Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:33])[CH:9]([NH:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:34](Cl)(=[O:36])[CH3:35].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:33])[CH:9]([N:21]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:34](=[O:36])[CH3:35])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: OC(c1ccc(F)cc1)C(Cc1ccc(C(F)(F)F)cc1)NCc1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N(Cc1cccc2ccccc12)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-2-((1-naphthalenylmethyl)amino)-3-(4-(trifluoromethyl)phenyl)-1-propanol (100 mg, 0.22 mmol) in ethyl acetate (5 ml) were added acetyl chloride (225 ml, 3.3 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (45 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][CH:36]=[CH:37][N:38]=2)=[C:30]([F:39])[C:29]=1[F:40]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[O:35][CH:36]=[CH:37][N:38]=3)=[C:30]([F:39])[C:29]=2[F:40])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Fc1c(CBr)ccc(-c2ncco2)c1F
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Reaction time: 2 h
Yield: 47 %

Procedure:
A suspension of 4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide Compound 15 (130 mg, 0.43 mmol), cesium carbonate (167 mg, 0.51 mmol), and 2-(4-(bromomethyl)-2,3-difluorophenyl)oxazole (141 mg, 0.51 mmol) in dimethylformamide (2 mL) was stirred for 2 h. The reaction was partitioned between ethyl acetate and saturated sodium bicarbonate, dried over magnesium sulfate, concentrated and purified by flash chromatography on silica gel using a gradient of 0 to 100% ethyl acetate in hexane to give 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (100 mg, 47%). Recrystallization from methanol yielded a crystalline product which was analyzed by X-Ray crystallography, verifying the stereochemistry as R,R. 1H NMR (400 MHz, CDCl3) δ ppm 7.77-7.83 (m, 2H), 7.75 (m, 2H), 7.51-7.57 (m, 1H), 7.50 (m, 2H), 7.32 (s, 1H), 4.60 (d, J=15.86 Hz, 1H), 4.40 (d, J=15.86 Hz, 1H), 3.57-3.66 (m, 2H), 2.98-3.17 (m, 1H), 2.45-2.63 (m, 1H), 1.59-1.75 (m, 3H), 1.39-1.54 (m, 2H), 0.98-1.21 (m, 4H). MS [M+H]+=497. HRMS [M+H]+ calc'd 497.1113, found 497.1093. Chiral LC: R.T.=8.21 min, 100% ee.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[N:14][CH:15]=[CH:16][CH:17]=1)SC)#[N:2].[CH3:18][NH2:19]>>[C:1]([NH:3][C:4]([NH:19][CH3:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[N:14][CH:15]=[CH:16][CH:17]=1)#[N:2]
Reactant: CN
Reactant: CSC(=NCCSCc1cccnn1)NC#N
Product: CNC(=NCCSCc1cccnn1)NC#N

Procedure:
Reacting this isothiourea with methylamine by the procedure of Example 3(c)(ii) gives N-cyano-N'-methyl-N"-[2-(3-pyridazinylmethylthio)ethyl]guanidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4](B2OC(C)(C)C(C)(C)O2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Br[C:24]1[N:25]=[CH:26][S:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([C:24]2[N:25]=[CH:26][S:27][CH:28]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cscn1
Temperature: 95 °C

Procedure:
Into a microwave vial was added 1-[5-chloro-2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (0.040 g, 0.12 mmol), 4-bromo-1,3-thiazole (0.024 g, 0.15 mmol), 1 M sodium carbonate solution (0.30 mL, 0.31 mmol), 1,4-dioxane (1 mL) and tetrakis(triphenylphosphine)palladium(0) (8.5 mg, 0.0074 mmol). The mixture was bubbled with N2 for 5 minutes, and then heated at 95° C. overnight. The cooled reaction was purified on silica gel column (eluting with 0 to 30% EtOAc in hexanes) to give the desired product. LCMS calculated for C13H13ClNO2S (M+H)+: m/z=282.0. found: 282.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O.O>O1CCCC1>[Br:23][C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)c1ccc(-c2cccn2-c2ccc(F)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc(Br)n2-c2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 71 %

