Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[F:32][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:13])=[O:14])[CH:7]=2)[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])=[N:3][CH:4]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate PPP) (58.34 mg, 0.118 mmol), (2-methoxyphenyl)boronic acid (35.9 mg, 0.236 mmol), Pd(AmPhos)2Cl2 (8.36 mg, 0.012 mmol), potassium phosphate (75 mg, 0.354 mmol), 1,4-dioxane (443 μl), and water (148 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 30 min h at 90° C. LC/MS showed conversion to the protected product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with MeOH and concentrated, and the crude product was purified by chromatography on silica gel (12-g column, 3% MeOH/DCM) to give 4-fluoro-1-(2-methoxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (49 mg, 0.118 mmol, 100% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.99 (br. s., 1H), 8.70 (d, J=1.7 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H), 7.99 (dd, J=1.8, 8.9 Hz, 1H), 7.78 (dd, J=1.8, 8.8 Hz, 1H), 7.58-7.50 (m, 1H), 7.38-7.27 (m, 2H), 7.23 (d, J=8.3 Hz, 1H), 7.16-7.10 (m, 1H), 6.89 (d, J=4.6 Hz, 1H), 3.65 (s, 3H); m/z (ESI) 416.2 (M+H)+.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]3)[C:14]([C:31](=[O:33])[NH2:32])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:34][C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)[NH:38][C:39](=[O:41])[CH3:40].CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:39]([NH:38][C:37]1[CH:36]=[C:35]([NH:34][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20]3)[C:14]([C:31](=[O:33])[NH2:32])=[CH:13][N:12]=2)[CH:44]=[CH:43][CH:42]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc(On3nnc4ccccc43)ncc2C(N)=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCN(C(=O)OC(C)(C)C)C3)n2)c1
Reaction time: 18 h
Yield: 56.5 %

Procedure:
A mixture of tert-butyl 3-((2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5-carbamoylpyrimidin-4-ylamino)methyl)pyrrolidine-1-carboxylate (118 mg, 0.260 mmol), 3′-amino-acetanilide (47 mg, 0.31 mmol) and pTsOH (57 mg, 0.30 mmol) in dioxane (2 mL) was stirred at 100 C for 18 h, during which time white solids precipitated out, which were collected and purified by HPLC to give the titled compound (69 mg). MS 470.6 (M+H); UV 202.2, 248.6 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1.[C:18](OC=O)(=[O:20])C>O1CCCC1>[CH:18]([N:12]1[CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8][C:7]2[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]1=2)=[O:20]
Reactant: COc1ccc2c(c1)Sc1ccccc1CN2
Reactant: CC(=O)OC=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)Sc1ccccc1CN2C=O
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
To a solution of 10,11-dihydro-7-methoxydibenzo[b,f][1,4]thiazepin (6.5 g,26.6 mmoles) in tetrahydrofuran (100 ml) was added 5 ml of formic acetic anhydride. The mixture was stirred at from 0 to 5° C. for 15 minutes. The mixture was then concentrated in vacuo. The residue was taken up in ether and a solid crystallized out. The solid was filtered, washed with ether and air-dried to give the title compound, m.p. 98°-100°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Cl.[NH2:15][OH:16].C[O-].[Na+].CO>CO>[OH:16][N:15]=[C:10]([NH2:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:1])[F:13])[CH:4]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(Cc1cccc(C(F)(F)F)c1)=NO
Yield: 20.6 %

Procedure:
m-(Trifluoromethyl)phenylacetonitrile (30.0 g, 0.16 mol) was added to a suspension of hydroxylamine hydrochloride (18.8 g, 0.27 mol), methanol (145 mL) and 25% sodium methoxide/methanol (62 mL, 0.27 mol) at room temperature. The reaction mixture was then heated to reflux for 2 hours, cooled and concentrated in vacuo. The residue was partitioned between methylene chloride and water. The organic layer was separated and dried over magnesium sulfate. The organic layer was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with elution by hexane/ethyl acetate (8/2). The desired product (7.2 g, 21%) was obtained as a white solid, m.p. 91°-92° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)[N:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+:30]1C=CC=CC=1.C(OCC)C>ClCCl>[NH2:30][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(CO)cc2)n1
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(C=O)cc2)n1
Reaction time: 6 h
Yield: 6.7 %

