Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC[N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:32][C:33]#[N:34])[CH2:26][N:25]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=O)C(C)(C)C.[OH-].[Na+]>CO.O1CCCC1>[N:14]1[C:13]2[NH:9][CH:10]=[CH:11][C:12]=2[C:17]([C:18]2[CH:19]=[N:20][N:21]([C:23]3([CH2:32][C:33]#[N:34])[CH2:24][N:25]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])[CH2:26]3)[CH:22]=2)=[N:16][CH:15]=1
Reactant: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COC(=O)C(C)(C)C)cn2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
A suspension of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 1.0 g, 2.06 mmol) in methanol (MeOH, 5 mL) and tetrahydrofuran (THF, 20 mL) was treated with a 1 M aqueous sodium hydroxide solution (NaOH, 2.3 mL, 2.3 mmol, 1.12 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 2-3 h. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and a 1 N aqueous HCl solution (0.2 mL) to adjust pH to 7-7.5 at room temperature. The resulting mixture was stirred at room temperature for 30 min before the solids were collected by filtration. The solids were washed with a mixture of acetonitrile and water (⅔ by volume, 2×4 mL) and dried in vacuum at 40-45° C. for 24 h to afford crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (14, 658 mg, 765 mg theoretical, 86% yield) as off-white solids, which was found to be identical to the material prepared by Method A. For crude 14: 1H NMR (DMSO-d6, 300 MHz) δ 12.15 (s, 1H), 8.94 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 7.63 (d, 1H), 7.09 (d, 1H), 4.62 (d, 2H), 4.25 (d, 2H), 3.71 (s, 2H), 3.24 (q, 2H), 1.26 (t, 3H) ppm; C16H17N7O2S (MW, 371.42), LCMS (EI) m/e 372 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:15][NH:16][C:17](=O)[C@H:18]([CH2:20][CH2:21][CH2:22][CH3:23])[NH2:19].C(N[C@H](C(O)=O)CCCC)(OC(C)(C)C)=O.CN>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH:10]([C:12]([NH:19][C@H:18]([CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])=[O:14])[CH3:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1.[CH3:15][NH-:16]
Reactant: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: CCCC[C@H](N)C(=O)NC
Agent: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN
Product: CCCC[C@H](C)NC(=O)C(C)Nc1cc(Cl)cc(Cl)c1
Product: C[NH-]

Procedure:
Following General Procedure D and using N-(3,5-dichlorophenyl)-D,L-alanine and L-norleucine N-methyl amide (prepared by coupling BOC-L-norleucine (Bachem) with methylamine (Aldrich) using General Procedure E, followed by removal of the BOC group using General Procedure F), the title compound was prepared. The reacticon was monitored by tlc (Rf=0.25 in 3% methanol/dichloromethane) and purification of this compound was by thin layer chromatography with 3% methanol/dichloromethane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH2:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:21]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)(=O)[CH3:22].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[NH3:20].[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH3:22])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC(=O)c1cccnc1
Reactant: CCOC(=O)c1oc2cccc(OCCCN)c2c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cccc(OCCCNC(C)c3cccnc3)c2c1C
Product: N
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %
Yield: 25 %

Procedure:
4-(3-Amino-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (40 mg), 3-acetylpyridine (19 mg) and acetic acid (100 μl) were dissolved in THF (5 ml). The solution was stirred at room temperature for one hour. To the solution was added NaB(OAc)3H (100 mg) and the resulting suspension was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogencarbonate solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography (using dichloromethane:MeOH:ammonia solution (25-28%)=10:1:0.2 as a developing solvent) to give 3-methyl-4-[3-(1-pyridin-3-yl-ethylamino)-propoxy]-benzofuran-2-carboxylic acid ethyl ester (9 mg) as a colorless oil. ESI-MS: m/z 383 (MH+); 1H-NMR (CDCl3): δ 1.40 (3H, d, J=6.5 Hz), 1.44 (3H, t, J=7 Hz), 2.03 (2H, m), 2.58 (3H, s), 2.66 (1H, dt, J1=12 Hz, J2=7 Hz), 2.80 (1H, dt, J1=12 Hz, J2=7 Hz), 3.87 (1H, q, J=6.5 Hz), 4.12 (2H, t, J=6 Hz), 4.43 (2H, q, J=7 Hz),6.59 (1H, d, J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.17 (1H, dd, J1=8 Hz, J2=5 Hz), 7.29 (1H, t, J=8 Hz), 7.68 (1H, br d, J=8 Hz), 8.46 (1H, dd, J1=5 Hz, J2=2 Hz), 8.55 (1H, d, J=2 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:34][CH3:35])=[CH:4][C:5]([C:10]2[CH:29]=[CH:28][C:13]([O:14][CH2:15][CH2:16][CH:17]3[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)=[C:12]([C:30]([F:33])([F:32])[F:31])[CH:11]=2)=[N:6][C:7]=1[C:8]#[N:9].Cl.[N:37]([O-])=O.[Na+]>CN1C(=O)CCC1.O.CCOC(C)=O>[C:8]([C:7]1[C:2]2[N:1]=[N:37][N:34]([CH3:35])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:29]=[CH:28][C:13]([O:14][CH2:15][CH2:16][CH:17]3[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:20]3)=[C:12]([C:30]([F:33])([F:31])[F:32])[CH:11]=2)[N:6]=1)#[N:9]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCCC3CN(C(=O)OC(C)(C)C)C3)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CN(C(=O)OC(C)(C)C)C4)c(C(F)(F)F)c3)cc21
Reaction time: 1 h
Yield: 84 %

