Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH3:16])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5].CN(C=O)C.[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[NH:1]([C:28]([O:30][CH2:31][CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:29])[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:26])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:18])[CH3:16])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5]
Reactant: BrCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
The Fmoc-β-Ala-Ile-Ala-Leu SEQ ID NO: 117 (24.34 g, 0.04 mol) is added into a round bottom flask with DMF (350 mL) and a magnetic stirrer. After the tetrapeptide is dissolved, benzyl bromide (4.76 mL, 0.04 mol), followed by cesium carbonate (13.04 g, 0.04 mol), is added to the solution with stirring. The reaction mixture is stirred at room temperature for 1.5 hrs. Then the reaction mixture is slowly poured into a flask with 450 mL of iced water. A large amount of white solid precipitates out which is collected by suction filtration. The product is washed with water (2×200 mL) and placed in a vacuum desiccator.
Reaction SMILES: N[CH:2]1[N:6]2[C:7](=[O:20])[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:5]2[C:4]2[S:21][CH:22]=[CH:23][C:3]1=2.O>C(O)(=O)C.[Zn]>[O:20]=[C:7]1[N:6]2[CH2:2][C:3]3[CH:23]=[CH:22][S:21][C:4]=3[C:5]2=[C:10]([C:11]([OH:13])=[O:12])[CH:9]=[C:8]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC1c2ccsc2-c2c(C(=O)O)cc(-c3ccccc3)c(=O)n21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1C2
Yield: 97.3 %

Procedure:
A suspension of 45.7 g of 4-amino-4,6-dihydro-6-oxo-7-phenylthieno[2',3':3,4]pyrrolo[1,2-a]pyridine-9-carboxylic acid in 915 ml of acetic acid was treated with 27.6 g of zinc powder and heated to boiling under reflux for 2 hours. The suspension was then cooled and poured into 3,000 ml of water. The excess zinc was for the most part removed by decantation. The separated crystals were filtered off under suction and dried in a vacuum. There was obtained 42.4 g of 4,6-dihydro-6-oxo-7-phenylthieno[2',3':3,4]-pyrrolo[1,2-a]pyridine-9-carboxylic acid with a m.p. of >300° (purity 85-90%). This material was purified further by recrystallization from methanol/N,N-dimethylformamide.
Reaction SMILES: [OH-].[Na+].[O:3]([N:5]=[C:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:7]([O:9]C)=[O:8])[CH3:4].O>CO>[CH3:4][O:3][N:5]=[C:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:7]([OH:9])=[O:8]
Reactant: CON=C(C(=O)OC)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CON=C(C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
2N-Sodium hydroxide (8.27 ml.) was added to a solution of methyl 2-methoxylimino-2-(thien-2-yl)-acetate (syn-isomer) (3.28 g.) in methanol (50 ml.) and the solution was stirred at room temperature for 18 hours. Water (20 ml.) was added and the solution was evaporated to remove methanol, and then washed with ethyl acetate. The pH of the solution under ethyl acetate (50 ml.) was altered to 2 with 2N-hydrochloric acid. The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried, and evaporated to a white solid (2.58 g.). This was crystallised from cyclohexane, producing the title compound (2.23 g., 73%), m.p. 105.5°, λmax.EtOH 289 nm (λ 10,100), λinf. 262 and 271 nm. (ε 7,750 and 8.150), τ (CDCl3) values include 0.32 (OH) and 5.92 (OCH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11](O)[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.S([Cl:34])(C)(=O)=O>C(Cl)Cl>[Cl:34][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(O)C(=O)OCc2ccccc2)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(Cl)C(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To 6D (450 mg, 1.5 mmol) in CH2Cl2 (5 mL) at 0° C. was added triethylamine (0.42 mL, 3.0 mmol) followed by mesyl chloride (0.14 mL, 1.8 mmol). After stirring at rt overnight, the reaction was concentrated and purified via silica gel chromatography (0-25% ethyl acetate/hexanes) to provide 6E (268 mg, 56%). 1H NMR (400 MHz, CD3OD) δ ppm 3.81 (s, 3H) 3.87 (s, 3H) 5.19 (m, 2H) 5.36 (s, 1H) 6.81 (d, J=8.35 Hz, 1H) 6.93-7.07 (m, 2H) 7.20-7.42 (m, 5H).
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH3:45])[CH:40]=2)[CH2:35]1)[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10](=[O:33])[C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[C:13]([O:25]CC2C=CC=CC=2)[CH:12]=1)[CH3:3].O>[Pd].C(O)C>[ClH:1].[CH2:2]([N:4]([CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH3:45])[CH:40]=2)[CH2:35]1)[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10](=[O:33])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:25])[CH:12]=1)[CH3:3]
Reactant: CCN(CCCCOC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C1CCc2cc(OC)ccc2C1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCN(CCCCOC(=O)c1ccc(O)c(O)c1)C1CCc2cc(OC)ccc2C1
Yield: 84 %

