmosphere was added at −5° C. LDA (2M in THF/heptane/ethylbenzene, 16.24 ml) then dropwise piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (4.4 g, 4.2 ml) in THF (50 ml). The mixture was stirred between −5° C. to 0° C. for 3 hour and 1-bromo-3-methoxypropane (4.97 g) was added slowly at 0° C. The mixture was then stirred overnight at RT, the solvent was evaporated off, the residue taken up in ethyl acetate and washed with water then brine. The layers were separated, the organic layer dried over sodium sulphate and then evaporated off to give the desired 4-(3-methoxy-propyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester a light brown oil (6.058 g) oil that was used in next reaction step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]([OH:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12.N.[H][H]>C1(C)C=CC=CC=1.[Pt]=O>[OH:1][C:2]1[C:11]([CH:12]([OH:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23][C:3]=12
Reactant: [H][H]
Reactant: CCCc1cc(=O)oc2c(C(O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Agent: O=[Pt]
Agent: N
Solvent: Cc1ccccc1
Product: CCCc1cc(=O)oc2c(C(O)CC)c(O)c3c(c12)OC(C)(C)CC3
Yield: 62.7 %

Procedure:
A mixture of 5-hydroxy-6-(1-hydroxypropyl)-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (11a) (400 mg, 1.16 mmol) and platinum oxide poisoned with ammonia (100 mg) in toluene (50 mL) was hydrogenated under atmospheric pressure of hydrogen at ambient temperature for 2 hours. Column chromatography on silica gel eluted with 30% ethyl acetate in hexanes and subsequent crystallization from 20% acetone in hexanes provided 252 mg of 12a (63% yield). 1H NMR (CDCl3): 1.02 (t, J=7.5 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H), 1.41 (s, 6H), 1.62 (m, 2H), 1.82 (t, J=6.5 Hz, 2H), 2.75 (t, J=6.5 Hz, 2H), 2.91 (m, 4H), 3.78 (s, 3H), 6.01 (s, 1H); 13C NMR (CDCl3): 7.97, 13.84, 17.20, 23.19, 26.66, 31.33, 38.48, 38.99, 62.14, 76.35, 106.14, 110.66, 112.48, 116.55, 151.24, 153.50, 157.51, 157.92, 159.92, 203.40; IR: 1724, 1704 cm−1; MS (ACPI+): 359 (M+1); Anal. Calcd. for C21H26O5: C 70.37, H 7.31; Found: C 70.15, H 7.28.
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:6]([N:8]1[CH2:28][CH2:27][CH2:26][C@H:9]1[C:10]([NH:12][CH2:13][C:14](OC1C=CC([N+]([O-])=O)=CC=1)=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH2:36][C@H:37]([C:48]([NH:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:49])[CH2:38][CH:39]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:40](=[O:42])[OH:41].Cl.C(N(CC)CC)C>CN(C)C=O>[NH:1]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C@H:2]([C:6]([N:8]1[CH2:28][CH2:27][CH2:26][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:36][C@H:37]([C:48]([NH:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:49])[CH2:38][CH:39]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[C:40](=[O:41])[OH:42])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CNC(=O)[C@@H](N)CC(OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)[C@H](CC(OC(C)(C)C)C(=O)O)NC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of XV (1.66 g, 3.38 mmol) in dimethyl formamide (5 ml) were added XVII (1.05 g, 3.38 mmol) and triethylamine (0.57 ml, 4.06 mmol) in dimethyl formamide (5 ml) and the mixture was stirred for 2 days at room temperature. The reaction mixture was evaporated and the residue, dissolved in ethyl acetate, was washed with 10% citric acid solution, 4% sodium bicarbonate solution, water and dried over sodium sulfate. The solution was evaporated to dryness. An oil obtained gave a single spot on TLC; yield 1.64 g (77%), Rf1 0.57.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][CH:13]([CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:12][C@@H:13]([CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CCC(C)CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC[C@H](C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A solution of p-toluenesulfonyl chloride (19.9 g, 0.1 mol) dissolved in toluene (30 ml) was dropwise added with stirring under ice cooling, to a solution of 6-methyloctanol (15.4 g, 0.1 mol) prepared according to the method of a literature (M.C.L.C. 27,417 (1974)) and dissolved in dry pyridine (43 ml), followed by slowly returning the temperature to room temperature, allowing the resulting material to stand overnight, extracting the reaction mixture with toluene after completion of the reaction, washing the resulting organic layer with 6N-hydrochloric acid, then with 2N-NaOH aqueous solution, further with water until the washing water became neutral, drying the layer, and distilling off toluene to obtain oily (S)-6-methyloctyl-p-toluenesulfonate (26.1 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1O>C(Cl)Cl.N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: CC(C)c1ccc(O)c(Cl)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Trifluoromethanesulfonic anhydride (2.14 g, 7.6 mmol) was dissolved in DCM (5 ml) and cooled to 5° C. To this was added 2-chloro-4-isopropyl-phenol (1.23 g, 7.2 mmol), in 10 ml DCM and 1.75 ml pyridine, dropwise. The reaction mixture was stirred at 110° C. for 2 hours. The resultant dark solution was washed with 1M HCl (20 ml), water (20 ml) and saturated aqueous NaHCO3 (20 ml). The DCM extract was dried and concentrated in vacuo to provide the title compound as a dark orange oil (1.71 g, 78%). 1H NMR (CDCl3) 1.22-1.29 (6H, d, J=6.87 Hz), 2.88-3.00 (1H, sept, J=6.89 Hz), 7.15-7.20 (1H, m), 7.24 (1H, d, J=8.36 Hz), 7.36 (1H, d, J=2.17 Hz).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([C:7]1[N:8]([CH2:20][CH2:21][C:22](OCC)=[O:23])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:5][CH3:6]>C1COCC1>[CH3:1][N:2]([CH3:3])[C:22](=[O:23])[CH2:21][CH2:20][N:8]1[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=[C:7]1[CH2:4][CH2:5][CH3:6]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Reactant: CNC
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCC(=O)N(C)C
Temperature: 110 °C

