Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15].O>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(CBr)Nc1cccc(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To a solution of 2-amino-6-fluorobenzoic acid (8.0 g, 0.052 mol) in anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) at 0° C. in a 250 mL 3-necked flask fitted with a constant additional funnel was added, dropwise, bromoacetyl bromide (10.4 g, 100 mol%) while keeping the internal temperature between 0° C. and 2° C. After the addition was completed (~30 min), the reaction mixture was stirred at rt overnight. Water (100 mL) was added, and the light crystalline compound which precipitated was filtered, washed sequentially with 5% HBr and water, and then dried in a vacuum oven at 40°-45° C., affording 9.5 g (67%) of the title compound: mp 168.9°-170.3° C.; 1H NMR (DMSO-d6) δ13.80 (bs, 1H, OH), 10.60 (s, 1H, NH), 7.69 (d, 1H, J=8.4), 7.54 (dt, 1H, J=8.4, J=10.4), 7.13-7.08 (m, 1H), 4.16 (s, 2H); 13C NMR (DMSO-d6) δ165.22 (d, J=32.4, C=O), 160.18 (d, J=251), 137.83, 132.69 (d, J=10.0), 118.58, 118.20, 112.18 (d, J=22.9), 30.04; MS (EI, m/z) 275 (M+). HRMS (EI) calcd for C9H7NO3FBr 274.9593, found 274.9595. Anal. Calcd for C9H7NO3FBr: C, 39.16; H, 2.56; N, 5.08. Found: C, 38.96; H, 2.48; N, 5.07.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.[CH:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](OC2C=CC=CC=2)=[N:20][C:21]#[N:22])=[CH:14][CH:13]=1>C(O)(C)C>[C:21]([NH:20][C:19](=[N:11][C@H:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:10])[O:18][C:15]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)#[N:22]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ccc([C@H](C)N)cc1
Solvent: CC(C)O
Product: COc1ccc([C@H](C)N=C(NC#N)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
(S)-(−)-1-(4-methoxyphenyl)ethylamine (321 mg) was dissolved in isopropanol (6 ml). Thereafter, diphenyl N-cyanocarbonimidate (508 mg) was added to the solution, and the obtained mixture was stirred at a room temperature for 2 hours. The precipitated crystals were collected by filtration, and the collected crystals were then washed with isopropyl ether to obtain (S)-1-cyano-3-[1-(4-methoxyphenyl)ethyl]-2-phenyl isourea (339 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C)C=O>[Si:13]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 133.1 %

Procedure:
A mixture of 300.0 g (1.7 mol) of 3-bromophenol, 392.1 g (2.6 mol) of tert-butylchlorodimethylsilane and 295.1 g (4.3 mol) of imidazole in 1 L of N,N-dimethylformamide was stirred at room temperature under nitrogen for 18 hours. The reaction mixture was poured into cold water and extracted with diethyl ether. The ether extracts were washed with water and brine, dried over sodium sulfate, and the solvent was evaporated under vacuum to give 650 g of crude 3-bromophenyl tert-butyldimethylsilyl ether as an orange oil. NMR (CDCl3, 200 MHz) δ0.2 (s, 6H); 0.95 (s, 9H); 6.8 (m, 1H); 7.0-7.1 (m, 3H).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[N:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1>C1COCC1>[C:1]1([N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: ClN1C=Cc2ccccc2C1
Solvent: C1CCOC1
Product: C1=CN(c2ccccc2)Cc2ccccc21
Reaction time: 0.83 h
Yield: 56.5 %

