Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]3[O:17][CH2:16][O:15][C:11]=3[CH:12]=2)[NH:7]1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.C([S:30][CH2:31][CH:32]([CH3:36])[C:33](Cl)=[O:34])(=O)C>C(OCC)C>[SH:30][CH2:31][CH:32]([CH3:36])[C:33]([N:7]1[C:8]2[C:13](=[CH:12][C:11]3[O:15][CH2:16][O:17][C:10]=3[CH:9]=2)[CH2:14][CH:6]1[C:4]([O-:3])=[O:5])=[O:34].[CH:8]1([NH2+:7][CH:6]2[CH2:4][CH2:33][CH2:32][CH2:31][CH2:14]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CCOC(=O)C1Cc2cc3c(cc2N1)OCO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: CC(CS)C(=O)N1c2cc3c(cc2CC1C(=O)[O-])OCO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of 0.65 g of 5,6-methylenedioxyindoline-2-carboxylic acid ethyl ester, 0.76 g of powdered potassium carbonate and 8 ml of methylene chloride is added 0.50 g of 3-acetylthio-2-methylpropanoyl chloride while stirring at room temperature. It is refluxed for 2 hours, poured into 16 ml of diethyl ether and washed with 8 ml of water, 8 ml of N hydrochloride acid and 8 ml of saturated aqueous sodium bicarbonate. The organic phase is separated, dried and evaporated. The residue is taken up in 5 ml of methanol and 4.0 ml of 2.03N aqueous potassium hydroxide are each deoxygenated by bubbling nitrogen through the solutions for 10 minutes. The latter solution is added to the former and the mixture stirred at room temperature under nitrogen. After 2 hours, 15 ml of 2N hydrochloric acid are added and the mixture is extracted thrice with 25 ml of diethyl ether. The extract is dried, evaporated, the residue taken up in 10 ml of diethyl ether and the solution combined with 0.44 g of dicyclohexylamine, producing a white precipitate. It is collected, washed thrice with 3 ml of diethyl ether and dried to give the dicyclohexylammonium 1-(3-mercapto-2-methylpropanoyl)-5,6-methylenedioxyindoline-2-carboxylate melting at 194°-196°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.[I:25]N1C(=O)CCC1=O.[CH2:33]([Sn:37]([CH2:46]O)([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>O.C(OCC)C>[CH2:33]([Sn:37]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:46][I:25])[CH2:34][CH2:35][CH3:36]
Reactant: CCCC[Sn](CO)(CCCC)CCCC
Reactant: O=C1CCC(=O)N1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CI)(CCCC)CCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a mixture of triphenylphosphine (70 g, 0.27 mol) and tetrahydrofuran (500 mL) was added dropwise a mixture of N-iodosuccinimide (60 g, 0.27 mol) and tetrahydrofuran (500 mL) at 0° C., and then the reaction mixture was stirred for 30 minutes at 0° C. To this mixture was added dropwise tributylstannyl-methanol (71 g, 0.22 mol) described in Manufacturing Example 197-2-1 at 0° C., and then the reaction mixture was stirred for 20 minutes at 0° C. The reaction mixture was stirred overnight at room temperature. Diethyl ether and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed first with a saturated sodium thiosulfate aqueous solution and then with saturated aqueous sodium chloride. The organic layer was separated, and was concentrated under a reduced pressure. Heptane (400 mL) was added to the residue and filtered. The solvent in the filtrate was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane) to obtain the title compound (90 g, 94%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li+].CCC[CH2-].[CH:16]([Si:19]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[N:20]1[C:24]2[N:25]=[CH:26][CH:27]=[C:28]([C:29]#[N:30])[C:23]=2[CH:22]=[CH:21]1)([CH3:18])[CH3:17].C(Br)(Br)(Br)[Br:38]>O1CCCC1>[Br:38][C:27]1[CH:26]=[N:25][C:24]2[N:20]([Si:19]([CH:16]([CH3:18])[CH3:17])([CH:31]([CH3:33])[CH3:32])[CH:34]([CH3:36])[CH3:35])[CH:21]=[CH:22][C:23]=2[C:28]=1[C:29]#[N:30]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C#N)ccnc21
