Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(O)(=O)C.C(OC(=O)C)(=O)C.CS(O)(=O)=O>C(OCC)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Reaction time: 1.67 h

Procedure:
N-acetoacetyl-L-aspartic acid, 21.7 parts, was mixed with 20 parts by volume of glacial acetic acid and 12.3 parts of acetic anhydride. Methanesulfonic acid, 0.20 parts by volume, was added to the slurry and the mixture was stirred for 100 minutes. The mixture initially thinned and then became thicker. Dry ethyl acetate, 20 parts by volume, was added and the resulting slurry was stirred for an additional 20 minutes. A solid was collected on a filter under a nitrogen atmosphere, rinsed with dry ethyl acetate, and then dried in a vacuum dessicator at 0.1 mm to afford 16.3 parts of N-acetoacetyl-L-aspartic anhydride, identified by the NMR spectrum in dimethylsulfoxide-D6.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[C:14]([C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:21][C:17]=1[C:18](Cl)=[O:19])#[N:15]>C1(C)C=CC=CC=1>[C:14]([C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:21][C:17]=1[C:18]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:19])#[N:15]
Reactant: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)Cl
Reactant: OC1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)OC1CCOC1
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-cyano-5-(2,4-dichlorophenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-cyano-5-(2,4l -dichlorophenoxy)benzoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.I[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25]I>>[CH2:19]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:9]([B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:1])([CH3:16])[O:3]2)[CH:14]=[CH:13][CH:12]=1)[CH2:18][O:15][CH2:11][CH2:10][O:15][C:11]1[CH:10]=[C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: ICCOCCOCCI
Product: CC1(C)OB(c2cccc(OCCOCCOCCOc3cccc(B4OC(C)(C)C(C)(C)O4)c3)c2)OC1(C)C

Procedure:
By following the process described in Example R65, Example R67 is prepared by dimerization of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol with 1-iodo-2-[2-(2-iodoethoxy)ethoxy]ethane (Example R5). A white powder is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:33]([C@@H:36]([OH:38])[CH3:37])=[N:34][N:35]=3)[N:11]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[C:12](=[O:20])[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:39]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:42]([O:41][C:39]([NH:46][C@@H:47]([CH:48]([CH3:50])[CH3:49])[C:51]([O:38][C@H:36]([C:33]1[N:10]2[N:11]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=3)[C:12](=[O:20])[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9]2=[N:35][N:34]=1)[CH3:37])=[O:52])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccccc2)c(-c2ccc(Cl)cc2)c2nnc([C@H](C)O)n21
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C(F)(F)F)ccc1Cn1c(=O)c(-c2ccccc2)c(-c2ccc(Cl)cc2)c2nnc([C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)n21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask was added (S)-8-(4-chlorophenyl)-3-(1-hydroxyethyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one (35 mg, 0.0648 mmol), Boc-L-Valine (15.5 mg, 0.0713 mmol), CH2Cl2(3 ml), DMAP (cat, 3 mg) and DIC (12.3 mg, 0.0973 mmol). The reaction was stirred at rt for 30 min. After this time, the solution was concentrated. The crude product was purified by silica gel column chromatography (8 g silica gel) eluting with a gradient of 0-50% EtOAc/Hex to give product (S)—((S)-1-(8-(4-chlorophenyl)-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-7-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl) 2-(tert-butoxycarbonylamino)-3-methylbutanoate, as a white solid (39 mg, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1.O1CCOCC1.N#N>O=[Mn]=O.C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[N:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Agent: O=[Mn]=O
Agent: N#N
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 80 °C

Procedure:
(4-Chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol (0.552 g, 1.158 mmol, Intermediate 45: step e), 1,4-dioxane (25 mL), dry THF (3 mL) and activated MnO2 (0.503 g, 5.788 mmol) were combined in a round-bottom flask and the mixture was heated at 80° C. under a condenser and a positive pressure of N2 overnight. The reaction was allowed to cool to ambient temperature and was filtered through Celite®, rinsing with THF. The filtrate was concentrated to provide the title compound which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]([C:9]1([CH2:26][OH:27])[CH2:14][CH2:13][N:12]([C:15](=[O:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1)=[O:8].[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1)[CH3:33]>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:42])[O:27][CH2:26][C:9]2([C:7](=[O:8])[NH:6][CH2:5][C:4]3[CH:28]=[CH:29][CH:30]=[C:2]([F:1])[C:3]=3[CH3:31])[CH2:14][CH2:13][N:12]([C:15](=[O:25])[CH2:16][NH:17][C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[CH2:11][CH2:10]2)=[CH:36][CH:35]=1)[CH3:33]
Reactant: Cc1c(F)cccc1CNC(=O)C1(CO)CCN(C(=O)CNC(=O)OC(C)(C)C)CC1
Reactant: CCc1ccc(N=C=O)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)OCC2(C(=O)NCc3cccc(F)c3C)CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)cc1
Reaction time: 8 h
Yield: 4.9 %

