Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C=CC(=O)OCC
Reactant: Oc1cccc(Br)c1
Solvent: CO
Product: CCOC(=O)CCOc1cccc(Br)c1
Yield: 52.9 %

Procedure:
A mixture of 20 g of 3-bromophenol, 92 g of ethyl acrylate and 1.8 ml of Triton B (35% in methanol) was boiled at reflux overnight. After distilling off the excess acrylate at normal pressure, the residue was distilled in a high vacuum. There were obtained 16.7 g of ethyl 3-(m-bromophenoxy)propionate as a colorless oil, boiling point 107°-110° C./67 Pa.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH2:14][NH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I-:22].[Na+].[OH-].[Na+].Cl[O-].[Na+]>CO>[I:22][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])=[CH:14][N:13]=2)[CH:20]=[CH:19][C:18]=1[OH:21]
Reactant: O=C(C1=CC=C(c2ccc(O)cc2)NC1)N1CCOCC1
Reactant: [I-]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccc(-c2ccc(O)c(I)c2)nc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 61.4 %

Procedure:
A mixture of Example 44B (4.25 g, 15.0 mmol) sodium iodide (2.36 g, 15.7 mmol) and sodium hydroxide (0.63 g, 15.7 mmol) was stirred in methanol (90 mL) with heating until a clear solution was obtained. The solution was then cooled to 0° C. and to this was slowly added sodium hypochlorite (22 mL of 5.25%, 1.15 g, 15.5 mmol) (Clorox™) over 45 minutes. While maintaining 0° C., two sequential additions of NaI (0.3 g, 1.5 mmol) and Clorox (2.2 mL, 0.12 g, 1.5 mmol) were made both 2 hours and 4 hours later. The mixture was stirred for 12 hours at ambient temperature, quenched by the sequential addition of aqueous sodium thiosulfate (10 mL), water (800 mL) and sufficient aqueous sodium dihydrogen phosphate (NaH2PO4) to adjust the pH to 7. The mixture was extracted with dichloromethane, and the combined extracts dried (Na2SO4), filtered and concentrated under reduced pressure to give a tan foam. The product was crystallized from ethanol to give the titled compounds as a tan solid (3.78 g, 61%). MS (DCI) m/z 411 (M+H)+;
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26]([N:33]=[C:34]=[O:35])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O1CCCC1>[CH2:26]([NH:33][C:34](=[O:35])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: CCCCCCCN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) and triethylamine in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, n-heptyl isocyanate (505 mg/ml, 3.14 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8h as solid. Yield: 0.600 g, 75.6%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:13][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:12]
Reactant: Cc1cc(Br)cc(C)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1c(C)cc(Br)cc1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A solution of 4-bromo-2,6-dimethyl-benzoic acid (4.04 g, 17.6 mmol) in acetone (50 mL), was treated with anhydrous K2CO3 (4.14 g, 30 mmol) followed by methyl iodide (1.43 g, 21 mmol). The reaction mixture was stirred at 70° C. for 2 h. GC-MS and TLC indicated that the reaction was completed. The solids were removed by filtration and the filtrate evaporated under reduced pressure. Silica gel column chromatography using 10% ethyl acetate in hexanes afforded 4-bromo-2,6-dimethyl-benzoic acid methyl ester (3.44 g, 80%). GC-MS: m/z 244 M+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH3:16])[C:4](=[O:17])[C:3]1=[O:18].[O:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:20]1=2.C(N(CC)CC)C>ClCCl>[O:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([NH:29][S:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]([CH3:1])[C:3](=[O:18])[C:4](=[O:17])[N:5]4[CH3:16])(=[O:14])=[O:13])[CH:27]=[CH:28][C:20]1=2
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Cn1c(=O)c(=O)n(C)c2cc(S(=O)(=O)Cl)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)c(=O)n(C)c2cc(S(=O)(=O)Nc3ccc4c(c3)OCCO4)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride (example 6-3a, 450 mg, 1.6 mmol) was added to a stirred solution of the 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (215 mg, 1.4 mmol) and triethylamine (170 mg, 1.7 mmol) in dichloromethane (10 mL). The reaction was stirred at ambient temperature overnight then concentrated. The crude product was purified by silica gel chromatography (0-30% ethyl acetate in hexanes) to provide N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a white solid. MS (M+H, 404.10); 1H NMR (400MHz, DMSO-d6): δ, ppm: 3.47 (s, 3H), 3.49 (s, 3H), 4.12 (m, 4H), 6.55 (m, 1H), 6.61 (d, J=2.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 7.53 (m, 1H), 7.59 (d, J=2 Hz, 1H), 10.00 (s, 1H).
Reaction SMILES: CN(C)[CH2:3][CH2:4][OH:5].C([Li])CCC.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1.C(=O)C>CCCCCC.O>[CH3:18][C:14]1[C:13]([CH:4]([OH:5])[CH3:3])=[N:12][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccnc1
Reactant: CN(C)CCO
Agent: CC=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: Cc1cccnc1C(C)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve N,N-dimethylethanolamine (70.45 mmol) in hexane (90 mL) at 0° C., add 2.5M n-butyl lithium in hexane (140.9 mmol,) and stir for 30 min at this temperature. Add a solution of 3-picoline (35.23 mmol) in hexane (10 mL) and continue stirring at 0° C. for 1 h. Cool the resulting mixture to −78° C., add acetaldehyde (70.45 mmol) and continue stirring at −78° C. for 1 h. Dilute with water, warm to ambient temperature, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography eluting with hexane/EtOAc (85:15) to give the desired intermediate as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH3:20]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCCBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 84.2 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) in N,N-dimethylformamide (1.6 mL) was added cesium carbonate (798 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromopropane (301 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (161 mg) as a white solid.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([S:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][N:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33]C)=[CH:30][CH:31]=3)[CH2:26][CH2:25][C:24]2([C:36]2[CH:41]=[CH:40][C:39]([O:42]C)=[CH:38][CH:37]=2)[CH3:35])[CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:5]([S:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][N:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]2[C:32]3[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=3)[CH2:26][CH2:25][C:24]2([C:36]2[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=2)[CH3:35])[CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCSCCc1cnn(CCCCC2c3ccc(OC)cc3CCC2(C)c2ccc(OC)cc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCSCCc1cnn(CCCCC2c3ccc(O)cc3CCC2(C)c2ccc(O)cc2)c1
Temperature: -70 °C

