Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4](=[O:6])[CH3:5].[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[O:9][CH2:8][C:3]([C:4]([CH3:5])=[O:6])([CH3:7])[CH2:2][O:1]2)=[CH:14][CH:13]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(=O)C(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)C1(C)COC(c2ccc(N(C)C)cc2)OC1

Procedure:
3,3-bis(Hydroxymethyl)butanone (29.0 g), p-dimethylaminobenzaldehyde (29.8 g), toluene-p-sulphonic acid (250 mg) and toluene (140 ml) were heated under reflux in a Dean and Stark water trap until the theoretical amount of water had separated. The solution was concentrated in vacuo, the crude residue was washed with 8% aqueous sodium bicarbonate solution (100 ml) and crystallised from petroleum ether (b.p. 80°-100°)/ethyl acetate as a crystalline solid m.p.118°-120° (Cis-trans 96:4).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[Cl:14].S(Cl)(Cl)=O.O.N.[CH3:21]O>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([O:13][CH3:21])=[O:12])[C:3]=1[Cl:14]
Reactant: CO
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Agent: N
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 5 °C

Procedure:
To a solution of 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid (i.e. the product of Step D1 or D2 of Example 2) (2.0 g, 8.5 mmol) in methanol (20 mL) was added dropwise thionyl chloride (4 mL, 70 mmol). The mixture was heated at reflux for 24 h. Concentrated sulfuric acid (5 drops) was added, and the reaction mixture was heated at reflux for 16 h. After the mixture was cooled, water (30 mL) was added, and aqueous ammonia (28%, 10 mL) was added dropwise. The mixture was cooled to 5° C., and the solid was isolated by filtration, washed with water and dried in a vacuum oven at 40° C. to afford the title product (2.3 g), a compound of the present invention.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Ic1ccccn1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.5 %

Procedure:
A mixture of 2-iodopyridine (1.00 g, 4.88 mmol), picolinic acid (0.060 g, 0.488 mmol), copper(I) iodide (0.046 g, 0.244 mmol), cesium carbonate (4.77 g, 14.63 mmol) and diethyl malonate (1.563 g, 9.76 mmol) in dioxane (10 mL) was stirred under nitrogen at room temperature for 15 h. The mixture was diluted with ethyl acetate (200 mL), washed with saturated ammonium chloride (20 mL), water (20 mL), brine (20 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane-hexanes (1:1) and eluting with 5 to 30% ethyl acetate in hexanes, gave diethyl 2-(pyridin-2-yl)malonate (700 mg, 42% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.58 (1H, δ, J=4.77 Hz), 7.71 (1H, dd, J=7.78, 1.51 Hz), 7.50 (1H, δ, J=7.78 Hz), 7.18-7.24 (1H, m), 4.94 (1H, s), 4.14-4.32 (4H, m, J=7.15, 7.15, 7.03, 3.51 Hz), 1.19-1.35 (6H, m); MS (ES+) m/z: 238 (M+H); LC retention time: 1.88 min (analytical HPLC Method A).
Reaction SMILES: C(C(CC)(OC1C=CC(CCN[C:17]([C:19]2[S:27][C:26]3[CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][C:21]=3[CH:20]=2)=[O:18])=CC=1OCC([O-])=O)C([O-])=O)C.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=C[CH:48]=1>ClCCl>[C:17]([C:19]1[S:27][C:26]2[CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:22][C:21]=2[CH:20]=1)(=[O:18])[CH3:48]
Reactant: CCC(CC)(Oc1ccc(CCNC(=O)c2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)cc1OCC(=O)[O-])C(=O)[O-]
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Product: CC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.67 h
Yield: 92 %

Procedure:
To the solution of the compound prepared in (a) (847 in dichloromethane (30 ml) was added Molecular Sieves 4A (3 g), followed by pyridinium chlorochromate (966 mg) under ice-cooling. The mixture was stirred for 40 minutes. After the reaction mixture was filtered through FLORISIL, the filtrate was concentrated to give 772 mg of 2-acetyl-5-t-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (yield, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:10][C:11]([NH:14][NH:15][C:16](=O)[CH2:17][C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)=[N:12][CH:13]=1.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:10][C:11]2[N:12]([C:16]([CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)=[N:15][N:14]=2)[CH:13]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)nc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Solvent: CC(=O)O
Solvent: CCO
Product: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)cn23)cn1
Temperature: 25 °C

