Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-]#N.[K+].CC(C)(O)[C:6]#[N:7].[C:10]([O:14][C:15](=[O:39])[C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:37])/[CH:23]=[C:24](\[C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=2)/[C:25]([F:28])([F:27])[F:26])=[CH:18][C:17]=1[CH3:38])([CH3:13])([CH3:12])[CH3:11].O>C1(C)C=CC=CC=1>[C:10]([O:14][C:15](=[O:39])[C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:37])[CH2:23][C@:24]([C:6]#[N:7])([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=2)[C:25]([F:26])([F:28])[F:27])=[CH:18][C:17]=1[CH3:38])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(O)C#N
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C[C@](C#N)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 18 h
Yield: 70.5 %

Procedure:
Potassium cyanide (0.0090 g, 0.138 mmol) and acetone cyanohydrin (0.040 ml, 0.435 mmol) were added to a solution of 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (0.0645 g, 0.140 mmol) in toluene (1.0 ml). To this vigorously stirred suspension was added 2,3,4,5,6-pentafluorophenyl-methyl quininium chloride (0.015 g, 0.028 mmol). The reaction mixture was stirred at 45° C. for 18 hours. At this time water was added and the reaction mixture was extracted with dichloromethane (3×). The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-benzoic acid tert-butyl ester (0.048 g, 66%) as a white foam. Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol:diethylamine=95:5:0.1, 1 ml/min, retention time 6.52 minutes (major enantiomer), 6.02 minutes (minor enantiomer) indicated that the reaction proceeded with 88% enantioselectivity. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H), 7.78-7.72 (m, 2H), 7.48 (s, 2H), 7.46-7.42 (m, 1H), 4.17 (d, 1H), 4.02 (d, 2H), 2.62 (s, 3H), 1.62 (s, 9H)
Reaction SMILES: [N+:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.[N+:8]([O-])([OH:10])=[O:9].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[N+:8]([C:4]1[CH:5]=[CH:6][N+:1]([O-:7])=[N:2][CH:3]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1ccccn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1cc[n+]([O-])nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
With cooling and stirring, 5.1 grams (0.053 mole) of pyridazine-1-oxide was dissolved in 50 ml of fuming sulfuric acid. To this was added 8.83 ml of fuming nitric acid. Upon completion of addition the reaction mixture was warmed to 130°-135° C. where it stirred for two hours. Analysis of the reaction mixture by thin layer chromatography (TLC) indicated the reaction was not complete. The reaction mixture was allowed to cool to ambient temperature where it stood for 16 hours. An additional 1.3 ml of fuming nitric acid was added and the reaction mixture was heated to 130°-135° C. where it stirred for 4 hours. Analysis of the reaction mixture by TLC indicated the reaction still had not gone to completion. An additional 1.3 ml of fuming nitric acid was added to the reaction mixture, which was stirred an additional 4 hours at 130°-135° C. The reaction mixture was poured into ice-water where it stood for several hours. The pH of the mixture was adjusted to near 7 with sodium bicarbonate, then the mixture was extracted with methylene chloride using a continuous extractor. The extract was dried with sodium sulfate and filtered. The filtrate was subjected to column chromatography on silica gel using 10% acetone in methylene chloride as eluent. The appropriate fractions were combined and concentrated under reduced pressure to give 1.1 grams of 4-nitropyridazine-1-oxide, m.p. 149°-151.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:21]=[N:22][C:23](Cl)=[C:24]([Br:26])[CH:25]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[H-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1.Cl>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:21]=[N:22][C:23]([O:38][C:35]4[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=4)=[C:24]([Br:26])[CH:25]=3)(=[O:18])=[O:19])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cnc(Oc2ccc(Cl)cc2)c(Br)c1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
The mixture of {(R)-4-[(5-Bromo-6-chloro-pyridine-3-sulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (80 mg, 0.16 mmol), sodium hydride (60% dispersed in mineral oil, 40 mg) and 4-chlorophenol (315 mg, 2.45 mmol) in N,N-dimethylformamide (2 mL) was heated in a microwave oven at 100° C. for 15 minutes, and then acidified with 0.1N hydrochloric acid to pH 5. The precipitate was filtered through a glass funnel and purified by preparative HPLC to afford ((R)-4-{[5-bromo-6-(4-chloro-phenoxy)-pyridine-3-sulfonyl]-methyl-amino}-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (70 mg, 75%) as a white powder. MS cald. for C23H24BrClN4O5S 582, obsd. (ESI+) [(M+H)+]: 583.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](=[N:31][OH:32])[NH2:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[C:44](N1C=CN=C1)(N1C=CN=C1)=[O:45]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][C:29]3[NH:30][C:44](=[O:45])[O:32][N:31]=3)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(N)=NO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCC(CC)N1C(=O)[C@@](C)(Cc2noc(=O)[nH]2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of 385 mg (0.81 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N′-hydroxyacetimidamide (Example 82, Step C) in dioxane (12.5 mL) was added 211 μL (1.41 mmol) of DBU and 262 mg (1.62 mmol) of 1,1′-carbonyldiimidazole. The resulting colorless solution was heated at 100° C. for 25 min, and then was quenched with water and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride, and then was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Mlford, Mass.), gradient elution of 55% MeCN in water to 80% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH2:3][CH2:2]1.[N+:13]([CH:16]([CH:19]=O)[CH:17]=O)([O-:15])=[O:14]>C(O)(=O)C>[N+:13]([C:16]1[CH:17]=[C:10]2[CH:9]=[N:8][N:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:11]2=[N:12][CH:19]=1)([O-:15])=[O:14]
Reactant: Nc1ccnn1C1CCOCC1
Reactant: O=CC(C=O)[N+](=O)[O-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2c(cnn2C2CCOCC2)c1
Temperature: 108 °C
Yield: 67.1 %