Procedure:
A solution of boron tribromide (0.4 g.) in methylene chloride (3 ml.) was added to a stirred solution of the (1RS,2RS)-1-{4-[4-(2-hexylthioethyl)-pyrazol-1-yl]butyl}-1,2,3,4-tetrahydro-6-methoxy-2-p-methoxyphenyl-2-methylnaphthalene thus obtained in methylene chloride (10 ml.) which was cooled to -70° C. under an atmosphere of argon and the mixture was allowed to warm up to laboratory temperature and was then poured into saturated aqueous sodium bicarbonate solution (20 ml.). The mixture was extracted three times with methylene chloride (10 ml. each time) and the combined extracts were washed with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 6:1 v/v mixture of methylene chloride and ethyl acetate as eluent. There was thus obtained as an oil (1RS,2RS)-1-{4-[4-(2-hexylthioethyl)pyrazol-1-yl]butyl}-1,2,3,4-tetrahydro-2-p-hydroxyphenyl-2-methylnaphth-6-ol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH:19]([OH:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].[H-].[Na+].Cl[C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:26]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:25]([O:21][CH:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19](=[O:20])[N:11]2[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[N:1]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2cnccc2n1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1CCN(C(=O)OC2c3ccccc3C(=O)N2c2ccc3cnccc3n2)CC1
Yield: 80.6 %

