Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:24][OH:25])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCCCCCC.O1CCCC1>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:25][CH2:24]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC1(Cc2ccccc2F)CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: c1ccc(CN2CCC3(CC2)COc2ccccc2C3)cc1
Yield: 88.4 %

Procedure:
Sodium hydride (350 mg, 7.0 mmol, 50% disp in oil) was washed three times with heptane, under nitrogen atmosphere, and then dissolved in tetrahydrofuran (50 mL). A solution of [1-benzyl-4-(2-fluorobenzyl)piperidin-4-yl)methanol (1 g, 3.2 mmol) in tetrahydrofuran (30 mL) was added and the resulting mixture was refluxed for 3 hrs. The cooled solution was partitioned between water and ethyl acetate and the organic layer was dried over magnesium sulphate and concentrated. The crude product was purified on silica (dichloromethane/methanol) to give 0.83 g (89%) of the subtitle compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:8]=2[CH:21]=1)(O)=[O:2].[F:22][C:23]([F:29])([F:28])[S:24]([NH2:27])(=[O:26])=[O:25].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[ClH:20].[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:8]2[CH:21]=[C:4]([C:1](=[O:2])[NH:27][S:24]([C:23]([F:29])([F:28])[F:22])(=[O:26])=[O:25])[CH:5]=[CH:6][C:7]=2[N:11]=[C:10]1[CH3:12]
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Reactant: NS(=O)(=O)C(F)(F)F
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)C(F)(F)F)cc2n1Cc1ccccc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
N,N'-carbonyldiimidazole (0.647 g) was added at a time to a solution of 0.600 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 20 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 0.596 g of trifluoromethanesulfonamide and 0.609 g of diazabicycloundecene in 5 ml of N,N-dimethylformamide was added thereto, and the mixture was stirred at 100° C. for 72 hours. The reaction solution was cooled, and the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue, and 10% hydrochloric acid was added thereto while being stirred until the aqueous layer was acidified. The crystals precipitated were washed with a mixed solvent of 25 ml of ethanol and 25 ml of methanol. The crystals were dried to give 0.420 g of 1-(2-chlorobenzyl)-2-methyl-6-trifluoromethanesulfonylcarbamoylbenzimidazole hydrochloride (214).
Reaction SMILES: [CH:1]1([CH:6]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][N:26]=2)[C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([N:14]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[N:15]3)=[C:9]([CH3:23])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:6]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][N:26]=2)[C:7]2[CH:8]=[C:9]([CH3:23])[C:10]([N:14]3[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[N:15]3)=[C:11]([CH3:13])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(NC(c2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CCCC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(Nc2ccc(C(=O)O)cn2)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Reaction time: 16 h

Procedure:
To a solution of methyl (+/−)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinate (753 mg, 1.59 mmol) in tetrahydrofuran (7.97 mL) and methanol (7.97 mL) was added 1 N aq sodium hydroxide (7.97 mL, 7.97 mmol). After 16 h, the solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 1 N aq hydrochloric acid was added until the mixture was at pH 4. The mixture was diluted with sat. aq sodium chloride (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were dried (Na2SO4) and filtered, and the filtrate was concentrated under reduced pressure to provide (+/−)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinic acid. 1H NMR (400 MHz, CDCl3, δ): 8.68 (s, 1H), 8.14 (d, J=9.2 Hz, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.15 (s, 2H), 6.39 (d, J=9.2 Hz, 1H), 4.28-4.18 (m, 1H), 2.44-2.31 (m, 1H), 2.12-2.05 (m, 1H), 2.01 (s, 6H), 1.78-1.40 (m, 6H), 1.36-1.28 (m, 1H). MS (M+1): 459.5.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:39])=[N:4][O:5][C:6]=1[N:7]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20]([OH:32])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)(=[O:10])=[O:9].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:39])=[N:4][O:5][C:6]=1[N:7]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[C:20](=[O:32])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)CCc2ccc3c(c2)OCO3)sc2ncccc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(=O)CCc2ccc3c(c2)OCO3)sc2ncccc12
Yield: 73.3 %

