Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22]>>[OH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Oc1ccccc1I
Product: COC(=O)CCc1ccc(C#Cc2ccccc2O)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (102 mg, 0.53 mmol) and 2-iodophenol (130 mg, 0.58 mmol) according to the general procedure IF to give 19 mg (13%) of a white solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:10). Rf=0.28 (EtOAc:PE, 1:5); 1H NMR (CDCl3): δ 7.79 (dt, J=8.3 Hz, 2.0 Hz, 2H), 7.56 (d, J=1.0 Hz, 1H), 7.50 (d, J=1.0 Hz, 1H), 7.29-7.21 (m, 3H), 6.98 (d, J=1.0 Hz, 1H), 3.68 (s, 3H), 2.99 (t, J=7.8 Hz, 2H), 2.60 (t, J=7.8 Hz, 2H); 13C NMR (CDCl3): δ 173.2, 155.9, 154.8, 141.1, 129.3, 128.7, 128.8, 125.1, 124.1, 122.9, 120.9, 111.1, 100.9, 51.6, 35.5, 30.7; ESI-MS m/z 303.1 (M+Na+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:13]([NH:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[C:3]=1[N+:10]([O-:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(O)n1
Reactant: NCc1ccccc1
Solvent: CCO
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(O)n1

Procedure:
Stir a solution of 4-chloro-6-methyl-3-nitro-pyridin-2-ol (10.0 g, 53.0 mmol) and benzyl amine (17.3 g, 159 mmol) in EtOH (30 mL) at ambient temperature for 12 h, then concentrate in vacuo. Pour the resulting residue into water, acidify to pH 3 with 1N HCl and filter. Wash the precipitate several times with water to obtain the title compound as a yellow solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C@@H:19]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:33])[CH3:32])[C:18]2=[O:43])=[CH:12][CH:11]=1)=[C:2]=[O:3].[CH2:44]([CH2:46][NH2:47])[OH:45]>>[OH:45][CH2:44][CH2:46][NH:47][C:2]([NH:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C@@H:19]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:33])[CH3:32])[C:18]2=[O:43])=[CH:14][CH:15]=1)=[O:3]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N=C=O)cc2)C1=O)NC(=O)OC(C)(C)C
Reactant: NCCO
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3NC(=O)NCCO)cc2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from N-[1-[[(2'-isocyanato)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide and ethanolamine by the procedure described in Example 6, Step A. FAB-MS: calculated for C36H45N5O6 643; found 666 (M+Na). 1H NMR (400 MHz, CDCl3): δ 1.29 (s, 3H), 1.31 (s, 3H), 1.38 (s, 9H), 1.90 (m, 1H), 2.5 (dd, 2H), 2.58 (m, 2H), 2.7 (m, 1H), 3.21 (t, 2H), 3.54 (m, 2H), 4.49 (m, 1H), 4.88 (d, 1H), 5.10 (d, 1H), 6.81 (d, 1H), 7.21 (m, 11H), 7.74 (d, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4](F)[C:3]=1[F:14].C(=O)(O)[O-].[Na+].C(#[N:22])C>N>[NH2:22][C:4]1[C:3]([F:14])=[C:2]([F:1])[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]=1[C:11]#[N:12]
Reactant: CC#N
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1c(N)c(F)c(F)c(C#N)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 2.0 g of tetrafluoroisophthalonitrile in 20 ml of acetonitrile, 0.6 ml of 28% aqueous ammonia was dropwise added. After the dropwise addition, the mixture was stirred at room temperature for one hour. An aqueous sodium bicarbonate solution was added to the mixture and the resultant mixture was extracted with chloroform and was washed with an aqueous sodium chloride solution. After drying with sodium sulfate, the chloroform was distilled off to obtain yellow crystal. The resultant crystal was recrystallized from chloroform to obtain 1.2 g (61% yield) of the desired compound No. 1.
Reaction SMILES: Br.[CH:2]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:24])=[C:12]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[CH2:20][NH:19][CH2:18]5)[CH:13]=3)[C:8](=[O:25])[C:7]([C:26]([OH:28])=[O:27])=[CH:6]2)[CH2:4][CH2:3]1.C=O.O.[C:32](=O)([O-])O.[Na+]>C(O)=O>[CH:2]1([N:5]2[C:14]3[C:9](=[CH:10][C:11]([F:24])=[C:12]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[CH2:20][N:19]([CH3:32])[CH2:18]5)[CH:13]=3)[C:8](=[O:25])[C:7]([C:26]([OH:28])=[O:27])=[CH:6]2)[CH2:3][CH2:4]1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cn(C2CC2)c2cc(-c3ccc4c(c3)CNC4)c(F)cc2c1=O
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CN1Cc2ccc(-c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)cc2C1

