Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14](O)[CH3:15].S(=O)(=O)(O)O.C(Cl)(Cl)Cl>O>[C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/C(=O)c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)/C=C/C(=O)c1ccccc1
Yield: 92.9 %

Procedure:
A mixture of 7.50 g of trans-β-benzoylacrylic acid, 2.36 g of ethanol, 0.50 g of sulfuric acid and 30 ml of chloroform was refluxed for 5 hours while azeotropically removing water produced from the reaction system. After cooling, the reaction mixture was washed with a saturated solution of NaHCO and then with water. The solvent was distilled away to give 8.08 g of ethyl trans-β-benzoylacrylate.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]1[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.[ClH:26].O1CCOCC1>C(OCC)(=O)C>[ClH:26].[C:7]1([N:6]2[CH:5]=[CH:4][N:3]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:2]2=[O:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccn(-c3ccccc3)c2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1n(-c2ccccc2)ccn1C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
tert-Butyl 4-(2-oxo-3-phenyl-2,3-dihydroimidazol-1-yl)piperidine-1-carboxylate (290 mg, 844 μmol) was dissolved in ethyl acetate (3.0 mL). 4M Hydrogen chloride in 1,4-dioxane (3.0 mL, 12 mmol) was added to the mixture. Reaction was allowed to stir at room temperature for 18 hours. Material was concentrated by roto-vap. Residue was triturated in diethyl ether. Solids were filtered and washed with diethyl ether. Air was pulled through the filter cake to dry. Title compound was obtained as tan solid in 91% yield. MS (M+H)+=244.1.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].C([O-])(=O)C.[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15]>O.C(O)C>[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[NH:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][S:5]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1CSC(c2ccc([N+](=O)[O-])cc2)N1
Temperature: 0 °C
Yield: 87 %

Procedure:
3 g (17.08 mmoles) of L-Cysteine hydrochloride and 2.18 g (22.2 mmoles) of sodium acetate are dissolved in 75 ml of water. The solution is agitated vigorously during the addition, by portions, of 3.10 g (20.5 mmoles) of 4-nitrobenzaldehyde in solution in 80 ml of 95% ethanol. A white precipitate rapidly appears in this pale yellow solution which forms abundantly. Agitation is maintained for one hour, the reaction mixture is then cooled down to 0° C. and filtered. The precipitate is successively rinsed with 200 ml of water, 100 ml of cold ethanol and 100 ml of ethyl ether. After drying, a white powder is obtained with a yield of 87%. Melting point: 120-121° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:7]2=[N:6][C:5]=1[CH3:17].[C:18]1([CH3:30])[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1.[ClH:31]>C1(C)C=CC=CC=1>[ClH:1].[ClH:31].[C:18]1([CH3:30])[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:7]4=[N:6][C:5]=3[CH3:17])[CH2:28][CH2:29]2)[CH:19]=1
Reactant: Cc1cc(C)n2c(=O)c(CCCl)c(C)nc2c1
Reactant: Cc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCN(CCc3c(C)nc4cc(C)cc(C)n4c3=O)CC2)c1

