Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25]([O:27][C:28]([C:30]1[N:31]=[C:32](Br)[S:33][CH:34]=1)=[O:29])[CH3:26]>CC#N>[CH2:25]([O:27][C:28]([C:30]1[N:31]=[C:32]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:18])[CH2:13]2)[S:33][CH:34]=1)=[O:29])[CH3:26]
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: O=C(NCC1CCCNC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1csc(N2CCCC(CNC(=O)OCc3ccccc3)C2)n1

Procedure:
To a stirred solution of piperidin-3-ylmethyl-carbamic acid benzyl ester (43 mg, 0.17 mmol) in CH3CN (5 mL), at RT under N2, K2CO3 (26 mg, 0.19 mmol) and 2-bromo-thiazole-4-carboxylic acid ethyl ester (41 mg, 0.17 mmol) were added. The resulting mixture was heated at reflux for 29 h. The solvent was evaporated in vacuo. The residue was treated with a saturated solution of NH4Cl (aq) (10 mL) and extracted with EtOAc (10 mL). The organic layer was separated, dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel (1:2, EtOAc:hexane) to yield the title compound as a colorless oil. MS m/z: 404.2 (M+H). Calc'd. for C20H25N3O4S-403.50.
Reaction SMILES: O=[CH:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH:12]1([CH2:15][NH:16][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:14][CH2:13]1
Reactant: NCC1CC1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNCC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl N-(2-oxoethyl)carbamate (1 g) was dissolved in dry methanol (40 ml) and treated with cyclopropane methylamine (0.709 ml) and 4A° molecular sieves (1 g) and the resultant mixture stirred at room temperature for 5 h. Sodium borohydride (0.38 g) was added and the reaction stirred for a further 18 h at room temperature. Sodium hydroxide (2N, 3 ml) was added, the mixture filtered and the filtrate concentrated under reduced pressure. The residue was partitioned between sodium hydroxide solution (2N) and ethyl acetate. The separated organic layer was dried (over magnesium sulphate), filtered and concentrated under reduced pressure to give the title compound (1 g) as a colourless oil
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=[O:2].Cl[CH2:10][C:11]1[NH:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:10][C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: O=CN1CCNCC1
Reactant: ClCc1nc2ccccc2[nH]1
Product: O=CN1CCN(Cc2nc3ccccc3[nH]2)CC1
Yield: 78.1 %

Procedure:
In the same manner as described in Reference Example 4, N-formylpiperazine (17 g) and 2-chloromethylbenzimidazole (9.0 g) are reacted, and the crude crystal thus obtained is recrystallized from ethyl acetate to give 2-(4-formyl-1-piperazinyl)methylbenzimidazole (10.3 g) as pale yellow flakes, m.p. 194.5°-197.5° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:18]CC3C=CC=CC=3)[CH:13]=[C:14]([F:17])[CH:15]=2)[CH:10]=[C:9]1[C:26]([NH2:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([OH:18])[CH:13]=[C:14]([F:17])[CH:15]=2)[CH:10]=[C:9]1[C:26]([NH2:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc2c(OCc3ccccc3)cc(F)cc2n1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1cc2c(O)cc(F)cc2n1Cc1ccccc1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
1-Benzyl-4-benzyloxy-6-fluoro-1H-indole-2-carboxylic acid amide (570 mg, 1.52 mmol) in EtOH (20 ml) was added to a Parr vessel containing catalytic amount of 5% Pd on carbon. The vessel was purged with H2 at the pressure of 3.45 Bar. After shaking overnight, the reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash chromatography to give 1-benzyl-6-fluoro-4-hydroxy-1H-indole-2-carboxylic acid amide as yellow solid (312 mg, 72%). MS: 285.2 (M+H)+.
Reaction SMILES: [CH2:1](N1C(=O)C2N(C)C=NC=2N(C)C1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[Mg].II.C(Br)CCCCCCCCC=C.C=[O:42].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([OH:42])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: C=O
Agent: C=CCCCCCCCCCBr
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CCCCCCCCCCCO
Reaction time: 0.5 h
Yield: 67 %