Procedure:
The title compound was prepared by the method of Example 12(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[1-hydroxy-3 -(3,4-methylenedioxyphenyl)propyl]thieno[2,3-b]pyridine-3-sulfonamide (0.51 g, 0.85 mmoles), CH2Cl2 (20 ml), celite, and PCC (0.27 g, 1.3 mmoles) except the reaction mixture was stirred 24 hours prior to filtering. Flash chromatography (40% EtOAc/hexanes) provided 0.37 g (74%) of the title compound as a yellow oil/solid.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:11][CH2:12][NH2:13].[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:14](=[O:15])[NH:13][CH2:12][CH2:11][CH:3]12
Reactant: CC1c2ccccc2NC1CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1c2ccccc2N2C(=O)NCCC12
Temperature: 110 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To a solution of crude 2-(2,3-dihydro-3-methylindol-2-yl)ethylamine (1.75 g) in tetrahydrofuran (12 ml) at room temperature was added in small portions 1,1'-carbonyldiimidazole (1.1 g). After being stirred for 2 hours, the reaction mixture was evaporated in vacuo. The oil obtained was dissolved in toluene (25 ml) and the solution was heated at 110° C. for 1.5 hours. After evaporation of the solvent, the residue was purified by silica gel column chromatography (1% methanol-chloroform) to give crystals. Recrystallization from chloroform-ethyl acetate-hexane gave 3,4,4a,5-tetrahydro-5-methylpyrimido-[1,6-a]indol-1(2H)-one (0.65 g).
Reaction SMILES: B.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH2:8][CH2:7]2.[OH-:20].[Na+].OO>O1CCCC1.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:9]([OH:20])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCC=C2c1ccccc1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H](O)[C@@H]2c1ccccc1
Yield: 37 %

Procedure:
Borane in tetrahydrofuran (34 mL of a 1M solution, 34 mmol) was added to tetrahydrofuran (50 mL) and the resultant solution was cooled to 0° C. A solution of 6-methoxy-1-phenyl-3,4-dihydronaphthalene 28 (5.0 g, 21.2 mmol) in tetrahydrofuran (10 mL) was added. The resultant mixture was stirred at ambient temperature for 18 h. A solution of water (5 mL) in tetrahydrofuran (20 mL) was slowly added to the cooled solution which resulted in considerable foaming. Additional water (10 mL) was added followed by 10% aqueous sodium hydroxide (15 mL) and 30% hydrogen peroxide (30 mL). The resultant mixture was stirred at room temperature for 6 h. The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic solutions were washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography using 30 to 40% ethyl acetate in hexanes as the eluent, to afford trans-6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ol 29 as an oil (2.0 g, 37%). 1H NMR(CDCl3) δ1.77 (d, 1H), 1.83-1.97 (m, 1H), 2.13-2.22 (m, 1H), 2.94-3.05 (m, 2H), 3.78 (s, 3H), 3.90 (d, 1H), 3.98-4.07 (m, 1H), 6.59-6.70 and 7.16-7.39 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]=[C:17](Br)Br)[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:26]=[O:27]>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:26][OH:27])[CH2:12][CH2:11]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C[C@H]1CC[C@H](C=C(Br)Br)CC1)C(=O)OC(C)(C)C
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C[C@H]1CC[C@H](C#CCO)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 32.9 g (80 mmol) of trans-[4-(2,2-dibromo-vinyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester in 640 ml tetrahydrofuran was treated at −78° C. with 105 ml (168 mmol) of n-butyl-lithium (ca 1.6 M in hexane). After 2 hours at this temperature, 24 g (800 mmol) of paraformaldehyde were added. The reaction mixture was warmed up to room temperature for 3 hours and after 0.5 hours at this temperature extracted with water/ether (3×). The organic phases were washed with aqueous 10% NaCl, dried over sodium sulfate and evaporated. Purification by flash-chromatography on silica gel (hexane/EtOAc 9:1 to 2:1) yielded 12.1 g (54%) of trans-[4-(3-hydroxy-prop-1-ynyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester as orange viscous oil, MS: 282 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5]1.S(OC)(O[CH3:15])(=O)=O.C(N(CC)CC)C.C1COCC1>C(OCC)C>[CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[N:5]1[CH3:15]
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: COS(=O)(=O)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)[C@@H]1CCC(=O)N1C
Temperature: 60 °C

