Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)C.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:24]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)CSc1nc2ccccc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1nc2ccccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
To a stirred solution of ethyl 2-(1H-benzo[d]imidazol-2-ylthio)acetate 4a (11.2 g, 47.6 mmol, 1.0 eq.) in 10:1 diethyl ether:dimethylformamide (450 mL) at 0° C., was added 60% sodium hydride in mineral oil (2.09 g, 52.3 mmol, 1.1 eq.), and the reaction was stirred at 0° C. for 20 minutes. Benzyl bromide (9.78 g, 57.1 mmol, 1.2 eq.) was added at 0° C., and the reaction was stirred with warming to room temperature for 16 hours. The reaction mixture was quenched with methanol (100 mL) and concentrated in vacuo. The residue was taken into hot chloroform (400 mL) and filtered. The filtrate was washed with water (200 mL), 1M HCl (200 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (10% EtOAc:90% petroleum ether) gave 4b as a pale-yellow solid (4.82 g, 30%).
Reaction SMILES: CO[C:3](=[O:22])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[CH3:23][NH:24][C:25]([NH2:27])=[O:26].C[O-].[Mg+2].C[O-]>CO>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([NH:27][C:25]([NH:24][CH3:23])=[O:26])=[O:22])=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: COC(=O)C(CC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Yield: 5.9 %

Procedure:
A solution of 2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid methyl ester (75 mg, 0.23 mmol), methylurea (34 mg, 0.46 mmol), and a solution of magnesium methoxide in methanol (7.4 wt. %, 0.49 mL, 0.35 mmol) and methanol (0.5 mL) was heated at 100° C. for 8 h. Over time, the reaction mixture turned cloudy in appearance. At this time, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and then filtered through a pad of silica gel. The filtrate was concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 30/70 hexanes/ethyl acetate) afforded 1-[2-(4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionyl]-3-methyl-urea (5 mg, 6%) as a colorless oil: FAB-HRMS m/e calcd for C17H24N2O5S (M+H)+ 369.1484, found 369.1495.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:23])[CH3:24])=[CH:18][CH:17]=2)[CH2:9][CH2:10][N:11]([C:35](=[O:36])[NH:34][C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)[CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCN(C(=O)Nc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 36 mg (0.1 mmol) [4-(4-Isopropyl-phenylcarbamoyl)-piperidin-4-yl]-carbamic acid tert-butyl ester, 16.5 mg (0.12 mmol) 4-fluorophenyl isocyanate and 32 mg (0.31 mmol) NEt3 in 1 mL DCM was shaken at room temperature over night. After evaporation to dryness the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and HCOOH. The product containing fractions were evaporated to yield 38.5 mg (77%) of the title compound. MS (m/e): 499.3 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][OH:31])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:34]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][O:31][CH3:34])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(CO)nccc4o3)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1nccc2oc(-c3nc(COC4CCN(C(=O)OC(C)(C)C)CC4)no3)cc12
Reaction time: 1.5 h

Procedure:
To a stirred solution of 4-[5-(4-hydroxymethylfuro[3,2-c]pyridine-2-yl)-[1,2,4]oxadiazole-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 24, 50 mg, 116 μmol) in THF was added sodium hydride (60% dispersion in mineral oil, 6 mg, 150 μmol). After effervescence had ceased, MeI (10 μL, 161 μmol) was added. After 90 min, the mixture was poured into H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried and concentrated. Purification via column chromatography afforded the title compound: RT=3.54 min; m/z (ES+)=445.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=3)=[CH:11][N:10]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1.O>CN(C)C=O>[C:20]([NH:19][C:15]1[CH:14]=[C:13]([C:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:38]4[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:40][CH:39]=4)=[O:43])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH:11]=2)[CH:18]=[CH:17][N:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(N)c3)n2)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
40 mg (0,094 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-tert-butylpyridin-2-amine were dissolved in 2 ml of dry dimethylformamide and 12 μL (0.094 mmol) of p-trifluoromethylphenylisocyanate were added. The solution was stirred at room temperature for 3 hours. The reaction mixture was then poured into water and the product extracted several times with ethylacetate. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on a silica gel column eluted with dichloromethane-acetone 9/1, affording 40 mg (70% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].C(O)(=O)C.[N+:27]([O-])([OH:29])=[O:28]>O>[N+:27]([C:13]1[CH:12]=[C:11]([O:14][CH3:15])[C:10]([O:16][CH3:17])=[CH:9][C:8]=1[C:6]([C:5]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:7])([O-:29])=[O:28]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
A mixture of 2.93 g (9.7 mmol) of 3,3',4,4'-tetramethoxybenzophenone (prepared according to Example 1), 9 g of glacial acetic acid and 1.88 g (19.4 mmol) of 65 percent strength nitric acid was stirred at room temperature for 7.5 h. 22 ml of water was then added dropwise, and the resulting precipitate was filtered off, washed 2×6 ml of water and dried to give 2.41 g of a beige solid. The yield of the product was 71.5 percent of theory. Further data concerning the product was:
Reaction SMILES: Br[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:16])[CH2:6][S:5][C:4]=2[CH:3]=1.[CH3:17][Sn](C)(C)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:16])[CH2:6][S:5][C:4]=2[CH:3]=1
Reactant: COC(=O)c1nc2c(cc1Br)SCC(=O)N2
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1nc2c(cc1C)SCC(=O)N2
Yield: 84.8 %

