Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[CH3:3][C:4]1([CH3:51])[O:8][C@@H:7]2[C@@H:9]([CH2:22][NH:23][CH2:24][CH:25]3[CH2:28][CH:27]([CH2:29][C:30]4[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:33]5[CH:43]=[CH:44][C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:32]=5[N:31]=4)[CH2:26]3)[CH2:10][C@@H:11]([N:12]3[C:16]4[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=4[CH:14]=[CH:13]3)[C@@H:6]2[O:5]1.[BH3-][C:53]#N.[Na+]>CO.C1COCC1>[CH3:3][C:4]1([CH3:51])[O:8][C@@H:7]2[C@@H:9]([CH2:22][N:23]([CH3:53])[CH2:24][CH:25]3[CH2:26][CH:27]([CH2:29][C:30]4[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[C:33]5[CH:43]=[CH:44][C:45]([C:47]([F:50])([F:48])[F:49])=[CH:46][C:32]=5[N:31]=4)[CH2:28]3)[CH2:10][C@@H:11]([N:12]3[C:16]4[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=4[CH:14]=[CH:13]3)[C@@H:6]2[O:5]1
Reactant: [BH3-]C#N
Reactant: CC1(C)O[C@@H]2[C@@H](CNCC3CC(Cc4nc5cc(C(F)(F)F)ccc5n4COCC[Si](C)(C)C)C3)C[C@@H](n3ccc4c(N)ncnc43)[C@@H]2O1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CC1CC(Cc2nc3cc(C(F)(F)F)ccc3n2COCC[Si](C)(C)C)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Formaldehyde (36 μl, 0.49 mmol, 37%(aq)) was added to a solution of 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-({[(3-{[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutyl)methyl]amino}methyl)-hexahydro cyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine in MeOH (5 ml) and THF (5 ml), and the reaction was stirred at RT for 30 mins. NaCNBH3 (18 mg, 0.29 mmol) was added portionwise, and the reaction stirred for a further 2 hours at RT after which LC MS showed the reaction to be complete. The reaction mixture was concentrated under in vacuo, and the residue partitioned between water (20 ml) and DCM (20 ml) and the layers were separated. The aqueous layer was extracted with DCM (2×20 ml), the combined organics were then dried over Na2SO4, and concentrated. Purification by prep. TLC, eluting with 7N NH3 in MeOH:DCM (5:95) gave the desired product (114 mg, 66%) as a colourless oil; MS (EST+) for C36H50F3N7O3Si m/z 714.45 [M+H]+; HPLC purity 100% (ret. time, 1.77 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm −0.14-0.05 (9H, m), 0.85-0.99 (2H, m), 1.18-1.35 (3H, m), 1.37-1.53 (2H, m), 1.52-1.64 (3H, m), 1.89-2.15 (3H, m), 2.18-2.28 (2H, m), 2.29-2.70 (6H, m), 2.72-2.96 (1H, m), 2.97-3.20 (2H, m), 3.48 (3H, s), 3.50-3.58 (2H, m), 4.37-4.58 (1H, m), 4.85-5.05 (2H, m), 5.11-5.38 (2H, m), 5.41-5.57 (2H, m), 6.35 (1H, d, J=3.63 Hz), 6.84-7.19 (1H, m), 7.50 (1H, d, J=8.35 Hz), 7.68 (1H, s), 7.78 (1H, d, J=8.35 Hz), 8.13-8.52 (1H, m)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12]/[C:11](=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])/[CH2:10][C@@H:9]1[C@H:19]1[O:23][C:22]([CH3:25])([CH3:24])[N:21]([C:26](=[O:28])[CH3:27])[C@H:20]1[CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][C@@H:9]1[C@H:19]1[O:23][C:22]([CH3:25])([CH3:24])[N:21]([C:26](=[O:28])[CH3:27])[C@H:20]1[CH2:29][C:30]1[CH:31]=[C:32]([F:37])[CH:33]=[C:34]([F:36])[CH:35]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCCCC/C=C1/C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CCCCCCC1C[C@H]([C@H]2OC(C)(C)N(C(C)=O)[C@H]2Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1

Procedure:
Combine (R)-2-[(4S,5S)-3-Acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-hex-(Z)-ylidene-pyrrolidine-1-carboxylic acid tert-butyl ester (0.04 g, 0.076 mmol), 10% palladium on carbon (4 mg) and methanol (2 mL) and stir for 2 days under 1 atmosphere of hydrogen. Add filter agent, filter and concentrate under reduced pressure to provide the desired compound as a mixture of isomers (2:1 4(S):4(R); 0.036 g, 90%). Subject isomer mixture to HPLC chromatography under acidic conditions: TFA 0.05% at pH 2.5; Organic solvent: acetonitrile; Gradient from 90 to 95% acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:26]2([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:28][CH2:27]2)[CH:22]=[CH:23][C:24]=1[F:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([NH:18][C:19]2[CH:20]=[C:21]([C:26]3([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:28]3)[CH:22]=[CH:23][C:24]=2[F:25])=[O:11])=[CH:6][CH:7]=1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: COC(=O)CC1(c2ccc(F)c(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)CC1(c2ccc(F)c(NC(=O)[C@H](c3ccc(Cl)cc3)[C@@H](C)C(F)(F)F)c2)CC1

