Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[F:30]>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=4[F:30])=[C:11]3[CH:10]=[N:9]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ncc3c(Oc4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Temperature: 100 °C

Procedure:
A stirred mixture of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (22.00 g, 86.18 mmol) cesium carbonate (28.08 g, 86.18 mmol), 1,2-difluoro-4-nitrobenzene (13.71 g, 86.18 mmol) and DMA (100 mL) was heated to 100° C. for 1 hour. After cooling to room temperature, the mixture was partitioned between DCM (500 mL) and water (500 mL). The phases were separated, and the organic phase washed with water (3×200 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was triturated with diethyl ether (100 mL) and hexanes (200 mL) co-solvent, and the resulting beige powder was filtered. A second crop was obtained after cooling in a −10° C. freezer overnight. The two crops were combined (28 g, 82%). 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.5 Hz, 1H), 8.16 (m, 2H), 7.86 (s, 1H), 7.39 (m, 1H), 7.35 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.2 Hz, 2H), 6.48 (d, J=5.5 Hz, 1H), 5.65 (s, 2H), 3.76 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −124.2 (m).
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]([OH:8])[CH:6]([OH:9])[CH:5]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].N1C=CN=C1.[Si:39](Cl)([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>C(Cl)Cl>[Si:39]([O:8][CH:7]1[CH:6]([OH:9])[CH:5]([O:10][Si:11]([C:24]([CH3:27])([CH3:25])[CH3:26])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][C:3](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:2]1=[CH2:1])([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C=C1C(=CC(=O)OCC)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(O)C1O
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C=C1C(=CC(=O)OCC)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
Ethyl (2-methylene-3,4-dihydroxy-5-(tert-butyldiphenylsilyloxy)cyclohexylidene)acetate (0.466 g) was dissolved in 5 ml of methylene chloride, and 0.204 g of imidazole and 0.30 g of tert-butyldiphenylsilyl chloride were added, followed by stirring the mixture at room temperature for 3 hours. The reaction mixture was poured into water, and extracted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 0.664 g of ethyl (3,5-bis-(tert-butyldiphenylsilyloxy)-4-hydroxy-2-methylene-cyclohexylidene)acetate having the following property.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: CCCCCCCCCN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: CCCCCCCCCNc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.5 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 1.07 g (7.5 mmol) of n-nonylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 1.10 g (yield: 100%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:5]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:24]=[C:23]4[C:18]([C:19](=[O:32])[C:20]([C:25]5[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=5)=[CH:21][O:22]4)=[CH:17][CH:16]=3)[N:12]=2)[CH:7]=1.[P:37]([O:49][CH2:50]Cl)([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CC(C)([O-])C.[K+].[I-].[Na+]>CN(C)C=O.O>[P:37]([O:49][CH2:50][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]2[C:19](=[O:32])[C:18]3[C:23](=[CH:24][C:15]([O:14][CH2:13][C:11]4[N:12]=[C:8]([C:6]5[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([C:33]([F:34])([F:36])[F:35])[CH:5]=5)[O:9][CH:10]=4)=[CH:16][CH:17]=3)[O:22][CH:21]=2)=[CH:30][CH:29]=1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:38]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(OCc3coc(-c4cc(F)cc(C(F)(F)F)c4)n3)ccc12
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OP(=O)(OCOc1ccc(-c2coc3cc(OCc4coc(-c5cc(F)cc(C(F)(F)F)c5)n4)ccc3c2=O)cc1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a 50 mL round bottomed flask 7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-3-(4-hydroxyphenyl)chromen-4-one (150.0 mg, 0.302 mmol) was treated with di-tert-butyl chloromethyl phosphate (156.2 mg, 0.604 mmol, 1.0 equiv) in the presence of potassium t-butoxide (67.8 mg, 0.604 mmol, 1.0 equiv) and sodium iodide (89.9 mg, 0.604 mmol, 1.0 equiv) in N,N-dimethylformamide (2 ml), and the mixture stirred at room temperature for 15 hours. To the mixture was added water (30 ml), and the whole was extracted with ethyl acetate (30 ml×3). The combined organic layers were washed with brine (30 ml), dried with Na2SO4, and solvent removed under reduced pressure, to give a crude mixture (345.1 mg). This mixture was purified by column-chromatography (SiO2=80 g, hexane/EtOAc=1:1) to give di-tert-butyl {4-[7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-4-oxochromen-3-yl]phenoxy}methyl phosphate as a colorless oil.
Reaction SMILES: [C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7](Cl)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH3:17][OH:18]>>[C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7]([O:18][CH3:17])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1Cc2ccccc2SC(Cl)C1
Reactant: CO
Product: C=CC(=O)N1Cc2ccccc2SC(OC)C1

