Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[OH:2].[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][NH:4]1.OO.O>C(Cl)Cl.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N+:4]=1[O-:2]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CO
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: [O-][N+]1=Cc2ccccc2CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A magnetic stirrer was placed in a 300-ml eggplant-type flask, followed by an addition of sodium tungstate (0.33 g, 1.0 mmol). The internal atmosphere was replaced with nitrogen. Thereafter, methanol (200 ml) and 1,2,3,4-tetrahydroisoquinoline (6.65 g, 50.0 mmol) were added successively. To the resulting mixed solution, a 30% solution of hydrogen peroxide in water (17.0 g, 150.0 mmol) was added dropwise with stirring at 0° C. in the course of 30 minutes. After stirring the mixture at room temperature for 3 hours, the solvent was driven off under reduced pressures. The residue was taken up in methylene chloride (100 ml) and then washed twice with saturated saline (30 ml). The organic phase was separated and then dried with anhydrous magnesium sulfate. The solvent was driven off under reduced pressures, thereby obtaining an yellowish oily product. The oily product was subjected to silica gel column chromatography. The column as eluted with acetone to obtain 3,4-dihydroisoquinoline-2-oxide as a nitrone (6.54 g, 89 %).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.CC(N)[CH2:15][C:16]1[CH:21]=CC=CC=1.OP(O)(O)=O.[Br-].C1([Zn+])CC1.[OH-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([CH:21]2[CH2:16][CH2:15]2)[N:7]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C2CC2)nc(Cl)n1
Temperature: 80 °C
Yield: 1592.7 %

Procedure:
In a 5 mL glass microwave tube methyl 2,4-dichloropyrimidine-6-carboxylate (621 mg, 3.00 mmol) (Astatech Inc.) and Amphos (53.1 mg, 0.075 mmol) were treated with cyclopropylzinc(II) bromide (Rieke, 0.5 M in THF) (1.2 mL, 6.00 mmol) via syringe under an atmosphere of argon. The solution was then heated in the microwave at 80° C. for 20 min. The mixture was treated with EtOAc and 1N NaOH resulting in a white suspension as the zinc hydroxide salts precipitated out. The suspension was extracted with EtOAc (50 mL) a second time and washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 100% DCM) to give methyl 2-chloro-6-cyclopropylpyrimidine-4-carboxylate (254 mg, 40%) as a clear, colorless, viscous oil. MS (ESI, pos. ion) m/z: 213.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (1H, s), 3.99-4.04 (3H, m), 2.06-2.15 (1H, m), 1.20-1.31 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:37][CH2:38][N:39]([CH3:48])[C:40]2[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:37][CH2:38][N:39]([CH3:48])[C:40]5[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=5)=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN(C)c1ccc(C#N)cc1
Temperature: 75 °C
Yield: 98 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin4(3H)-one (96 mg, 0.25 mmol, the preparation of which can be found in the section detailing the preparation of Example K1) in DMF was added 2-[4-cyano(methyl)anilino]ethyl p-toluenesulfonate (165 mg, 0.50 mmol) and cesium carbonate (0.24 g, 0.75 mmol) and the mixture was stirred with heating at 75° C. for 12 h. The reaction was allowed to cool and 10 mL solution of 20% water/ethanol was added. The resulting precipitate was filtered and dried in a vacuum oven to give the title compound (133 mg, 98%). 1H NMR (DMSO-D6) δ 3.10 (3H, s), 3.76 (3H, s), 3.87 (2H, t, J=3.7 Hz), 4.21 (2H, t, J=3.7 Hz), 6.87 (1H, d, J=7.3 Hz), 7.02-7.20 (3H, m), 7.58 (4H, m), 7.99 (3H, m), 8.38 (1H, s). LCMS m/z=543 (m+H+). Calcd. for C29H23ClN4O3S×1HCl: C, 60.11; H, 4.17; N; 9.67. Found: C, 59.78; H, 4.18; N, 9.44.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[N:21]=[C:20]([C:22]([NH:24][C:25]3[C:26]([CH3:36])=[C:27]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:28]([O:30][CH3:31])=[O:29])=[O:23])[C:19]([CH3:37])=[CH:18][CH:17]=2)[CH2:11]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[N:21]=[C:20]([C:22]([NH:24][C:25]3[C:26]([CH3:36])=[C:27]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:28]([O:30][CH3:31])=[O:29])=[O:23])[C:19]([CH3:37])=[CH:18][CH:17]=2)[CH2:11]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2nc(N3CCCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2C)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2nc(N3CCCC(CO)C3)ccc2C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.1 %

