Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:8]3[CH:13]=[C:12]([CH3:14])[C:11]([CH3:15])=[CH:10][C:9]=3[OH:16])[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C1(C)C=CC=CC=1.[Na].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>O.CCOCC>[C:1]12([C:8]3[CH:13]=[C:12]([CH3:14])[C:11]([CH3:15])=[CH:10][C:9]=3[O:16][CH2:25][CH:27]3[O:29][CH2:28]3)[CH2:7][CH:4]([CH2:3][CH2:2]1)[CH2:5][CH2:6]2
Reactant: Cc1cc(O)c(C23CCC(CC2)C3)cc1C
Reactant: ClCC1CO1
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(OCC2CO2)c(C23CCC(CC2)C3)cc1C

Procedure:
108g (0.5 mole) of 2-norbornyl-4,5-dimethyl phenol, 600 cm3 anhydrous toluene and 11.5g (0.5 mole) sodium are introduced into a three-necked flask supplied with a nitrogen stream. The reaction mixture is refluxed for 4 hours, the solvent is then removed and the residue taken up in 500 cm3 tetrahydrofuran. 39.4 cm3 (0.5 mole) epichlorohydrin are added and the mixture is heated under reflux for 8 hours. One extracts with ether, washes the ethereal phase with water, dries and evaporates the solvent. 123.6g of 1-(2'-norbornyl-4',5'-dimethyl phenoxy) 2,3-epoxypropane are obtained in the form of oil. 27.2g (0.1 mole) of the preceding product are dissolved in 100 cm3 isopropylamine. After 5 days contact, the excess amine is evaporated under reduced pressure and extracted with ether. After washing with water and drying, the ether is evaporated and the residue taken up in chloroform. One precipitates by adding gaseous hydrochloric acid. By crystallisation in methylethyl ketone, 20g of pure product are obtained. M.Pt. 183°-185° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH:12]=[C:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.[OH-:17].[Na+].OO>C1COCC1.O>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][C@@H:11]([CH2:14][OH:15])[C@H:12]([OH:17])[CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1=CCN(Cc2ccccc2)CC1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
A mixture 1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol (0.367 mol) and THF (1000 ml) was stirred at -70° C. and a solution of borane in THF (1 M) was added dropwise thereto. After the addition, the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 18 h. The reaction mixture was cooled to -10° C. and water (23 ml) was added dropwise, NaOH (3M in water, 18 ml) was added dropwise and hydrogen peroxide (30% solution in water, 28 ml) was added dropwise at the same time. Then, simultaneously, NaOH (3M in water, 36 ml) and the hydrogen peroxide (30% solution in water, 29 ml) was added dropwise. Again NaOH (50% in water, 80 ml) was added. The reaction mixture was stirred at reflux for 4 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated. The resulting precipitate was dissolved in water (500 ml) and saturated with K2CO3. The product was extracted with CH2Cl2. The resulting solution was dried over MgSO4 and evaporated. The residue was crystallized from DIPE/CH3CN. After several crystallizations a total yield of 40, 8 g of (±)-trans-1-(phenylmethyl)-3-hydroxy-4-piperidinemethanol was obtained (Yield: 50.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][N:3]=1.C1C[O:16]CC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1.[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2([OH:16])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Clc1ccc(C2=CCCC2)cn1
Product: Clc1ccc(C2CCCC2)cn1
Product: OC1(c2ccc(Cl)nc2)CCCC1
Temperature: 25 °C
Yield: 26 %
Yield: 29 %