Procedure:
A solution of N′-(5-(2-chlorophenyl)-4-(4-chlorophenyl)pyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetohydrazide (40 mg, 0.075 mmol) and acetic acid (0.25 mL) in ethanol (0.5 mL) was heated in a microwave oven at 180° C. for 45 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was taken into EtOAc, and the solution was washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-70%) in hexanes to obtain the product with about 85% purity as an oil. The product was further purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 50% to 100% B, 10 min gradient, 100% B hold for 4 min, (A=90% H2O, 10% MeOH, 0.1% TFA and B=10% H2O, 90% MeOH, 0.1% TFA); Flow rate at 20 mL/min, UV detection at 220 nm) to yield the desired product, which was taken into EtOAc, washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The residue was lyophilized in acetonitrile to afford 9 mg (24% yield, 99% pure) of the title compound as a white powder. HPLC/MS (method A): retention time=3.88 min, [M+H]+=499.0.
Reaction SMILES: Br[C:2]1[C:3]([F:20])=[CH:4][C:5]2[CH:17]3[CH2:18][CH:15]([CH2:16]3)[C:8]3[S:9][C:10]([C:12]([NH2:14])=[O:13])=[CH:11][C:7]=3[C:6]=2[CH:19]=1.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O.C(N(CC)CC)C>[F:20][C:3]1[C:2]([C:25]#[C:24][C:22]([OH:26])([CH3:23])[CH3:21])=[CH:19][C:6]2[C:7]3[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[S:9][C:8]=3[CH:15]3[CH2:16][CH:17]([C:5]=2[CH:4]=1)[CH2:18]3
Reactant: NC(=O)c1cc2c(s1)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)c1sc(C(N)=O)cc1-2
Temperature: 80 °C
Reaction time: 0.03 h
Yield: 62.5 %

Procedure:
Into a pressure tube containing a solution of 9-bromo-8-fluoro-5,6-dihydro-4H-4,6-methanobenzo[3,4]cyclohepta[1,2-b]thiophene-2-carboxamide (31 mg, 0.08 mmol) in 1:1 N,N-dimethylformamide/triethylamine (0.8 mL) was introduced 2-methyl-3-butyn-2-ol (181 mg, 2.16 mmol), copper(I) iodide (2 mg, 0.01) and nitrogen gas bubbled through the solution for 3 minutes. Bis(triphenylphosphine)palladium(II) chloride (8 mg, 0.01 mmol) was added and nitrogen bubbling continued a further two minutes before the pressure tube was closed under nitrogen. The reaction mixture was warmed to 80° C. for 20 hr, re-treated with 2-methyl-3-butyn-2-ol (181 mg, 2.16 mmol), copper(I) iodide (2 mg, 0.01) and bis(triphenylphosphine)palladium(II) chloride (8 mg, 0.01 mmol) and warmed to 100° C. for an additional 7 hr. After cooling to room temperature, the reaction mixture was evaporated in vacuo and the residue re-dissolved in ethyl acetate (20 mL). This solution was washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered and the filtrate absorbed onto silica gel. Purification by silica gel flash column chromatography (eluent:heptane/ethyl acetate) furnished partially purified product as a brown solid. After several acetonitile solubilisation-evaporation (in vacuo) cycles, the resulting solid residue was slurried in acetonitrile (1.0 mL) and collected by filtration to furnish the title compound (17 mg, 0.05 mmol, 62%) as a pale-brown solid: 1H NMR (500 MHz, CDCl3) δ1.68 (s, 6H), 1.71-1.73 (m, 2H), 2.87-2.96 (m, 2H), 3.53-3.62 (m, 2H), 6.87 (d, J=10.09 Hz, 1H), 7.92 (d, J=6.94 Hz, 1H), 8.06 (s, 1H); M+H=356.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][O:8][CH3:9].CC([O-])(C)C.[K+].CS[C:18](SC)=[CH:19][N+:20]([O-:22])=[O:21]>C(O)C>[CH3:9][O:8][N:7]1[CH2:6][CH2:5][CH2:4][NH:3][C:18]1=[CH:19][N+:20]([O-:22])=[O:21]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CONCCCN
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CON1CCCNC1=C[N+](=O)[O-]

