Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.Cl.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:21]N)[CH:18]=[CH:19][CH:20]=1.O>CC(O)=O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:18]([C:7]3[CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3][C:2]=3[NH:21]2)=[CH:19][CH:20]=1
Reactant: COc1cccc(NN)c1
Reactant: CC(=O)NC1CCCC(=O)C1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c3c([nH]c2c1)CC(NC(C)=O)CC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.05 mol of N-(3-oxocyclohexyl)acetamide and 0.05 mol of 3-methoxyphenylhydrazine hydrochloride in 50 ml of glacial HOAc was stirred for 2 hr at room temperature and then refluxed for 2 hr. The cooled reaction mixture was poured into H2O and the product triturated until solid. Filtration, drying, and recrystallization from ethanol gave the title compound, mp 192°-193°.
Reaction SMILES: [I:1][C:2]1[C:3]([CH2:11][NH:12]C(=O)C)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1>Cl>[I:1][C:2]1[C:3]([CH2:11][NH2:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CC(=O)NCc1cc2c(cc1I)OCO2
Agent: Cl
Product: NCc1cc2c(cc1I)OCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
N-((6-Iodobenzo[d][1,3]dioxol-5-yl)methyl)acetamide (2.4 g, 7.5 mmol) was added to methanolic hydrochloric acid solution (4 N) (60 mL). The mixture was stirred at 80° C. overnight. Solvent was removed and the residue was dissolved in water, adjusted to PH 7 with 10% NaHCO3, filtered to obtain (6-iodobenzo[d][1,3]dioxol-5-yl)methanamine as a yellow solid (1.76 g, 85%). LC-MS: 278 [M+1]+. 1H-NMR (DMSO-d6): δ 1.88 (s, 2H), 3.57 (s, 2H), 6.02 (s, 2H), 7.13 (s, 1H), 7.33 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=[C:16]([NH2:23])[C:15]=2[N:14]=[C:13]1[CH3:24].[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>C(Cl)(Cl)Cl>[NH2:23][C:16]1[C:15]2[N:14]=[C:13]([CH3:24])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C:20]=2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)C(C)C)c2c1C
Reaction time: 0.25 h
Yield: 25.3 %

Procedure:
Triethylamine (0.78 mL, 5.6 mmol) was added to a solution of 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin4-amine (1.00 g, 4.3 mmol) in chloroform (50 mL). The solution was cooled in an ice bath and then isobutyryl chloride (0.49 mL, 4.7 mmol) was added. The reaction mixture was stirred for 15 minutes then the ice bath was removed and the reaction mixture was stirred for an additional 15 minutes. The reaction mixture was diluted with chloroform to a volume of 150 mL. Water (50 mL) was added then the pH was adjusted to 11 with solid potassium carbonate and then to pH 14 with 50% sodium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 0.33 g of N-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]-2-methylpropanamide as a white solid, m.p. 178.1-178.8° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:10]=[C:3]2[C:2]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: COc1ccccc1Nc1nc2c(Br)cccn2n1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1ccccc1Nc1nc2c(-c3ccccc3)cccn2n1

Procedure:
(2-Methoxy-phenyl)-(8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and phenylboronic acid (21.0 mg, 0.172 mmol) with Pd(dppf)Cl2 (0.012 g) as the catalyst in a manner analogous to Step 2c and was isolated as a white solid (0.012 g, 24%). MP=155-157° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.44 (dd, J=6.6, 0.9 Hz, 1H), 8.40 (dd, J=8.0, 1.4 Hz, 1H), 8.02-7.97 (m, 2H), 7.61 (s, 1H), 7.56 (dd, J=7.4, 0.9 Hz, 1H), 7.55-7.50 (m, 2H), 7.45-7.40 (m, 1H), 7.07-7.02 (m, 1H), 6.98-6.88 (m, 3H), 3.91 (s, 3H). MS=317 (MH)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[N:11]1[CH2:22][CH2:21][C:14]2([NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1.C1COCC1.[CH3:28][C:29]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=1[CH2:31]Cl>[NH4+].[Cl-]>[CH3:28][C:29]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=1[CH2:31][N:19]1[C:14]2([CH2:21][CH2:22][N:11]([C:2]3[CH:3]=[N:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:12][CH2:13]2)[CH2:15][CH2:16][CH2:17][C:18]1=[O:20]
Reactant: O=C1CCCC2(CCN(c3cnc4ccccc4n3)CC2)N1
Reactant: Cc1ccc(C)c(CCl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(CN2C(=O)CCCC23CCN(c2cnc4ccccc4n2)CC3)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.8 %