Procedure:
In 0.50 ml of formic acid was suspended 50 mg of 1-cyclopropyl-6-fluoro-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrobromide, and 27 mg of formalin was added to the suspension, after which the mixture was heated under reflux for two hours. The solvent was then removed by distillation under reduced pressure. To the residue obtained was added 5 ml of water and the pH was adjusted to 7 with a saturated aqueous sodium hydrogencarbonate solution, after which the resulting mixture was extracted with five 5 ml portions of chloroform. The resulting chloroform layer was dried over anhydrous magnesium sulfate and then the solvent was removed by distillation under reduced pressure. Ethanol was added to the residue obtained and the crystals formed were collected by filtration, to obtain 29 mg of pale yellow, crystalline 1-cyclopropyl-6-fluoro-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)=[N:6][CH:7]=1.[CH:22](O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:21]=[CH:22][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:10]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=CO
Reactant: Nc1cc(Br)cnc1Nc1cccc(-c2cccnc2)c1
Product: Brc1cnc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Temperature: 80 °C

Procedure:
A mixture of crude 5-bromo-N2-[3-(pyridin-3-yl)phenyl]pyridine-2,3-diamine and 98% formic acid was heated at 80° C. for 3 hours. The reaction was cooled, evaporated to dryness, the residue suspended in water and made basic by the cautious addition of solid sodium hydrogen carbonate. This was then extracted with ethyl acetate, the organics dried over anhydrous sodium sulphate, filtered and pre-adsorbed on to silica. Purification by silica gel chromatography eluting with dichloromethane/methanol/0.88 NH3 (95:4.5:0.5) furnished 6-bromo-3-[3-(pyridin-3-yl)phenyl]-3H-imidazo[4,5-b]pyridine as a tan solid (3.1 g, 89% over 2 steps), m.p. 212-213° C. (Found C, 57.24; H, 2.98; N, 15.57. C17H11BrN4. 0.25H2O requires C, 57.40; H, 3.26; N, 15.75); δH (400 MHz, d6-DMSO) 7.55 (1H, dd, J 5 and 5), 7.76 (1H, t, J 8), 7.86 (1H, d, J 8), 8.04 (1H, d, J 8), 8.22 (1H, d, J 8), 8.27 (1H, s), 8.56 (2H, d, J 6), 8.64 (1H, d, J 5), 9.04 (1H, s), 9.11 (1H, s); m/z (ES+) 351 and 353 (M++H).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:14][CH2:15][CH3:16].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][C:30](O)([CH3:32])[CH3:31].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:5]([C:6]([O:8][C:30]([CH3:32])([CH3:31])[CH3:29])=[O:7])=[CH:4][C:3]=1[O:14][CH2:15][CH3:16]
Reactant: CC(C)(C)O
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1Br
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC(C)(C)C)cc(OCC)c1Br
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-Bromo-3,5-diethoxybenzoic acid (2.8 g) in DMF (25 ml) was added CDI (1.8 g) at room temperature and the mixture was stirred at 40° C. for 2 h. To the reaction mixture, t-BuOH (1.85 ml) and DBU (1.752 ml) were added and further stirred at 40° C. for over night. After cooling to room temperature, the mixture was poured into ice-H2O and extracted with EtOAc. The organic layer was washed with H2O, brine and dried over sodium sulphate. After filtration and concentration, the residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>ClCCl>[F:8][C:6]1[C:5]([F:9])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:3]([F:11])=[C:2]([F:1])[N:7]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: C1COCCN1
Solvent: ClCCl
Product: Fc1nc(F)c(F)c(N2CCOCC2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pentafluoropyridine (3.4 g; 20 mmol) was dissolved in dichloromethane (50 mL) and chilled in an ice bath. To the solution was added morpholine (3.48 g; 40 mmol) and the reaction was allowed to warm to room temperature with stirring overnight. The organic phase was washed with saturated ammonium chloride solution (2×20 mL), dried over magnesium sulfate, evaporated, and purified by column chromatography to give 4-(2,3,5,6-tetrafluoro-pyridin-4-yl)-morpholine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].I[CH3:13]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:13]
Reactant: CI
Reactant: Oc1cc(F)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1Br
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 2-bromo-5-fluorophenol (2 mL, 17.8 mmol)), sodium hydride (0.5 g, 20.8 mmol) and iodomethane (5 mL, 82 mmol) in DMF (20 mL) was heated to 60° C., stirred for 16 hours, diluted with ethyl acetate (100 mL), washed sequentially with 1M HCl, water, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:18])([F:17])[CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)(=O)=O.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C)C=O>[F:17][C:8]([F:18])([CH2:7][N:25]1[C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[C:21]1=[O:31])[CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: O=S(=O)(OCC(F)(F)COC1CCCCO1)C(F)(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)COC1CCCCO1
Temperature: 85 °C

