Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[C:12]([C:13]([O:15]C)=[O:14])[C:6]=2[N:5]=1.O.[OH-].[Li+].O.Cl>CO>[CH3:1][O:2][CH2:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:6]=2[N:5]=1
Reactant: COCc1nc2c(C(=O)OC)cc([N+](=O)[O-])cc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1nc2c(C(=O)O)cc([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
To a suspension of methyl 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylate (Example 11, Step 3) (4.8 g) in MeOH (120 mL), were added lithium hydroxide hydrate (4.56 g) and water (54 mL). The mixture was stirred at room temperature for 16 hours. Under ice-cooling, 1N hydrochloric acid was added slowly to the reaction mixture to adjust the pH to about 2. The precipitate was collected by filtration and dried to obtain 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid (4.6 g). To the solution of 2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxylic acid (4.6 g) in DMF (90 mL), HBTU (8.23 g), triethylamine (2.19 g) and 3-chloro-2-methylaniline (3.07 g) were added sequentially, and the solution was stirred for 18 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate and stirred for 1 hour. The precipitate was collected by filtration and washed sequentially with water and ethyl acetate to obtain N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide (7.2 g) as pale yellow powder. To the solution of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-nitro-1H-benzimidazole-4-carboxamide (7.2 g) in MeOH-THF (1:1, 120 mL), were added 1% platinum+0.1% copper-activated carbon (Degussa type CF105 R/W) (1.4 g). The mixture was stirred under hydrogen atmosphere (3 atm) for 4 hours. The catalyst was filtered off, and the mother liquid was concentrated. The residual solid was washed with ethyl acetate to obtain 6-amino-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (5.1 g) as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][N:12]([CH3:25])[C:13]([C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)=[O:14]>Cl>[CH3:11][N:12]([CH3:25])[C:13]([C:15]1[CH:16]=[C:17]([S:21]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)=[O:14]
Reactant: COC(=O)c1sccc1N
Reactant: CN(C)C(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Product: COC(=O)c1sccc1NS(=O)(=O)c1cccc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
Methyl 3-aminothiophene-2-carboxylate (93 mg, 0.592 mmol) was dissolved in Py (1.5 ml). 3-(dimethylcarbamoyl)benzene-1-sulfonyl chloride (220 mg, 0.887 mmol) was added, and the reaction was stirred at RT for 3 hrs to achieve completion. The reaction mixture was diluted with HCl 1N and extracted with AcOEt. The organic phase was washed with HCl 1N and brine, dried over Na2SO4 and concentrated under vacuum to give methyl 3-(3-(dimethylcarbamoyl)phenylsulfonamido)thiophene-2-carboxylate (Int. 79, 200 mg, 0.543 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH:8]=[CH:9][S:10]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:25]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH:8]=[CH:9][S:10]([N:13]=[C:14]([Cl:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(C=CS(=O)(=O)N=C(Cl)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A suspension of N-(4-nitrostyrylsulfonyl)benzamide (14.9 g., 0.045 mole) in 500 ml. of dry benzene is refluxed and stirred with phosphorus pentachloride (10.4 g., 0.05 mole) for 8 hr. The reaction mixture after standing overnight at 25° C. provides 8.2 g. of solid, m.p. 158°-166° C. Concentration of the mother liquor to about 100 ml. provides an additional 2.5 g. of solid, m.p. 158°-161° C. The combined crude solid crystallized from ethyl acetate affords analytically pure N-(4-nitrostyrylsulfonyl)benzimidoyl chloride, m.p. 168°-175° C.
Reaction SMILES: [C:1]1([C:7](=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+]>C(O)CO>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C=C(C(=O)O)c2ccccc2)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: COc1cc(C=Cc2ccccc2)ccc1O
Yield: 69 %