Procedure:
A solution of 70 mg (0.31 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid, 84 mg (0.31 mmol) of methyl [1-(3-amino-4-fluorophenyl)cyclopropyl]acetate, 179 mg (0.47 mmol) of 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and 0.6 ml of pyridine in 2.4 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the mixture was separated directly, without further work-up, by preparative HPLC. This gave 106 mg (0.22 mmol, 72% of theory) of the title compound as a colourless oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].C([O-])(=O)C.[K+].[CH3:31][O:32][CH:33]1[CH2:38][CH2:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH2:34]1.O>CC#N>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:36]3[CH2:37][CH2:38][CH:33]([O:32][CH3:31])[CH2:34][CH:35]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Reactant: COC1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC1CC=C(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
(1H-Benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (1.0 g, 2.8 mmol), potassium acetate (2.1 g, 21.0 mmol), 2-(4-methoxy-1-cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.88 g, 3.7 mmol), and bis[di-tert-butyl(phenyl) phosphane]dichloropalladium (0.13 g, 0.213 mmol) were taken up in 40 mL of 3:1 MeCN:water. The mixture was purged with nitrogen and heated to 100° C. After 12 hours, the mixture was cooled to room temperature and diluted with 40 mL of water. The mixture was extracted twice with 30 mL of 9:1 chloroform:IPA. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (0.5 to 5% MeOH/DCM) afforded 1H-Benzimidazol-2-yl(4-((3-(4-methoxy-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)phenyl)methanone as a yellow solid. MS (ESI, pos. ion) m/z: 427.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1.N1C(C)=CC(C)=CC=1C>CC1C=CC=C(C)C=1C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: c1ccc2c(c1)CCCN2
Agent: Cc1cccc(C)c1C
Solvent: Cc1cc(C)nc(C)c1
Product: O=[N+]([O-])c1ccccc1N1CCCc2ccccc21
Yield: 22.2 %

Procedure:
A stirred mixture, under nitrogen, of 70.6 g (0.50 mole) of 1-fluoro-2-nitrobenzene, 133.2 g (1.00 mole) of 1,2,3,4-tetra hydroquinoline and 121.2 g (1.00 mole) of symmetrical collidine in 500 ml of 1,2,3-trimethylbenzene was refluxed (bp 178°) for 5 days. The mixture was concentrated in vacuo. The residue was taken up in 1000 ml of chloroform and extracted with 500 ml of 2N-hydrochloric acid. The aqueous phase was back extracted with 250 ml of chloroform. The combined organic layers were washed 3 times with 2N-hydrochloric acid, once with 2N-sodium hydroxide solution, twice with water and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residual oil was dissolved in 300 ml of 1:1 hexane:toluene and adsorbed on a chromatography column containing 2 kg of silica gel packed in hexane. Elution with 1:1 hexane:toluene gave fractions containing product. The fractions were combined and concentrated to afford 28.2 g (22%) of product. Recrystallization from hot isopropyl ether afforded the analytical sample, mp 69°-71° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Mg]Br.[CH3:9][CH:10]([CH3:14])[CH2:11]C#C.O1CCCC1.C1OC1.[Cl-].[NH4+]>O1CCCC1>[CH3:9][CH:10]([CH3:14])[CH2:11][C:5]#[C:4][CH2:3][CH2:2][OH:1]
Reactant: C#CCC(C)C
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CO1
Product: CC(C)CC#CCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
22 ml of dry tetrahydrofuran and 25 ml of a 1 Methyl magnesium bromide tetrahydrofuran solution were added to a nitrogen-substituted flask, and thereafter, 2.9 ml of 4-methylpentine was slowly added dropwise to the mixed solution. The obtained solution was stirred at a room temperature for 1 hour, and thereafter, 25 ml of a 1.1 M ethylene oxide tetrahydrofuran solution was slowly added dropwise to the reaction solution at a room temperature. The obtained solution was further stirred at a room temperature overnight. Thereafter, 100 ml of a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained solution was then extracted with 100 ml of diethyl ether twice. It was dried over magnesium sulfate. The magnesium sulfate was filtrated, and the organic layer was then concentrated. The generated alcohol was directly used in the subsequent reaction (yield: 3.78 g).
