Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[C:9](=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:26]5[CH2:32][C:28]6([CH2:31][O:30][CH2:29]6)[CH2:27]5)[CH2:22][CH2:21]4)[N:11]=[CH:12][N:13]=3)[C:8]1=2)(=O)=O.[C-:33]#[N:34].[Na+]>CS(C)=O>[CH2:31]1[C:28]2([CH2:27][N:26]([CH:23]3[CH2:24][CH2:25][CH:20]([O:19][C:10]4[N:11]=[CH:12][N:13]=[C:14]5[C:9]=4[C:8]4[C@@H:7]([CH2:6][C:33]#[N:34])[CH2:18][CH2:17][C:16]=4[S:15]5)[CH2:21][CH2:22]3)[CH2:32]2)[CH2:29][O:30]1
Reactant: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CC6(COC6)C5)CC4)c3c21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CC6(COC6)C5)CC4)c3c21
Yield: 65.6 %

Procedure:
A solution of [(3S)-12-[(4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]methyl methanesulfonate (250 mg, 0.52 mmol, 1.00 equiv) and NaCN (153 mg, 3.12 mmol, 5.99 equiv) in DMSO (10 mL) was stirred for 3 h at 60° C. After cooling, the reaction was quenched by the addition of 30 mL of saturated aqueous sodium bicarbonate and extracted with 3×50 mL of ethyl acetate. The combined organic layers combined were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to give 2-[(3R)-12-[(4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetonitrile (140 mg, 65%) as a colorless oil.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]([NH:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[S:19]>ClCCl>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:2](=[O:8])[C:3](=[O:5])[N:20]([CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:18]1=[S:19]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)CNC(=S)Nc1ccc(F)cc1F
Solvent: ClCCl
Product: CC(C)(C)CN1C(=O)C(=O)N(c2ccc(F)cc2F)C1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
Ethyl chlorooxoacetate (0.57 mL, 5.03 mmol) was added to a stirring solution of the above thiourea (1.00 g, 3.87 mmol) in dichloromethane (15 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.66 g (55%) of 1-(2,4-difluoro-phenyl)-3-(2,2-dimethyl-propyl)-2-thioxo-imidazolidine-4,5-dione as a yellow solid: mp 156.2–156.9° C.; 1H NMR (DMSO-d6): δ 7.55 (m, 2H), 7.30 (m, 1H), 3.76 (m, 2H), 0.95 (s, 9H); IR (KBr): 3510 2920, 2230, 1775 cm1; MS (m/z) 312 (M+).
Reaction SMILES: [Si:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].Br[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.CCN(CC)CC>CC#N.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.[Cu]I>[CH3:2][Si:1]([C:5]#[C:6][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1)([CH3:4])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1