Procedure:
To a suspension of the title compound of Example 41 (375 mg, 1.1 mmol) in dichloromethane (100 ml) was added pyridinium chlorochromate (810 mg, 2.7 mmol) and crushed molecular sieves (1.25 g, 3A). After stirring for 6 hours, diethyl ether (150 ml) was added and the mixture was filtered through a pad of silica gel under suction. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3 followed by 1:2 followed by 1:1) to provide the title compound (25 mg, 7% yield). 1H NMR (DMSO-d6) 10.10 (s, 1H), 9.86 (s, 1H), 8.07 (d, J=8.6 Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 7.79 (s, 1H), 7.43 (m, 2H), 7.34 (m, 2H), 2.53 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.C(OCC)(=O)C>[CH3:3][C:4]1[N:5]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[N:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1[nH]cnc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Reaction time: 0.17 h
Yield: 10.2 %

Procedure:
Sodium hydride (900 mg, 80% oil dispersion, 30 mmol) was added in portions over 5 minutes to a stirred solution of ethyl 4-methyl-imidazole-5-carboxylate (3.85 g, 25 mmol) in dry tetrahydrofuran (100 ml) at room temperature under nitrogen. After 10 minutes, trityl chloride (8.36 g, 30 mmol) was added in one portion. After 1 h, the mixture was diluted with ethyl acetate (500 ml) and washed with water (200 ml). The washings were extracted with ethyl acetate (2×75 ml) and the combined organic solutions were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate to give ethyl 5-methyl-1-(triphenylmethyl)imidazole-4-carboxylate (1.01 g, 10%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O.[H][H]>C(O)C.[Pd]>[O:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[C:16]([NH2:17])=[CH:15][CH:14]=2)[CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CN2CCOCC2)cc1N
Reaction time: 24 h
Yield: 65 %

Procedure:
4-(3,4-Dinitrobenzyl)morpholine (200 mg, 0.748 mmol) and 10% Pd/C (10 mg) were suspended in ethanol (10 mL) under nitrogen. The reaction mixture's atmosphere was exchanged for hydrogen and hydrogenation continued at ambient temperature and pressure for 24 h. The vessel was purged with nitrogen, and then the mixture was filtered through Celite with an ethanol (10 mL) rinsing. The solvent was removed in vacuo and purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound in a 65% yield. 1H NMR: (400 MHz, DMSO-d6): δ 6.46 (s, 1H), 6.40 (d, 1H, J=7.6 Hz), 6.27 (d, 1H, J=7.2 Hz), 4.37 (s, 2H), 4.32 (s, 2H), 3.52 (m, 4H), 3.18 (m, 4H), 2.26 (m, 4H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)(=O)=O>CN(C=O)C.CCOC(C)=O>[N:1]([CH2:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)OCCCc1nc(-c2ccccc2)cs1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCCCc1nc(-c2ccccc2)cs1
Temperature: 100 °C
Yield: 91 %

Procedure:
Sodium azide (263 mg, 4.05 mmol) was added to a solution of 3-(4-phenylthiazol-2-yl)propyl methanesulfonate (0.4 g, 1.35 mmol) in dry DMF (8 mL), and the reaction mixture was heated to 100° C. for 2 h. The mixture was allowed to cool down to room temperature and diluted with EtOAc. The organic product was extracted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 2-(3-azidopropyl)-4-phenylthiazole (0.3 g, yield 91%) as a pale orange liquid, which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 7.91-7.89 (m, 2H), 7.46-7.41 (m, 2H), 7.36-7.31 (m, 2H), 3.49-3.44 (t, J=6.7 Hz, 2H), 3.20-3.15 (t, J=7.5 Hz, 2H), 2.21-2.12 (m, 2H). MS (ESI) m/z: Calculated for C12H12N4S: 244.08. found: 245.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5].C(N(CC)CC)C.[O:25](S(C(F)(F)F)(=O)=O)[S:26]([C:29]([F:32])([F:31])[F:30])(=O)=[O:27]>ClCCl>[F:30][C:29]([F:32])([F:31])[S:26]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([CH3:17])[C:3]=1[CH:4]=[O:5])(=[O:27])=[O:25]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Temperature: -78 °C

