Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:35])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1.[CH:36]1(B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:36]1([C:2]2[C:3]([NH2:35])=[N:4][CH:5]=[N:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[N:15]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=4)[N:18]=3)[CH2:10][CH2:9]2)[CH2:38][CH2:37]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2Br)CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C2CC2)CC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
In a microwave vial containing 5-bromo-6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine (70.00 mg; 0.13 mmol; 1.00 eq.) in Toluene (3.50 ml) and water (0.35 ml) was added 2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.09 ml; 0.50 mmol; 4.00 eq.), Palladium acetate (4.24 mg; 0.02 mmol; 0.15 eq.), Tricyclohexyl-phosphane (10.58 mg; 0.04 mmol; 0.30 eq.) and Potassium phosphonate (112.16 mg; 0.53 mmol; 4.20 eq.). The mixture was stirred at 100° C. for 5 h before the reaction mixture was filtered, concentrated and purified via waters pre-HPLC. LC-MS: (M+1=518, obsd.=518).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>CN(C)C=O>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][N:6]1[C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([CH3:1])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: OCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2ncn(CCCCO)c2cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.46 g of 5,6-dimethylbenzimidazole dissolved in 50 ml of dry N,N-dimethylformamide was added 0.9 g of NaH, the mixture was stirred at room temperature for 30 minutes, 8 ml of 4-chloro-1-butanol was added dropwise, and after stirring at room temperature for one day, 0.65 g of NaH and 2 ml of 4-chloro-1-butanol were further added to carry out the reaction for 8 days. Following the same processes as in Example 1, crude 1-(4-hydroxybutyl)-5,6-dimethylbenzimidazole was obtained. The conversion to this compound from 5,6-dimethylbenzimidazole was found to be 50%.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=[CH:13]2.[CH2:25]([N:32]1[CH2:37][CH:36]2[C:38](=O)[CH:33]1[CH2:34][CH2:35]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:25]([N:32]1[CH2:37][CH:36]2[CH:38]([NH:9][C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[N:14]=[CH:13]4)[CH:33]1[CH2:34][CH2:35]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)C(=O)n1ncc2cc(N)ccc21
Reactant: O=C1C2CCC1N(Cc1ccccc1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)n1ncc2cc(NC3C4CCC3N(Cc3ccccc3)C4)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
To a solution of 1-(5-amino-1H-indazol-1-yl)-2,2-dimethylpropan-1-one maleate salt (580 mg, 1.7 mmol, prepared as described in U.S. Ser. No. 08/021,4614) and 2-benzyl-2-azabicyclo[2.2.1]heptan-7-one (250 mg, 1.7 mmol) (J. R. Malpass, S. Handa, and R. White, Org. Lett., 2005, 7, 2759-2762) in THF (9 mL) was added sodium triacetoxyborohydride (740 mg, 3.5 mmol), and the mixture was stirred at ambient temperature for 24 h. The reaction mixture was partitioned between aqueous sodium bicarbonate and ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by normal phase chromatography followed by reversed phase HPLC to afford 175 mg (25%) of 1-(5-((1SR,4SR,7RS)-2-benzyl-2-azabicyclo[2.2.1]heptan-7-ylamino)-1H-indazol-1-yl)-2,2-dimethylpropan-1-one.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[CH3:19])[N:8]=[N:9]2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22].C([O-])([O-])=O.[Na+].[Na+]>C(O)(C)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>[OH:20][C:6]1[C:5]2[C:10](=[CH:11][C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[CH:3][CH:4]=2)[N:9]=[N:8][C:7]=1[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CCCN1CCc1nnc2cc(Br)ccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: C[C@@H]1CCCN1CCc1nnc2cc(-c3ccc(C#N)cc3)ccc2c1O
Temperature: 90 °C
Yield: 33 %

Procedure:
A mixture of the product from Example 168D (0.30 g, 0.805 mmol), 4-cyanophenylboronic acid (0.15 g, 1.05 mmol), Pd(PPh3)2Cl2 (0.03 g, 0.04 mmol), and 1 M Na2CO3 (2.01 mL, 2.01 mmol) in isopropanol (15 mL) was heated to 90° C. under a dry nitrogen atmosphere for 2 days. After cooling, the reaction mixture was filtered through celite and concentrated under reduced pressure. The crude material was purified by column chromatography (100% dichloromethane to 90:10 dichloromethane/methanol) to afford the product in 33% yield as a light brown solid. 1H NMR (CD3OD, 300 MHz) δ 8.29 (d, J=9 Hz, 1H), 7.95 (q, J=9 Hz, 4H), 7.83 (d, J=3 Hz, 1H), 7.75 (dd, J=3, 9 Hz, 1H), 3.49–3.42 (m, 2H), 3.17–3.12 (m, 2H), 2.78–2.73 (m, 2H), 2.62–2.59 (m, 1H), 2.12–2.09 (m, 1H), 1.92–1.84 (m, 2H), 1.61–1.53 (m, 1H), 1.25 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 359.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]1([NH:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CNCCN.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I.[Fe]>[CH3:19][C:18]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:17]=1
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CC(=O)Nc1ccccc1
Agent: [Cu]I
Agent: [Fe]
Agent: CNCCN
Solvent: Cc1ccccc1
Product: Cc1nc2ccccc2n1-c1ccccc1
Temperature: 100 °C
Yield: 78.7 %

Procedure:
A reaction tube containing 2-iodonitrobenzene (125 mg, 0.5 mmol), N-phenylacetamide (81 mg, 0.6 mmol), CuI (4.8 mg, 0.025 mmol), N-methylethylenediamine (4.4 μL, 0.05 mmol), potassium phosphate (212 mg, 1 mmol) in dry toluene (3 mL) was purged with dry argon for 3 min. Then the mixture was heated at 100° C. for 18 h. After cooling, the reaction was hydrolyzed with 3 mL of water and filtered through a Varian cartridge Chem Elut 12198007, rinsing with ethyl acetate. The crude mixture was dissolved in 10 mL of glacial acetic acid and refluxed for 30 min in the presence of iron powder (279 mg, 5 mmol). The acid was removed under reduced pressure and the residue was suspended in saturated sodium bicarbonate solution and extracted with ethyl acetate. The obtained crude was purified by preparative HPLC, affording the title compound as a yellow solid (82 mg, 78% yield). mp 46-48° C. 1H NMR δ 2.63 (m, 3 H), 7.32 (d, J=Hz, 1 H), 7.47 (t, J=Hz, 1 H), 7.53 (t, J=Hz, 1 H), 7.66-7.72 (m, 5 H), 7.88 (d, J=7.2 Hz, 2 H); 13C NMR δ 12.6, 111.8, 115.1, 125.3, 127.1, 130.2, 130.3, 132.9, 133.8, 152.2, 158.3. HRMS (FAB): cal. for C14H13N2 [M+H+]: 209.1079; found: 209.1072. The same reaction was also performed on 25 mmol scale, obtaining the final product in 75% yield (3.9 g). The same product was obtained from 2-bromonitrobenzene (101 mg, 0.5 mmol) in 80% yield (83 mg).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13](O)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:34])[NH:26][C:27]([CH3:33])=[CH:28][C:29]=1[CH2:30][CH2:31][CH3:32].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([NH:22][CH2:23][C:24]3[C:25](=[O:34])[NH:26][C:27]([CH3:33])=[CH:28][C:29]=3[CH2:30][CH2:31][CH3:32])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccncc2)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-Methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg, 0.531 mmol), 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (115 mg, 0.531 mmol), EDC (122 mg, 0.638 mmol), HOAt (72.3 mg, 0.531 mmol), and N-methylmorpholine (0.233 mL, 2.12 mmol) were suspended in DMF (5 mL) and stirred at room temperature overnight. water was added to the reaction mixture, and the contents were filtered. The filter cake was washed with additional water (2×). The crude solid was purified by reverse phase HPLC (mobile phase: 10-30% ACN in H2O, 0.1% TFA). The isolated solid was then neutralized with saturated NaHCO3, and washed with EtOAc (5×15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as an off-white solid, 0.060 g (24%). LCMS E-S (M+H)=445.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.84-0.92 (m, 3H), 1.47-1.54 (m, 2H), 1.57 (d, J=6.82 Hz, 6H), 2.14 (s, 3H), 2.48-2.52 (m, 2H), 4.42-4.49 (m, 2H), 5.33-5.43 (m, 1H), 5.90-5.96 (m, 1H), 8.28-8.37 (m, 3H), 8.44-8.48 (m, 1H), 8.82-8.87 (m, 2H), 8.99-9.04 (m, 1H), 11.58 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:49])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:48])=[C:36]([O:50][CH2:51][CH3:52])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:49])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:48])=[C:36]([O:50][CH2:51][CH3:52])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(OCC)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(OCC)c2)CCN3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.85 g) was dissolved in ethanol (200 ml), and to the solution, sodium borohydride (0.13 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 11) (0.66 g) as yellow crystals.