Procedure:
To a solution of methyl 3-[[6-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-piperidyl]-3-methyl-pyridine-2-carbonyl]amino]-2,4-dimethyl-benzoate (0.20 g, 0.38 mmol) in THF (4 ml) is added Bu4NF 1.0 M in THF (1.5 ml) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 8 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (neutral alumina) over a gradient using 50% ethyl acetate in hexane to afford the title compound as a white solid (0.18 g, 115%). Mass spectrum (m/z): 412.2 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[S:13][CH2:12][C:4]2([CH:9]3[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]3)[CH2:5]2)[O:3]1.[S:14](=[O:18])(=[O:17])([OH:16])[OH:15]>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[S:13][CH2:12][C:4]2([CH:9]3[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]3)[CH2:5]2)[O:3]1.[S:14]([O-:18])([O-:17])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)O
Agent: CC1OC2(CS1)CN1CCC2CC1
Solvent: Cc1ccccc1
Product: O=S(=O)([O-])[O-]
Temperature: 2.5 °C
Reaction time: 0.21 h

Procedure:
Charged toluene (50 ml) and to this charged cevimeline free base with cis isomer >90% (5.0 g) (prepared by any one of the above methods given in examples III to V). Stirred for 10 to 15 minutes to obtain a clear solution. Cooled the solution to 0 to 5° C. Charged concentrated sulfuric acid (1.3 ml) drop wise over 30 minutes and stir the resultant liberated sulfate salt for 30 minutes at 0 to 5° C. Then slowly raised the temperature to reflux temperature (100 to 115° C.) and continued the reflux for 60 to 90 minutes. The reaction mass was then cooled and processed as in Example VI to yield 3.5 g of cevimeline sulfate with cis isomer >97% purity by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([N+:13]([O-])=O)[CH:5]=1.C(N(CC)CC)C.C(O)=O>CC#N.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([NH2:13])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC#N
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
3,5-Dinitro-benzoic acid methyl ester (Example 312, 13.7 g, 60.6 mmol), Pd/C (Aldrich, 1.34 g, 10%, 0.61 mmol), triethylamine (Aldrich, 36.4 mL, 273 mmol) was dissolved in 30 mL of CH3CN. To the above solution was added a solution of HCOOH (Aldrich, 9.7 mL, 261 mmol) in 30 mL of CH3CN dropwise. The mixture was then refluxed for 2 h. After cooled to room temperature, the mixture was filtered through a Celite pad, washed with EtOAc, and the filtrate was concentrated. The residue was purified by chromatography (5%-10% EtOAc/CH2Cl2) to give 7.0 g (59%) of product. 1H NMR (400 MHz, DMSO-d6) δ 7.74 (t, J=2.0 Hz, 1H), 7.59 (t, J=2.2 Hz, 1H), 7.55 (t, J=2.0 Hz, 1H), 6.16 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2([C:21]#[N:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1.O.[OH-].[Na+]>C(OCC)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH2:21][NH2:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(C2(C#N)CCOCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1cccc(C2(CN)CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a stirred suspension of LiAlH4 (3.7 g, 96.7 mmol) in diethyl ether (100 mL) cooled at 0° C. was added dropwise a solution of 4-(3-methoxyphenyl)-tetrahydro-pyran-4-carbonitrile (4.2 g, 19.3 mmol) in diethyl ether (100 mL). After being stirred at room temperature for 30 min, the reaction mixture was refluxed for another 15 min. The mixture was cooled to 10° C. and water, sodium hydroxide (15% w/v in water, 0.48 mL) and water again were successively added dropwise. After being stirred for 15 min at room temperature, the mixture was filtered over diatomaceous earth and concentrated. The residue was purified with flash chromatography (DCM/MeOH: 95/5) to provide (4-(3-methoxyphenyl)tetrahydro-pyran-4-yl]methylamine (4 g, 94%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.ClCCl.[NH2:60][CH2:61][CH2:62][CH2:63][N:64]1[CH2:69][CH2:68][N:67]([CH2:70][CH2:71][OH:72])[CH2:66][CH2:65]1>C(N(CC)CC)C.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:60][CH2:61][CH2:62][CH2:63][N:64]5[CH2:65][CH2:66][N:67]([CH2:70][CH2:71][OH:72])[CH2:68][CH2:69]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCCN1CCN(CCO)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCCN2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1.5 h
Yield: 8 %

