Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([Si](C)(C)C)[CH:10]=2)[CH:7]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>CC#N.C([O-])([O-])=O.[Na+].[Na+]>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:3]=[CH:4][C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: C[Si](C)(C)c1cc2cnc(Br)cn2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Fc1ccc(-c2cn3nccc3cn2)cc1
Temperature: 150 °C
Yield: 28.5 %

Procedure:
A mixture of 6-bromo-2-trimethylsilanyl-pyrazolo[1,5-a]pyrazine (60 mg, 0.23 mmol), 4-fluorophenylboronic acid (40 mg, 0.29 mmol) and PdCl2dppf (10 mg, 0.014 mmol) in CH3CN (1 ml) and 2N Na2CO3 (aq, 1 ml) in a microwave vial was deoxygenated by bubbling N2 through for 20 seconds. The vial was sealed and then stirred and heated at 150° C. in the microwave for 20 minutes. After cooling the reaction mixture was partitioned between CH2Cl2/H2O. The mixture was passed through a phase separating cartridge. The organic layer was evaporated and the residue was purified by chromatography on silica (5→20% EtOAc/Petrol) to give the title compound (14 mg, oil) 1H NMR (400 MHz, CDCl3): 9.15 (1H, d), 8.75 (1H, s), 8.06 (1H, d), 7.98-7.92 (2H, m), 7.24-7.14 (2H, m), 6.84 (1H, d).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[O:9][CH:8]([CH3:10])[CH:7]([CH3:11])[O:6]1)[CH3:2].[N+:12]([C:15]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[N+:35]([O-:37])=[O:36])=[CH:23][C:16]=1[O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])([O-:14])=[O:13]>C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH:5]1[O:6][CH:7]([CH3:11])[CH:8]([CH3:10])[O:9]1)[C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:23]=[C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[N+:35]([O-:37])=[O:36])[CH:25]=[CH:26][C:15]=1[N+:12]([O-:14])=[O:13])[CH3:22])[CH3:2]
Reactant: CC(Oc1cc(Oc2ccc(Br)cc2[N+](=O)[O-])ccc1[N+](=O)[O-])C(=O)Cl
Reactant: CCNCC1OC(C)C(C)O1
Solvent: ClCCl
Product: CCN(CC1OC(C)C(C)O1)C(=O)C(C)Oc1cc(Oc2ccc(Br)cc2[N+](=O)[O-])ccc1[N+](=O)[O-]
Temperature: -15 °C

Procedure:
N-Ethyl-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)amine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(2-nitro-4-bromophenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. The residue is then recrystallized from a toluene/hexane mixture to yield the desired product N-ethyl-N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)-2-[2-nitro-5-(2-nitro-4-bromophenoxy)phenoxy]propionamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH:13]=O)[O:8][N:7]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:15]([N:22]1[CH2:27][CH2:26][N:25]([CH2:13][CH2:12][CH2:11][C:9]2[O:8][N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:10]=2)[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2nccs2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CN2CCN(CCCc3cc(-c4nccs4)no3)CC2)cc1
Yield: 55.9 %

Procedure:
About 2 min after dissolving 3-(3-(1,3-thiazol-2-yl)isoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-benylpiperazine (8.3, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (31 mg, 0.14 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.1 hr and followed the same processes as in Example 1 to obtain 10.3 mg (58.2%) of the target compound.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:21]/[N:22]([CH3:24])[CH3:23])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1[N+](=O)[O-]
Product: CN(C)/C=C/c1ccc(S(=O)(=O)NC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 76.6 %

Procedure:
A solution of N-tert-butyl-4-methyl-3-nitrobenzenesulfonamide (5.89 g, 21.6 mmol) in N,N-dimethylformamide dimethyl acetal (10 ml) was stirred with heating at 110° C. for 10 hr. The reaction solvent was evaporated under reduced pressure and diethyl ether was added. The precipitated solid was collected by filtration, washed with diethyl ether and dried in vacuo to give N-tert-butyl-4-((E)-2-dimethylaminovinyl)-3-nitrobenzenesulfonamide (5.41 g, yield 76.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:18]([Cl:27])=[CH:17][N:16]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)=[C:30]=[O:31].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:30](=[O:31])[NH:29][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:41])[F:40])[CH:33]=3)[CH2:23][CH2:22]2)[C:18]([Cl:27])=[CH:17][N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCNCC2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of tert-butyl(2-((5-chloro-4-(piperazin-1-yl)pyrimidin-2-yl)amino)phenyl)carbamate (28 mg, 0.068 mmol) in DCM (0.7 mL) was added 1-isocyanato-3-(trifluoromethyl)benzene (0.011 mL, 0.082 mmol) and triethylamine (0.015 mL, 0.1 mmol) and the mixture was stirred at 23° C. for 16 h. reaction. The crude reaction mixture was loaded onto silica gel and purified using 0-50% EtOAc/Hexanes gradient to give the title compound (25 mg, 62%). MS (ES+) C27H29C1F3N7O3 requires: 591. found: 592 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13]C)=[O:12])[CH2:8][CH2:7][N:6]1[C:15]([O:17][CH3:18])=[O:16].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][N:6]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2c(F)cccc2F)C1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1c(F)cccc1F
Yield: 82.5 %