Reaction SMILES: C(O[CH2:5][CH:6]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]([C:34](=[O:36])[CH3:35])[C:31](=[O:33])[CH3:32])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:7]([O:9][CH3:10])=[O:8])(=O)C.C(N(CC)CC)C>C(Cl)Cl>[C:31]([N:30]([C:34](=[O:36])[CH3:35])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:6](=[CH2:5])[C:7]([O:9][CH3:10])=[O:8])(=[O:33])[CH3:32]
Reactant: COC(=O)C(COC(C)=O)N(Cc1ccccc1N(C(C)=O)C(C)=O)S(=O)(=O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC)N(Cc1ccccc1N(C(C)=O)C(C)=O)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 g (1.97 mmol) of methyl 3-acetoxy-2-[(2-diacetylaminobenzyl)-(4-methoxybenzenesulfonyl)amino]propionate and 0.826 ml (5.92 mmol) of triethylamine in 5 ml of CH2Cl2 was stirred at room temperature overnight. The solution was diluted with 30 ml of CH2Cl2 and washed with 20 ml each of H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give a brown oil. Anal. for C22H24N2O7S: Calc'd: C, 57.4; H, 5.3; N, 6.1; S, 7.0; Found: C, 56.2; H, 5.5; N, 5.6; S, 7.2.
Reaction SMILES: O[CH:2]1CN(C(=O)C2C=CC3OCOC=3C=2)C(C(O)=O)C1.[OH:21][CH:22]1[CH2:26][N:25]([C:27](=[O:40])[C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)[CH:24]([C:41]([OH:43])=[O:42])[CH2:23]1>>[CH3:2][O:42][C:41]([CH:24]1[CH2:23][CH:22]([OH:21])[CH2:26][N:25]1[C:27](=[O:40])[C:28]1[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=1)=[O:43]
Reactant: COc1cc(C(=O)N2CC(O)CC2C(=O)O)cc(OC)c1OC
Reactant: O=C(O)C1CC(O)CN1C(=O)c1ccc2c(c1)OCO2
Product: COC(=O)C1CC(O)CN1C(=O)c1cc(OC)c(OC)c(OC)c1
Yield: 40 %

Procedure:
By carrying out the procedure as in Example 11, but replacing 4-hydroxy-1-(3,4-methylenedioxybenzoyl)pyrrolidine-2-carboxylic acid by the 4-hydroxy-1-(3,4,5-trimethoxybenzoyl)pyrrolidine-2-carboxylic acid obtained in Example 8, the title product is obtained.