Procedure:
To a mixture of 0.051 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.0494 g (0.13 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.6 mL of dichloromethane, 0.6 mL of dimethylformamide, 0.12 mL of triethylamine was added followed by 0.0235 g (0.13 mmole) of 2-[4-(3-amino-propyl)-piperazin-1-yl]-ethanol. After stirring 1.5 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with acetonitrile-water (gradient, 5:95-0:100) to give 0.0054 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-3-methoxy-benzamide (I-96).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH2:21][CH2:22][C:23]#[N:24])[C:13]3=[O:25])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:26]([Si](C)(C)C)=[N+:27]=[N-:28].C([Sn](=O)CCCC)CCC.O>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH2:21][CH2:22][C:23]4[NH:28][N:27]=[N:26][N:24]=4)[C:13]3=[O:25])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2scc(Cn3c(=O)n(CCC#N)c4ccccc43)c12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2scc(Cn3c(=O)n(CCc4nnn[nH]4)c4ccccc43)c12
Temperature: 150 °C
Yield: 22.6 %

Procedure:
3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionitrile (58 mg, 0.17 mmol), azidotrimethylsilane (0.047 mL, 0.33 mmol) and dibutyltin oxide (4.2 mg, 0.017 mmol) are dissolved in dry DMF (2.0 mL) in microwave vial. It is then heated at 150° C. for 2 hrs in microwave reactor. Then another 0.05 mL of azidotrimethylsilane and 4.0 mg of dibutyltin oxide are added and the mixture is heated for another 2 hr at 150° C. in microwave reactor. Then water (2 mL) is added and the mixture is extracted with EtOAc (2×30 mL). The organic layers are combined and extracted with 2.0M NaOH (2×30 mL). The NaOH layers are combined and washed with EtOAc (30 mL). Then the NaOH layers are acidified with 1.0M HCl to pH=3 and it is then extracted with EtOAc (2×30 mL). All the organic layers are combined, dried (MgSO4) and concentrated to give crude product. Purification by preparative TLC using 3% MeOH in CH2Cl2 affords 15 mg (65%) of 1-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-3-[2-(1H-tetrazol-5-yl)-ethyl]-1,3-dihydro-benzimidazol-2-one. LCMS (ESMS): m/z 391.07 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C[Al](C)C.CCCCCCC.C[O:20][C:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=1>ClCCCl.C(Cl)Cl.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:21]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=2)=[O:20])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CN1CCNCC1
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: O
Solvent: ClCCCl
Product: CN1CCN(C(=O)c2ccc(CO)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-methyl piperazine (3.33 ml, 30.09 mmol) was added a solution of trimethylaluminium in heptane (15.04 ml, 30.09 mmol) and the mixture was stirred 10 min at room temperature. To this solution was added a solution of 4-(hydroxymethyl)benzoic acid methyl ester (1000 mg, 6.02 mmol) in DCE and the mixture was refluxed under inert atmosphere for 3 h. The mixture was diluted with DCM then water was added. The suspension was filtered through celite. The filtrate was washed with a solution 5% of NaHCO3 (2×) then water and brine. The organic layers were dried over MgSO4, evaporated and dried at 40° C. under vacuum to afford 307 mg (Y=21%) of the title compound as an oil. 1H NMR (DMSO-d6) δ 7.45-7.37 (m, 4H), 5.33 (t, J=5.6 Hz, 1H), 4.58 (br d, 2H), 3.77-3.50 (m, 4H), 2.46-2.30 (m, 4H), 2.26 (s, 3H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.[Cl:45][C:46]1[C:51]([O:52][CH3:53])=[CH:50][C:49]([O:54][CH3:55])=[C:48]([Cl:56])[C:47]=1[C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[N:63]=[C:62]([NH:67][C@H:68]1[C@H:72](O)[CH2:71][C@@H:70]([C:74]([O:76][CH3:77])=[O:75])[CH2:69]1)[N:61]=[CH:60]2>C1COCC1>[Cl:56][C:48]1[C:49]([O:54][CH3:55])=[CH:50][C:51]([O:52][CH3:53])=[C:46]([Cl:45])[C:47]=1[C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[N:63]=[C:62]([NH:67][C@H:68]1[C@@H:72]([N:38]3[C:34](=[O:44])[C:35]4[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:37]3=[O:39])[CH2:71][CH:70]([C:74]([O:76][CH3:77])=[O:75])[CH2:69]1)[N:61]=[CH:60]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)[C@@H]1C[C@@H](O)[C@H](Nc2ncc3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc3n2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1C[C@@H](Nc2ncc3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc3n2)[C@@H](N2C(=O)c3ccccc3C2=O)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Ph3P (0.213 g, 0.812 mmol) was taken up in THF (6 ml) and cooled to −78° C. under N2. DIAD (0.126 ml, 0.650 mmol) was added followed by addition of phthalimide (0.105 g, 0.711 mmol) and stirred at −78° C. for 1 hour, followed by addition of (1S,3R,4R)-methyl 3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-hydroxycyclopentanecarboxylate (0.100 g, 0.203 mmol) in 4 ml of THF at −78° C. The reaction was stirred overnight while warming to room temperature, after which the solvent was removed under reduced pressure. The residue was purified via flash chromatography (0-100% Hex/EtOAc; 12 g column) to afford methyl (3R,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-(1,3-dioxoisoindolin-2-yl)cyclopentane-1-carboxylate (0.126 g, 0.203 mmol). MS (ES+) C31H26Cl2N4O6 requires: 621, found: 622 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC.CO>>[CH3:8][O:10][C:11](=[O:12])[C:6]1[C:5]([F:13])=[C:4]([F:14])[C:3]([F:15])=[C:2]([F:1])[CH:7]=1
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Solvent: CO
Product: COC(=O)c1cc(F)c(F)c(F)c1F
Yield: 92.4 %

