Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12]([I:13])=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-].C(Cl)Cl>CO.[Fe]>[CH:1]1([C:4]2[O:5][C:6]3[C:12]([I:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(I)c2oc(C3CC3)cc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(I)c2oc(C3CC3)cc2c1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a solution of the title compound from Step 1 (2.0 g, 6.0 mmol) and Fe (1.0 g, 18 mmol) in MeOH (80 mL) was added sat. NH4Cl solution (10 mL). The reaction mixture was refluxed for 1 h. The mixture was cooled to room temperature and poured into 400 mL of DCM. The resulting mixture was filtered and the filtrate was washed with water (100 mL) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (1.5 g, 83% yield) as red oil that was used for the next step directly. 1H NMR (CDCl3, 400 MHz): δ 6.87 (d, J=2.4 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.19 (s, 1H), 3.45 (br, 2H), 1.97-1.90 (m, 1H), 0.95-0.85 (m, 4H). LCMS: 300 (M+1)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 85 °C

Procedure:
The title compound was prepared as a white solid from [4-(methylsulfonyl)phenyl]boronic acid (0.44 g, 2.15 mmol), 1,1-dimethylethyl 4-{[(6-chloro-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.54 g, 1.65 mmol), 2M Na2CO3 (5 mL) and PdCl2(PPh3)2 (0.12 g) in DMF (20 mL). The reaction mixture was heated at 85° C. under N2 for 5 h, then cooled to ambient temperature, and extracted with EtOAc (70 mL×2). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a gray solid. The crude product was purified by chromatography on a silica gel column eluted with 25% EtOAc/CH2Cl2 to give the title compound (0.44 g, 60%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.36 (d, 1H, J=2.9 Hz), 8.18 (d, 2H, J=8.6 Hz), 8.02 (d, 2H, J=8.3 Hz), 7.92 (d, 1H, J=8.8 Hz), 7.49 (dd, 1H, Ja=8.8 Hz, Jb=2.9 Hz), 4.20-4.10 (m, 2H), 3.99 (d, 2H, J=6.3 Hz), 3.15 (s, 3H), 2.90-2.75 (m, 2H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.25 (m, 2H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:35]=[CH:34][C:11]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19](=O)[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=4)[NH:24][CH:23]=3)=O)[CH2:15][CH2:14]2)=[CH:10][CH:9]=1>O1CCCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[CH:29]=4)[NH:24][CH:23]=3)[CH2:17][CH2:18]2)=[CH:34][CH:35]=1
Reactant: COc1ccc2[nH]cc(C(=O)C(=O)N3CCC(Oc4ccc(F)cc4)CC3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(CCN3CCC(Oc4ccc(F)cc4)CC3)c2c1

Procedure:
By following the manipulative procedure described in Example 2(d), 8.0 g of lithium aluminum hydride in 235 ml. of tetrahydrofuran and 18.0 g of 4-(p-fluorophenoxy)-1-(5-methoxyindol-3-ylglyoxyloyl)piperidine in 190 ml. of tetrahydrofuran are reacted to produce a white solid. The solid is recrystallized twice from 95% ethanol (charcoal treatment) to give white crystals of 3-{2-[4-(p-fluorophenoxy)piperidyl]ethyl}5-methoxyindole, m.p. 132°-134° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:25][CH2:26][CH2:27][CH2:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30]([OH:32])=O.Cl.Cl.[CH3:42][O:43][C:44]1[CH:45]=[C:46](/[CH:56]=[CH:57]/[C:58]([NH:60][NH2:61])=[O:59])[CH:47]=[CH:48][C:49]=1[N:50]1[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:42][O:43][C:44]1[CH:45]=[C:46](/[CH:56]=[CH:57]/[C:58]([NH:60][NH:61][C:30](=[O:32])[CH:29]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH2:28][CH2:27][CH2:26][Cl:25])=[O:59])[CH:47]=[CH:48][C:49]=1[N:50]1[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]1
Reactant: COc1cc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Reactant: O=C(O)C(CCCCl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(/C=C/C(=O)NNC(=O)C(CCCCl)c2ccc(Cl)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 158.4 %