Procedure:
To a solution of 9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one (80 mg, 0.27 mmol) in THF (5 mL) sodium hydride 95% (32 mg, 0.81 mmol) was added and the mixture was stirred for 10 min at rt. Then 2,5-dimethylbenzylchloride (70 mg, 0.35 mmol) was added and the reaction mixture was heated at 60° C. over 18 h. Saturated aqueous NH4Cl solution (40 mL) was added and the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by reversed phase preparative HPLC (column Zorbax eclipseXDB C18, flow 20 mL/min, mobile phase 0.1% TFA in water (A): acetonitrile (B) gradient) to yield the title compound (49 mg, 22%). [1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 7.88 (d, 1H), 7.70-7.55 (m, 2H), 7.48-7.35 (t, 1H), 7.05-6.85 (m, 2H), 6.72 (s, 1H), 4.55 (s, 2H), 4.55-4.39 (m, 2H), 3.12 (t, 2H), 2.65 (t, 2H), 2.30 (s, 3H), 2.15 (s, 3H), 2.20-1.88 (m, 6H), 1.85-1.63 (m, 2H); LCMS RtE=1.64 min, [M+H]+=415.2].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:9][CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([F:8])[CH:7]=1.[Cl:17][CH2:18][C:19]([O-])=O.[Na+].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]2[N:9]([CH2:10][CH2:11][C:12]([F:13])([F:14])[F:15])[C:19]([CH2:18][Cl:17])=[N:16][C:4]=2[CH:3]=1
Reactant: O=C([O-])CCl
Reactant: Nc1cc(Cl)cc(F)c1NCCC(F)(F)F
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: [Na+]
Product: Fc1cc(Cl)cc2nc(CCl)n(CCC(F)(F)F)c12

Procedure:
5-Chloro-2-chloromethyl-7-fluoro-1-(3,3,3-trifluoro-propyl)-1H-benzoimidazole was prepared according to the procedure described in Example 2-1 by using 4-chloro-6-fluoro-N-(3,3,3-trifluoropropyl)benzene-1,2-diamine and sodium 2-chloroacetate instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine. MS obsd. (ESI+) [(M+H)+] 315.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][C:13](=[O:15])[CH3:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O.[CH3:24]C(O)C>>[CH:21]([O:20][C:18](=[O:19])[CH2:17][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=1)[C:13](=[O:15])[CH3:14])([CH3:22])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: CC(C)O
Agent: [Na]
Solvent: O
Product: COc1ccc(C(CC(=O)OC(C)C)C(C)=O)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.12 g (5.30 mM) sodium was dissolved in 5 ml of 2-propanol and the resultant solution was stirred over night at room temperature. 1.00 g (5.15 mM) of 3,4-dimethoxyphenylacetone dissolved in 1 ml of 2-propanol was dropwise added to the solution. The solution was cooled to 0° C. 0.89 g (5.30 mM) of ethyl bromoacetate dissolved in 1 ml of 2-propanol was dropwise added to the solution, and the mixture was stirred for about 2 hours at that temperature. The solution obtained was poured to water and the resultant product was extracted with methylene chloride. The organic extract was dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo to obtain a yellow oily crude product. The crude product was purified by chromatography (SiO2: eluted with a gradient of 20% methyl acetate/hexane to 25% methyl acetate/hexane). The solvent was evaporated in vacuo and was dried to obtain 0.67 g of colorless 3-(3,4-dimethoxyphenyl)4-oxovaleric acid isopropyl ester.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.S(OCC)(O[CH2:12][CH3:13])(=O)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30].Cl>ClC1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:4](=[O:5])/[CH:3]=[CH:2]/[C:1]([O:6][CH2:12][CH3:13])=[O:7])[CH:26]=[CH:25][C:24]=1[O:29][CH3:30]
Reactant: O=C1C=CC(=O)O1
Reactant: COc1ccccc1OC
Reactant: CCOS(=O)(=O)OCC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCOC(=O)/C=C/C(=O)c1ccc(OC)c(OC)c1
Temperature: 10 °C
Yield: 70.2 %