Reaction SMILES: CO[C:3](=[O:38])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[C:22]([O:28][CH2:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[C:21]=1[F:35])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.Cl.[NH:40]([C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([OH:46])=[O:45])[NH2:41]>>[CH3:32][N:31]([CH3:33])[C:30]([CH2:29][O:28][C:22]1[C:21]([F:35])=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:38])[N:40]([C:42]3[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=3[C:44]([OH:46])=[O:45])[N:41]=2)[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=1)=[O:34]
Reactant: NNc1ccccc1C(=O)O
Reactant: CCc1cc(OCC(=O)N(C)C)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Agent: Cl
Product: CCc1cc(OCC(=O)N(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)c1
Yield: 60.2 %

Procedure:
The same procedure was carried out as in Example (2f), except that 0.409 g of {2-(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester was used instead of the [2-(4-cyanophenylimino)-2-(2-fluoro-3,5-dimethoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester in Example (2f), and 0.160 g of 2-hydrazinobenzoic acid hydrochloride was used instead of (1-oxypyridin-2-yl)hydrazine, to give the title compound (0.280 g) as a white solid.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[C:3](=O)[CH2:4][CH2:5]2.[C:8]1([CH2:14][CH2:15][CH2:16][SH:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C.C(N(CC)CC)C>[C:8]1([CH2:14][CH2:15][CH2:16][S:17][C:2]2[C:6](=[O:1])[CH2:5][CH2:4][CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC2OC12
Reactant: SCCCc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1CCC=C1SCCCc1ccccc1
Yield: 63.7 %

Procedure:
2,3-Epoxycyclopentanone (1.0 g) and 1.06 g of 3-phenylpropyl mercaptan were dissolved in 20 ml of diethyl ether, and 20 drops of triethylamine were added. They were reacted at room temperature for 2 hours. After the reaction, the solvent was distilled off from the reaction mixture under reduced pressure. The residue (1.50 g) was chromatographed on a dry column with cyclohexane/ethyl acetate (=8/2) to afford 1.03 g of 2-(3-phenylpropylthio)cyclopent-2-en-1-one in a yield of 64%. The product had the following characteristics.
Reaction SMILES: C([O:4][C:5]1([O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:14]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([F:13])([F:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[F:13][C:6]([F:12])([C:5]1([O:33][C@H:32]([CH2:34][OH:35])[C@@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:14]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:4])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(F)(F)C1(OC(C)=O)O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(F)(F)C1(O)O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1.83 g of 2-deoxy-2,2-difluoro-4,5-bis-O-(phenylmethyl)-D-arabino-3-heptulofuranosonic acid, ethyl ester diacetate in 5.1 ml of ethanol was added 3.4 ml of 1.5M sodium ethoxide in ethanol at 25° C. After 1.5 hours, the mixture was treated with 0.61 ml of glacial acetic acid and partitioned with ether and water. The organic layer was washed with water, sodium bicarbonate solution, and brine, dried and concentrated. The residue was subjected to column chromatography on silica gel to give an oil; CMR δ 100.1 (triplet, J=29.6 Hz, anomeric carbon)
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=[O:6])#[N:2].BrC1C=CC(S)=CC=1.CO.I([O-])(=O)(=O)=[O:33].[Na+]>O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:15]1[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=1)=[O:33])=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CSc1ccc(Br)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Sc1ccc(Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
trans-N-Cyanomethyl-2-(4-bromophenylsulfanylmethyl)cyclohexanecarboxamide (197 mg, 0.536 mmol), prepared as in Example 1 but substituting 4-fluorothiophenol with 4-bromothiophenol, was weighed into a 50 mL round bottom flask fitted with a stirrer and vented cap. Methanol (20 mL) was added to the flask and the reaction mixture was warmed to 50° C. until a clear colorless solution formed. Added sodium periodate (128 mg, 0.599 mmol) solution in water (2.0 mL). A white precipitate slowly formed. The reaction mixture was stirred at 50° C. for 8 h and then concentrated on a rotary evaporator. The residue was triturated in hot water (20 mL) and the reaction mixture was cooled to room temperature. Solids were isolated by filtration, washed thoroughly with water and dried under high vacuum to give trans-N-cyanomethyl-2-(4-bromophenylsulfinylmethyl)cyclohexanecarboxamide as a white solid.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][C:29](=[O:34])CCCC)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].CC1(C)C(C)(C)OB(C2C=[C:48]([CH2:52][NH:53][C:54](=[O:59])[CH2:55]CCC)[CH:49]=[CH:50][CH:51]=2)O1>>[C:54]([N:53]1[CH2:52][CH2:48][CH:49]([C:29]([NH:28][CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH:26]=[CH:25][CH:24]=2)=[O:34])[CH2:50][CH2:51]1)(=[O:59])[CH3:55]
