Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][N:4]=1.C(N(CC)CC)C.CS([Cl:22])(=O)=O>ClCCl>[Cl:22][CH2:9][C:6]1[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ncc(CO)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ncc(CCl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a cold solution of [2-(methylthio)pyrimidin-5-yl]methanol (0.7813 g, 5.0 mmol) in anhydrous dichloromethane (10 mL, 0° C.) was added triethylamine (0.836 mL, 8.2 mmol) followed by the addition of methanesulfonyl chloride (0.465 mL, 6.0 mmol). The reaction mixture stirred at 0° C. under a nitrogen atmosphere for 30 minutes then at room temperature for 3.5 hours. The reaction was quenched with sodium bicarbonate (5%, 100 mL)) and extracted with dichloromethane (50 mL). The organic extracts were concentrated and the residue was purified by flash chromatography (silica gel) using 15% ethyl acetate in hexane to afford the desired compound (0.720 g, 82%) as a white solid. 1H-NMR ((CD3OD, 400 MHz) δ 8.60 (s, 2H), 4.64 (s, 2H), 2.54 (s, 3H); ES-HRMS m/z 175.0106 (M+H C6H7N2ClS requires 175.0091).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH:17](OC)(OC)OC>CO>[CH3:17][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=1)[OH:11]
Reactant: COC(OC)OC
Reactant: O=C(O)c1cc(F)ccc1O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(F)ccc1O
Temperature: 66 °C

Procedure:
5-Fluorosalicylic acid (272.6 g, 1.74 mol) was dissolved in methanol (1.3 L) to form a clear solution. Concentrated sulfuric acid (50 ml) was slowly added to the methanol solution with vigorous stirring. The solution was heated to reflux for 4 hours. Trimethyl orthoformate (200 ml) was added slowly to the reaction solution. 300 ml of solvents (methyl formate and methanol) was distilled off. The remaining reaction solution was heated at 66° C. (refluxing temperature) for 16 hours. HPLC analysis indicated that the reaction was complete. Reaction solution was cooled to ambient temperature. Solvent was removed under reduced pressure. The residue was partitioned between water (140 ml) and methylene chloride (220 ml). Organic layer was separated. Aqueous layer was extracted with methylene chloride (3×220 ml). The combined organic layer was washed with water (270 ml), brine (270 ml) and dried with MgSO4. The organic solution was concentrated to dryness to afford crude product (293.8 g). This crude material was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 3.96 (s, 3H), 6.94 (dd, 1H, J=4.5 Hz and J=9.0 Hz), 7.19 (m, 1H), 7.50 (dd, 1H, J=3.3 Hz and J=8.7 Hz), 10.508 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[CH3:26])[C:13]21[C:34]1[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=1)[NH:28][C:27]2=[O:36].[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>CN(C=O)C>[Cl:35][C:31]1[CH:30]=[C:29]2[NH:28][C:27](=[O:36])[C:13]3([CH:12]([C:6]4[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:17][C:16](=[O:18])[NH:15][CH:14]3[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[CH3:26])[C:34]2=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCN)C12C(=O)Nc1cc(Cl)ccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCNS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
At 0° C., to a mixture of racemic (2′S,3S,4′R)-4′-[2-(2-amino-ethoxy)5-chloro-phenyl]-6-chloro-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.076 mmol) and methanesulfonyl chloride (85 mg, 0.76 mmol) in DMF (1 mL) was added triethylamine slowly (75 mg, 0.76 mmol). After stirring for 0.5 h, the mixture was filtered, concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (20 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:5]=[N:6][CH:7]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH:26][C:27](=[O:29])[CH3:28])(=[O:25])=[O:24])=[CH:21][CH:22]=3)[CH:10]=[C:11]([C:13]([F:14])([F:16])[F:15])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cncc(C)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
A mixture of 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.5 g, 1.3 mmol), acetic anhydride (0.40 g, 3.9 mmol), DMAP (0.09 g, 0.7 mmol) and triethylamine (0.16 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.4 g (72%) of N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC) 268-270° C. Anal. Calc'd. for C18H15F3N4O3S: C, 50.94; H, 3.56; N, 13.20; S, 7.56. Found: C, 50.68; H, 3.47; N, 12.53; S, 7.43.
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:14])=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:14][CH2:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nccc2c1OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1nccc2c1OCO2