Procedure:
Into a 500 ml four-neck flask were charged 66.9 g (0.682 mol) of maleic anhydride, 150 ml of chlorobenzene, 71.6 ml (0.546 mol) of diethyl sulfate under a nitrogen atmosphere. Then, the whole was cooled to 10° C. or lower and 67.6 g (0.507 mol) of aluminum chloride was added thereto. While temperature was maintained at 10 to 15° C., 25 ml (0.195 mol) of 1,2-dimethoxybenzene was added dropwise, followed by 4 hours of reaction. After termination of the reaction was confirmed by HPLC analysis, the reaction solution was added dropwise to 200 ml of a 1N hydrochloric acid aqueous solution cooled to 0° C. to decompose excess aluminum chloride. After liquid separation, the organic layer was washed with 200 ml of a 10% sodium bicarbonate aqueous solution to remove excess maleic anhydride. After the solvent was removed by evaporation under reduced pressure, the residue was crystallized from 5 ml of ethanol to obtain 36.2 g (yield 70.3%) of the aimed compound as light yellow crystals. As a result of HPLC analysis, the purity was found to be 99.8%.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:16]2[S:15][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:17]=2)=[CH:23][CH:22]=1
Reactant: N#C[S-]
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Product: COc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Yield: 80.7 %

Procedure:
The reaction procedure of Example 6 was followed except that 5.00 g of chloronicotinic acid, 25 ml of thionyl chloride, 2.42 g of ammonium thiocyanate and 3.91 g of p-anisidine were used. As a result, 7.31 g of 2-(4-methoxyanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[CH2:5]2.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C(#N)C.O>[OH:1][C@H:2]1[C@H:6]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:12])[Cl:13])=[O:8])[CH2:3]1
Reactant: Oc1ccccc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC2OC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(OCC(Cl)(Cl)Cl)N1C[C@@H](O)[C@H](Oc2ccccc2)C1

Procedure:
2.6 g (0.01 mol) of the 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine described in Example 1 are heated together with 1.88 g (0.02 mol) of phenol and 10 ml of 1 N sodium hydroxide solution in 30 ml of acetonitrile for 5 hours under reflux. After cooling, the reaction mixture is diluted with water and extracted 3 times with methylene chloride, and the organic phase is washed twice with 2 N sodium hydroxide solution and then once with water, dried over sodium sulphate and evaporated under a water pump vacuum. The resulting oil crystallises from methylene chloride/hexane and gives trans-3-hydroxy-4-phenoxy-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine with a melting point of 100°-103°.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([N:7]([CH3:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:6].[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([CH2:4][C:5](=[O:6])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH3:15])[N:17]=1
Reactant: NC(N)=S
Reactant: CN(C(=O)CC(=O)CBr)c1ccc(Cl)cc1
Solvent: CCO
Product: CN(C(=O)Cc1csc(N)n1)c1ccc(Cl)cc1
Yield: 66.7 %

