Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[C:8](Cl)(=[O:10])[CH3:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]3[CH2:26][CH2:27][S:28][C:29]4[S:33][CH:32]=[CH:31][C:30]=4[C:21]3=[N:20]2)=[CH:15][CH:14]=1>O>[C:8]([C:32]1[S:33][C:29]2[S:28][CH2:27][CH2:26][C:22]3[C:21](=[N:20][N:19]([C:16]4[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=4)[C:24](=[O:25])[CH:23]=3)[C:30]=2[CH:31]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1ccsc1SCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2

Procedure:
To a mixture of 50 ml of methylene chloride and 1.9 g of aluminum chloride is added 1.0 ml of acetyl chloride with stirring under ice-cooling and then the mixture is stirred at room temperature for 10 minutes. To the mixture is further added 2.0 g of 2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one under ice-cooling and the mixture is stirred for 3 hours at room temperature. To the mixture is added water and the solution is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crystals are recrystallized from a mixed solvent of chloroform and ethanol to give 2.0 g of 9-acetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one, as white crystals, melting at 248°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:15]([OH:19])[C:16](O)=[O:17])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[OH:27][C@H:28]1[C@@H:32]([OH:33])[CH2:31][NH:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:20]([C@H:14]([NH:13][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:12])[C@@H:15]([OH:19])[C:16]([N:30]1[CH2:31][C@H:32]([OH:33])[C@H:28]([OH:27])[CH2:29]1)=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O[C@@H]1CNC[C@@H]1O
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)C(=O)N1C[C@@H](O)[C@@H](O)C1)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 0.08 h

Procedure:
To a solution of (S)-3-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-2-(R)-hydroxy-4-phenylbutyric acid (EXAMPLE 44, 50 mg, 0.13 mmol), cis-3,4-dihydroxypyrrolidine (Preparation 23, 15 mg, 0.15 mmol) and HOBt (27 mg, 0.20 mmol) in DMF (5 mL), was added DIPEA (47 μL, 0.27 mmol). After stirring for 5 min, EDCI (28 mg, 0.15 mmol) was added and the reaction stirred at rt for 72 h. The solvent was removed in vacuo and the residue partitioned between water (30 mL) and ethyl acetate (3×30 mL). The combined organic fractions were dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with methanol/dichloromethane (1:9) to give the title compound as a white solid. m/z (ES+)=459 [M+H]+. RT=3.07 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([CH2:12][Cl:13])=[N:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:25])=O>COCCOC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:25])=[N:7][C:8]([CH2:12][Cl:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(CCl)nc2cc(Br)ccc12
Solvent: COCCOC
Solvent: Cc1cccc(C)n1
Product: ClCc1nc(Cl)c2ccc(Br)cc2n1
Temperature: 25 °C

Procedure:
Heat a mixture of 7-bromo-2-chloromethyl-3H-quinazolin-4-one (5 g, 18.2 mmol), 2,6-lutidine (5 g), and phosphorus oxychloride (5 mL) in 1,2-dimethoxyethane (500 mL) at 80° C. for 16 hours. Cool the mixture to room temperature and fully evaporate the mixture, then dilute with ether and wash with water. Dry the solvent (Na2SO4) and evaporate the ether to obtain 7-bromo-4-chloro-2-chloromethylquinazoline (3.5 g) as a yellow solid.
Reaction SMILES: [Si](OC[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.C([Mg]Cl)C1C=CC=CC=1.[CH2:27]([O:29]CC)C.[Cl-].[NH4+]>O1CCCC1.O>[C:13]1([CH2:14][CH2:27][OH:29])[CH:12]=[CH:11][CH:10]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C=O)cc1
Reactant: CCOCC
Agent: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccccc1
Temperature: -40 °C