Procedure:
To a solution of crude tert-butyl 2-(4-(3-fluoro-2-methylbenzylcarbamoyl)-4-(hydroxymethyl)piperidin-1-yl)-2-oxoethylcarbamate (185 mg, ˜0.422 mmol, 1.0 equiv.) in THF (2 mL) were added DMAP (10 mg, 0.085 mmol, 0.2 equiv.) and 4-ethylphenylisocyanate (61 μL, 0.422 mmol, 1.0 equiv.). The reaction mixture was stirred overnight, and then concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (1-(2-(tert-butoxycarbonylamino)acetyl)-4-(3-fluoro-2-methylbenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (12 mg, 5% for three steps). LRMS (M-Boc+H+) m/z 485.2.
Reaction SMILES: [NH2:1][CH:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[CH:10](OC)=[O:11]>>[CH:10]([NH:1][CH:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:11]
Reactant: COC=O
Reactant: CSCCC(N)C(N)=O
Product: CSCCC(NC=O)C(N)=O
Yield: 55 %

Procedure:
30 g (0.20 mole) DL-methionine amide were agitated with 250 ml methyl formate for two days at room temperature, during which fine, slightly yellow crystals developed. They were filtered off and recrystallized out of a mixture of 150 ml hexane and 160 ml ethanol. After cooling off, filtering, washing and drying, 23 g (55%) Nα -formyl-DL-methionine amide were obtained in the form of colorless crystals with a melting point of 121-122° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C@@H:14]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].Cl>O1CCCC1.[OH-].[Na+].C(OCC)(=O)C>[CH:16]1([CH2:15][C@@H:14]([C:12]2[NH:11][C:8]3=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]3[CH:13]=2)[C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1cnc2[nH]c([C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)c2cc3cc(C(=O)O)cnc3[nH]2)cc1
Temperature: 70 °C
Yield: 86.5 %

Procedure:
A mixture of 2-[2-cyclopentyl-1(R)-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (prepared as in Example 55, 610 mg, 1.43 mmol) in tetrahydrofuran (8 mL) and 10% aqueous sodium hydroxide solution (3 mL) was heated at 70° C. for 10 h. The mixture was neutralized with a 3N aqueous hydrochloric acid solution, diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[2-cyclopentyl-1(R)-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (510 mg, 86.6%, 93% ee) as a light yellow solid which was further separated by Agilent high performance liquid chromatography (chiral column: Daicel OJ-H, 250 mm×20 mm i. d., 5 μm-particle size, temperature: 25° C., flow rate of 15 mL/min, 30% ethanol/hexanes as mobile phase and UV detection: 214 and 254 nm) to afford two pure enantiomers. The first peak, 2-[2-cyclopentyl-1(R)-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (220 mg) was isolated as a light yellow solid: LC/MS m/e calcd for C22H24N2O4S [M+H]+ 413.51, observed 412.9; 1H NMR (400 MHz, CD3OD) δ ppm 8.73 (br. s., 1H), 8.47 (d, J=1.5 Hz, 1H), 8.03 (br. s., 1H), 7.83-7.87 (m, J=8.3 Hz, 2H), 7.53-7.58 (m, J=8.3 Hz, 2H), 6.48 (s, 1H), 4.28 (t, J=7.8 Hz, 1H), 3.04 (s, 3H), 2.20-2.28 (m, 1H), 2.04-2.12 (m, 1H), 1.55-1.82 (m, 5H), 1.38-1.51 (m, 2H), 1.05-1.26 (m, 2H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23]>>[OH:23][CH2:22][CH:21]([NH:20][C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:24][OH:25]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: NC(CO)CO
Product: O=C(NC(CO)CO)c1nc(Cl)c2ccccc2c1O

Procedure:
Prepared from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 2-amino-propane-1,3-diol analogously to Example C-1: MS-(−)-ion: 295.2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:13]([NH2:15])=O>>[I:12][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][CH:10]=1)[N:1]=[CH:13][NH:15][C:4]2=[O:5]
Reactant: NC=O
Reactant: COC(=O)c1cc(I)ccc1N
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 25 °C

