Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2].OC1C([O:29][S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])=C(I)C=CC=1>>[S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)([O:32][CH:4]([C:1](=[O:3])[CH3:2])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:16])([F:15])[F:17])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=[O:31])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Reactant: CC(=O)Cc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Product: CC(=O)C(OS(=O)(=O)c1ccc(C)cc1)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 25.3 %

Procedure:
α-(Acetyl)4-(trifluoromethyl)-2,6-dinitrotoluene (5.00 g, 17.10 mmol) was heated to 80° C. for 10 minutes under nitrogen. Hydroxy(tosyloxy) iodobenzene (13.40 g, 34.18 mmol) was then added slowly keeping the temperature constant at 80° C. The reaction mixture was allowed to stir for 1 hour, carefully avoiding overheating. After cooling, the reaction mixture was purified by column chromatography over silica gel (60-200 mesh) using CH2Cl2 /hexane (1:1) as the eluant. Recrystallization with chloroform/petroleum ether gave 2 g (25%) of pure product.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1>CN(C=O)C.C(Cl)Cl>[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]3[CH:34]=[C:33]([NH:35][C:8](=[O:10])[CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:12][CH:11]=4)[CH:32]=[CH:31][C:29]=3[N:30]=2)[CH2:22]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: Cc1ccc(C=CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C=CC(=O)Nc2ccc3nc(N4CCC(N(C)C)C4)sc3c2)cc1
Yield: 62 %

Procedure:
Combine 4-methylcinnamic acid (0.093 g, 0.572 mmol), CH2Cl2 (5.0 mL), and DMF (3 drops) with stirring. Add oxalyl chloride (0.17 mL, 1.91 mmol) and stir the mixture for 2.5 h at room temperature. Concentrate the mixture in vacuo, add hexane (approximately 10 mL), re-concentrate in vacuo, and add CH2Cl2 (4.0 mL). Transfer the mixture to a 40 mL reaction vial and add a solution of 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (0.100 g, 0.381 mmol) (example 1, step 3) in CH2Cl2 (5.0 mL). Shake the reaction vial for 1 h at room temperature. Dilute the reaction mixture with CH2Cl2 (25 mL), wash with aqueous 1.0 M NaOH (50 mL), concentrate in vacuo, and purify using silica gel chromatography (12 g column, 10-20% MeOH/CH2Cl2 for 16 min.) to afford the title compound as a yellow solid (96 mg, 62%). mass spectrum (m/e): 407.3 [M+1], 405.2 [M−1]. 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.71 (d, 1H, J=15.6 Hz), 7.67 (s, 1H), 7.50 (d, 1H, J=9.2 Hz), 7.39 (d, 2H, J=7.2 Hz), 7.13-7.19 (m, 3H), 6.51 (d, 1H, J=15.6 Hz), 3.82 (t, 1H, J=8.0 Hz), 3.71 (t, 1H, J=9.2 Hz), 3.53 (m, 1H), 3.39 (t, 1H, J=8.0 Hz), 2.89 (m, 1H), 2.36 (s, 3H), 2.30 (s, 6H), 2.25 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[Na+].S(=O)(=O)(O)O>O.CC(C)=O>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 20 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To 35.0 g of L-arginine were added 118.7 g of acetone and 200 g of water. Thereto were concurrently added dropwise 36.5 g of lauroyl chloride (“lauroyl chloride” manufactured by Nippon Oil and Fats Co., Ltd.) and 45 ml of 8N NaOH aqueous solution over a period of 2 hours with the pH being maintained at 11.5 to 12.0 and the reaction temperature being maintained at 15 to 25° C. After 2 hours of aging, the reaction mixture was adjusted to pH 5.0 with 6N sulfuric acid with cooling and then poured into about 300 ml of ice-water to precipitate crude crystals of mono-Nα-lauroyl-L-arginine, which were collected by filtration and then dried (yield 55 g). The crude crystals were washed by stirring in 300 ml of petroleum benzine and then filtered, and the crystals were dried under reduced pressure to obtain 51 g of mono-Nα-lauroyl-L-arginine (yield 85%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8]C(=O)[C:6]2=[O:13])[CH3:2].[OH:14]O>[OH-].[Na+]>[NH2:8][C:9]1[CH:10]=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=1[C:6]([OH:13])=[O:14]
Reactant: OO
Reactant: CCc1ccc2c(c1)C(=O)C(=O)N2
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc(N)c(C(=O)O)c1
Temperature: 50 °C

