Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][N:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>C1COCC1>[Br:39][CH2:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:18])([F:17])[F:1])[CH:14]=1
Reactant: OCc1ccnc(-c2ccccc2C(F)(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1-c1cc(CBr)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
495 mg (1.96 mmol) of the compound from Example 61A and 615 mg (2.35 mmol) of triphenylphosphine were dissolved in 15 ml of THF, and 778 mg (2.35 mmol) of carbon tetrabromide were added at RT. After the addition had ended, the mixture was stirred ar RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: first cyclohexane/ethyl acetate 70:30, then ethyl acetate). This gave, in a purity of 90%, 149 mg (22% of theory) of the target compound, which were immediately reacted further.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[F:36][C:37]([F:41])([F:40])[CH2:38][NH2:39].C(N(CC)CC)C>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:5][OH:6])=[N:39][CH2:38][C:37]([F:41])([F:40])[F:36]
Reactant: ON=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: NCC(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: ONC(=NCC(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 75 °C
Yield: 40 %

Procedure:
To a solution of 2-Chloro-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzaldehyde oxime (i.e. the product of Step 3, 250 mg) in DMF (5 mL) was added N-chloro succinimide (81 mg) and heated to 75° C. for 1 h. After cooling, the reaction mixture was poured onto ice-water and extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4) and concentrated in vacuo to ¼ the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of 2,2,2-trifluoro ethylamine (57 mg) and triethylamine (0.15 mL, 0.11 g) in THF (10 mL) and stirred at room temperature over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (122 mg, 40%).
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[Cl:22][C:23]1[CH:24]=[C:25]([O:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[CH:26]=[C:27]([Cl:35])[C:28]=1[CH2:29]OS(C)(=O)=O>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([O:36][S:37]([C:40]([F:42])([F:43])[F:41])(=[O:39])=[O:38])[CH:26]=[C:27]([Cl:35])[C:28]=1[CH2:29][CH:10]1[CH2:11][CH2:12][N:8]([C@H:5]2[CH2:6][CH2:7][C@@H:2]([F:1])[CH2:3][CH2:4]2)[C:9]1=[O:13]
Reactant: O=C1CCCN1[C@H]1CC[C@@H](F)CC1
Reactant: CS(=O)(=O)OCc1c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1[C@H]1CC[C@@H](F)CC1
Reaction time: 8 h

Procedure:
To a solution of cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one (252 mg, 1.36 mmol) in 13 mL dry THF, add 1.09 mL of 2M LDA (1.2 eq.) in THF dropwise at −78° C. Then, add 821 mg of trifluoro-methanesulfonic acid 3,5-dichloro-4-methanesulfonyloxymethyl-phenyl ester (1.5 eq) at −78° C. Allow the resulting solution to stand at room temp for overnight. Quench the mixture with saturated aqueous NH4Cl and extract with CH2Cl2. Wash the organic layer with water, then brine, and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 358 (M+1).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17](=[O:26])(=[O:25])[NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>C1COCC1>[CH3:24][N:22]([CH3:23])[CH2:21][CH2:20][CH2:19][NH:18][S:17]([C:4]1[S:3][CH:2]=[C:6]([C:7]2[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=2[CH3:16])[CH:5]=1)(=[O:26])=[O:25]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCCN(C)C)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)NCCCN(C)C)c2)s1
Temperature: -70 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
N-{5-[2-Bromo-5-(3-dimethylamino-propylsulfamoyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (200 mg; 0.42 mmol; 1 eq), is dissolved in anhydrous THF (50 ml). The reaction mixture is cooled to down to −70° C. and put under nitrogen. n-Butyllithium (2.1 ml; 1.6 M; 3.32 mmol; 8 eq) is added dropwise. After 2 h 30, the reaction is complete and is quenched with water. Solvents are evaporated and the resulting mixture is purified by preparative HPLC affording Compound (27) as a brown oil (120 mg; 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:30]C(OC(C)(C)C)=O)[C:10](=[O:29])[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:23]3[CH:27]=[CH:26][NH:25][C:24]3=[O:28])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[C:39]([N:46]1[CH2:49][CH:48]([C:50]([OH:52])=O)[CH2:47]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:30][C:50]([CH:48]2[CH2:47][N:46]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:49]2)=[O:52])[C:10](=[O:29])[N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:23]3[CH:27]=[CH:26][NH:25][C:24]3=[O:28])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2-n2cc[nH]c2=O)CC1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3-n3cc[nH]c3=O)CC2)C1
Yield: 76 %