Procedure:
2.5 g of N-ethyl-N-{4-[3,4-bis(benzyloxy)benzoyloxy]-butyl}-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride, 70 ml of water, 70 ml of ethanol and 0.5 g of a 5% palladium on carbon were mixed and reduced catalytically at a usual temperature under usual pressure. After absorption of the theoretical amount of hydrogen, the palladium on carbon catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 1.5 g of N-ethyl-N-[4-(3,4-dihydroxybenzoyloxy)butyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride as a colorless resinous material.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:27][C:26]1[CH:28]=[CH:29][C:23]([S:20]([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCCOCCOCCOCCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCO)cc1
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
To a chilled (0° C.) solution of hexaethylene glycol (5.41 g, 19.2 mmol) in DCM (191 mL) were added TsCl (4.02 g, 21.1 mmol), Ag2O (6.67 g, 28.8 mmol), and KI (0.64 g, 3.84 mmol). After stirring for 20 min the reaction mixture was filtered through a 4 cm pad of celite and flushed with EtOAc. The resulted filtrate was concentrated under reduced pressure to give a yellow oil. The crude product was purified via silica flash chromatography using 3:2 DCM/Acetone as an eluent, providing 33 (6.24 g, 75%): 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 4.23-4.07 (m, 2H), 3.82-3.51 (m, 22H), 2.55 (d, J=6.0 Hz, 1H), 2.44 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:23][C:11]=2[C:12]([O:14]CC2C=CC(F)=CC=2)=[O:13])=[CH:4][CH:3]=1.[Li+].[OH-]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)=[CH:23][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)OCc3ccc(F)cc3)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)O)c2)cn1

Procedure:
(4-Fluorophenyl)methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-(1-methyl-1H-pyrazol-4-yl)benzoate (may be prepared as described in Description 120; 360 mg, 0.83 mmol) was dissolved in tetrahydrofuran (20 ml) and water (5 ml). Then LiOH (99 mg, 4.14 mmol) was added. The resultant mixture was stirred at room temperature for 16 hours. The solvent was removed. The residue was dissolved in water (20 ml). The solution was acidified by 1N HCl to pH<5. The precipitate was filtered, washed with ether, and dried in vacuo to yield the title compound as a white solid. 260 mg.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].CC1C=C(C)[N:12]([C:16]([NH:18][C:19]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[S:20])=N)N=1>CS(C)=O>[C:16]([N:18]1[C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[CH2:2][S:20]/[C:19]/1=[N:21]\[CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:12]
Reactant: Cc1cc(C)n(C(=N)NC(=S)NCCNC(=O)OC(C)(C)C)n1
Reactant: O=C(CBr)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCC/N=C1\SCC(O)(C(F)(F)F)N1C#N
Temperature: 60 °C