Procedure:
2-Chloro-5-(cyclopent-1-enyl)pyridine (1.5 g, 8.5 mmol) was dissolved in THF (30 mL) in an oven-dried, nitrogen-flushed 250 mL round bottom flask and the resulting solution cooled in a dry ice/acetone bath under nitrogen. BH3.THF complex (2.4 g, 28.0 mmol, 28 mL of a 1 M solution in THF) was added dropwise with stirring via syringe and the mixture was allowed to warm slowly to room temperature and stir overnight. 2 N NaOH (15 mL), ethanol (15 mL) and 35% H2O2 (10 mL) were added and the mixture stirred for 0.5 h and then diluted with EtOAc and 1 N HCl. The layers were separated and the organic layer washed with brine and aqueous NaHSO3, dried over Na2SO4, filtered through celite, and concentrated. Purification by flash chromatography (hexanes:EtOAc/10:1→2:1) gave in order of elution by-products 2-chloro-5-cyclopentylpyridine (0.45 g, 29%) and 1-(6-chloropyridin-3-yl)cyclopentanol (0.44 g, 26%) followed by the desired product trans-2-(6-chloropyridin-3-yl)cyclopentanol (0.25 g, 15%) as a clear oil: LC/MS (ESI) m/z 197, 1H NMR (300 MHz, CDCl3) δ 8.26 (d, 1H, J=2.4 Hz), 7.55 (dd, 1H, J=8.4, 2.4 Hz), 7.25 (d, 1H, J=8.4 Hz), 4.12 (m, 1H), 2.88 (m, 1H), 2.24-1.62 (m, 6H).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:19][N:18]=4)[N:14]=[CH:15][C:10]=3[C:9]([CH3:30])=[C:8]([C:31]([O:33]CC)=[CH2:32])[C:7]2=[O:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(Cl)(Cl)Cl>[C:31]([C:8]1[C:7](=[O:36])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)=[CH:19][N:18]=3)[N:14]=[CH:15][C:10]=2[C:9]=1[CH3:30])(=[O:33])[CH3:32]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 108.3 %

Procedure:
To a solution of 8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (237 mg, 0.48 mmol) in chloroform (5 ml) was added hydrogen chloride (2 M ethereal solution, 2.0 ml, 4.0 mmol). The reaction mixture was stirred at RT for 12 h. The solvents were evaporated and the residue was dissolved in ethanol. The ethanol was evaporated to give 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (239 mg, 0.52 mmol). MS (APCI+) 462 (M+1, 100); 1H NMR δ(400 MHz, DMSOd6) 10.83 (m, 2H), 9.00 (s, 1H), 8.1 (m, 1H), 7.88-7.82 (m, 2H), 5.89-5.80 (m, 1H), 3.88-3.85 (m, 2H), 3.54-3.51 (m, 2H),3.23-3.11 (m, 4H), 2.83-2.82 (m, 3H), 2.43 (s, 3H), 2.34 (s, 3H), 2.23-2.11 (m, 2H), 1.93 (br, 2H), 1.81-1.77 (m, 2H), 1.60-1.59 (m, 2H); Anal. Calc'd for C25H31N7O2, 2.70HCl, 1.05C2H5OH: C, 53.50; H, 6.63;N, 16.12. Found: C, 53.45; H, 6.47; N, 15.85.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:20][CH2:21][CH2:22][OH:23])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:26]1[CH:27]=[C:28](O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:20][CH2:21][CH2:22][O:23][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:24]#[N:25])[CH:31]=1)[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCO)C(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCOc1cccc(C#N)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.77 g (21 mmol) of benzyl 2-(2R)-t-butoxycarbonylamino-5-hydroxypentanoate was dissolved in 105 ml of tetrahydrofuran. 2.74 g (23 mmol) of 3-cyanophenol, 6.6 g (25 mmol) of triphenylphosphine and 10 g (23 mmol) of diethyl azodicarboxylate (40% solution in toluene) were added to the solution, and they were stirred at room temperature for one hour. The solvent was distilled off, and the residue was treated with ethyl acetate as the extractant in an ordinary manner. The solvent was distilled off, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.[Na+]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(Cl)cc3)c(C)o2)cc1
Yield: 67.3 %

Procedure:
Reaction of chloride 2 (268 mg, 1.0 mmol) and sodium 4-chlorobenzenesulfinate (198 mg, 1.0 mmol) gave benzoate 19 (273 mg, 67%) as a white powder: mp (EtOAc) 186-188° C.; 1H NMR (CDCl3) δ 8.08 (ddd, J=8.7, 1.9, 1.6 Hz, 2H, H-2, H-6), 7.90 (ddd, J=8.7, 1.9, 1.6 Hz, 2H, H-3, H-5), 7.74 (ddd, J=8.7, 2.4, 2.0 Hz, 2H, H-2′, H-6′), 7.49 (ddd, J=8.7, 2.4, 2.0 Hz, 2H, H-3′, H-5′), 4.32 (s, 2H, CH2SO2), 3.94 (s, 3H, OCH3), 2.37 (s, 3H, CH3); MS m/z 407.0 (MH+, 100%), 409.0 (MH+, 35%). Anal. calcd for C19H16ClNO5S: C, 56.23; H, 3.97; N, 3.45. Found: C, 56.11; H, 3.80; N, 3.35%.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C1C2C(=CC=CC=2)C=CC=1S([N:25]=[N+:26]=[N-])(=O)=O.C(N(CC)CC)C.C(OCC)C>C(#N)C>[N+:25](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[N-:26]
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])C(=O)OCC
Temperature: 25 °C
Yield: 100 %