Procedure:
The methyl ester compound from step 5a above (18.3 kg, 127.8 mol) and dimethyl sulfate (20.09 kg, 159.3 mol) were introduced into a reactor, and the mixture was heated to 60° C. under an N2 atmosphere. Heating was continued until the concentration of starting material dropped below 15%. An additional 6.25 kg (0.5 eq) of dimethyl sulfate was added with exothermic response. The thick reaction mixture was then cooled to 25° C., and a solution of triethylamine (16.12 kg) in diethyl ether (19.2 L) was added at such a rate that the temperature did not rise above 30° C. The emulsion was washed with two 50 L portions of water. The ether layer was separated, and the residue was extracted with ethyl acetate (60 l). The combined organic layers were dried over Na2SO4 and azeotroped with toluene until no more triethylamine remained in the residue. The residue was mixed with dimethyl sulfate (1.7 kg, 13.5 mol) and THF (70 L) and refluxed under nitrogen until the reaction was complete. The solvents were evaporated under vacuum, and the residue was distilled under high vacuum to yield a colorless product.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]([O:24]C(=O)C3C=CC=CC=3)[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[OH:24])=[N:9][N:8]=2)=[CH:33][CH:34]=1
Reactant: O=C(OC(c1ccncc1)c1nnc(Nc2ccc(Cl)cc2)c2ccccc12)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: OC(c1ccncc1)c1nnc(Nc2ccc(Cl)cc2)c2ccccc12
Reaction time: 16 h