Procedure:
A mixture of 2,2-difluoro-3-tetrahydropyranyloxypropyl trifluoromethanesulfonate (2.3 g, 7 mmol), potassium phthalimide (1.4 g, 7.7 mmol) and anhydrous dimethylformamide (50 ml) under nitrogen was stirred and heated at 85° C. overnight. After cooling, salts are filtered off, and the solvent was removed in uacuo. The residue was taken up in dichloromethane (100 ml), washed with 0.5M NaOH (30 ml) and brine. The organic phase was separated, dried over magnesium sulfate and concentrated. The desired compound 2,2-difluoro-3-phthalimido-1-tetrahydropyranyloxypropane was purified by flash chromatography on silica gel (ethyl acetate:hexane; 20:80) (2 g, 90%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9]Br.[C:11]([C:14]1[CH:15]=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([OH:24])=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[CH:19]=1)(=[O:13])[CH3:12]>CN(C)C=O>[C:21]([N:20]1[C:18]2[CH:19]=[C:14]([C:11](=[O:13])[CH3:12])[CH:15]=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]=2[O:24][CH2:9][CH2:8]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1cc(C(C)=O)cc(C(C)(C)C)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2C(C)=O
Temperature: 70 °C
Reaction time: 17 h
Yield: 97.8 %

Procedure:
Potassium carbonate (113 g, 818 mmol) and 1,2-dibromoethane (64.1 g, 341 mmol) were added to a solution of the N1-[5-acetyl-3-(tert-butyl)-2-hydroxyphenyl]acetamide (34.0 g, 137 mmol) in dimethylformamide (280 ml) under a nitrogen atmosphere, and then the mixture was stirred at 70° C. for 17 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue and the mixture was washed with water (3 times) and brine in that order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield the title compound (36.9 g, 98.1% yield) as light red crystals. These were used without purification for the following reaction.
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]=1[C:12]([O:14][CH3:15])=[O:13].F[B-](F)(F)F.[CH3:21][O+](C)C>C(OCC)(=O)C>[Br:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:21])[N:7]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(Br)c(Cl)cc2[nH]ncc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Br)c(Cl)cc2nn(C)cc12
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of methyl 5-bromo-6-chloro-1H-indazole-4-carboxylate (390 mg, 1.35 mmol) in ethyl acetate (27 mL) was added trimethyloxonium tetrafluoroborate (260 mg, 1.76 mmol) at room temperature, and the mixture was stirred for 2 hr. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=10/90→40/60) to give the title compound (336 mg, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:43][CH:44]=[CH:45][C:30]=34)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:43][CH:44]=[CH:45][C:30]=34)[CH2:27][CH2:28]2)=[O:22])=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](CNC(C)C)c3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
(S)-tert-Butyl 2-(4-chlorophenyl)-3-(4-(5-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.041 g, 0.065 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(5-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.028 g, 81% yield) as the dihydrochloride salt. MS ESI (+) m/z 533 detected.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:16]3[O:15][CH2:14][CH2:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl[C:24]1C(=O)C(C#N)=C(C#N)C(=O)[C:29]=1Cl.O>O1CCOCC1>[CH2:24]([O:19][C:18](=[O:20])[CH2:17][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:22][CH:21]=2)[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[CH:11]=1)[CH3:29]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1ccc(C(=O)c2cc(CC(=O)O)cc3c2OCC3)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(C)cc2)c2occc2c1