Reactant: BrC(Br)(Br)Br
Agent: CC1(C)CCCC(C)(C)N1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C#N)c(Br)cnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
2,2,6,6-Tetramethylpiperidine (380 μL, 2.25 mol) was dissolved in tetrahydrofuran (3 mL) and cooled to 0° C. N-Butyllithium (2.5 M in hexanes, 1.06 mL, 2.66 mmol) was added dropwise and the mixture was stirred at 0° C. for 10 min, then cooled to −78° C. A solution of 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (613 mg, 2.04 mmol) in tetrahydrofuran (2 mL) was added at −78° C. and the mixture was stirred at −78° C. for 1 h. A solution of carbontetrabromide (2 g, 6.1 mmol) in tetrahydrofuran (5 mL) was added quickly at −78° C. and the mixture was stirred for 15 min. The reaction was quenched with saturated ammonium chloride solution. The mixture was warmed to ambient temperature and applied to a Varian chemelut cartridge and eluted with ethyl acetate. The crude product was purified by flash silica gel chromatography using a gradient of dichloromethane in hexanes to afford 5-Bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (160 mg, 0.42 mmol, 21% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.88 (d, J=3.5 Hz, 1H), 6.83 (d, J=3.5 Hz, 1H), 1.85 (septet, J=7.5 Hz, 3H), 1.04 (d, J=7.5 Hz, 18H). MS: m/z 378.0/380.0 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1OCC[O:15]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(O)(=O)C.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][CH:2]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:15])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CCCC(C)OCCCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCCC(C)OCCCCC=O
Yield: 26 %

Procedure:
{4-[(1,5-dimethylhexyl)oxy]butyl}-1,3-dioxolane (1.4 g, 43% pure by GC RPA, 3.9 mmol), acetic acid (10 mL), tetrahydrofuran (16 mL) and water (20 mL) were added to a 100 mL three-necked flask fitted with thermocouple, magnetic stirrer and condenser. The reaction mixture was refluxed for 2 hrs, cooled and saturated sodium carbonate (150 mL) added. The crude reaction mixture was extracted with hexane (4×100 mL), the combined organic phase dried over magnesium sulphate, filtered and the solvent removed in vacuo. The crude product was chromatographed over silica gel (hexane/methyltert-butyl ether) to yield pure 5-[(1,5-dimethylhexyl)oxy]pentanal as a colourless oil (0.22 g, 1.02 mmol, chemical yield 26%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cc(Cl)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Yield: 83 %

Procedure:
To a degassed solution of 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (270 mg, 1.0 mmol), 4-fluorobenzeneboronic acid (155 mg, 1.0 mmol), 2N Na2CO3 (1.5 mL) in DME (10 mL) was added tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) under argon. The mixture was heated to 85° C. for 6 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (5-20% methylene chloride in heptane) to give the product as an off white solid (275 mg, 83%). 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=7.91 Hz, 2H), 8.12 (dd, J=5.27, 9.04 Hz, 2H), 7.74 (d, J=8.29 Hz, 2H), 7.54 (d, J=3.01 Hz, 2H), 7.18 (t, J=8.67 Hz, 2H), 2.50 (s, 3H). MS m/e 332.3 (M+H)
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>ClC(Cl)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)c2ccc(C#N)cc2)cc1
Reaction time: 2.5 h

Procedure:
825 mg of 4-cyanobenzoyl chloride was dissolved in 9 ml of dichloroethane, and mixed with 0.69 ml of 4-methoxybenzylamine and 1.57 ml of triethylamine, followed by stirring for 2.5 hours. Thereafter, the reaction was stopped by the addition of 1 ml of distilled water. After the product was extracted with chloroform, the extract was successively washed with 2 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the resulting crude product was purified by silica gel column chromatography (using a 20:1 mixture of chloroform and acetone as the eluent) to obtain 1.29 g of 4-cyano-N-(4-methoxy-benzyl)benzamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]=O>[NH2:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]([C:9]#[N:10])=[C:6]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Cu]
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(-c2cnccn2)c1C#N
Temperature: 25 °C
Yield: 31.2 %

Procedure:
To a stirred solution of 1.11 g (4.52 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 10 ml dry DMF under argon at room temperature were added 2.00 g (5.42 mmol) 2-(tri-n-butylstannanyl)pyrazine, 190 mg (0.27 mmol) bis(triphenylphosphine)palladium(II) chloride and 431 mg (5.42 mmol) copper(II) oxide. The reaction mixture was heated at reflux for 18 h, then cooled to room temperature and concentrated in vacuo. Flash chromatography (ethyl acetate/hexane 1/1 then ethyl acetate) afforded 344 mg (31%) 2-amino-4-methylsulfanyl-6-pyrazin-2-yl-pyrimidine-5-carbonitrile as an off-white crystalline solid. EI-MS m/e (%): 244 (M+, 100), 243 ([M—H]+, 40), 190 (55).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[CH3:18][O:17][C:15]([C:14]1[S:13][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=2[CH:4]=1)=[O:16]
Reactant: COC(=O)CS
Reactant: O=Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2c(F)cccc2s1

Procedure:
Using 5.0 g (35.2 mmol) of 2,6-difluorobenzaldehyde, 2.11 g (52.8 mmol) of sodium hydride (60% pure) and 4.11 g (38.7 mmol) of methyl mercaptoacetate, 5.61 g (72.8% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[C:4]([O:14][CH3:15])[CH:3]=1.C(OCC)(=[O:18])C>C(O)(=O)C.O.CCCCCC.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[C:4]([O:14][CH3:15])[CH:3]=1)[C:6](=[O:18])[CH2:7][CH2:8][C:9]2([CH3:12])[CH3:13]
Reactant: COc1cc(Br)cc2c1CCCC2(C)C
Reactant: CCOC(C)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCCCCC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)cc2c1C(=O)CCC2(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
A solution of 7-bromo-5-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalene (Intermediate 63, 5.6 g, 20.81 mmol) in glacial acetic acid (20 mL) was cooled to 0° C. and treated with a solution of chromium trioxide (6.16 g, 61.6 mmol) in acetic acid and water (25 mL). The reaction mixture was then allowed to warm to ambient temperature and stirred for 48 h. It was diluted with water and extracted with diethyl ether (×2). The combined organic phase was washed with water (×3), saturated aqueous sodium bicarbonate (×1) and brine (×1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford an oil. Flash column chromatography over silica gel (230-400 mesh) using 10-20-100% ethyl acetate in hexane as the eluent afforded the title compound (2 g, 33%) as a yellow oil and recovered starting material (2.2 g, 39%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][C:25]([C@@H:27]([NH2:29])[CH3:28])=[N:24][CH:23]=3)[CH:19]=[CH:18][CH:17]=2)[CH:10]=1>N1C=CC=CC=1>[CH3:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][C:25]([C@@H:27]([NH:29][C:5](=[O:7])[CH3:6])[CH3:28])=[N:24][CH:23]=3)[CH:19]=[CH:18][CH:17]=2)[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccnc(Nc2cccc(-c3cnc([C@H](C)N)s3)n2)c1
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](C)c1ncc(-c2cccc(Nc3cc(C)ccn3)n2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