Procedure:
Methyl 2-amino-5-iodobenzoate (17.8 g, 64 mmol) was heated in 300 mL of formamide at 190° C. for 2 hours. The mixture was cooled to room temperature and the solid product was filtrated and dried in vacuum. The formed product 1403-174 was used without further purification. (10 g, 56.1%): LC-MS: 273 [M+1]+, 1H NMR (DMSO-d6): δ 7.46 (d, J=9.0 Hz, 1H), 8.10 (m, 2H), 8.36 (d, J=2.1 Hz, 1 H), 12.40 (s, 1H).
Reaction SMILES: [O-2].[Zn+2:2].[NH:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6]>C(O)C>[Zn:2].[NH:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6]
Reactant: [Zn+2]
Agent: O=C(O)[C@@H]1CCCN1
Agent: [O-2]
Solvent: CCO
Product: [Zn]

Procedure:
Into a 500 ml beaker on a magnetic hot plate place magnetic stirrer, 2.07 g Zinc oxide DAB 6 and 25.36 g L-proline DAB 6 (1:9 molecular ratio) and 200 ml 65% ethanol. Heat to gentle boiling under stirring. After a few minutes the ZnO has dissolved. Allow the solution to cool, transfer into a 250 ml volumetric flask and fill to the mark with 65% ethanol. Filter into a bottle for storage. 150 μl of this stock solution contain 1 mg zinc and 16.1 mg L-proline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[C:22]3[N:21]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Product: Cc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)cc1C(F)(F)F
Yield: 57.8 %

Procedure:
Reaction of 1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 4-methyl-3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (122 mg, 58%). MS (ISP) 423.1 [(M+H)+]; mp 218° C.
Reaction SMILES: F[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[C:23]1([CH3:35])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.Cl>CN(C=O)C>[CH3:14][C:4]1[CH:3]=[C:2]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH3:35])[CH2:30][CH2:31]2)[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1C(=O)O
Reactant: Cc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCN(c3ccccc3C)CC2)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-fluoro-2-methyl-5-nitro-benzoic acid (5.0 g, 25.10 mmol) in anhydrous DMF (100 mL), potassium carbonate (10.4 g, 75.3 mmol) was added under N2 atmosphere followed by 1-o-tolyl-piperazine 2 HCl (8.13 g, 32.6 mmol). The reaction mixture was allowed to stir at room temperature overnight. The progress of the reaction was checked by TLC, upon completion of the reaction, solvent was removed in vacuo. The residue obtained was acidified with conc. HCl (≈pH=2-3). Yellow solid obtained was filtered and washed with water (3×75 mL), diethyl ether and dried under vacuo to obtain the pure product 2-methyl-5-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid. Yield (6.5 g, 73%; and yellow solid).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:23][CH2:22][O:21][C:5]2=[C:6]2[C:15]=1[CH2:14][CH:13]1[CH:8]([CH2:9][CH2:10][CH2:11][N:12]1[C:16](=O)[CH2:17][CH3:18])[C:7]2=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:16]([N:12]1[CH2:11][CH2:10][CH2:9][C@H:8]2[C@@H:13]1[CH2:14][C:15]1[C:6]([CH2:7]2)=[C:5]2[O:21][CH2:22][O:23][C:4]2=[CH:3][CH:2]=1)[CH2:17][CH3:18]
Reactant: CCC(=O)N1CCCC2C(=O)c3c(c(Br)cc4c3OCO4)CC21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN1CCC[C@@H]2Cc3c(ccc4c3OCO4)C[C@@H]21
Reaction time: 0.67 h