Reaction SMILES: C(O)(=[O:3])C.[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][N:7]=1.OO.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][N+:7]=1[O-:3]
Reactant: Cc1cnc(C)c(C)c1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: OO
Solvent: O
Product: Cc1cc(C)c(C)[n+]([O-])c1
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
To acetic acid (1.43 kg, 23.83 mol), 2,3,5-trimethylpyridine (1.43 kg, 11.80 mol) was added over 15 minutes. After 15 minutes, a 35% hydrogen peroxide solution (1.38 kg, 14.2 mol) was added dropwise over 30 minutes, the mixture was stirred at 90° C. to 95° C. overnight. To the reaction mixture, sodium sulfite (220 g) was added. The reaction mixture was poured into a mixture of sodium carbonate (2.5 kg) and water (12 L) and the mixture was extracted with chloroform (3.0 L×4). The organic layer obtained was concentrated until crystal precipitated. To the precipitate, n-hexane (2.5 L) was added. The resultant mixture was stirred under ice-cool overnight The resultant solid was filtrated to obtain a desired compound (1.53 kg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1/[CH:13]=[CH:14]/[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2C(=O)C3C(=CC=CC=3)C2=O)[CH:18]=[CH:19][CH:20]=1>CO>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1/[CH:13]=[CH:14]/[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1c(/C=C/c2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)ccc2ccccc12
Solvent: CO
Product: COc1c(/C=C/c2cccc(CCCN)c2)ccc2ccccc12

Procedure:
(E)-2-(3-(3-(2-(1-methoxynaphthalen-2-yl)vinyl)phenyl)propyl)isoindoline-1,3-dione was deprotected following the method used in Example 76 except that the reaction was conducted in MeOH at room temperature for 2 h. The reaction was concentrated under reduced pressure. The white solid was washed with diethyl ether and the decanted solution was concentrated under reduced pressure. The residue was purified by preperative thin layer chromatography on silica gel (1:10:89 NH4OH:MeOH:CH2Cl2) to give Example 92. Yield (0.020 g, 57%): 1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.8 Hz, 1H), 7.46-7.57 (m, 5H), 7.38 (d, J=16.4 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 3.91 (s, 3H), 2.62-2.66 (m, 2H), 2.57 (t, J=6.8 Hz, 2H), 1.64-1.72 (m, 2H).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][C:28]#[N:29])[CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].C(N)CN>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][C:28]#[N:29])[CH2:22]3)[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4CCCC(CC#N)C4)c3)ncnc21
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1CCCC(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylacetonitrile (30.1 mg, 0.0689 mmol) was added DCM (1.0 mL) and TFA (1.0 mL). The resulting mixture was stirred for 1 hour at ambient temperature, at which point LCMS indicated complete cleavage to the N-hydroxymethyl intermediate. The solvent was removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (37 μL, 0.55 mmol), after which the reaction was stirred for 5 hours, at which point LCMS indicated complete reaction. The solvent was removed and the residue was purified by preparative LCMS to provide the product as a TFA salt (24 mg, 83%). 1H NMR (400 MHz, CD3OD): δ 8.91 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 7.84 (s, 1H), 7.31 (s, 1H), 4.69 (s, 1H), 2.58 (d, 2H), 2.5-1.5 (m, 9H). MS (EI) m/z=307.10 (M+H).
Reaction SMILES: [C:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].NN.[OH-].[K+].C(O)COCCOCCO>O>[CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCC(=O)c1ccccn1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CCCCCCCCCCCc1ccccn1
Reaction time: 7 h
Yield: 58.6 %

Procedure:
A mixture of 21.5 g (87 mmol) of 2-n-undecanoylpyridine, 13.7 g (0.27 mol) of hydrazine.monohydrate, 10.1 g (0.18 mol) of potassium hydroxide, and 50 ml of triethylene glycol was heated at 110° to 125° C. for one hour, and further, at 180° to 185° C. for 7 hours. After cooling, 400 ml of water was added, the mixture was extracted with diethyl ether, washed with water and dried over anhydrous potassium carbonate. After concentration under a reduced pressure, the residue was separated by silica gel column chromatography (ethyl acetate:hexane=1:9), and further, purified by distillation under a reduced pressure to give 11.9 g of the desired product (yield 58.7%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:15]=[C:16]([C:20]([NH:22][CH2:23][C:24]([NH:26][CH:27]([C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)[CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[O:21])[CH:17]=[CH:18][CH:19]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[NH:13][C:14]1[CH:15]=[C:16]([C:20]([NH:22][CH2:23][C:24]([NH:26][CH:27]([C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCN2)c1)c1cc(Cl)cc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCN2)c1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
