Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[CH2:12]([Si:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)F)[CH2:13][CH:14]=[CH2:15]>C1COCC1>[CH2:12]([Si:16]([CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: C=CCC[Si](F)(c1ccccc1)c1ccccc1
Reactant: C1CSCSC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC[Si](c1ccccc1)(c1ccccc1)C1SCCCS1
Reaction time: 2 h

Procedure:
To a solution of 1,3-dithiane (6.77 g, 56.3 mmol) in THF (120 mL) at −78° C. was added dropwise over 10 min n-butyllithium (1.6 Min hexane, 50 mmol), and the solution was stirred for 2 h under argon. A solution of 31 (11.1 g, 43.3 mmol) in THF (100 mL) was added, the mixture was stirred for 3 h at −78° C., and overnight at rt. The reaction mixture was quenched with water (100 mL) and the organic layer isolated. The aqueous layer was extracted with two 100-mL portions of ethyl ether. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave 32 contaminated with 1,3-dithiane. The latter was removed by sublimation (54° C., 8.0 mM Hg). Recrystallization from Et2O provided pure 32 as a colorless solid (14.8 g, 96%): Rf=0.40 (1/49 EtOAc:hexane); mp 474° C.; 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=7.8 Hz, 4H), 7.43 (m, 6H), 5.90 (m, 1H), 5.02 (dd, J=17.1, 1.7 Hz, 1H), 4.91 (dd, J=10.2, 1.7 Hz, 1H), 4.26 (s, 1H), 2.92 (t, J=11.8 Hz, 2H), 2.71 (m, 2H), 2.19 (m, 2H), 2.07 (m, 2H), 1.37 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 141.1, 135.9, 132.4, 130.2, 128.0, 113.2,32.3, 31.5, 27.5,25.8, 10.5; IR (film) 3068 (m), 3047 (m), 2897 (s), 2840 (m), 1961 (w), 1890 (w), 1826 (w), 1639 (m), 1490 (w), 1429 (s), 1275 (m), 1112 (s), 1003 (m), 911 (s), 785 (m), 744 (s), 703 (s) cm−1; MS (FAB) m/e (rel. intensity) 357 (MH+, 11), 356 (11), 355 (25), 301 (18), 279 (13), 237 (36), 227 (11), 225 (18), 221 (14), 215 (14), 213 (18), 212 (12), 211 (100), 209 (9), 207 (15); HRMS (FAB) calcd for C20H23S2Si: 355.1010 (MH+−2), found: 355.1020. Anal. Calcd for C20H24S2Si: C, 67.36; H, 6.78. Found: C, 67.08; H, 6.78.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:33](=[O:34])[N:32]([C:35]3[CH:45]=[CH:44][C:38]([C:39]([N:41]([CH3:43])[CH3:42])=[O:40])=[CH:37][CH:36]=3)[C:31]([CH3:46])=[N:30][C:29]=2[CH2:47][CH2:48][CH3:49])=[CH:23][CH:22]=1)#[N:14]>O.C(OCC)(=O)C>[CH3:43][N:41]([CH3:42])[C:39](=[O:40])[C:38]1[CH:37]=[CH:36][C:35]([N:32]2[C:33](=[O:34])[C:28]([CH2:27][C:24]3[CH:23]=[CH:22][C:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[C:13]4[NH:3][C:4](=[O:7])[O:5][N:14]=4)=[CH:26][CH:25]=3)=[C:29]([CH2:47][CH2:48][CH3:49])[N:30]=[C:31]2[CH3:46])=[CH:45][CH:44]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(C(=O)N(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(C(=O)N(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.30 g), sodium hydrogen carbonate (1.88 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]-N,N-dimethylbenzamide (0.92 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (12 mL). N,N′-carbonyldiimidazole (0.48 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.44 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid 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 colorless crystals (0.37 g, 36%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[H][H].C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1COCC1.[Pd]>[CH3:1][N:2]1[C:3]2[CH:4]=[C:5]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[CH:7][C:8]=2[NH:9][C:28]1=[O:29]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNc1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2ccc(CNC(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