Procedure:
Dimethyl 2-(2,6-difluorobenzyl)piperidine-1,4-dicarboxylate (5.98 g, 18.27 mmol) was dissolved in acetonitrile (50 mL) and water (1 mL), then lithium bromide (12.69 g, 146.16 mmol) and triethylamine (10.13 mL, 73.08 mmol) were added. The suspension was heated to reflux for 3.5 h, then water (60 mL) and MTBE (180 mL) were added. The organic phase was extracted with water (×2). The combined water phases were acidified to pH 1 with 3.8 M HCl and extracted with MTBE (×2). The combined organic phases were washed with water, dried with MgSO4, filtered through celite and concentrated to give 2-(2,6-difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.72 g, 82%) as a light yellow solid. MS m/z 314 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=1[CH:13]=[CH:14][CH2:15][C:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:22](=[O:24])[CH3:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=1[CH:13]=[CH:14][CH2:15][C:16]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:22](=[O:24])[CH:23]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CC=Cc1ccccc1Cl)(CCC(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(CC=Cc1ccccc1Cl)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (2.81 g., 0.02 mole) in ethanol (10 ml.) is added to a solution of 4-(o-chlorocinnamyl)-4-phenyl-5-oxohexanoic acid (3.57 g., 0.01 mole) and sodium hydroxide (0.56 g., 0.014 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (250 ml.), and extracted with ether to remove the excess p-chlorobenzaldehyde. The aqueous phase is acidified with dilute hydrochloric acid (10 ml.), and the gum that separates out is extracted into ether. The ether extract is washed with brine solution, and dried over anhydrous Na2SO4. Filtration and removal of the ether in vacuo gives a viscous yellow residue, which upon trituration with petroleum ether (30°-60°C., 150 ml.) yields 4.3 g. of material, m.p. 90°-125°C. (cloudy). Recrystallization from n-butyl chloride, followed by ethanol, produces a material with m.p. 143°-146°C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11](O)(=O)[C:12]1C(=CC=C[CH:20]=1)C(O)=O.[BH4-].[Na+].[OH-].[Na+]>O.CC(C)=O>[CH:12]([NH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:20])[CH3:11]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: Cc1ccc(C#N)c(N)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(C#N)c(NC(C)C)c1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 264 g. of 2-amino-4methylbenzonitrile, 504 g. of phthalic acid and 2.32 liters of reagent grade acetone is added 80 g. of sodium borohydride portionwise over 40 minutes at a temperature of 18°-30° C. The resulting solution is stirred for 30 minutes during which the temperature rises from 29°-30° C. to 35° C. and then dropped to 34° C. The resulting solution is then heated from 34° C. to 53° C. over a period of 30 minutes and their maintained at 55° C. for one hour. The mixture is cooled to 37° C., 500 ml. of water added followed by addition of 417 g. of 50% aqueous sodium hydroxide, after which the temperature is allowed to rise to 56° C. to maintain the solution. An additional 92 ml. of water is added and the acetone and aqueous salt layers separated at 45°-50° C. The acetone layer is concentrated in vacuo to obtain a brown oil and salt solution which is diluted with 800 ml. of heptane and the aqueous and heptane layers separated. The heptane layer is dried, filtered and cooled to 10° C. to obtain the major portion of the desired 2-isopropylamino-4-methylbenzonitrile, m.p. 55°-57° C. Additional product is also recovered from the mother liquor and phthalic acid is recovered to a high degree from aqueous salt layer above referred after dilution with a total of 4.5 liters of water, filtering and acidifying with sulfuric acid (other aqueous alkaline solutions obtained in the work up being combined with said aqueous salt layer).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[N:7]([C:10]3[S:11][C:12]([C:21]#[N:22])=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].O>CN1CCCC1=O>[CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[N:7]([C:10]3[S:11][C:12]([C:21]4[NH:29][N:28]=[N:27][N:22]=4)=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: COc1cc2ncn(-c3nc(-c4ccccc4)c(C#N)s3)c2cc1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(-c4nnn[nH]4)s3)c2cc1OC
Temperature: 110 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A mixture of 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carbonitrile (261 mg, 0.72 mmol), sodium azide (220 mg) and ammonium chloride (250 mg) in N-methylpyrrolidone (2.5 ml) was stirred at 110° C. for 1 hr. Water was added and the mixture was extracted with methylene chloride. After removal of solvent, the residue was purified by HPLC to yield the product (138.1 mg, yield 47%). 1H-NMR (DMSO-D6) 8.78 (s, 1H); 8.21-8.29 (m, 2H); 7.86 (s, 1H); 7.36-7.50 (m, 3H); 3.90 (s, 3H); 3.88 (s, 3H). MS M/z 406 (M+1).
Reaction SMILES: O1CCOCC1.O.C([O:10][C:11](=[O:28])[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)C.O.[OH-].[Li+]>O1CCOCC1>[C:22]1([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][CH2:12][C:11]([OH:28])=[O:10])=[CH:17][CH:18]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CCCOc1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A suspension in 1:1 dioxane/water (70 mL) of 4-(4-phenylphenoxy)butanoic acid ethyl ester (10.29 g, 36 mmol), prepared as in step 1, and lithium hydroxide hydrate (2.05 g, 49 mmol) was heated at reflux for 18 hours. Dioxane (35 mL) was then added and an additional 2.0 equivalents of lithium hydroxide hydrate was added four hours later. The reaction mixture was heated at reflux for two more hours, then was cooled to ambient temperature and concentrated in vacuo. The resulting white solids were shaken with ethyl ether and aqueous 1M NaOH and the residual solid (4-(4-phenylphenoxy)butyric acid, 3.53 g) was filtered off. The organic phase was discarded and the aqueous phase was acidified with concentrated HCl. The aqueous phase was extracted with ethyl acetate. The ethyl acetate extracts were dried over MgSO4, filtered, and concentrated in vacuo to give an additional 6.25 g of 4-(4-phenylphenoxy)butanoic acid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][CH2:7][O:8][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(=O)OCCO
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CC(=O)OCCOC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A 500 ml round-bottom flask was initially charged with 51.1 g of hydroxyethyl acrylate in 100 ml of pyridine/toluene (1:1, v/v) together with 0.05 g of 2,6-di-tert-butyl-4-methylphenol at 0° C. and 65.0 g of benzoyl chloride were slowly added dropwise. The mixture was stirred at room temperature until the hydroxyethyl acrylate content had fallen below 0.1%. Thereafter, the mixture was poured onto 0.5 l of ice-water and acidified with 1 N aqueous hydrochloric acid. The aqueous phase was extracted three times with 0.5 l each time of tert-butyl methyl ether. The organic phase was washed with 10% sodium hydrogencarbonate solution, dried over sodium sulfate and filtered. Another 0.05 g of 2,6-di-tert-butyl-4-methylphenol was added and the organic solvents were distilled off. The product was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[CH:11][C:5]2[CH2:6][O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[OH:26]O>>[Cl:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:26])=[CH:11][C:5]2[CH2:6][O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2cc3c(cc2Cl)NC(=O)OC3)cc1
Product: Cc1ccc(S(=O)CCCCOc2cc3c(cc2Cl)NC(=O)OC3)cc1

