Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:13]1([S:19]([N:10]2[C:7]3=[N:8][CH:9]=[C:4]([Br:3])[CH:5]=[C:6]3[CH:12]=[CH:11]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100.8 %

Procedure:
Sodium hydroxide (4.1 g, 102.8 mmol) was added to a solution of tetrabutylammonium bromide (331 mg, 1.0 mmol) and 5-bromo-1H-pyrrolo[2,3-b]pyridine (6.7 g, 34.7 mmol) in dichloromethane (80 mL) at 0° C. The mixture was stirred at 0° C. for 5 min. Benzene sulfonyl chloride (5.7 mL, 44.5 mmol) was added to the above mixture slowly at 0° C. The resulting mixture was stirred at 0° C. for 15 min before it was warmed to 25° C. and kept stirring at that temperature for 12 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo and then washed with hexanes to afford 1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridine as a white solid (11.8 g, 100%): LC/MS m/e calcd for C13H10BrN2O2S [M+H]+ 338.20, observed 337.1, 339.1; 1H NMR (400 MHz, CDCl3) δ ppm 6.56 (d, J=4.0 Hz, 1H), 7.51 (m, 2H), 7.60 (m, 1H), 7.75 (d, J=4.0 Hz, 1H), 7.98 (d, J=2.1 Hz, 1H), 8.18 (m, 2H), 8.45 (d, J=2.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH:12](OCC)(OCC)OCC>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:12]=[N:11][C:9](=[O:10])[C:3]=2[N:4]=1
Reactant: NC(=O)c1nc(Cl)ccc1N
Reactant: CCOC(OCC)OCC
Product: O=c1nc[nH]c2ccc(Cl)nc12
Temperature: 25 °C
Yield: 82 %

Procedure:
A suspension of 3-amino-6-chloropicolinamide (1.67 g, 9.74 mmol) in triethyl orthoformate (73.0 mL) was refluxed for 3 hours. The reaction mixture was cooled to room temperature, and then filtered. The filtercake was dried under vacuum to give 6-chloropyrido[3,2-d]pyrimidin-4(1H)-one (1.45 g, 82%) as a brown solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.66 (1H, d, J=8.4 Hz), 8.00 (1H, s), 8.03 (1H, d, J=1.2 Hz), 12.57 (1H, brs).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(=O)([O-])O.[Na+].[CH2:15]([O:22][C:23]([NH:25][CH2:26][C:27](C1CC(=O)N(O)C1=O)=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O.C(COC)OC.C(OCC)(=O)C>[CH2:15]([O:22][C:23]([NH:25][CH2:26][C:27]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(NCC(=O)C1CC(=O)N(O)C1=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: O=C(NCC(=O)N1C[C@H](O)C[C@H]1C(=O)O)OCc1ccccc1
Yield: 68.9 %