Procedure:
To a stirred solution of 24.52 grams (0.15 mole) of diethyl malonate and 34.0 grams (0.15 mole) of 2-naphthalenesulfonyl azide in 100 milliliters of acetonitrile was added 15.49 grams (0.15 mole) of triethylamine, dropwise, with cooling at 0° C.-5° C. On completing the feed the mixture was allowed to warm to room temperature while stirring for an approximate 16-hour period. Volatiles were stripped from the mixture under reduced pressure and the residue was slurried with ethyl ether and the inorganic salt filtered off. The filtrate was evaporated free of ether and purified by silica column chromatography to give 27.03 grams (0.15 mole) of diethyl diazomalonate as a yellow liquid. NMR analysis of the product indicated the following:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:18](N(CC)CC)C.COS(OC)(=O)=O.O>CN(C)C=O>[CH3:18][O:16][C:15](=[O:17])[C@H:12]([CH2:13][OH:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CCN(CC)CC
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-CBZ-L-serine (25 g) was dissolved in 100 ml of dry N, N-dimethylformamide at 0° C. under argon. Triethylamine (2 e.g., 30 ml) and dimethylsulfate (20 ml) were added. The contents of the vessel were stirred overnight at room temperature and then poured into 500 ml of water and extracted with ethyl acetate (3×200 ml). The organic layer was washed with water and brine and dried with sodium sulfate. Rotary evaporation afforded an oil which crystallized after silica gel chromatography in pure ethyl ether. The structure of the product, N-CBZ-L-serine methyl ester, was confirmed by NMR spectroscopy.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:15][CH3:16].CCCCCC.C([Li])CCC.CN(C)[CH:30]=[O:31].O>O1CCCC1>[CH:30]([C:2]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:15][CH3:16])=[O:31]
Reactant: CN(C)C=O
Reactant: COc1c(C)c(Br)c(OC)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1c(C)c(C=O)c(OC)c2ccccc12
Reaction time: 0.17 h
Yield: 48.8 %

Procedure:
A solution of 5.0 g (17.8 mmol) of 2-bromo-1,4-dimethoxy-3-methylnaphthalene in 30 ml of tetrahydrofuran was cooled to -78° C., to which 11.2 ml (17.9 mmol) of 1.6M n-butyllithium hexane solution was added dropwise, and stirred at the same temperature for 10 minutes after completion of the addition. Then 1.3 g (17.8 mmol) of dimethylformamide was added dropwise to the reaction mixture, and stirred at room temperature for 1 hour after completion of the addition. Water was added to the reaction mixture, from which the product was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified with silica gel column chromatography (hexane-isopropyl ether (8:2), and crystallized from hexane-isopropyl ether, to give 2.0 g (48.9%) of 2-formyl-1,4-dimethoxy-3-methylnaphthalene. m.p. 95°-96° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([CH3:11])=[C:6]([NH2:12])[CH:5]=1.[N+:14]([O-])(OCCC(C)C)=O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7]([CH:11]=[N:14][NH:12]2)=[C:8]([I:10])[CH:9]=1)=[O:13]
Reactant: CC(C)CCO[N+](=O)[O-]
Reactant: COC(=O)c1cc(N)c(C)c(I)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of 3-amino-5-iodo-4-methyl-benzoic acid methyl ester (1.22 g, 4.21 mmol) in acetic acid (20 mL) was added isoamyl nitrate (0.675 mL, 4.63 mmol). The mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 1.15 g (91%) of 4-iodo-1H-indazole-6-carboxylic acid methyl ester, MS (M+H)=303.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C@H:7]([OH:9])[CH3:8])[CH2:4][O:3]1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:13]=1>C1COCC1.[H-].[Na+]>[Cl:11][C:12]1[CH:17]=[C:16]([O:9][C@@H:7]([C@@H:5]2[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]2)[CH3:8])[N:15]=[C:14]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:13]=1
Reactant: C[C@@H](O)[C@@H]1COC(C)(C)O1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iii) using (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (prepared according to Liebigs. Ann. Chem. 1987, 7-14) (0.25 g) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii) (0.53 g) in THF (20 mL) and 60% sodium hydride (80 mg). Crude material was purified by column chromatography on silica gel using EtOAc/isohexane (1:3) as eluent to give the subtitle compound as a clear, colourless oil. Yield: 0.37 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH3:10][Li].[Cl-].[NH4+].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[CH3:10])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(F)cn1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)cn1
Yield: 33 %