To a suspension of tert-butyl [(3-methylamino-4-nitrophenyl)methyl]carbamate (864 mg, 3.07 mmol) and 10% Pd—C (100 mg) in THF was charged with hydrogen carefully. After stirring for 6 hours at room temperature, the reaction was recharged with nitrogen. Then, filtration, evaporation gave the residue, which was used for further reaction without purification. To the THF solution of the above, CDI (597 mg, 3.68 mmol) was added and the mixture was stirred for 4 hours at room temperature. After evaporation, purification through silica gel column chromatography eluting with CH2Cl2/MeOH (15:1) gave tert-butyl [(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl]carbamate as white solid (658 mg, 77%). 1H NMR (CDCl3): δ 1.47 (9H, s), 4.35 (2H, d, J=5.2 Hz), 4.92 (2H, brs), 6.86-7.10 (3H, m), 9.73 (1H, brs) MS (ESI) m/z 278 (M+H)+.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:9](=[O:16])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH2:10].O.O.O.O.O.[N+]([O-])([O-])=O.[Bi+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(OCC)(=O)C>C(Cl)Cl.O>[O:8]=[C:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:10][C:9](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:2]1
Reactant: CC(C)(C)OC(N)=O
Reactant: O=C1C=CCCCC1
Agent: O=[N+]([O-])[O-]
Agent: [Bi+3]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCCC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
To a stirring mixture of cyclohept-2-enone (26.96 g, 245.0 mmol) and tert-butyl carbamate (28.7 g, 245 mmol) in DCM (245 mL) was added bismuth nitrate pentahydrate (22.79 g, 47.0 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was diluted reaction with ethyl acetate (500 mL) and water (300 mL) and the biphasic mixture was filtered through a bed of Celite. The bed of Celite was washed well with ethyl acetate and water, and layers of the filtrate separated. The organic layer was concentrated to an oil that was purified by silica gel chromatography (0-40% ethyl acetate in hexanes). Product containing fractions were concentrated to afford the title compound (31.09 g, 137 mmol, 55.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.92 (d, J=7.03 Hz, 1H), 3.60 (d, J=8.59 Hz, 1H), 2.55-2.69 (m, 1H), 2.26-2.45 (m, 2H), 1.69-1.93 (m, 3H), 1.44-1.61 (m, 2H), 1.37 (d, J=5.08 Hz, 11H). MS (ESI) m/z 228.5 [M+H]+.
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](O)(=O)[CH2:16][SH:17].[OH2:20]>FC(F)(F)C(O)=O>[CH:1]([CH2:15][C:16]([OH:20])=[S:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CS
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: O
Solvent: O=C(O)C(F)(F)F
Product: OC(=S)CC(c1ccccc1)c1ccccc1
Yield: 99.3 %

Procedure:
To a solution of benzhydrol (100 g, 0.542 mol) in trifluoroacetic acid (300 mL) at room temperature (about 22 degrees C.) was added thioglycolic acid (50 g, 0.542 mol) drop wise over 20 minutes. Reaction progress was monitored by thin layer chromatography (TLC). The reaction was complete within one hour at which point water (1000 mL) was added slowly into the reaction mixture causing the product to precipitate. The resulting precipitate was filtered, washed with water and dried overnight under high vacuum to give benzhydrylthioacetic acid (139.3 g, 99.3%) as a pale yellow solid. (See Prisinzano, T. et al, Tetrahedron Asymm., 2004, 15, 1053-1058)
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]#[C:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)C.C(OC([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=O)(C)(C)C>>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([CH:6]([N:43]2[C:44]3[C:40](=[CH:39][C:38]([O:37][CH2:36][CH2:35][C:32]4[CH:31]=[CH:30][C:29]5[CH2:28][CH2:27][CH2:26][NH:25][C:34]=5[N:33]=4)=[CH:46][CH:45]=3)[CH:41]=[CH:42]2)[CH2:5][C:4]([OH:3])=[O:17])[CH:8]=1