Reactant: CCCCC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCCC(=O)NCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC(=O)C5CCN(C(C)=O)CC5)c4)cc23)CC1

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1H-indole-7-carboxamide substituting 1-acetyl-N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-4-piperidinecarboxamide (56 mg, 0.144 mmol) for N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was purified by Gilson Preparatory HPLC to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH:1]=[O:2])[CH:4]=2)=[CH:26][CH:27]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)Cc1ccc(-c2cccc(C=O)c2)cc1
Yield: 96 %

Procedure:
3-Formylphenylboronic acid (2.25 g), potassium carbonate (4.15 g) and tetrakis(triphenylphosphine)palladium(0) (0.58 g) was added to a solution of (4-bromophenyl)-acetic acid methyl ester (2.3 g) in a nitrogen degassed mixture of toluene and methanol [9:1] (20 mL) and heated to reflux for 18 hours. On cooling the reaction was filtered through a pad of Celite, the pad was washed with ethyl acetate (2×50 mL) and the combined filtrates were concentrated. Purification on silica, eluting with iso-hexane/ethyl acetate [1:0 to 4:1], afforded the subtitle compound as yellow oil (2.45 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:28]([CH3:27])(=[O:30])=[O:29])=[CH:6][CH:7]=1
Reactant: Clc1ccc(CCNCc2ccncc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N(CCc1ccc(Cl)cc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 7.4 g. portion of 4-[2-(4-chlorophenyl)ethylaminomethyl]pyridine was dissolved in 50 ml. of dichloromethane, and to it were added 4 g. of potassium carbonate and 4 g. of methanesulfonyl chloride. The mixture was stirred at ambient temperature overnight, and then 100 ml. of additional dichloromethane was added, followed by 200 ml. of water. The organic phase was separated, washed with water, dried and concentrated under vacuum. The residue was chromatographed on silica gel, using acetone as the eluant. The product-containing fractions were combined and evaporated, and the residue crystallized upon standing. The solids were triturated with petroleum ether and filtered and dried to obtain 4.0 g. of the desired product, m.p. 96°-99°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][O:19][C:18]2=[O:27])[CH2:13][CH2:12]1>C(O)(=O)C.O1CCCC1.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[CH2:20][O:19][C:18]3=[O:27])[CH2:15][CH2:16]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1OCc2ccccc2N1C1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Iron powder (1.5 g) was added to a solution of the product from step (i) (1.37 g) in acetic acid (50 ml) and tetrahydrofuran (20 ml). After stirring at room temperature for 5 h, the mixture was filtered through celite, the solvent removed under reduced pressure and the residue partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution. The organic layer was washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 50% ethyl acetate/isohexane. Yield 1.05 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:38]=[CH:37][C:20]2[N:21]([CH2:25][C:26]3[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=3[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:38]=[CH:37][C:20]3[N:21]([CH2:25][C:26]4[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=4[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:23][O:24][C:19]=3[CH:18]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1ccccc1CN1CCOc2cc(N)ccc21
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1CN1CCOc2cc(NC(=O)c3nc(Cl)c(CC)[nH]3)ccc21
Yield: 77.3 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.14 g, 0.8 mmol), thionyl chloride (3 mL), ethyl 2-[(7-amino-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (104b) (0.35 g, 1.12 mmol) and pyridine (5 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/3, 2/3, 3/2, 3/1) to obtain 0.29 g of the title compound as a yellow solid (77%).