Procedure:
A mixture of Example 1B (11.7 g, 66.9 mmol) in 1M NaOH (300 mL) was treated dropwise with 30% aqueous hydrogen peroxide (300 mL), heated to 50° C. for 30 minutes, cooled to room temperature, and filtered. The filtrate was adjusted to pH 4 with concentrated HCl, cooled to 4° C., and filtered. The filter cake was dried under vacuum to provide the desired product (4.46 g). MS (ESI(−)) m/e 164 (M−H)−.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](=[O:22])[N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=[C:7]2[C:6]=1[O:23][CH3:24])=O.CC(C[AlH]CC(C)C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[OH:2][CH2:3][C:5]1[CH:10]=[CH:9][N:8]2[C:11](=[O:22])[N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[N:13]=[C:7]2[C:6]=1[O:23][CH3:24]
Reactant: COC(=O)c1ccn2c(=O)n(COCC[Si](C)(C)C)nc2c1OC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COc1c(CO)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a stirred solution of 8-methoxy-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid methyl ester (1.51 g, 4.27 mmol) in dry DCM (50 mL), cooled to −78° C., was added 1 M DIBAL in DCM (8.54 mL, 8.54 mmol) over 3 minutes. The reaction mixture was allowed to warm to −50° C. over 45 minutes, followed by cooling to −78° C. and addition of MeOH (5 mL) to quench the reaction. The reaction mixture was allowed to warm to 0° C. and was diluted with DCM. An aqueous solution of Rochelle salt (200 mL, 10% w/v) was added and the mixture was stirred vigorously for 30 minutes. The aqueous phase was isolated and extracted with DCM. The combined organic phases were washed with water, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 50 to 100% EtOAc in cyclohexane) to afford the title compound (1.23 g, 89%) as a pale yellow solid. LCMS (Method A): RT=4.18 min, [M+H]+=326.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:10][CH2:9][CH2:8][C:7](=O)[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[NH:4][C:3]1=[O:16].C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>C(O)C>[CH3:1][C:2]1([CH3:17])[O:10][CH2:9][CH2:8][C:7](=[N:24][OH:25])[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[NH:4][C:3]1=[O:16]
Reactant: CC1(C)OCCC(=O)c2ccccc2NC1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1(C)OCCC(=NO)c2ccccc2NC1=O

Procedure:
A solution of the compound of formula V, 5,6-dihydro-3,3-dimethyl-4,1-benzoxazonine-2,7(1H,3H)-dione (described in Example 1, 50 g), sodium acetate (37.5 g) and hydroxylamine hydrochloride (31.5 g) in ethanol (1,200 ml) is stirred at room temperature for two days. The precipitate is removed by filtration and the filtrate evaporated. Water and diethyl ether are added to the residue. The organic phase is separated, dried and evaporated. The residue is crystallized from ethanol to give 5,6-dihydro-3,3-dimethyl-4,1-benzoxazonin-2,7(1H,3H)-dione 7-oxime, mp 205°-206° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH3:17].[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>C(O)C>[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[N:21]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[C:8]=3[N:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1N
Reactant: COc1cccc2c(Cl)c(CCCCl)cnc12
Solvent: CCO
Product: COc1cccc2c3c(cnc12)CCCN3c1ccccc1C
Yield: 26.7 %