Procedure:
A mixture of α-phenyl-4-hydroxy-3-methoxy cinnamic acid (0.0083 mol), NaHCO3 (10%, 5 mL) methylimidazole (2 mL) and ethylene glycol (15 mL) were taken in a 250 mL round bottom flask fitted with reflux condenser. The flask was shaken well and placed on the heating mental and refluxed for 12 h. After completion of reaction, the reaction mixture was worked (yield 69%) as in example I. Spectral data as given in example I.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16](O)=[O:17])[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[OH:17][CH2:16][C:9]1[S:10][C:11]([C:12]([F:15])([F:13])[F:14])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Solvent: C1CCOC1
Product: OCc1cc(-c2ccccc2)c(C(F)(F)F)s1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A solution of 2.10 g (7.7 mmol) of 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid (Step C) in 20 mL of THF was treated with 5.0 mL of 2.0 M borane dimethylsulfide complex in THF. The resulting solution was heated at reflux for 3 h, cooled to rt, quenched with 10 mL of MeOH and concentrated. Chromatography on a Biotage 40M cartridge using 9:1 v/v hexanes/ethyl acetate as the eluant afforded 1.95 g (98%) of the title compound: 1H NMR (500 MHz) δ 2.05 (app s, 1H), 4.87 (s, 2H), 6.99 (s, 1H), 7.41 (app s, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:33])[NH:12][C:11]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CBr)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Yield: 69.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (1.23 g, 3 mmol) was reacted with NBS (0.54 g, 3 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (1.02 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: S([O-])(=O)(=O)C.CS(O[CH2:11][C:12]([O:24][CH:25]([CH3:27])[CH3:26])([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[CH2:13][CH2:14][CH3:15])(=O)=O.[Na].[NH:29]1[CH:33]=[N:32][CH:31]=[N:30]1>CS(C)=O>[N:29]1([CH2:11][C:12]([O:24][CH:25]([CH3:27])[CH3:26])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH2:13][CH2:14][CH3:15])[CH:33]=[N:32][CH:31]=[N:30]1
Reactant: c1nc[nH]n1
Reactant: CCCC(COS(C)(=O)=O)(OC(C)C)c1ccc(Cl)cc1Cl
Agent: CS(=O)(=O)[O-]
Agent: [Na]
Solvent: CS(C)=O
Product: CCCC(Cn1cncn1)(OC(C)C)c1ccc(Cl)cc1Cl
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The mesylate prepared in accordance with (a) is dissolved in 100 ml of absolute dimethyl sulfoxide, and 3.2 g (35 mmoles) of the sodium salt of 1,2,4-triazole are added. The reaction mixture is stirred for 8 hours at a bath temperature of 120° C. and is then cooled to room temperature and poured into ice water, and the mixture is extracted twice with ethyl acetate. The combined extracts are washed 4 times with half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified by column chromatography (silica gel; 1:1 ethyl acetate/petroleum ether) and affords a colourless oil. n50D =1.5299. 100 MHz -1H-NMR (CDCl3): δ=7.75 and 7.65 ppm (s, 2H of triazole); 7.1-7.6 ppm (m, 2H, aromatic); 4.85 ppm (dd, 2H, CH2 -N); 4.0 ppm (m, 1H, --CH(CH3)2); 0.8-2.6 ppm (m, 14H, --CH(CH3)2, --CH2 --CH2 --CH3);
Reaction SMILES: [OH:1][CH:2]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:33])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl>[OH:1][CH:2]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:33])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][S:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:42]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CCCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CSc1ccccc1
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CS(=O)c1ccccc1

