Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:19]([F:28])=[CH:18][CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>O1CCCC1>[F:28][C:19]1[CH:18]=[CH:17][C:16]([CH:11]2[C:10]([CH3:29])([CH3:30])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)=[CH:21][C:20]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 57.8 %

Procedure:
A mixture of 2-(4-fluoro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.11 g, 0.27 mmol), lithium hydroxide hydrate (0.11 g, 2.7 mmol), water (2 mL) in tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(4-fluoro-3-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (60 mg, 57%) as a white solid: LC/MS m/e calcd for C22H25FN2O3 (M+H)+: 385.5, observed: 385.3.
Reaction SMILES: C([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6](C)[C:5]2[CH:16]=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19][C:4]1=2)C.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C(OCC)(=O)C>[N:28]1([C:18]2[CH:17]=[CH:16][C:5]3[C:4]([N:19]=2)=[N:3][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]=3)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNC1
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Solvent: CCOC(C)=O
Product: O=c1nc2ccc(N3CCCC3)nc2nc2ncccc12

Procedure:
5,11-Dihydro-11-ethyl-5-methyl-2-trifluoromethanesulfonyloxy-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.25 g) was dissolved in pyrrolidine (1 ml) and refluxed 30 min. The cooled solution was diluted with ethyl acetate, washed with water, and the organic phase was dried (anhydrous magnesium sulfate) and concentrated. The resulting oily residue was crystallized from ethyl acetate/hexane to provide 0.11 g of 5,11-dihydro-11-ethyl-5-methyl-2-n-(pyrrolidino-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, m.p. 185°-188° C.
Reaction SMILES: [Br:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].[Sn](Cl)(Cl)(Cl)Cl.CCOCC>C1C=CC=CC=1>[C:11]([C:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:7]=2[S:8][CH:9]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Brc1cccc2ccsc12
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(=O)c1csc2c(Br)cccc12
Temperature: 0 °C
Yield: 64 %

Procedure:
7-Bromo-benzo[b]thiophene (See Amin et al., J. Chem Soc. Perkin Trans., vol. 2, pp.1489-1492 (1982), incorporated herein by reference), (2.49 g, 11.7 mmol) was stirred in benzene (25 mL) with acetic anhydride (3.31 mL, 35.1 mmol) under argon. Tin (IV) chloride (4.1 mL, 35.1 mmol) in benzene (15 mL) was added slowly, and the reaction stirred at reflux under argon for 2 h. The red solution was allowed to cool, and was poured over ice water (60 mL). Ether (100 mL) was added, and organics were separated, washed with water (50 mL), sat NaHCO3 (50 mL), brine (50 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (10% EtOAc/hexanes) gave 1.92 g (64%) of 3-acetyl-7-bromo-benzo[b]thiophene as a white solid. 1H NMR (300 MHz, CDCl3) δ8.74 (d, 1H, J=7.8 Hz), 8.33 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.38 (t, 1H, J=7.8 Hz),2.65 (s, 3H). Anal. (C10H7BrOS) C, H. Calculated C=47.08, H=2.77; found C=47.03; H=2.78. In addition, 490 mg (16%) of the more polar 2-acetyl-7-bromo-benzo[b]thiophene was isolated. 1H NMR (300 MHz, CDCl3) □ 8.02 (s, 1H), 7.85 (d, 1H, J=7.8 Hz), 7.62 (d, 1H, J=7.8 Hz), 7.30 (t, 1H, J=7.8 Hz), 2.67 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10](Br)[CH:11]=[CH:12][C:13]=2[O:17][CH3:18])[NH:8][CH:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+]>C(O)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:17][CH3:18])[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(Br)ccc(OC)c2c1=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2cccc(OC)c2c1=O
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 8-bromo-5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (2.3 g, 7.1 mmol), sodium acetate (580 mg, 7.1 mmol) and 10% Pd/C (100 mg) in glacial acetic acid (50 ml) was stirred under H2 (2.5 atm) overnight. The catalyst was removed via filtration, and the reaction mixture was concentrated under reduced pressure. The resulting oil was dissolved in CH2Cl2 (100 mL) and washed with aqueous sodium bicarbonate solution and water. The organic layer was dried, filtered and concentrated. The crude product was purified by column chromatography to afford 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester as a yellow solid (1 g, 57%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Cl[C:13]1[N:22]=[C:21]([NH2:23])[C:20]2[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=2)[N:14]=1>>[NH2:23][C:21]1[C:20]2[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=2)[N:14]=[C:13]([N:9]2[CH2:10][CH2:11][N:6]([C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[CH2:7][CH2:8]2)[N:22]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CC1)N1CCNCC1
Product: COc1cc2nc(N3CCN(C(=O)C4CC4)CC3)nc(N)c2cc1OC