Procedure:
A solution of 3-(3-chloropropyl)-4-chloro-8-methoxyquinoline (6.4 g, 23.6 mmol) and 2-methylaniline (5.0 ml, 47.2 mmol) in ethanol (250 ml) was heated at reflux for 4 days, then cooled and evaporated. Dichloromethane and aqueous sodium bicarbonate solution were added, and the organic layer washed with water, dried and evaporated. Chromatography (silica gel, 1% methanolic ammonia in dichloromethane) followed by crystallisation from ethyl acetate gave 1-(2-methylphenyl)-7-methoxy-1,2,3,4-tetrahydropyridino-[3,2-c]quinoline (1.92 g, 27%), m.p. 160°-161°.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:20]#[N:21])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].Cl.[NH2:23][OH:24].C(N(CC)CC)C>CO>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4](=[N:3][O:2][CH3:1])[C:20](=[N:23][OH:24])[NH2:21]
Reactant: CON=C(C#N)c1ccccc1COc1ccccc1C
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C(C(N)=NO)c1ccccc1COc1ccccc1C
Yield: 67 %

Procedure:
A mixture of part of the sample of isomer 1 of 2-(2-methylphenoxymethyl) benzoyl cyanide O-methyloxime (280 mg), hydroxylamine hydrochloride (80 mg) and triethylamine (110 mg) in methanol (5 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated and the residue, dissolved in ethyl acetate, was washed with water, dried, concentrated, and chromatographed using ethyl acetate:hexane (1:1) as eluant to give two stereoisomers of 2-[2-(2-methylphenoxymethyl)phenyl]-2-methoxyimino acetamide oxime. Isomer I (200 mg, 67% yield), eluted first, was a white solid, mp 140° C., 1H NMR (CDCl3): δ 2.3 (3H,s), 4.0 (3H,s) and 5.05 (2H,s) ppm. Isomer II (100 mg, 33% yield), was also a white solid, mp 110°-2° C., 1H NMR (CDCl3): δ 2.3 (3H,s), 4.0 (3H,s) and 5.2 (2H,s) ppm.
Reaction SMILES: [CH3:1][C:2](=[N:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:3].[H][H]>[Pd].C(O)(=O)C.CO>[CH:2]([NH:4][NH:5][C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])([CH3:3])[CH3:1]
Reactant: [H][H]
Reactant: CC(C)=NNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NNC(=O)OC(C)(C)C

Procedure:
tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 was reduced with palladium catalyst on carbon with hydrogen gas in acetic acid and methanol to give tert-butyl 2-isopropylhydrazinecarboxylate 3 (CAS Reg. No. 16689-35-3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=3[CH3:34])=[CH:25][C:20]=2[N:19]=[CH:18]1>C(O)(C)C.ClCCCl>[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=5)[N:5]=[CH:4][N:3]=4)=[CH:29][C:28]=3[CH3:34])=[CH:25][C:20]=2[N:19]=[CH:18]1
Reactant: Cc1cc(N)ccc1Oc1ccc2ocnc2c1
Reactant: COCCOc1ccc2ncnc(Cl)c2c1
Solvent: ClCCCl
Solvent: CC(C)O
Product: COCCOc1ccc2ncnc(Nc3ccc(Oc4ccc5ocnc5c4)c(C)c3)c2c1
Temperature: 80 °C
Yield: 27.2 %

Procedure:
To a solution of 4-chloro-6-(2-methoxyethoxy)quinazoline (0.199 g, 0.83 mmol) and 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine (0.200 g, 0.83 mmol) in isopropanol (2 mL) and DCE (2 mL). After heating to 80° C. for 12 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between saturated NaHCO3 and EtOAc. The aqueous phase was extracted 2× with EtOAc, the combined organic phase was washed with brine, dried (Na2SO4), filtered and condensed. The residue was chromatographed to provide the product (0.100 g, 27%) as off-white solids. MS APCI (+) m/z 443 (M+1) detected; 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.76 (s, 1H), 8.50 (s, 1H), 7.96 (s, 1H), 7.75 (m, 4H), 7.52 (dd, 1H), 7.26 (m, 1H), 7.10 (m, 1H), 6.97 (d, 1H), 4.30 (m, 2H), 3.76 (m, 2H), 3.36 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:11][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=[C:7]2[C:6]1=[O:19])[CH:2]([CH3:4])[CH3:3].O>CO.[BH4-].[K+]>[CH:16]([O:15][C:12]1[CH:11]=[C:8]2[C:7](=[CH:14][CH:13]=1)[C:6](=[O:19])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:9]2[OH:10])([CH3:18])[CH3:17]
Reactant: CC(C)CN1C(=O)c2ccc(OC(C)C)cc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)CN1C(=O)c2ccc(OC(C)C)cc2C1O
Temperature: 20 °C
Reaction time: 17 h
Yield: 92.4 %