Procedure:
trans-4-Hydroxy-L-proline 1 (0.28 g, 2.13 mmol) and sodium hydrogen carbonate (0.18 g, 2.13 mmol) were dissolved in water (3 cm3) at room temperature. N-benzyloxycarbonyl-glycyl-N-hydroxysuccinimide 2 (0.44 g, 1.44 mmol) in dimethoxyethane (3 cm3) was added dropwise over a period of 5 min. The solution was stirred for 2.5 then acidified with conc. hydrochloric acid (38%) to pH 1. The solution was placed in a refrigerator overnight. Ethyl acetate (2×20 cmr3) was added and the resulting organic layers dried (MgSO4), filtered and evaporated under reduced pressure to yield a light pinky foam, which was purified by flash column chromatography (10% methanol/methylene chloride) to produce acid 3 (0.32 g, 70%) as a clear foam. Acid 3 was shown to be an 77:23 trans:cis mixture of conformers by 1H NMR analysis (the ratio was estimated from the integration of the signals at (δ 4.33-4.38 and 4.52-4.54, assigned to the Proα-H of the major and minor conformers respectively): [α]D −75.5 (c 0.08 in MeOH); OH (300 MHz; CD3OD) 1.89-1.94 (0.77H, m, Proβ-HAHB), 2.08-2.14 (1H, m, Proβ-HAHB), 2.14-2.16* (0.23H, m, Proβ-HAHB), 3.17-3.20 (1H, m, Proδ-HAHB), 3.53-3.57 (1H, m, Proδ-HAHB), 3.73-3.78 (1H, d, J 17.1, Glyα-HAHB), 3.87-3.93 (1H, d, J 17.1, Glyα-HAHB), 4.20-4.30* (0.23H, m, Proγ-H), 4.33-4.38 (1.54H, m, Proγ-H and Proα-H), 4.52-4.54* (0.23H, t, J 7.0, Proα-H) 4.94 (2H, s, OCH2Ph) and 7.11-7.23 (5H, m, Ph); δC (75 MHz, CD3OD) 39.0 (CH2, Proβ-C), 41.3* (CH2, Pro-C), 44.2* (CH2, Proδ-C), 44.8 (CH2, Proδ-C), 55.9 (CH2, Glyα-C), 56.2* (CH2, Glyα-C), 59.5* (CH, Proα-C), 60.1 (CH, Proα-C), 68.5 (CH2, OCH2Ph), 68.7* (CH2, OCH2Ph), 69.7* (CH, Proγ-C), 71.7 (CH, Proγ-C), 129.6 (CH, Ph), 129.7 (CH, Ph), 130.2 (CH, Ph), 138.9 (quat., Ph), 159.6 (quat., NCO2), 170.1 (quat., Gly-CO), 171.6* (quat., Gly-CO), 175.9* (quat., CO2H) and 176.3 (quat., CO2H),; m/z (FAB+) 323.1240 (M+.C16H20N2O5 requires 320.1243).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:27](OCC)(=[O:29])[CH3:28]>>[C:27]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[C:19](=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:29])[CH3:28]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2cc([N+](=O)[O-])ccc21
Reactant: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2cc([N+](=O)[O-])ccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-1-(ethoxycarbonyl)-5-nitroindole (step 2). tlc: Rf=0.2 (50% ethyl acetate in hexanes)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=1[CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CCOC(C)=O.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:31][C:28]4[CH:29]=[CH:30][C:25]([F:24])=[C:26]([CH:32]5[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]5)[CH:27]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: CN1CCC(c2cc(N)ccc2F)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2cc(Nc3ncnc4[nH]c(C5=CCN(C(=O)OC(C)(C)C)CC5)cc34)ccc2F)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (167 mg, 0.500 mmol), 4-fluoro-3-(1-methylpiperidin-4-yl)-phenylamine (149 mg, 0.600 mmol), N,N-dimethylformamide (3 mL), and trifluoroacetic acid (385 μL, 5.18 mmol) in a sealed tube was heated at 100° C. for 15 h. The mixture was concentrated in vacuo, charged with sodium bicarbonate (504 mg, 6.00 mmol), di-tert-butyldicarbonate (120 mg, 0.550 mmol), and N,N-dimethylformamide (2 mL), and stirred at rt under N2 for 24 h. After that time, the mixture was filtered, and the filtrate was concentrated in vacuo to obtain a brown oil, which was dissolved in EtOAc (30 mL) and washed with water (3×20 mL). The organic phase was concentrated in vacuo to obtain a light-brown oil that was purified by HPLC to give the title compound. 1H NMR (CD3OD, 400 MHz): δ=1.51 (s, 9H), 1.87 (brs, 4H), 2.13-2.20 (m, 2H), 2.32 (s, 3H), 2.54 (brs, 2H), 2.83-2.91 (m, 1H), 2.99-3.01 (m, 2H), 3.65 (brs, 2H), 4.12 (brs, 2H), 6.27 (brs, 1H), 6.56 (s, 1H), 7.03 (t, 1H, J=8.8 Hz), 7.57-7.60 (m, 2H), 8.19 (s, 1H). MS (ES+): m/z 507.17 (75) [MH+]. HPLC: tR=2.16 min (ZQ2000, polar—5 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.Cl.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=2)[CH:7]=[CH:6][N:5]=1
Reactant: FC(F)(F)c1cc(Cl)ccn1
Reactant: CC1(C)OB(c2ccc(CN)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NCc1ccc(-c2ccnc(C(F)(F)F)c2)cc1
Temperature: 96 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-2-(trifluoromethyl)pyridine 28-1 (54 mg, 0.3 mmol), (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride 28-2 (81 mg, 0.3 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol) and K3PO4 (212 mg, 1.0 mmol) in dioxane (1.6 mL) and water (0.2 mL) was stirred at 96° C. under argon overnight. After cooling to room temperature, the mixture was filtered through celite (washed with ethyl acetate) and the filtrate was redistributed between ethyl acetate and water. The organic phase was dried over Na2SO4 and concentrated with rotavap. The residue was subjected to silica gel column chromatography with 7% ammonia-saturated methanol in dichloromethane as eluent to give (4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)methanamine 28-3 as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C@@H:6]([C:8]([O:10]C)=[O:9])[C@H:5]([C:12]([O:14]C)=[O:13])[CH2:4][C:3]=1[CH3:16].[OH-].[Na+]>CO>[CH3:16][C:3]1[CH2:4][C@@H:5]([C:12]([OH:14])=[O:13])[C@H:6]([C:8]([OH:10])=[O:9])[CH2:7][C:2]=1[CH3:1]
Reactant: COC(=O)[C@@H]1CC(C)=C(C)C[C@H]1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C)C[C@@H](C(=O)O)[C@H](C(=O)O)C1
Yield: 77 %