Procedure:
N-(Cyclopropylcarbonyl)piperazine (3.08 g., 0.02 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (4.74 g., 0.02 mole) are reacted according to the procedure of Example 1(a). The crude product crystallized from ethanol affords analytically pure 4-amino-2-[4-(cyclopropylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 283.5°-285.5° C. (corr.).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:9])([C@H:6]([OH:8])[CH3:7])[CH3:5].[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([I:18])=[CH:13][N:12]=1.[Na+].[Cl-]>C(OCC)C.C(#N)C>[Cl:10][C:11]1[N:16]=[C:15]([O:8][C@H:6]([CH3:7])[C:4]([CH3:5])([OH:9])[CH3:3])[C:14]([I:18])=[CH:13][N:12]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: C[C@@H](O)C(C)(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: C[C@@H](Oc1nc(Cl)ncc1I)C(C)(C)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
1.84 g (42.3 mmol) of sodium hydride (55%) was added in portions, with stirring at 0° C., to a solution of 4.40 g (42.3 mmol) (R)-2-methyl-butane-2,3-diol in 83 ml diethyl ether and was stirred for 10 minutes. It was stirred for a further 3 minutes at room temperature and the mixture was then added to an ice-cooled solution of 9.68 g (35.2 mmol) of 2,4-dichloro-5-iodo-pyrimidine in 97 ml acetonitrile. The mixture was stirred for 4 hours at 40° C. and, after cooling, ice and saturated NaCl solution were added. It was then extracted with ethyl acetate (3×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified chromatographically (hexane/ethyl acetate 4:1). 4.96 g (14.5 mmol; yield: 41%) of the product was obtained.
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([N:25]=[C:26]=[O:27])[CH2:22][CH2:23][CH3:24]>C(N(CC)CC)C>[CH2:21]([NH:25][C:26]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN=C=O
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)OCCCCC/C=C(\c1ccccc1)c1cccnc1
Yield: 84.8 %

Procedure:
In the presence of triethylamine, (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (2.0 g, 7.4 mmoles) was reacted with n-butyl isocyanate (0.8 g) in the same manner as Example 9 to give 1-(n-butyl)aminocarbonyloxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (Compound Id-25, 2.3 g) as an oil
Reaction SMILES: [Na+].[F:2][C:3]1[C:8](C)=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-:14])=O)=[C:5]([N+:15]([O-])=O)[CH:4]=1.O.O.[Sn](Cl)Cl.[CH2:23](O)C>>[F:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:14])[N:15]2[CH3:23])=[CH:7][CH:8]=1
Reactant: CCO
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1F
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CN1C(=O)CNc2ccc(F)cc21
Temperature: 25 °C