Procedure:
A solution of phenylmagnesium bromide (1M in THF, 3.6 mL, 3.6 mmol) is added to a solution of 2-chloro-isoquinoline (258 mg, 1.57 mmol)) and Fe(acac)3 (28 mg, 0.078 mmol) in THF (10 mL) at −30° C. After stirring for 50 min at that temperature, the reaction is quenched with brine, the aqueous layer is extracted with Et2O, the combined organic phases are dried over Na2SO4 and evaporated, and the residue is purified by flash chromatography (hexane/ethyl acetate, 10:1). After eluting a first fraction containing biphenyl (60 mg), one obtains 2-phenyl-isoquinoline as a colorless solid (184 mg, 57%). 1H NMR (300 MHz, CD2Cl2) δ 8.60 (d, 1H), 8.11 (d, 1H), 7.91 (d, 1H), 7.66–7.72 (m, 4H), 7.48–7.57 (m, 4H); 13C NMR (75 MHz, CD2Cl2) δ 160.9, 142.6, 140.1, 137.2, 130.3, 130.2, 128.8, 128.5, 127.7, 127.5, 127.3, 127.0, 120.1.
Reaction SMILES: [C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].Cl[CH2:28][CH2:29]CC(OC(=O)C)CCCCCCC.ClCCCC(OC(=O)C)CCCCC>>[C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCC(CCCCl)OC(C)=O
Reactant: CCCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CCCCCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O

Procedure:
This compound is prepared by the method described in Example 1 for 4-(4-acetyl-8-hydroxytridecyl)benzoic acid except that in Step D an equivalent quantity of 1-chloro-4-acetoxyundecane is substituted for 1-chloro-4-acetoxynonane. The intermediates and final product thus obtained are, Step D: ethyl 4-(4-acetyl-4-tert-butoxycarbonyl-8-acetoxypentadecyl)benzoate; Step E: ethyl 4-(4-acetyl-8-acetoxypentadecyl)benzoate; and Step F: 4-(4-acetyl-8-hydroxypentadecyl)benzoic acid.
Reaction SMILES: C1C2C3C=[C:11]4[C:16](=CC=3SC=2C=CC=1)[CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12]4.[CH2:20]([N:22]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[C:29]=2C2C=CC=C(C)C1=2)[CH3:21]>C(Cl)Cl.CCCCCC>[CH2:20]([N:22]1[C:34]2[CH:33]=[CH:32][C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[C:29]=2[C:16]2[C:15]1=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12][CH:11]=2)[CH3:21]
Reactant: O=Cc1ccc2cc3c(cc2c1)sc1ccccc13
Reactant: CCn1c2ccc3ccccc3c2c2cccc(C)c21
Solvent: CCCCCC
Solvent: ClCCl
Product: CCn1c2ccc3ccccc3c2c2cccc(C=O)c21
Yield: 17.2 %