Acetic anhydride (0.02 ml, 0.24 mmol) was added to a solution of N—((S)-1-{5-[6-(4-methyllpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}ethyl)amine (50 mg, 0.16 mmol) obtained in Example 9 in pyridine (3 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and extracted with a mixed solution of ethyl acetate-tetrahydrofuran. The organic layer was washed with a saturated brine and dried over magnesium sulfate. The obtained residue was washed with diisoprpyl ether and dried in vacuo and the title compound (43 mg, 76%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][OH:35]>C(#N)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]3[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]3[N:3]=[C:2]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH2:34][OH:35])[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Cc1nn2c(-c3ccc(F)cc3)cc(Cl)nc2c1I
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nn2c(-c3ccc(F)cc3)cc(N3CCC[C@H]3CO)nc2c1I
Yield: 61.2 %

Procedure:
5-Chloro-7-(4-fluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine (241 mg), DIPEA (0.2 mL) and (S)-2-pyrrolidinemethanol (152 mg) are stirred at 90° C. for 16 hours in an acetonitrile (60 mL) solvent. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound (172 mg). 1H NMR (CDCl3, 300 MHz); δ 7.92 (m, 2H), 7.22 (m, 2H), 6.10 (s, 1H), 4.45 (br, 1H), 3.85-3.57 (m, 4H), 2.38 (s, 3H), 2.08-2.01 (m, 3H), 1.72 (m, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:29])=O>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2cc(OC3CCCCC3)ccc2c1O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1nc(Br)c2cc(OC3CCCCC3)ccc2c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
A mixture of 7-cyclohexyloxy-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (Compound A-74 c1) (1.3 g) and phosphorus oxybromide (1.35 g) in anhydrous toluene (25 ml) was heated in a microwave reactor (sealed tube) at 130° C. for 15 min. After cooling, reaction mixture was concentrated. The residue was treated with saturated sodium bicarbonate aqueous solution (100 ml) and stirred at room temperature for 20 min. Extracted with ethyl acetate. Organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated to give the title compound (1.2 g). MS-(+)-ion M+1=422.12, 424.12.
Reaction SMILES: [CH3:1][N:2]([CH2:19][CH2:20][CH3:21])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=1)[C:8]([OH:10])=O)=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>CN(C=O)C>[F:79][C:77]1[CH:78]=[C:73]([CH:74]=[C:75]([F:80])[CH:76]=1)[CH2:72][C@H:58]([NH:57][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([C:14]2[O:15][CH:16]=[CH:17][N:18]=2)[CH:13]=[C:5]([C:3]([N:2]([CH3:1])[CH2:19][CH2:20][CH3:21])=[O:4])[CH:6]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-{[Methyl(propyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoic acid (350 mg, 1.2 mmol) in DMF (5 mL) is added diisopropylethylamine (835 μL, 4.8 mmol), HATU (554 mg, 1.5 mmol), then (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (488 mg, 1.2 mmol). The reaction is stirred for 16 h at room temperature. The reaction is partitioned between chloroform and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9% methanol/chloroform) gives the title compound. ESI MS m/z 605.3 [M+H]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:4]2=[N:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:27][CH:28]([CH3:30])[CH3:29].CCOC(C)=O>CS(C)=O.C1COCC1>[CH3:27][CH:28]([CH3:30])[CH2:29][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:4]3=[N:3][S:2](=[O:1])(=[O:19])[CH2:7][CH2:6][N:5]3[CH:8]=[CH:9][CH:10]=2)=[CH:13][CH:14]=1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)COc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a mixture of 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (200 mg), potassium carbonate (260 mg) in DMSO (4 mL) was added 1-iodo-2-methylpropane (173 mg). The mixture was stirred at 130° C. for 1 hr. Another 1-iodo-2-methylpropane (0.10 mL) was added and the mixture was stirred at room temperature overnight. 