Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[N:35]=[C:34](CN)[CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C1(O)C=CC=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)[N:35]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: CN1CCC(Oc2cccc(CN)n2)CC1
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: CN1CCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (1.39 g, 4.29 mmol) and 1-{6-[(1-methylpiperidin-4-yl)oxy]pyridin-2-yl}methanamine (0.950 g, 4.29 mmol, from step b above) were mixed with 4 g of phenol and heated to 130° C. on an oil bath for 1 h. When the mixture had cooled down it was diluted with 150 mL of diethyl ether. The mixture became opaque and left overnight. Very little had precipitated but when evaporation of ether was commenced much precipitate was formed and filtered off. The material was recrystallized from ethanol, filtered, washed with ethanol and dried to give 0.675 g (32%) of the desired compound. Mp 202-203° C. 1H NMR (600 MHz, CD3OD) δ 8.43 (s, 1H), 7.75 (m, 2H), 7.65 (s, 1H), 7.60 (t, 1H), 7.45 (m, 2H), 6.95 (d, 1H), 6.55 (d, 1H), 5.30 (s, 2H), 4.55 (br, 1H), 2.52 (m, 2H), 2.05 (s, 3H), 1.84 (m, 2H), 1.70 (m, 2H), 1.51 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 162.7, 157.9, 157.0, 151.9, 151.6, 149.1, 140.1, 135.9, 131.7, 129.7, 127.9, 123.0, 121.1, 115.7, 111.2, 51.4, 50.3, 44.6, 28.7, 22.1. MS (ESI+) 467/469 (M+1H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH2:16])[CH3:15].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH:16][CH2:22][C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)[CH3:15]
Reactant: CC(N)COc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccco1
Product: CC(COc1ccc2ccccc2c1Cl)NCc1ccco1
Yield: 85 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]propan-2-amine and furan-2-carbaldehyde in 85% yield as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:10]3=[N:11][CH:12]=[CH:13][C:14]([S:15][CH3:16])=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:33]=1.[OH:34]O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[C:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:23]3)[C:10]3=[N:11][CH:12]=[CH:13][C:14]([S:15]([CH3:16])=[O:34])=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:33]=1
Reactant: OO
Reactant: CSc1ccnc2c1CCc1cc(Cl)ccc1C2=C1CCN(C(=O)Cc2cccnc2)CC1
Solvent: C1CCOC1
Product: CS(=O)c1ccnc2c1CCc1cc(Cl)ccc1C2=C1CCN(C(=O)Cc2cccnc2)CC1
Temperature: 73 °C
Reaction time: 12 h