Procedure:
A mixture of 2.5 g of 3-(2-chloroethyl)-2,6,8-trimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 5.3 g of 1-(m-tolyl)piperazine and 20 ml of toluene was refluxed for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by means of column chromatography using alumina. The oil obtained from the eluate was converted into the hydrochloride, which was then recrystallized from ethanol to give 0.8 g of the desired compound as pale yellow powders, m.p. 274°C (decomp.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([CH:14]=O)[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:25][CH2:26][CH2:27]P(OCC)(OCC)=O)(=[O:24])[CH3:23].CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:13]=[C:12](/[CH:14]=[CH:23]/[C:22]([O:25][CH2:26][CH3:27])=[O:24])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Reactant: O=Cc1cc(OCc2ccccc2)nn1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(OCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-5-carbaldehyde (6.24 g), diethylphosphonoethyl acetate (5.55 g) and N,N-dimethylformamide (50 ml) was added sodium hydride (60% in oil, 960 mg) at 0° C. and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl (E)-3-(3-benzyloxy-1-phenyl-1H-pyrazol-5-yl)propenoate (7.33 g, yield 94%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH:23](SC)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)Cl.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=3)[CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(NCC1Cc2ccccc2C1)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)SC
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 110 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
16.1 g (50.0 mmol) of [2-[(4-chlorophenyl)sulfonylaminomethyl)indan and 9.27 g (55.0 mmol) of ethyl alpha-chloro-alpha-(methylthio)acetate were dissolved in 50 ml of methylene chloride, to which 6.44 ml (55.0 mmol) of stannic chloride was slowly added dropwise. After stirring for 3 hours, the reaction mixture was poured into ice-water, and the organic phase was collected, washed, dried and condensed. The residue was dissolved in 180 ml of acetic acid, added with 40 g of zinc powder and heated at 110° C. for 1 hour. After cooling, the precipitates were filtrated and washed thoroughly with chloroform and the solvent was removed. The residue was dissolved in 300 ml of ethyl acetate, and washed with water, saturated aqueous sodium bicarbonate solution and water in this order, and dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a solvent mixture of ethyl acetate and hexane to obtain 16.7 g of colorless needles. Yield: 82%.
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([OH:14])[CH2:11][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[C@H:9]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:14][C@@H:12]1[CH2:13][NH:8][C@H:9]([C:19]([OH:21])=[O:20])[C@@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]1
Reactant: COC(=O)[C@H]1C[C@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](O)CN[C@@H]1C(=O)O

Procedure:
A solution of 2-benzyl 3-methyl (2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (2.00 g, 0.00522 mol) in 30 mL of methanol was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, overnight. After filtered off the catalyst, the filtration was concentrated to dry and used directly in next step.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:10]=2)=[CH:4][CH:3]=1.[CH:28]([Mg]Cl)([CH3:30])[CH3:29].O>O1CCCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:28]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])[CH:10]=2)=[CH:4][CH:3]=1)([CH3:30])[CH3:29]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Cl)nc2)c2cccnc21
Reactant: CC(C)[Mg]Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)cn1
Temperature: 20 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To 3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6, 54.0 mg, 0.000135 mol, prepared as described in Example 2) in Tetrahydrofuran (4.0 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (23.0 mg) and Isopropylmagnesium Chloride (0.15 mL, 2.0 M in Tetrahydrofuran). The reaction was stirred at 20° C. under an atmosphere of Nitrogen for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound 39 (38 mg, 70.4%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]1[O:18][CH2:17][CH2:16][O:15]1.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>C(Cl)Cl>[C:19]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH:14]1[O:15][CH2:16][CH2:17][O:18]1)(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: OCCOCCC1OCCO1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCOCCC1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 500 ml four-neck round bottom flask equipped with a mechanical stirrer, condenser, thermometer and addition funnel were added 22.0 g triethylamine, 32.4g.2-[2-(2-hydroxyethoxy)ethyl-1,3-dioxolane, and 180 ml methylene chloride. The temperature was reduced to about 0° C. to -5° C. A total of 23.22 g. methacryloyl chloride was added dropwise through an addition funnel. While maintaining the temperature at about 0 to -5°, the mixture was then allowed to warm to room temperature and stirred for 30 min. and added to an equal volume (180 ml) of ice-water. The methylene chloride layer was separated from the aqueous layer, a small amount of anhydrous magnesium sulfate (3 g) was added, the solution was filtered, and methylene chloride was stripped off to isolate the product. Purification was done by distillation at 106° C. under 0.2 Hg pressure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11](=[O:13])[NH:10][N:9]=2)[CH:5]=[C:4]([CH3:14])[CH:3]=1.[OH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1.[H-].[Na+].O>CN1CCCC1=O>[CH3:14][C:4]1[CH:5]=[C:6]([C:8]2[NH:12][C:11](=[O:13])[NH:10][N:9]=2)[N:7]=[C:2]([O:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]2)[CH:3]=1
Reactant: Cc1cc(Cl)nc(-c2n[nH]c(=O)[nH]2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc(-c2n[nH]c(=O)[nH]2)c1
Temperature: 140 °C