Procedure:
The title compound was prepared according to the procedure described in Example 10 (Step b) using N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(2-oxo(4-imidazolinyl))phenyl]-piperidyl)ethyl) (tert-butoxy)carboxamide (Example 18 Step b) (0.227 g, 0.433 mmol) and satd HCl in EtOAc (20 mL), followed by Boc-azetidine-3-carboxylic acid (PepTech Corporation) (0.105 g, 0.52 mmol), EDC (Advanced ChemTech) (0.125 g, 0.65 mmol), HOBT (Novabiochem) (0.058 g, 0.433 mmol) and TEA (Aldrich) (0.058 mL, 0.433 mmol) in CH2Cl2 (10 mL). Purification by silica gel chromatography (100% EtOAc then 1:9 MeOH:EtOAc) provided the title compound as a white foam (0.2 g). MS (ESL pos. ion) m/z: 608 (M+1). Calc'd for C32H38ClN5O5: 607.26.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][SH:8])=[CH:5][CH:4]=1.C[O-].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:8][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:5][CH:4]=1
Reactant: OCCCCCCCCCCCCBr
Reactant: COc1ccc(CS)cc1
Agent: C[O-]
Solvent: CO
Product: COc1ccc(CSCCCCCCCCCCCCO)cc1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
Na (800 mg, 34.8 mmol) was dissolved in 30 mL of dry MeOH. Under argon, p-methoxybenzylmercaptan (2.75 mL, 3.04 g, 19.7 mmol) was added to the methoxide solution. After a few minutes, 12-bromododecanol (2.5 g, 9.43 mmol) was dropped into the reaction mixture. Within 5 minutes a solid began to come out of solution. After a minimum of 3 h, the reaction was filtered and washed 3× with cold MeOH, yielding 2.874 g (8.49 mmol, 90%) of pure product after drying. 1H NMR (CDCl3): d 7.23 (d, J=8.8 Hz, 2H, AA′ of AA′ BB′ aromatic system), 6.85 (d, J=8.8 Hz, 2H, BB′ of AA′ BB′ aromatic system), 3.80 (s, 3H, methoxy), 3.66 (s, 2H, benzyl), 3.64 (dt, J1=6.6 Hz, J2=5.5 Hz, 2H, RCH2OH), 2.40 (t, J=7.3 Hz, 2H, RSCH2R), 1.50–1.65 (cm, 4H, CH2 b to heteroatoms), 1.2–1.4 (cm, 16H, bulk methylenes).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[NH:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]([NH2:29])=[O:28])=[CH:26][C:21]=2[N:20]=[CH:19]1>>[F:17][C:13]1[CH:12]=[C:11]([CH:9]([NH:8][C:6]2[N:7]=[C:2]([N:20]3[C:21]4[CH:26]=[C:25]([C:27]([NH2:29])=[O:28])[CH:24]=[CH:23][C:22]=4[N:18]=[CH:19]3)[CH:3]=[N:4][CH:5]=2)[CH3:10])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(Nc1cncc(Cl)n1)c1cccc(F)c1
Reactant: NC(=O)c1ccc2[nH]cnc2c1
Product: CC(Nc1cncc(-n2cnc3ccc(C(N)=O)cc32)n1)c1cccc(F)c1
Yield: 21.3 %

Procedure:
In an analogous fashion, to Example 3, 6-chloro-N-[1-(3-fluorophenyl)ethyl]pyrazin-2-amine (025 g, 1 mmol) was reacted with 1H-benzimidazole-5-carboxamide (0.2 g, 1.2 mmol) to afford the product as a mixture of isomers. These were separated by chromatography using dichloromethane-methanol (98:2-92:8) as eluant to afford from the less polar fractions 1-(6-{[1-(3-fluorophenyl)ethyl]amino}pyrazin-2-yl)-1H-benzimidazole-6-carboxamide (80 mg).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][N:32]=2)[C:27]([CH:34]=O)=[CH:26]1>CO.N1CCCCC1>[NH:25]1[C:33]2=[N:32][CH:31]=[CH:30][CH:29]=[C:28]2[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[CH:26]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2c[nH]c4ncccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0251 g, 0.0755 mmol) obtained in Example A56, Step 3 in methanol (2 mL) was added with 7-azaindole-3-carboxaldehyde (0.0116 g, 0.0793 mmol) and piperidine (5 drops), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0269 g, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)[CH:13]=[CH2:12]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(CC(=O)O)cc1

