Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)N([O])C(C)(C)CCC1.[O-]Cl.[Na+]>C(OC(C)C)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@H]1C(=O)O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (92 g, 0.398 mol) in isopropyl acetate (460 mL) was added TEMPO (2.49 g, 0.05 eq) at 0° C. A solution of NaClO (12.5 wt %, 370 mL) was added dropwise to the reaction mixture while maintaining the temperature at 0-5° C. The reaction was slowly allowed to warm to room temperature and stirred at room temperature overnight. The organic layer was separated and the aqueous layer was treated with 1M KHSO4 solution and extracted with isopropyl acetate (2×150 mL). The combined organic layers were washed with 5% Na2S2O3 (100 mL), brine, dried (Na2SO4), filtered and evaporated to provide the title compound as a solid. It was triturated with acetonitrile (40 mL), filtered and dried to give a white solid (52.3 g). The filtrate was concentrated, treated with 50% ethyl acetate in hexanes (20 mL) and stored in refrigerator for overnight before being filtered and dried to give a white solid (3.94 g). Totally obtained 56.24 g (62%). 1H NMR (500 MHz, DMSO-d6): 12.99 (br s, 1H), 4.54-4.50 (m, 1H), 3.84-3.77 (m, 1H), 3.68-3.63 (m, 1H), 3.15-3.06 (m, 1H), ˜2.49 (m, 1H, overlapped with DMSO), 1.40 and 1.37 (2 s, 9H).
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[N:17]=[C:16]([NH:18][C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[C:15]2[CH2:14][C:13](=O)[CH2:12][CH2:11][C:10]=2[N:9]=1)=[O:6])([CH3:4])[CH3:3].Cl.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31]([CH2:35][O:36][NH2:37])[CH:32]=[CH:33][CH:34]=1.C(N(CC)CC)C>C(O)C>[CH3:3][C:2]([C:5]([NH:7][C:8]1[N:17]=[C:16]([NH:18][C:19]([C:21]([CH3:22])([CH3:23])[CH3:24])=[O:20])[C:15]2[CH2:14][C:13](=[N:37][O:36][CH2:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:27])([F:39])[F:38])[CH:30]=3)[CH2:12][CH2:11][C:10]=2[N:9]=1)=[O:6])([CH3:4])[CH3:1]
Reactant: NOCc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=O)CC2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=NOCc1cccc(C(F)(F)F)c1)CC2

Procedure:
This compound is prepared in a manner analogous to that of Step E of Example 12, using 3.5 grams (0.010 mole) of 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone (prepared in Step C of Example 12) and 2.7 grams (0.012 mole) of O-(3-trifluoromethylphenylmethyl)hydroxylamine hydrochloride in about 45 mL of ethanol. This preparation differs from Step E of Example 12 in that prior to heating at reflux for four hours, 1.5 grams (0.015 mole) of triethylamine is added as an acid acceptor, yielding 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-(3-trifluoromethylphenylmethoxyimino)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH3:21][C@H:22]([C@H:34]([CH3:38])[CH2:35][CH2:36][CH3:37])[CH:23]=[N:24][S:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[O:26]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[C:17]([O:16][C:13](=[O:15])[CH2:14][C@@H:23]([NH:24][S:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[O:26])[C@H:22]([CH3:21])[C@H:34]([CH3:38])[CH2:35][CH2:36][CH3:37])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCC[C@@H](C)[C@@H](C)C=NS(=O)c1ccc(C)cc1
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC[C@@H](C)[C@@H](C)[C@@H](CC(=O)OC(C)(C)C)NS(=O)c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
Butyl lithium (26.3 mL, 42.04 mmol) was added to a solution of diisopropylamine (4.6 g, 45.6 mmol) in dry THF (40 mL) under nitrogen at 0° C. and stirred for 20 minutes. The solution was cooled to −78° C. followed by the addition of t-butyl acetate (4.1 g, 35.0 mmol) and stirred at that temperature for 45 minutes. Chlorotitanium triisopropoxide (9.4 g, 36.2 mmol) was added dropwise and stirring was continued for 30 minutes at −78° C. A −50° C. solution of 4-methyl-benzenesulfinic acid ((2R,3R)-2,3-dimethyl-hexylidene)-amide (3.1 g, 11.7 mmol) in dry THF (10 mL) was added to the reaction and the resulting mixture was stirred at −78° C. for 4 hours. The reaction was quenched with a saturated solution of NaH2PO4 and extracted into ethyl acetate. The solution was dried over MgSO4 and concentrated. The resulting residue was chromatographed on silica, eluting with 15% ethyl acetate in hexane to give the titled compound (2.4 g, 53.9% yield) as white solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (m, 6 H) 1.0 (d, J=6.6 Hz, 3 H) 1.1 (m, 1 H) 1.3 (m, 2 H) 1.4 (m, 9 H) 1.5 (m, 2 H) 2.4 (s, 3 H) 2.6 (m, 2H) 3.8 (m, 1 H) 4.4 (d, J=10.0 Hz, 1 H) 7.3 (d, J=8.1 Hz, 2 H) 7.6 (d, J=8.1 Hz, 2 H). MS, m/z (relative intensity): 382 [M+1H, 100%], 326 [M+1H—C(CH3)3, 50%].
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH2:20])=[N:16][NH:17]2)=[CH:13][CH:12]=1>N1C=CC=CC=1>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])=[N:16][NH:17]2)=[CH:13][CH:12]=1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(Cl)ccc12)c1ccccc1
Temperature: 3 °C
Reaction time: 12 h