Procedure:
A mixture of 3-(6-chloro-4-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (428 mg, 2.032 mmol), (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (457 mg, 2.439 mmol) and sodium hydride (81 mg, 2.032 mmol) in N-methyl-2-pyrrolidinone (7 mL) was heated in a microwave reactor at 140° C. for 30 minutes. After cooling, water was added and the mixture was extracted with EtOAc. The aqueous layer was acidified with 1M HCl aq and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo to give the title compound, which was used without further purification. ESI-MS [M+H-tert-butyl]+ 306.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][CH2:18][CH2:19]Br.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:19][CH2:18][O:17][CH3:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCBr
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a suspension of 3,4-difluorophenol (2 g) and cesium carbonate (7.51 g) in N,N-dimethylformamide (15 mL) was added 2-methoxyethyl bromide (2.14 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 3,4-difluoro-1-(2-methoxyethoxy)-benzene (2.49 g). To the solution of the obtained 3,4-difluoro-1-(2-methoxyethoxy)benzene (1.47 g) in tetrahydrofuran (39 mL) was added n-butyllithium (2.64 mol/L n-hexane solution, 3.25 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dry ice (10 g), and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. To the reaction mixture was added 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.48 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[C:15]([C:17]1[CH:31]=[C:30]([CH2:32][OH:33])[CH:29]=[CH:28][C:18]=1[O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=1)#[N:16]>CN(C=O)C>[C:15]([C:17]1[CH:31]=[C:30]([CH2:32][O:33][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)[CH:29]=[CH:28][C:18]=1[O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=1)#[N:16]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2C#N)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)nc3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50 mg, 0.269 mmol), sodium hydride (21.55 mg, 0.539 mmol) and 5-(2-cyano-4-(hydroxymethyl)phenoxy)picolinonitrile (67.7 mg, 0.269 mmol) in DMF (2 mL).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:21]C(C)([O-])C.[K+].C1COCC1.IC>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:21])[CH:6]=[C:5]2[S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(c1ccc(F)cc1)c1c[nH]c2ccc(Br)cc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cc(S(=O)(=O)c2ccc(F)cc2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a stirred solution of 5-bromo-3-(4-fluoro-benzenesulfonyl)-1H-indole (0.315 g, 0.89 mmole) in tetrahydrofuran (4 mL) was added 1M potassium t-butoxide/THF (1.0 mL, 1.0 mmol). After 10 minutes iodomethane (0.16 g, 1.1 mmole) was added. The reaction mixture was stirred at room temperature overnight and then passed through a pad of silica gel (230–400 mesh) eluting with 50% ethyl acetate/hexane. The eluate was concentrated under reduced pressure to provide a residue that was crystallized from ethanol/hexanes to give 0.3 g of 5-Bromo-3-(4-fluoro-benzenesulfonyl)-1-methyl-1H-indole.
Reaction SMILES: O.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)C>[OH:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([NH:2][C:14](=[O:16])[CH3:15])=[CH:4][CH:5]=1
Reactant: Nc1ccc(O)c2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(O)c2ccccc12
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Into a 500 ml round bottom flask (fitted with a magnetic stirrer), a 50:50 mixture of water:ethanol was combined with 4-amino1-naphthol (20 g, 125 mmole) until the solid was completely dissolved. The solution was warmed to boiling, and to it was added acetic anhydride (14 g) and the resulting solution was stirred for 1 hour. Upon cooling, crystals of N-(4-hydroxy-1-naphthyl)acetamide (20 g, 79% yield) formed.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1.[OH-].[Na+].[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>O.C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])=[CH:7][CH:8]=2)[C:3]=1[N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1
Reactant: C=C(C)C(=O)Cl
Reactant: Oc1ccc2ccc(O)c(-n3nc4ccccc4n3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=C(C)C(=O)Oc1ccc2ccc(O)c(-n3nc4ccccc4n3)c2c1
Yield: 40 %