Procedure:
To a −78° C. solution of 5-fluoro-2-formylpyridine (0.66 g, 5.3 mmol) in THF (20 mL) was methyl lithium (1.6 M in diethyl ether, 4.0 mL) added dropwise. After stirring for 1.5 h at −78° C. a saturated solution of ammonium chloride (25 mL) followed by water (25 mL) was added. The mixture was extracted with chloroform and the organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: chloroform:methanol 98:2) affording the title compound (0.25 g, 33% yield).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]([O-:14])=O)[CH:8]=2)[NH:3][CH:2]=1.Cl.O=C1CC2C(=CC=C(/C=C/C(O)=O)C=2)N1.[CH3:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH2:41][NH:42][CH3:43])=[CH:33]1.CC1NC2C(C=1CNC)=CC=CC=2>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]([N:42]([CH3:43])[CH2:41][C:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]([CH3:31])[CH:33]=3)=[O:14])[CH:8]=2)[NH:3][CH:2]=1
Reactant: CNCc1cn(C)c2ccccc12
Reactant: O=C([O-])/C=C/c1cnc2[nH]cnc2c1
Agent: CNCc1c(C)[nH]c2ccccc12
Agent: Cl
Agent: O=C(O)/C=C/c1ccc2c(c1)CC(=O)N2
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2[nH]cnc2c1
Yield: 90 %

Procedure:
According to the procedure of Example 4, except substituting (E)-3-(3H-imidazo[4,5-b]pyridin-6-yl)acrylate (0.14 g, 0.74 mmole), from Preparation 6, for the (E)-3-(2-oxo-2,3-dihydro-1H-indol-5-yl)acrylic acid hydrochloride salt, and substituting 1-methyl-3-(methylaminomethyl)indole (0.14 g, 0.81 mmole) for the 2-methyl-3-(methylaminomethyl)-1H-indole, the title compound (0.23 g, 89%) was prepared as a light yellow solid: MS (ES) m/e 346 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=1)/[CH:19]=[CH:20]/[C:21]([O:23]C)=[O:22])=[O:14].Cl>O.CO>[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=1)/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[O:14]
Reactant: COC(=O)/C=C/c1cccc(NC(=O)c2cccn2C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: Cn1cccc1C(=O)Nc1cccc(/C=C/C(=O)O)c1
Yield: 91.3 %

Procedure:
A solution of Cs2CO3 (3.26 g) in H2O (2 mL) was diluted with MeOH (8 mL) and ester 10 (0.91 g, 3.2 mmol) was added. The mixture was heated under reflux for 2.5 h then cooled and acidified with 0.5N HCl. The precipitated solid was collected, dried and dissolved in warm EtOAc. The solution was concentrated to a small volume under reduced pressure below 40° C. and then diluted with i-Pr2O to provide (E) -3- (1-methylpyrrole-2-carboxamido)cinnamic acid (11) (0.79 g, 91%) mp 202-204° C. 1H NMR [(CD3)2SO] δ12.44 (br s, 1 H, CO2H), 9.82 (s, 1 H, NH), 7.99 (s, 1 H, H-2), 7.79-7.73 (m, 1 H, H-4), 7.56 (d, J=16.0 Hz, 1 H, PhCH═CH), 7.40-7.34 (m, 2 H, H-5,6), 7.05 (dd, J=4.0, 1.7 Hz, 1 H, H-pyrrole), 7.02 (t, J=2.0 Hz, 1 H, H-pyrrole), 6.44 (d, J=16.0 Hz, 1 H, PhCH═CH), 6.11 (dd, J=3.8,2.6 Hz, 1 H, H-pyrrole), 3.89 (s, 3 H, NCH3).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH:7]1([NH:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13](F)[N:12]=2)[CH2:9][CH2:8]1.ClCCl>O1CCCC1>[CH:7]1([NH:10][C:11]2[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[N:14]=[C:13]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[N:12]=2)[CH2:8][CH2:9]1
Reactant: Fc1nc(NC2CC2)cc(C(F)(F)F)n1
Reactant: COCCCN
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCCNc1nc(NC2CC2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 977.9 %