Procedure:
To the title compound from Example 255 (0.18 grams) dissolved in anhydrous THF (10 mL) was added 30% aqueous hydrogen peroxide (3 mL) and the resulting solution was stirred for 12 hours at 73° C. The solution was concentrated in vacuo, diluted with CH2Cl2, and washed with water. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the title compound after preparative plate chromatography (silica gel) using 3% MeOH-CH2Cl2 (0.04 grams, 26%, MH+ 492).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[NH2:3].[CH2:13]([O:15][CH:16]=[C:17]([C:20]#N)[C:18]#[N:19])C.[O-:22]CC.[Na+].O>CCO>[CH3:13][O:15][C:16]([C:17]1[CH:20]=[N:3][N:2]2[C:4]3[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:6](=[O:8])[NH:19][C:18]=12)=[O:22]
Reactant: CC[O-]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cnn2c1[nH]c(=O)c1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-hydrazinylbenzoic acid hydrochloride (10 g, 53 mmol), 2-(ethoxymethylene)malononitrile (6.5 g, 53.2 mmol) and sodium ethoxide (4.85 g, 257 mmol) in EtOH (100 mL) was refluxed overnight then cooled to ambient temperature. Water was added and the mixture was stirred at ambient temperature for 1 h then filtered. The solid was washed with H2O, EtOH and Et2O then dried.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C([O-])(=O)C.[Na+]>C(O)C>[C:12]1([CH3:15])[CH:13]=[CH:14][C:9]([NH:8][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:10][CH:11]=1
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1ccc(C)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
Ethyl bromoacetate (4.0 g, 30.0 mmol) was added to a solution of p-toluidine (2.1 g, 20 mmol) and sodium acetate (2.1 g, 26 mmol) in ethanol (26 mL). The resulting solution was warmed to 80° C. and stirred for 1 h before being cooled to room temperature. The reaction was quenched with water (20 mL) and the aqueous fraction extracted with ethyl acetate (3×20 mL). The organic fractions were combined, dried (MgSO4) and filtered, and the solvent was removed under reduced pressure. Silica chromatography (0-20% ethyl acetate/hexane) provided ethyl 2-(p-tolylamino)acetate as a pale oil (1.9 g, 50%). Ethyl 2-(p-tolylamino)acetate (260 mg, 1.4 mmol) was dissolved in toluene (5 mL). Methyl benzylisocyanate (200 mg, 1.4 mmol) was added to this solution. The mixture was heated to reflux and stirred for 5 h, until TLC analysis demonstrated that the reaction was complete. The reaction mixture was then cooled to room temperature, and the solvent was removed under reduced pressure. Silica chromatography (0-20% ethyl acetate/hexane) provided ethyl 2-[3-(4-methylbenzyl)-1-p-tolylureido]acetate as a pale oil (455 mg, 98%). Ethyl 2-[3-(4-methylbenzyl)-1-p-tolylureido]acetate (455 mg, 1.3 mmol) was dissolved in THF (10 mL) and added dropwise to a solution of NaH (68 mg, 2.8 mmol) in THF (10 mL) at 0° C. The reaction mixture was allowed to warm to room temperature slowly and stirred for 18 h before the reaction was quenched with water (5 mL). The aqueous fraction was then extracted with dichloromethane (3×20 mL). The organic fractions were combined, dried (MgSO4), and filtered, and the solvent was removed under reduced pressure. Column chromatography (0-20% ethyl acetate/hexane) provided 14 as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][C:9]1=2)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.CCOC(C)=O>[N:29]([CH2:6][CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][C:9]1=2)=[N+:30]=[N-:31]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCOS(C)(=O)=O)c3ccccc23)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCN=[N+]=[N-])c3ccccc23)CC1
Temperature: 60 °C
Reaction time: 14.5 h
Yield: 94.3 %

Procedure:
tert-Butyl 6-{2-[(methylsulfonyl)oxy]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.224 g, 0.549 mmol) and NaN3 (0.357 g, 5.49 mmol, 10.0 equiv.) were dissolved in DMF (2.5 mL) and the solution was stirred at 60° C. under N2 for 14.5 h. The reaction mixture was taken up in EtOAc and washed with water (2×15 mL). The aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated. The crude product (0.214 g) was chromatographed (SiO2 25 g, eluted with 3:1 hexane:EtOAc) to give tert-butyl 6-(2-azidoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.184 g) in 94% yield. 1H NMR (300 MHz, CDCl3) δ 1.51, 2.99-3.10, 3.60, 3.66-3.84, 4.26, 7.14, 7.21, 7.27, 7.51; MS (ESI+) for C19H25N5O2 m/z 356.2 (M+H)+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.F[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[C:14]([F:21])[N:13]=1>C1(C)C=CC=CC=1>[F:21][C:14]1[N:13]=[C:12]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(F)nc1N1CCc2ccccc2C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
1,2,3,4-Tetrahydroisoquinoline (34.8 ml, 0.28 mol) was added to a solution of 2,6-difluoro-3-nitropyridine (44.55 g, 0.28 mol) prepared in Step 1 in toluene (200 ml). The reaction mixture was stirred overnight at 60° C. and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/n-hexane=1/4, v/v) to give 5.38 g of the titled compound as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[NH:13][CH:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=1
Reactant: COC(=O)c1c[nH]c(Sc2ccccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1Sc1cc(C(=O)O)c[nH]1