Procedure:
This example illustrates the synthesis of 1-(11-Dodecenyl)-3,7-dimethylxanthine (CT2516). To a suspension of magnesium (6.4 g, 265 mmol) and a crystal of iodine in tetrahydrofuran (40 ml) was added 10-undecenyl bromide (12.25 g, 53.0 mmol) in tetrahydrofuran (30 ml) over 30 min and the reaction stirred for a further 30 min after the addition was complete. The solution was added via a canula over 5 min to a suspension of paraformaldehyde (1.80 g, 60.0 mmol) in tetrahydrofuran (40 ml) and stirred at 25° C. for 16 hr. Saturated ammonium chloride (80 ml) was added and extracted with diethyl ether (2×100 ml). The combined organic extracts were dried (magnesium sulfate) and evaporated to give a residue which was distilled at 2 mm Hg to afford 11-dodecenyl alcohol as a clear liquid (6.53 g, 67%, b.p. 105°-107° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(C1NC=CN=1)([C:15]1[NH:16][CH:17]=CN=1)=O.Cl.CNC.O>CN(C)C=O>[CH3:15][N:16]([CH3:17])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1n[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1H-Indazole-3-carboxylic acid (5.0 g, 30.8 mmol) and carbonyl diimidazole (5.0 g, 33.9 mmol) were dissolved in N,N-dimethylformamide (150 mL) and heated to 60° C. After 2 hours, dimethylamine hydrochloride (4.0 g, 33.9) was added, and the reaction was stirred for an additional hour at 60° C. The reaction was poured into water, and the aqueous phase was extracted with ethyl acetate (3×150 mL). The combined organic phases were washed sequentially with aqueous sodium bicarbonate, 10% hydrochloric acid, water and brine. After drying over magnesium sulfate, filtering and concentrating in vacuo, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([N:41]([CH3:48])[CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:48][N:41]([C:38]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:40][CH:39]=1)[CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOCCN(C)c1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOCCN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-[N-methyl-N-(2-propoxyethyl)amino]phenyl borate (205 mg) and potassium carbonate (176 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (40 mg), and the mixture was refluxed for 8 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:4) to give crystals, which were recrystallized from ethanol to give pale yellow crystals of 7-[4-[N-methyl-N-(2-propoxyethyl)amino]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 72) (210 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[OH-].[Na+:9].[Br:10][CH:11]([CH3:15])[C:12](Br)=[O:13]>O.ClCCl>[Br:10][CH:11]([CH3:15])[C:12]([NH:1][CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5])=[O:13].[Na+:9]
Reactant: NCCS(=O)(=O)O
Reactant: CC(Br)C(=O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(Br)C(=O)NCCS(=O)(=O)[O-]
Reaction time: 1 h

Procedure:
25.6 g of taurine (204 mmol) and 16.38 g of NaOH (409 mmol) were dissolved in 20 ml of deionized water. 2-Bromopropionyl bromide (44 g, 21.36 ml, 204 mmol) dissolved in 50 ml of dichloromethane was then added to the solution drop wise at 0° C. over 30 minutes. During the addition, a large amount of solid was produced. The reaction flask was manually agitated to thoroughly mix the compounds until no more exotherm was observed with additional agitation. The reaction mixture was then allowed to sit for 1 hour. The solid was filtered and washed with a small amount of absolute ethanol and then ethyl ether and then dried in vacuo. The compound can be used in this state or recrystallized from methanol.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(C1C=C(C=C(C(C)(C)C)C=1O)CC1C(C)=C(CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)C(C)=C(CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)C=1C)(C)(C)C.[C:78]1(=[O:84])[O:83][C:81](=[O:82])[CH:80]=[CH:79]1>CCCCCCC>[CH:1]([CH:79]1[CH2:80][C:81](=[O:82])[O:83][C:78]1=[O:84])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C=CCCCCCCCCCCCCCCCCCC
Reactant: O=C1C=CC(=O)O1
Agent: Cc1c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c1Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCCCCCC
Product: CCCCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Temperature: 210 °C

