Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:64][C@H:65]([C:70](O)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:64][C@@H:65]([CH2:66][CH:67]([CH3:69])[CH3:68])[C:70]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:71]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a solution of ethyl 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoate (11, 200 mg, 0.48 mmol), DCC (120 mg, 0.58 mmol) and DMAP (6 mg, 0.048 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (168 mg, 0.48 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 30% ethyl acetate in petroleum ether as an eluent to yield 150 mg (60%) of the title compound as a colorless semi solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([O:21]CC3C=CC=CC=3)=[O:20])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([OH:21])=[O:20])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CC(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)C(=O)O
Yield: 90.7 %

Procedure:
A solution of benzyl 3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionate (630 mg) in methanol (10 ml) was hydrogenated under 40 PSI pressure for 18 hours in the presence of palladium on charcoal (63 mg, 10%). The catalyst was removed by filtration and the solvents were removed in vacuo to give 3-[4(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionic acid (460 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:28])=[CH:16][C:17]([NH:18]CC3C=CC(OC)=CC=3)=[C:12]2[N:11]=[C:10]1[CH3:29].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O>C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:28])=[CH:16][C:17]([NH2:18])=[C:12]2[N:11]=[C:10]1[CH3:29]
Reactant: COc1ccc(CNc2cc(C)nc3c2nc(C)n3-c2ccc(Cl)cc2Cl)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(N)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 0 °C

Procedure:
Stir a solution of [3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-yl](4-methoxybenzyl)amine (4.23 g, 10 mmol), anisole (3.2 mL, 29.6 mmol), trifluoroacetic acid (80 mL), and concentrated sulfuric acid (2 mL) at ambient temperature for 14 h. Add the resulting mixture dropwise to ice-water and dilute with NaHCO3. Filter the resulting precipitate and wash thoroughly with water to obtain the title compound as a brown solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(O)(=O)C.[CH2:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:34].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH2:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:28][CH:27]=2)[CH2:37][CH2:36]1)[CH3:34]
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.54 mmol) in dichloromethane (30 mL) was added acetic acid (1 mL) followed by the addition of 1-ethylpiperazine (121 mg, 1.63 mmol). After the addition, the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. NaBH(OAc)3 (173 mg, 0.81 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. dichloromethane was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by prep-HPLC to give 8-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (135 mg, yield 47%) as white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.22 (t, 3H), 2.36-2.44 (m, 1H), 2.74-3.11 (m, 8H), 4.01-4.10 (m, 3H), 4.33 (dd, 1H), 4.78 (dd, 1H), 7.13-7.31 (m, 10H), 7.37 (d, 1H), 7.47 (s, 1H), 7.58 (t, 3H); LC-MS (ESI) m/z: 452(M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N:9]([CH2:12][CH3:13])=[C:10]=[O:11]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:10]([NH:9][CH2:12][CH3:13])=[O:11])[CH:3]=1
Reactant: Nc1cc(Br)ccn1
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1cc(Br)ccn1
Temperature: 110 °C
Yield: 76.2 %

Procedure:
To a mixture of 4-bromopyridin-2-amine (2 g, 11.56 mmol) in chloroform (10 mL), isocyanatoethane (0.913 mL, 11.56 mmol) was added, and the resulting reaction mixture was heated at 110° C. for 2 h. The reaction mixture was concentrated under reduced pressure and triturated with acetonitrile, then collected by filtered to give the title compound as a white solid (2.15 g).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cu](C#N)[C:14]#[N:15]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1[C:14]#[N:15]
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1N
Reaction time: 0.08 h