Procedure:
tert-Butyl 3-(2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoro-methyl)phenoxy)ethyl)azetidine-1-carboxylate (100 mg) was dissolved in NMP (1000 μl) and hydrochloric acid (1M, 407 μl) added. A solution of sodium nitrite (20 mg) in water (150 μl) was added at room temperature and the reaction stirred for 1 hour. The reaction mixture was diluted with EtOAc (30 ml) and washed with water (3×20 ml) and brine (20 ml). Organics were dried over sodium sulphate and solvent evaporated under reduced pressure to yield crude product as a brown oil. Purification by flash chromatography (DCM to 2% MeOH in DCM mobile phase, 10 g silica column) afforded product tert-butyl 3-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate (84% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[C:15]([N:19]1[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][C:21]([CH:27]=[O:28])=[N:20]1)([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+].C(OCC)(=O)C.CCCCCC>O1CCCC1.[Li]CCCC>[C:15]([N:19]1[C:23]([CH:24]([CH3:25])[CH3:26])=[CH:22][C:21]([CH:27]([OH:28])[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=3)=[CH:4][CH:3]=2)=[N:20]1)([CH3:17])([CH3:18])[CH3:16]
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Reactant: CC(C)c1cc(C=O)nn1C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(O)c2ccc(C3=NC(C)(C)CO3)cc2)nn1C(C)(C)C
Yield: 53.9 %

Procedure:
To 20 ml of a solution of 1.15 g of 4-bromo-1-(4,4-dimethyl-1,3-oxazolin-2-yl)benzene in tetrahydrofuran, 3.23 ml of n-BuLi (1.53M hexane solution) were added dropwise at −78° C. under stirring, followed by stirring at the same temperature for 15 minutes. To the reaction mixture was added dropwise a solution of 0.8 g of 1-tert-butyl-5-isopropylpyrazole-3-carbaldehyde in 5 ml of tetrahydrofuran. The resulting mixture was stirred for 30 minutes. After the reaction, 10 ml of a saturated aqueous solution of ammonium chloride were added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 50% ethyl acetate/n-hexane), whereby 0.82 g of the title compound was obtained in the form of a colorless oil.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClC[CH2:19][C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)C>[C:20]([CH2:21][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)(=[O:22])[CH3:19]
Reactant: CC(=O)CCCl
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of benzyl 1-piperazinecarboxylate (4.1 ml), chloromethyl acetone (1.8 ml) and potassium carbonate (8.8 g) in acetonitrile (40 ml) was stirred overnight at ambient temperature. The reaction mixture was diluted in diethyl ether and the solution was partitioned between diethyl ether and water. The water phase was extracted with diethyl ether, the organic phases were combined and washed with water, brine, dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography using dichloromethane/methanol saturated with ammonia (3.5 M) (98/2). Evaporation of the solvent gave benzyl 4-(acetylmethyl)-1-piperazinecarboxylate (3.7 g, 63%) as a yellow oil.
Reaction SMILES: [OH:1][NH2:2].C(O[C:6](=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(F)cc2)ccn1
Reactant: NO
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccc(F)cc2)ccn1)NO
Reaction time: 23 h
Yield: 54 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (34 mg, 0.08 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 23 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:6) to furnish IV as a colourless oil (18 mg, 54%).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:16])([F:15])[C:7]1[N:8]=[C:9]([C:12](=[NH:14])[NH2:13])[S:10][CH:11]=1.[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH:20]=O.O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH:20]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([CH3:35])[NH:13][C:12]([C:9]2[S:10][CH:11]=[C:7]([C:6]([F:5])([F:15])[F:16])[N:8]=2)=[N:14]1
Reactant: N=C(N)c1nc(C(F)(F)F)cs1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(c2nc(C(F)(F)F)cs2)=NC1c1ccc(Cl)cc1Cl
Yield: 63.6 %