Procedure:
A 500 ml reaction flask equipped with a condenser, magnetic stirrer, thermometer and heating mantle was charged with 20.2 g (0.066 mole) of 4-bromo-4'-chloro-N-methylacetoacetanilide, 200 ml of ethanol and 5.4 g (0.071 mole) of thiourea. The reaction solution was refluxed for three hours. After cooling, about one-half of the solvent was removed on the rotary evaporator and the solution was poured into 300 ml of water. After adding sufficient ammonium hydroxide to pH 8, additional water was added. The precipitated crystalline product was dried in a vacuum oven. There was obtained 12.4 g (66.7%) of white material, M.P. 148°-50°. N.M.R. (dimethyl-d6 sulfoxide, CDCl3) ∂3.2 (NCH3), 3.3 (CH2), 6.0 (heteroaromatic), 7.3-7.5 (aromatic).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[CH:11]=[CH:12][C:13]([OH:15])=O.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:33]([N:35]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:37]([CH2:38][C@@H:39]([C:41]([O:43][CH3:44])=[O:42])[NH2:40])=[CH:36]1)[CH3:34]>C(Cl)Cl>[CH2:33]([N:35]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:37]([CH2:38][C@@H:39]([C:41]([O:43][CH3:44])=[O:42])[NH:40][C:13](=[O:15])[CH:12]=[CH:11][C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[F:8])=[CH:36]1)[CH3:34]
Reactant: CCn1cc(C[C@H](N)C(=O)OC)c2ccccc21
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)OC)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
Triethylamine (1.5 mL), 2-fluorocinnamic acid (1.8 g) and WSC.HCl (2.1 g) were at 0° C. added to methylene chloride (70 mL) suspension of the compound obtained in Example 143 (2.8 g). The mixture was stirred for 4 hours at room temperature. The reaction mixture was washed with water, and thereafter the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel column chromatography (chloroform), to give the captioned compound (2.7 g, 70%) as crystals.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][CH3:32])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.Cl[C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35]>CN1C(=O)CCC1.O>[CH2:31]([C:20]1[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:8][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH3:39])[C:18]=2[N:19]=1)[CH3:32]
Reactant: CCCOC(=O)Cl
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCOC(=O)Nc1nc2ccccc2c2c1nc(CC)n2CCCCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 34.5 %

Procedure:
Triethylamine (1.93 mL, 5 eq) was added to a chilled (ice/water bath) suspension of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (1.0 g, 1 eq) in NMP (6.0 mL). Propyl chloroformate (1.02 g, 3 eq) was added dropwise. The reaction mixture was allowed to come to ambient temperature and stirred for 24 hours. The reaction mixture was diluted with cold water (25 mL) and then extracted with dichloromethane (50 mL). The organic layer was washed sequentially with water (2×50 mL), 4% sodium carbonate (50 mL), water (50 mL), and brine (50 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a linear gradient of 0-25% CMA in chloroform, 2000 mL) followed by recrystallization from acetonitrile to provide 0.427 g of propyl 2-ethyl-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-ylcarbamate as a white solid, mp 155-157° C. Anal calcd for C21H29N5O4S: C, 56.36; H, 6.53; N, 15.65. Found: C, 56.37; H, 6.37; N, 15.70.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Br:9])[CH:3]=1.O1CCCC1.C([Li])CCC.Cl[Si:21]([CH3:24])([CH3:23])[CH3:22]>CO.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]([Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:5]=[C:4]([Br:9])[CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)c1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g of 1,3,5-tribromobenzene was added to 20 mL of tetrahydrofuran and the temperature was adjusted to −78° C. Subsequently, 1.65 mL of butyllithium was slowly added dropwise. The mixture was stirred for 2 hr while maintaining its temperature, and 0.45 g of chlorotrimethylsilane was slowly added dropwise, after which the temperature of the mixture was raised to room temperature. After completion of the reaction, triethylamine and methanol were added, and the reaction mixture was stirred and extracted, followed by drying the solvent. The resulting solid was filtered and purified, yielding (3,5-dibromophenyl)trimethylsilane as an intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])/[CH:14]=[CH:4]/[C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: CC(C)=O
Reactant: O=Cc1c(F)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(/C=C/c1c(F)cccc1Cl)/C=C/c1c(F)cccc1Cl
Temperature: 25 °C
Yield: 51.8 %