0.5N NaOHaq, EtOAc and THF were added and the extracted organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from THF-MeOH/IPE to give the title compound (104 mg) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH2:17][C:18]([O:20][CH2:21][CH2:22][C:23]#[N:24])=[O:19])(=[O:16])[CH2:13][CH2:14][CH3:15]>CC(O)C.N1CCCCC1.C(O)(=O)C>[C:23]([CH2:22][CH2:21][O:20][C:18](=[O:19])[C:17](=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:12](=[O:16])[CH2:13][CH2:14][CH3:15])#[N:24]
Reactant: CCCC(=O)CC(=O)OCCC#N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCCC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
A suspension of 4-nitrobenzaldehyde (16.61 g, 110 mmol), 2-cyanoethyl butyrylacetate (19.34 g, 100 mmol), piperidine (430 mg, 5.00 mmol) and acetic acid (300 mg, 5.00 mmol) in 350 ml of 2-propanol was stirred at room temperature for 48 hrs. The reaction mixture was filtered and resulting solid was air dried to give 2-[(4-nitrophenyl)methylene]-3-oxohexanoic acid 2-cyanoethyl ester as a white powder (31.0 g, 95%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:10]=2[C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.[CH2:25]([N:27]([CH2:39][CH3:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH:29]=1)[CH3:26].C(OC(=O)C)(=O)C>CO>[CH2:35]([N:34]([CH2:37][CH3:38])[C:30]1[CH:29]=[C:28]([N:27]([CH2:25][CH3:26])[CH2:39][CH3:40])[CH:33]=[CH:32][C:31]=1[C:7]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:24])[CH3:1])=[CH:23][CH:22]=2)[C:9]2[C:10](=[C:14]([Cl:21])[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=2[Cl:18])[C:11](=[O:13])[O:8]1)[CH3:36]
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(CC)CC)c1
Temperature: 91 °C

Procedure:
A mixture of 2-(4-(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (16.28 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (9.68 g.) and acetic anhydride (10 ml.) was heated (at 91° C.) during two hours. Addition of methanol (20 ml., then 12 ml., then 10 ml.) afforded 3-(2,4-bis(diethylamino)phenyl)-3-(4-(dimethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X=(CH3CH2)2N, Y2 =H, Y4 =(CH3)2N, Z4 =Z5 =Z6 =Z7 =Cl) in three fractions (m.p. 174°-176° C., m.p. 180°-181° C. and m.p. 180°-181° C.).
Reaction SMILES: [OH-].[Na+].[OH:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]([NH:24]O)=[NH:23])=[CH:18][C:16]=3[CH:17]=2)=[CH:9][CH:8]=1)=[NH:6].S([O:31][CH3:32])(OC)(=O)=O.[CH3:33]S(C)=O>O>[CH3:33][O:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][O:31][CH3:32])=[NH:23])=[CH:18][C:16]=3[CH:17]=2)=[CH:9][CH:8]=1)=[NH:6]
Reactant: N=C(NO)c1ccc(-c2cc3cc(C(=N)NO)ccc3o2)cc1
Reactant: COS(=O)(=O)OC
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CONC(=N)c1ccc(-c2cc3cc(C(=N)NOC)ccc3o2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1 M aqueous NaOH solution (20 mL) was added to a stirred solution of 178 (1.70 g, 5.5 mmol) in DMSO (20 mL). The mixture was cooled and dimethyl sulfate (1.5 mL, 15.9 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 4 hours and then overnight at room temperature, diluted with water (100 mL). The product was separated as a white solid and purified by column chromatography (SiO2, EtOAc, Hexanes) and recrystallized from aq HCl to give 0.4 g (22%): mp 270-271° C. (dec). 1H NMR (DMSO-d6) δ7.96 (s, 1H), 7.94 (d, J=8.2 Hz, 2H), 7.80 (d, J=8.2 Hz, 2H), 7.64 (s, 2H), 7.55 (s, 2H), 6.16 (br, 2H), 6.13 (br, 2H), 3.77 (s, 3H), 3.76 (s, 3H). HPLC (method A) tR 9.41 min (100.0 area %). Anal. (C18H18N4O3.2HCl) C, H, N, Cl.