Procedure:
In a separate reaction vessel was placed 560 grams of the above isomerized eicosene and 200 ml heptane. The 3.1 grams of tri-(3,5-di-tert-butyl-4-hydroxybenzyl)mesitylene stabilizer was added and the mixture heated to 210° C. Over a 2.5-hour period, 156.8 grams of maleic anhydride was added at about 225° C. Following this unreacted maleic anhydride was distilled out under vacuum at 210° C. leaving isomerized eicosenyl succinic anhydride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16](C)[C:17](OC(C)(C)C)=O)[N:9]=[CH:8][N:7]=[C:6]2[O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([CH3:35])=[CH:29]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([CH3:35])=[CH:29]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCOc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methyl-N-tert-butoxycarbonylamino)ethoxy)quinazoline (550 mg, 1.15 mmol), (prepared as described in Example 149), in methylene chloride (10 ml) containing TFA (12 ml) was stirred for 3 hours at ambient temperature. After removal of the volatiles under vacuum, the residue was partitioned between methylene chloride and sodium hydrogen carbonate. The pH of the aqueous layer was adjusted to 11 with 2N sodium hydroxide. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated with ether, filtered and dried under vacuum to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(2-(N-methylamino)ethoxy)quinazoline (356 mg, 82%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:22])([F:21])[C:12]1[C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:45]=[C:46]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)[CH2:47][NH:48][C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)=[O:50]>CN(C=O)C.O>[O:45]=[C:46]([N:63]1[CH2:68][CH2:67][N:66]([C:18]([C:17]2[CH:16]=[N:15][CH:14]=[CH:13][C:12]=2[C:11]([F:10])([F:22])[F:21])=[O:20])[CH2:65][CH2:64]1)[CH2:47][NH:48][C:49]([C:51]1[CH:52]=[CH:53][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:55][CH:56]=1)=[O:50]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cnccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 4-trifluoromethyl-nicotinic acid (49.2 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 80% EtOAc in hexane as eluent) to afford 48 mg (47.6% yield) of biphenyl-4-carboxylicacid {2-oxo-2-[4-(4-trifluoromethyl-pyridine-3-carbonyl)-piperazin-1-yl]-ethyl}-amide, LC-MS purity: 94.74%, 1H NMR: (DMSO) δ 9.0-8.84 (d, 2H), 8.7-8.6 (t, 1H), 8.0 (d, 2H), 7.9 (d, 1H), 7.84-7.7 (q, 4H), 7.6-7.4 (m, 3H) 4.2 (d, 2H), 3.8-3.6 (d, 4H), 3.3-3.2 (s, 4H).
Reaction SMILES: C([O-])(=O)C([O-])=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:15]([N:17]2[CH2:22][CH2:21][C:20]([F:33])([CH2:23][NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH2:19][CH2:18]2)=[O:16])[CH:11]=[CH:12][C:13]=1F.[Cl:34]C1C=C(C=CC=1Cl)C(N1CCC(F)(C=O)CC1)=O>>[Cl:7][C:8]1[CH:9]=[C:10]([C:15]([N:17]2[CH2:22][CH2:21][C:20]([F:33])([CH2:23][NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH2:19][CH2:18]2)=[O:16])[CH:11]=[CH:12][C:13]=1[Cl:34]
Reactant: O=CC1(F)CCN(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC(F)(CNCCc2ccccn2)CC1
Agent: O=C([O-])C(=O)[O-]
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCC(F)(CNCCc2ccccn2)CC1

Procedure:
This compound is obtained in the form of the oxalate according to the same procedure as that used to prepare (3-chloro-4-fluorophenyl){4-fluoro-4-[(2-pyrid-2-ylethylamino)methyl]-1-piperidyl}methanone, but replacing the 1-(3-chloro-4-fluorobenzoyl)-4-fluoropiperidine-4-carbaldehyde with 1-(3,4-dichlorobenzoyl)-4-fluoropiperidine-4-carbaldehyde.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:18].[C:19](=N)(OCC)[CH3:20]>C(O)C>[ClH:18].[ClH:18].[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]3[NH:16][C:19]([CH3:20])=[N:17][C:12]=3[CH:11]=2)[CH:7]([CH3:8])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)C(c1ccc(N)c(N)c1)n1ccnc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: Cc1nc2cc(C(C(C)C)n3ccnc3)ccc2[nH]1
Reaction time: 3 h
Yield: 44 %

Procedure:
A mixture of 6.2 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-1,2-benzenediamine, 6.5 parts of ethyl ethanimidate hydrochloride and 80 parts of ethanol was stirred for 3 hours at reflux temperature. After evaporation to dry, the residue was taken up in water and sodium carbonate. The product was extracted three times with 120 parts of trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was convened into the hydrochloride salt in a mixture of 2-propanone and ethanol. The salt was filtered off and crystallized from a mixture of ethanol and 2-propanone. The product was filtered off and dried, yielding 4 parts (44% ) of 5-[1-(1H-imidazol-1yl)-2-methylpropyl]-2-methyl-1H-benzimidazole dihydrochloride.monohydrate; mp. 214.8° C. (comp. 22).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH:13]=[O:14])=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].C[Si](C)(C)[O:17][CH2:18][CH2:19]O[Si](C)(C)C.C(Cl)Cl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>N1C=CC=CC=1>[O:14]1[CH2:19][CH2:18][O:17][CH:13]1[C:5]1[S:4][C:3]([CH2:1][CH3:2])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=1
Reactant: CCOC(=O)c1cc(C=O)sc1CC
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C2OCCO2)sc1CC
Reaction time: 2 h