Procedure:
p-Hydroxyphenylacetic acid (5.0 g) is dissolved in 30 ml of dimethyl formamide, 10 ml of allyl bromide and 10 g of anhydrous potassium carbonate are added thereto, and the mixture is heated at 70°-80° C. for six hours with stirring. The reaction solution is diluted with 300 ml of water, extracted with ether, the resulting extract is dissolved in 100 ml of methanol, and the mixture is heated to reflux for one hour with 30 ml of 15% aqueous solution of potassium carbonate. The reaction solution is then concentrated in vacuo, 100 ml of water is added thereto, the mixture is washed with ether, acidified with hydrochloric acid, and extracted with ether to give 5.0 g of p-allyloxyphenylacetic acid, melting point: 61°-62° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([O:22]CC)=O.[CH:25]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([CH2:31][NH:32][C:20]([C:3]2[C:4](=[O:19])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=3)=[O:22])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NCC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Product: O=C(NCC1CCCCC1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2 dihydro-1,5-naphthyridine-3-carboxylate and cyclohexylmethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.80 (1H, br), 8.32 (1H, br s), 7.39 (1H, s), 7.35-7.22 (5H, m), 4.05 (2H, br s), 3.17 (2H, t, J=6 Hz), 1.71-0.79 (11H, m); HRMS calcd for C23H25N3O3+H+: 392.1974. Found: 392.1956.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([NH:21][C@H:22]([CH:27]([CH3:29])[CH3:28])[C:23]([O:25]C)=[O:24])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[N:9][CH:10]=1.Cl>O.CO.O1CCCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([NH:21][C@H:22]([CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[N:9][CH:10]=1
Reactant: COC(=O)[C@H](NS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](NS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1)C(=O)O
Temperature: 45 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of lithium hydroxide monohydrate (0.35 g, 8.3 mmol) in water (5 ml) was added to a solution of methyl (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1 sulfonyl]amino}-3-methylbutyrate (1.7 g, 4.2 mmol), [prepared as described in Example 2], in methanol/tetrahydrofuran (1:1, 25 ml) and the reaction mixture was warmed to 45° C. After stirring overnight, reaction mixture was adjusted to pH 6 using 1M HCl and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (SiO2, 2% methanol/methylene chloride) to give 2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyric acid as a white gummy solid (66%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Br:23])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([C:15]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)=[O:16])[CH:18]=[C:19]([Br:23])[C:20]=1[O:21][CH3:22]
Reactant: c1cc2c(cn1)NCCO2
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ccncc32)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
To a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (100 mg, 0.73 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (240 mg, 0.73 mmol) were dissolved in dichloromethane. Triethylamine (0.51 ml, 3.7 mmol) was added thereto and then stirred at room temperature for 5 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=20:1. The fractions containing the product were collected and evaporated to obtain the target compound 2 as white solid (190 mg, 61%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:16][CH2:17][OH:18])([CH3:15])[C:12](=[O:14])[N:13]=1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:20]([O:18][CH2:17][CH2:16][C:11]1([CH3:15])[S:10][C:9]([NH:8][CH:2]2[CH2:3][CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[N:13][C:12]1=[O:14])(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1
Reactant: CC1(CCO)SC(NC2CC3CCC2C3)=NC1=O
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(CCOC(=O)c2ccncc2)SC(NC2CC3CCC2C3)=NC1=O
Temperature: 120 °C

Procedure:
A mixture of 2-(bicyclo[2.2.1]heptan-2-ylamino)-5-(2-hydroxyethyl)-5-methylthiazol-4(5H)-one (0.080 g, 0.30 mmol), isonicotinoyl chloride hydrochloride (0.056, 0.30 mmol), and N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) in CH2Cl2 (1.0 mL) was heated in a sealed tube in a microwave oven (SmithSynthesizer from Personal Chemistry) at 120° C. for 10 min. The reaction mixture was conc. in vacuo, and the residue was partitioned between EtOAc and water. The organic portion was separated, washed with brine, conc. in vacuo, and purified by RP-HPLC to give the title compound as a white solid. MS m/z: 374.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=3)[CH:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:7][C:6]2=[O:22])[CH2:3][CH2:2]1.[H-].[Na+].[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29]Cl)[CH3:26].O.N>O.CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=3)[CH:8]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:7]([CH2:26][CH2:25][N:27]([CH2:31][CH3:32])[CH2:28][CH3:29])[C:6]2=[O:22])[CH2:2][CH2:3]1
Reactant: O=C1NC(c2ccccc2)c2cc(Cl)ccc2N1CC1CC1
Reactant: CCN(CC)CCCl
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCN1C(=O)N(CC2CC2)c2ccc(Cl)cc2C1c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 3.1 g. of 1-cyclopropylmethyl-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone in 50 ml. of dimethylformamide was added 0.42 g. of 63% sodium hydride, and the resulting mixture was stirred at 50° C. for 30 minutes. Thereafter, 2.7 g. of β-diethylaminoethyl chloride was added, and the mixture was stirred at 100° C. for 8 hours. After cooling, the reaction mixture was poured into 300 ml. of water, and ammonia water was added thereto to make alkaline. The resulting mixture was extracted with benzene. The benzene layer was washed with water and dried, and then the solvent was removed under reduced pressure. The residue was dissolved in 50 ml. of ether, and the insoluble material were separated by filtration. The filtrate was extracted with 50 ml. of 5% hydrochloric acid, and the water layer was further washed with ether, made alkaline by addition of ammonia water and then extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed to obtain oily 1-cyclopropylmethyl-3-(β-diethylaminoethyl)-3,4-dihydro-4-phenyl-6-chloro-2(1H)-quinazolinone.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][C:20]4(OCC[O:23]4)[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:14]([CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCN1CCC2(CC1)OCCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCN(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 119.4 %