Procedure:
Trans-dimethyl 1,2-dimethylcyclohex-1-ene-4,5-dicarboxylate (4.52 g, 0.02 mol) was refluxed with NaOH (4.0 g, 0.1 mol) in methanol (40 ml) for 4 hr. The solution was allowed to cool and partitioned between aqueous NaOH (2M, 50 ml) and ether (60 ml). The aqueous layer was then acidified (1M HCl) and extracted with ethyl acetate (3×50 ml). The solvent was removed in vacuo to give the title compound in 77% yield. N.m.r: δH (90 MHz CD3Cl3) 2.58 (m,2H), 2.08 (m,4H), 1.70 ppm (s,6H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[F:60][CH:61]([F:64])[CH2:62][OH:63]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:60][CH:61]([F:64])[CH2:62][O:63][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: OCC(F)F
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(OCC(F)F)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 110 °C
Reaction time: 10 h
Yield: 20.4 %

Procedure:
A mixture of 5-bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.400 g, 1 mmol), palladium(II) acetate (0.004 g, 0.02 mmol), rac-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.009 g, 0.025 mmol), and cesium carbonate (0.488 g, 1.5 mmol) in toluene (5 mL) was treated with 2,2-difluoro ethanol (0.164 mL, 2 mmol) and stirred at 110° C. for 8-12 h. After this time the solvent was evaporated and silica gel column chromatography using, typically 30% ethyl acetate in hexane, afforded the desired product (0.082 g, 20%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.74 (s, 3H), 4.22 (m, 4H), 4.73 (s, 2H), 5.94-6.32 (m, 1), 6.75 (d, 2H), 7.18 (d, 2H), 7.35 (d, 2H). GC-MS: m/z 401 (M)+, 316 (M−85)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: COC(=O)c1ccc(C)cc1Br
Reactant: OB(O)c1ccccc1Cl
Product: COC(=O)c1ccc(C)cc1-c1ccccc1Cl