Procedure:
Methyl 5-(2-methylphenylthio)pyrrole-3-carboxylate (1.1 g.) was combined with 20 ml. of 1 N sodium hydroxide and 50 ml. of methanol and refluxed for 2.5 hours, at which time thin layer chromatography with hexane-5/ethyl acetate-1/5% acetic acid as eluant indicated reaction to be complete. Methanol was removed by evaporation, the aqueous residue was diluted with approximately one volume of water, and extracted with ether. The aqueous phase was acidified with 6 N hydrochloric acid and the product extracted into ethyl acetate. The ethyl acetate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to crude product (1.0 g.). Recrystallization from methylene chloride/hexane gave purified 5-(2-methylphenylthio)pyrrole-3-carboxylic acid (590 mg., m.p. 151°-153° C., m/e 233).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si](C)(C)[N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>C1COCC1.O>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][CH:17]2[CH2:18][CH2:19][NH:15][C:16]2=[O:20])=[CH:26][CH:25]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=C1NCCC1Cc1ccc(Cl)cc1
Temperature: -76 °C
Reaction time: 0.17 h
Yield: 19.5 %

Procedure:
In a flask was added diisopropylamine (3.22 g, 31.8 mmole) and dry THF (60 ml). The content of the flask was kept under nitrogen, and was then cooled to −76° C. To the cool solution was dropwise added n-butyllithium (n-BuLi, 32 mmole, 20 ml, 1.6 M in hexane). After completed addition, the solution was stirred for 10 minutes, and a solution of 1-Trimethylsilanyl-pyrrolidin-2-one (5.00 g, 31.8 mmole, prepared according to literature methods) in dry THF (5 ml) was added dropwise. The solution was then stirred for an additional 20 minutes and a solution of 4-Chlorobenzyl chloride (5.13 g, 32 mmole) in THF (5 ml) was added via a syringe during 5 minutes. The resulting mixture was stirred at −76° C. for 1 hour, and was then allowed to reach the ambient temperature and was stirred over night. Water (40 ml) was added and the mixture was stirred vigorously for 60 minutes. The phases were separated and the organic phase was washed with brine, and was finally evaporated, giving an oil which crystallized on standing. The solid was triturated with heptane:EtOAc 2:1 and was filtered, giving a partly purified solid. The solid was purified on silica (DCM to DCM:MeOH 99:1 to 98:2 to 97:3 gradient) giving 1.3 g (20%) of the sub-title compound.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[C:14]2[C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]([CH3:18])([CH3:17])[C:9]=2[CH:8]=CC=1CO.[CH2:23]1C[O:26][CH2:25][CH2:24]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:24]([CH:25]([C:3]1[CH:4]=[CH:5][C:14]2[C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]([CH3:17])([CH3:18])[C:9]=2[CH:8]=1)[OH:26])#[CH:23]
Reactant: CC1(C)CCC(C)(C)c2c1ccc(CO)c2C#C[Si](C)(C)C
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 1 h

Procedure:
29.9 g (92.5 mmol) of α-trimethylsilylethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol and 100 ml of THF were introduced into a round-bottomed flask and 103.8 ml (114.2 mmol) of a tetrabutylammonium fluoride solution (1.1M in THF) were added dropwise. Stirring was carried out at room temperature for one hour and the reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of ethyl acetate and hexane (1/4). After evaporating the solvents, 18.1 g (79%) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol, with a melting point of 56°-57° C., were recovered.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].S(Cl)([Cl:17])=O>>[N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:17])=[O:14])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=NCc1ccc(CC(=O)O)cc1
Product: [N-]=[N+]=NCc1ccc(CC(=O)Cl)cc1

Procedure:
By stirring a mixture of the thus obtained p-azidomethylphenylacetic acid in thionyl chloride at room temperature for 20 hours the corresponding acid chloride is obtained after removal of the excess reagent under high vacuum at room temperature.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:21])[CH2:14][CH2:15]CSCCS)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:24]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:21])[CH2:14][CH:15]=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCOCc1ccccc1)CCCSCCS
Reactant: CC(C)=O
Product: O=CCC(=O)CCCCOCc1ccccc1