Procedure:
A mixture of N-(4-fluoro-5-methyl-2-nitrophenyl)glycine sodium salt(0. 125 g, 0.548 mmol) and tin (II) chloride dihydrate (0.370 g, 1.64 mmol, Aldrich, used as received) in ethanol (3.0 mL) was refluxed for 30 min. It was then cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with water (4.0 mL) and basified with saturated NaHCO3 to pH ˜8. The resulting. suspension was extracted with ethyl acetate (30 mL). The extract was dried over Na2SO4 and evaporated to yield 0.032 g of the tide compound as a yellow powder, which was used for the next reaction; 1H NMR (DMSO-d6): 2.024 (s, 3H), 3.607 (s, 2H), 5.751 (s, 1H), 6.453 (d, 1H, J=9.9 Hz), 6.456 (d, 1H, J=8.1 Hz), 10.162 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[Br:7][C:8]1[S:12][C:11]([C:13](=[O:19])[CH2:14][CH2:15]C(O)=O)=[CH:10][CH:9]=1.C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[Br:7][C:8]1[S:12][C:11]([C:13](=[O:19])[CH2:14][CH2:15][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:10][CH:9]=1
Reactant: N#CCC(=O)O
Reactant: O=C(O)CCC(=O)c1ccc(Br)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: N#CCC(=O)CCC(=O)c1ccc(Br)s1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 2-cyanoacetic acid (13 g, 50 mmol) in THF (100 mL) was added dropwise i-PrMgC1 (16 g, 250 mmol) at −78° C. for 1 h. A solution of 4-(5-bromothiophen-2-yl)-4-oxobutanoic acid (8A) and CDI (12 g, 74 mmol) in THF was added dropwise at −78° C. and the resultant mixture was stirred at −78° C. for 1 h and at room temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride (200 mL). The organic phase was separated, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=5:1) to afford 8B as a black oil (9.7 g, 69%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.[CH:12]12[O:17][CH:13]1[CH2:14][CH2:15][CH2:16]2.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:1][N:2]1[C:6]([C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[OH:17])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1cccn1
Reactant: C1CC2OC2C1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nccc1[C@H]1CCC[C@@H]1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 21.3 %

Procedure:
To a solution of 1-methylpyrazole (13.4 g, 163 mmol) in THF (1 L), n-butyl lithium (1.63 M solution in hexane; 100 mL, 163 mmol) was added dropwise at −78° C. for 40 minutes. To the reaction solution, cyclopentene oxide (15.1 g, 179 mmol) was added at −78° C., and the reaction solution was stirred at room temperature for 20 hours. To the reaction solution, a saturated aqueous solution of sodium hydrogencarbonate (100 mL) was added, followed by extraction with ethyl acetate (500 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (dichloromethane/methanol=97:3) to yield the title compound (5.77 g, 21%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Yield: 71 %

Procedure:
A stirred mixture of 7.8 grams (0.05 mole) of 3-fluoro-4-nitrophenol, 8.1 grams (0.05 mole) of 4-chlorophenylmethyl chloride and 6.9 grams (0.06 mole) of potassium carbonate in 80 mL of methyl ethyl ketone was heated at reflux for about 18 hours. After this time the reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography using silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 10.0 grams of 2-fluoro-4-(4-chlorophenylmethoxy)nitrobenzene, mp 86°-88° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([OH:14])[CH2:8][CH2:7]2)[CH3:2].[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][N:19]=1>C1COCC1.CCOCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([O:14][C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=1)[CH2:8][CH2:7]2)[CH3:2]
Reactant: Clc1ncnc2ccccc12
Reactant: CCOc1ccc2c(c1)CCC(O)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1ccc2c(c1)CCC(Oc1ncnc3ccccc13)C2
Temperature: 25 °C