Procedure:
Using the procedure outlined in 8A, 7-ethyl-8-methyl-7H-benzo[c]carbazole gave a 17.2% of 7-ethyl-7H-benzo[c]carbazole-8-carbaldehyde, mp 148°-149°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(N(CC)CC)C>ClCCl>[O:11]=[C:12]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COC(=O)CCC(O)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
To a solution of 0.39 ml of oxalyl chloride in 12 ml of dichloromethane was added under nitrogen atmosphere at -70° C. while stirring a solution of 0.60 ml of dimethyl sulfoxide in 4 ml of dichloromethane. To the mixture was added a solution of 0.95 g of 1-t-butyl 5-methyl 2-hydoxyglutarate obtained as above in 3.5 ml of dichloromethane. The whole mixture was stirred for 15 minutes at -70° C., to which was added 3.0 ml of triethylamine. The temperature of the reaction mixture was raised to -40° C., and the reaction mixture was poured into ice-water, followed by extraction with dichloromethane. The extract was wahsed with water, dilute acetic acid and water, in sequence, which was then dried (Na2SO4), followed by distilling off the solvent. The residue was subjected to a silica gel column chromatography, eluting with hexane-ethyl acetate (5:1), followed by combining fractions containing the end product. Thus combined eluate was concentrated under reduced pressure to give 0.60 g of 1-t-butyl 5-methyl 2-oxoglutarate as a colorless oily substance.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][C:24](=[O:26])[N:23]([CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[S:22]2(=[O:34])=[O:33])=[C:17]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:16]=1)(C)(C)C.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[S:22](=[O:33])(=[O:34])[N:23]([CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[C:24](=[O:26])[CH2:25]2)=[C:17]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:16]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3N)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzyl}-phenyl)-carbamic acid tert-butyl ester (1.7 g, 2.73 mmol) in methylene chloride (10 mL) is added TFA (5 mL) and the mixture is stirred at RT for 20 min. The solvent is removed under reduced pressure and methylene chloride is added to the residue and evaporated (6×) to give the title compound as its TFA salt.
Reaction SMILES: P(O)(O)(O)=O.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([CH2:11][O:12][NH2:13])=[CH:9][C:8]=1[OH:16].C(=O)(O)[O-].[Na+].[CH:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=O)[C:31]([OH:33])=[O:32])[N:29]=1)=[O:23]>O.C(O)C>[CH:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:13][O:12][CH2:11][C:10]2[CH:14]=[CH:15][C:7]([Br:6])=[C:8]([OH:16])[CH:9]=2)[C:31]([OH:33])=[O:32])[N:29]=1)=[O:23]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: NOCc1ccc(Br)c(O)c1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=CNc1nc(C(=NOCc2ccc(Br)c(O)c2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
The solution of 4-bromo-3-hydroxybenzyloxyamine phosphate (17.4 g.) in water (200 ml.) and ethanol (200 ml.) was stirred at room temperature and adjusted to pH 7.0 with sodium bicarbonate. 2-(2-Formamidothiazol-4-yl)glyoxylic acid (10.0 g.) was added to the solution and the resulting suspension was adjusted to pH 4.0 to 4.5. After stirring the solution at room temperature for 2 hours, ethanol was removed from the resultant solution in vacuo. Ethyl acetate was added to aqueous residue and adjusted to pH 2.5 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate. The solution was concentrated in vacuo to give 2-(2-formamidothiazol-4-yl)-2-(4-bromo-3-hydroxybenzyloxyimino)acetic acid (syn isomer, 14.8 g.).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:14]1=2)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].O.NN>C(O)C.C(OCC)(=O)C.[Ni]>[NH2:23][C:21]1[CH:20]=[CH:19][C:15]2[S:16][CH2:17][CH2:18][N:13]([CH2:12][CH2:11][N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[C:14]=2[CH:22]=1
Reactant: CCN(CCN1CCSc2ccc([N+](=O)[O-])cc21)C(=O)OC(C)(C)C
Agent: [Ni]
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCN(CCN1CCSc2ccc(N)cc21)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
To a stirred solution of tert-butyl ethyl(2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (925 mg, 2.52 mmol) in ethanol (10 mL) was added Raney-Nickel (˜148 mg, 2.52 mmol) followed by hydrazine hydrate (1.225 mL, 25.2 mmol). The resulting mixture was stirred vigorously at 50° C. for 10 minutes. The mixture was then cooled to room temperature, diluted with ethyl acetate, and then washed sequentially with a 1:1 mixture of water and saturated sodium carbonate (3×) and saturated sodium carbonate. The organic phase was dried, filtered, and concentrated giving a red oil (810 mg, 95%); ESI-MS (m/z, %): 338 (MH+, 100), 282 (53), 238 (36).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.C(OCC)C>FC(F)(F)C(O)=O.CO.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([CH3:19])[OH:17])[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3c(c2n1CC(C)(C)O)CCCC3
Reaction time: 72 h
Yield: 69.1 %