Procedure:
A mixture of 0.39 g of 1-[2-(4-chloro-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4,4-ethylenedioxypiperidine and 4 ml of concentrated sulfuric acid was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice-water, adjusted to pH 11 with 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and dried, and then the solvent was evaporated to give 0.42 g of a colorless liquid. The resulting liquid was purified by alumina column chromatography using ethyl acetate—n-heptane (1:1) as an eluting solvent to give 0.32 g of colorless crystals. Recrystallization from isopropanol gave colorless needles having the melting point of from 163 to 165° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(O[CH2:17][CH3:18])=O>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:17]([O:11][C:10]([C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 1.62 g of (1R, 2R)-2-phenyl-cyclopropane carboxylic acid (from racemic trans-2-phenyl-cyclopropane carboxylic acid by resolution on a chiral HPLC column) and 2.0 mL of triethylamine and 0.12 g of 4-dimethylaminopyridine was added 1.2 mL of ethyl chloroformate The mixture was allowed to warm and stir for 1 h, then washed with 25 mL of 3N HCl, 25 mL of water, 25 mL of saturated sodium carbonate and dried over magnesium sulfate. Removal of solvents under reduced pressure gave 1.9 g of product as an oil: MS (m+1)=191.1; 1H NMR (400 MHz, CDCl3) 7.3 (dd, 2H), 7.2 (t, 1H), 7.1 (d, 2H), 4.18 (q, 2H), 2.5 (m, 1H), 1.9 (m, 1H), 1.6 (m, 1H), 1.3 (overlapping m and t, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:18]Br.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:18][C:7]1[CH:6]=[C:5]([CH:8]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)C(CC(C)C)c1ccc(O)cc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1ccc(O)c(Br)c1

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)-4-methylpentanoate E-9 (15 g, 63.55 mmol) in 100 ml of glacial acetic acid at 0° C., slowly added bromine (20.26 g, 64.14 mol) and stirred at same temperature for 2.5 h. After completion the reaction, the reaction mixture was poured into water and neutralized with saturated sodium carbonate solution and extracted with ethyl acetate (300 ml×3). The organic layer was washed with water, saturated sodium bicarbonate solution and brine. The organic layer was then distilled off to yield product ethyl 2-(3-bromo-4-hydroxyphenyl)-4-methylpentanoate. Yield: (16 g, 80%). 1H NMR (CDCl3): δ 7.20 (m 2H), 6.80 (d, J=7.9 Hz, 1H), 4.90 (bs,1H),4.15 (q, 2H), 3.60 (t, 1H),1.95-2.00(m,1H), 1.75-1.80(m,1H), 1.45-1.50(m,1H), 1.20 (t,3H), 1.00 (m, 6H). Mass: (315, M+1, 100%).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH:15]=[O:16]>O1CCCC1>[F:11][C:12]1[CH:13]=[C:14]([CH:15]([OH:16])[CH2:4][N+:1]([O-:3])=[O:2])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add nitromethane (200 mL, 2.5 eq) to a suspension of potassium carbonate (30 g) and 3,5-difluorobenzaldehyde (200 g) in tetrahydrofuran (600 mL) at room temperature. Stir at room temperature overnight, filter, wash with ethyl acetate and concentrate to give the title compound as a crude oil (330 g) which is used in the next step without further purification.