Procedure:
0.135 mole=44 g of 7-benzyloxy-1-(2,5-dithiapentyl)-heptane-3-one were heated for 1 hour under nitrogen and under reflux in 1 liter of acetone with [0.275 mole]=47 g of CuCl2 . 2 H2O and [0.57 mole]=44 g of CuO, the copper salts were filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ether, washed twice with 2N- HCl and thrice with water, dried and the solvent was removed by distillation under reduced pressure. The residue was distilled under reduced pressure. B.p.0.5 mm 185°-192° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:14])=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1.[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[CH:15]([NH:1][C:2]1[S:3][C:4]([CH3:14])=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:17]
Reactant: CON=C(C(=O)O)c1nc(N)sc1C
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CON=C(C(=O)O)c1nc(NC=O)sc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-amino-5-methylthiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 2.6 g.), acetic anhydride (31 ml.) and formic acid (13 ml.) was stirred at room temperature for 2 hrs. and then evaporated in vacuo. The residue was dissolved in a mixture of water and ethyl acetate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and then filtered. The filtrate was evaporated in vacuo. The oily residue was treated with n-hexane and diisopropyl ether, and the precipitates were collected by filtration to give 2-(2-formamido-5-methylthiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 2.8 g.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N+:6]([O-])=[CH:7]2.C[CH2:14][N:15](CC)CC.[Si](C#N)(C)(C)C>CC#N>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[C:14]#[N:15]
Reactant: CCN(CC)CC
Reactant: [O-][n+]1ccc2c(Br)cccc2c1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: N#Cc1nccc2c(Br)cccc12
Yield: 89.7 %

Procedure:
A mixture of Example 795A (0.30 g, 1.34 mmol), Et3N (0.270 g, 2.68 mmol) and TMSCN (0.18 g, 2 mmol) in CH3CN (10 mL) was heated under reflux overnight. More Et3N (0.27 g, 2.68 mmol) and TMSCN (0.18 g, 2 mmol) were added, and the reaction mixture was heated under reflux for another 16 hours. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 4:1 Hexanes/EtOAc to give 0.28 g of the title compound (90%). MS (APCI) m/e 234 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 8.85 (d, J=5.62 Hz, 1H), 8.35 (d, J=7.49 Hz, 1H), 8.29-8.33 (m, 2H), 7.85 (m, 1H).
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.[NH2:40][C:41]([CH3:62])([CH3:61])[CH2:42][N:43]1[C:55]2[C:54]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[N:48]=[C:47]([NH2:56])[C:46]=2[N:45]=[C:44]1[CH2:57][O:58][CH2:59][CH3:60]>CN(C=O)C.O>[NH2:56][C:47]1[C:46]2[N:45]=[C:44]([CH2:57][O:58][CH2:59][CH3:60])[N:43]([CH2:42][C:41]([NH:40][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)([CH3:61])[CH3:62])[C:55]=2[C:54]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[N:48]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)N
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.3 %

Procedure:
To a solution of 6-(carbobenzyloxyamino) caproic acid (8.49 grams (g), 32.0 millimole (mmol)) in DMF (50 mL) at 0° C. was added N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). After a short period, the solution was added to a 0° C. solution of 1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in U.S. Patent Publication No. 2004/0091491, 10 g, 32 mmol) in DMF (100 mL). The mixture was allowed to warm to room temperature and was stirred for 3 days. The solution was diluted with water (400 mL) and extracted with ethyl acetate (3×). The organic layers were combined and washed with water (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by HPFC on silica gel three times (gradient elution with CMA in chloroform) to provide 4.90 g of benzyl 6-({2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-6-oxohexylcarbamate as a white foam.
Reaction SMILES: C(Cl)Cl.[CH3:4][S:5][C:6]1[CH:7]=[C:8]([CH2:20][C:21]([OH:23])=[O:22])[CH:9]=[C:10]2[C:15]=1[NH:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2.Cl[C:25]1C=CC=C(C(OO)=O)C=1.C(=O)([O-])O.[Na+].[OH2:40]>>[CH3:4][S:5]([C:6]1[CH:7]=[C:8]([CH2:20][C:21]([O:23][CH3:25])=[O:22])[CH:9]=[C:10]2[C:15]=1[NH:14][CH:13]([C:16]([F:17])([F:18])[F:19])[CH2:12][CH2:11]2)=[O:40]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(CC(=O)O)cc2c1NC(C(F)(F)F)CC2
Reactant: O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)Cc1cc2c(c(S(C)=O)c1)NC(C(F)(F)F)CC2