Procedure:
In a 20 mL microwave vial, 2-bromo-4-(trifluoromethyl)aniline (238 mg, 1 mmol) and copper cyanide (90 mg, 1 mmol) were dissolved in N-methylpyrrolidone (NMP) (10 mL). The reaction was placed in a microwave reactor for 5 minutes at 200° C. The crude was dissolved in ethyl acetate and the precipitate was removed by filtration. The clear solution was washed with water. The organic layer was collected, dried over sodium sulfate, and evaporated under vacuum. The residue was purified by Varia HPLC (10% acetonitrile/water) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:9]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)=[N:8][C:7]=2[N:6]([CH3:34])[C:5]1=[O:35].[CH3:36][CH:37]([S:39](Cl)(=[O:41])=[O:40])[CH3:38]>C(Cl)Cl.O>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:4]([CH2:3][CH2:2][NH:1][S:39]([CH:37]([CH3:38])[CH3:36])(=[O:41])=[O:40])[C:5](=[O:35])[N:6]([CH3:34])[C:7]=3[N:8]=[C:9]2[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:31])[F:32])[CH:24]=2)=[CH:20][CH:19]=1
Reactant: Cn1c(=O)n(CCN)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)S(=O)(=O)NCCn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 16.5 %

Procedure:
To a solution of 1-(2-aminoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.197 mmol) and TEA (40 mg, 0.393 mmol) in DCM (10 mL) was added propane-2-sulfonyl chloride (42 mg, 0.295 mmol) dropwise at 0° C. The resulting mixture was stirred at 40° C. for 16 h. The mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product. This crude material was recrystallized from ethanol to give N-(2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)propane-2-sulfonamide (20 mg, 16.5% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.63-7.59(t, 1H), 7.48(s, 1H), 7.45-7.41(m, 5H), 7.35-7.33(d, 1H), 7.26-7.18(m, 1H), 5.45(s, 2H), 4.01-3.97(t, 1H), 3.29(s, 6H). LCMS retention time 3.195 min; LCMS MH+ 616.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1>C(O)C.[Pd]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH:9]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=2)[OH:10])=[CH:16][CH:15]=1
Reactant: COc1cccnc1C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COc1cccnc1C(O)c1ccc(N)cc1
Reaction time: 3 h
Yield: 91 %

Procedure:
A mixture of (3-methoxypyridin-2-yl)-(4-nitrophenyl)methanol (600 mg) and 5% Pd—C (0.06 g) in ethanol (20 ml) was vigorously stirred under hydrogen atmosphere for 3 hours, and the Pd—C was filtered off. The filtrate was concentrated under reduced pressure to give (4-aminophenyl)-(3-methoxypyridin-2-yl)-methanol (483 mg) as pale yellow crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][N:11]([CH3:20])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[OH-].[Na+]>CO.[Al]>[C:4]1([C:1](=[O:3])[CH:2]=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([N:11]([CH3:20])[CH3:10])=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Al]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1ccc(C=CC(=O)c2ccccc2)cc1
Reaction time: 48 h