Procedure:
To a solution of BDHN or 2(2,7-dihydroxynaphthyl) 2H-benzotriazole (5.0 g 18 m mol) and NaOH (0.8 g, 20 m mol) in water (100 ml) a solution of methacryloyl chloride (20 m mol, 4 ml) in chloroform (50 ml) was added dropwise with vigorous stirring. The mixture was stirred for 1 additional hour. The organic layer was separated and washed thoroughly with water before evaporation to yield a crude product that was recrystallized from carbon tetrachloride to give a yellow solid (2.5 g, 40% yield) of 2(2-hydroxy-7-methacryloxynaphthyl) 2H-benzotriazole--m.p. 167°-168° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:42][CH:43]([CH3:62])[CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH:52]=2)[NH:47][CH:46]=1>>[CH2:55]([O:54][C:51]1[CH:52]=[C:53]2[C:48](=[CH:49][CH:50]=1)[NH:47][CH:46]=[C:45]2[CH2:44][CH:43]([NH:42][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])[CH3:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: CC(N)Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: Cl
Product: CC(Cc1c[nH]c2ccc(OCc3ccccc3)cc12)NC(=O)[C@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 33.6 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (68 mg, 0.12 mmol) and 3-(2-aminopropyl)-5-(benzyloxy)-indole hydrochloride (46 mg, 0.15 mmol) according to Method C with HPLC purification to give the title compound (32 mg) as a diasteromeric mixture. IR (KBr) 3409, 1681, 1652 cm−1; HRMS m/z 792.3360 (calc. of monoisotopic mass for C44H48N4O10 gives 792.3370).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C:5]1[N:14]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[N:27][CH:26]=1>>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:10]2[N:11]=[CH:12][C:7]3[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:21])[CH3:1])[N:14]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:8]=3[N:9]=2)=[N:27][CH:26]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCC1
Product: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCCC4)c3n2)nc1
Yield: 65.1 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (800 mg, 2.61 mmol), was combined with 6-amino-nicotinic acid methyl ester (397 mg, 2.61 mmol) which gave 6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid methyl ester (720 mg, 1.70 mmol) in 65% yield. MS m/z 423.6 (M+H)+.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].C1(N2CCN([C:17](=[O:50])[C@@H:18]([NH:29]S(C3C=CC=C(N4CCCCC4=O)C=3OC(F)F)(=O)=O)[CH2:19][NH:20][C:21]([C:23]3[S:24][C:25]([Cl:28])=[CH:26][CH:27]=3)=[O:22])CC2)CC1.Cl>C(OCC)(=O)C>[ClH:28].[CH3:3][O:4][C:17](=[O:50])[C@@H:18]([NH2:29])[CH2:19][NH:20][C:21]([C:23]1[S:24][C:25]([Cl:28])=[CH:26][CH:27]=1)=[O:22]
Reactant: O=C(NC[C@H](NS(=O)(=O)c1cccc(N2CCCCC2=O)c1OC(F)F)C(=O)N1CCN(C2CC2)CC1)c1ccc(Cl)s1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)CNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
33 g (110.24 mmol) of intermediate 8 from step 22.4) were dissolved in 600 ml ethyl acetate and 250 ml HCl (2N in diethyl ether) was added. After 20 h stirring at RT the reaction was filtered and the solid dried under reduced pressure.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[F:26][C:22]1[CH:21]=[C:20]([S:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[C:7]([CH2:6][CH2:5][C:4]([OH:27])=[O:3])=[CH:8][CH:9]=[CH:10]3)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCc1cccc2cc(S(=O)(=O)c3cccc(F)c3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)CCc1cccc2cc(S(=O)(=O)c3cccc(F)c3)ccc12
Temperature: 25 °C
Yield: 86.3 %

Procedure:
3-[6-(3-Fluoro-benzenesulfonyl)-naphthalen-1-yl]-propionic acid ethyl ester (2.0 g) was dissolved in 25 mL ethanol, and 10 mL of 25% aqueous NaOH was added. The reaction mixture was heated to reflux for one hour, then cooled to room temperature. The ethanol was removed under reduced pressure, and the liquid residue was acidified by addition of 10% aqueous HCl. The mixture was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude oil. The oil was dissolved in warm toluene and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give 1.6 g of 3-[6-(3-fluoro-benzenesulfonyl)-naphthalen-1-yl]-propionic acid.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=2)=[N:11][CH:12]=1)C.[CH2:34]([NH:36][CH3:37])[CH3:35]>>[CH2:34]([N:36]([CH3:37])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=2)=[N:11][CH:12]=1)[CH3:35]
Reactant: CCNC
Reactant: CCOC(COc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1)OCC
Product: CCN(C)CCOc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1

Procedure:
Using 6-{[5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine obtained in Example 5-1) and ethyl(methyl)amine, and in the same manner as in Example 5-2) and 5-3) or according to a method similar to it or according to a combination thereof with an ordinary method, 6-[(5-{2-[ethyl(methyl)amino]ethoxy}pyridin-2-yl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (76 mg) was obtained.