Procedure:
4-(t-Butyldimethylsilyloxymethyl)benzaldehyde (Synthesis (1995), 12, 1529-33) (6.65 gm, 26 mmol) was dissolved in dry tetrahydrofuran (50 mL) and the solution cooled to −40° C. Benzyl magnesium chloride in diethyl ether (1 M, 35 mL, 35 mmol) was added slowly. The reaction was allowed to warm to 0° C. over three hours. The reaction was then quenched by the addition of ammonium chloride (2.3 gm, 43 mmol) in water (60 mL). The product was extracted into diethyl ether, washed with NaHCO3 solution, dried (over Na2SO4), and filtered. The solution was evaporated to give 1-[4-t-butyldimethylsilyloxymethyl)-phenyl]-2-phenylethanol as an oil which was used as is. 1H-NMR (500 MHz, CDCl3): δ 7.19-7.34 (9H, m), 4.90 (1H, dd, J=4.9, 8.3 Hz), 4.75 (2H, s), 2.98-3.07 (2H, dt), 0.95 (6H, s), 0.11 (9H, s).
Reaction SMILES: FC1C=C([C:8]2[C:17](N(C(C)C)C)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)C=CC=1.CO.[OH-].[Na+]>O>[N:9]1[C:10]2[C:15](=[CH:14][C:13]([C:23]([OH:25])=[O:24])=[CH:12][CH:11]=2)[N:16]=[CH:17][CH:8]=1
Reactant: COC(=O)c1ccc2nc(-c3cccc(F)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nccnc2c1
Temperature: 50 °C
Reaction time: 0.13 h

Procedure:
Into a 50-mL round-bottom flask, was placed methyl 2-(3-fluorophenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (75 mg, 0.21 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (42 mg, 1.05 mmol, 4.94 equiv), water (2 mL). The resulting solution was stirred for 2 hs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with aqueous hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (50% CH3CN up to 80% in 8 min, up to 100% in 1.5 min); Detector, uv 220 & 254 nm. This resulted in 20 mg (27%) of 2-(3-fluorophenyl)-3-(isopropylmethyl)amino)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:33][C@H:32]1[CH2:44][CH2:45]Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(OCC)(=O)C>CN(C)C(=O)C>[C:24]([O:28][C:29]([N:31]1[CH2:35][C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:33][C@H:32]1[CH2:44][CH2:45][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Oc1ccc(F)cc1CCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOc1ccc(F)cc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
248 mg of 4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenol (prepared as described in Preparation 6) were dissolved in 10 ml of N,N-dimethylacetamide, and then 125 mg of potassium t-butoxide and 405 mg of (2S,4R)-1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2-(2-chloroethyl)pyrrolidine were added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred at room temperature for 3 hours, after which 150 ml of ethyl acetate were added to the reaction mixture. The reaction mixture was then washed with water and with a saturated aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then concentrated by evaporation under reduced pressure. The resulting oily substance was purified by silica gel column chromatography, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 433 mg (yield 73%) of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:15]=[CH:14][N:13]3[C:16]([CH3:29])=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[N:18]=[C:12]3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+].C(OCC)(=O)C.C(O)C.N>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:15]=[CH:14][N:13]3[C:16]([CH3:29])=[C:17]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:42])[NH2:28])=[CH:25][CH:26]=4)[N:18]=[C:12]3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C#N)cc3)nc2c1)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Yield: 62 %

Procedure:
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 62% of theory, C29H31N5O3 (497.60); Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5); EKA mass spectrum: (M+H)+=498.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([I:12])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:14][C:15]1[CH:19]=[C:18]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[O:17][N:16]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[C:8]([I:12])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(I)nc1C
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc(I)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 500 mg 2-Iodo-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester in 2 ml DMF 1.1 g caesium carbonate and 547 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 630 mg.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8](O)=[O:9])=[CH:3][CH:2]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([N:19]([O:20][CH3:21])[CH3:18])=[O:9])=[CH:3][CH:2]=1
Reactant: CNOC
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A mixture of 2-(biphenyl-4-yl)acetic acid (1 g, 4.7 mmol), N,O-dimethylhydroxylamine hydrochloride (458 mg, 4.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (900 g, 4.7 mmol), hydroxybenzotriazole (635 mg, 4.7 mmol), and triethylamine (1.42 g, 14.1 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. When TLC indicated that 2-(biphenyl-4-yl)acetic acid was consumed, the reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE: EtOAc=8:1) to afford 2-(biphenyl-4-yl)-N-methoxy-N-methylacetamide (1.0 g, yield 83%).
Reaction SMILES: [CH3:1][Si:2]([O:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1>[CH3:13][Si:12]([CH3:15])([CH3:14])[O:11][CH2:10][CH2:9][N:8]([CH2:7][CH2:6][O:5][Si:2]([CH3:1])([CH3:3])[CH3:4])[S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C[Si](C)(C)OCCNCCO[Si](C)(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCCN(CCO[Si](C)(C)C)S(=O)(=O)c1ccccc1
Yield: 88 %