Procedure:
7-(4-Methylbenzoyl)-2,3-dihydrobenzofuran-5-ylacetic acid (1.0 g) was dissolved in dioxane (20 ml). To this was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (1.2 g) and the solution heated at reflux for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate, dried with magnesium sulfate and evaporated to dryness. The residue was run on a silica gel column eluting with ethyl acetate/hexane to give ethyl(7-(4-methylbenzoyl)-benzofuran-5-yl)acetate. The acetate was hydrolyzed by the same method set out in Example 3 to give (7-(4-methylbenzoyl)benzofuran-5-yl)acetic acid melting points. This method is especially useful when the 2,3-dihydro starting material contains an alkyl group.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.C(N(C(C)C)CC)(C)C>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Clc1ccccc1Cl
Product: Clc1ccc(-n2ccnc2)nn1
Yield: 37.5 %

Procedure:
A solution of 3,6-dichloropyridazine (Aldrich, 300 mg, 2.0 mmol), imidazole (Aldrich, 163 mg, 2.4 mmol), and diisopropylethylamine (620 mg, 4.8 mmol) in 1.5 mL 1,2-dichlorobenzene was heated in a sealed tube to 120° C. at 330 watts for 45 min in an Emry™ Creator microwave. The crude reaction mixture was purified by column chromatography (SiO2, 1% methanol-CH2Cl2) to give 135 mg of the title compound (0.75 mmol, 38% yield) as the major product. MS (DCl/NH3) m/z 181 (M+H)+.
Reaction SMILES: O(C([N:8]1[CH2:39][CH2:38][CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:9]1[C:10]([N:12]1[CH2:36][CH2:35][CH2:34][C@H:13]1[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[CH2:25][NH:26]C(OC(C)(C)C)=O)=[O:15])=[O:11])=O)C(C)(C)C.Cl>CO.CCOCC>[C:40]1([CH:37]2[CH2:38][CH2:39][NH:8][C@@H:9]2[C:10]([N:12]2[CH2:36][CH2:35][CH2:34][C@H:13]2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[CH2:25][NH2:26])=[O:15])=[O:11])[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@@H]1C(c2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1c1ccccc1