Procedure:
0.32 g (1.0 mmol) of 1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)pyrrole (prepared as described in Example 33) was dissolved in 10 ml of anhydrous tetrahydrofuran, and 0.18 g (1.0 mmol) of N-bromosuccinimide was added to the resulting solution, whilst ice-cooling. The mixture was then stirred, whilst ice-cooling for 1 hour and then at room temperature for a further 1 hour. At the end of this time, water was added to the mixture, and the resulting mixture was extracted with methylene chloride. The organic extract was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under reduced pressure. The resulting residue was applied to a silica gel chromatography column and eluted with a 1:3 by volume mixture of ethyl acetate and hexane, to give 0.28 g of the title compound as a white powder (yield 70%), melting at 174-176° C.
Reaction SMILES: C([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16]([CH3:18])=[CH2:17])=[N:11]2)CCC.[BrH:24].C(O)(=O)C>>[Br:24][CH2:17][CH:16]([C:10]1[C:9]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:8]=2[C:7]2[C:6](=[O:5])[NH:15][CH:14]=[CH:13][C:12]=2[N:11]=1)[CH3:18]
Reactant: C=C(C)c1nc2ccnc(OCCCC)c2c2cc(F)ccc12
Reactant: Br
Solvent: CC(=O)O
Product: CC(CBr)c1nc2cc[nH]c(=O)c2c2cc(F)ccc12

Procedure:
A solution of 1-butoxy-9-fluoro-6-isopropenylbenzo[c]-1,6-naphthyridine (26 mg, 0.063 mmol) in HBr/acetic acid (33% wt) (1.0 ml) was stirred for 18 hr at room temperature. The reaction mixture was concentrated to a crude solid that was taken up into acetonitrile (5 mL) and concentrated again in an attempt to drive off more acetic acid. The resulting solid was triturated with EtOAc (1 mL), then collected by vacuum filtration to afford 6-(2-bromo-1-methylethyl)-9-fluorobenzo[c]-1,6-naphthyridin-1(2H)-one (HBr salt). LRMS (ESI) calc'd for (C15H12BrFN2O) [M+H]+, 335.0; found 335.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:19][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[O:17][CH3:18])[CH:7]([CH2:6][C:5]1[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:3]([O:2][CH3:1])[CH:4]=1)[N:8]([CH2:20][C:21](=[O:22])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH2:10]2)[CH3:42]
Reactant: CCOC(=O)CBr
Reactant: COc1cc2c(cc1O)CCN(CC(=O)NCc1ccccc1)C2Cc1ccc(OC)c(OC)c1
Product: CCOC(=O)COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl bromoacetate
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:21][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH3:23].FC(F)(F)C(O)=O>>[NH2:1][C@@H:2]([C:11]([NH:21][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH3:23])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(O)cc1)C(=O)O
Reactant: COC(=O)[C@@H](C)N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](C)NC(=O)[C@H](N)Cc1ccc(O)cc1

Procedure:
t-Boc-D-Tyr-OH was coupled with D-Ala-OMe by the N-hydroxy-succinimide ester method (The Peptides, 1, p. 105). Deprotection was carried out using trifluoroacetic acid (The Peptides, 1, p. 39) and the resulting dipeptide methyl ester salt was purified by chromatography on Sephadex G-10 using 0.2 N HOAc.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[C:17]=1[O:18][CH:19]([CH3:21])[CH3:20])([O-:5])=[O:4].I[CH3:23]>CN(C=O)C>[CH3:23][N:15]1[C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[C:17]([O:18][CH:19]([CH3:21])[CH3:20])[C:10]=2[CH2:11][CH2:12][CH2:13][C:14]1=[O:16]
Reactant: CI
Reactant: CC(C)Oc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
750 mg of potassium nitrate are added, in portions, to a solution of 1.3 g of 6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 13 ml of trifluoroacetic anhydride brought back to −5° C. The reaction medium is stirred for 5 minutes at −5° C. and then brought back to pH 5 by adding a saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate and the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of heptane and of ethyl acetate (80/20 to 50/50). 450 mg of 7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are obtained in the form of a beige solid. 91 mg of sodium hydride at 50% are added to a solution of 445 mg of 7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 10 ml of DMF. The reaction medium is stirred for 10 minutes at ambient temperature and then 263 mg of iodomethane are added. The reaction medium is stirred for 1 hour at ambient temperature, poured into ice-cold water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure, so as to give 417 mg of 1-methyl-7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a yellow gum.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1.[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:24]([NH:23][C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[S:25])[S:3][C:4]=1[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1
Reactant: Cc1ccnc(-c2sc(N)nc2C)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: Cc1ccnc(-c2sc(NC(=S)NC(=O)c3ccccc3)nc2C)c1