Procedure:
6.1 g (0.068 mol) of 3-methoxypropylamine are added dropwise at room temperature to 7 g (0.0031 mol) of 4-cyclopropylamino-2-fluoro-6-trifluoromethylpyrimidine dissolved in 100 ml of tetrahydrofuran, and the mixture is stirred for 6 hours at room temperature. After addition of 2 l of ice-water, extraction with dichloromethane, drying of the organic phase and concentrating, 8.8 g (95.4% of theory) of the desired pyrimidine are obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)[C:9]=1[CH3:25].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[S:15][CH2:14][C:10]1[C:9]([CH3:25])=[C:8]([S:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][N:11]=1)(=[O:35])[CH3:34]
Reactant: Cc1c(SCc2ccco2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1c(SCc2nccc(SCc3ccco3)c2C)nc2ccccc21
Temperature: 20 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
2-{[[4-(2-Furylmethylthio)-3-methyl-2-pyridinyl]methyl]thio}-1H-benzimidazole (5.0 mmol) is suspended in anhydrous methylene chloride (50 ml), triethylamine (11 mmol and acetyl chloride (8 mmol) are added and the mixture is stirred at 20° C. for 20 h. The clear reaction solution is washed with sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated and the residue is crystallized by addition of diisopropyl ether. The title compound is obtained as a colorless powder; m.p. 168-169° C. (decomp.); yield: 97% of theory.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[Cl:41].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:38]4[CH:37]=[CH:36][C:35]([Cl:34])=[C:40]([Cl:41])[CH:39]=4)[N:7]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(Cl)cc21
Reactant: OB(O)c1ccc(Cl)c(Cl)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: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(Cl)c(Cl)c5)n4)cc3)c(Cl)cc21
Temperature: 100 °C
Yield: 90.4 %

Procedure:
To a solution of ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (0.050 g, 0.094 mmol), 3,4-dichlorophenylboronic acid (0.023 g, 0.12 mmol), and sodium carbonate (0.030 g, 0.28 mmol) in toluene (1 ml) and water (0.1 ml) degassed with argon was added tetrakis(triphenylphosphine)palladium (0.0054 g, 0.0047 mmol), and the reaction was heated to 100° C. for 16 hours. The reaction was loaded directly onto silica gel and eluted with a linear gradient of 5-70% EtOAc/hexanes to yield the desired compound (0.051 g, 0.085 mmol, 91% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[CH:4][C:3]=1Cl.NC1C=CC(O)=CC=1[Cl:27]>>[NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([Cl:27])[CH:3]=1
Reactant: NC(=O)c1cc(Oc2ccc(N)c(Cl)c2)ccn1
Reactant: Nc1ccc(O)cc1Cl
Product: NC(=O)c1cc(Oc2ccc(N)cc2Cl)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-amino-3-chloro-phenoxy)pyridine-2-carboxamide, substituting 4-aminophenol for 4-amino-3-chlorophenol. 1H-NMR (DMSO-d6) δ 8.43 (d, J=5.7 Hz, 1H), 8.07 (broad s, 1H), 7.66 (broad s, 1H), 7.31 (d, J=2.7 Hz, 1H), 7.07 (dd, J=5.7 Hz, 2.7 Hz, 1H), 6.85 (d, J=9.0 Hz, 2H), 6.62 (d, J=8.7 Hz, 2H), 5.17 (broad s, 2H).
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([O:15]C)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([NH2:2])=[O:15])[CH3:5]
Reactant: [NH4+]
Reactant: COC(=O)c1sccc1N=NN(C)C
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1ccsc1C(N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (20 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (600 mg) in THF (5 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and the precipitated solid was filtered and dried to give crude product, which was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product as an off-white solid (400 mg, 72%), mp 168-170° C. IR (neat) νmax 3337, 3172, 2923, 1636, 1599, 1348, 1219, 1117, 884, 771 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.28 (2H, br s), 7.35 (1H, d, J=5.6 Hz), 7.31 (1H, d, J=5.6 Hz), 3.58 (3H, br s), 3.20 (3H, br s); LC-MS (positive ion mode): m/z 221 (M+Na)+.