Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([OH:18])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[C:19]([O-])([O-])=O.[K+].[K+].CN(C=O)C.CI>CCOC(C)=O>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(O)c2ccn(C3CC3)c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a stirred suspension of 14.56 g of ethyl 1-cyclopropyl-4-hydroxy-1H-indole-6-carboxylate and 16.2 g of K2CO3 and 220 ml of DMF was added 7.48 ml of MeI and the mixture was stirred at 60° C. for 3 hrs. The mixture was allowed to cool, diluted with EtOAc, washed with water and saturated brine successively, dried over Na2SO4, then concentrated. The residue was purified on SiO2 column chromatography (n-hexane-EtOAc) to afford 15.15 g of ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][O:15][CH3:16])[C:8](=[O:17])[C:7](=[O:18])[NH:6]2.S(=O)(=O)(O)O.[I:26](O)(=O)=O.II>C(O)(=O)C.O>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[I:26])[N:9]([CH2:13][CH2:14][O:15][CH3:16])[C:8](=[O:17])[C:7](=[O:18])[NH:6]2
Reactant: COCCn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)ccc21
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COCCn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(I)cc21
Yield: 49.4 %

Procedure:
288 mg of 6-trifluoromethyl-1-(1-methoxyeth-2-yl)-1,2,3,4-tetrahydro-2,3-dioxoquinoxaline is mixed in 5 ml of glacial acetic acid with 0.05 ml of water, 0.012 ml of concentrated sulfuric acid, 34.4 mg of iodic acid and 88.4 mg of iodine and heated for 4 hours to 80° C. After concentration by evaporation, it is taken up in water, adjusted alkaline and extracted with methylene chloride. The organic phase is dried, filtered and concentrated by evaporation and the residue is chromatographed on silica gel with toluene:glacial acetic acid:water=10:10:1 as eluant. 40 mg of 6-trifluoromethyl-7-iodo-1-(1-methoxyeth-2-yl)-1,2,3,4-tetrahydro-2,3-dioxoquinoxaline is obtained. The residue is starting material, which can be used again in the reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[CH:18]4)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1COCC1.C(C(O)=O)(F)(F)F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2nc(-c3ccc4c(c3)CCN4)no2)cc1Cl
Yield: 98.7 %

Procedure:
To a solution of the product of Step E (0.11 g; 0.34 mmol) in 1M BH3 in THF (0.68 ml; 0.68 mmol) CF3CO2H (1 ml) was added drop wise at 0° C. with stirring. After the addition was completed (˜5 min) the reaction was quenched with H2O (0.5 ml) and the solvents were removed under reduced pressure. The residue was diluted to 15 ml with EtOAc and was washed with 1 M NaOH (2×2 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.11 g; 100%) as a creamy foam, which was used in the next step without further purification. 1H-NMR (CDCl3) 2.6 (broad s, 1H+H2O); 3.12 (tr, 2H, J=8.4 Hz); 3.66 (tr, 2H, J=8.4 Hz); 3.98 (s, 3H); 6.71 (d, 1H, J=8.1 Hz); 7.07 (d, 1H, J=8.7 Hz); 7.83-7.88 (m, 2H); 8.05 (dd, 1H, J=2, 8.7 Hz); 8.21 (d, 1H, J=2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO>[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:7]1[C:3]([O:2][CH3:1])=[N:4][S:5](=[O:11])(=[O:10])[N:6]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: COC1=NS(=O)(=O)N=C1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: COC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1C

Procedure:
To a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) [prepared according to the procedure described in J. Org. Chem., 40, 2743 (1975)] in 200 ml of methanol at ambient temperature was added a solution of 2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 2.73 g; 11.2 mmoles) [prepared according to Belgian Patent 779,775] in 25 ml of methanol. After stirring for 30 minutes, a methanolic solution of the title compound was produced. The TLC [Silica/CH2Cl2 :CH3OH (90:10)] gave Rf=0.44.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:27][S:28]([O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:10][CH:11]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of 2-(4-((tert-butyl(dimethyl)silyl]oxy}phenyl)ethanol (653 mg) and diisopropylethylamine (1.8 ml) in DCM (15 ml) at 0° under nitrogen was treated with methanesulfonyl chloride (0.44 ml) and the mixture was stirred at 0° C. for 6 h. Saturated NaHCO3 solution was added and the mixture stirred for 15 min. Water (20 ml) was added and the mixture was extracted with DCM. The extract was dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound (904 mg). LCMS RT=3.85 min.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:27]=1[CH:28]=O.C(Cl)Cl.CO>C1COCC1>[CH3:24][O:25][C:26]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:27]=1/[CH:28]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Reactant: Cc1ccc2nc(-c3ccc(CO[PH](=O)[O-])cc3)cn2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1/C=C/c1ccc(-c2cn3cc(C)ccc3n2)cc1
Yield: 74 %