Procedure:
Into a 50-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, were placed a solution of 2-hydroxy-6-methyl-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (300 mg, 1.27 mmol, 1.00 equiv) in dichloromethane (20 mL) and triethylamine (510 mg, 5.05 mmol, 3.97 equiv). This was followed by the addition of a solution of Tf2O (720 mg, 2.55 mmol, 2.01 equiv) in dichloromethane (5 mL) dropwise with stirring at −78° C. The resulting solution was stirred for 2 h at −78° C., then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×30 mL of dichloromethane. The organic layers were combined, washed with 3×10 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10). This resulted in 110 mg (19%) of 2-formyl-3-methyl-5-(tetrahydro-2H-pyran-2-yloxy)phenyl trifluoromethanesulfonate as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:33])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:34]([C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([CH3:44])[CH:38]=1)=[C:35]=[O:36]>C(Cl)Cl>[CH3:44][C:39]1[CH:38]=[C:37]([NH:34][C:35](=[O:36])[NH:1][C:2]2[C:3]([CH3:33])=[C:4]([C:8]3[C:20]4[C:19]5[C:14](=[CH:15][C:16]([C:21]([N:23]6[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]6)=[O:22])=[CH:17][CH:18]=5)[NH:13][C:12]=4[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:42]=[CH:41][C:40]=1[CH3:43]
Reactant: Cc1ccc(N=C=O)cc1C
Reactant: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2cccc(-c3ccc(C(N)=O)c4[nH]c5cc(C(=O)N6CCN(C)CC6)ccc5c34)c2C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(3-amino-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-2, 25 mg, 0.028 mmol) and TEA (8 μL, 0.057 mmol) in DCM (2 mL) was treated with 4-isocyanato-1,2-dimethylbenzene (8.33 mg, 0.057 mmol) and the mixture was stirred at rt overnight.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH2:16]([O:18][CH2:19][CH2:20][NH2:21])[CH3:17].C(N(CC)CC)C>>[CH2:16]([O:18][CH2:19][CH2:20][NH:21][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: CCOCCN
Solvent: CCN(CC)CC
Product: CCOCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 100.5 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.50 g, 5.16 mmol), 2-aminoethyl ethyl ether (0.46 g, 5.16mmol) and triethylamine (1.42 mL, 10.32 mmol) were reacted to form the desired product (1.78 g, 100%). LC-MS (m/z) 345.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[N:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[NH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Fc1cc(-c2cncc(NCC3CCOCC3)n2)c(Cl)cn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O[C@H]1CC[C@H](Nc2cc(-c3cncc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (375 mg, 1.162 mmol), DMSO (3.5 ml) and trans-4-aminocyclohexanol (1204 mg, 10.46 mmol) was stirred at 100° C. for 18 hours and the progress was followed by LCMS. The reaction mixture was let cool, added 300 ml of ethyl acetate, washed with saturated sodium bicarbonate solution (3×), water (2×), saturated salt solution (1×), dried with sodium sulfate, filtered and concentrated to crude solid. The crude material was purified by silica gel chromatography using 40 g column, eluting slowly from (80% ethyl acetate 20% heptane with 2% MeOH) to 100% ethyl acetate with 2% MeOH. The desired fractions are concentrated to a constant mass, lyapholized from 1:1 ACN/water (does not fully dissolve), re-lyophilized from 80 ml of (60/40) ACN/water solution with sonicating to dissolve solid, giving 270 mg of title compound as free base. LCMS (m/z): 418.3 (MH+), retention time=0.52 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.19-1.55 (m, 6H) 1.71 (d, J=12.89 Hz, 2H) 1.85-2.15 (m, 5H) 3.28-3.32 (dMeOH, 2H App.) 3.40 (td, J=11.72, 1.76 Hz, 2H) 3.50-3.73 (m, 2H) 3.94 (dd, J=11.28, 3.08 Hz, 2H) 6.66 (s, 1H) 7.86 (s, 2H) 7.99 (s, 1H)
Reaction SMILES: [OH:1][C@:2]([C@H:9]1[CH2:13][N:12]([C@H](C2C=CC(OC)=CC=2)C)[C:11](=[O:24])[CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3]>C(O)(C(F)(F)F)=O.CC(O)C>[OH:1][C@:2]([C@H:9]1[CH2:13][NH:12][C:11](=[O:24])[CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3]
Reactant: COc1ccc([C@H](C)N2C[C@H]([C@@](C)(O)c3nccs3)CC2=O)cc1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@](O)(c1nccs1)[C@H]1CNC(=O)C1
Temperature: 25 °C