Procedure:
2.0 g (0.011 mol) of 1-amino-3-methoxyaminopropane dihydrochloride and 2.53 g (0.023 mol) of potassium tert-butylate are refluxed in 120 ml of ethanol for 1 hour. Subsequently, 1.86 g (0.011 mol) of 1,1-bis(methylthio)-2-nitroethylene is added and the mixture is refluxed for a further 6 hours until no more gas evolves. The salts are separated off by filtration and the solvent is removed. The crude product is purified by flash chromatography using toluene/ethanol as developer. The desired product is obtained as slightly yellowish crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[O:33])[CH:26]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[C:4](=[O:3])[C:6]3[CH:7]=[N:8][C:9]4[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[N:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[C:32]2=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCCC3)c12
Yield: 27.2 %

Procedure:
3-(3-Chloro-phenyl)-1-cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (55 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.48 mmol) and 1-chloro-3-isocyanato-benzene (0.72 mmol) following general procedure C. LCMS: m/z 422 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].Br[CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: CC(Br)c1ccnc2ncnn12
Reactant: Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(F)cc1F)c1ccnc2ncnn12
Reaction time: 0.5 h

Procedure:
A solution of 2,4-difluorophenol (1.30 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue was dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of dichloromethane and ethanol (in the ratio 97:3 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-[1-(2,4-difluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 1.8 g, (m.p. 96°-97° C.).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]([CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:7]([C:9]1[N:13]=[CH:12][N:11]([CH3:14])[N:10]=1)=[O:8].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].NC1CCCCC1N>C(Cl)(Cl)Cl.[Cu](I)I.O1CCOCC1>[N:24]1([C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[CH2:5][N:6]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:7]([C:9]2[N:13]=[CH:12][N:11]([CH3:14])[N:10]=2)=[O:8])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: Cn1cnc(C(=O)N(Cc2cccc(I)c2)C2CCOCC2)n1
Reactant: c1c[nH]cn1
Agent: I[Cu]I
Agent: NC1CCCCC1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cn1cnc(C(=O)N(Cc2cccc(-n3ccnc3)c2)C2CCOCC2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
A mixture of N-(3-iodobenzyl)-1-methyl-N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,4-triazole-3-carboxamide (100 mg), imidazole (38 mg), copper iodide (9 mg), cesium carbonate (321 mg), 1,2-diaminocyclohexane (23 μL) and dioxane (1 mL) was stirred overnight at 120° C. After being left to cool, the mixture was diluted with chloroform, and the chloroform layer was washed with 12% aqueous ammonia and saturated saline, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvents were distilled off under reduced pressure and the resulting residue was purified by column chromatography (NH silica gel cartridge; hexane, ethyl acetate, chloroform/methanol=100:0 to 90:10) to give the titled compound (17 mg).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH3:7][NH:8][C:9]([C:11]1[C:15]2[CH:16]=[C:17]([O:26][CH2:27][CH3:28])[C:18]([N:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH3:21])=[CH:19][C:14]=2[O:13][C:12]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:10]>C(#N)C>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:12]2[O:13][C:14]3[CH:19]=[C:18]([N:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH3:21])[C:17]([O:26][CH2:27][C:28]4[CH:14]=[CH:15][C:11]([C:1]([OH:2])=[O:4])=[C:12]([OH:13])[CH:29]=4)=[CH:16][C:15]=3[C:11]=2[C:9](=[O:10])[NH:8][CH3:7])=[CH:30][CH:31]=1
Reactant: O=C([O-])[O-]
Reactant: CCOc1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2cc1N(C)S(C)(=O)=O
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(OCc3ccc(C(=O)O)c(O)c3)cc12
Yield: 192.8 %