Procedure:
5-Isopropyloxy-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 1.16 g of N-isobutyl-4-isopropyloxyphthalimide in 20 cm3 of methanol and 0.24 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 17 hours and then cooled to a temperature in the region of 0° C. and 30 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C., and 50 cm3 of water are added. The aqueous phase is extracted 3 times with 70 cm3 of ethyl acetate. The organic extracts are combined, washed with 100 cm3 of saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.08 g of 5-isopropyloxy-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a viscous colorless oil. (Rf=0.50, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:56]1([N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:58][CH2:57]1>CN(C=O)C>[CH:56]1([N:59]2[CH2:64][CH2:63][N:62]([C:31](=[O:32])[CH2:30][C:26]3[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])[CH2:61][CH2:60]2)[CH2:58][CH2:57]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: C1CN(C2CC2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (208 mg, 0.4 mmol), HOBt (54 mg, 1 eq.) and EDAC (153 mg, 2 eq.) in DMF (1.5 mL) was stirred at rt for 30 mins. To the mixture was added 1-cyclopropyl-piperazine (101 mg, 2 eq.) in DMF (1.5 mL). After stirring at rt for overnight, the precipitate was collected by vacuum filtration, washed with water, sodium bicarbonate and ether to give 108 mg (43%) of the titled compound.
Reaction SMILES: C[O:2][C:3](=[O:49])[CH2:4][C:5]([CH3:48])([CH3:47])[CH2:6][CH2:7][N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:16]2[N:17]=[N:18][N:19]([CH3:21])[N:20]=2)[C:10]2[CH:37]=[C:38]([CH3:46])[C:39]([C:42]([F:45])([F:44])[F:43])=[C:40]([CH3:41])[C:9]1=2>[OH-].[Na+].CO>[F:31][C:29]([F:30])([F:32])[C:27]1[CH:28]=[C:23]([CH:24]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:26]=1)[CH2:22][N:15]([C:16]1[N:17]=[N:18][N:19]([CH3:21])[N:20]=1)[C@H:11]1[CH2:12][CH2:13][CH2:14][N:8]([CH2:7][CH2:6][C:5]([CH3:47])([CH3:48])[CH2:4][C:3]([OH:49])=[O:2])[C:9]2[C:40]([CH3:41])=[C:39]([C:42]([F:43])([F:44])[F:45])[C:38]([CH3:46])=[CH:37][C:10]1=2
Reactant: COC(=O)CC(C)(C)CCN1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc(C)c(C(F)(F)F)c(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(CCC(C)(C)CC(=O)O)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Yield: 88.6 %

