Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:9][CH2:10][C:11]([C:14]([F:17])([F:16])[F:15])(O)[N:12]=2)[CH:5]=[C:4]([O:18][CH3:19])[CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:14]([F:17])([F:15])[F:16])[N:12]=2)[N:7]=1
Reactant: COc1cc(Cl)nc(C2=NC(O)(C(F)(F)F)CS2)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(-c2nc(C(F)(F)F)cs2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of compound 20 (8.67 mmol) in THF (30 mL) was added Burgess Reagent (9.5 mmol). The reaction mixture was stirred at 60° C. for 30 min. The solution was concentrated in vacuo and H2O and DCM were added. The layers were separated and the organic layer was concentrated. The crude was purified by silica gel chromatography (eluent: petroleum ether/DCM 50 to 100%) to give compound 21 as a beige solid in 48% yield. MS (ESI, EI+): m/z=294.87 (MH+).
Reaction SMILES: [S:1]([O:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:14][CH:13]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:39]([NH2:42])[CH2:40][CH3:41]>>[CH2:39]([NH:42][C:15]1[C:16]2[C:17](=[O:27])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24](=[O:26])[C:25]=2[C:12]([O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])=[CH:13][CH:14]=1)[CH2:40][CH3:41]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OS(=O)(=O)c3ccc(C)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Reactant: CCCN
Product: CCCNc1ccc(OS(=O)(=O)c2ccc(C)cc2)c2c1C(=O)c1ccccc1C2=O
Yield: 73 %

Procedure:
1-(n-propylamino)-4-tosyloxyanthraquinone was prepared by reaction of 1,4-ditosyloxyanthraquinone with n-propyl amine. The isolated and purified reaction product has the structure illustrated below (where "Ts" is ##STR9## The yield was 73% and the m.p. 163°-164° C. Mass spec m/e 435 (M+), 406 (M-C2H5), 280 (M-C7H7SO2), 252 (280-CO), 155 (C7H7SO2), 91 (C7H7); 1H-NMR (CD2Cl2)δ10.01 (br s, 1H), 8.21-7.87 (m, 2H), 7.81-7.65 (m, 4H), 7.35-6.96 (m, 4H), 3.41-3.20 (m, 2H), 2.31 (s, 3H), 1.91-1.67 (m, 2H), 1.16-1.00 (t, 3H); IR (Nujol) 1368 cm-1 (asymmetrical stretch), 1170 cm-1 (symmetric stretch), 932, 898, 865, 830, 785 cm-1 (S--O--C stretch); UV/VIS max (Xylenes) 501 nm (ε6380).
Reaction SMILES: [OH:1][CH:2]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:7]([CH2:26][CH2:27][CH3:28])[N:6]2[N:29]=[C:30]([CH3:32])[N:31]=[C:5]12.N1C(C)=CC=CC=1C.O1CCCC1.FC(F)(F)S(O[Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])(=O)=O>C(OCC)(=O)C>[Si:56]([O:1][CH:2]([C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)=[C:7]([CH2:26][CH2:27][CH3:28])[N:6]2[N:29]=[C:30]([CH3:32])[N:31]=[C:5]12)([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)C(C)(C)C)c2nc(C)nn12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
To a mixture of 4′-{[4-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.9 g), 2,6-lutidine (0.32 mL) and tetrahydrofuran (20 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.64 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.9 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[C:17]([CH2:19][C:20](O)=[O:21])#[N:18]>>[C:17]([CH2:19][C:20]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)=[O:21])#[N:18]
Reactant: N#CCC(=O)O
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Product: N#CCC(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 2, starting from 4-(3-fluoro-benzyloxy)-phenylamine (prepared as in example 1b) and cyanoacetic acid. Yield after recrystallisation from methanol: 50%. Colorless crystals with mp=164-166° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.ClC1C=CC(NC(=O)[NH:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([O:31][C:32]3[CH:40]=[CH:39][C:35](C(O)=O)=[CH:34][CH:33]=3)[CH2:27][CH2:26]2)=CC=1C(F)(F)F>>[CH3:7][NH:10][C:11](=[O:12])[C:39]1[CH:35]=[CH:34][CH:33]=[C:32]([O:31][C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=3)=[O:12])=[CH:30][CH:29]=2)[CH:40]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N[C@H]1CC[C@H](Oc2ccc(C(=O)O)cc2)CC1
Product: CNC(=O)c1cccc(Oc2ccc(NC(=O)Nc3ccc(OC(F)(F)F)cc3)cc2)c1
Yield: 70 %