Procedure:
500 mg (2.18 mmol) of methyl 2-bromo-4-methylbenzoate and 512 mg (3.27 mmol) of 2-chlorophenylboronic acid were reacted analogously to the preparation of Example 107A. This gave 275 mg (48% of theory) of the target compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](Cl)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[NH3:15]>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH2:15])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: N
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc2cccnc12
Temperature: -60 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
Quinoline-8-sulfonyl chloride (1.0 g, 4.39 mmol) was slurried into DCM (20 mL) and cooled to −60° C. Then ammonia (˜5 g, 294 mmol) was bubbled into the reaction over 5 min (volume increased by ˜5 mL). The reaction was stirred and allowed to come to rt overnight. The residue was partitioned between water (50 mL) and EtOAc (50 mL) and the organic layer was washed with brine (20 mL) and diluted with hexanes (˜50 mL). The solution was stirred 20 min and the solids were collected by filtration to yield quinoline-8-sulfonamide (432 mg, 2.07 mmol, 47% yield) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.25 (s, 2H), 7.73 (dd, J=8.3, 4.3 Hz, 1H), 7.76 (dd, J=8.6, 7.3 Hz, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.31 (d, J=7.3 Hz, 1H), 8.56 (br d, J=8.6 Hz, 1H), 9.08 (dd, J=4.3, 0.9 Hz, 1H). LC-MS retention time: 1.27 min; m/z 209 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:18])=[C:13]([OH:17])[C:14]=1[CH2:15][OH:16])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1>>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:18])=[C:13]([O:17][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)[C:14]=1[CH2:15][OH:16])[C:19]1[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(CO)c1O
Product: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(CO)c1OCc1cccc(C#N)c1
Yield: 122.4 %

Procedure:
The coupling of (4-cyano-phenyl)-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (105) (8.7 g, 19.9 mmol) and α-bromo-m-tolunitrile (5.6 g, 28 mmol), as described in Example 1, gave [5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (106) (11.8 g, 68% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:8][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-bromophenol (9.50 g, 54.9 mmol) in degassed DMF (150 mL) at 0° C., under argon, was added Cs2CO3 (35.8 g, 109 mmol). The resulting mixture was stirred for 1 hour, then benzyl bromide (10.3 g, 60.2 mmol) was added and stirring was continued for 2 hours at 0° C. The solvent was removed under reduced pressure, and the residue was partitioned between 20% aqueous NaOH (250 mL) and CHCl3 (500 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting first with two column volumes of hexane, then with hexane—2% EtOAc to yield the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([CH:65]1[CH2:70][CH2:69][CH2:68][CH2:67][NH:66]1)[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][CH2:69][CH2:70][CH:65]1[CH2:63][CH3:64])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-ethyl-piperidine in DMSO at ambient temperature.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([CH2:19][N:25]2[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: OC1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1
Yield: 52.7 %

Procedure:
The title compound was prepared from 500 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 196 mg of 4-hydroxypiperidine and 597 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 348 mg of the title compound. RF : 0.16 (5% MeOH in CH2Cl3). 1H NMR (300 MHz, CDCl3): δ1.35-1.54 (m, 2H), 1.69-1.83 (m, 2H), 1.93-2.05 (m, 2H), 2.36-2.71 (m, 7H), 3.89-3.01 (m, 3H), 3.55-3.72 (m, 3H), 7.14-7.38 (m, 10H). Mass Spectrum (NH3 -CI): 351.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].C[N:20](C)C=O.CC(O)C>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:20])[C:7]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: O=C(c1ccncc1)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC(C)O
Product: Nc1ccc(C(=O)c2ccncc2)cc1[N+](=O)[O-]