Reactant: CCOC(=O)C#Cc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: O=C(O)CC(c1cnc2ccccc2c1)n1ccc2cc(OCCc3ccc4c(n3)NCCC4)ccc21
Yield: 81 %

Procedure:
The title compound was synthesized from quinolin-3-yl-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 81% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) δ 8.90 (m, 1H), 8.14 (m, 1.3H), 8.04 (m, 0.7H), 7.79 (m, 2H), 7.58 (m, 1H), 7.30 (d, 1H, J=7.6 Hz), 7.13 (m, 2H), 6.93 (m, 1.3H), 6.75 (m, 1.7H), 6.63 (d, 0.7H, J=3.2 Hz), 6.53 (d, 0.3H, J=3.2 Hz), 6.38 (s, 0.7H), 6.32 (s, 0.3H), 4.38 (m, 2H), 4.05 (m, 2H), 3.75 (t, 2H, J=6.4 Hz), 3.19 (t, 2H, J=6.4 Hz), 2.72 (t, 2H, J=6.4 Hz), 1.91 (m, 2H), 1.51 (s, 9H), 1.13 (t, 0.9H, J=7.0 Hz), 1.05 (t, 2.1H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])[CH:12]=[CH:11][C:10]=1[CH:20]=[CH:21][C:22]1[S:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([C:31]1[C:32](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[O:33][C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:37]([F:40])([F:39])[F:38])[C:35]=1[CH3:36])#[N:30]>C(O)C.C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])[CH:12]=[CH:11][C:10]=1[CH:20]=[CH:21][C:22]1[S:26][C:25]([CH:27]=[CH:36][C:35]2[C:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:37]([F:40])([F:38])[F:39])[O:33][C:32](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[C:31]=2[C:29]#[N:30])=[CH:24][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCO)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CN(CCO)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In a mixed solvent of ethanol (40 ml) and THF (10 ml) were dissolved 5-(2-{2-benzyloxy-4-[(2-hydroxyethyl)-methylamino]-phenyl}-vinyl]-thiophene-2-carbaldehyde (2.16 g, 5.49 mmol) and 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-5H-furan-2-ylidene)malononitrile (1.73 g, 5.49 mmol). The mixture was stirred at room temperature for 18 hours and further at 50° C. for 3 hours. The mixture was cooled and the solid was collected. The solid was washed with cold ethanol (40 ml) 3 times to give a reddish brown crystal (yield: 3.72 g (98.2%)).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24]3(O)[CH2:28][CH2:27][CH2:26][CH2:25]3)N=2)=[CH:4][CH2:3]1.[CH2:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:32].S(Cl)(Cl)=O.[CH2:43](Cl)Cl>>[CH3:1][C:2]1([CH3:30])[CH2:7][CH2:6][C:5]([C:8]2[CH:43]=[C:10]([C:24]3([N:36]4[CH2:37][CH2:38][N:33]([CH2:31][CH3:32])[CH2:34][CH2:35]4)[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:11]=[CH:12][C:13]=2[NH:14][C:15]([C:17]2[NH:23][CH:22]=[C:20]([C:19]#[N:18])[N:21]=2)=[O:16])=[CH:4][CH2:3]1
Reactant: ClCCl
Reactant: CC1(C)CC=C(c2nc(C3(O)CCCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CCN1CCNCC1
Solvent: O=S(Cl)Cl
Product: CCN1CCN(C2(c3ccc(NC(=O)c4nc(C#N)c[nH]4)c(C4=CCC(C)(C)CC4)c3)CCCC2)CC1

Procedure:
The title compound is prepared from 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(1-hydroxy-cyclopentyl)-pyridin-3-yl]-amide (as prepared in the previous step), N-ethylpiperazine, and thionyl chloride in DCM solvent according to the procedure in Example 43.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([N:15]([CH2:21][CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH3:14].[C:23]1([S:29]([CH2:32][CH2:33][NH:34][CH:35]([CH3:37])[CH3:36])(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:13]([N:15]([CH2:21][CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:1](=[O:2])[N:34]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:32][S:29]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:30])=[O:31])[CH3:14]