Procedure:
Into 30 ml of methylene chloride were dissolved 1.17 g of methyl ester of 8-methylthio-1,2,3,4-tetrahydro-2-trifluoromethylquinoline-6-acetic acid, and the mixture was stirred under cooling with ice. To this were added 870 mg of m-chloroperbenzoic acid and 336 mg of sodium hydrogen-carbonate, and the mixture was stirred for 1 hours. Water was added and the reaction mixture was extracted with methylene chloride, which was washed with saturated aqueous sodium bicarbonate, with water and with saturated saline solution and then dried over anhydrous sodium sulfate. Solvent was distilled off and the residue was purified by means of silica gel chromatography (development solvent; ethyl acetate:hexane=1:1) to obtain 620m g of dia-stereoisomer A and 300 mg of diastereoisomer B of methyl 8-methylsulfinyl-1,2,3,4-tetrahydro-2-trifluoromethylquinoline-6-acetate as white crystals. Moreover, 180 mg of methyl ester of 8-methylsulfonyl-1,2,3,4-tetrahydro-2-trifluoromethylquinoline-6-acetic acid were obtained as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][CH:14]3[C:9](=[C:10]([OH:22])[C:11](=[O:21])[N:12]([CH3:20])[CH:13]3[C:17](O)=[O:18])[C:8]2=[O:23])=[CH:4][CH:3]=1.C(Cl)CCl.Cl.[CH3:31][NH:32][CH3:33].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH3:31][N:32]([CH3:33])[C:17]([CH:13]1[N:12]([CH3:20])[C:11](=[O:21])[C:10]([OH:22])=[C:9]2[CH:14]1[CH2:15][CH2:16][N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=1)[C:8]2=[O:23])=[O:18]
Reactant: CNC
Reactant: CN1C(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC2C1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1C2CCN(Cc3ccc(F)cc3)C(=O)C2=C(O)C(=O)N1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione-5-carboxylic acid (0.012 g, 0.0.034 mol) in DMF (0.5 mL) was added EDC (0.007 g, 0.038 mmol), dimethylamine hydrochloride (0.003 g, 0.038 mmol) and HOBT (0.006 g, 0.038 mmol). After stirring at room temperature, triethylamine (0.008 g, 0.076 mmol) was added. After 2 hours, the reaction mixture was concentrated under vacuum. The residual material was partitioned between CHCl3 and water. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified using reverse phase HPLC on a C18 stationary phase eluting with 15%-85% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 4.75 (m, 1H), 4.44 (m, 1H), 3.95 (d, J=12.3 Hz, 1H), 3.29 (m, 4H), 3.18 (s, 3H), 1.81 (m, 1H), 1.65 (s, 6H), 1.49 (m, 1H) ppm. ES MS M+1=376.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[C:6]([S:12][CH3:13])[N:7]=[N:8][C:9]=1[CH:10]=O)[CH3:2].CO[C:16]1[CH:17]=[C:18]([CH2:24][C:25]#[N:26])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.[C:27](=[O:30])([O-])[O-].[K+].[K+]>C1COCC1>[CH3:23][O:22][C:20]1[CH:19]=[C:18]([C:24]2[C:25](=[NH:26])[N:3]([CH2:1][CH3:2])[C:4]3[N:5]=[C:6]([S:12][CH3:13])[N:7]=[N:8][C:9]=3[CH:10]=2)[CH:17]=[C:16]([O:30][CH3:27])[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(CC#N)cc(OC)c1
Reactant: CCNc1nc(SC)nnc1C=O
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1c(=N)c(-c2cc(OC)cc(OC)c2)cc2nnc(SC)nc21
Temperature: 65 °C
Yield: 60 %

Procedure:
To a solution of 5.0 g (25.2 mmol) of 5-ethylamino-3-methylsulfanyl-1,2,4-triazine-6-carbaldehyde in 125 mL of THF was added 6.7 g (37.8 mmol) of 3,5-dimethoxyphenylacetonitrile followed by 17.4 g (126.1 mmol) of potassium carbonate. The reaction mixture was warmed at 65° C. for 2 days, concentrated under vacuum, diluted with ethyl acetate, and washed three times with a saturated solution of sodium bicarbonate, once with water and brine. The organic phase was dried over magnesium sulfate, filtered, decolorized with charcoal, filtered through celite, and concentrated to give a dark orange oil. The crude oil was chromatographed through silica eluted with 2:2:6 to 2:3:5 dichloromethane/ethyl acetate/hexane to give 5.4 g (59%) of the title compound as a yellow amorphous solid. MS (APCI) (m+1)/z 358.1.