Procedure:
The procedure of Example 24 was followed except 4-(3-nitro-4-chlorobenzoyl)pyridine was used in place of 3-(3-nitro-4-chlorobenzoyl)pyridine. The product was orange prisms, mp. 294° -295° C. (dimethylformamide-2-propanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:25])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCSc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCS(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
The product from Example 70 Step B (70 mg) was stirred in 2 mL of dichloromethane with 3-chloroperoxybenzoic acid (MCPBA) (40 mg) for 1 hour at 0° C. An additional 5 mg of MCPBA was added and the reaction stirred 30 minutes more, then diluted with EtOAc and washed with saturated NaHCO3 and brine. The solution was dried over Na2SO4 and concentrated in vacuo to give the titled compound. ESI+ MS: 218 [MH-Boc]+.
Reaction SMILES: [CH3:1][N:2]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:3].[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].B(F)(F)F.C[CH2:20][O:21]CC.[Li]CCCC.CN(C=O)C>C1COCC1>[CH:20]([C:5]1[C-:4]([N:2]([CH3:3])[CH3:1])[CH:8]=[CH:7][CH:6]=1)=[O:21].[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14]
Reactant: CCOCC
Reactant: CN(C)[c-]1cccc1
Agent: [Fe+2]
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)[c-]1cccc1C=O
Yield: 75.1 %

Procedure:
A solution of 11 (100 mg, 0.44 mmol) in THF (5 mL) was sequentially treated with BF3.OEt2 (58 μL, 0.46 mmol), n-BuLi (0.51 mL, 1.70 M, 0.87 mmol) and DMF (0.17 mL, 2.18 mmol). Standard workup followed by gradient column chromatography (silica gel, 94:5:1 hexanes/Et2O/Et3N, then 84:15:1 hexanes/Et2O/Et3N) gave 12d (85 mg, 76%) as a red-orange oil; IR (KBr, neat) vmax 3097, 2943, 2851, 2826, 2785, 1667 cm−1, 1H NMR (300 MHz, CDCl3) 10.13 (s, 1H), 4.61 (m, 1H), 4.40 (t, 1H, J=2.7 Hz), 4.29 (m, 1H), 4.27 (s, 5H), 2.70 (s, 6H) ppm; 13C NMR (75.5 MHz, CDCl3) 192.8, 117.5, 71.8, 69.5, 67.7, 66.2, 60.2, 45.6 ppm; EIMS [m/z (%)] 257 (M+, 100), 229 (13), 119 (54), 44 (66); HRMS (EI) calcd for C13H15NO56Fe: 257.0503. Found 257.0504.
Reaction SMILES: [Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].C(OC(=O)CC)(=O)CC.C(OC=C)(=O)CC>COC(C)(C)C>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4]
Reactant: OC(CBr)c1cccc(Cl)c1
Agent: C=COC(=O)CC
Agent: CCC(=O)OC(=O)CC
Solvent: COC(C)(C)C
Product: O[C@@H](CBr)c1cccc(Cl)c1

Procedure:
To a mixture of 100 mg (0.4 mmol) of 2-bromo-1-(3-chlorophenyl)ethanol, 10 mg of Lipase QL (Meito Sangyo Co., Ltd.) and 39 mg (0.3 mmol) of propionic anhydride or 30 mg (0.36 mmol) of vinyl propionate as an acylating agent was added t-butyl methyl ether to make the total volume to 1 ml. These reaction mixtures were respectively allowed to undergo reaction at a temperature of 35° C. for 22 hours. The results are set forth in Table 4.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.C1(P(=[CH:28][C:29]([O:31][CH3:32])=[O:30])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])/[CH:28]=[CH:7]/[C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)s1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 19 h
Yield: 87.9 %

Procedure:
To a solution of 5-chloro-2-thiophene-carboxaldehyde (5.10 g, 34.8 mmol) in 100 mL of dry CH2Cl2 is added methyl (triphenylphosphoranylidene)acetate (11.8 g, 35.3 mmol). The resulting brown-green mixture is stirred for 19 h at room temperature. The mixture is filtered through a Celite pad, concentrated in vacuo and triturated with hexane. The white precipitate (triphenylphosphine oxide) is filtered off and the filtrate is concentrated. The crude residue is purified via flash column chromatography eluting with a gradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes to provide the title compound (6.20 g, 30.6 mmol) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ7.65 (d, 1H), 7.05 (d, 1H), 6.89 (d, 1H), 6.10 (d, 1H), 3.80 (s, 3H).