Procedure:
2.57 g (13.3 mmol) of 6-ethoxytetralin-2-ol in 5 ml of THF were added, with ice-cooling, to a suspension of 400 mg of NaH (80% pure, 13.3 mmol in 40 ml of THF). The mixture was subsequently refluxed for 1 hour and cooled to room temperature, and 2.0 g (12.2 mmol) of 4-chloroquinazoline were added. The mixture was refluxed for 24 hours and cooled and then diluted with ether and washed with saturated sodium hydrogen carbonate and saturated sodium chloride solution. After the organic phase had been dried and concentrated, the residue was chromatographed on silica gel using petroleum ether/ethyl acetate (9:1, 8:2). This gave 2.39 g (61% of theory) of colorless crystals (m.p.115-117° C.).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:27][C@@H:24]([S:25][CH3:26])[C@H:23]([NH:28][C:29](=[C:31]2[C:36](=[O:37])[CH2:35][C:34]([CH3:39])([CH3:38])[CH2:33][C:32]2=[O:40])[CH3:30])[C@@H:22]([O:41][C:42](=[O:50])[C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C@@H:21]1[OH:51])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:52]1[CH:57]=[CH:56][CH2:55][CH2:54][CH2:53]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(#N)C>[Si:1]([O:18][CH2:19][C@H:20]1[O:27][C@@H:24]([S:25][CH3:26])[C@H:23]([NH:28][C:29](=[C:31]2[C:32](=[O:40])[CH2:33][C:34]([CH3:39])([CH3:38])[CH2:35][C:36]2=[O:37])[CH3:30])[C@@H:22]([O:41][C:42](=[O:50])[C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C@@H:21]1[O:51][CH:53]1[CH2:54][CH2:55][CH2:56][CH2:57][O:52]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H](OC(=O)c2ccc(Cl)cc2)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OC2CCCCO2)[C@H](OC(=O)c2ccc(Cl)cc2)[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Yield: 85 %

Procedure:
A mixture of methyl 6-O-(t-butyldiphenylsilyl)-3-O-(p-chlorobenzoyl)-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-1-thio-β- D-glucopyranoside (500 mg, 0.6 mmol), 3,4-dihydro-2H-pyran (5 mL) and -p-toluenesulphonic acid (5 mg) in dry acetonitrile (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 7 with the addition of triethylamine and then evaporated to dryness. The residue was taken up in dichloromethane (30 mL), washed with water (2×10 mL) and the organic phase dried over MgSO4. The solvent was removed in vacuo and the residue was chromatographed using hexane—EtOA 2:1 as the mobile phase to give methyl 6-O-(t-butyldiphenylsilyl)-3-O-(p-chlorobenoyl)-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-4-O-tetrahydropyranyl-1-thio-β-D-glucopyranoside (5) (420 mg, 85%).
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[C:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].Cl>C(O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[C:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)CCC#Cc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC#Cc1ccccn1
Temperature: 25 °C
Yield: 132.6 %

Procedure:
To a aqueous solution of 1M NaOH (9.9 mL) heated at 50° C., was added slowly a solution of ethyl 5-(pyridin-2-yl)pent-4-ynoate (2 g, 9.90 mmol) in 3 mL of ethanol. The reaction mixture was stirred 1h 30 at 50° C. and cooled to room temperature. An aqueous 1N HCl (9.9 mL, 9.90 mmol) was then added and the solvent was removed under pressure to afford 2.3 g of 5-(pyridin-2-yl)pent-4-ynoic acid (Yield: 99%) as a brown solid which can be used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Li].O>CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
To a solution of 1-benzyl-4-piperidone (5.00 mL, 27.0 mmol, 1.00 equiv, Aldrich) in anhydrous ether at −78° C. under argon was added methyllithium (1.4 M in Et2O, 54.0 mL, 53.9 mmol, 2.00 equiv). Stirring was continued at −78° C. for 1.5 hours. Ether (200 mL) and water (40 mL) were added, and the two phases were separated. The aqueous solution was extracted with Et2O (3×50 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc to EtOAc-MeOH 9:1) to give 4.81 g (87%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:30])[CH3:29])[C:23]=1[S:31]([NH2:34])(=[O:33])=[O:32]>>[CH3:29][N:28]([CH3:30])[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([NH:21][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=3)[N:3]=2)[C:23]=1[S:31]([NH2:34])(=[O:33])=[O:32]
Reactant: COc1cc(Nc2nccc(Cl)n2)cc(OC)c1OC
Reactant: CN(C)c1cccc(N)c1S(N)(=O)=O
Product: COc1cc(Nc2nccc(Nc3cccc(N(C)C)c3S(N)(=O)=O)n2)cc(OC)c1OC