Reactant: CCN(CC)CCCCN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)NCCS(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)CCCCNC(=O)N(CCS(=O)(=O)c1ccccc1)C(C)C
Yield: 26.2 %

Procedure:
A solution of 4.40 g (0.0272 mole) of 1,1'-carbonyldiimidazole and 3.46 g (0.024 mole) of N,N-diethyl-1,4-butanediamine in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 5.00 g (0.0220 mole) of N-[2-(phenylsulfonyl)ethyl]-2-propanamine in 50 ml of tetrahydrofuran was added, and the solution was refluxed overnight. The solvent was removed in vacuo, and the residue was dissolved in 600 ml of a 50/50 mixture of ether and methylene chloride. The organic solution was extracted with three portions of water and was dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. Flash chromatography on silica gel (methanol) gave 2.29 g (26.2%) of clear colorless oil:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.C(C(CCCC)C([O-])=O)C.[Na+:21]>O1CCCC1.CO.C(O)(C)C>[S-:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[Na+:21].[Na+:21]
Reactant: O=C(O)c1ccnc(S)c1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])c1ccnc([S-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-mercapto-4-pyridinecarboxylic acid (7.65 g) in a mixture of tetrahydrofuran (60 ml) and methanol (60 ml) was added a solution of sodium 2-ethylhexanoate in isopropyl alcohol (27.5%) and the mixture was stirred for 2 days at room temperature. The reaction mixture was evaporated and the residue was washed with a mixture of acetone and ethanol. The crystals were collected by filtration dried over phosphorus pentoxide to give disodium 2-sulfido-4-pyridinecarboxylate (8.5 g).
Reaction SMILES: O[CH:2]1[CH2:7]SC(O)C[S:3]1.[C:9]([CH2:11][C:12]([NH2:14])=[O:13])#[N:10].CO>O.C(N(CC)CC)C>[NH2:10][C:9]1[S:3][CH:2]=[CH:7][C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: N#CCC(N)=O
Reactant: OC1CSC(O)CS1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: NC(=O)c1ccsc1N
Temperature: 25 °C
Yield: 141.7 %

Procedure:
2,5-Dihydroxy-1,4-dithiane (76 g) and cyanoacetamide (84 g) were added to a mixture of methanol (180 mL), water (10 mL) and triethylamine (10 g). The resulting mixture was heated at 35–40° C. for about 30 minutes while stirring, and then heated to 50–60° C. for an additional 30 minutes with stirring. The reaction mixture was then cooled to room temperature and poured into a mixture of ice (100 g)/water (300 mL). A fine precipitate formed upon addition, which was filtered and dried overnight to give 100.6 g of the title compound as a pale gray powder ((M+H)+=143, M.P.=159.0–159.6° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:19]3[C:20]([F:40])=[C:21]([N:25](COC)[S:26]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[C:41](O)(=O)C.C=O.[C:47]([BH3-])#[N:48].[Na+]>CO>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][CH3:41])[CH:7]=3)=[CH:12][N:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=2)[C:20]=1[F:40])(=[O:27])=[O:28].[CH3:41][N:48]([CH3:47])[C:4]1[CH:5]=[C:6]([C:8]2[C:9]([C:19]3[C:20]([F:40])=[C:21]([NH:25][S:26]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[F:36])(=[O:27])=[O:28])[CH:22]=[CH:23][CH:24]=3)=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:12]=2)[CH:7]=[CH:2][N:3]=1
Reactant: CC(=O)O
Reactant: COCN(c1cccc(-c2nn(C3CCOCC3)cc2-c2ccnc(N)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)c1cc(-c2cn(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)ccn1