Procedure:
0.69 cm3 of benzoyl chloride is added to 1 g of 6-chloro-1H-indazole-3-amine in 15 cm3 of pyridine, cooled to about 3° C. The reaction medium is allowed to return to about 19° C. over 12 hours and is then evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 25 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed with 25 cm3 of distilled water and 25 cm3 of saturated aqueous sodium chloride solution. The resulting solution is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a dichloromethane/methanol mixture (99/1 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 990 mg of N-[6-chloro-1H-indazol-3-yl]benzenamide are obtained in the form of a white solid melting at 188° C.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(=O)(SC)O[CH2:22][CH2:23][CH:24]1CCCCC1>>[CH:2]1([C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]2[CH2:18][C:17](=[O:19])[NH:16][C:14]2=[O:15])=[O:11])[CH3:8])=[O:5])[CH2:4][CH2:24][CH2:23][CH2:22][CH2:3]1
Reactant: CSC(=O)OCCC1CCCCC1
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Product: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C1CCCCC1

Procedure:
Following the procedures for synthesizing [(1-isobutanoyloxyethoxy)carbonyloxy]succinimide (17) and replacing compound (2) with compound (6) affords [(1-cyclohexanoyloxyethoxy)carbonyloxy]succinimide (20).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][N:8]=[C:7]([CH3:13])[N:6]=1>>[CH2:11]([C:10]1[C:5]([NH:2][NH2:3])=[N:6][C:7]([CH3:13])=[N:8][CH:9]=1)[CH3:12]
Reactant: CCc1cnc(C)nc1Cl
Reactant: NN
Solvent: O
Product: CCc1cnc(C)nc1NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
Hydrazine monohydrate (0.398 mL, 5.24 mmol) was added to 4-chloro-5-ethyl-2-methylpyrimidine (216 mg, 1.31 mmol). The reaction mixture was stirred in a sealed tube at room temperature overnight. Remaining hydrazine was evaporated. Purification by column chromatography (SiO2, methanol/ammonia/dichloromethane) to afforded the desired product (136 mg, 68.2%) as an amorphous off-white solid. MS: m/z=153.11 (M+H+)
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([O:6][CH3:7])[C:4]=1[Cl:11].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].Cl>ClCCCl>[Cl:11][C:4]1[C:3]([OH:2])=[C:10]([CH:9]=[CH:8][C:5]=1[O:6][CH3:7])[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:13]([F:12])([F:23])[F:24])=[O:17]
Reactant: COc1cccc(OC)c1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccccc2C(F)(F)F)c(O)c1Cl
Reaction time: 18 h

Procedure:
To a solution of 1.7 g of 2-chlororesorcinol dimethyl ether and 2.08 g of o-trifluoromethyl benzoyl chloride in 50 ml of 1,2-dichloroethane at 5°-7° C., 1.6 g of ferric chloride is added gradually. The mixture is brought to room temperature and allowed to stand 18 hours. The reaction mixture is refluxed 30 minutes and poured into 5% HCl and ice. The aqueous phase is extracted with additional organic solvent. The combined organic extracts are washed with water, dried over Na2SO4 and evaporated to give 3-chloro-2-hydroxy-4-methoxy-2'-trifluoromethylbenzophenone, mp 101°-102° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[S:8][C:9]([C:16]([OH:18])=O)=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:27][NH2:28])=[CH:22][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCOC(C)=O>C(#N)C.O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:27][NH:28][C:16]([C:9]2[S:8][C:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:11][C:10]=2[C:12]([F:13])([F:14])[F:15])=[O:18])=[CH:22][CH:21]=1
Reactant: NCC(c1ccc(Cl)cc1)N1CCCCC1
Reactant: O=C(O)c1sc(-c2ncccn2)nc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCC(c1ccc(Cl)cc1)N1CCCCC1)c1sc(-c2ncccn2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-pyrimidin-2-yl-4-trifluoromethyl-thiazole-5-carboxylic acid (60 mg), 2-(4-chloro-phenyl)-2-piperidin-1-yl-ethylamine (60 mg), BOP (100 mg) and TEA (40 mg) in ACN (1 mL) is stirred at RT overnight. EtOAc and water added to the mixture and the organic layer is separated, washed twice with water and concentrated in vacuo. The residue is purified by PTLC (10% MeOH in methylene chloride) to give the title compound. MS (M+1)=496.09; RT=1.14 min. *IC50.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2C=CC=CC=2)=[CH:4][CH:3]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][C:28]([OH:30])=O>ClCCl.C(N(CC)CC)C.O.C(=O)(O)[O-].[Na+]>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:30])[CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[CH:3][CH:4]=1)(=[O:15])[CH3:9]
Reactant: O=C(O)COc1ccc2ccccc2c1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(NC(=O)COc2ccc3ccccc3c2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 121.7 %