Procedure:
To a suspension of 2-amino-4-methyl-5-(4-methylpyridin-2-yl)-thiazole (615 mg) in acetone (5 ml) was added a solution of benzoyl isothiocyanate (0.443 ml) in acetone (5 ml) dropwise, and the mixture was heated under reflux for 3 hours. After cooling, the resulting precipitate was collected by filtration and dried to give N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-N′-benzoylthiourea (490 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.Cl.[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:21]>CN(C=O)C.O>[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=2)[CH2:25][CH2:24]1)=[O:21]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: COc1nc(Cl)nc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
A solution of 2,4-dichloro-6-methoxy-1,3,5-triazine (commercially available) (0.05 g, 0.32 mmol) in DMF (0.5 ml) was added to a solution of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1, 0.1 g, 0.32 mmol) and TEA (0.06 g, 0.64 mmol) in DMF (1.5 ml). The resultant mixture was stirred for 1 h at room temperature, then was diluted with water and extracted with EtOAc. During the aqueous workup, some of the product precipitated and was collected by suction filtration. The organic extract was dried over magnesium sulphate, filtered and concentrated to give the desired product with small amount of impurities.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:18][CH3:19])[C:8]2[C:13]([C:14]#N)=[CH:12][CH:11]=[C:10]([CH2:16][CH3:17])[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.[OH-:30].[Na+]>ClCCl>[CH:1]1([CH2:6][N:7]([CH2:18][CH3:19])[C:8]2[N:9]=[C:10]([CH2:16][CH3:17])[CH:11]=[CH:12][C:13]=2[CH:14]=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: CCc1ccc(C#N)c(N(CC)CC2CCCC2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc(C=O)c(N(CC)CC2CCCC2)n1
Reaction time: 4 h
Yield: 48 %

Procedure:
A solution of 2-[(cyclopentylmethyl)(ethyl)amino]-6-ethylpyridine-3-carbonitrile (484 mg, 1.87 mmol) in dichloromethane (5 mL) was added with diisobutylaluminum hydride (0.99 M solution in toluene, 1.99 mL, 1.97 mmol) at −78° C., and the mixture was stirred at the same temperature for 4 hours. The mixture was further added with diisobutylaluminum hydride (0.99 M solution in toluene, 0.2 mL, 0.198 mmol) at the same temperature, and the mixture was stirred at the same temperature for 45 minutes. Then, the mixture was added with 2 M aqueous sodium hydroxide, stirred at room temperature for 30 minutes, and extracted with chloroform. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to obtain 2-[(cyclopentylmethyl)(ethyl)amino]-6-ethylnicotinaldehyde (233 mg, 48%) as yellow oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.O>[C:5]([N:1]=[N+:2]=[N-:3])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium azide (19.0 g: 0.283 Mol.) in dimethyl-formamide (130 ml) is added trityl chloride (76.0 g: 0.273 Mol.), and the mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with water and extracted with ether. The extract is washed with brine, dried over sodium sulfate, and concentrated to give trityl azide. To a solution of this azide in acetone (300 ml) is added methyl propiolate (24 ml: 0.27 Mol.), and the mixture is heated under reflux for 6 days. The reaction mixture is cooled to the room temperature and diluted with ether. The separating crystals are collected by filtration to give 1-trityl-1,2,3-triazol-4-ylcarboxylic acid methyl ester (62.0 g) as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([NH:14][CH3:15])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=O.[NH2:16][OH:17]>CO>[OH:17][N:16]=[CH:1][C:3]1[N:4]=[C:5]([NH:14][CH3:15])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: CNc1nc(C=O)c(-c2ccncc2)s1
Reactant: NO
Solvent: CO
Product: CNc1nc(C=NO)c(-c2ccncc2)s1
Reaction time: 2 h

Procedure:
A solution of 4-formyl-2-methylamino-5-(4-pyridyl)-thiazole (0.9 g) in methanol (15 ml) was added to a 1N-methanolic hydroxylamine solution (5.8 ml) at ambient temperature with stirring, which was continued under the same condition for 2 hours. The precipitate was collected by filtration and recrystallized from an aqueous tetrahydrofuran to afford 4-hydroxyiminomethyl-2-methylamino-5-(4-pyridyl)thiazole (1.02 g).
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH3:12])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:9]([C:7]3[N:8]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]([CH3:12])[CH:6]=3)=[O:11])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: Cn1cc(C(=O)O)nc1C1CC1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(C)c(C2CC2)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-cyclopropyl-1-methyl-1H-imidazole-4-carboxylic acid (260 mg, 1.56 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (435 mg, 1.56 mmol). Yield 123 mg. 1H-NMR (400 MHz; DMSO-d6): δ 0.81-0.91 (m, 4H), 1.08 (d, 3H), 1.95 (m, 1H), 3.65 (s, 3H), 4.27-4.38 (m, 3H), 7.01 (s, 1H), 7.46 (s, 1H), 7.69 (d, 1H), 7.87 (d, 2H), 7.96 (s, 1H).
Reaction SMILES: [N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7](Cl)=[O:8])([O-:3])=[O:2].[N:16]([CH2:19][CH:20]([OH:25])[CH2:21][N:22]=[N+:23]=[N-:24])=[N+:17]=[N-:18]>C(Cl)CCl>[N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7]([O:25][CH:20]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:19][N:16]=[N+:17]=[N-:18])=[O:8])([O-:3])=[O:2]
Reactant: [N-]=[N+]=NCC(O)CN=[N+]=[N-]
Reactant: O=C(Cl)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Solvent: ClCCCl
Product: [N-]=[N+]=NCC(CN=[N+]=[N-])OC(=O)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Yield: 73.5 %