Procedure:
Prepared as described in the Alkene Formation section using sodium hydride (60% dispersion in mineral oil, 33 mg, 0.838 mmol), diethyl[4-(6-methylimidazo[1,2-a]pyridin-2-yl)benzyl phosphonate (250 mg, 0.698 mmol) and 2-methoxy-4-nitrobenzaldehyde (126 mg, 0.698 mmol) in dry THF (15 ml) to give the title compound (199 mg, 74%) as an orange solid after work-up and flash chromatography (25:1 DCM/MeOH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O>CC(O)(C)C.O>[C:14]([O:13][C:11]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:10])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of γ-aminobutyric acid (1 equivalent) in t-BuOH (4 ml/gram) and H2O (3 ml/gram) was added NaOH (1 equivalent), BOC2O (1 equivalent), and the mixture was stirred at room temperature for 24 hours. The solvent was thereafter evaporated and the residue was partitioned between hexane and water. The aqueous layer was acidified with KHSO41N to reach pH=2, and was thereafter extracted with CH2Cl2. The organic layer was dried over MgSO4 and the solvent was evaporated to give the desired product as a white solid (85% yield).
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2cccc(C)n2)C[C@@H]1C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2cccc(C)n2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-2-methyl-4-[(6-methyl-2-pyridinyl)amino]-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate for a preparation see Intermediate 69) (107.9 mg, 0.208 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 1.5 h then concentrated in vacuo. The residue was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined and concentrated in vacuo to give a residue which was dissolved in DCM (5 mL). The resulting solution was treated with HCl (1M in Et2O, 0.22 mL, 0.220 mmol) then concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-(6-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (79.5 mg, 0.161 mmol, 77% yield) as a beige solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:36])/[CH:23]=[C:24](\[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)/[CH2:25][O:26][CH3:27])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[NH4+:47]>CO>[CH3:27][O:26][CH2:25]/[C:24](/[C:28]1[CH:29]=[C:30]([C:34]([NH2:35])=[NH:47])[CH:31]=[CH:32][CH:33]=1)=[CH:23]/[C:22](=[O:36])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:20][CH:19]=1
Reactant: [NH4+]
Reactant: COC/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC/C(=C/C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-4-methoxybut-2-enamide (150 mg, 0.298 mmol) in 10 ml 1:1 ethyl acetate:anhydrous methanol cooled to −78° C. was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (77 mg, 1 mmol) was added, and the reaction heated to reflux for 2 hours. The reaction was concentrated, treated with trifluoroacetic acid (10 ml) for 2 hrs, concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1E)-1-(methoxymethyl)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzenecarboxamidine (34 mg, (25%) as a fluffy off-white powder after lyophilization. ES-MS (M+H+): 465.15
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][S:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH2:41][C:42](O)=[O:43])[S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:42](=[O:43])[CH2:41][N:36]([C:33]1[CH:34]=[CH:35][C:30]([S:29][CH3:28])=[CH:31][CH:32]=1)[S:37]([CH3:40])(=[O:38])=[O:39]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CSc1ccc(N(CC(=O)O)S(C)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(N(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide 30 mg, 0.071 mmol), 2-(N-(4-(methylthio)phenyl)methyl-sulfonamido)acetic acid (39.3 mg, 0.143 mmol), DMAP (17.44 mg, 0.143 mmol), and EDC (41.1 mg, 0.214 mmol) were dissolved in DMF (1.5 ml). The reaction was stirred at RT overnight to achieve completion. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with HCl 1N, Na2CO3 sat. sol. and brine, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(N-(4-(methylthio)phenyl)methylsulfonamido)-acetoxy)ethyl)pyridine 1-oxide (20 mg, 41.3% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.C(N(CC)CC)C.[CH2:29]([Si:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[C:32]#[CH:33])[CH3:30]>[Cu]I.C1COCC1>[F:21][C:5]1[CH:4]=[CH:3][C:2]([C:30]#[C:29][Si:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:7][C:6]=1[C@:8]1([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]1
Reactant: C#C[Si](CC)(CC)CC
Reactant: NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[Si](C#Cc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1)(CC)CC
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 76 %