Procedure:
Prepared analogously to Example 2 from 7-chloro-6-[4-(4-methyl-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:17][CH:18]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH2:19][CH3:20])(=[O:16])[CH2:13][CH2:14][CH3:15]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:17][CH:18]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH2:19][CH3:20])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCC(=O)OC(CC)OC(=O)ON1C(=O)CCC1=O
Solvent: COC(C)(C)C
Solvent: O
Solvent: CC(C)=O
Product: CCCC(=O)OC(CC)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]propyl butanoate (575 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 29 (408 mg, 62% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.81-0.94 (br. m, 8H), 1.17-1.38 (br. m, 3H), 1.47-1.58 (m, 2H), 1.64-1.75 (m, 4H), 1.83-1.92 (br. m, 2H), 2.10 (tt, J=12.0, 3.6 Hz, 1H), 2.26 (t, J=7.2 Hz, 2H), 2.75-2.88 (m, 2H), 6.55 (t, J=5.2 Hz, 1H), 7.42 (t, J=5.6 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 352.18 (M+Na)+; 328.14 (M−H)−.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)([F:4])[F:3].[Na].Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17]>>[F:1][C:2]([F:4])([F:3])[S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C@H:15]([C:16]([OH:18])=[O:17])[CH:19]([CH3:21])[CH3:20])=[CH:8][CH:7]=1
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc(SC(F)(F)F)cc1
Agent: [Na]
Product: CC(C)[C@H](Nc1ccc(SC(F)(F)F)cc1)C(=O)O