Procedure:
To a solution of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (1.6 g, 9.6 mmol) in 70% acetic acid (15 mL) is added nitromalonaldehyde (1.3 g, 9.6 mmol) and the reaction mixture is heated to 108° C. for 3 h. The solvent is evaporated under reduced pressure and the residue is purified by flash column chromatography using a gradient of 20% ethyl acetate/petroleum ether to afford the title compound as a pale yellow solid (1.6 g, 70%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8](Cl)[C:7]=2[N+:18]([O-:20])=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[OH2:23]>>[N:1]1([C:6]2[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8]([OH:23])[C:7]=2[N+:18]([O-:20])=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O
Reactant: NS(=O)(=O)c1c(Cl)cc(N2CCCC2)c([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: NS(=O)(=O)c1c(Cl)cc(N2CCCC2)c([N+](=O)[O-])c1O
Yield: 85.9 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, (N-pyrrolidinyl)-2,6 dichloro-3-nitrobenzenesulfonamide (1.12 g, 3.4mmol), 80% NaH (0.31 g, 10.3 mmol) and water (74 μL, 4.1mmol) were reacted to form the desired product (0.94 g, 69%). LC-MS m/z 307(M+).
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[ClH:49]>CO>[ClH:49].[CH3:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:24]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Cc1ccnc(F)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccnc(-n2c(/C=C/c3ccccc3)nc3ccccc32)c1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-fluoro-4-methylpyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound. MW: 358.68; mp: 221.0-222.5° C.; 1H-NMR (DMSO) δ: 8.66 (1H, d, J=5.1 Hz), 8.22-8.15 (1H, m), 7.86 (1H, d, J=7.7 Hz), 7.71-7.66 (3H, m), 7.59-7.44 (7H, m), 7.20 (1H, d, J=16.1 Hz), 2.53 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=3[F:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.[ClH:43]>C(Cl)Cl>[ClH:43].[NH2:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:21])[C:13]4[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=4[F:20])[C:4]=23)[CH2:23]1
Reactant: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](N)C4)c23)c1
Yield: 61 %