Procedure:
A 25 mL microwave vial was charged with (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.465 g, 3.93 mmol), triethylamine (2.74 mL, 19.63 mmol), 10 mL of THF, triethyl(ethynyl)silane (2.176 mL, 11.78 mmol), Pd(0) tetrakis(triphenylphosphine) (0.343 g, 0.297 mmol), and copper(I) iodide (0.112 g, 0.589 mmol). The resulting mixture was then heated at 110° C. for 30 min in a Biotage microwave synthesizer (waited for 25 min to get on the instrument). The solids were filtered off and the solvent was removed under vacuum and the residue was redissolved in 60 mL of EtOAc, washed with 50 mL of saturated NH4Cl solution twice, dried (Na2SO4) and concentrated to give an oil that was purified by Shoko silica gel instrument (pre-packed GRACE column 120 g, with EtOAc in hexane as eluent, 0-10% 17 min; 10% 8 min; 10-30% 5 min; 30% 10 min) to give the titled compound as a light yellow oil, 1.285 g, 76% yield. MS m/z=433.0 [M+H]+. Calculated for C20H25F5N2OSi: 432.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[C:43]1[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[CH:45][N:44]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:43]4[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[CH:45][N:44]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(S(C)(=O)=O)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of 20 mg (0.043 mmol) [(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester, 11.2 uL (0.065 mmol) DIPEA and 12.8 mg (0.054 mmol) 2-bromo-5-(methylsulfonyl)pyridine in 1 mL DMF was heated to 60° C. over night. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions the title compound as light yellow viscous oil. MS m/e: 615.3 [M]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.CS[C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18].C(O)C>CO.ClCCl>[N+:17]([CH:16]=[C:15]1[NH:12][CH2:11][CH2:10][CH2:9][N:8]1[C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([O-:19])=[O:18]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCNc1ccc(Cl)nc1
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])C=C1NCCCN1c1ccc(Cl)nc1
Yield: 38 %

Procedure:
A mixture of N-(6-chloro-3-pyridyl)-1,3-diaminopropane (6.0 g, 0.032 mol)(ex Example 2), 1,1-bis(methylthio)-2-nitroethene (5.34 g, 0.032 mol) and ethanol (100 ml) was heated under reflux for 24 hours. The resulting mixture was evaporated to leave a dark brown oil which was subjected to flash chromatography on a silica column using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), and with 2% w methanol in dichloromethane as eluent. The resulting product was recrystallized from ethanol to give 2-nitromethylene-1-(6-chloro-3-pyridyl)hexahydropyrimidine as a pale yellow solid (3.1 g, 38%), m.p. 202° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=O)[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:4][CH:3]=1.[CH3:26][NH:27][NH2:28].O>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[N:28][NH:27][CH3:26])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:4][CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3cc(C=O)oc23)c1=O
Reactant: CNN
Solvent: O
Solvent: C1CCOC1
Product: CNN=Cc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
0.4 g (1.0 mmol) of 3-(4-chloro-2-formylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 5 ml of tetrahydrofuran, and 0.1 g (21.7 mmol) of monomethylhydrazine was added thereto under cooling with ice, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.2 g (yield: 47.6%) of the desired product as a pale yellow glassy substance. Refractive index: unmeasurable, 1H-NMR (solvent, CDCl3): 2.90(3H,s), 3.52(3H,s), 6.18(1H,bs), 6.40(1H,s), 6.85(1H,s), 7.05 (1H,d), 7.25(1H,s), 7.29(1H,d) ppm
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5]1.[C-:29]#[N:30].[Na+]>CS(C)=O.O.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][C@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:7][C@@H:6]([C:29]#[N:30])[CH2:5]1
Reactant: [C-]#N
Reactant: COC[C@H]1C[C@H](S(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC[C@@H]1C[C@H](C#N)CN1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
trans-5-Methoxymethyl-3-tosyl-Cbz-pyrrolidine (3.55 g, 8.8 mmol) was dissolved in DMSO (8.8 mL). Finely ground NaCN(0.65 g, 13.2 mmol) was added, and the resulting reaction mixture was stirred 4 h at 80° C. The solution was cooled to room temperature, diluted with H2O (9 mL) and brine (9 mL), and extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with hexanes/ethyl acetate (2/1, v/v) to afford 2.09 g (87% yield) of the desired product as an oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([Li])[CH2:15][CH2:16][CH3:17].[O:19]1CC[CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[CH:17]1([CH2:21][C:20]([N:9]2[CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:19])[CH2:16][CH2:15][CH2:14]1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Solvent: ClC(Cl)Cl
Product: O=C(CC1CCC1)N1C(=O)OCC1Cc1ccccc1
Reaction time: 0.08 h
Yield: 58 %