Procedure:
Platinum (IV) oxide (0.3 g) was added to a suspension of 4-amino-2-butyl-α,α,-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol (1.0 g, 3.2 mmole) in trifluoroacetic acid (20 mL). The mixture was hydrogenated at 50 psi (3.44×105Pa) for 3 days. The reaction mixture was filtered to remove the catalyst then concentrated under vacuum. The resulting residue was covered with water and aqueous sodium bicarbonate. A white solid was isolated by filtration then recrystallized for ethyl acetate. The reaction was repeated using 1.5 g of starting material. The combined products were taken up in dichloromethane, washed with 10% sodium hydroxide, dried over magnesium sulfate, then concentrated under vacuum. The material was recrystallized from ethyl acetate then from toluene to provide 1.15 g of crude product. This material was dissolved in methanol then combined first with one equivalent of hydrochloride acid then with diethyl ether. The resulting salt was converted back to the free base then purified by silica gel column chromatography diluting with 10% methanol in ethyl acetate. The resulting material was recrystallized from toluene then dried under vacuum at 110° C. to provide 0.7 g of 4-amino-2-butyl-α,α,-dimethyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-ethanol as a solid, m.p. 160°-161.5° C. Analysis: Calculated for C18H28N4O: % C, 68.32; % H, 8.92; % N, 17.70; % C, 67.96; % H, 89.95; % N, 17.48.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][NH:5][C:6](=[O:23])[CH2:7][CH2:8][CH:9]=[C:10]([CH2:12][CH2:13][CH:14]=[C:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:16])[CH3:11].[CH3:25][Cl:26]>C(#N)C>[Cl-:26].[CH2:8]([CH2:7][C:6]([NH:5][CH2:4][CH2:3][N+:2]([CH3:25])([CH3:1])[CH3:24])=[O:23])[CH:9]=[C:10]([CH2:12][CH2:13][CH:14]=[C:15]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:16])[CH3:11]
Reactant: CCl
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)NCCN(C)C
Solvent: CC#N
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)NCC[N+](C)(C)C
Product: [Cl-]

Procedure:
A three-necked flask equipped with a thermometer, a reflux condenser and a gas inlet tube was charged with 10 g of N,N-dimethyl-N'-farnesylacetylethylenediamine prepared by the procedure of Example 1 and 100 ml of acetonitrile. The contents were refluxed for 6 hours while methyl chloride was introduced. Thereafter, the methyl chloride and acetonitrile were distilled off and the remaining product was purified by column chromatography to give 8.6 g of farnesylacetylaminoethyltrimethylammonium chloride. The product was identified by proton NMR and elemental analysis. The NMR data were as follows:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]2[C:25]([O:27][C:28](=O)[C:16]=12)=[O:26]>C1(C)C=CC=CC=1>[CH3:8][N:9]1[C:13]([N:14]2[C:28](=[O:27])[C:16]3[CH:15]=[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]4=[CH:18][C:17]=3[C:25]2=[O:26])=[CH:12][CH:11]=[N:10]1
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Reactant: Cn1nccc1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1nccc1N1C(=O)c2cc3ccccc3cc2C1=O
Temperature: 25 °C
Yield: 87.6 %

Procedure:
Triethylamine (1.10 mL) was added to a toluene (14 mL) suspension that contained 1-methyl-1H-pyrazol-5-amine (400 mg) and 2,3-naphthalenedicarboxylic anhydride (816 mg), and the obtained solution was then heated to reflux for 2 hours. Thereafter, the reaction solution was cooled to a room temperature, and the precipitated solid was then collected by filtration. The collected solid was washed with ethyl acetate, so as to obtain the title compound (1.00 g) in the form of a colorless solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]([O:13][CH3:14])=[C:6]([O:15][CH2:16][CH3:17])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:16]([O:15][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]=1[O:13][CH3:14])[CH3:17]
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(CO)cc(OCC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3,5-diethoxy-4-methoxy-benzoic acid methyl ester (0.34 g, 1.34 mmol, 1.0 equiv; prepared as described in EP 0 419 905 B1, Eisai Co.) in anhydrous THF (5 mL) was added lithium aluminium hydride (0.15 g, 4.01 mmol, 3.0 equiv) and the reaction mixture stirred at rt for 4 h. The crude reaction mixture was filtered over Hyflo Super Cel, the filtrate extracted with diethyl ether (3×50 mL) and the combined organic phases dried over MgSO4 providing 0.26 g (86%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.36 (t, J=7.0 Hz, 6H), 3.77 (s, 3H), 4.02 (q, J=7.0 Hz, 4H), 4.53 (s, 2H), 6.51 (s, 2H). MS (EI): 227.3 [M]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][N:14]=[N:13][C:12]=2[SH:16])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[K].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][S:16][C:12]1[N:13]=[N:14][S:15][C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:10][CH:9]=1)[CH3:24]
Reactant: CC(C)(C)c1ccc(-c2snnc2S)cc1
Reactant: CCOC(=O)CBr
Agent: [K]
Solvent: CCO
Product: CCOC(=O)CSc1nnsc1-c1ccc(C(C)(C)C)cc1
Yield: 83.2 %