Procedure:
2-Hydroxymethyl-3,4-methylenedioxypyridine (90 mg, 0.59 mmol) was dissolved in methylene chloride (10 ml) and thionyl chloride (240 mg, 2 mmol) was added. After 10 min at ambient temperature the mixture was hydrolysed with sodium hydrogen carbonate and the phases were separated. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 90 mg (88%) of the title compound (crude).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([NH:10][C@H:11]([C:24]([OH:27])([CH3:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([NH:10][C@@H:11]([C:12]2[O:13][C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:15][N:14]=2)[C:24]([OH:27])([CH3:26])[CH3:25])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)C(C)(C)O)ccc(C#N)c1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 36.3 %

Procedure:
The crude material of (R)-N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)benzohydrazide (intermediate 14b) (218 mg, 0.54 mmol) was added to THF (50 mL) stirred at room temperature. PS-BEMP (742 mg, 1.63 mmol base) was added to the solution, followed by slow addition of p-TSCl (114 mg, 0.60 mmol). The reaction mixture was stirred for 1.5 h and the progress of the reaction was monitored by TLC. After the completion of the reaction, the BEMP reagent was filtered off and the solution concentrated to give the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to give the title compound (75 mg, 28%): 1H NMR (500 MHz, CDCl3, δ in ppm) 7.94 (d, J=9 Hz, 2H), 7.54 (m, 1H), 7.46 (m, 2H), 7.34 (d, J=9 Hz, 1H), 6.56 (d, J=9 Hz, 1H), 5.45 (d, J=9 Hz, 1H), 4.71 (d, J=9 Hz, 1H), 3.12 (s, 1H), 2.37 (s, 3H), 1.50 (s, 3H), 1.37 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]#[CH:14])[CH:12]=[C:6]2[C:5]=1[NH:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]1)(=[O:3])[NH2:2].C(N(CC)CC)C.[OH:37]/[N:38]=[C:39](\Cl)/[CH3:40]>ClCCl>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:37][N:38]=[C:39]([CH3:40])[CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:17]1)(=[O:3])[NH2:2]
Reactant: C/C(Cl)=N/O
Reactant: C#Cc1cc2c(N[C@@H]3CN(C(=O)OC(C)(C)C)C[C@@H]3CC)c(C(N)=O)cnn2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cc(C)no3)cc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3-((3-carbamoyl-6-ethynylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate from Step 2 (88 mg, 0.221 mmol) in dichloromethane (2 mL) and triethylamine (0.046 mL, 0.332 mmol) was added (Z)—N-hydroxyacetimidoyl chloride (25.9 mg, 0.277 mmol). The solution was stirred at 40° C. overnight. After stirring overnight, the reaction was cooled to room temperature and diluted with dichloromethane. This solution was washed once with aqueous potassium carbonate, and once with water. It was then dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography, eluting with 0-100% ethyl acetate in hexanes. Concentration of the pure fractions afforded the title compound (64 mg, 60.4% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (t, J=9.1 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J=1.3 Hz, 1H), 7.30 (br. s., 1H), 6.72 (s, 1H), 5.01-4.74 (m, 1H), 3.81-3.58 (m, 2H), 3.48-3.34 (m, 1H), 3.10-2.96 (m, 1H), 2.42 (d, J=12.8 Hz, 1H), 2.28 (s, 3H), 1.60-1.46 (m, 2H), 1.37 (d, J=19.1 Hz, 9H), 0.96-0.75 (m, 3H). MS (ES+) m/z: 455.2 (M+H); LC retention time: 3.038 min (analytical HPLC Method O).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[C:28]([N+:34]([O-])=O)[CH:27]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][C:28]=2[NH2:34])[CH2:12]1)=[O:9])=[O:5]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCl
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Nc1cc(Cl)ccc1CN1CC[C@@H](NC(=O)CNC(=O)c2cc(OC(F)(F)F)ccc2N)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-3-[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 4-chloro-2-nitrobenzyl chloride (0.050 mmol), peperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) was stirred overnight at 50° C. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with 50% CHCl3/CH3OH (10 mL) and CH3OH (10 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material was added ethanol (3 mL) and 10% Pd-C (15 mg), and the mixture was stirred under H2 at room temperature for 1.5 h. Filtration, concentration, and preparative TLC afforded (R)-3-[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}amino]-1-(2-amino-4-chlorobenzyl)pyrrolidine (Compound No. 1921) (2.2 mg, 6%): The purity was determined by RPLC/MS (81%); ESI/MS m/e 486.2 (M++H, C21H23ClF3N5O3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:18])[CH:12]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH3:20][C:21]1[CH:22]=[N+:23]([O-])[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH:12]2[CH2:13][C:14]([CH3:16])([CH3:17])[CH2:15]2)[NH:18][C:22]2[C:21]([CH3:20])=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C(N)C2CC(C)(C)C2)cc1
Reactant: Cc1cc2ccccc2[n+]([O-])c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 64.3 %