Procedure:
To (S)(-)-4-benzyl-2-oxazolidinone (2.65 g, 1.8 equiv) dissolved in tetrahydrofuran (25 mL) at -78° C. was added 2.5M butyl lithium (5.98 mL, 1.8 equiv). After 5 minutes, this solution was cannulated into the above solution. The reaction mixture was allowed to come to room temperature and stirred for 2 hours. The reaction mixture was diluted with chloroform (150 mL), washed with 10% sodium bisulfite (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane/ethyl acetate to afford the title compound in 58% yield.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C@H:7]1[CH2:12][C:11]([CH3:13])=[CH:10][CH2:9][N:8]1[C:14](=[O:40])[C@H:15]([CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)[NH:16][S:17]([C:20]1[CH:29]=[C:28]2[C:23]([CH2:24][CH2:25][N:26]([CH3:30])[CH2:27]2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:6])[CH3:3].[Cl-:41].[NH4+:42]>C(O)C>[ClH:41].[CH2:2]([O:4][C:5]([C@H:7]1[CH2:12][C:11]([CH3:13])=[CH:10][CH2:9][N:8]1[C:14](=[O:40])[C@H:15]([CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38](=[NH:42])[NH2:39])[CH:33]=1)[NH:16][S:17]([C:20]1[CH:29]=[C:28]2[C:23]([CH2:24][CH2:25][N:26]([CH3:30])[CH2:27]2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@H]1CC(C)=CCN1C(=O)[C@H](Cc1ccnc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C)CC2
Reactant: [NH4+]
Reactant: [Cl-]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC(C)=CCN1C(=O)[C@H](Cc1ccnc(C(=N)N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C)CC2
Product: Cl
Reaction time: 1 h
Yield: 66.1 %

Procedure:
Sodium metal (30 mg, 1.3 mmol) was added to a stirred solution of 4-methyl-1-[N-(2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulphonyl)-3-(2-cyano-4-pyridyl)-(S)-alanyl]-1,2,3,6-tetrahydropyridine-2(R)-carboxylic acid ethyl ester (Preparation 54; 243 mg, 0.44 mmol) in ethanol (4 ml) at room temperature. After 1 hour, ammonium chloride (140 mg, 2.6 mmol) was added and the resulting mixture stirred for 18 hours and then filtered. Evaporation under reduced pressure of the filtrate followed by purification of the residue by chromatography on silica gel, using dichloromethane:methanol:0.880 aqueous ammonia solution (90:10:1) as eluent, furnished the title compound (176 mg) as a foam. Rf 0.21 (SS 13). Found: C,55.64; H,6.31; N,13.47. C28H36N6O5S; HCl requires C,55.56; H,6.16; N,13.88%.
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[NH:6][CH2:5][CH2:4][O:3]1.C1C=CC=CC=1.C(N(CC)CC)C.[Cl:21][CH:22]([Cl:26])[C:23](Cl)=[O:24]>O>[CH3:1][C:2]1([CH3:7])[N:6]([C:23](=[O:24])[CH:22]([Cl:26])[Cl:21])[CH2:5][CH2:4][O:3]1
Reactant: CC1(C)NCCO1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)OCCN1C(=O)C(Cl)Cl

Procedure:
Five and one-tenth (5.1g.) grams of 2,2-dimethyl oxazolidine dissolved in 50 ml. of benzene was treated with 5.5 g. of triethylamine and 7.4 g. of dichloroacetyl chloride was added dropwise with stirring and cooling in an ice bath. The mixture was poured into water, the benzene solution separated, dried over anhydrous magnesium sulfate and the solvent stripped under vacuum. The product was a waxy solid which had a melting point of 113°-115° C. on recrystallization from diethyl ether.