Procedure:
The above-mentioned 4-acryloyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.20 g), methanol (0.1 ml) and stannic chloride (0.31 g) were reacted in the same manner as in Experimental Example 13 to give 4-acryloyl-2-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.19 g). This compound (0.18 g) and 4-benzyl piperidine (0.19 g) were reacted in the same manner as in Experimental Example 5 to give 4-[3-[1-(4-benzyl)piperidinyl]propionyl]-2-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.25 g).
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][O:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][O:21]1
Reactant: Cc1cn([C@H]2CO[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cn([C@H]2CO[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 9 (93.3 mg, 0.2 mmole) in tetrahydrofuran (THF) (3 ml) was added a 1.0 M solution of tetra-n-butylammonium fluoride in THF (0.24 ml, 0.24 mmole) and the mixture stirred at room temperature for 1 hour. The mixture was then concentrated and purified by column chromatography over silica gel to yield 11 (42 mg, 92.1%) as white solid: [α]25D-18.8° (C o.17, MeOH); 1H NMR (DMSO-d6) δ 1.75 (d, J=1.2 Hz, 3H, CH3), 3.63 (dd, J+6.0, 2.6 Hz, 2H, CH2OH), 4.03 (dd, J=9.9, 5.5 Hz, 1H, 5-H), 4.22 (dd, J=9.9, 2.0 Hz, 1H, 5-H), 4.90 (t, J=2.6 Hz, 1H, 2-H), 5.16 (t, J-t.0 Hz, 1H, OH), 6.21 (dd, J=5.5, 2.0 Hz, 1H, 4-H), 7.67 (d, J=1.2 Hz, 1H, 6'-H), 11.27 (br s, 1H NH); UV (H2) max 266.0 (ε 10757); 266.5 (ε 9894) (pH 2); 266.3 (ε 8397) (pH 11); Anal. Calcd for C9H12O5N2 : C, 47.36; H, 5.31; N, 12.28. found: c, 47.28; H, 5.34; N, 12.29.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl.[CH3:19][C@H:20]1[CH2:25][N:24]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:23][CH2:22][NH:21]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>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].C1(C)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:22][CH2:23][N:24]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH2:25][C@@H:20]2[CH3:19])=[CH:3][CH:4]=1)([OH:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccccc2)CCN1
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H]1CN(S(=O)(=O)c2ccccc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 100 °C
Yield: 17.8 %

Procedure:
A 20 mL vial was charged with 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1.52 g, 4.70 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), (S)-2-methyl-4-(phenylsulfonyl)piperazine hydrochloride (1.00 g, 3.61 mmol), sodium tert-butoxide (1.13 g, 11.7 mmol), and 10 mL of anhydrous toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.051 g, 0.11 mmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (0.033 g, 0.036 mmol, Strem Chemical Inc, Newburyport, Mass.). The vial was sealed and the mixture was heated at 100° C. for 12 h. After that time, the reaction was diluted with water (5 mL) and extracted with EtOAc (2×20 mL). The organics were dried (MgSO4) and concentrated to give an oil that was purified via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-methyl-4-(phenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.310 g). 1H NMR (400 MHz, CD3OD) δ 7.83-7.74 (m, 2H), 7.72-7.60 (m, 3H), 7.53 (d, J=8.8 Hz, 2H), 6.94 (d, J=9.2 Hz, 2H), 4.18-4.02 (m, 1H), 3.70 (dd, J=2.4, 11.2 Hz, 1H), 3.56-3.36 (m, 2H), 3.20 (dt, J=3.4, 11.8 Hz, 1H), 2.69 (dd, J=3.4, 11.4 Hz, 1H), 2.53 (dt, J=3.5, 11.2 Hz, 1H), 1.13 (d, J=6.5 Hz, 3H). M/Z (ESI, +ve ion) 483.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.821 μM; GK-GKRP EC50 (LC MS/MS)=0.884 μM.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][C:22]#[N:23])=[CH:15][CH:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-:42].[Ca+2].[OH-:44]>C(Cl)Cl>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][C:22]#[N:23])=[CH:15][CH:14]=2)(=[O:44])=[O:42])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)CCC#N)cc2)ccc(C(C)=O)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)CCC#N)cc2)ccc(C(C)=O)c1O
Reaction time: 1.5 h

Procedure:
The nitrile from Example 40, Step E, (680 mg, 1.6 mmole) and m-chloroperbenzoic acid (85%, 760 mg, 3.75 mmole) were stirred at 0° for two hours in 20 ml of CH2Cl2. Calcium hydroxide (400 mg) was added to the reaction mixture which was stirred for 1.5 hours. The reaction mixture was filtered and evaporated to dryness, affording the title compound, mp 143°-144°.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[NH:7][C:8](=[O:11])[NH:9][CH:10]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14]>Cl>[CH3:5][C:6]1[NH:7][C:8](=[O:11])[NH:9][C:10]=1[C:12](=[O:15])[CH2:13][CH3:14]
Reactant: Cc1c[nH]c(=O)[nH]1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=O)c1[nH]c(=O)[nH]c1C