Procedure:
A stirred mixture of para-aminobenzophenone (6.75 g) in dichloromethane (75 mL) and triethylamine (20 mL) was chilled to -78° C. and treated with the acid chloride prepared from 2-naphthoxyacetic acid (10.1 g). The mixture was stirred for 30 minutes at -78° C. and for 1 hour at room temperature. The mixture was diluted with water and sodium bicarbonate solution and the solids were recovered by filtration and washed with water and dichloromethane to give 13.3 g of N-(4-acetylphenyl)-2-naphthoxyacetamide, 208°-210° C.
Reaction SMILES: [Na+].[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=O)=[O:14])=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.S(Cl)([Cl:19])=O.CN(C=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([Cl:19])(=[O:16])=[O:14])=[CH:9][CH:8]=2)[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(OCC2CC2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCC2CC2)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a suspention of 100 g (399.6 mmol) of 4-cyclopropylmethoxy-benzenesulfonic acid sodium salt, 186.55 ml (2557.5 mmol) of thionyl chloride and 6.19 ml (80 mmol) of DMF are added dropwise at r.t. After stirring for 15 h, the mixture is poured into ice water and extracted with CH2Cl2. The combined extracts are washed with H2O, dried over MgSO4 and concentrated under reduced pressure to give the title compound as a colorless solid; 1H-NMR (400 MHz, CDCl3): 0.35–0.45 (m, 2H), 0.65–0.75 (m, 2H), 1.25–1.35 (m, 1H), 3.91 (d, 2H, J=7.04 Hz), 7.02 (d, 2H, J=9.04 Hz), 7.96 (d, 2H, J=9.04 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6](=[O:13])[CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][CH:10]=1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>O1CCCC1.O>[CH3:3][O:4][C:5]1[C:6](=[O:13])[CH:7]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([CH3:11])([CH3:12])[CH2:9][CH:10]=1
Reactant: COC1=CCC(C)(C)CC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)C1C(=O)C(OC)=CCC1(C)C
Reaction time: 0.25 h
Yield: 2084.3 %

Procedure:
60% sodium hydride in mineral oil (2.41 g, 60.3 mmol) was suspended in anhydrous tetrahydrofuran (60 mL) under argon atmosphere and treated with a solution of 2-methoxy-5,5-dimethyl-cyclohex-2-enone (6.20 g, 40:2 mmol) in anhydrous tetrahydrofuran (50 mL). After 15 minutes, a solution of diethyl oxalate (8.17 mL, 60.3 mmol) in anhydrous tetrahydrofuran (50 mL) was added and the mixture was refluxed for 1 hour. The slurry was diluted with water (800 mL), acidified with 1N HCl (50 mL) and extracted with ethyl acetate (500 mL×2). The organic layers were collected, washed with brine, dried on Na2SO4 and evaporated to dryness to obtain the crude title compound (10.60 g) as an orange oil, which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:33]1([NH:43]N)[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:34]4[C:33](=[C:42]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]5=[CH:36][CH:35]=4)[NH:43][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCc3c(-c4ccccc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide and 1-(1-naphthyl)hydrazine hydrochloride: ESMS m/e: 544.3 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[CH3:16][C:17]1[N:21]2[C:22]3[CH:28]=[C:27]([CH3:29])[NH:26][C:23]=3[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1>CN(C=O)C.CC#N>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:26]1[C:23]2[CH:24]=[CH:25][C:20]3[N:21]([C:17]([CH3:16])=[N:18][N:19]=3)[C:22]=2[CH:28]=[C:27]1[CH3:29]
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccccc1Cl
Temperature: 50 °C