Procedure:
A solution of 484 mg (2.4 mmol) of 3-bromo-1,1,1-trifluoropropan-2-one in 12 ml of DMSO is added dropwise to the crude mixture from Example 72A while cooling in ice, and the mixture is then heated at 60° C. for 1 h. The crude mixture is poured into ice-water and extracted three times with ethyl acetate. After the combined organic phases have been dried, the solvent is completely removed and the residue is purified by subsequent purification by preparative HPLC. 640 mg (67% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:7].C(N(CC)C(C)C)(C)C.[Cl:36][C:37]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C(Cl)Cl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:25]([NH:26][C:39](=[O:40])[C:38]4[CH:42]=[CH:43][C:44]([Cl:46])=[CH:45][C:37]=4[Cl:36])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1N
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
A mixture of 1.0 g of 5-(3-methoxy-4-amino-benzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.47 g of N,N-diisopropylethylamine and 0.76 g of 2,4-dichlorobenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to give 1.39 g of the desired product as a crystalline solid, m.p. 212°-214° C.
Reaction SMILES: [CH:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[CH:8][CH:7]=1)[C:4]#[N:5])=O.O.Cl.[NH2:22][NH:23][C:24]([NH2:26])=[O:25]>CO>[NH2:5][C:4]1[N:23]([C:24](=[O:25])[NH2:26])[N:22]=[CH:1][C:3]=1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[CH:8][CH:7]=1
Reactant: NNC(N)=O
Reactant: Cc1cccc(Cc2ccc(C(C#N)C=O)cc2)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cccc(Cc2ccc(-c3cnn(C(N)=O)c3N)cc2)c1
Reaction time: 13 h

Procedure:
To a solution obtained by dissolving α-formyl-4-(3-methylphenylmethyl)phenylacetonitrile thus obtained in methanol (50 ml) and water (10 ml) was added semicarbazide hydrochloride (3.2 g) under stirring on ice-cooling. Ice bath was removed, and after 13 hours, the mixture was adjusted to alkaline (pH 10 to 11) with 5N-sodium hydroxide aqueous solution, and stirred for 1 hour. Next, the reaction mixture was neutralized (pH 8 to 9) with 10% hydrochloric acid aqueous solution, and the precipitate was separated by filtration. By washing and drying, 3-amino-2-carbamoyl-4- {4-(3-methylphenylmethyl)phenyl}pyrazole (6.3 g) was obtained. The product was used in subsequent procedure without purification.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])=[N:5]2.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN1CCCC1=O.[OH-].[Na+]>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([NH:14][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=[CH:16][CH:17]=1)=[N:5]2
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(Oc2ccc3nccn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nccn3n2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (113 mg, 0.50 mmol) in N-methylpyrrolidone (1.0 mL) was added benzoyl chloride (0.116 mL, 1.00 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→75/25) and precipitated from ethyl acetate to give the title compound (122 mg, 74%) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:40])([CH3:39])[CH2:4][NH:5][C:6](=[O:38])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([NH:20][C:21]3([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[CH2:23][CH2:22]3)[N:17]=[C:16]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])[N:15]=2)=[C:9]([F:37])[CH:8]=1.[O:41]=[C:42]([N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)[C:43](O)=[O:44].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2([NH:20][C:18]3[N:17]=[C:16]([O:31][CH2:32][C:33]([F:35])([F:36])[F:34])[N:15]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][C:3]([CH3:40])([CH3:39])[CH2:2][NH:1][C:43](=[O:44])[C:42](=[O:41])[N:46]5[CH2:50][CH2:49][CH2:48][CH2:47]5)=[O:38])=[CH:8][C:9]=4[F:37])[N:19]=3)[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: CC(C)(CN)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Reactant: O=C(O)C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CNC(=O)C(=O)N1CCCC1)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Temperature: 25 °C
Yield: 14.9 %