Procedure:
A solution of 2.9 g of 5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazole-4-thiol, potassium salt in 50 ml of ethanol was stirred overnight with 1.67 g of ethyl bromoacetate, then concentrated in vacuo. The residue was taken up in ether, filtered and evaporated in vacuo. The oily residue was dissolved in dichloromethane and purified as described in Example 50, giving an oil which was crystallized from methylcyclohexane, giving 2.8 g of the desired compound as white needles, mp 62.5°-63.5° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 1.21 (t, 3H, J=7.0Hz, CH3); 1.37 (s, 9H, t-butyl); 4.11 (s, 2H, SCH2); 4.15 (q, 2H, CH2O); 7.55 (s, 4H, C6H4). Infrared absorption spectrum (KBr pellet): 1739(s); 1606(w); 1520(w); 1480(w); 1445(w); 1385(w); 1365(w); 1305(s); 1175(s); 1040(w); 935(s); 840(s).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[O:18][C:17](=[O:19])[CH2:16][CH2:15]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH:14]2[O:18][C:17](=[O:19])[CH2:16][CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCC(CO)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
p-Toluenesulfonyl chloride (23.65 g, 124.03 mmol) was added portion wise to a solution of (±)-dihydro-5-hydroxymethyl-2(3H)-furanone (example 56) (11.07 g, 95.43 mmol) and pyridine (15.4 mL, 190.86 mmol) in methylene chloride (300 mL) at 0° C. The solution was allowed to. warm to rt and stirred overnight. The solution was then washed with water (2×100 mL), 0.5 n HCl until the washings were acidic and finally with saturated NaHCO3. After drying and concentrating, the residue was triturated with toluene to give the title compound as a white solid (19.63 g, 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].I[CH3:37].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:37])[C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1N(C)c1cc(Br)cnc1N1CCOCC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (described herein) (18.0 mg, 0.035 mmol) in N,N-dimethylformamide (2 mL) was added 60% sodium hydride (2.11 mg, 0.053 mmol), followed by iodomethane (7.5 mg, 0.053 mmol). Stirring continued for 1.5 h. Water was added to quench the reaction and the resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-60% EtOAc/hexanes) to give N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-N,3-dimethyl-2-(pyridin-2-yl)quinolin-4-amine as a yellow foam. Mass Spectrum (ESI) m/e=526.2, (M+1).
Reaction SMILES: C([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:31](=[N:34]O)([NH2:33])[CH3:32]>ClCCl.N1C=CC=CC=1>[NH2:8][C@H:9]([C:13]1[O:15][N:34]=[C:31]([CH3:32])[N:33]=1)[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(N)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1noc([C@@H](N)C(C)C)n1

Procedure:
A solution of BOC-L-valine (4.34 g, 20.0 mmol) in dichloromethane (20 mL) was cooled to 0° C. and treated dropwise with a solution of dicyclohexylcarbodiimide (2.06 g, 10.0 mmol) in dichloromethane (5 mL). After 1 hour the white solid which had formed was removed by filtration and the filtrate concentrated under reduced pressure. The residue was dissolved in pyridine (15 mL) and treated with acetamidoxime (488 mg, 6.6 mmol) in pyridine (5 mL) and the mixture heated at reflux for 1 hour. The pyridine was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was washed several times with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using 10% ethyl acetate in hexanes to elute the product (0.62 g, 25%) as a white solid.