Procedure:
IPEA (6.02 mL) and BOPCl (1.79 g) were added to a solution of 5-chloro-2-(4-chlorophenyl)pentanoic acid (1.55 g) and (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid hydrazide dihydrochloride (2.03 g) in methylene chloride (80 mL), and the reaction solution was stirred at room temperature for two hours. Dichloromethane and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 4.67 g of the title compound in an unrefined state. The property value of the compound is as follows.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.O.[CH2:20]([O:22][C:23]([CH2:25][S:26][C:27]1[S:28][C:29]([SH:32])=[N:30][N:31]=1)=[O:24])[CH3:21].P(Cl)(Cl)(OP(Cl)(Cl)=O)=O>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:32][C:29]3[S:28][C:27]([S:26][CH2:25][C:23]([O:22][CH2:20][CH3:21])=[O:24])=[N:31][N:30]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCOC(=O)CSc1nnc(S)s1
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CSc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Yield: 91.9 %

Procedure:
The procedure was carried out in accordance with Example 22, while utilizing 1.36 g of 7-ACA, 0.36 g of water, 8.0 ml of acetonitrile, 1.54 g of 2-ethoxycarbonylmethylthio-5-mercapto-1,3,4-thiadiazole and 5.04 g of diphosphoryl tetrachloride, and there was obtained 2.06 g (91.8%) of 7-amino-3-(2-ethoxycarbonylmethylthio-1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11](CC3C=CC(OC)=C(OC)C=3)[CH:10]([CH2:25][N:26]([CH:40]([CH3:42])[CH3:41])[C:27](=[O:39])[C:28]3[CH:33]=[CH:32][C:31]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:30][CH:29]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH2:25][N:26]([CH:40]([CH3:42])[CH3:41])[C:27](=[O:39])[C:28]3[CH:33]=[CH:32][C:31]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:30][CH:29]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2CN(C(=O)c2ccc(NS(C)(=O)=O)cc2)C(C)C)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CC1CN(c2cccc(Cl)c2)CCN1)C(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
In a manner similar to Example 11, react N-[[4-(3-chlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]piperazin-2-yl]methyl]-N-(1-methylethyl)-4-[(methylsulfonyl)amino]benzamide with methoxybenzeneand a 5% solution of concentrated H2SO4 in trifluoroacetic acid to obtain the title compound.
Reaction SMILES: C([S:4][CH2:5][CH2:6][N:7]1[C:25](=[O:26])[N:10]2[C@@H:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=[CH:13][C@H:14]([C:15]([O:17]C)=[O:16])[N:9]2[C:8]1=[O:27])(=O)C.Cl>>[SH:4][CH2:5][CH2:6][N:7]1[C:25](=[O:26])[N:10]2[C@@H:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=[CH:13][C@H:14]([C:15]([OH:17])=[O:16])[N:9]2[C:8]1=[O:27]
Reactant: COC(=O)[C@H]1C=C[C@H](c2ccccc2)n2c(=O)n(CCSC(C)=O)c(=O)n21
Agent: Cl
Product: O=C(O)[C@H]1C=C[C@H](c2ccccc2)n2c(=O)n(CCS)c(=O)n21
Yield: 43 %

Procedure:
Methyl trans-2-(2-acetylthioethyl)-2,3,5,8-tetrahydro-1,3-dioxo-8-phenyl-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate was hydrolyzed in 2-M hydrochloric acid at 100° C. for 3.5 hours. Partial evaporation then gave in 43% yield trans-2,3,5,8-tetrahydro-2-(2-mercaptoethyl)-1,3-dioxo-8-phenyl-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid of melting point 153°-154° C.
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][O:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:26][C:27]1[CH:41]=[CH:40][C:30]([CH2:31][S:32][CH:33]2[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.O>CCCCCC.CS(C)=O>[CH3:4][O:5][CH:6]=[C:36]1[CH2:37][CH2:38][CH:33]([S:32][CH2:31][C:30]2[CH:40]=[CH:41][C:27]([Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(SCc2ccc(Cl)cc2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: O
Product: COC=C1CCC(SCc2ccc(Cl)cc2)CC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
After 146 mg (3.34 mmol) of 55% sodium hydride were washed with hexane, it was suspended in 18 ml of dimethyl sulfoxide, followed by stirring of the resulting suspension at 55° C. for 2 hours. The mixture was cooled to room temperature and 1.26 g (3.34 mmol) of methoxymethyltriphenylphosphonium chloride were added to the mixture. Further, a solution in which 426 mg (1.67 mmol) of 4-[(4-chlorobenzyl)thio]cyclohexanone were dissolved in 5 ml of dimethyl sulfoxide was added to the resulting mixture. Water was added to the mixture and the resulting mixture was extracted with toluene. After the extract was dried, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 20 g of silica gel and eluted with a mixed solvent of methylene chloridehexane (1:4) to obtain 370 mg (yield: 78%) of the title compound as an oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH:14](C(OC(C)(C)C)=O)[CH2:13]1)(=[O:4])=[O:3].Cl>CCOC(C)=O>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)C1CC(c2ccccc2NS(C)(=O)=O)CCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccccc1C1CCNCC1