Procedure:
Into a 100 ml glass reactor equipped with a reflux condenser and a stirrer, 20 g (0.091 mol) of the tetrafluorophthalic anhydride prepared in Example 3 and 32.2 g (0.091 mol) of tri-n-octylamine were charged and 3.5 g (0.109 mol) of methanol was dropwise added thereto. Then, the mixture was reacted at 140° C. for 4 hours. After completion of the reaction, the reaction mixture was separated by distillation to obtain 17.5 g of 3,4,5,6-tetrafluorobenzoic acid methyl ester. The yield was 92.3%.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O>CC(C)=O>[CH:9]1[C:8]2[NH:7][C:6]3[C:5](=[CH:3][CH:2]=[CH:10][CH:9]=3)[C:4]=2[CH:3]=[CH:2][CH:10]=1
Reactant: Fc1ccc2[nH]ccc2c1
Solvent: CC(C)=O
Solvent: O
Product: c1ccc2c(c1)[nH]c1ccccc12
Reaction time: 0.08 h
Yield: 64 %

Procedure:
15 ml of acetone was poured into a 200 ml three-neck flask, and 1.62 g of 5-fluoroindole was dissolved therein. On the other hand, preparation of an oxidant solution was performed by dissolving 32.2 g of cupric chloride anhydrate and 12.9 g of water in 55 ml of acetone and agitating the mixture for 5 minutes. Then the prepared oxidant solution was dripped into the 5-fluoroindole solution for two hours and the resultant mixture solution was agitated for 5 hours at the temperature of 30° C. Color of the reaction solution changed from white to dark blue with slight heat generation. pH of the reaction solution was less than 1. After the end of the reaction, the reaction liquid was suction-filtered with a perforated funnel, and the filtrate was washed with acetone and then methanol and dried to obtain 1.04 g of 2,9,14-trifluoro-6,11-dihidro-5H-diindolo [2,3,-a:2′,3′-c] carbazole (5-fluoroindole trimer) (yield: 64%). The resultant trimer was pressure-molded with a tablet molding machine and the mold was cut into a piece with the diameter of 10 mm and thickness of 1 mm. A conductivity thereof was measured by the four terminal method and found to be 0.88 S/cm. The result of elemental analysis was: <C8.00H3.95N1.10F0.96Cl0.10>3.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:12].C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([NH:12][C:21]([O:23][CH3:24])=[O:22])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6]
Reactant: Nc1c(C(=O)O)ccc(Cl)c1Cl
Reactant: COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Nc1c(C(=O)O)ccc(Cl)c1Cl
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
3,4-Dichloroanthranilic acid (61.8 g) was stirred in THF at -15° C., and triethylamine was added. Methyl chloroformate (36.9 g) was then added at -15° C. and the mixture stirred for 45 minutes. Water was then added, followed by concentrated hydrochloric acid solution until pH 1 was achieved, and the solution was stirred overnight. Excess water was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (anhydrous magnesium sulphate) and the solvent evaporated. The resulting solid was recrystallized from a solution of toluene and cyclohexane to give 3,4-dichloro-2-(methoxycarbonylamino)benzoic acid (65.1 g) as a fawn solid, m.p. 155-156° C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4](/[C:7](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8]\[CH2:9][OH:10])=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:42]([O:44][C:45](=[O:58])[C@@H:46]([O:55][CH2:56][CH3:57])[CH2:47][C:48]1[CH:53]=[CH:52][C:51](O)=[CH:50][CH:49]=1)[CH3:43].N(C(OCC)=O)=NC(OCC)=O>>[CH2:42]([O:44][C:45](=[O:58])[C@@H:46]([O:55][CH2:56][CH3:57])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:10][CH2:9]/[CH:8]=[C:7](\[C:4]2[CH:3]=[CH:2][C:1]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:5]=2)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:50][CH:49]=1)[CH3:43]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OC/C=C(/c1ccccc1)c1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(/c2ccccc2)c2ccc(-c3ccccc3)cc2)cc1)OCC
Yield: 52.6 %