Procedure:
(2S)-2-[1-Hydroxy-2-(phenylthio)ethyl]-1-[N-(4-phenyl-butyryl)-L-prolyl]pyrrolidine (1.25 g) was subjected to oxidation in the same manner as in Example 2-A) in dichloromethane (9 ml) using 1.1 equivalent of m-chloroperbenzoic acid to give 1.18 g of (2S)-2-[1-hydroxy-2-(phenylsulfinyl)ethyl]-1-[N-(4-phenylbutyryl)-L-prolyl]-pyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1cccnc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (5-fluoro-2-nitrophenyl)pyridin-3-ylamine (2.21 g, 9.5 mmol) in EtOAc (65 mL) was added to a slurry of palladium on carbon (10% by wt, 220 mg) in EtOAc (10 mL) under N2. The reaction mixture was stirred at RT under an atmosphere of hydrogen for 16 h. The mixture was filtered through Celite® and the filtrate concentrated in vacuo to give the title compound as a white solid that turned red upon standing (1.83 mg, 95%). LCMS (Method B): RT 0.81 min [M+H]+ 204. 1H NMR (CDCl3, 400 MHz): δ 8.23 (1H, dd, J=3.0, 1.0 Hz), 8.13 (1H, dd, J=4.5 1.5 Hz), 7.15 (1H, ddd, J=8.0, 4.5, 0.5 Hz), 7.10 (1H, ddd, J=8.5, 2.5, 1.5 Hz), 6.85 (1H, dd, J=9.5, 2.5 Hz), 6.76-6.68 (2H, m), 5.50 (1H, bs), 3.56 (2H, bs).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:17]=2)[N:12]=[C:11](Cl)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[NH:27][NH2:28]>C(#N)C>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH:17]=2)[N:12]=[C:11]([NH:28][NH:27][C:26]([O:30][CH2:31][CH3:32])=[O:29])[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)NN
Reactant: O=c1c(Cl)nc2ccc(-n3ccnc3)cc2n1OCc1ccccc1
Solvent: CC#N
Product: CCOC(=O)NNc1nc2ccc(-n3ccnc3)cc2n(OCc2ccccc2)c1=O
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 4-benzyloxy-2-chloro-6-(1H-imidazol-1-yl)-quinoxalin-3(4H)-one (9.4 g; ~27.6 mmol) in 500 ml acetonitrile was added ethyl carbazate (28 g; ~270 mmol). The reaction mixture was refluxed overnight. Cooling to room temperature gave the title compound (11.1 g; 99%) as a precipitate. M.p. 197°-199° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:14])=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH3:14])=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(C)n[nH]c(=O)c2c1
Product: COc1ccc2c(C)nnc(Cl)c2c1
Temperature: 120 °C
Yield: 100 %

Procedure:
The solution of 7-methoxy-4-methyl-2H-phthalazin-1-one (3) in POCl3 (15 mL) is heated at reflux (120° C.) for 3 h 50 min and then cooled to room temperature. Unreacted POCl3 is removed at reduced pressure followed by azeotroping with toluene (2×10 mL). The residue is diluted with sat. NaHCO3 (60 mL) and extracted with dichloromethane (200 mL, 60 mL, and 50 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is dried under high vacuum to give 2.08 g (100%) of 4 as a yellow solid, mp 151-153° C. IR 2968, 1613, 1218 cm−1; 1H NMR (CDCl3) δ 2.97 (s, 3H, CH3), 4.07 (s, 3H, CH3O), 7.50-7.59 (m, 2H, 6,8-PhthH), 8.01 ppm (d, J=8.7 Hz, 1H, 5-PhthH).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CC(CC)=O>[CH2:22]([N:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[CH2:6][C:5]1[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:21]=[CH2:20]
Reactant: Clc1ccc(CC2CCCN2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCN1CCCC1Cc1ccc(Cl)cc1

Procedure:
Boil 5 g of 2-(4-chlorobenzyl)pyrrolidine, 3.53 g of anhydrous potassium carbonate, 3.4 g of allyl bromide and 50 ml of ethyl methyl ketone under reflux for 1 hour. Evaporate off the solvent. Take up the residue with 50 ml of water and extract 3 times with, in each case, 30 ml of diethyl ether. Combine the ether phases and dry them over sodium sulfate. Distil off the solvent from the combined ether extract and distil the resulting residue under a vacuum to obtain 5.12 g (85% of theory) of the title compound (b.p. 84° to 87° at 0.005 mm of Hg). m.p. of the picrate (from ethanol): 115° to 117°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].[NH4+].[Cl-].O>CCO.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([NH2:9])[C:3]=1[CH3:12]
Reactant: Cc1c(Br)ccc(F)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1c(Br)ccc(F)c1N
Yield: 76.5 %