Procedure:
Methyl 7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (Example 304b) (1.50 g, 4.95 mmol), tetramethyltin (1.71 mL, 12 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.84 g, 1.2 mmol) in dimethylformamide (30 mL) were heated at 120° C. for 24 h. The mixture was filtered through Kieselguhr, washed through with ethyl acetate and evaporated. Chromatography on silica gel (10-50% ethyl acetate/petroleum ether) gave the title compound (1.0 g, 85%).
Reaction SMILES: [Br:1][C:2]1(C=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH2:3]1.BrC1C=CC(F)=CC=1[CH2:22][O:23][CH2:24][O:25][CH3:26]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:22][O:23][CH2:24][O:25][CH3:26]
Reactant: COCOCc1cc(F)ccc1Br
Reactant: O=CC1(Br)CC=Cc2ccccc21
Product: COCOCc1ccc2ccccc2c1Br

Procedure:
This compound was made from 1-bromonaphthaldehyde in the same manner as compound 5b: 1H NMR (300 MHz, CDCl3) δ (ppm) 3.42 (s, 3H), 4.75 (s, 2H), 4.81 (s, 2H), 7.5-7.7 (m, 3H), 7.99 (d, J=7.7 Hz, 2H), 8.22 (d, J=7.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH:13]=[O:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][CH2:16][Mg+].[Br-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH:13]([OH:14])[CH2:15][CH3:16])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC[Mg+]
Reactant: O=Cc1ncc(-c2ccc(F)cc2)s1
Agent: [Br-]
Product: CCC(O)c1ncc(-c2ccc(F)cc2)s1
Yield: 72.7 %

Procedure:
Using 5-(4-fluorophenyl)thiazole-2-carbaldehyde (0.12 g, 0.58 mmol) and EtMgBr (0.577 mL, 1.73 mmol) and following the procedure described for example 7 and step 2, the crude compound was obtained and further purified by column chromatography (using 100-200μ silica gel and 38% ethyl acetate and hexane) to give 1-(5-(4-fluorophenyl)thiazol-2-yl)propan-1-ol as pale yellow liquid (0.1 g, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.68-7.65 (m, 2H), 7.25 (t, 2H), 6.11 (d, 1H), 4.72-4.67 (m, 1H), 1.84 (m, 1H), 1.88-1.67 (m, 1H), 0.91 (t, 3H); LC-MS m/z calculated for [M+H]+ 238.06. found 238.5.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[CH:31]1[CH2:34][S:33](=[O:36])(=[O:35])[CH2:32]1>CO>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH:31]4[CH2:34][S:33](=[O:36])(=[O:35])[CH2:32]4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: O=S1(=O)CC(Br)C1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5CS(=O)(=O)C5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (30 mg, 0.072 mmol) in MeOH (1 mL) was added 3-bromothietane 1,1-dioxide (15 mg, 0.079 mmol) followed by TEA (15 mg). The resulting mixture was stirred at room temperature for 5 hr and then concentrated. The resulting residue was purified by preparative RP-HPLC to provide 5-chloro-N2-(2-fluoro-5-methyl-4-(1-(1,1-dioxido-3-thietanyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine. 1H NMR (400 MHz, DMSO-d6+1 drop D2O) δ 8.02 (s, 1H), 7.37 (s, 1H), 7.02 (s, 1H), 6.23 (s, 1H), 4.28-4.22 (m, 2H), 4.12-4.07 (m, 2H), 3.22-3.18 (m, 1H), 2.95-2.92 (m, 2H), 2.68-2.62 (m, 1H), 2.22 (s, 3H), 2.13 (s, 3H), 2.07-2.01 (m, 2H), 1.71-1.55 (m, 4H). ESMS m/z 520.2 (M+H+).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][OH:24].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[C:1]([NH:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][OH:24])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: N[C@@H](CO)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H](CO)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of hydroxysuccinimide ester of oleic acid (395 mg, 1 mmole) in tetrahydrofuran (10 ml) was added to a solution of L-serine (105 mg, 1 mmole) and sodium bicarbonate 84 mg, 1 mmole) in water (10 ml). The reaction mixture was let stirring overnight at room temperature, evaporated down to 10 ml, and acidified to pH 1 with 1 N HCl. The product was extracted with methylene chloride (2×20 mL) and dried (MgSO4) and the solvent evaporated under reduced pressure. The crude material was chromatographed on silica gel (eluting with chloroform:methanol) to give 221.7 mg (60%) as a white powder, m.p. 118 C, NMR (CD3OH, ppm): 5.35-5.32 (m, 2H), 4.57-4.36 (m, 1H), 3.90-3.85 (dd, J=12 Hz, 6 Hz, 1H), 3.82-3.78 (dd, J=12Hz, 6 Hz, 1H), 2.29-2.24 (t, 2H), 2.03-1.98 m, 4H), 1.68-1.58 (m, 2H), 1.32-1.29 (m, 22H), 0.91-0.87 (t, 3H). GC-MS (dTMS): 513, 498, 250, 132 m/z; LC-MS(−p): (M-H)+=368 m/z.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O.[OH-].[Na+].S(OC)(O[CH3:21])(=O)=O>C(Cl)Cl>[CH3:21][O:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5]
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CON=C(C(C)=O)C(=O)OC(C)(C)C
Yield: 93.3 %