Procedure:
To a 25 ml, round-bottomed flask equipped with stirring was added tert-butyl 4-(2-[{methylsulfonyl)amino]phenyl}piperidino-carboxylate (Step d) (610 mg, 1.72 mmol) followed by a saturated soln of HCl in EtOAc (10 mL). The reaction mixture was stirred at RT for 1 h and the title compound (HCl salt) was isolated by filtration as a white solid (460 mg). MS (ESI, pos. ion) m/z: 255 (M+1). Calc'd for C12H19ClN2O2S: 290.81.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.Br>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(-c3ccc(Br)cc3)csc2c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2c(-c3ccc(Br)cc3)csc2c1
Yield: 98.4 %

Procedure:
7.4 g (23.17 mmol) 3-(4-Bromo-phenyl)-6-methoxy-benzo[b]thiophene in 47 ml acetic acid were treated with 27 ml (62% aq) HBr at 125° C. for 4 h. The solution was concentrated in vacuo and the residue was dissolved in NaHCO3 and EtOAc. Prior to extraction with EtOAc the pH was adjusted with 2M NaOH (pH 8). The combined organic phases were washed with brine and dried with Na2SO4. Trituration with hexane gave 6.96 g (98%) 3-(4-Bromo-phenyl)-benzo[b]thiophen-6-ol as light green solid, MS: 304 (M, 1Br).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2[nH]ncc2c1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 7.6 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1H-indazol-5-yl)pyridin-2(1H)-one (0.362 g, 1.14 mmol) in DMSO (1.5 mL) was added 4-(2-chloroethyl)morpholine (0.466 g, 2.50 mmol) and Cs2CO3 (1.85 g, 5.67 mmol). After stirring at ambient temperature for 5.5 h, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×40 mL). The organics were washed with brine (2×25 mL), dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) yielded the title compound (37.3 mg, 7%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J=1.0 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.43-7.38 (m, 6H), 7.29 (d, J=7.5 Hz, 1H), 6.09-6.06 (m, 2H), 5.06 (s, 2H), 4.53 (t, J=7.0 Hz, 2H), 3.68 (t, J=4.5 Hz, 4H), 2.88 (t, J=6.5 Hz, 2H) 2.52 (t, J=4.5 Hz, 4H); ESI MS m/z 431 [M+H]+; HPLC (Method A) 98.9% (AUC), tR=14.0 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([CH2:14][CH3:15])=[CH:12][C:11]([C:16](=[O:18])[CH3:17])=[C:10]([OH:19])[CH:9]=1.[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:16]([C:11]1[C:10]([OH:19])=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:22])[CH3:21])=[C:13]([CH2:14][CH3:15])[CH:12]=1)(=[O:18])[CH3:17]
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCCN
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CCc1cc(C(C)=O)c(O)cc1OCCCCCNC(C)=O

Procedure:
In a manner analogous to that taught in Example 77, 265 mg of the amine from Example 137 was acylated with acetyl chloride and pyridine to provide 158 mg of the desired title product, m.p. =115°-116° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:30]1([S:33]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][N:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=c1[nH]c2cc3snnc3c(F)c2n1-c1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c3nnsc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d][1,2,3]thiadiazol-6(7H)-one (60 mg, 0.14 mmol) in CH2Cl2 (3 mL) was added triethylamine (43 mg, 0.42 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (31 mg, 0.21 mmol) and DMAP (5 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (75 mg, 100% yield). 1H NMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 7.75-7.73 (d, 2H), 7.34 (m, 1H), 3.34 (m, 1H), 1.68 (m, 2H), 0.85 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:24][NH:25][O:26][CH3:27].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(OCC)(=O)C.O.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([N:25]([O:26][CH3:27])[CH3:24])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1sccc1OCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1sccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 3-(benzyloxy)-2-thiophenecarboxylic acid (3.00 g, 12.81 mmol) in CH2Cl2 (30 mL) were added oxalyl chloride (1.34 mL, 15.4 mmol) and DMF (0.05 mL). The mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL). Then the solution was added to a mixture of N,O-dimethylhydroxyamine hydrochloride (1.50 g, 15.37 mmol) and K2CO3 (3.54 g, 25.62 mmol) in ethyl acetate (30 mL) and water (30 mL) at 0° C. The mixture was vigorously stirred at 0° C. for 0.5 hrs, and at room temperature for 1.5 hrs. The organic phase was separated, washed with 1 N HCl, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give 3-(benzyloxy)-N-methoxy-N-methyl-2-thiophenecarboxamide as a pale yellow solid (3.473 g, yield; 98%).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[C:8]([CH3:28])=[N:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:2][CH2:6][C:7]1[C:8]([CH3:28])=[N:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1CBr
Reaction time: 1.5 h
Yield: 37.2 %