Procedure:
A solution of 25g (0.1 mole) of 4,4,4-trinitrobutyryl chloride, 14.7g (0.1 mole) of 1,3-diazido-2-propanol, and 50 ml of ethylene dichloride was refluxed for one week. The solution was cooled, washed with water, dried, and concentrated to give 25.5g (73.5%) of amber liquid. The product was purified by dissolving in carbon tetrachloride and passing through a neutral alumina column. Concentration of this solution gave a yellow liquid, nD24 = 1.5029, d25 = 1.464. The infrared spectrum showed the expected strong absorption for azide (4.7μ), carbonyl (5.8μ), and nitro (6.2μ).
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>CC(O)C>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:13]=[CH:14][C:15]([NH:16][C@H:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[CH:17][CH:18]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)CC(=O)OC
Solvent: CC(C)O
Product: CC[C@H](CC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 10.3 %

Procedure:
[RuCl(p-cymene)((R)-segphos)]Cl(17.6 mg, 0.0192 mmol), methyl 3-oxopentanoate (500 mg, 3.842 mmol), 4-trifluoromethylaniline (619 mg, 3.842 mmol) and 2-propanol (2.5 mL) were placed in a 2.5 mL-stainless autoclave under atmosphere of nitrogen, and the mixture was stirred under a hydrogen pressure of 3 MPa at 80° C. for 15 hours. After completion of the reaction, the solvent was removed by evaporation in vacuo, and the residue was purified by column chromatography on silica gel (eluent: hexane ethyl acetate=3/1) to give methyl (3R)-3-(4-trifluoromethylphenylamino)-pentanoate (109 mg) as a colorless oil in 10.3% yield. The enantiomeric excess of the product was found to be 92.7% ee determined by HPLC analysis using a SUMICHIRAL OA-2500 column (available from SUMIKA CHEMICAL ANALYSIS SERVICE LTD.).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:7]=1I)(=[O:4])=[O:3].[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:7]=1[CH:22]=[CH2:23])(=[O:4])=[O:3]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)NCc1ccc(NS(C)(=O)=O)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(CNC(=O)OC(C)(C)C)ccc1NS(C)(=O)=O
Reaction time: 4 h
Yield: 98.6 %

Procedure:
tert-Butyl N-[4-(methanesulfonylamino)-3-iodobenzyl]carbamate (1.0 g, 2.3 mmol) was dissolved in toluene (20 mL). Tributyl vinyltin (0.8 mL, 2.8 mmol) and Pd(PPh3)4 (140 mg, 0.12 mmol) were dropwisely added. The reaction mixture was stirred for 4 hrs in reflux. Toluene was removed in vacuo. The residue was extracted with EtOAc. A combined organic layer was washed with H2O, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified with column chromatography (EtOAc: n-hexane=1:2) to yield title compound (740 mg, 97%).
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][S:8][C:9]([CH3:40])([CH3:39])[C@H:10]([NH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[C:18](=[O:32])[NH:19][CH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([NH2:31])=[N:26][CH:25]=[CH:24]2)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:31][C:27]1[C:28]2[C:23](=[CH:22][C:21]([CH2:20][NH:19][C:18]([C@@H:14]3[CH2:15][CH2:16][CH2:17][N:13]3[C:11](=[O:12])[C@@H:10]([NH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([S:8][CH2:7][C:6]([OH:41])=[O:5])([CH3:39])[CH3:40])=[O:32])=[CH:30][CH:29]=2)[CH:24]=[CH:25][N:26]=1
Reactant: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)C(C)(C)SCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)C(C)(C)SCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
A mixture of (3-{2-(S)-[(1-amino-isoquinolin-6-ylmethyl)-carbamoyl]-pyrrolidin-1-yl}-2-(R)-ethoxycarbonylamino-1,1-dimethyl-3-oxo-propylsulfanyl)-acetic acid tert.-butyl ester hydroacetate (0.031 g; 0.048 mmol) and 1 mL trifluoroacetic acid in 1 mL of dichloromethane was stirred for 3 h at ambient temperature. The volatiles were pumped off followed by lyophilization to give 0.016 g (52%) of the title compound as a white solid. (+)-APCI-MS: 532 (MH+).