Procedure:
To 13.3 g (0.1 mole) of aluminum chloride under 150 ml of dry dichloromethane is added 4.9 g (0.05 mole) of 1,3-dihydro-4-methyl-2H-imidazol-2-one and, dropwise, 5.1 g (0.055 mole) of propionyl chloride. The mixture is stirred and heated to reflux temperature for 6 hours. The mixture is cooled and 2 N hydrochloric acid (150 ml) is added dropwise. The resulting precipitate is collected, washed with water and dichloromethane and recrystallized from 50% aqueous ethanol to give the title compound, m.p. 270°-271° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:5]=[C:4]([C:18]#[N:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:6]2[C:7]([O:8][CH3:9])=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:3]=[C:4]([C:18]#[N:19])[N:5]=2)=[CH:12][CH:13]=1
Reactant: C1CNCCN1
Reactant: COc1c(Cl)nc(C#N)nc1Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: COc1c(Nc2ccc(Cl)cc2)nc(C#N)nc1N1CCNCC1

Procedure:
A solution of the product from step (v) (0.25 g) and piperazine (0.366 g) in tetrahydrofuran (8 ml) was heated at 60° C. for 6 h then the solvent removed under reduced pressure. The residue was purified by RPHPLC 15–75% acetonitrile in aqueous trifluoroacetic acid. Yield 0.139 g
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([F:18])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccnc(F)c1
Product: Cc1c2n(c3c(-c4ccnc(F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (63 mg, 80%), MS (ISP) m/z=314.5 [(M+H)+], mp 240° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CC(O)C>[Cl:23][CH2:22][CH2:21][CH2:20][N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: ClCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: ClCCCn1c(-c2ccccc2)nc2ccccc21
Temperature: 50 °C

Procedure:
A mixture of 38.8 parts of 2-phenyl-1H-benzimidazole, 44 parts of a sodium methoxide solution 30% and 320 parts of 2-propanol is stirred and heated for 15 minutes at 50° C. After cooling, there are added 47.25 parts of 1-bromo-3-chloropropane. The whole is stirred and refluxed for 3 hours. The reaction mixture is evaporated. The residue is diluted with water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 1-(3-chloropropyl)-2-phenyl-1H-benzimidazole as a residue.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#N)[CH3:10].C[O-].[Na+].C(O)(=O)C>CO.O>[CH2:9]([C:11]1[CH:12]=[C:13]([C:14]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)[CH:16]=[CH:17][CH:18]=1)[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CCc1cccc(C#N)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCc1cccc(-c2nc3ccccc3[nH]2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2.2 g. of o-phenylenediamine and 3.1 g. of m-ethylbenzonitrile were dissolved in 30 ml. of methanol. To the solution was added 1.1 g. of sodium methoxide in methanol. The mixture was stirred at 60° C. for 2 hours, acidified with acetic acid, stirred again at 100° C. for additional 3 hours and poured in 100 ml. of water. The resulting crystals were filtered off, dried and recrystallized from ethyl acetate. 2.7 g. of the product (60% of theory) was obtained. The product was identical to that obtained in Example 23.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[Na+].Cl>N1C=CC=CC=1>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: NCCCCCCC(=O)O
Reactant: Fc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(O)CCCCCCNc1ccccn1

Procedure:
To a stirring solution of 7-aminoheptanoic acid in pyridine (0.5 M) was added 2-fluoropyridine (2 eq) and 2N NaOH (1 eq), and the reaction was refluxed overnight. The mixture was adjusted to neutral pH with 6N HCl and concentrated in vacuo. The residue was suspended in 10:1:1 EtOH/NH4OH/H2O, filtered through a plug of silica, and concentrated in vacuo to afford a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]1([S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:23][C@H:13]2[CH2:14][C@H:15]([CH2:20][CH:21]=C)[S:16](=[O:19])(=[O:18])[NH:17][C@H:12]2[CH2:11][CH2:10]1.[O:37]=[O+][O-].[BH4-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]1([S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:23][C@H:13]2[CH2:14][C@H:15]([CH2:20][CH2:21][OH:37])[S:16](=[O:19])(=[O:18])[NH:17][C@H:12]2[CH2:11][CH2:10]1
Reactant: C=CC[C@H]1C[C@@H]2C[C@](c3cc(F)ccc3F)(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC[C@@H]2NS1(=O)=O
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Product: O=S1(=O)N[C@H]2CC[C@@](c3cc(F)ccc3F)(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@H]2C[C@@H]1CCO