To the product from Example 190 (200 mg, 0.00032 mole) in H2O (10 mL) and CH3CN (10 mL) was added LiOH (54 mg, 0.0013 mole). The reaction mixture was stirred at room temperature for 1.5 hours. The pH was lowered to ~2.5 with TFA and the product was isolated by RPHPLC to yield the title product (190 mg after lyophilization) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:5]([C:7]2[C:8]([F:29])=[C:9]([N:14]([CH2:26][O:27][CH3:28])[S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])(=[O:17])=[O:16])[CH:10]=[CH:11][C:12]=2[F:13])[N:6]=1.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>O1CCOCC1>[CH2:36]([NH:38][C:39]([NH:1][C:2]1[S:3][C:4]([C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)=[C:5]([C:7]2[C:8]([F:29])=[C:9]([N:14]([CH2:26][O:27][CH3:28])[S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])(=[O:17])=[O:16])[CH:10]=[CH:11][C:12]=2[F:13])[N:6]=1)=[O:40])[CH3:37]
Reactant: COCN(c1ccc(F)c(-c2nc(N)sc2-c2ccncc2)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc(-c2c(F)ccc(N(COC)S(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
N-{3-[2-amino-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide (prepared as described in Example 3, 50 mg, 0.1 mmol) was dissolved in 2 mL of dry 1,4-dioxane and a total amount of 320 μL (4 mmol) of ethylisocyanate were added portionwise until the reaction was complete. The solution was heated at 80° C. under stirring for 18 h. The solvent was then removed and the residue taken up with DCM and washed with water. The organic phase was dried over Na2SO4 and evaporated to dryness, giving N-(3-{2-[(ethylcarbamoyl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl}-2,4-difluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide. The latter, without any further purification, was dissolved in 9 mL of TFA and 1 mL of water and the resulting mixture was maintained at 60° C. under stirring for 8 h. The solvent was evaporated and the residue taken up with DCM and washed with aqueous NaHCO3. The organic layer was then dried over Na2SO4 and evaporated again. The product was purified by flash chromatography on a silica gel precoated column eluted with DCM-MeOH 95/5, affording, after trituration with diethylether-diisopropyl ether, 17 mg (31%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]([CH3:15])[CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1.[C:16](OC(=O)C)(=[O:18])C>C(O)=O>[CH:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]([CH3:15])[CH3:14])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)ON=C(C(=O)O)c1csc(N)n1
Solvent: O=CO
Product: CC(C)ON=C(C(=O)O)c1csc(NC=O)n1
Yield: 83.5 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 4 g.), acetic anhydride (7.6 g.) and formic acid (3.4 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-iso-propoxyiminoacetic acid (syn isomer, 3.75 g.), mp. 168° to 169° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=[O:9].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:9]1[CH2:14][CH2:15][O:16][CH:8]1[C:7]1[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C2OCCO2)c1
Yield: 85 %

Procedure:
The mixture 5-methoxy-2-nitrobenzaldehyde (1 eq), ethylene glycol (1.4eq) and p-toluene sulfonic acid monohydrate (catalytic amount) in toluene was heated to reflux with a Dean-Stark apparatus for 16 hours. The mixture was then concentrated and passed through a plug of silica to give 2-(1,3-dioxolan-2-yl)-4-methoxy-1-nitrobenzene in 85-90% yield.
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][NH:10][C:11](=[O:12])[CH:5]2[CH2:4][NH:3][CH2:2]1.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:3]2[CH2:2][CH2:1][N:6]3[C:7]4[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=4[CH2:9][NH:10][C:11](=[O:12])[CH:5]3[CH2:4]2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1NCc2ccccc2N2CCNCC12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C1NCc2ccccc2N2CCN(Cc3ccc(F)cc3)CC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3,4,4a,6,7-Hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one (680.0 mg, 3.13 mmol, Example 2A) was dissolve in methanol (15 mL). 4-Fluorobenzaldehyde (653.5 mg, 5.27 mmol) was added to the reaction and stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (565.3 mg, 9.00 mmol) was then added, and the reaction was stirred at ambient temperature for 17 hours. The reaction was then diluted with 1 MNaOH (50 mL) and extract with dichloromethane (3×50 mL). The organic layers were combined, and purified by silica gel chromatography (ethyl acetate, Rf 0.40) to give the title compound: 1H NMR (400 MHz, benzene-d6) δ ppm 1.93 (td, J=11.0, 2.8 Hz, 1H), 2.42 (t, J=10.6 Hz, 1H), 2.49-2.51 (m, 1H), 2.60 (dt, J=11.0, 2.6 Hz, 1H), 2.85 (td, J=11.2, 2.9 Hz, 1H), 3.02-3.10 (m, 2H), 3.30 (d, J=13.2 Hz, 1H), 3.50 (dt, J=10.7, 2.3 Hz, 1H), 3.75 (dd, J=10.4, 2.8 Hz, 1H), 4.51 (dd, J=13.6, 4.0 Hz, 1H), 6.72-6.73 (d, J=8.1 Hz, 1H), 6.75 (dd, J=7.3, 1.5 Hz, 1H), 6.81-6.84 (m, 3H), 7.02-7.09 (m, 3H); MS (DCI/NH3) m/z 326 (M+H)+.