Procedure:
Compound 2576 was prepared in 70% yield from 4-(trifluoromethoxy)phenyl isocyanate using the procedure detailed for compound 2221 in Example 4. 1H NMR (300 MHz, DMSO-d6): δ 8.75 (q, J=5 Hz, 1H), 8.45 (d, J=6 Hz, 1H), 7.33 (d, J=3 Hz, 1H), 7.07 (dd, J=6 and 3 Hz, 1H), 6.86 (d, J=9 Hz, 2H), 6.64 (d, J=9 Hz, 2H), 5.19 (br s, 2H), 2.77 (d, J=5 Hz, 3H).
Reaction SMILES: FC(F)(F)C1C=C(C(Cl)=O)C=CC=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[NH2:18].[F:37][C:38]([F:51])([F:50])[C:39]1[CH:40]=[C:41]([C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:42]=[CH:43][CH:44]=1>C1(C)C=CC=CC=1.C(O)C>[F:50][C:38]([F:37])([F:51])[C:39]1[CH:40]=[C:41]([C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:42]=[CH:43][CH:44]=1.[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:48]([NH:47][C:45](=[O:46])[C:41]2[CH:42]=[CH:43][CH:44]=[C:39]([C:38]([F:37])([F:51])[F:50])[CH:40]=2)=[S:49])[CH:19]=[CH:20][C:21]=1[O:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C(N=C=S)c1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C(F)(F)F)c4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (75 mg, yield 88%).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:31]([C:32]#[N:33])=[CH:30][C:10]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:16][C@H:15]2[O:28][CH3:29])=[O:12])=[C:9]([O:34][CH3:35])[CH:8]=1.[OH-:36].[NH4+]>>[NH2:6][C:7]1[CH:8]=[C:9]([O:34][CH3:35])[C:10]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:16][C@H:15]2[O:28][CH3:29])=[O:12])=[CH:30][C:31]=1[C:32]([NH2:33])=[O:36]
Reactant: COc1cc(N)c(C#N)cc1C(=O)N[C@H]1CCN(Cc2ccc(F)cc2)C[C@H]1OC
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: COc1cc(N)c(C(N)=O)cc1C(=O)N[C@H]1CCN(Cc2ccc(F)cc2)C[C@H]1OC
Reaction time: 7 h

Procedure:
To 65 parts of a sulfuric acid solution 96% were added portionwise (slowly) 3.6 parts of cis-4-amino-5-cyano-N-[1-[(4-fluorophenyl)methyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide while cooling in an ice-bath. The reaction mixture was allowed to reach room temperature and stirring was continued for 7 hours at room temperature. The reaction mixture was poured onto crushed ice and the whole was alkalized with ammonium hydroxide. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The most pure fractions were collected and the eluent was evaporated. The residue was further purified by HPLC using a mixture of methylbenzene and ethanol (90:10 by volume) as eluent. The pure fraction was collected and the eluent was evaporated. The residue was boiled in acetonitrile. The product was filtered off and dried, yielding 2.67 parts of cis-4-amino-N1 -[1-[(4-fluorophenyl)methyl]-3-methoxy-4-piperidinyl] -6-methoxy-1,3-benzenedicarboxamide; mp. 243.7° C. (compound 234).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20](Br)[CH:19]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[C:27]([NH2:30])(=[O:29])[CH3:28].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu](I)I.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([NH:30][C:27](=[O:29])[CH3:28])[CH:19]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1c1ccccc1n2-c1ccc(C#N)c(Br)c1
Reactant: CC(N)=O
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1ccccc1n2-c1ccc(C#N)c(NC(C)=O)c1
Temperature: 160 °C
Yield: 54.2 %