Procedure:
A solution of (4R)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one (3.6 g, 10.4 mmol) in TFA (10 mL) was heated to 70° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with IPA (30 mL), and stirred until the color dissipated. The reaction mixture was then absorbed on silica gel and purified by silica gel chromatography to afford (4R)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidin-2-one. MS ESI calc'd. for C9H13N2O2S [M+H]+ 213. found 213. 1H NMR (600 MHz, DMSO-d6) δ 7.69 (d, J=3.2 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.35 (s, 1H), 6.12 (s, 1H), 3.08 (dd, J=9.1, 7.3 Hz, 1H), 2.96-2.86 (m, 1H), 2.82 (t, J=9.0 Hz, 1H), 2.22 (dd, J=16.8, 8.7 Hz, 1H), 2.14 (dd, J=16.8, 9.6 Hz, 1H), 1.42 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH2:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[F:14])[CH3:2].Cl[Sn]Cl>C1COCC1.Cl>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[F:14])[CH2:15][CH3:16])[CH3:2]
Reactant: CCN(CC)Cc1cc([N+](=O)[O-])ccc1F
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: CCN(CC)Cc1cc(N)ccc1F
Yield: 72.4 %

Procedure:
To a solution of diethyl-(2-fluoro-5-nitro-benzyl)-amine (0.155 mg, 0.69 mmoles) in THF (20 mL) was added a solution of SnCl2 (520 mg, 2.74 mmoles) in THF (5 mL) and HCl 1M (2.1 mL). The reaction mixture was refluxed for 8 h and concentrated. Saturated solution of NaHCO3 was added until pH8. Aqueous layer was extracted with CH2Cl2 (5×50 mL). The organic layer was dried over MgSO4, filtered, evaporated. Expected compound was precipited with MeOH and purified by TLC DCM/MeOH/NH4OH//9/1/0.2) and obtained as a yellow oil (98 mg, 73% yield). MALDI-TOF: m/z 197.2 [M+H]+. 1H NMR (300 MHz, CDCl3) δ6.80; (dd, J=8.7 Hz and 8.7 Hz, 1H), 6.75; (dd, J=5.7 Hz and 3.0, 1H), 6.49; (ddd, J=8.7 Hz, 3.9 Hz and 3.0 Hz, 1H), 3.65-3.75; (s large, 2H), 3.57; (s, 2H), 2.57; (q, J=7.2 Hz, 4H), 1.07; (t, J=7.2 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ118.2; (CH, d, J=3.8 Hz), 116.4; (CH, d, J=23.3 Hz), 115.7; (CH, d, J=7.9 Hz), 49.8; (CH2), 47.3; (CH2), 12.4; (CH3).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]1([CH3:24])[N:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:18]2[CH2:17][O:16]1.C(N(CC)CC)C>CN(C)C=O>[F:12][C:10]1[CH:9]=[CH:8][C:7]([CH3:13])=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:22]2[CH2:21][CH2:20][N:19]3[C:15]([CH3:24])([CH3:14])[O:16][CH2:17][CH:18]3[CH2:23]2)[CH:11]=1
Reactant: CC1(C)OCC2CNCCN21
Reactant: Cc1ccc(F)cc1NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1NC(=O)CN1CCN2C(COC2(C)C)C1
Temperature: 70 °C