Procedure:
Heat the mixture of (S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-3,3-dimethyl-pentanoic acid methyl ester (0.120 g, 0.169 mmol) in 5.0 N NaOH (1 mL) and methanol (5 mL) under reflux for 2 h. Evaporate the solvents and re-dissolve in water (10 mL). Adjust to pH=4 by adding 4.0 N HCl. Extract with ethyl acetate (2×10 mL). Combine the organic layers, dry over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (0-100%), to provide the title compound as white foam (0.104 g, 88%). MS (ES+): 695 (M+H); 693 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C@H:11]3[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C@@H:11]3[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12]3)[C:7]([CH2:9][N:26]3[C:27]4=[CH:28][N:29]=[CH:30][CH:31]=[C:32]4[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=S1(=O)CC[C@H](n2c(CCl)nc3cc(Cl)ccc32)C1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCS(=O)(=O)C2)c2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A mixture of compound 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole(115 mg, 0.36 mmol), 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (60 mg, 0.36 mmol) and Cs2CO3 (236 mg, 0.76 mmol) in 4 mL of DMF was stirred at room temperature for 1 h. The mixture was filtered, the filtrate was collected, then to the filtrate was added oxone (300 mg). The mixture was stirred for 4 hrs and purified by prep-HPLC to give the product (60 mg, yield: 34.6%) as an off-white solid.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:40])[C@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:32])[CH2:23][NH:24]C(OC(C)(C)C)=O)[CH2:18][N:17]2C(OC(C)(C)C)=O)[C@H:11]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[CH2:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:40])[C@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:32])[CH2:23][NH2:24])[CH2:18][NH:17]2)[C@H:11]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@H]1C[C@H](C(=O)N2CCN(Cc3ccccc3)C[C@H]2CCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N[C@@H]1CN[C@@H](C(=O)N2CCN(Cc3ccccc3)C[C@H]2CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (5 mL) was added to a solution of (2R)-4-Benzyl-1-[trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-D-Prolyl]-2-Phenethylpiperazine (D, 161 mg) in 1,4-dioxane (5 mL) at room temperature. After stirring at room temperature for 20 min, the reaction mixture was concentrated in vacua. The residue was washed with ether to give the titled compound (103 mg) as a beige powder: 1H NMR (400 MHz, D2O) δ 2.00 (m, 2H), 2.19 (m, 1H), 2.41 (quintet, J=7.3 Hz, 1H), 2.58 (m, 1H), 2.71 (m, 2H), 3.18 (t, J=11.7 Hz, 1H), 3.27 (m, 1H), 3.37 (m, 1H), 3.46 (m, 1H), 3.63 (m, 2H), 3.77-3.93 (m, 2H), 3.85 (s, 2H), 4.33-4.49 (m, 3H), 4.58 (m, 1H), 7.24 (t, J=6.8 Hz, 2H), 7.30 (t, J=6.8 Hz, 1H), 7.36 (m, 2H), and 7.48-7.58 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:44]=[CH:43][C:27]([C:28]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[O:29])=[CH:26][CH:25]=2)[N:14]=1>[Pd].CCN(CC)CC>[CH3:1][O:2][C:3](=[O:45])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:44]=[CH:43][C:27]([C:28]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[O:29])=[CH:26][CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 10% Pd/C (53% water; 0.660 g), tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate (A23) (0.337 g, 0.540 mmol) and Et3N (1 mL) was stirred at room temperature for 16 hours under an atmosphere of hydrogen. The mixture was filtered through a pad of Celite, washing with EtOAc (80 mL). The filtrates were evaporated in vacuo affording a yellow oil which was purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-80% EtOAc in petroleum benzine 40-60° C.) to yield the title compound A24 as a pale yellow oil (0.245 g, 72%); 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.19 (s, 1H), 7.72 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.6 Hz, 2H), 7.25-7.13 (m, 4H), 3.73 (s, 2H), 3.65 (s, 3H), 3.84-3.30 (m, 8H), 3.18-3.00 (m, 4H), 1.46 (s, 9H). LCMS-A: rt 6.500 min; m/z 628 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][N:20]=[CH:19]1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[CH:30][CH:29]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3ccnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-imidazol-1-yl-benzaldehyde, of Preparation 43, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.40 (d, 2H), 7.28 (d, 2H), 7.22 (m, 2H), 7.13 (m, 1H), 6.89 (m, 2H), 6.73 (m, 1H), 4.47 (s, 2H), 3.78 (s, 2H), 3.74 (s, 2H), 1.43 (s, 9H); MS 394 (M+1).