Procedure:
In a microwave reactor, a mixture of 1.015 g of 9-(3-bromo-4-cyanophenyl)-9H-carbazole-4-carboxylic acid methyl ester, obtained according to stage 3 of Example 1, 444 mg of acetamide, 71 mg of trans-N,N′-dimethylcyclohexane-1,2-diamine, 1.039 g of potassium carbonate and 95 mg of copper iodide in 20 ml of dioxane is heated at 160° C. for 1.5 hours. The reaction medium is poured into 200 ml of ethyl acetate. The organic phase is washed with 100 ml of a saturated solution of sodium bicarbonate. The aqueous phase is re-extracted with twice 100 ml of ethyl acetate. The combined organic phases are washed with twice 50 ml of a saturated solution of sodium bicarbonate and once with 100 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (40-63 μm), elution being carried out with pure dichloromethane. 520 mg of 9-(3-acetylamino-4-cyanophenyl)-9H-carbazole-4-carboxylic acid methyl ester are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:20]2[CH:25]=[CH:24][NH:23][C:22](=[O:26])[C@@H:21]2[CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])(=[O:19])=[O:18])=[C:12]([CH3:35])[CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:20]2[CH:25]=[CH:24][NH:23][C:22](=[O:26])[C@@H:21]2[CH2:27][C:28]([OH:30])=[O:29])(=[O:19])=[O:18])=[C:12]([CH3:35])[CH:11]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2C=CNC(=O)[C@@H]2CC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2C=CNC(=O)[C@@H]2CC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (1.5 ml) was added to a cooled (0° C.) solution of (S)-tert-butyl 2-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)-3-oxo-1,2,3,4-tetrahydropyrazin-2-yl)acetate (210 mg, 1 eq) in DCM (6 ml) and the mixture was stirred for 2 h at room temperature. The solvent was removed under vacuum and the residue used in the subsequent stage.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42](O)=O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:18]=[C:42]([CH2:41][CH2:40][N:37]3[CH2:38][CH2:39][N:34]([C:32]([O:31][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:33])[CH2:35][CH2:36]3)[O:20][N:19]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCC(=O)O)CC1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(CCN3CCN(C(=O)OC(C)(C)C)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 70 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 3-[4-(tert-butoxycarbonyl)-1-piperazinyl]propanoic acid, the title compound was obtained in 70% yield (78% purity by HPLC).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[N:37][CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J23) (290 mg, 1.0 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow oil (430 mg, 84%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[CH3:9][C:10]([S@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].O>C1COCC1>[CH3:9][C:10]([S@:13](/[N:15]=[CH:7]/[C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cn1cc(C=O)cn1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(/C=N/[S@](=O)C(C)(C)C)cn1
Temperature: 65 °C
Yield: 93.8 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-4-carbaldehyde (2.2 g, 20 mmol) in THF (50 mL) was added (R)-2-methylpropane-2-sulfinamide (4.8 g, 40 mmol) and Ti(OEt)4 (9.2 g, 40 mmol). The reaction mixture was heated at 65° C. for 14 h. After cooling, the mixture was poured into water. The solid was filtered off, and the filtrate was extracted with EtOAc. The organic layer was concentrated and purified by SiO2 chromatography eluting with petroleum ether/EtOAc (5:1) to afford 4.0 g (83%) of (R,E)-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide (46). LCMS (ESI) m/z: 214.1 [M+11]+.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:33]=[C:32]([C:34](=[NH:37])[NH:35]O)[CH:31]=[C:30]([CH3:38])[C:19]=1[O:20][CH2:21][C@@H:22]([OH:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][OH:27]>>[Cl:17][C:18]1[CH:33]=[C:32]([C:34]2[N:37]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)[O:11][N:35]=2)[CH:31]=[C:30]([CH3:38])[C:19]=1[O:20][CH2:21][C@@H:22]([OH:29])[CH2:23][NH:24][C:25](=[O:28])[CH2:26][OH:27]
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1OC[C@@H](O)CNC(=O)CO
Product: COc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(Cl)c3)no2)cc(C2CCCC2)n1
Yield: 57.8 %

Procedure:
The title compound (135 mg) is prepared in analogy to Example 6 starting from 2-cyclopentyl-6-methoxy-isonicotinic acid (100 mg, 452 μmol) and (S)—N-(3-[2-chloro-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (150 mg, 452 μmol): LC-MS**: tR=0.85 min, [M+H]+=517.21; 1H NMR (CDCl3): δ1.69-1.80 (m, 2H), 1.83-1.95 (m, 4H), 2.06-2.15 (m, 2H), 2.42 (s, 3H), 3.19-3.29 (m, 1H), 3.53-3.61 (m, 1H), 3.81 (ddd, J=14.1, 6.5, 3.5 Hz, 1H), 3.97-4.01 (m, 1H), 4.01 (s, 3H), 4.06 (dd, J=9.5, 4.8 Hz, 1H), 4.21 (s, 2H), 4.21-4.26 (m, 1H), 7.12 (t br, J=6.0 Hz, 1H), 7.27 (d, J=1.3 Hz, 1H), 7.48 (d, J=1.0 Hz, 1H), 7.92 (d, J=1.5 Hz, 1H), 8.05 (d, J=1.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.[BrH:14].C(O)(=O)C.O>C(O)(=O)C>[Br:14][C:11]1[S:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:12]=1
Reactant: Br
Reactant: N#CSCC(=O)c1cccc(F)c1
Solvent: CC(=O)O
Solvent: O
Product: Fc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 2-(3-fluorophenyl)-2-oxoethyl thiocyanate (1.76 g, 9.02 mmol) in acetic acid (15 ml) was added a 25% hydrogen bromide/acetic acid solution (15 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1) to give the desired product (2.31 g, 99.0%) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:14]2[CH:18]=[C:17]([C:19]([O:21]CC)=[O:20])[CH:16]=[N:15]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:14]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[N:15]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)C)c(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)COc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 80 °C
Yield: 55.7 %