Procedure:
To a stirred solution of diastereomer A of 1-(tert-butoxylcarbonyl)-3-phenylprolyl-N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)-L-prolinamide (60 mg, 0.09 mmol) from the previous step in approx. 2 mL MeOH at room temperature was added excess of a solution of 1.0 M HCl in ether. The reaction was monitored for completeness by LCMS. The solvent was removed in vacuo to give the HCl salt of the title compound as a white solid. LCMS RT=0.94 min. LCMS (M+H)=441.1. 1H NMR (CD3OD, 500 MHz): δ 7.50-7.23 (m, 8H), 4.58-4.51 (m, 1H), 4.41-4.24 (m, 3H), 4.08-3.96 (m, 1H), 3.80-3.74 (m, 1H), 3.49-3.43 (m, 1H), 3.39-3.31 (m, 3H), 3.05-2.92 (m, 1H), 2.57-2.37 (m, 2H), 2.06-1.64 (m, 2H), 1.56-1.26 (m, 2H). Diastereomer B (73 mg, 0.11 mmol) was deprotected in similar fashion to afford the HCl salt of the title compound as a white solid. LCMS RT=0.98 min. LCMS (M+H)=441.2. 1H NMR (CD3OD, 400 MHz): δ 8.90 (m, 1H), 7.49-7.32 (m, 8H), 4.49 (d, J=15.6 Hz, 1H), 4.31 (d, J=15.6 Hz, 1H), 4.23 (s, 2H), 4.02-3.95 (m, 1H), 3.90-3.87 (m, 1H), 3.79-3.75 (m, 1H), 3.48-3.30 (m, 2H), 3.13-3.03 (m, 1H), 2.91-2.85 (m, 1H), 2.50-2.43 (m, 1H), 2.39-2.28 (m, 1H), 1.73-1.59 (m, 3H), 1.18-1.12 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C1(C)C=CC=CC=1.[OH-].[Na+].[C:16](Cl)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O>[O:6]=[C:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:16]([O:18][CH2:19][CH:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=C1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Into a 500 mL four neck flask were added 2-pyrrolidone (8.51 g) [mw. 85.10, 100 mmol] and toluene (170 mL), and the mixture was dissolved. Powder sodium hydroxide (4.00 g) [mw. 40.00, 100 mmol] was added thereto, Dean-Stark trap was set, and the mixture was subjected to dehydration reflux for 4 hr. After cooling to 0° C., Fmoc-Cl (25.70 g) [mw. 258.70, 99 mmol] was added at not more than 5° C., the mixture was stirred at 25° C. for 2 hr, and water (43 mL) was added to allow for partitioning. The organic layer was washed with 5 w/w aqueous potassium hydrogen sulfate solution (43 mL), and further washed twice with water (43 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Pale-yellow oil, 30.56 g, yield 99.4%, 1H-NMR (500 MHz, CDCl3, TMS) δ 1.13 (d, J=6.3 Hz, 1H), 2.04 (quin, J=7.7 Hz, 2H), 2.57 (t, J=8.2 Hz, 2H), 3.75-3.82 (m, 2H), 4.49 (d, J=7.6 Hz, 2H), 7.30-7.36 (m, 2H), 7.37-7.45 (m, 2H), 7.70-7.79 (m, 4H). 13C-NMR (125 MHz, CDCl3, CDCl3) δ 17.56, 32.87, 46.41, 46.72, 68.59, 119.97, 125.35, 127.22, 127.87, 141.31, 143.53, 151.75, 173.79.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18][O:19][N:20]4C(=O)C5=CC=CC=C5C4=O)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:9]=2[CH:38]=1>C(O)C>[NH2:20][O:19][CH2:18][C:15]1[N:14]2[C:8]3[CH:7]=[CH:6][C:5]([Cl:4])=[CH:38][C:9]=3[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[N:11][CH2:12][C:13]2=[N:17][N:16]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: CCO
Solvent: O
Product: NOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-chloro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([CH2:1][C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1)=[O:21]
Reactant: O=C(Cl)CCCCCBr
Reactant: O=C1Cc2cccc3c2N1CCC3
Product: O=C(CCCCCBr)c1cc2c3c(c1)CC(=O)N3CCC2

Procedure:
Using 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one and 6-bromohexanoyl chloride according to the same method as that of Reference Example 1, the title compound (5.13 g) was obtained as colorless crystals having a melting point of 86 to 87° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:10])=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12].C(OCC)(=O)C.Cl>O1CCCC1>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:11]1=[O:12])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCNc1ccccc1N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of crude N-ethyl-benzene-1,2-diamine (8.4 g, 62 mmol) in anhydrous tetrahydrofuran (200 mL) was added 1,1′-carbonyldiimidazole (10 g, 62 mmol). The mixture was stirred at room temperature under nitrogen for 12 hours and ethyl acetate (250 mL) followed by a cold 3N aqueous solution of hydrochloric acid (200 mL) were added. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to afford 1-ethyl-1,3-dihydro-benzimidazol-2-one as a white solid (8.5 g, 69% for three steps). MS (ES) m/z 163.2.