Procedure:
Dimethylamine (15 mL of a 40% aqueous solution) was added to a solution of ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.02 g, 12.9 mmol, prepared in Part B of Example 18) in THF (7 mL), and the reaction mixture was heated at 110° C. overnight in a pressure vessel. The reaction was allowed to cool to ambient temperature and concentrated under reduced pressure to provide 4.1 g of N,N-dimethyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide as a dark brown solid.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[N:9][N:10]=1)(=[O:3])[CH3:2].[Na].[CH3:19]I>C(O)C>[C:1]([N:4]([CH3:19])[NH:5][C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[N:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1nnc(-c2ccccc2C)s1
Reactant: CI
Agent: [Na]
Solvent: CCO
Product: CC(=O)N(C)Nc1nnc(-c2ccccc2C)s1
Yield: 68.7 %

Procedure:
2-(2-Acetylhydrazino)-5-(2-methylphenyl)-1,3,4-thiadiazole (6.30 g) was added to a stirred solution of sodium (0.57 g) in ethanol (63 ml) at room temperature. After 15 minutes methyl iodide (7.10 g) was added and the solution kept at room temperature for 31/2 hours. The solvent was removed in vacuo and the residue chromatographed on a silica column (315 g) using mixtures of methanol and chloroform, finally eluting with 5% methanolchloroform. The resultant product was crystallised from ethyl acetate to give 2-(2-acetyl-2-methylhydrazino)-5-(2-methylphenyl)-1,3,4-thiadiazole (4.57 g) m.p. 106°-8°.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]=[C:20]=S>>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[NH:2][C:3]=2[CH:7]=1
Reactant: CCCCCCN=C=S
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: CCCCCCNC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and n-hexyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 207°-209° C.; 1H-NMR (DMSO-d6): δ 0.87 (distorted t, 3H), 1.28 (m, 6H), 1.51 (m, 2H), 3.17 (q, 2H), 7.05 (s, 1H), 7.30 (br. s, 1H), 11.01 (s, 1H).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)(O)=[O:2].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[Cl:17][C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N1CCC(C(=O)O)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C(=O)Cl)CC1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 578.2 g of 4-carboxy-1-ethoxycarbonylpiperidine in 1200 ml of toluene is treated firstly with 1.0 g of N,N-dimethylformnamide and then, at from 68 to 70° C. and within the space of 2 hours, with 369.0 g of thionyl chloride. The mixture is subsequently stirred at 70° C. for a further 30 min, after which the toluene is distilled off in vacuo and the residue is then degassed at RT for approximately 30 min under HV. This results in the title compound in the form of a weakly yellow oil [IR (Film): 2960, 2870, 1790, 1695, 1470, 1435, 1300, 1230, 1130, 960, 765 cm-1 ]. The product distils without decomposition at a m.p. of 96-98° C. (0.08-0.09 Torr).