Procedure:
Prepared from the product of Example 56 by treatment with ozone followed by sodium borohydride using the procedure described in Example 55 Step 2.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:9]1[N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[C:11]([CH2:15]O)=[C:12]([Cl:14])[N:13]=1)[CH2:6][CH2:7][CH3:8].C(Cl)(Cl)Cl.[C-:30]#[N:31].[Na+]>CS(C)=O.O>[CH2:5]([C:9]1[N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[C:11]([CH2:15][C:30]#[N:31])=[C:12]([Cl:14])[N:13]=1)[CH2:6][CH2:7][CH3:8]
Reactant: [C-]#N
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCc1nc(Cl)c(CC#N)n1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
Thionyl chloride (3.60 mL, 49 mmol, 5 eq) was slowly dripped into a solution of 2-butyl-4-chloro-1-(4-cyanobenzyl)-5-hydroxymethylimidazole (3.0 g, 9.9 mmol, 1 eq) in a minimum of CHCl3. The mixture was stirred for 2 hours at room temperature after which the solvent was removed in vacuo and the residue suspended in toluene (200 mL). The toluene was removed on the rotary evaporator and this procedure was repeated again to remove all traces of thionyl chloride. The chloride was then dissolved in DMSO (minimum to dissolve) and added to a solution of sodium cyanide (2.90 g, 59 mmol, 6 eq) in DMSO (200 ml). The solution was stirred overnight under N2 at room temperature after which 500 mL H2O was added and the aqueous layer was extracted three times with 300 mL of ethyl acetate. The organic layers were dried and concentrated and the residue flash chromatographed in 4:1 hexane/ethyl acetate over silica gel to give 1.62 g of a light yellow solid; m.p. 109.5°-113.0° NMR (200 MHz, CDCl3) δ 7.70 (d, 2H, J=10Hz); 7.12 (d, 2H, J=10Hz); 3.51 (s, 2H); 2.60 (t, 2H, J=7Hz); 1.70 (m, 2H); 1.40 (m, 2H); 0.90 (t, 3H, J=7Hz). Mass spectrum shows M+ =312/314. Mass Calcd. for C17H17ClN4 : 312.1139, Found 312.1126.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[C:9]1([C:6]2[N:5]=[CH:4][C:3]([CH2:2][C:18]3[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1cnc(-c2ccccc2)nc1
Reactant: OB(O)c1ccncc1
Product: c1ccc(-c2ncc(Cc3ccncc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 64a (102 mg, 0.41 mmol) and 4-pyridineboronic acid (76 mg, 0.61 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:2) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. White solid. Yield: 57 mg, 56%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.98 (s, 2H), 7.10-7.16 (m, 2H), 7.46-7.53 (m, 3H), 8.41-8.46 (m, 2H), 8.54-8.60 (m, 2H), 8.64 (s, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=35.6, 123.8, 128.0, 128.5, 128.6, 129.6, 130.7, 137.1, 147.5, 150.2, 157.4, 163.4; (ESI): m/z=247.80 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[N:5][C:6]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][C:8]=1[S:9]([CH3:11])=O)#[N:2].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[C:1]([C:3]1[C:4]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[N:5][C:6]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][C:8]=1[S:9][CH2:11][CH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=1)#[N:2]
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(NC(=O)c2ccccc2)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(NC(=O)c2ccccc2)nc1-c1ccco1

Procedure:
From N-(5-cyano-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl)-benzamide, 2-pyridylethylmercaptan and DBU in DME. ES-MS m/e (%): 428 (M+H+, 100).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:18][C:17]=3[CH:27]=2)=[C:7]([Br:28])[CH:6]=1.[OH-].[K+]>C(O)C>[Br:28][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:29])=[O:2])[CH:10]=[C:9]([Br:11])[C:8]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:17]=2[CH:27]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc3oc(-c4ccccc4)cc3c2)c(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cc(Br)c(Oc2ccc3oc(-c4ccccc4)cc3c2)c(Br)c1

Procedure:
Methyl[3,5-dibromo-4-(2-phenyl-5-benzofuranyloxy)phenyl]acetate (200 mg) was diluted in ethanol (2 mL) and treated with an aqueous saturated solution of potassium hydroxide (0.5 mL). The reaction mixture was refluxed for 1.5 hours. The reaction mixture was concentrated, diluted with chloroform and washed with an aqueous solution of hydrochloric acid (1 N). The organic phase was dried over magnesium sulphate, filtered and concentrated. This gave 0.13 g (70%) of 3,5-dibromo-4-(2-phenyl-5-benzofuranyloxy)-phenylacetic acid as a beige solid mass. 1H-NMR (300 MHz, DMSO-d6): δ 12.5 (br s, 1H), 7.86 (d, J=7.2 Hz, 2H), 7.34 (s, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.50 (t, J=5.1 Hz, 3H), 7.42 (d, J=7.1, 1H), 7.35 (s, 1H), 6.87 (s, 1H), 3.70 (s, 2H).