Procedure:
Preparation of compound 39(c) (5-(2,2-dimethyl-4-oxo-4H-benzo[1,3]dioxin-7-ylmethoxy)-2-(4-fluoro-phenyl)-6-(methanesulfonyl-methyl-amino)-benzofuran-3-carboxylic acid methylamide). Potassium carbonate (0.19 g, 1.38 mmol) and compound 39(b) (0.25 g, 0.917 mmol) were added to a solution of compound 38(d) (0.18 g, 0.459 mmol, which can be prepared according to Example 38 step d above), in acetonitrile (15 mL). The reaction mixture was refluxed for 4 hours and then concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with water. The organic layer was concentrated to a solid, which was triturated in 20% ethyl acetate/hexanes, filtered, and dried to provide 240 mg (90%) of the desired product as an off-white solid.
Reaction SMILES: C(OC(=O)[N:7]=[C:8]([NH:27]C(OC(C)(C)C)=O)[N:9]([CH3:26])[CH2:10][C:11](=[O:25])[N:12]1[C@H:17]([CH2:18][OH:19])[C@@H:16]([OH:20])[CH:15]([OH:21])[C@H:14]([OH:22])[C@H:13]1[CH2:23][OH:24])(C)(C)C>FC(F)(F)C(O)=O.O>[CH3:26][N:9]([CH2:10][C:11](=[O:25])[N:12]1[C@H:17]([CH2:18][OH:19])[C@@H:16]([OH:20])[CH:15]([OH:21])[C@H:14]([OH:22])[C@H:13]1[CH2:23][OH:24])[C:8]([NH2:27])=[NH:7]
Reactant: CN(CC(=O)N1[C@H](CO)[C@@H](O)C(O)[C@H](O)[C@H]1CO)C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(CC(=O)N1[C@H](CO)[C@@H](O)C(O)[C@H](O)[C@H]1CO)C(=N)N

Procedure:
In a dry, round bottomed flask, equipped with a magnetic stirrer, 10.12 g (0.020 mol) of tert-butyl(tert-butoxycarbonylamino)(methyl(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6-bis(hydroxymethyl)piperidin-1-yl)ethyl)amino)methylenecarbamate is dissolved in 150 mL of a trifluoroacetic acid:H2O (1:1) mixture. The resultant mixture is stirred for 2 hours at room temperature, after which it is concentrated under reduced pressure and then purified by flash chromatography (ethyl acetate/hexanes; 1/5) to yield the creatine homomannojirimycin amide, 1-methyl-1-(2-oxo-2-((2R,3R,5R,6R)-3,4,5-trihydroxy-2,6-bis(hydroxymethyl)piperidin-1-yl)ethyl)guanidine.
Reaction SMILES: [C:1]([NH:9]/[C:10](/SC)=[N:11]/[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([NH:29][NH2:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:22]([N:29]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NNCc1ccccc1
Reactant: CS/C(=N\C(=O)c1ccccc1)NC(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc(-c2ccccc2)n(Cc2ccccc2)n1)c1ccccc1
Reaction time: 48 h

Procedure:
To a stirred solution of the crude (Z)-methyl N,N′-dibenzoylcarbamimidothioate (0.895 g, 3 mmol) in DMF (8 ml) was added benzylhydrazine (0.367 g, 3.00 mmol) at 40° C. The reaction was stirred for 2 days. The stirred reaction was diluted with water. The resulting precipitates were collected to yield the crude N-(1-benzyl-5-phenyl-1H-1,2,4-triazol-3-yl)benzamide. LCMS method A, (M+H)+355.1, ret T=1.32 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1.[BH4-].[Na+]>CO.O>[OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCCCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCCCC(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of tert-butyl 3-oxocycloheptylcarbamate (31.09 g, 137 mmol) in methanol (454 mL) was added sodium borohydride (15.52 g, 410 mmol) portion-wise over ˜10 minutes with mixing. The resulting solution was stirred for 2 h at room temperature and then diluted with water (200 mL). The methanol was removed in-vacuo and the resulting aqueous mixture was diluted further with 500 mL ethyl acetate and 100 mL saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer back-extracted with 2×1000 mL ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil that was purified by silica gel chromatography (0-50% ethyl acetate in hexanes). Product containing fractions were concentrated to afford tert-butyl 3-hydroxycycloheptylcarbamate (21.1 g, 92 mmol, 67.3% yield). MS (ESI) m/z 230.3 [M+H]+. The above two reactions were repeated starting with 9.52 g cyclohept-2-enone and yielding 9.27 g of tert-butyl 3-hydroxycycloheptylcarbamate. The two batches of tert-butyl 3-hydroxycycloheptylcarbamate were then combined. 29.2 g of the combined material was separated into the 4 constituent stereoisomers (two diastereomers and their corresponding enantiomers) by preparative chiral SFC utilizing multiple injections over a series of 3 separate columns. First column: ChiralPak IC-H, 250×30 mm I.D., isocratic 15% ethanol in CO2, 38° C. Second column: ChiralCel OJ-H, 250×30 mm I.D., isocratic 10% isopropanol in CO2, 38° C. Third column: ChiralPak AD-H, 250×50 mm I.D., isocratic 20% isopropanol in CO2, 38° C. The separated isomers were characterized on an analytical scale Phenomenex Lux Amylose-2 column, 250×4.6 mm I.D., isocratic 15% ethanol in CO, (10 min run time) and labeled as Intermediate 1 to Intermediate 4.
Reaction SMILES: [CH:1]([NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([C:26]3[C:31]([CH3:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[S:23][C:22]=2[CH:34]=1)(=[O:17])=[O:16])([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(N(C(C)C)CC)(C)C.[NH2:44][CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]1>O1CCOCC1>[CH:1]([NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([C:26]3[C:31]([CH3:32])=[CH:30][N:29]=[C:28]([NH:44][CH2:45][CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]4)[N:27]=3)[S:23][C:22]=2[CH:34]=1)(=[O:17])=[O:16])([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: CN1CCN(CCCN)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(S(=O)(=O)NC(c3ccccc3)c3ccccc3)cc2s1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(S(=O)(=O)NC(c3ccccc3)c3ccccc3)cc2s1
Temperature: 97 °C