Procedure:
To a mixture of ethyl 2-ethyl-5-formylthiophene-3-carboxylate (7.82 g) synthesized above, 1,2-bis(trimethylsiloxy)ethane (9.93 mL) and methylene chloride (80 mL) was added trimethylsilyl trifluoromethanesulfonate (661 μL) at −78° C., and the mixture was stirred for 2 hr under a nitrogen atmosphere. Pyridine (890 μL) was added to quench the reaction, and saturated aqueous sodium hydrogen carbonate solution was added. Methylene chloride was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (9.71 g, quantitative) as a yellow oil.
Reaction SMILES: FC1C=C2C(C(=O)NC=N2)=CC=1.[F:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=O)[NH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[N+:25]([O-:27])=[O:26].S(Cl)([Cl:30])=O>>[Cl:30][C:18]1[NH:19][CH2:20][N:21]=[C:22]2[C:17]=1[CH:16]=[C:15]([N+:25]([O-:27])=[O:26])[C:14]([F:13])=[CH:23]2
Reactant: O=c1[nH]cnc2cc(F)c([N+](=O)[O-])cc12
Reactant: O=S(Cl)Cl
Agent: O=c1[nH]cnc2cc(F)ccc12
Product: O=[N+]([O-])c1cc2c(cc1F)=NCNC=2Cl

Procedure:
4-Chloro-7-fluoro-6-nitroquinazoline (7) can be prepared by methods similar to those described in J. Med. Chem. 1996, 39, 918-928. Generally, 2-amino-4-fluoro-benzoic acid (1) can be reacted with formamidine (2) and acetic acid (3) in the presence of 2-methoxyethanol to provide 7-Fluoro-3H-quinazolin-4-one (4). The 7-fluoro-3H-quinazolin-4-one (4) can then be nitrated to 7-fluoro-6-nitro-3H-quinazolin-4-one (5), which can be treated with thionyl chloride to yield 4-chloro-6-nitro-7-fluoro-3H-quinazoline (6). The 4-chloro-quinazoline compound (6) can be combined with a desirably substituted aniline, represented above by 4-fluoro-3-chloro-aniline, in the presence of a tertiary amine and isopropanol to provide the 4-anilino-6-nitro-7-fluoro-quinazoline (7).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Cl[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([N:4]2[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]2)[CH:15]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2cc(Cl)ccn2)C[C@H](C)O1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
cis-2,6-Dimethylmorpholine (2.029 g, 17.62 mmol) was added to a suspension of 2,4-dichloropyridine (2.37 g, 16.01 mmol) and potassium carbonate (6.64 g, 48.0 mmol) in anhydrous acetonitrile (120 mL). After addition, the reaction mixture was stirred at 100° C. overnight. Crude LC/MS showed starting material and desired product so cis-2,6-dimethylmorpholine (0.500 equivalents) was added to the reaction mixture and then stirred and heated at 100° C. overnight. Crude LC/MS showed starting material and desired product so cis-2,6-dimethylmorpholine (0.500 equivalents) was added to the reaction mixture and then stirred and heated at 100° C. overnight. Crude LC/MS showed starting material and desired product so cis-2,6-dimethylmorpholine (0.500 equivalents) was added to the reaction mixture and then stirred and heated at 100° C. overnight. Crude LCMS showed desired product can be seen and no starting material left, so the reaction mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-100% ethyl acetate in isohexanes).
Reaction SMILES: Cl.[C:2]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18](=[O:30])[N:19]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:14]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:13]=2)[CH2:8][CH2:7]1)([CH3:5])([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>>[C:2]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18](=[O:30])[N:19]3[C:22]3[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=3[Cl:28])=[C:14]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH:13]=2)[CH2:10][CH2:11]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N1CC=C(c2cc(-c3ccc(F)cc3)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N1CCC(c2cc(-c3ccc(F)cc3)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
The title compound was prepared from HCl salt of 7-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,6-dichlorophenyl)-5-(4-fluorophenyl)quinolin-2(1H)-one (EXAMPLE ABA11, Step A) by procedures analogous to that described in EXAMPLE HHH1, Step B, as a TFA salt. 1H NMR (CD3OD, 500 MHz) of TFA salt: δ 7.97 (d, J=9.8 Hz, 1H); 7.73 (m, 2H); 7.62 (m, 1H); 7.49 (m, 1H); 7.28 (m, 3H); 6.69 (d, J=9.8 Hz, 1H); 6.47 (s, 1H); 3.67 (m, 2H); 3.08 (m, 2H); 2.96 (m, 1H); 2.1 (m, 2H); 1.99 (m, 2H); 1.42 (s, 9H). Mass spectrum (ESI): 523.3 (M+1).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2c(F)cc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2c(F)cc(F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclohexyl(5,7-difluoro-3-methyl-1-benzofuran-2-yl)methanone (3.1 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (50 mL) and methanol (5 mL), and sodium borohydride (90%, 0.93 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (5 mL) and 1N hydrochloric acid (10 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (3.1 g, quantitative) as a pale-yellow oil.