Procedure:
Reaction of (Z)-3-biphenyl-4-yl-3-phenyl-prop-2-en-1-ol (171 mg, 0.60 mmol), triphenylphosphine (142 mg, 0.63 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (149 mg, 0.63 mmol) and diethyl azodicarboxylate (95 mg, 0.55 mmol) in an identical manner to example 1 gave the title compound (160 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1)(=[O:12])=[O:11].NC1N=NC(Cl)=CC=1.ClC1C=C(Cl)C(C)=CC=1S(Cl)(=O)=O.[N:42]1([S:48]([C:51]2[CH:56]=[CH:55][C:54]([SH:57])=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1.CC(C)([O-])C.[K+].O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1>CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[N:15]=[N:16][C:17]([S:57][C:54]2[CH:53]=[CH:52][C:51]([S:48]([N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)(=[O:49])=[O:50])=[CH:56][CH:55]=2)=[CH:18][CH:19]=1)(=[O:12])=[O:11]
Reactant: Cc1cc(S(=O)(=O)Nc2ccc(Cl)nn2)c(Cl)cc1Cl
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(S(=O)(=O)Nc2ccc(Sc3ccc(S(=O)(=O)N4CCCCC4)cc3)nn2)c(Cl)cc1Cl
Yield: 20 %

Procedure:
To a solution of 3-(2, 4-dichloro-5-methylphenylsulfonylamino)-6-chloropyridazine (by reaction of 3-amino-6-chloropyridazine and 2,4-dichloro-5-methylphenylsulfonyl chloride (100 mg, 0.28 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was added 4-(N -piperidinylsulfonyl)thiophenol (80 mg, 0.31 mmol), potassium tert-butoxide (37 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (0) (25 mg, 27 μmol) and (oxydi-2,1-phenylene)bis-(diphenylphosphine) (30 mg, 56 μmol). The mixture was stirred using a vortex stirrer until homogeneous, sealed under nitrogen, and microwaved at 120° C. for 5 minutes using powerMAX™. The reaction mixture was then added to ethyl acetate (50 mL), extracted with sodium bicarbonate (sat., aq., 3×25 mL), dried over magnesium sulphate, and concentrated under reduced pressure to a dark brown oil. Flash chromatography (SiO2, ethyl acetate:cyclohexane 1:2) afforded a pale yellow solid (32 mg, 20%). 1H NMR (CDCl3): 7.98 & 7.39(2×1H, 2×s, A-ring CH's), 7.73 & 7.5 (2×2H, 2×d, 2×J 10 Hz, Ar CH's of C-ring), 7.15.& 7.08 (2×1H, 2×d, 2×J 12 Hz, B-ring CH's), 2.99-2.92 (4H, m, CH2NCH2), 2.32 (3H, s, CH3), 1.65-1.53 (4H, m, CH2CH2CH2CH2CH2), 1.43-1.30 (2H, m, CH2CH2CH2CH2CH2). Hplc (Luna 2, Gradient 5): rt=6.38 minutes. LC/MS rt=7.15 minutes, 573/575 (MH+).