Procedure:
To a solution of N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamide (80 mg, 0.14 mmol) and 2-oxo-2-(pyrrolidin-1-yl)acetic acid (20 mg, 0.137 mmol) in DMF (2 mL) were added O-(benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (66 mg, 0.21 mmol) and iPr2NEt (0.050 ml, 0.28 mmol). After stirring at rt for 16 hs, the mixture was purified by preparative HPLC to give 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(2,2-dimethyl-3-(2-oxo-2-(pyrrolidin-1-yl)acetamido)propyl)-3-fluorobenzamide (14.4 mg, 14%) as product. 1H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.01 (6H, s), 1.42 (4H, m), 1.81-2.02 (4H, m), 3.14 (2H, m), 3.29 (2H, d, J=6.0 Hz), 3.60 (2H, t, J=6.9 Hz), 3.91-4.12 (2H, m), 4.70-4.80 (2H, m), 7.14-7.38 (3H, m), 7.48-7.59 (1H, m), 7.69-7.80 (1H, m), 7.94-8.06 (1H, m), 8.24-8.31 (1H, m).
Reaction SMILES: [O:1]1CCCC1.[F:6][C:7]1[C:12]([N:13]2[C:17]([CH3:18])=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[CH:23](OC(C)=O)[CH2:22]4)[N:15]=[N:14]2)=[CH:11][CH:10]=[CH:9][N:8]=1>[OH-].[Na+].C(Cl)(Cl)Cl>[F:6][C:7]1[C:12]([N:13]2[C:17]([CH3:18])=[C:16]([C:19]3[C:20]([OH:1])=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[CH2:23][CH2:22]4)[N:15]=[N:14]2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: C1CCOC1
Reactant: CC(=O)OC1Cc2cc(-c3nnn(-c4cccnc4F)c3C)ccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccc3c(c2O)CCC3=O)nnn1-c1cccnc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Three drops of 2 M sodium hydroxide aqueous solution was added at room temperature to 1 ml solution of tetrahydrofuran with 6 mg of 1-(2-fluoropyridine-3-yl)-4-(1-oxo-2-methylcarbonyloxy-indane-5-yl)-5-methyl-1H-[1,2,3]triazole, obtained in Example 45. After stirring at room temperature for 1 hour, the resultant was diluted with chloroform, washed with water and saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the obtained residues were purified by silicagel column chromatography (hexane:ethyl acetate=80:20) to obtain 1.3 mg of the above compound as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH2:14])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:15](=S)=[S:16].C(O)C.[K+].[Br-]>O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:15]([SH:16])=[N:14][C:9]=3[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: S=C=S
Reactant: Nc1ccc(N2CCNCC2)cc1N
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Sc1nc2cc(N3CCNCC3)ccc2[nH]1
Yield: 84.3 %

Procedure:
5-(Piperazin-1-yl)-2-mercapto-1H-benzimidazole (7.9 g, 85%) was prepared by an analogous procedure to that described in preparation 1 (step 5) using the diamine (8.0 g, 0.04 mol) (obtained in step 2 above), carbon disulfide (3.6 g, 0.048 mol), ethanol (40 nmL) and water (4 nmL). mp 260-261° C.; IR (KBr) 3350, 1498 cm-1 ; 1H NMR (DMSO-d6) δ 2.40 (s, 1H, SH), 3.00 (t, J=4.4 Hz, 4H, N(CH2)2), 3.50 (brs, 1H, NH), 4.42 (t, J=4.5 Hz, 4H, N(CH2)2), 6.68 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H) ; Mass (m/z) 234 (M+.).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:12]#[N:13])([CH:9]1[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:14]1(=O)[CH2:21]CCCCC[CH2:15]1.C1(C(C)=O)CC1>>[C:1]([NH:5][NH:6][C:7]1([C:12]#[N:13])[CH2:8][CH2:21][CH2:14][CH2:15][CH2:10][CH2:11][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCCCCCC1
Reactant: CC(C)(C)NNC(C)(C#N)C1CC1
Agent: CC(=O)C1CC1
Product: CC(C)(C)NNC1(C#N)CCCCCCC1
Yield: 100 %