Procedure:
To a mixture of 4.97 g of bis(2-trimethylsilyloxylethyl)amine, 3.03 g of triethylamine and 50 ml of benzene, 3.21 g of benzenesulfonyl chloride was added at 0° C. under stirring. After the addition, the mixture was taken out of the cooling bath and stirred further for 2 hours. The reaction mixture was filtered, mixture was taken out of the cooling bath and stirred further for 2 hours. The reaction mixture was filtered, and the filtrate was subjected to vacuum distillation. The residue was passed through a silica gel column with the eluent varying from benzene to benzen-acetic acid (9:1). As a result, 6.23 g of the title compound was obtained as a colorless oily substance. NMRδ: 7.83 (2H,d,J=8.0 Hz),7.52 (3H,m), 3.72, 3.31 (each 4H,t,J=6.5 Hz), 0.09 (18H,s)
Reaction SMILES: [F:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:3]([O:5]CC)=[O:4].[OH-].[K+].Cl>CO.O>[F:1][C:2]([C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)([CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)(c1ccc(Cl)cc1)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C(F)(C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.9 %

Procedure:
A mixture of ethyl α-fluoro-α-isopropyl-4-chlorophenylacetate (1.42 g) and potassium hydroxide (0.35 g) in methanol (5 ml) was stirred at ambient temperature for 2.5 hours. The reaction mixture was acidified with hydrochloric acid, diluted with water and the aqueous mixture extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and the solvent removed by distillation under reduced pressure to give α-fluoro-α-isopropyl-4-chlorophenylacetic acid (1.10 g; 87%) m.p. 120° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[Br:13]Br>C(Cl)(Cl)(Cl)Cl.O>[Br:13][C:9]1[C:8]([CH3:11])=[CH:7][C:6]([OH:12])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1
Reactant: BrBr
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(O)c(C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-t-butyl-5-methylphenol (24.6 g, 150 mmol) in CCl4 (100 mL) at 0° C. was added a solution of bromine (7.7 mL, 150 mmol) in CCl4 (100 mL) over a 4 hour period. The mixture was stirred at room temperature for 30 minutes and then diluted with H2O. The organic phase was separated, washed with saturated sodium bisulfite and brine, and dried (MgSO4). Concentration gave a residue which was chromatographed on silica gel, eluting with 6:1 hexanes:EtOAc, to give the title compound. 1H NMR (CDCl3) δ 1.34 (s, 9 H), 2.24 (s, 3 H), 5.20 (s, 1 H), 6.54 (s, 1 H), 7.32 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[CH3:14]
Reactant: COC(CN)OC
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CNCC(OC)OC

Procedure:
The title compound was synthesized by the method of Example 4 starting with 2,2-dimethoxyethylamine and ethyl bromoacetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[N:15]=[CH:16]\[N:17](C)C)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.ON.CC([OH:26])C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[N:15]=[CH:16]\[NH:17][OH:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: CN(C)/C=N\c1cc(OCc2ccccc2)ccn1
Agent: Cl
Agent: NO
Solvent: C1CCOC1
Product: ON/C=N\c1cc(OCc2ccccc2)ccn1
Temperature: 50 °C

Procedure:
A 100 mL, single-neck, round-bottomed flask was charged with (Z)-N′-(4-(benzyloxy)pyridin-2-yl)-N,N-dimethylformamidine (7.66 g, 30.0 mmol), hydroxyl amine hydrochloride (2.40 g, 34.5 mmol), propan-2-ol (33.3 ml), and THF (5 ml). The reaction was heated to 50° C. for 7 hours, then concentrated. The residue was titrated with EtOAc/THF and filtered. The filtrate was concentrated and triturated with dichloromethane to provide the product as a white solid.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[N+:13]([C:16]1[C:17]([NH2:23])=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>CC#N>[N+:13]([C:16]1[C:17]2[NH:23][C:5](=[O:11])[NH:22][C:18]=2[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Product: O=c1[nH]c2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C