Product: CNc1cc(-c2cn(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6 %
Yield: 54 %

Procedure:
To a solution of N-{3-[4-(2-amino-pyridin-4-yl)-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (55 mg, 0.095 mmol) (prepared as described in Example 4) in MeOH (1 mL) at r.t. absolute acetic acid (0.011 mL, 0.2 mmol), formaldehyde (37% aq., 0.008 mL, 0.1 mmol) and sodium cyanoborohydride (7 mg, 0.11 mmol) were added and the reaction was stirred at r.t. for 1 h. All the reagents were added a second time in the same quantity and the reaction mixture was left stirring for an hour more. The reaction mixture was concentrated under reduced pressure and the crude was dissolved in a mixture of TFA:water 9:1 (1.5 mL) and stirred for 2 h at 70° C. The reaction mixture was concentrated under reduced pressure, then taken up with NaOH 1N and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM/MeOH/NH3 7N in MeOH 96:3:1) affording 3 mg of 2,5-difluoro-N-(2-fluoro-3-{4-[2-(methylamino)pyridin-4-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl}phenyl)benzenesulfonamide (6% yield) and 29 mg of N-(3-{4-[2-(dimethylamino)pyridin-4-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (54% yield). HPLC (254 nm): Rt: 4.44 min; 1H NMR (DMSO-d6) Shift: 10.71 (br. s., 1H), 8.25 (s, 1H), 7.76 (d, J=5.4 Hz, 1H), 7.60-7.51 (m, 1H), 7.51-7.40 (m, 2H), 7.32 (dt, J=2.1, 7.5 Hz, 1H), 727-7.09 (m, 2H), 6.34-6.22 (m, 1H), 6.17 (s, 1H), 6.16-6.12 (m, 1H), 4.51-4.35 (m, 1H), 4.01-3.92 (m, 2H), 3.47 (dt, J=2.6, 11.6 Hz, 2H), 2.63 (d, J=4.8 Hz, 3H), 2.10-1.88 (m, 4H); HRMS (ESI) calcd for C26H25F3N5O3S [M+H]+ 544.1625. found 544.1622.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:33][CH2:32][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)[C@H](C)O)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f4) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9]N)[CH:6]=[CH:7][CH:8]=1.[Br:11][C:12]1[CH:13]=[C:14]([S:18][CH2:19][C:20](=O)[CH3:21])[CH:15]=[N:16][CH:17]=1.Cl.CCOCC>C(O)(C)(C)C.C(O)(=O)C>[Br:11][C:12]1[CH:13]=[C:14]([S:18][C:19]2[C:6]3[C:5](=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)[NH:9][C:20]=2[CH3:21])[CH:15]=[N:16][CH:17]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CC(=O)CSc1cncc(Br)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1cncc(Br)c1
Temperature: 80 °C

Procedure:
(3-Chloro-phenyl)-hydrazine hydrochloride (0.828 g, 4.63 mmol) and 1-(5-bromo-pyridin-3-ylsulfanyl)-propan-2-one (1.1 g, 4.63 mmol) were dissolved in tert-butanol (50 mL) and heated to 80° C. After heating overnight the reaction was cooled and concentrated. Purification on silica gel (0-50% EtOAc in hexanes) revealed the existence of hydrazone intermediates. The material was therefore resubmitted to the reaction conditions, with the addition of HCl in ether (13.9 mmol). After 2 hours acetic acid (2 mL) was added and the reaction continued to stir at 80° C. After stirring for 1 hour the reaction was cooled, concentrated and submitted to silica gel chromatography (10% MeOH in CH2Cl2) to afford a separable mixture of isomers, of which the first to elute from the column was the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C:34](=[N:36]O)[NH2:35]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C:34]1[N:36]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:35]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1ccc(F)cc1F
Product: CCc1ccc(C2CC(c3nc(-c4ccc(F)cc4F)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 47 mg (47% of theory)