Procedure:
To a stirred suspension of 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-6-sulfonic acid benzhydrylamide (457 mg, 0.903 mmol) in dry 1,4-dioxane (4.5 mL) is added diisopropylethylamine (0.315 mL, 1.81 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (213 mg, 1.35 mmol). The mixture is heated at 97° C. for 1 day. After concentration and subsequent chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane: 0-10%, the title compound is obtained as a yellow solid (317 mg, 57% yield). ES+(m/z) 627 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8](=[N:10][OH:11])[NH2:9])[NH:5][C:6]=1[Cl:7].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCOCC1>[C:19]([O:11][N:10]=[C:8]([C:4]1[NH:5][C:6]([Cl:7])=[C:2]([Cl:1])[N:3]=1)[NH2:9])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=NO)c1nc(Cl)c(Cl)[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=NOC(=O)c1ccccc1)c1nc(Cl)c(Cl)[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
19.5 g (0.1 mol) of 4,5-dichloro-imidazole-2-carbamide-oxime and 10.1 g (0.1 mol) of triethylamine were dissolved in 150 ml of dioxane. 14.05 g (0.1 mol) of benzoyl chloride were added dropwise to this solution at 15°-20° C. The mixture was stirred for a further 1 hour at room temperature and for 2 hours at 50° C. and was then introduced into 500 ml of water. The crystals which had separated out were filtered off, washed with water and dried. 18 g (60.2% of theory) of 4,5-dichloro-imidazole-2-carbamide-O-benzoyl-oxime were obtained. Melting point: 177°-178° C. (from toluene).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]([C@H:21]1[C:24](=[O:25])[NH:23][C@@H:22]1[CH2:26][C:27]([OH:29])=[O:28])([O:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:9])[CH3:6]>CCOCC.C(Cl)Cl.CO.C(O)(=O)C>[CH3:6][C:5]([C@H:21]1[C:24](=[O:25])[NH:23][C@@H:22]1[CH2:26][C:27]([O:29][CH3:3])=[O:28])([O:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)=[O:9])[CH3:4]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)O
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C[C@H]1NC(=O)[C@@H]1C(C)(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of diazomethane in ether (1 ml) was added to a solution of [(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl]-acetic acid (29 mg) in a mixture of methylene chloride (1 ml) and methanol (1 ml) at 0° C. and the mixture was stirred for 15 minutes at 0° C. Acetic acid (1 drop) was added to the mixture at 0° C. and the mixture was evaporated in vacuo. The residue was chromatographed on silica gel (1 g) eluting with a mixture of methylene chloride and ethyl acetate (10:1) to give methyl [(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl]acetate (31 mg).