Procedure:
To the tert-butyl 2-hydroxyimino-3-oxobutyrate was added water [6 l ], to which was added 30% sodium hydroxide [800 ml] at 28° C. while stirring to render the pH to 9.0. To the resultant solution was added dimethyl sulfate [1324 g] at 28° to 30° C. in the course of 20 minutes, which was stirred for 4 hours while adding thereto at 25° to 30° C. a 30% aqueous solution of sodium hydroxide [500 ml] to adjust the pH within the range of 8.7 to 9.0. After completion of the reaction, extraction was conducted with methylene chloride [4 l ], and the aqueous layer was subjected to further extraction with methylene chloride [2 l ]. The methylene chloride layers were combined and washed with a 1N aqueous solution of sodium hydroxide, 1N HCl, a 5% aqueous solution of sodium hydrogencarbonate and water, each one litre portion, successively. The resultant solution was dried over anhydrous sodium sulfate [700 g], followed by concentration under reduced pressure to obtain tert-butyl 2-methoxyimino-3-oxobutyrate [1878 g] as an oily product. The yield was 93.3%.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2([O:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4].Cl>CO>[CH3:33][N:2]([CH3:1])[C:3](=[O:4])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2([O:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[CH:7]=1
Reactant: COCCOC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: COCCOC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCNCC1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 4-(3-(dimethylcarbamoyloxy)-phenylcarbamoyl)-4-(2-methoxyethoxy)-piperidine-1-carboxylate from step C (150 mg, 0.322 mmol) in methanol (2 mL) was added HCl (4 M solution in dioxane, 0.3 mL). The reaction was heated at 50° C. for 1 hour, and then concentrated under vacuum to provide the title compound as the hydrochloride salt. MS (ES+) [M+H]+=366.3.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]3[CH2:13][CH2:12][CH2:11][C:8]=3[C:9](=[O:10])[N:4]2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:1]3[C:5]4=[N:6][C:7]5[CH2:13][CH2:12][CH2:11][C:8]=5[C:9](=[O:10])[N:4]4[CH:3]=[CH:2]3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=c1c2c(nc3[nH]ccn13)CCC2
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cn2ccn3c(=O)c4c(nc23)CCC4)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,6,7,8-tetrahydro-5H-cyclopent[d]imidazo[1,2-a]pyrimidin-5-one (0.345 g, 1.967 mmol) and 4-(4-chlorobenzoyl)benzyl bromide (0.0650 g, 2.10 mmol) in DMF (15.0 ml)-DMSO (5 ml) was added potassium carbonate (0.30 g, 2.17 mmol) and the mixture was stirred at room temperature overnight. The solvent was then distilled off and the residue was purified by preparative TLC (methylene chloride: methanol=20:1) to provide a colorless amorphous solid.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24]OS(C3C(C)=CC=CC=3)(=O)=O)=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:36].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][F:36])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)OCCCCc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(SCc2ccc(CCCCF)cc2)c(Cl)c1=O
Reaction time: 0.5 h