Procedure:
(+/−)-4-[amino-(3,3-dimethyl-cyclobutyl)-methyl]-benzoic acid ethyl ester (Intermediate 24) (45 mg, 0.17 mmol) was combined with 3-methylquinoline-N-oxide (27.4 mg, 0.172 mmol, Alfa Aesar, Ward Hill, Mass., USA) and dichloromethane (2 mL). Diisopropylethylamine (0.112 mL, 0.645 mmol) was added followed by bromotripyrrolidinophosphonium hexafluorophosphate (109 mg, 0.224 mmol). The solution was stirred at room temperature for 28 h before partitioning between ethyl acetate and aq. sat. NaHCO3. The separated aqueous layer was extracted with additional ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid ethyl ester (44.0 mg) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.4 Hz, 2H) 7.56-7.62 (m, 2H) 7.46-7.53 (m, 3H) 7.38-7.46 (m, 1H) 7.12-7.20 (m, 1H) 5.33 (dd, J=9.5, 6.7 Hz, 1H) 4.77 (d, J=6.6 Hz, 1H) 4.34 (q, J=7.2 Hz, 2H) 2.67 (sxt, J=8.8 Hz, 1H) 2.30 (s, 3H) 1.97 (ddd, J=11.1, 8.1, 3.2 Hz, 1H) 1.74-1.85 (m, 1H) 1.66-1.73 (m, 2H) 1.36 (t, J=7.1 Hz, 3H) 1.16 (s, 3H) 1.10 (s, 3H); MS (M+1): 403.3.
Reaction SMILES: C(#N)C.[ClH:4].[CH3:5][N:6]([CH3:13])[CH2:7]/[CH:8]=[CH:9]/[C:10](O)=[O:11].C(Cl)(=O)C([Cl:17])=O.C(OC)(=O)C(OC)=O>CN(C)C=O>[ClH:17].[CH3:5][N:6]([CH3:13])[CH2:7][CH:8]=[CH:9][C:10]([Cl:4])=[O:11]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: COC(=O)C(=O)OC
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)CC=CC(=O)Cl

Procedure:
A 1 L multi-neck flask equipped with agitator, thermometer, addition funnel, and nitrogen protection is charged with acetonitrile (0.67 kg, 0.85 L) followed by adding dimethylformamide (0.00086 kg, 0.91 mL, d=0.944 g/mL). At ambient temperature, is added 4-dimethylaminocrotonic acid hydrochloride (0.0709 kg) and the mixture stirred until homogeneous. Cool the reaction mixture to (0–10° C.) and add oxalyl chloride (0.0473 kg, 0.0325 L, d=1.45 g/mL) dropwise over (20 minutes) at (0–10° C.) followed by a rinse with acetonitrile (0.02 kg, 0.03 L). The temperature (0–10° C.) is maintained for about (20 minutes). The temperature of the reaction mixture is adjusted to (22–26° C.) over (20 minutes) and maintained over (2 hours). The temperature of reaction mixture is adjusted to (40–45° C.) and held for about (5 minutes). Cool the light suspension to about (20–25° C.) and check for reaction completion by high-pressure liquid chromatography (HPLC). The reaction is complete when there is ≦15% of the starting material (4-dimethylaminocrotonic acid hydrochloride) present and/or ≦2% of oxalyl chloride (detected as the dimethyl oxalate).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.[OH:31][C:32]1[C:36](/[CH:37]=[CH:38]/[C:39]2[N:40]=[C:41]([N:45]3[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]3)[S:42][C:43]=2[CH3:44])=[CH:35][N:34]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[N:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]3[CH:27]=[CH:28][C:3]([CH2:2][O:31][C:32]4[C:36](/[CH:37]=[CH:38]/[C:39]5[N:40]=[C:41]([N:45]6[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]6)[S:42][C:43]=5[CH3:44])=[CH:35][N:34]([C:58]5[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=5)[N:33]=4)=[CH:4][C:5]=3[O:29][CH3:30])[N:10]=2)=[CH:20][CH:19]=1)[CH3:26]
Reactant: Cc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1/C=C/c1cn(-c2ccccc2)nc1O
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCN(C(=O)OC(C)(C)C)CC5)sc4C)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.66 g), tert-butyl 4-{4-[(E)-2-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-5-methyl-1,3-thiazol-2-yl}piperazine-1-carboxylate (0.81 g), potassium carbonate (0.22 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with tetrahydrofuran-hexane (1:5, v/v) to give tert-butyl 4-{4-[(E)-2-(3-{[4-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)-3-methoxybenzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)ethenyl]-5-methyl-1,3-thiazol-2-yl}piperazine-1-carboxylate as crystals (0.53 g, yield 41%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 112-114° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH3:22].[CH3:23][S-:24].[Na+]>CN(C)C=O>[CH3:22][C:9]1[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:24][CH3:23])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCCCCl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCCCCCn1c(C)nc2c(N)nc3ccccc3c21
Temperature: 160 °C
Yield: 57.1 %