Procedure:
1-t-Butylhydrazo-1-cyanocyclooctane was prepared in 100% yield using the same procedure described in Example XIIIB for the preparation of 1-t-butylhydrazo-1-cyano-1-cyclopropylethane, substituting the t-butylhydrazone of cyclooctanone for the t-butylhydrazone of methyl cyclopropyl ketone.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH2:29])[C:25]([NH2:28])=[CH:26][CH:27]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[CH:3][CH:2]=1.[C:30](N1C=CN=C1)(N1C=CN=C1)=[S:31]>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]5[NH:28][C:30](=[S:31])[NH:29][C:24]=5[CH:23]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[CH:3][CH:2]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(-c2ccc3c(c2)CN(c2ccnc4ccccc24)CCO3)cc1N
Solvent: C1CCOC1
Product: S=c1[nH]c2ccc(-c3ccc4c(c3)CN(c3ccnc5ccccc35)CCO4)cc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51 %

Procedure:
To a solution of 4-(4-quinolin-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-benzene-1,2-diamine (630 mg, 1.65 mmol, synthesized according to the method of example 2 step) in tetrahydrofuran (30 mL) was added 1,1′-thiocarbonyldiimidazole (587 mg, 3.29 mmol), and the reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue crystallized from methanol to give 5-(4-quinolin-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-dihydro-2H-benzimidazole-2-thione (357 mg, 51% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6): 12.74 (s, 1H), 12.66 (s, 1H), 8.57 (d, 1H), 8.28 (d, 1H), 8.00 (d, 1H), 7.95 (m, 1H), 7.88 (d, 1H), 7.67 (m, 1H), 7.53 (dd, 1H), 7.49 (dd, 1H), 7.40 (s, 1H), 7.24 (d, 1H), 6.97 (m, 2H), 5.21 (s, 2H), 4.58 (m, 2H), 4.33 (m, 2H); MS (EI) for C25H20N4OS: 425 (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C1(C)C=CC=CC=1.C1(C=CC(O)=CC=1)O>[C:19]([O:9][C:6]1[CH:7]=[CH:8][C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])=[CH:4][CH:5]=1)(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: C[Si](C)(C)c1ccc(O)cc1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc([Si](C)(C)C)cc1
Yield: 83.5 %

Procedure:
8.32 g (0.05 mole) of p-trimethylsilylphenol was dissolved in 25 ml toluene. 6.1 g (0.06 mole) triethyl amine and 0.05 g hydroquinone was added. The solution was warmed. 5.43 g (0.06 mole) of acryloyl chloride was added over a 15 minute period. After 11/2 hours, the solution was washed two times with 5 percent sodium carbonate in water and separated. After washing with brine and separating, the organic phase was dried over magnesium sulfate, filtered, and the solvent removed in a rotary evaporator under reduced pressure. Vacuum distillation yielded 9.2 g of pure p-trimethylsilylphenyl acrylate.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:35])[C@H:18]([NH:27]C(=O)OC(C)(C)C)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[CH:10][C:4]=23)[CH2:12][CH2:13]1)=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
(R)-tert-Butyl 1-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate (0.022 g, 0.039 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added. The reaction was stirred at room temperature for 1 hour and then concentrated. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid (R)-2-amino-1-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)propan-1-one (0.016 g, 88% yield) was collected and dried as the dihydrochloride salt. MS ESI (+) m/z 463 detected.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.Cl.[NH2:16]O.[OH-].[Na+].O>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[O:11][N:16]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)CC(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(O)on2)cc1

Procedure:
According to method of U.S. Pat. No. 3,781,438, 2 g of methyl 3-(4-methylphenyl)-3-oxopropanoate was dissolved in methanol, slightly excessive hydroxylamine hydrochloride and equivalent amount of sodium hydroxide were added, the mixture was heated to reflux. 3 hr later, the reaction was traced by Thin-Layer Chromatography, after the reaction, water was added to the reaction mixture, extracted with ethyl acetate, The combined organic extracts were dried and concentrated to obtain 3-(4-methylphenyl)isoxazol-5-ol as solid (compound III-3).