Procedure:
TMS-acetylene (Aldrich) (5.0 mL, 35.5 mmol), ethyl 4-bromobenzoate (58 mL, 35.5 mmol) and Et3N (20 mL, 144 mmol) were combined in 50 mL CH3CN in a glass pressure tube. (Ph3P)2PdCl2 (198 mg, 0.28 mmol) and CuI (100 mg, 0.53 mmol) were added, and the reaction was sealed and heated at 100° for 18 h. Dilution with EtOAc, washing twice with water, then brine, drying and concentration provided 29-1 as a brown liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:32])=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:16]=[C:17]([C:18]([O:20]C)=[O:19])[C:12]=3[N:11]=[C:10]2[C:28]([F:31])([F:30])[F:29])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO.O1CCCC1.CS(C)=O>[Cl:1][C:2]1[C:3]([CH3:32])=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]=[C:15]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:12]=3[N:11]=[C:10]2[C:28]([F:31])([F:29])[F:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CO
Product: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(C(=O)O)cc(N3CCOCC3)cc21
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A suspension of methyl 1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 49 (1.09 g, 2.330 mmol) in Methanol (12 mL) and Tetrahydrofuran (THF) (4 mL) was treated with 1 M aq. sodium hydroxide (12 mL, 12.00 mmol) and stirred at 70° C. for 1.5 h (mixture turned homogeneous). The reaction was cooled to room temperature, the volume reduced to half and the residue was acidified (pH 4) by the addition of 1 N HCl. The precipitate was collected, washed with water and dried to give crude desired product (918.6 mg, 2.024 mmol, 87% yield) as a yellow solid. A portion of it (140 mg) was suspended in 3.5 mL of DMSO. After sonication and heating, the solid went into solution but it crashed out. The precipitate was collected and washed with DMSO, but it still showed impurities by LC/MS. Another aliquot (132 mg) was dissolved with heating in 5 mL of DMSO and purified by reverse phase-HPLC (15 to 95% AcCN in water plus 0.1% TFA). The desired product was isolated by evaporation of the organic solvent: the precipitate was collected by filtration, washed with water and dried in a vacuum oven to afford pure desired product (89 mg, 0.192 mmol, 8.25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (s, 1H), 7.63 (d, J=2.27 Hz, 1H), 7.36 (d, J=7.83 Hz, 1H), 7.30 (d, J=2.27 Hz, 1H), 7.05 (t, J=7.96 Hz, 1H), 5.98 (d, J=7.58 Hz, 1H), 5.70 (s, 2H), 3.66-3.83 (m, 4H), 3.08-3.24 (m, 4H), 2.47 (s, 3H). MS (ES+) m/e 453.9 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4]1.[C:9]([C:13]1[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1)([CH3:12])([CH3:11])[CH3:10].[Cl-].[NH4+]>CCOCC.C(O)C>[O:21]=[C:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:14]=1)[CH2:20][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][OH:7]
Reactant: CC(=O)c1cccc(C(C)(C)C)c1
Reactant: O=C1CCCO1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)c1cccc(C(=O)CC(=O)CCCO)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirring suspension of NaH (60% in oil, 7.66 g) in ether (480 ml) at 0° C. was added ethanol (479 μL), followed by γ-butyrolactone (6.18 ml). This was followed by dropwise addition of 1-(3-tert-butyl-phenyl)-ethanone (13.5 g) in ether (80 ml). The resulting mixture was allowed to warm to room temperature and stirred for 72 hours. After careful addition of ethanol (10.5 ml), ammonium chloride solution (10 g in 250 ml water) was then added, ether layer was then separated and washed with brine (300 ml), dried over MgSO4 and concentrated in vacuo to give 1,3-dioxo-6-hydroxy-1(3′-tert-butyl-phenyl)-hexane as crude product (18.5 g). This required no purification and was immediately used in the next reaction.
Reaction SMILES: Cl.N1C=CC=CC=1N1CCN(CC[CH2:16][CH2:17][N:18]2[C:27](=[O:28])[C:26]3[CH:29]=[CH:30][CH:31]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[C:19]2=[O:32])CC1.[Br:33][CH2:34][CH2:35][CH2:36][CH2:37]CCBr.BrCCCCBr>>[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:16][CH2:17][N:18]1[C:19](=[O:32])[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:25]=2[C:26](=[CH:29][CH:30]=[CH:31]3)[C:27]1=[O:28]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccn2)CC1
Reactant: BrCCCCCCBr
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr

Procedure:
Following the procedure of part (a) of example 46 but substituting 1,6-dibromohexane for the 1,4-dibromobutane, one obtains 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 95°-96°.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[CH:3]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)[O:4][C:5]1[C:6]([N:15](COCC[Si](C)(C)C)[S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2>FC(F)(F)C(O)=O>[F:37][C:2]([F:1])([F:36])[CH:3]([C:30]1[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=1)[O:4][C:5]1[C:6]([NH:15][S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1ccncc1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1OC(c1ccncc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 102.9 %