Procedure:
Following the procedure of Example 4 but starting with 2-(1,6-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (1.7 g.) in anhydrous tetrahydrofuran (17 cc.), sodium hydride (50% dispersion in mineral oil) (0.58 g.), 1-chlorocarbonyl-4-methylpiperazine (0.5 g.) in anhydrous tetrahydrofuran (5 cc.) and hexamethylphosphotriamide (4.5 cc.), a product (1.3 g.), melting at 215° C., is obtained. After washing with diisopropyl ether (30 cc.), this product is dissolved in methylene chloride (40 cc.). After filtration, the solution is concentrated to dryness to yield 3-(4-methylpiperazin-1-yl)carbonyloxy-2-(1,6-naphthyridin-2-yl)isoindolin-1-one (1 g.) melting at 215° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1.C([Li])CCC.[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>CCOCC.CCCCCC>[CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21])=[N:3]1
Reactant: CC1(C)COC(c2cccs2)=N1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccsc1C1=NC(C)(C)CO1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4.5 g of 4,5-dihydro-4,4-dimethyl-2-(2-thienyl)-oxazole in 200 ml of anhydrous ether at -70° C. is added 11 ml of a 2.5M solution of n-butyl lithium in hexane, dropwise under a nitrogen atmosphere. The reaction mixture is stirred at -78° C. for 45 minutes and 8.3 g of tri-n-butyltin chloride in dry ether added dropwise. The reaction mixture is stirred at room temperature for 1 hour and quenched with water. The reaction mixture is extracted with ether, washed with water, dried over sodium sulfate and concentrated in vacuo to an oily residue.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH:9]([CH2:11][O:12]CC2C=CC=CC=2)[O:8][CH:7]([CH2:20][O:21][CH2:22][C:23]([N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[O:24])[CH2:6]1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.C(Cl)(Cl)Cl.[Pd]>[CH2:1]([N:5]1[CH2:10][CH:9]([CH2:11][OH:12])[O:8][CH:7]([CH2:20][O:21][CH2:22][C:23]([N:25]([CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH3:31])=[O:24])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CC(COCC(=O)N(CCC)CCC)OC(COCc2ccccc2)C1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCN1CC(CO)OC(COCC(=O)N(CCC)CCC)C1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a solution of 10.86 g of 2-[[4-butyl-6-[(phenylmethoxy)methyl]-2-morpholinyl]methoxy]-N,N-dipropylacetamide (0.025 mole) in 125 ml of glacial acetic acid is added 4.0 g of 10% Pd/C and the mixture is hydrogenated at 50 psi at 60° over a period of 28 hours (debenzylation taking up 94% of the calculated theory). The mixture is cooled to room temperature and the Pd/C removed via filtration through a pad of "celite" filter aid. The acetic acid is removed in vacuo yielding a pale yellow oil. The oil is taken up in 200 ml of chloroform and washed with 100 ml of saturated NaHCO3 solution. The CHCl3 layer is separated, dried over anhydrous Na2SO4 and then the CHCl3 is removed in vacuo yielding 8.2 g (95%) of crude product as a dark brown oil. The oil is chromatographed on 150 g of neutral Alumina III to give 0.5 g of forerun (eluted with 100 ml of chloroform) and 7.6 g (88%) of the desired product (eluted with 400 ml of chloroform and 200 ml of 2% methanolic chloroform). The 7.6 g of product is dried in vacuo to give the desired product, a dense yellow-orange oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1)[CH3:2].[C:8]1([OH:18])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[OH-].[K+]>>[C:8]1([O:18][CH2:4][CH:5]([OH:7])[CH2:6][NH:3][CH2:1][CH3:2])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CCN1CC(O)C1
Reactant: Oc1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Product: CCNCC(O)COc1cccc2ccccc12
Temperature: 160 °C
Yield: 70 %

Procedure:
To a mixture of 10.2 parts of 1-ethyl-3-azetidinol and 14.4 parts of α-naphthol 0.2 part of potassium hydroxide was added, and the mixture was heated under nitrogen gas at 160° C. for 18 hours. The reaction mixture was cooled and extracted with ether. The ether extract was washed with 2 N-NaOH aqueous solution and then with water. The liquor was dried over anhydride sodium sulfate and the solvent was distilled off. The residue was recrystallized from cyclohexane to yield 17.2 parts of 1-(α-naphthoxy)-3-ethylamino-2-propanol. The melting of the product was 106°-107° C. The yield was 70%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9]Br.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Fc1ccc(CBr)c(Br)c1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(CN2CCOCC2)c(Br)c1
Temperature: 81 °C
Yield: 95.5 %

Procedure:
Combine 2-bromo-1-bromomethyl-4-fluoro-benzene (4 g, 14.9 mmol), morpholine (2.6 mL, 29.8 mmol), and diisopropylethylamine (5.2 mL, 29.8 mmol) in acetonitrile (10.0 mL). Heat the reaction mixture at 81° C. for 2 h and cool to RT. Remove the solvent under reduced pressure. Dilute with DCM and wash with water and then aqueous saturated sodium chloride. Dry the organics over sodium sulfate. Filter and remove the solvent under reduced pressure to obtain the title compound (3.9 g, 95%). LCMS (ES) m/z 274 [M+1]+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.[OH-].[Na+]>CC#N.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:10][C@@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(O)[C@H]1CC[C@@H](Nc2nc(Cl)nc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of cyanuric chloride (493.65 mg, 2.7 mmol, 1 equivalent) in CH3CN/H2O (1/1, 20 ml) was cooled to 0° C. cis-4-aminocyclohexylcarboxylic acid (283.26 mg, 2.7 mmol, 1 equivalent) was added, followed by 1N NaOH (10.7 ml, 2 equivalents). The reaction was stirred at 0° C. for 15 min. LCMS analysis showed the complete consumption of the 2,4,6-trichloro-1,3,5-triazine. The crude product was used in the next step.
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[NH:26][CH2:27][C:28](O)=[O:29])[CH:21]=[CH:22][CH:23]=1.S(Cl)(Cl)=O>>[CH3:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[NH:26][CH2:27][C:28]([N:1]([CH2:8][C:9]([O:11][CH2:12][C:13]([F:14])([F:15])[F:16])=[O:10])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:29])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: O=C(CNc1ccccc1)OCC(F)(F)F
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OCC(F)(F)F)c2ccccc2)c1
Yield: 14.4 %