Procedure:
4-(trifluoromethyl)thiazole-2-carboximidamide acetate (0.38 g, 1.49 mmol) was reacted with 2,4-dichlorobenzaldehyde (0.26 g, 1.49 mmol) and ethyl 3-oxobutanoate (0.2 g, 1.49 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (0.44 g, 64%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C@@H:11]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C@@H:12]([OH:25])[CH2:13][C:14]1([CH3:24])[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][CH2:16][S:15]1(=[O:23])=[O:22].C(N(CC)CC)C>ClCCl>[CH:27]1([CH2:26][C@H:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[C@@H:12]([OH:25])[CH2:13][C:14]2([CH3:24])[S:19](=[O:20])(=[O:21])[CH2:18][CH2:17][CH2:16][S:15]2(=[O:22])=[O:23])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC1(C[C@H](O)[C@@H](N)CC2CCCCC2)S(=O)(=O)CCCS1(=O)=O
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C[C@H](O)[C@H](CC2CCCCC2)NC(=O)Nc2ccccc2)S(=O)(=O)CCCS1(=O)=O
Reaction time: 5 h

Procedure:
A mixture of 1.19 g of phenyl isocyanate, 3.67 g of 2-[(2S,3S)-3-amino-4-cyclohexyl-2-hydroxybutyl ]-2-methyl- 1,3-dithiane 1,1,3,3-tetroxide, 1.01 g of triethylamine and 60 ml of dichloromethane is stirred at 20° for 5 h. The usual working up gives 2-[(2S,3S)-4-cyclohexyl-2-hydroxy-3-(N'-phenylureido)-butyl]-2-methyl-1,3-dithiane 1,1,3,3-tetroxide, m.p 238°-240°, FAB 487.
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[C:11](=[O:23])[CH:12]=[C:13]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[N:14]([CH3:16])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:2]([O:9][C:10]1[C:11](=[O:23])[CH:12]=[C:13]([CH:17]([O:22][S:32]([CH3:31])(=[O:34])=[O:33])[C:18]([F:21])([F:19])[F:20])[N:14]([CH3:16])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1cc(OCc2ccccc2)c(=O)cc1C(O)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cn1cc(OCc2ccccc2)c(=O)cc1C(OS(C)(=O)=O)C(F)(F)F
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a tap-water cooled suspension of 5-benzyloxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (1.81 g, 5.8 mmol) in dichloromethane (95 mL) was added triethylamine (0.80 mL, 5.8 mmol) dropwise, followed by methanesulfonyl chloride (0.45 mL, 5.8 mmol). The suspension cleared and a slightly cloudy solution was obtained. The progress of the reaction was monitored by HPLC Method 1 (Example 24), which indicated about 75% conversion at this time. Another portion of triethylamine (0.30 mL, 2.1 mmol) and methanesulfonyl chloride (0.160 mL, 2.1 mmol) was added to the reaction mixture, and a bright yellow clear solution resulted. The reaction was completed within 10 min after the addition. The resulting solution was washed with a brine solution (2×50 mL). The organic layer was dried over Na2SO4, and then filtered. To the filtrate was added morpholine polymer-bound beads (1% cross-linked w/DVB, 200-400 mesh, 2.5-4.0 mmol N/g, 4.3 g), and the mixture was vortexed for 1 h. The solid morpholine beads were removed by filtration. The filtrate was evaporated to dryness, and the residual oil was taken up in dichloromethane and ethyl ether, and a solid product was obtained upon stirring. A first crop of the title compound was collected by filtration (1.80 g, 80% yield, HPLC Method 1 (Example 24); RT=15.0 min, HPLC purity (peak percent area): 99.3% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 7.77 (s, 1H), 7.40 (m, 5H), 6.61 (q, J=6 Hz, 1H), 6.43 (s, 1H), 5.01 (s, 2H), 3.77 (s, 3H), 3.50 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].[CH2:19]([O:21][C:22]([C:24]1[C:25](Cl)=[C:26]2[C:32]([CH3:33])=[N:31][O:30][C:27]2=[N:28][CH:29]=1)=[O:23])[CH3:20]>CN1CCCC1=O>[CH2:19]([O:21][C:22]([C:24]1[C:25]([N:17]([S:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:3][C:4]#[C:5][CH3:6])=[CH:9][CH:10]=2)(=[O:15])=[O:16])[CH3:18])=[C:26]2[C:32]([CH3:33])=[N:31][O:30][C:27]2=[N:28][CH:29]=1)=[O:23])[CH3:20]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC)cc1
Reactant: CCOC(=O)c1cnc2onc(C)c2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(C(=O)OCC)cnc3onc(C)c23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a suspension of 0.105 g (0.63 mmol) of 60% sodium hydride in 8 mL of 1-methyl-2-pyrrolidinone was added 0.628 g (2.63 mmol) of the product of Example 5 and the resulting mixture was stirred for 30 minutes at room temperature. A solution of 0.601 g (2.50 mmol) of ethyl-4-chloro-3-methylisoxazolo[5,4-b]pyridine-5-carboxylate in 7 mL of 1-methyl-2-pyrrolidinone was added and the reaction was heated to 80-90° C. for 48 h. The reaction mixture was then concentrated in vacuo and the residue was diluted with dichloromethane. The organics were washed with water, 2N citric acid solution and brine, dried over Na2SO4, filtered through Magnesol® and concentrated in vacuo. The residue was triturated with ethyl acetate/hexanes and the resulting solid was filtered and dried in vacuo to provide 1.0 g (90%) of the product as a solid; m.p.85-90° C. Electrospray Mass Spec: 444 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:24][NH2:25].F[P-](F)(F)(F)(F)F.ClC(=[N+]1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)=[CH:7][C:3]=1[C:4]([NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=1)=[O:6]
Reactant: Cc1cc(C)cc(-c2cnc(Cl)c(C(=O)O)c2)c1
Reactant: COc1ccc(CN)cc1OC
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)cnc2Cl)cc1OC
Temperature: 23 °C
Reaction time: 20 h