Procedure:
2-(Dimethyl-amino)-6-[2-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide is prepared as described in Example 1 step C by using 4-chloro-pyrimidin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine (example 1 step A) and 2-amino-6-dimethylamino-benzenesulfonamide.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:24])[CH:7]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)C(OCC)=O)C.Cl>C(O)CO.O>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][CH2:13][CH2:7][C:6]([OH:24])=[O:5])[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(CCCc1cccc(OC)c1)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1cccc(CCCCC(=O)O)c1

Procedure:
KOH (7.0 g, 0.105 mol) was added slowly to a hot solution of the diester from Step C (14 g, 0.046 mol) in ethylene glycol (50 mL) with stirring under Ar. The reaction mixture was heated at reflux for 3 hr, cooled, acidified to pH=2 with HCl, diluted with H2O (150 mL), and extracted with benzene (3×50 mL). The organic layers were combined, washed with dilute NaHCO3 solution (2×100 mL), H2O (2×50 mL), dried, filtered, and concentrated to dryness to give the title compound after chromatography on SiO2 eluting with CHCl3:MeOH, 40:1.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[C:17]([CH:31]3[CH2:35][CH2:34][CH2:33][N:32]3[C:36](=[O:38])[CH3:37])=[CH:18][C:19]3[NH:23][C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[N:21][C:20]=3[CH:30]=2)=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:36]([N:32]1[CH2:33][CH2:34][CH2:35][CH:31]1[C:17]1[C:16]([O:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:3])[CH3:2])=[N:14][CH:13]=2)=[CH:30][C:20]2[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[NH:23][C:19]=2[CH:18]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(N)nc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(C)=O)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.005 ml of acetic anhydride was added to a pyridine (1 ml) solution of 13.7 mg of 1-(2-(6-(6-amino-pyridin-3-yloxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone, and the reaction liquid was stirred at room temperature for 3 hours. The reaction liquid was evaporated away under reduced pressure, the resulting residue was dissolved in 1 ml of trifluoroacetic acid, and the reaction liquid was stirred at room temperature for 3 hours. The reaction liquid was distilled under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid] and through silica gel column chromatography (developing solvent: chloroform/methanol=9/1) to obtain the entitled compound as an oily substance.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].O=S(Cl)Cl.[CH2:17]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[CH:30][C:31](O)=[N:32][CH:33]=2)=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH2:20][CH3:21]>N1C=CC=CC=1>[CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][C:31]2[CH:30]=[N:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=3)=[CH:33][N:32]=2)=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C(=O)O)cc1
Reactant: CCCCCc1ccc(-c2cnc(O)cn2)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCc1ccc(-c2cnc(OC(=O)c3ccc(CCC)cc3)cn2)cc1
Reaction time: 2 h

Procedure:
16.4 g of 4-propyl benzoic acid are boiled for hour with 24 g of SOCl2, which is followed by evaporating, dissolving the acid chloride obtained in 150 ml of toluene, adding 8 ml of pyridine and 24.2 g of 5-(4-pentylphenyl)-2-pyrazinol (obtainable analogously to Japanese Preliminary Published Application 144,770/84) and boiling for 2 hours. Cooling down and customary working up gives 5-(4-pentylphenyl)-pyrazin-2-yl 4-propylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24]CC)=[O:23].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:21][C:22]([OH:24])=[O:23])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reaction time: 0.33 h

Procedure:
A solution of 5.3 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole in 30 ml of dimethylformamide is added dropwise to a suspension of 0.65 g of sodium hydride (50% suspension in oil) in 30 ml of dimethylformamide. After stirring for 20 min, 1.4 ml of ethyl bromoacetate is added. The reaction mixture is stirred for 1 hr, poured into water and the precipitate is collected. The precipitate is added to 30 ml of 15% sodium hydroxide solution and 30 ml methanol and heated at reflux for 3 hr. The mixture is poured into water, acidified and filtered. Recrystallization from toluene and acetonitrile gives {[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}-acetic acid, mp 207° C.