Procedure:
To a solution of 1-bromo-4-fluoro-2-methyl-3-nitro-benzene (3 g, 12.82 mmol, 1.0 eq) in EtOH (60 mL) was added NH4Cl (30 mL), water (30 mL) and iron powder (2.87 g, 51.28 mmol, 4.0 eq). The reaction mixture was heated at reflux for 3h, then filtered through Celite. The filtrate was evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as a yellow solid (2 g, 77%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:24]1[CH2:25][CH2:26][CH2:27][CH:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[CH2:23]1
Reactant: COc1ccccc1C1CCCNC1
Reactant: BrCC1COc2ccccc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccccc1C1CCCN(CC2COc3ccccc3O2)C1
Temperature: 130 °C
Yield: 23.6 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (34 mg, 0.15 mmol), 3-(2-methoxyphenyl)piperidine HCl (38 mg, 0.165 mmol) and triethylamine (41 mg, 0.39 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 110-150° C. for 90 min. After evaporation to dryness, the crude product was purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 12 mg of the title compound.
Reaction SMILES: [CH:1](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)(O)[O-:20].[K+].OO>CO>[CH2:2]([CH:1]1[O:20][C:8]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C([O-])O
Reactant: CCCCCCC=C(C(=O)OCC)C(=O)OCC
Agent: OO
Agent: [K+]
Solvent: CO
Product: CCCCCCC1OC1(C(=O)OCC)C(=O)OCC
Reaction time: 16 h

Procedure:
A mixture of 31 g of diethyl heptylidenepropanedioate (B. Wojcik and H. Adkins, J. Am. Chem. Soc., 56, 2424 (1934), prepared by the method of A. C. Cope and K. E. Hoyle, J. Am. Chem. Soc., 63, 733 (1941)), 5 g of potassium bicarbonate and 17 g of 30% hydrogen peroxide in 200 ml of methanol was stirred for two hours at 40° C., then allowed to stand at 20° C. for 16 hours. The mixture then was concentrated to 50 ml; 100 ml of water was added and the solution was extracted with two 50-ml volumes of methylene chloride. The solvent was evaporated to give a colorless liquid, which was vacuum distilled to give diethyl 3-hexyloxiranedicarboxylate (2A), bp: 117°-126° C. at 0.1 Torr.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:21][NH2:22])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:21][NH:22][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[CH3:1])=[CH:16][CH:15]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: COc1ccc(C(CN)N2CCCCC2)cc1
Product: COc1ccc(C(CNC(=O)c2cccc(C)c2C)N2CCCCC2)cc1