Procedure:
Alternatively, using the procedure of Example 38, p-aminophenyl trifluoromethyl sulfide is reacted with the sodium salt of α-bromoisovaleric acid to yield N-(4-trifluoromethylthiophenyl)valine, which is esterified to yield the m-phenoxybenzyl ester of N-(4-trifluoromethylthiophenyl)valine.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH:38]=C)[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.C[N+]1([O-])CC[O:44]CC1.[BH4-].[Na+]>O1CCOCC1.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38][OH:44])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OC[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Reaction time: 14 h
Yield: 52.1 %

Procedure:
To a solution of the compound from Example 23, Step B (300 mg, 0.48 mmol) in 1,4-dioxane (5 mL) were added N-methylmorpholine-N-oxide (300 mg, 2.56 mmol) and osmium tetroxide (4% solution in water, 0.3 mL). The mixture was stirred in the dark for 14 h. The precipitate was removed by filtration through a celite plug, diluted with water (3×), and extracted with EtOAc. The EtOAc layer was dried over Na2SO4 and concentrated in vacuo. The oily residue was taken up in dichloromethane (5 mL) and stirred over NaIO4 on silica gel (3 g, 10% NaIO4) for 12 h. The silica gel was removed by filtration and the residue was evaporated and taken up in absolute ethanol (5 mL). The solution was cooled in an ice bath and sodium borohydride (300 mg, 8 mmol) was added in small portions. The resulting mixture was stirred at room temperature for 4 h and then diluted with EtOAc. The organic layer was washed with water (2×20 mL), brine (20 mL) and dried over Na2SO4. The solvent was evaporated and the residue purified by flash chromatography (SiO2, 2:1 hexanes/EtOAc) to give the title compound (160 mg, 0.25 mmol) as white flakes.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH3:7])=[O:3].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(N(CC)CC)C.O>C1COCC1>[CH2:5]([O:4][C:2]([O:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1)=[O:3])[CH2:6][CH3:7]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
A solution of propyl chloroformate (613 mg) in THF (3 ml) was added to a solution of 4-nitrophenol (693 mg) and triethylamine (0.836 ml) in THF (10 ml) at 0° C. After stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous sodium carbonate solution, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried, and concentrated to obtain the title compound (1.11 g) as a pale yellow solid.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16]([C@@H:18]3[CH2:22][C@@H:21]([O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([O:34][CH3:35])=[CH:26][N:25]=4)[CH2:20][NH:19]3)=[O:17])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:69]([O:73][C:74]([NH:76][CH:77]([C@H:81]([CH3:89])[CH2:82][CH:83]([CH3:88])[CH2:84][CH2:85][CH:86]=[CH2:87])[C:78](O)=[O:79])=[O:75])([CH3:72])([CH3:71])[CH3:70]>ClCCl>[CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16]([C@@H:18]3[CH2:22][C@@H:21]([O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([O:34][CH3:35])=[CH:26][N:25]=4)[CH2:20][N:19]3[C:78](=[O:79])[CH:77]([NH:76][C:74](=[O:75])[O:73][C:69]([CH3:72])([CH3:71])[CH3:70])[C@H:81]([CH3:89])[CH2:82][CH:83]([CH3:88])[CH2:84][CH2:85][CH:86]=[CH2:87])=[O:17])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2ncc(OC)c3ccccc23)CN1)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OC)c3ccccc23)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)—N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxamide (595 mg, 1.9 mmol) in dichloromethane (15 mL) was added HATU (755 mg, 1.9 mmol) followed by DIPEA (1.7 mL, 9.9 mmole) at room temperature. The reaction mass was stirred at the same temperature for 10 min. (3R)-2-(tert-butoxycarbonylamino)-3,5-dimethylnon-8-enoic acid (1.0 g, 1.9 mmole) was added to the reaction mass and the solution was stirred at room temperature for 30 min. The reaction mass was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get the crude compound. The crude compound was purified by silica gel chromatography (70% ethyl acetate in pet ether) to get desired product tert-butyl ((3R)-1-((2S,4R)-2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate as a pale yellow solid. MS: MS m/z 782.1 (M++1).