Procedure:
A solution of (R)-tert-butyl 1-(5-bromo-3-(2-fluoro-5-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (120 mg, 0.22 mmol) in DCM (3 mL) was treated with TFA followed by 1M HCl as described in Example 62, Step C, to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-5-methylbenzamide hydrochloride (0.070 g, 61% yield). 1H NMR (400 MHz, D2O) δ 8.17 (s, 1H), 7.50-7.48 (m, 1H), 7.45 (s, 1H), 7.33-7.30 (m, 1H), 7.09-7.04 (m, 1H), 3.50-3.48 (m, 1H), 3.31-3.29 (m, 2H), 3.18-3.13 (m, 1H), 3.06-3.03 (m, 1H), 1.86-1.82 (m, 1H), 1.68-1.64 (m, 1H), 1.43-1.41 (m, 2H); LCMS (APCI+) m/z 446, 448 (M+H)+.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([F:27])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:28])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[F:27][C:22]1[C:23]([O:25][CH3:26])=[CH:24][C:19]2[O:18][CH2:17][C:10]3([C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:28])[C:20]=2[CH:21]=1
Reactant: COc1cc2c(cc1F)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: COc1cc2c(cc1F)C1(CO2)C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (82%) as a colorless solid: mp 222-225° C.; 1H NMR (300 MHz, CDCl3) δ8.33 (s, 1H), 7.29-7.21 (m, 1H), 7.12 (d, J=6.7 Hz, 1H), 7.03 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 6.59 (d, J=6.8 Hz, 1H), 6.52 (d, J=10.1 Hz, 1H), 4.96 (d, J=9.1 Hz, 1H), 4.68 (d, J=9.1 Hz, 1H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ179.9, 157.2, 149.3, 149.1 (d, J=12.4 Hz), 146.1, 140.2, 132.2, 129.1, 123.8 (d, J=42.8 Hz), 118.6 (d, J=7.1 Hz), 110.7, 110.4, 96.3, 80.5, 58.6, 56.4; MS (ES+) m/z 286.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26](N)=[O:27])=[N:4][C:5]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:7]=1.[OH-:29].[Na+].Cl>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:26]([OH:27])=[O:29])=[N:4][C:5]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:7]=1
Reactant: [OH-]
Reactant: COc1ccc(-c2nc(N)c(C(N)=O)nc2-c2ccc(=O)n(C(C)C)c2)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(N)c(C(=O)O)nc2-c2ccc(=O)n(C(C)C)c2)cc1
Temperature: 100 °C

Procedure:
To a suspention of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-methoxyphenyl)-2-pyrazinecarboxamide (210 mg) in dioxane (2 ml) was added an aq. NaOH (2M, 4 ml) and this solution was heated at 100° C. for 4 hours. This reaction mixture was cooled to room temperature and the pH of this solution was adjusted to 2.5 with 2N aq. HCl. The precipitate was collected by filtration and washed with water to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-methoxyphenyl)-2-pyrazinecarboxylic acid (203 mg) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[F:23][C:24]([F:29])([F:28])[CH2:25][NH:26][NH2:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:27][NH:26][CH2:25][C:24]([F:29])([F:28])[F:23])=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[CH:4][CH:3]=1
Reactant: NNCC(F)(F)F
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NNCC(F)(F)F)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.1 %

Procedure:
5-(4-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (1000 mg, 3.02 mmol; CAN 1018782-82-5) and (2,2,2-trifluoroethyl)hydrazine (380 mg, 3.33 mmol; CAN 5042-30-8) were combined with DMF (10 mL) to give a colorless solution. TBTU (1.06 g, 3.32 mmol) and DIPEA (1.56 g, 2.05 mL, 12.1 mmol) were added. The reaction mixture was stirred for 15 h at room temperature. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined and washed with water (1×50 mL) and brine (1×50 mL). The organic layers were dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in hexane) to give the title compound (0.35 g, 27%) as white solid; LC-MS (UV peak area/ESI) 100%, 426.0451 (M−H)−.
Reaction SMILES: C([NH:11][C@H:12]([C:15]([N:17]1[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]1)=[O:16])[CH2:13][OH:14])(OCC1C=CC=CC=1)=O>CO.[Pd]>[NH2:11][C@H:12]([C:15]([N:17]1[CH2:18][CH:19]([C:21]([OH:23])=[O:22])[CH2:20]1)=[O:16])[CH2:13][OH:14]
Reactant: O=C(N[C@@H](CO)C(=O)N1CC(C(=O)O)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H](CO)C(=O)N1CC(C(=O)O)C1