Procedure:
The procedure is carried out in a manner analogous to that described in Example 1, but using 2.3 g of 2,2,2-trifluoroethyl 2-anilinoacetate, 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 0.7 cm3 of thionyl chloride as starting materials. The product obtained is purified by chromatography on 40 g of silica (0.063-0.200 mm) contained in a column 1.5 cm in diameter [eluent: methylene chloride/ethanol (98/2 by volume)], collecting 10-cm3 fractions. Fractions 5 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from diisopropyl ether, 0.6 g of 2,2,2-trifluoroethyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 172° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:15](OCC)(OCC)OCC>>[F:10][C:8]([F:11])([F:9])[C:6]1[CH:5]=[N:4][C:3]2[C:12](=[O:13])[NH:14][CH:15]=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1ncc(C(F)(F)F)cc1N
Product: O=c1[nH]cnc2cc(C(F)(F)F)cnc12
Temperature: 120 °C
Yield: 83.7 %

Procedure:
A vial was charged with 3-amino-5-(trifluoromethyl)picolinamide (615 mg, 3.00 mmol) and triethyl orthoformate (2496 μl, 14.99 mmol). The vial was sealed and the mixture was heated at 120° C. for 17 h. Upon cooling, the heterogeneous mixture was filtered and the solids were washed with heptane. 7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one (540 mg, 2.51 mmol, 84% yield) was isolated as a tan solid. LC/MS (ESI+) m/z=216.0 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]([CH:38]([CH3:40])[CH3:39])=[CH:26][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][NH2:42]>C(O)C>[CH2:1]([O:8][C:9]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]([CH:38]([CH3:40])[CH3:39])=[CH:26][C:10]=1[C:11](=[N:41][NH2:42])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)c1cc(C(=S)Nc2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CCO
Product: CC(C)c1cc(C(=NN)Nc2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
2,4-bis-benzyloxy-5-isopropyl-N-[4-(morpholin-4-yl)-phenyl]thiobenzamide (F370-IM3; crude product, 4.2 g) was suspended in ethanol (30 mL), mixed with 80% aqueous hydrazine solution (15 mL) and heated under reflux for 4 hours. At this time, it was observed that the suspension was decolored and became a homogeneous solution. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue thus obtained (crude F370-IM4) was used for the next reaction without purification.
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([C:17]([OH:20])([CH3:19])[CH3:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:21]I>C(Cl)Cl>[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([C:17]([O:20][CH3:21])([CH3:19])[CH3:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(O)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Agent: N#N
Solvent: ClCCl
Product: COC(C)(C)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)propan-2-ol (153 mg, 0.56 mmol) in CH2Cl2 (0.4 mL) was treated with MeI (0.08 mL, 1.35 mmol) followed by Ag2O (196 mg, 0.85 mmol). The resulting mixture (protected form light) was stirred overnight at 40° C. The reaction mixture was filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as an orange oil. TLC: rf (7:3 hept-EA)=0.40. LC-MS-conditions 07: tR=0.99 min, [M+H]+=286.20.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[CH3:16][C:17]1[N:18]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:20][CH:21]=1>>[OH:14][CH:3]1[CH:4]([N:20]2[CH:21]=[C:17]([CH3:16])[N:18]=[C:19]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]1([CH3:15])[CH3:1]
Reactant: Cc1c[nH]c(-c2ccccc2)n1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: Cc1cn(C2c3cc(C#N)ccc3OC(C)(C)C2O)c(-c2ccccc2)n1

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 4-methyl-2-phenyl-1H-imidazole as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:42])[N:16]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5])[CH3:3].[C:43]([NH:53][CH2:54][C:55](O)=[O:56])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>>[C:43]([NH:53][CH2:54][C:55]([NH:1][C@@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:42])[N:16]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5])[CH3:3])=[O:56])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](C)N
Product: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](C)NC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-D-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-dodecyl-dodecanamide and N-carbobenzoxy-glycine.