Procedure:
Acetophenone (28.0 g, 0.15 mole) and 4-dimethylaminobenzaldehyde (22.35 g, 0.15 mole) were dissolved in methanol (150 ml) in a 500 ml, 3-necked round bottom flask. The flask was wrapped in aluminium foil to exclude light and was fitted with a mechanical stirrer and a water cooled condenser. The third neck was stoppered and used to obtain samples for monitoring during the reaction. Aqueous sodium hydroxide solution (50 ml of 30% w/v) was added dropwise to the vigorously stirred clear methanolic solution. A yellow/orange solid started separating from the reaction solution (which had turned orange) after about 24 hours. Stirring was continued for about 48 hours at ambient temperature and the intermediate title compound was isolated by vacuum filtration, washed successively with water, methanol and petroleum ether (40-60° C.) and dried in vacuo to give 23.3 g (62% of theory) of 1-phenyl-3-(4-dimethylaminophenyl)-1-oxo-prop-2-ene with a melting point of 112-114° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.N1C=CC=CC=1>O1CCCC1>[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:9][NH:8][C:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[O:16])=[CH:13][CH:12]=1
Reactant: NNC(=O)c1ccc[nH]1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(NNC(=O)c1ccc[nH]1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.750 g of 1H-pyrrole-2-carbohydrazide (5.99 mmol) in 50 ml tetrahydrofuran was added 1.315 g 4-bromobenzoyl chloride (5.99 mmol) and 1 ml pyridine (11.99 mmol) at room temperature under nitrogen. After one hour of stirring at room temperature, the desired product precipitated. The precipitate was filtered, washed with minimum dichloromethane and methanol and dried to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 10.47 (s, 1H), 10.04 (s, 1H), 7.84-7.88 (m, 2H), 7.75 (d, J=8.8, 1H), 7.75 (q, J=4.2, 1H), 6.91-6.95 (m, 2H), 6.33-6.15 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1.Cl>C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:16][CH:17]2[O:21][CH2:20][CH2:19][O:18]2)=[N:4][CH:3]=1
Reactant: O=c1ccc2ncc(Br)cc2[nH]1
Reactant: BrCC1OCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1ccc2ncc(Br)cc2n1CC1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5 mL of N,N-dimethylformamide, 770 mg of 7-bromo-1,5-naphthyridin-2(1H)-one was dissolved, 278 mg of 60% sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 1.1 mL of 2-bromomethyl-1,3-dioxolan at 110° C. for 4 days. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1 mol/L hydrochloric acid were added. The organic layer was separated, washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60 made by KANTO CHEMICAL CO., INC., and an eluent of ethyl acetate:hexane 2:1 to obtain 467 mg of 7-bromo-1-(1,3-dioxolan-2-ylmethyl)-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][S:5][CH2:6][CH2:7][C:8]([OH:10])=O.[Cl:13][C:14]1(NCC)[CH:18]=[CH:17][N:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:15]1.[CH:28]([N:31](C(C)C)CC)(C)[CH3:29]>>[Cl:13][C:14]1[C:18]([N:31]([CH2:28][CH3:29])[C:8](=[O:10])[CH2:7][CH2:6][S:5][CH2:4][CH2:3][C:2]([F:1])([F:12])[F:11])=[CH:17][N:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:15]=1
Reactant: O=C(O)CCSCCC(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Reactant: CCNC1(Cl)C=CN(c2cccnc2)N1
Product: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A solution of 3-((3,3,3-trifluoropropyl)thio)propanoic acid (2.18 g, 10.78 mmol) and 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (2.00 g, 8.98 mmol) was cooled to 5° C. diisopropylethylamine (5.15 mL, 29.6 mmol) was added dropwise at 0-5° C. over 30 min, followed by the addition of 2,4,6-tripropyl-trioxatriphosphinane-2,4,-trioxide (4.00 g, 12.6 mmol) over 30 minutes at 0-5° C. The reaction was allowed to warm to 25-30° C. and stirred for 2 hours. Upon reaction completion, the reaction mixture was cooled to 0-5° C. and quenched with water (12 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were concentrated to afford the desired product as an oil (3.4 g, 94%). Characterization matched sample prepared by previous method.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH2:15][CH2:16][C:17]#[N:18]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[CH:15][CH2:16][C:17]#[N:18].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]=[N:14][CH2:15][CH2:16][C:17]#[N:18]
Reactant: N#CCCNNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: Clc1ccccc1
Product: N#CCC=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Product: N#CCCN=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 65 °C

Procedure:
Cupric chloride (0.673 g, 2.5 equivalents) was added in one portion to a solution of 3-(2,6-dichloro-4-trifluoromethylphenylhydrazino)propionitrile (0.591 g, 2 mmol) in chlorobenzene, and the mixture heated at 65° C. for 50 minutes. The reaction was judged to be complete and was cooled, washed (water), dried (magnesium sulfate), evaporated and separated by chromatography on silica gel to give 3-(2,6-dichloro-4-trifluoromethylphenylhydrazono)propionitrile, NMR 3.37 (d, 2H), 7.03 (t, 1H), 7.5 (s, 2H), 7.75 (s, 1H) (35% yield), and 3-(2,6-dichloro-4trifluoromethylphenylazo)propionitrile, NMR 3.0 (t, 2H), 4.6 (t, 2H), 7.6 (s, 2H) (60% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH:17]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:32]=2[F:41])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:29]=C(C)O[N:26]=3)=[CH:21][CH:20]=2)=[N:12]1)=[O:5])[CH3:2].O.C(O)(=O)C>CO.[Fe]>[C:4]([OH:5])(=[O:3])[CH3:6].[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][C:10]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH:17]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:29])=[CH:23][CH:24]=2)[C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[CH:33][C:32]=2[F:41])=[N:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c(OC)cc2F)[nH]c1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(C(=N)N)cc2)c2cc(OC)c(OC)cc2F)[nH]c1=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 115.6 %