Procedure:
A solution of 1.57 g of 1D in 150 ml of methanol containing 0.40 g of palladium-on-carbon catalyst was hydrogenated (50 p.s.i.) in a Parr shaker overnight. The mixture was filtered and the methanol was evaporated from the filtrate under reduced pressure. The residue was dissolved in 100 ml of water, the solution was washed with ethyl acetate, the water was evaporated under reduced pressure, and the residue was subjected to very low pressure (<1 Torr.) and then recrystallized from methanol/ether to give 1, as a colorless solid, m.p.: 192°-193° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2].[F:16][C:17]([F:46])([C:42]([F:45])([F:44])[F:43])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:41]=[CH:40][C:25]([C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37](O)=[O:38])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCCCCC>CN(C)C1C=CN=CC=1.ClCCl>[F:16][C:17]([F:46])([C:42]([F:43])([F:44])[F:45])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:41]=[CH:40][C:25]([C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37]([O:15][CH2:14][CH2:13][C:5]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])=[O:38])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Reactant: O=C(O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)C(F)(F)F)cc2)cc1)OCCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
2.50 g (11.8 mmol) of 2-(2,4-dinitrophenyl)ethanol, 5.24 g (11.8 mmol) of (2E)-3-(4-{[4-(4,4,5,5,5-pentafluoropentoxy)benzoyl]oxy}phenyl)acrylic acid, 144 mg (1.2 mmol) of 4-Dimethylaminopyridine are dissolved in 30 ml of dichloromethane. 2.48 g (13.0 mmol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 200 g silica gel using toluene:ethyl acetate 95:5 as eluant and crystallization form ethylacetate:hexane mixture to yield 5.35 g (71%) 2-(2,4-Dinitrophenyl)ethyl (2E) 3-{4-[(4-(4,4,5,5,5-pentafluoropentoxy)benzoyl)oxy]phenyl}acrylate as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[C:24]([OH:26])=[O:25])[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[OH-].[Na+].[CH2:31](O)[CH3:32]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[C:24]([O:26][CH2:31][CH3:32])=[O:25])[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)[C@H]1CCCC[C@@H]1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Reactant: CCO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)[C@H]1CCCC[C@@H]1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a mixed slurry of (1S,2S)-2-[[2-(5-chloro-1H-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexane-1-carboxylic acid, 553, (0.090 g, 0.231 mmol), in ethanol (1.5 mL) at room temperature was added HCl (0.577 mL of 4 M solution, 2.309 mmol). The solution was warmed to 50° C. After 6 hours, the mixture was basified with 1N NaOH, brine was added and the aqueous layer was and extracted repeatedly with EtOAc. The organic layer was dried over MgSO4, and filtered through a short plug of silica gel and concentrated in vacuo to provide the desired product.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[C:7](=O)(O)[O-].[Na+].Cl[S:13]([C:16]1[C:17]([O:27][CH3:28])=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21]([OH:23])=[O:22])(=[O:15])=[O:14].BrCC(O)=O>O>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([O:27][CH3:28])[C:16]([S:13]([CH3:7])(=[O:15])=[O:14])=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]
Reactant: O=C([O-])O
Reactant: COc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Agent: O=C(O)CBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c(S(C)(=O)=O)cc1C(=O)O
Reaction time: 1 h

Procedure:
A 0.90 g portion of sodium sulfite and 1.81 g of sodium bicarbonate were dissolved in 6 ml of water, and 2.00 g of 5-chlorosulfonyl-2,4-dimethoxybenzoic acid was added thereto, followed by 1 hour stirring. Next, 1.50 g of bromoacetic acid was added, followed by stirring at 75° C. After completion of the reaction, the reaction solution was poured into cool water, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 2,4-dimethoxy-5-methylsulfonylbenzoic acid, which was used in the next reaction without purification.
Reaction SMILES: C(NC([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][NH:9]1)=O)(C)(C)C.C=O>>[CH2:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:8][NH:9]1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Agent: C=O
Product: c1ccc2c(c1)CCNC2
Yield: 66 %

Procedure:
U.S. Pat. No. 5,256,783 describes a method of producing decahydro(4aS, 8aS) isoquinoline-3(S)-carboxamides, by producing N-tertbutyldecahydro(4aS, 8as)isoquinoline-3(S)-carboxamide in which an amide is introduced into tertbutylamide. The method described in this patent comprises five steps (1) N-protecting L-phenylalanine with benzyl chloroformate, (2) forming a mixed acid anhydride into N-tertbutylamide (84.3%), (3) reacting the resulting amide with formaldehyde in the presence of an acid catalyst to form a tetrahydroisoquinoline compound (66%), (4) N-deprotecting this compound by catalytic reduction using Pd (79%), and (5) obtaining a decahydroisoquinoline compound using an Rh catalyst (59%). However, this method is problematic in that it requires many steps, it has a step with a low yield, Rh is expensive and the reaction has to be strictly controlled to maintain optical purity. Accordingly, the development of a simpler method is desirable.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:28][C:29]1[CH:30]=[C:31]([NH:35][NH2:36])[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=481.1 (M+H)+