Procedure:
100 mg (0.214 mMol) of rac benzoic acid-[4-(4-chloroanilino)phthalazin-1-yl](pyridin-4-yl)-methyl ester in 2 ml dioxane, 1 ml methanol and 1 ml water are saponified with 9.9 mg (0.235 mmol) lithiumhydroxide monohydrate. After 16 h, the title compound is filtered off: m.p. 196-197° C., FAB MS (M+H)+=363.
Reaction SMILES: [F:1][C:2]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([F:4])[CH3:3].[Li+].[OH-]>CCO.O>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:2]([F:1])([F:4])[CH3:3])[CH2:6][CH2:7]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(F)(F)[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
(R)-4-(6-(cis-4-(1,1-Difluoroethyl)cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (32 mg, 0.083 mmol) was dissolved in EtOH (5 mL). Then LiOH (60 mg, 2.5 mmol, 30.0 eq.) in 1 mL water was added to the mixture. The mixture was heated to 80° C. and stirred for 15 h. LCMS showed starting material was gone. Solvent was removed. DCM was added and filtered. The filtrate was concentrated and purified by silica gel chromatography using DCM/methanol (10/1) to give product (12 mg, 40%) as a slight yellow solid. EDI-MS (M−NH2): 347.0. HPLC: 98.82%. 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.72-7.66 (m, 2H), 7.49 (d, 1H), 7.10 (d, 2H), 4.30-4.27 (m, 1H), 3.78-3.68 (AB, 2H), 3.18 (b, 3H), 2.32-2.30 (m, 2H), 2.04-1.99 (m, 2H), 1.63-1.19 (m, 11H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:2][C:3]2[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[O:6][CH:7]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(CCCCCl)cc1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCCl)cc3)co2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
A suspension of 4-chloromethyl-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (13.4 g), 4-(4-chlorobutyl)phenol (8.63 g) and potassium carbonate (6.46 g) in DMF (200 ml) was stirred at 60° C. for 24 hr. The reaction mixture was combined with water to give crystals, which were collected by filtration and washed with methanol-water (2:1) to give crude 4-[[4-(4-chlorobutyl)phenoxy]methyl]-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (19.5 g) as colorless powders. A suspension of this product (18.5 g) and sodium iodide (31.8 g) in acetonitrile (240 ml) was refluxed for 22 hr. The reaction mixture was concentrated, diluted with ethyl acetate, successively washed with water, hypo-water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with hexane to give the titled compound (12.3 g) as colorless needle crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:36][CH3:37])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:23]([CH:31]=O)[NH:22][C:21]=1[CH:33]([CH3:35])[CH3:34])=[O:19])[CH3:13]>>[CH2:36]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:23]([CH:31]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH:33]([CH3:35])[CH3:34])=[O:19])[CH3:37]
Reactant: CCN(CC)CCNC(=O)c1c(C(C)C)[nH]c(C=O)c1-c1ccccc1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCNC(=O)c1c(C(C)C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1-c1ccccc1
Yield: 52.6 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (57 μg. 0.27 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (120 mg) to give 78 mg (53%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[CH3:16][O:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (1.0 g) in DMF (20 ml) was added NaH (235 mg; 60% oil suspension) under nitrogen atmosphere, and the mixture was stirred for 30 minutes at room temperature. MeI (665 μl) was added to the mixture, and the whole was stirred for 2 hours. Water was added to the mixture, and the whole was extracted with EtOAc. The extract was washed with water and brine and dried over MgSO4. Concentration under reduced pressure gave a residue, which was purified with silica gel chromatography eluting with n-hexane:EtOAc=5:1 to give tert-butyl 3-(methoxymethyl)azetidine-1-carboxylate (1.04 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH:25]=2)=[CH:20][CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:72]1([NH2:79])[C:73]([NH2:78])=[CH:74][CH:75]=[CH:76][CH:77]=1>CN(C)C=O>[NH2:78][C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][C:72]=1[NH:79][C:14](=[O:15])[CH:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:28](=[O:29])(=[O:30])[NH:27][C:26](=[O:31])[CH:25]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)O
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: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC(Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of (2S)-2-((2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoylamino)-3-[4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]-propanoic acid (15.0 mg, 0.0276 mmol) in N,N-dimethylformamide (3 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (10.5 mg, 0.027 mmol) and N,N-diisopropylethylamine (24 μL, 0.14 mmol) and premixed for 5 minutes. To the solution was added 1,2-benzenediamine (4.2 mg, 0.04 mmol) and stirred at room temperature overnight. Preformed ester was yellow in color and upon addition of the diamine continued to darken over several minutes. Product was purified by preparative LCMS to afford the desired product (7.3 mg, 42%). LCMS found for C32H36N5O7S (M+H)+: m/z=634.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[C:20]1([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C(OCC)(=O)C>[C:20]1([CH2:26][CH2:27][C:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccnc(N)c1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccnc(NC(=O)CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of ethyl 2-aminoisonicotinate (4.50 g, 27.08 mmol) and triethylamine (9.0 mL, 64.93 mmol) in tetrahydrofuran (100 mL) was added 3-phenylpropanoyl chloride (8.3 mL, 56.11 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=95/5-0/100) and recrystallized from hexane/ethyl acetate to give the title compound (6.85 g, yield 85%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[C:7](=O)[C:8](=[O:29])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[ClH:35].[NH2:36][OH:37].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CC(C)=O>[ClH:35].[N:36](=[C:7]1[C:6]2[CH:31]=[C:32]([O:33][CH3:34])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:8]1=[O:29])[OH:37]
Reactant: NO
Reactant: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=NO)C2=O)cc1OC

Procedure:
A mixture of 3.6 gm of (6.8 mmols) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl]-3-[N-methyl-N-(2-{3,4-dimethoxy-phenyl}-ethyl)-amino]-propane, 0.57 gm of hydroxylamine hydrochloride and 0.87 gm of sodium carbonate was refluxed for 8 hours in 100 ml of ethanol. The solvent was then distilled off in vacuo; the residue was dissolved in water/methylene chloride, and the organic phase was separated, dried over magnesium sulfate and concentrated by evaporation. The residue was purified on silica gel, using methylene chloride and 5% ethanol as the eluant. The free base product thus obtained was dissolved in acetone, and the hydrochloride was precipitated by the addition of ethereal hydrochloric acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[CH:21](N)=O.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:21]=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NC=O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Reaction time: 6 h

Procedure:
To a suspension of 2.8 parts of 7-chloro-2-hydrazino 5-phenyl-3H-1,4-benzodiazepine in 40 parts by volume of formamide is added 1 part by volume of concentrated sulfuric acid. The resulting solution is left standing for 6 hours and then warmed on a boiling water bath for 30 minutes. The solution is diluted with water, neutralized with sodium bicarbonate and extracted with chloroform. The chloroform extract is washed with water and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from ethyl acetate to give 8-chloro-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine as colorless flakes. Melting point: 226° C to 227° C.