Procedure:
(72) To a solution of the 2-chloro-6-fluoro-benzaldehyde (1.59 g, 10.0 mmol) and acetone (290 mg, 5.00 mmol) in 15 ml of ethanol was added 5 ml of 40% potassium hydroxide at 10° C. After stirring for several hours at room temperature, the solution was filtered. The precipitate was recrystallized from ethanol to afford 879 mg (51.7%) of a light-yellow powder: mp 143.5-144.3° C. 1H NMR (250 MHz) δ 7.98-7.91 (d, 2 H), 7.36-7.22 (m, 6 H), 7.13-7.03 (m, 2 H); 13C NMR (62.7 MHz) 189.6, 134.0, 132.1, 131.8, 131.2, 131.0, 126.3, 115.4, 115.0 ppm. Elemental Analysis. Calculated for C17H10Cl2F2O5: C, 60.20; H, 2.98. Found: C, 60.07; H, 2.99
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].N1C=CC=CC=1.[C:18](Cl)(=[O:21])[CH2:19][CH3:20].O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:18](=[O:21])[CH2:19][CH3:20])=[O:6]
Reactant: NNC(=O)c1cccc(I)c1
Reactant: CCC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCC(=O)NNC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 10.5 h
Yield: 65.8 %

Procedure:
3-Iodobenzohydrazide (500 mg, 1.91 mmol) obtained in Step 1 was dissolved in DMF (3.8 mL), and the mixture was stirred at room temperature for 10.5 hours after adding pyridine (0.231 mL, 2.86 mmol) and propionyl chloride (0.183 mL, 2.10 mmol) at 0° C. Water was added to the mixture, stirred, and the precipitated solid was filtered off and dried to give 3-iodo-N′-propionylbenzohydrazide (400 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[CH:11](=[N:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccc(F)cc1F
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(CN=Cc2ccccc2)c(F)c1

Procedure:
50.2 g (0.35 mol) of 2,4-difluorobenzylamine and 37.1 g (0.35 mol) of benzaldehyde are dissolved in 140 ml of toluene and heated to reflux. The water produced is separated off using a water separator. The reaction is complete (GC check) after two hours. The solution is evaporated on a vacuum rotary evaporator. 78.9 g (97% of theory) of a slightly yellow liquid are obtained.
Reaction SMILES: [CH:1]1([C@H:7]([OH:30])[C@H:8]([N:19]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCO.O.NN>CCOCC>[NH2:19][C@@H:8]([C@H:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[OH:30])[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15]
Reactant: CN(C[C@H]([C@@H](O)C1CCCCC1)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: NN
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CN(C[C@@H](N)[C@@H](O)C1CCCCC1)C(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
tert-butyl (2R,3S)-3-cyclohexyl-2-(1,3-dioxoisoindolin-2-yl)-3-hydroxypropyl(methyl)carbamate (500 mg, 1.20 mmol) was dissolved into a minimal volume of EtOH (12 mL) and hydrazine monohydrate (85% in EtOH, 0.35 mL, 6.00 mmol) was added. The solution was heated at 55° C. for 45 min and then the reaction temperature was raised to reflux for 2 h. A white solid formed. The reaction was cooled to rt, Et2O (50 mL) was added and the reaction was filtered. The filtrate was stripped and the residue was stirred in Et2O (15 mL) for 1 h and filtered. The filtrate was stripped to afford tert-butyl (2R,3S)-2-amino-3-cyclohexyl-3-hydroxypropyl(methyl)carbamate (300 mg, yield 87%), which was pure enough to use directly in the next step. MS (E/Z): 287 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=2[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=1.[OH:26][C:27]1[C:31]([CH:32]=[O:33])=[CH:30][N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:32]([C:31]1[C:27]([O:26][CH2:2][C:3]2[CH:23]=[CH:22][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:12][C:13]=3[CH3:14])=[C:5]([O:24][CH3:25])[CH:4]=2)=[N:28][N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=1)=[O:33]
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(CCl)cc2OC)c(C)o1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3C=O)cc2OC)c(C)o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
A mixture of ethyl (2E)-3-{4[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (2.50 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.22 g), potassium carbonate (0.90 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (2E)-3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate as colorless crystals (1.81 g, yield 54%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 150-151° C.