Procedure:
A mixture of 6.6 parts of 2-chloro-N-(5-fluoro-2-methylphenyl)acetamide, 5 parts of hexahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine, 6.1 parts of N,N-diethylethanamine and 67.5 parts of N,N-dimethylformamide was stirred and heated for 8 hours at about 70° C. After cooling overnight to room temperature, the reaction mixture was evaporated. The residue was dissolved in trichloromethane. The solution was washed with water, dried, filtered and evaporated, yielding 8.5 parts of N-(5-fluoro-2-methylphenyl)-tetrahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine-7(8H)-acetamide as an oily residue (intermediate 121).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:31][C:32]#[N:33]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:31][C:32]#[N:33])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC#N)CCN(Cc2ccccc2)CC1=O
Temperature: 0 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed a solution of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (10 g, 38.27 mmol, 1.00 equiv) in tetrahydrofuran (80 mL). This was followed by the addition of a solution of KHMDS in tetrahydrofuran (42 mL, 1M) dropwise with stirring at 0° C., and 30 min later, 2-bromoacetonitrile (6.89 g, 57.44 mmol, 1.50 equiv) was added dropwise with stirring at 0° C. The resulting solution was stirred for 4 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:21]([OH:22])=[N:20][C:11]2[N:12]=[C:13](S(C)(=O)=O)[N:14]=[CH:15][C:10]=2[CH:9]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>CN1CCCC1=O.C(OCC)(=O)C>[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:13]2[N:14]=[CH:15][C:10]3[CH:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:21]([OH:22])=[N:20][C:11]=3[N:12]=2)[CH2:26][CH2:25]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CS(=O)(=O)c1ncc2cc(-c3ccccc3Cl)c(O)nc2n1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N[C@H]1CC[C@H](Nc2ncc3cc(-c4ccccc4Cl)c(O)nc3n2)CC1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
To a solution of sulfone 2 (1.27 g, 3.78 mmol) in 15 mL of 1-methyl-2-pyrrolidinone was added trans-1,4-diaminocyclohexane (3.75 g, 32.8 mmol). The reaction mixture was stirred at 65° C. for 1.5 hours, cooled, and diluted with 80 mL of ethyl acetate. The resulting suspension was filtered and washed several times with ethyl acetate and methanol. The solid was dried to yield 1.31 g (94%) of 2-(trans-4-aminocyclohexylamino)-6-(2-chlorophenyl)-pyrido[2,3-d]pyrimidin-7-ol as an off-white powder (mass spec. M+H+=370). The free base was taken up in ethyl acetate and treated with a 1 M solution of HCl/Et2O to form the dihydrochloride salt of the title compound as a white powder with a melting point of >300° C.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[O+]=1.[PH3:32]>C(O)CCC>[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[P:32]=1
Reactant: Cc1ccccc1-c1cc(-c2ccccc2)cc(-c2ccccc2C)[o+]1
Reactant: P
Agent: F[B-](F)(F)F
Solvent: CCCCO
Product: Cc1ccccc1-c1cc(-c2ccccc2)cc(-c2ccccc2C)p1

Procedure:
The reaction was carried out twice using 15 g (35 mmol) each time of 2,6-bis(2-methylphenyl)-4-phenylpyrylium tetrafluoroborate in 150 ml of n-butanol. The two autoclave products obtained after the reaction with PH3 were combined and evaporated to about 50 ml under reduced pressure at about 80° C. The solid which precipitated was filtered off with suction, washed with n-pentane and subsequently dissolved in toluene. The toluene solution was then washed with water until the aqueous phase was neutral. After removal of the solvent, the residue was suspended in methanol, and dichloromethane was then added until the solid had completely dissolved. The resulting solution was evaporated under reduced pressure at about 40° C. until a solid precipitated. The solid was filtered off with suction, washed with a little n-pentane and subsequently dried in a high vacuum. Yield: 15.6 g (63%) of white solid.