Procedure:
1-(6-Chlorohexyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.5 g, 8 mmol), sodium thiomethoxide (1.13 g, 15.5 mmol) and N,N-dimethylformamide (15 mL) were combined and heated at 160° C. for 3 hours. The reaction was quenched with water and the precipitate isolated to provide 1.5 g of 2-methyl-1-[6-(methylthio)hexyl]-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]=O)=[C:6]([CH:15]=1)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.O>CC(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:7][C:8]3[C:13]([N:16]=2)=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=3)[CH:15]=1
Reactant: O=Nc1ccc(Br)cc1Nc1ccc(Br)cc1
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2nc3cc(Br)ccc3nc2c1
Yield: 16 %

Procedure:
5-bromo-N-(4-bromophenyl)-2-nitrosoaniline (13-1) (10 g, 28.1 mmol) in AcOH (300 mL) was heated under reflux for 1.5 hrs. Water (400 mL) was then added and the brown precipitate formed was collected by filtration after washing with water (2×200 mL). The product was purified by silica gel chromatography (SiO2, hexanes/DCM=1/1(v/v)) to afford a brown solid, 2,7-dibromophenazine 13-2 (1.52 g, 16% yield). 1H NMR (CDCl3): δ 8.43 (2H, dd, J 2.2, 0.4 Hz), 8.10 (2H, dd, J 9.2, 0.4 Hz), 7.91 (2H, dd, J 9.2, 2.2 Hz) ppm. LC-MS (ESI): m/z 338.6 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc(Cl)c2)cc1-c1c(Br)cnn1C
Yield: 92.2 %

Procedure:
To a stirred solution of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.015 g, 0.051 mmol) in CH2Cl2 (1 mL) was added 3-chlorophenyl isocyanate (0.008 g, 7 μL, 0.054 mol, 1.05 equiv.). After the TLC showed the consumption of the starting material, it was isolated by preparative thin layer chromatography (TLC) (Eluent: EtOAc/Hexane=1/1) and Compound 20 (0.020 g, 0.047 mmol, 92%) was obtained as a solid film. LCMS m/z (%)=435 (M+H79Br, 68), 437 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.29 (s, 1H), 8.19 (s, 1H), 7.80 (t, J=1.9 Hz, 1H), 7.29 (dd, J=2.7, 9.0 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([OH:3])=O.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:27]1([C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=[C:8]2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:3])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)O
Reactant: C1CCNC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 103.2 %

Procedure:
To a stirring solution of (RS) 1-[3-carboxybutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (0.700 g, 1.9 mmol) in N,N-dimethylformamide (40 ml) were added sequentially pyrroldine (155 mg, 1.1 eq), 1-hydroxybenzotriazole (282 mg, 1.1 eq), and dicyclohexylcarbodiimide (431 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concentrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 0.835 grams of the title product as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1.[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][CH2:23][NH:22][C:21]2=[O:26])[CH2:16][CH2:15]1>C(O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][CH2:23][NH:22][C:21]2=[O:26])[CH2:16][CH2:15]1
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: COc1ccccc1OCC1CO1
Solvent: CCO
Product: COc1ccccc1OCC(O)CN1CCC(N2CCCNC2=O)CC1

Procedure:
A solution of 9 g of 1-(o-methoxy-phenoxy)-2,3-epoxypropane and 9.15 g of 1(4-piperidyl)-2-oxo-hexahydro-pyrimidine in 7 ml of abs. ethanol is heated for 5 hours to 95° C and then evaporated in vacuo. The residue is recrystallised from ethyl acetate/petroleum ether to yield the 1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 130°-133° C.