Procedure:
Triphosgene (56 g, 188.8 mol) was added portionwise over 15 min to a solution of 3-nitro-1,2-phenylenediamine (25.5 g, 167 mol) in CH3CN (400 mL) at 0° C. and the mixture was allowed to warm to ambient temperature after 30 min. The reaction was concentrated in vacuo, diluted with toluene (100 mL) and the solid precipitate was collected by filtration to give the title compound. MS: m/z=80 (M+1).
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:31]([Cl:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>O.CN(C)C=O>[ClH:38].[CH2:31]([N:24]1[C:25]2[C:20](=[CH:19][C:18]([C:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:11][CH2:12]3)=[O:17])=[CH:27][CH:26]=2)[CH2:21][CH2:22][C:23]1=[O:28])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CCc2cc(C(=O)N3CCN(CCOc4ccccc4)CC3)ccc2N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2c(c1)CCC(=O)N2Cc1ccccc1)N1CCN(CCOc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
480 Milligrams of 6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril and 70 ml of 50%-sodium hydride in oil were mixed into 5 ml of dimethylformamide and stirred at a room temperature for 1 hour. Then to this mixture was added a solution of 0.17 ml of benzyl chloride with 3 ml of dimethylformamide was added dropwise slowly and stirred at a room temperature for 4 hours. The reaction mixture was poured in a voluminous amount of water and the organic matters were extracted with chloroform, and the chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue obtained was converted into hydrochloride by adding a concentrated hydrochloric acid and recrystallized from methanol-water to obtain 150 mg of 1-benzyl-6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril monohydrochloride. Colorless powdery crystals. Melting point: 261°-264° C.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:14]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]([C:9]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)=[CH2:14]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(-n2cncn2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(-n2cncn2)cc1
Temperature: 70 °C
Yield: 62.9 %

Procedure:
To a stirred solution of 4-[1,2,4]-triazol-1-yl-benzaldehyde (9.0 g, 52 mmol) in 1,4-dioxane (100 mL), were added K2CO3 (10.76 g, 78 mmol) and methyl triphenyl phosphonium bromide (22.2 g, 62.4 mmol) at room temperature. The resultant reaction mixture was heated to 70° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afforded the title compound as a white solid (5.6 g, 63%): ESIMS m/z 172.09 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:25][C:26]([N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36](Cl)[C:31]=2[CH:30]=[CH:29]1)=[O:27].C(Cl)(=O)C.[NH2:42][C:43]1[CH:44]=[C:45]([S:49]([NH2:52])(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>C(O)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:25][C:26]([N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36]([NH:42][C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([S:49](=[O:51])(=[O:50])[NH2:52])[CH:44]=3)[C:31]=2[CH:30]=[CH:29]1)=[O:27]
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=O)n1ccc2c(Cl)ncnc21
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: CCCCO
Solvent: CC(=O)Cl
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=O)n1ccc2c(Nc3cccc(S(N)(=O)=O)c3)ncnc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-phenyl}-amide resin (50 mg, 0.05 mmol), prepared as in reference 2, in n-butanol (2 mL) is mixed with acetyl chloride (17.8 μL, 0.25 mmol) and 3-aminobenzenesulfonamide (43 mg, 0.25 mmol), and shaken at 80° C. for 24 hours. The resulting mixture is filtered and the resin is treated with TFA/CH2Cl2/H2O (45/50/5) (600 μL) for 30 minutes before filtering and washing with CH2Cl2 (3×2 mL), MeOH (3×2 mL). The washes are then combined together with n-butanol and concentrated. The residue is purified by preparative HPLC-MS to give 4-(3-sulfamoyl-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-phenyl}-amide (18.0 mg, yield 55%); 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 10.27 (s, 1H), 10.09 (s, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 8.29 (s, 1H), 8.17 (d, J=7.95 Hz, 1H), 7.95 (d, J=7.94, 2H), 7.87 (d, J=3.85 Hz, 1H), 7.54 (dd, J=7.61, 15.51 Hz, 2H), 7.52 (s, 1H), 7.45 (d, J=7.88 Hz, 2H), 7.37 (s, 2H), 7.25 (d, J=8.30 Hz, 1H), 7.11 (d, J=3.88 Hz, 1H), 3.69 (s, 2H), 3.54-3.3.17 (m, 2H), 3.01-2.93 (m, 6H), 2.75 (s, 3H), 2.41 (s, 3H); ESIMS m/z 654.20 (M++1).