Procedure:
To a round bottom flask is added 2-tert-butyl-4-chloro-5-(4-(4-toluenesulfonyloxybutyl)benzyl)thio-3(2H)-pyridazinone (0.05 g, 0.093 mmol) and to it is added tetrabutylammonium fluoride (1.0 M solution in THF, 0.93 μl, 0.93 mmol) followed by 0.2 ml of THF. The reaction is heated to 60 C and stirred at that temperature for 30 minutes. The mixture is then cooled and concentrated and the crude subjected to flash chromatography to obtain the above mention compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13](Cl)[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(N(C(C)C)CC)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([N:27]2[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]2)[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Reaction time: 3 h
Yield: 80 %

Procedure:
The mixture of 4,7-dichloro-2-quinolinecarboxylic acid methyl ester (90.2 g, 379 mmol) and N-boc-piperazine (60.1 g, 387 mmol) in dry diisopropylethyl amine (300 mL) was kept at 140 degrees C. for 3 h. After the removal of diisopropylethyl amine in vacuo, ethyl ether was added to precipitate the product. The crude solid was collected by filtration and was purified by re-crystallization from EtOAc (500 mL) to afford 123 g (80%) of 7-chloro-4-[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]-2-quinolinecarboxylic acid methyl ester as an off-white solid. 1H NMR (DMSO-d6): δ 1.42 (s, 18H), 3.18 (m, 4H), 3.61 (m, 4H), 3.92 (s, 3H), 7.47 (s, 1H), 7.63 (d, 1H), 8.04 (d, 1H), 8.1 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH2:19][CH3:20]>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:5][CH2:4][CH3:8])[C:5]([O:7][CH2:10][CH2:2][CH3:3])=[O:6])[CH2:19][CH3:20]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1ccc(OCCC)c(OCCC)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 158.9 %

Procedure:
A mixture of 3,4-dihydroxybenzoic acid (0.65 g; 4.22 mmol), anhydrous K2CO3 (1.75 g; 12.7 mmol) and n-PrBr (1.5 ml; 4 mmol) in anhydrous DMF (5 ml) was stirred at ˜55° C. overnight. After cooling to room temperature, the mixture was diluted to 25 ml with EtOAc, washed with H2O (2×10 ml), brine, dried over anhydrous MgSO4, filtered and the filtrate evaporated to dryness to give the title compound (0.94 g; 80%), as heavy syrup, which was used in next step without further purification. 1H-NMR (CDCl3) 0.97-1.04 (m, 9H); 1.7-1.9 (m, 6H); 3.97-4.02 (m, 4H); 4.2-4.26 (m, 2H); 6.85 (d, 1H, J=8.4 Hz); 7.53 (s, 1H); 7.62 (d, 1H, J=8.4 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])([O-:8])=[O:7].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[N+:6]([C:9]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:10]=1[C:11]([O:13][CH:5]1[CH2:4][CH2:3][CH2:2][O:1]1)=[O:12])([O-:8])=[O:7]
Reactant: C1=COCC1
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(OC1CCCO1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Dihydrofuran (0.03 mole), 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (0.025 mole), methylene chloride (25 ml) and p-toluenesulfonic acid (1 spatula tip) are charged into a glass reaction vessel equipped with a magnetic stirrer. The reaction mixture is stirred at room temperature until the carboxylic acid group can no longer be detected by IR in the mixture. After this time, the reaction mixture is washed with dilute aqueous sodium carbonate and with water. The washed solution was dried and stripped of solvent and unreacted starting material to yield the desired product 2-tetrahydrofuryl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][CH:4]=[C:3]2[O:2][CH3:1]
Reactant: COc1ccnc2c(C)cccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccnc2c(CBr)cccc12

Procedure:
4-Methoxy-8-methylquinoline (346 mg, 2 mmole), N-bromosuccinimide (365 mg, 2.05 mmole) and benzoyl peroxide (10 mg) in CCl4 (8 ml) were heated under reflux for 2.5 hours. The mixture was cooled and the succinimide was filtered off. The filtrate was washed with dilute aqueous NaHCO3 (1×) and water (1×), dried (Na2SO4) and evaporated to yield the sub-title compound as a pale yellow solid which was recrystallised from petroleum ether/cyclohexane to give colourless needles.