Procedure:
Compound 25 (0.34 g dissolved in THF (5 mL)) was added to a suspension of LAH (0.3 g) in THF (5 mL) at 0° C. The mixture was stirred at for 40 min, before it was quenched with ice/water and basified with 27% aqueous NaOH. The product was extracted into 2-methyl-THF. The organic layer was washed with sat. aqueous NaHCO3, dried (MgSO4), and concentrated in vacuo. The residue was dissolved in MeOH (3 mL) and treated with a few mg of 5% Pd/C, 37% aqueous HCl (10 drops), and hydrogen gas (3 bar) at 50° C. for ˜1 h and further at rt (1 bar hydrogen pressure) overnight. Next morning, a few mg of additional 5% Pd/C were added, and the mixture was hydrogenated (3 bar) at 50° C. overnight (this procedure was repeated several times over a total of four days). The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was partitioned between 2M aqueous NaOH and DCM. The organic layer was washed with sat. aqueous NaHCO3, dried (MgSO4), and diluted with 2M HCl in Et2O and concentrated in vacuo. The residue was dissolved in MeOH, and treated with 2M HCl in Et2O at 0° C. The precipitated product was isolated by filtration. Yield of example 5d1: 53 mg as a white solid. LC/MS (method 111): RT 0.71 min, ELSD 100%, UV 61%. MH+: 274.1.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31]4)[C:19]([C:36]([F:39])([F:38])[F:37])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:40][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4([C:33]([NH2:35])=[O:34])[CH2:31][CH2:32]4)[C:19]([C:36]([F:39])([F:38])[F:37])=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:5][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2C(F)(F)F)CC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
Formaldehyde (37 wt % in H2O; 8.8 μL, 0.12 mmol) was added to a solution of 1-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (2) (20 mg, 39 μmol) in MeOH (5.0 mL) under an atmosphere of nitrogen. The resulting mixture was stirred for 10 minutes at room temperature then sodium triacetoxyborohydride (33 mg, 0.16 mmol) was added in one portion and stirring continued for 2.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and the volatiles were removed under reduced pressure. The residue was dissolved in DCM (1 mL) to which cyclohexane (5 mL) was added to form a cloudy suspension. The solvent was removed in vacuo and the resulting solid was dried under high vacuum to give the title compound 3 as a white powder (18 mg, 88%); 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 8.67 (s, 1H), 7.66 (d, J=8.5 Hz, 2H), 7.40-7.27 (m, 3H), 7.22 (dd, J=14.4, 8.0 Hz, 3H), 6.99 (s, 1H), 6.01 (s, 1H), 3.21-3.05 (m, 4H), 2.88 (d, J=10.9 Hz, 2H), 2.50-2.30 (m, 1H), 2.21 (s, 3H), 1.99 (s, 2H), 1.79-1.58 (m, 4H), 1.44 (s, 2H), 0.97 (s, 2H). LCMS-A: 5.028 min; m/z 524 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C@@H:3]1[C@H:8]([C:9](O)=[O:10])[CH2:7][CH:6]=[CH:5][CH2:4]1.[NH2:34][OH:35]>>[OH:35][NH:34][C:9]([C@H:8]1[C@@H:3]([N:2]([CH3:1])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH2:4][CH:5]=[CH:6][CH2:7]1)=[O:10]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CC=CC[C@H]3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CC=CC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 94 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 255.5 mg (0.4 mmol) of cis-6-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxylic acid with hydroxylamine provided 200.1 mg of cis-N-hydroxy-6-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxamide in 94% yield. MS: 482.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[C:5]([C:25]#[N:26])=[CH:4][N:3]=1.[NH2:27][OH:28].C(N(CC)CC)C>CCO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:21])([CH3:22])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[C:5]([C:25]([NH:27][OH:28])=[NH:26])=[CH:4][N:3]=1
Reactant: Cc1cn(-c2ccc3c(N)ncc(C#N)c3c2)c2c1C(=O)CC(C)(C)C2
Reactant: NO
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cn(-c2ccc3c(N)ncc(C(=N)NO)c3c2)c2c1C(=O)CC(C)(C)C2
Reaction time: 48 h
Yield: 45 %

Procedure:
A suspension of 1-amino-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carbonitrile (0.035 g, 0.1 mmol), hydroxylamine (7 mg, 0.1 mmol) and triethylamine (0.01 mL, 0.1 mmol) in EtOH (2 mL) is placed in an oil bath at 100° C. and stirred for 2 days. The solvent is evaporated under reduced pressure, and the residue is purified using a Biotage column (0-20% MeOH/CH2Cl2) to afford 0.017 g (48%) of 1-amino-N-hydroxy-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-isoquinoline-4-carboxamidine. LC/MS m/z=378 [M+H]+, RT=1.82 min.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH3:10][C:11]1([CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH3:10])([CH3:23])[CH:12]1[C:20]([NH2:22])=[O:21])=[O:8])(=[O:3])[CH3:2]
Reactant: CC1(C)c2ccccc2NC1C(N)=O
Reactant: CC(=O)SCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)SCCC(=O)N1c2ccccc2C(C)(C)C1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 0.052 g of 3-acetylthiopropanoyl chloride in 1 ml of methylene chloride is added slowly to the mixture of 60 mg of 3,3-dimethylindoline-2-carboxamide, 87 mg of potassium carbonate and 9 ml of methylene chloride. The mixture is stirred at room temperature overnight, diluted with methylene chloride and filtered. The filtrate is washed with saturated aqueous sodium bicarbonate, water, 0.5N hydrochloric acid and water, dried, evaporated and the residue crystallized from diethyl ether, to yield the 1-(3-acetylthiopropanoyl)-3,3-dimethylindoline-2-carboxamide melting at 156°-158°.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NC1CCOCC1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NC3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 4-aminotetrahydropyran and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.