Procedure:
To a solution of phosphorus tribromide (0.93 g) in tetrahydrofuran (10 ml) was dropwise added a suspension of 3-hydroxymethyl-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (1.65 g) in tetrahydrofuran (10 ml) at 5-10° C. After stirring for 1.5 hours at the same temperature, the reaction mixture was poured into icewater (20 ml), adjusted to pH 9.5 with saturated aqueous potassium carbonate and extracted with ethyl acetate (40 ml). The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel eluting with chloroform. The fractions containing the desired compound were combined and evaporated in vacuo to give 3-bromomethyl-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (0.49 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:43][CH:44]1[C@H:48]2[C@H:49](OC3CCCCO3)[N:50](C(OC(C)(C)C)=O)[C:51]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:52]=3[C:53](=[O:54])[N:47]2[CH2:46][CH2:45]1)[CH2:9][CH2:10][O:11][CH:12]1[C@H:16]2[C@H:17](OC3CCCCO3)[N:18](C(OC(C)(C)C)=O)[C:19]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=3[C:21](=[O:22])[N:15]2[CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:43][CH:44]1[C@@H:48]2[CH:49]=[N:50][C:51]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:52]=3[C:53](=[O:54])[N:47]2[CH2:46][CH2:45]1)[CH2:9][CH2:10][O:11][CH:12]1[C@@H:16]2[CH:17]=[N:18][C:19]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:20]=3[C:21](=[O:22])[N:15]2[CH2:14][CH2:13]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 62.5 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15a (75 mg, 0.08 mmol) at 0° C. This was then stirred for 1 h and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16a (30 mg, 0.05 mmol, 70%) as a solid: [α]20D=+477° (c=0.11, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 2.01-2.06 (m, 4H, 2-H, 2′-H), 2.28-2.31 (m, 4H, 1-H, 1′-H), 2.39-2.42 (m, 2H, 13-H), 3.55-3.60 (m, 2H, 3-H, 3′-H), 3.67-3.73 (m, 2H, 11a-H, 11a′-H), 3.77-3.87 (m, 2H, 3-H, 3′-H), 3.91 (s, 6H, 7-OMe, 7′-OMe), 4.23-4.31 (m, 4H, 12-H, 12′-H), 6.84 (s, 2H, 9-H, 9′-H), 7.50 (s, 2H, 6-H, 6′-H), 7.64 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 28.4, 29.6, 46.6, 53.6, 56.1, 58.4, 65.4, 110.8, 111.6, 120.4, 140.6, 147.8, 150.6, 162.3, 164.6; IR (neat): 3350, 2951, 1600, 1505, 1434, 1262, 1217, 1021 cm−1; MS (FAB) m/z (relative intensity) 597 ([M+2×MeOH]+., 16), 565 ([M+MeOH]+., 5), 533 (M+., 100).
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Na].CCOCC>[CH2:11]([O:18][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:8][CH2:9][NH2:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: N#C/C=C/C1CCCCC1
Agent: [Na]
Solvent: CCOCC
Product: NCCC(OCc1ccccc1)C1CCCCC1
Reaction time: 4 h

Procedure:
The foregoing mixture of 2-cis and 2-trans-3-cyclohexylacrylonitrile (26.50 g) was dissolved in sodium benzylate solution prepared from sodium (0.65 g) and benzyl alcohol (90 ml) and the resulting solution heated on the steam-bath with stirring for 4 hours then set aside at room temperature for 18 hours. The resulting dark solution was diluted with ether and washed with water. The ethereal extract was dried (Na2SO4), the solvent removed in vacuo, and the residual unchanged nitrile removed by distillation under high vacuum. The residual material was taken up in ether, colorised with activated charcoal, filtered, and the solvent removed in vacuo. The residual yellow syrup (ca. 22 g) was dissolved in dry ether (40 ml) and added dropwise at +5° to a stirred suspension of lithium aluminium hydride (3.4 g) in dry ether (125 ml). After 1 hour at room temperature, the reaction mixture was treated with water and the resulting gel filtered through Celite. The yellow organic phase was separated, dried (MgSO4), the solvent removed in vacuo, and the residual orange oil distilled, giving 3-benzyloxy-3-cyclohexylpropylamine as a colourless viscous oil. b.p. 120°-5°/0.05-0.06 mm.