Procedure:
K2CO3 (44 mg, 0.32 mmol) and 1-(bromomethyl)-2-chloro-benzene (0.022 g, 0.11 mmol, Aldrich) were added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20. mg, 0.11 mmol, from Example 2, Step 5) in DMF (3.0 mL). The reaction was heated to 50° C. for 35 minutes. The reaction mixture was diluted with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (2.6 mg, 8%).
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[CH3:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O>O.C(O)C>[CH3:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1/[CH:9]=[N:4]/[OH:1]
Reactant: NO
Reactant: Cc1ccccc1C=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1/C=N/O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium hydroxide (2.00 g, 50.0 mmol, 1.19 equiv) in water (25 mL) was added to a stirred solution of hydroxylamine hydrochloride (3.30 g, 47.8 mmol, 1.15 equiv) in water (25 mL) at 0° C. The resulting solution was stirred for 10 min at 0° C. Then a solution of 2-methylbenzaldehyde (5.00 g, 41.6 mmol, 1.00 equiv) in ethanol (25 mL) was added slowly over 5.0 min. The resulting solution was allowed to stir for an additional 1 h at RT. The solution was diluted with H2O (100 mL), extracted with ethyl acetate (120 mL) and the organic layers were combined, washed with brine (100 mL), dried over magnesium sulfate and concentrated under vacuum to give (E)-2-methylbenzaldehyde oxime as an off-white crystalline solid. MS m/z 136.0 (M+1).
Reaction SMILES: [CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28]N1C(=O)CCC1=O>O1CCOCC1>[CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([OH:20])[C:18]([Cl:28])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2cc(O)ccc2C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2cc(O)c(Cl)cc2C1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A solution of N-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (166 mg) and N-chlorosuccinimide (66.4 mg) in 1,4-dioxane (2 ml) was refluxed for 28 hours, cooled to room temperature, and partitioned between ethyl acetate and brine. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene-ethyl acetate) over silica gel (3.6 g) to afford N-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (139 mg) as a colorless gum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]3)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]1[N:40]=[CH:41][C:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[N:43][CH:44]=1>CN(C=O)C>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][CH2:38][C:39]4[N:40]=[CH:41][C:42]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[N:43][CH:44]=4)[CH:3]=3)=[O:30])=[CH:12][C:13]=2[C:26]([F:29])([F:28])[F:27])[CH2:19][CH2:20]1)[CH3:25]
Reactant: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(N)c3)cc2C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(NCc4cnc(NC(=O)OC(C)(C)C)cn4)c3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a solution N-(3-amino-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (70 mg, 0.17 mmol) in DMF (0.5 mL) were added K2CO3 (69 mg, 0.50 mmol) and tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (48 mg, 0.17 mmol). The reaction mixture was stirred for 8 hours at room temperature after which, it was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography using (5% MeOH/CH2Cl2) as a solvent to afford title compound (50 mg, 47% yield). MS m/z: 628 [M+1].
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([NH2:33])[N:25]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:49][CH:50]=[CH:51][N:52]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:43]=1>>[NH2:33][C:26]1[N:25]=[C:24]([NH:56][CH2:55][CH2:54][NH:53][C:44]2[N:43]=[C:42]([C:36]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:35]=3[Cl:34])[C:47]([C:48]3[NH:52][CH:51]=[CH:50][N:49]=3)=[CH:46][N:45]=2)[CH:29]=[CH:28][C:27]=1[N+:30]([O-:32])=[O:31]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Nc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2,4-dichlorophenyl)-5-imidazolyl-pyrimidin-2-yl]amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 2-chloro-5-nitro-6-aminopyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CC=1N.CC1C=C(C=CC=1)/C=C/[C:21](Cl)=[S:22].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1/[CH:42]=[CH:43]/[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1/[CH:42]=[CH:43]/[C:44]1[CH:45]=[CH:46][C:47]([S:22][CH3:21])=[CH:48][CH:49]=1
Reactant: Cc1cccc(/C=C/C(=S)Cl)c1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Nc1ccccc1Nc1ccccn1
Product: CSc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1

Procedure:
The titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-methylthiocinnamoyl chloride (Miller, R. D.; Reiser, O. J. Heterocycl. Chem. 1993, 30, 755) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 343.46; mp: 139.6-140.6° C.; 1H-NMR (CDCl3) δ: 8.78 (1H, dd, J=5.1, 2.2 Hz), 8.00 (1H, ddd, J=7.7, 7.7, 2.2 Hz), 7.96 (1H, d, J=16.1 Hz), 7.83 (1H, d, J=7.3 Hz), 7.54-7.39 (5H, m), 7.38-7.18 (4H, m), 7.10 (1H, d, J=16.1 Hz), 2.49 (3H, s).