Procedure:
To a solution of 2-chloro-5-(3,5-dimethylphenyl)nicotinic acid (1-2, 0.200 g, 0.764 mmol, 1 equiv) and 3,4-dimethoxybenzylamine (0.319g, 1.91 mmol, 2.50 equiv) in DMF (5 mL) was added 1-(chloro-1-pyrrolidinylmethylene)-pyrrolidinium hexafluorophosphate (PyClu, 0.383 mg, 1.15 mmol, 1.51 equiv), and diisopropylethylamine (0.667 mL, 3.82 mmol, 5.00 equiv). The resulting mixture was stirred at 23° C. for 20 hours. The reaction mixture was filtered and purified via reverse phase liquid chromatography (H2O/CH3CN gradient w/0.1% TFA present). The desired fractions were partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL). The combined organic layers were washed with brine then dried over sodium sulfate and concentrated to give 2-chloro-N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)nicotinamide (1-3) as a white powder. LRMS m/z (M+H) 262.3 found, 262.1 required.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[C:27]=[O:28]>CN(C)C=O.C(OCC)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[NH:26][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=1
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(C(F)(F)F)cc2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), 1-isocyanato-4-(trifluoromethyl)benzene (58 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 ml) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (130 mg, 71%) as a colorless powder.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:2]1.NN.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[O:1]1[CH2:5][CH2:4][CH:3]([O:6][NH:7][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCOC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NOC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(tetrahydro-3-furanyloxy)-1H-isoindole-1,3(2H)-dione (1.5 mmol, 357 mg) was combined with hydrazine (1.7 mmol, 0.053 mL) in anhydrous THF (3 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 1 hour. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (1.5 mmol, 316 mg) and diisopropylethylamine (1.8 mmol, 0.320 mL) was added. After stirring at room temperature for 18 hours, the reaction was concentrated to a solid. The resulting solid was partitioned between ethyl acetate and 1N HCl, and the organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The crude product was concentrated to a white solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate). The purified product was then combined with ether and filtered to remove the residual phthalimide-hydrazine biproduct. The filtrate was then crystallized by adding hexanes providing 203 mg (48%) white crystals. Rf=0.2 (1:1 hexanes/ethyl acetate); H1-NMR (CDCl3): 67 7.82 (2H,d), 6.99 (2H,d), 6.85 (1H,s), 4.82-4.79 (1H,m), 3.97-3.87 (2H, m), 3.87 (3H,s), 3.83-3.70 (2H,m), 2.12-1.99 (2H,m).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.O[N:35]=[C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]1[OH:44])[NH2:37].NC(=NO)C1CCN(C(OC(C)(C)C)=O)CC1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:37]=[C:36]([C@@H:38]3[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]3[OH:44])[N:35]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NC(=NO)[C@@H]1CCCC[C@H]1O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CCC(C(N)=NO)CC1
Product: CON=C1C[C@@H](c2nc([C@@H]3CCCC[C@H]3O)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and (1S,2R)-N′,2-dihydroxycyclohexane-carboximidamide (an Intermediate 7), the title compound was obtained in 85% purity by HPLC. MS(ESI+): m/z=461.2.