Procedure:
To a solution of 0.152 g of 5-(3-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-1H-pyrazole-4-carboxylic acid ethyl ester in 15 ml of a methanol:water:acetic acid=1:1:1 mixed solvent there was added 0.150 g of iron powder, and the mixture was heated and stirred at 60° C. for 20 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 0.091 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH2:30])=[CH:24][NH:25]2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([NH:30][CH2:29][CH2:28][C:23]2[C:22]3[C:26](=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[NH:25][CH:24]=2)=[O:13])[CH:7]=1
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Reactant: COc1ccc2c(CCN)c[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(CCNC(=O)c3cc(Cc4cccc(F)c4)on3)c[nH]c2c1
Yield: 34.6 %

Procedure:
A solution of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g; 0.257 mmol), 2-(6-methoxy-1H-indol-3-yl)ethanamine (0.054 g; 0.284 mmol), HATU (0.108 g; 0.284 mmol) and N,N-diisoprpylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.035 g (38%) of the title compound as a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[OH:7][C@H:8]([CH3:31])[C@H:9]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1)=[O:16])[C:10](OC)=[O:11].Cl>CO>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:15]([NH:14][C@H:9]([C:10]([NH:2][OH:3])=[O:11])[C@H:8]([OH:7])[CH3:31])=[O:16])=[CH:18][CH:19]=1)(=[O:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(C(=O)c2ccccc2)cc1)[C@@H](C)O
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)[C@H](NC(=O)c1ccc(C(=O)c2ccccc2)cc1)C(=O)NO
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
To a solution of hydroxylamine hydrochloride (121 mg, 1.74 mmol) in anhydrous MeOH (2.0 mL) at 0° C. under N2 atmosphere was added sodium methoxide (25 wt % in MeOH, 680 mg, 3.14 mmol). A precipitate was immediately observed and the cloudy white solution was stirred for 10 minutes at 0° C. A solution of methyl (2S,3R)-3-hydroxy-2-{[4-(phenylcarbonyl)phenyl]carbonylamino}butanoate (1) (534 mg, 1.56 mmol) in MeOH (3.0 mL) was added and the reaction stirred 3 h at 0° C., then warmed gradually to ambient temperature overnight (18 h total). Aqueous 0.5 M HCl (20 mL) was added and the solution extracted with 5:1 chloroform/isopropyl alcohol (4×40 mL). The organic layers were combined, dried over Na2SO4 and concentrated to give an orange foam. Purification by silica gel chromatography (increasing eluant polarity from 30:1 CH2Cl2/MeOH to 15:1 CH2Cl2/MeOH) afforded 228 mg (43%) of 4-benzoyl-N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C.CO>C(Cl)Cl>[C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1csc(N2CC[C@@H](O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCN(c2nc(C(N)=O)cs2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
To a solution of (3R)-1-(4-carbamoyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (290 mg, 1.36 mmol) (obtained as described in Reference Example 18(6)) suspended in methylene chloride (9 ml) were added methanesulfonyl chloride (0.684 ml, 8.85 mmol) and triethylamine (1.24 ml, 8.85 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature overnight. After checking the completion of the reaction, methanol (0.33 ml) was added to the reaction mixture in an ice bath, and then the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using 5% methanol in ethyl acetate→10% methanol in ethyl acetate as the eluant to afford (3R)-1-(4-carbamoyl-1,3-thiazol-2-yl)-3-methanesulfonyloxypyrrolidine (148 mg, yield 40%) as a pale yellow solid.