Procedure:
To a solution (15 ml) of ethyl 1-(3-cyano-4-isobutoxyphenyl)pyrazole-4-carboxylate (1.38 g) in ethanol was added 1.75 N aqueous sodium hydroxide solution (3 ml) with stirring, and the mixture was heated at 80° C. for 30 minutes. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solvent of dioxane and water to give 0.7 g of 1-(3-cyano-4-isobutoxyphenyl)pyrazole-4-carboxylic acid, melting point 192-194° C.
Reaction SMILES: C[C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2[F:29])=[N:12]1)=[O:10])[C:4](NC)=[O:5].N[C@H:33]([C:36]1C=CC=CC=1)[CH2:34]O>>[OH:5][CH2:4][C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2[F:29])=[N:12]1)=[O:10])[C:2]1[CH:30]=[CH:36][CH:33]=[CH:34][CH:31]=1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reactant: N[C@@H](CO)c1ccccc1
Product: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@@H](CO)c2ccccc2)C1

Procedure:
Compound 70 was prepared according to the procedure described for the synthesis of compound 37 by replacing tert-leucine methylamide with (R)-2-amino-2-phenylethanol. LCMS (+ESI) m/z=431.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:14]([OH:16])=O)=[C:5]2[OH:17].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][NH2:39])=[CH:34][CH:33]=1>CN(C)C=O.O.C(N(CC)CC)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][NH:39][C:14]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[OH:17])=[CH:3][C:2]([F:1])=[C:11]([F:12])[C:10]=3[F:13])=[O:16])=[CH:34][CH:33]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2c(F)c(F)c(F)cc2c1O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NNc1ccc(Cl)cc1)c1cnc2c(F)c(F)c(F)cc2c1O
Reaction time: 72 h

Procedure:
To a solution of 1.0 g of 6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxylic acid (J. Amer. Chem. Soc., 68, 1264 (1946)). (The sample used in this procedure was shown by Karl Fisher titration to be a hydrate containing 0.4 equivalents of water.) in 15 mL of a 99:1 (v/v) mixture of dimethylformamide and triethylamine is added 1.01 g of carbonyldiimidazole. The mixture is stirred for 3 days and then it is transferred to a volumetric flask and diluted with dimethylformamide to a total volume of 25 mL. To 1.22 mL of this solution is added 39 mg of 4-chlorophenyl-hydrazine hydrochloride. The mixture is stirred 18 h at 25° C. and then 15 mL of distilled water is added. The precipitate is collected by filtration and dried in a stream of air. This procedure gives the title compound as 45 mg of a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([NH2:21])=O)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]#[N:21])[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2Sc2cccc(C(N)=O)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1csc(Nc2ncc(Br)cc2Sc2cccc(C#N)c2)n1
Temperature: 70 °C
Reaction time: 4 h
Yield: 33.6 %

Procedure:
3-(5-Bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)benzamide (0.20 g, 0.48 mmol) was suspended in acetonitrile (4 mL). POCl3 (0.11 mL, 1.2 mmol) was added and the reaction stirred in a sealed tube at 70° C. for 4 hours. The solution was cooled and neutralized with saturated NaHCO3 solution. The material was extracted with EtOAc, dried, and concentrated. The crude material was triturated with ether/EtOAc and filtered. The solid was dried to give the title compound (0.065 g, 34%). 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 6.44 (bs, 1H), 7.58-7.68 (m, 3H), 7.83 (d, 1H), 7.92 (s, 1H), 8.36 (s, 1H).