Procedure:
From 2,3-dimethylbenzoic acid and 2-(4-methoxy-phenyl)-2-piperidin-1-yl-ethylamine.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([OH:16])[CH:15]=1)[C:11]#[N:12].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([OH:16])[CH:15]=1)[C:11]#[N:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(O)cc(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
Caesium carbonate (2.41 g, 7.4 mmol) was added to a solution of 3,5-dihydroxy benzonitrile (1.0 g, 7.4 mmol) in dimethylformamide (5 ml) at room temperature and the mixture stirred for 10 minutes. Benzyl bromide (0.880 ml, 7.4 mmol) was added dropwise and the mixture heated at 80° C. for 30 minutes. The solvent was removed in vacuo, the residue treated with water (10 ml), acidified with aqueous hydrochloric acid (2M) and extracted with ethyl acetate (3×25 ml). The combined organic layers were washed with water (2×10 ml), brine (10 ml), dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/pentane (20:80 to 50:50) to afford the title compound as a white solid in 26% yield, 445 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]Cl)([O-:15])=[O:14]>CN(C)C=O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]([CH3:12])[S:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])=[O:10])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: CNC(=O)Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN(Sc1ccccc1[N+](=O)[O-])C(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
N-4-chlorophenyl-N'-methyl urea (4.1 g) was dissolved in a mixture of dimethylformamide (20 ml) and pyridine (5 ml) and then 2-nitrophenylthiochloride (4.17 g) was added to and dissolved in the solution. After allowing the solution to stand overnight, it was poured into 200 ml of ice-water. The initial product was an oily product which solidified after a while. The solid product was separated by filtration, washed with water and dried. Recrystallization from a mixture of ethyl acetate and n-hexane gave 4.3 g of the object compound. (m.p.: 157°-158° C.)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:33]([NH2:41])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:33]([NH:41][C:28]1[N:27]=[C:26]([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[CH2:19][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[S:15]([CH3:18])(=[O:16])=[O:17])[CH:31]=[CH:30][N:29]=1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Reactant: NCCc1ccccc1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3ccccc3)n2)c1)C1CCNCC1

Procedure:
Intermediate 30 was coupled with phenethylamine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 466. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H), 8.1 (d, 2H) 7.7 (d, 2H) 7.5 (t, 2H), 7.2 (m, 3H), 7.1 (d, 1H), 4.6 (s, 2H), δ 3.4 (t, 2H), 3.09 (s, 3H), δ 3.05 (m, 7H), 2.0 (m, 4H).
Reaction SMILES: [CH3:1][C:2](=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:15][CH2:16][CH:17]([CH2:19][OH:20])O.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[OH:15][CH2:16][CH:17]1[CH2:19][O:20][C:2]([CH3:1])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:14]1
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCC1(C)OCC(CO)O1
Temperature: 25 °C

Procedure:
Firstly, 100 g (0.5 mol) of 2-tridecanone (Aldrich P/N 17,283-9), 56 g (0.6 mol) of glycerol (Aldrich P/N 32,00-5), 200 mL of benzene, and 1.8 grams of p-toluenesulfonic acid (Aldrich P/N 40,2885) were placed in a 500 mL round bottom flask fitted with a Dean Stark apparatus. The mixture was heated to reflux with stirring until no further separation of water appeared. The reaction mixture was cooled to room temperature and washed successively with a 100 mL portion of 5% sodium carbonate solution and three 100 mL portions of water. The organic layer was dried over sodium sulfate, filtered and the benzene was removed with a rotary evaporator. The residual oil was fractionated by distillation under reduced pressure to give the desired product (b.p. 140° C./0.3 mm Hg). The identity of the product was confirmed by 1H NMR in CDCl3.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:25]4)=[N:22][CH:23]=2)=[N:3][C:2]([C:43]2[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 59.1 %

Procedure:
Following general procedure II, (S)-tert-butyl 1-{5-[6-chloro-3-(cyclopropanecarbonyl)-1,5-naphthyridin-4-ylamino]pyridin-2-yl}piperidin-3-ylcarbamate (98 mg, 0.19 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (87 mg, 0.30 mmol) to afford the desired product (73 mg, 60%) as a red-brown solid: 1H NMR (500 MHz, CDCl3) δ 11.55 (br s, 1H), 9.29 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.46 (s, 2H), 7.32 (dd, J=9.0, 2.8 Hz, 1H), 6.67 (d, J=9.0 Hz, 1H), 4.78-4.72 (m, 1H), 3.87-3.69 (m, 3H), 3.29-3.07 (m, 2H), 2.79-2.71 (m, 1H), 1.98-1.69 (m, 2H), 1.45 (s, 9H), 1.31-1.22 (m, 2H), 1.16-1.06 (m, 2H); ESI MS m/z 649 [M+H]+