Procedure:
Compound B3 (48.9 mg, 0.0880 mmol) obtained in Step 1 was dissolved in trifluoroacetic acid (1.0 mL) and the solution was stirred at room temperature for 20 minutes. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give Compound 42 (38.6 mg, 100% yield).
Reaction SMILES: [F:1][C:2]1C(F)=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:37][C:38]([NH:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[S:39])[C@H:13]([CH2:14]O)[C@@H:12]([CH2:16][O:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:11][CH2:10]1.N1C=CC=CC=1.F[C:56]([F:69])(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[F:1][C:2]1[C:56]([F:69])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][C@H:12]([CH2:16][O:17][C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:13]1[CH2:14][S:39][C:38]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:37]2
Reactant: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-(((3S,4R,5S)-3-(2,3-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide, obtained in Preparation Example 1-(4), (19.06 g) was dissolved in DCM (75 mL). Pyridine (8.6 mL) was added, and the mixture cooled to 0° C. Trifluoromethanesulfonic anhydride (9.6 mL) was added dropwise and the reaction was allowed to stir at 0° C. After 90 min, the reaction was quenched by the careful addition of NaHCO3 (sat., aq., 250 mL) and extracted with EtOAc (3×250 mL). The combined organic extracts were dried over MgSO4, concentrated in vacuo and purified by silica gel column chromatography (0% to 30% EtOAc/hex) to obtain the title compound (14.52 g). 1H NMR (400 MHz, CDCl3) δ ppm 2.63-2.76 (m, 1H), 3.07-3.24 (m, 2H), 3.32-3.52 (m, 3H), 3.99-4.11 (m, 1H), 4.53-4.63 (m, 2H), 7.09-7.56 (m, 21H), 8.08-8.30 (m, 2H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH2:15][CH2:14][N:13](C(OCC2C=CC=CC=2)=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[CH:27]1([CH2:26][C:10]2([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)NCC1(CC2CC2)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1(CC2CC2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
In one portion, 10% Pd/C (0.159 g, 1.491 mmol) was added to a mixture of benzyl 4-((tert-butoxycarbonylamino)methyl)-4-(cyclopropylmethyl)piperidine-1-carboxylate (0.60 g, 1.5 mmol, prepared using AF from benzyl 4-cyanopiperidine-1-carboxylate [Oakwood] with (bromomethyl)cyclopropane, AE, O with Boc2O) in MeOH (50 mL) at rt. The mixture was stirred under H2 at rt overnight. The mixture was filtered and concentrated in vacuo to provide tert-butyl (4-(cyclopropylmethyl)piperidin-4-yl)methylcarbamate (0.40 g, 95%): LC/MS (Table 2, Method i) Rt=1.59 min; MS m/z: 269 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14](Cl)[C:15]([F:18])([F:17])[F:16].[CH2:20]([NH:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].C(N(CC)CC)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]([N:23]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH3:22])[C:15]([F:18])([F:17])[F:16]
Reactant: FC(F)(F)C(Cl)=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCCNCCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
First, 0.17 g (0.50 mmol) of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,2-trifluoroacetoimidoyl chloride was dissolved in 10 ml of N,N-dimethyl formamide, to which 0.10 g (0.50 mmol) of dipropylamine and 0.10 g (0.50 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 0.18 g of N′-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,2-trifluoro-N,N-dipropylacetamidine (hereinafter referred to as present compound 56).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][CH:9]([C:12](OCC)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[BH4-].[Li+].B(OC)(OC)OC>O1CCCC1.O>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][CH:9]([CH2:12][OH:13])[CH2:10][CH2:11]2)=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCN(C(=O)C2CC2)CC1
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(C1CC1)N1CCC(CO)CC1
Reaction time: 48 h
Yield: 63.7 %

Procedure:
A solution of 1-(cyclopropylcarbonyl)-4-carboethoxy piperidine (35 g, 156 mmol) in anhydrous tetrahydrofuran (350 mL) was stirred at ambient temperature under a nitrogen atmosphere. A solution of lithium borohydride in tetrahydrofuran (2M, 78 mL, 156 mmol) was added dropwise. Trimethyl borate (1.77 mL, 15.7 mmol) was added, then the reduction mixture was stirred for about 48 hours. Water was added dropwise with vigorous stirring until the vigorous gas evolution ceased. The mixture was diluted twofold with water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Vacuum distillation (bp 165° C., 0.5 mm Hg) gave a clear, colorless liquid (18.2 g): IR (neat): 3410 (br, s), 3094 (w), 3008 (s), 2918 (s), 2858 (s), 1738 (m), 1613 (s), 1448 (s), 1375 (s), 1316 (s); 1H-NMR: 4.7-4.5 (m, 1H), 4.4-4.1 (m, 1H), 3.6-3.4 (m, 2H), 3.2-2.5 (m, 3H), 2.0-1.7 (m, 4H), 1.4-1.1 (m, 1H), 1.0-0.8 (m, 2H), 0.8-0.65 (m, 2H); HRMS: Calcd for C10H17NO2 :183.1259; Found: 183.1250; Anal.: Calcd for C10H17NO2 :C, 65.54, H, 9.35, N, 7.64; Found: C, 65.83, H, 9.43, N, 7.50.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH2:13])(=[O:12])=[O:11])(=[O:4])=[O:3].C1N2CCN(CC2)C1.[C:22](Cl)(Cl)=[O:23]>C1(C)C(C)=CC=CC=1>[CH3:1][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([N:13]=[C:22]=[O:23])(=[O:12])=[O:11])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1sccc1S(N)(=O)=O
Reactant: O=C(Cl)Cl
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1C
Product: CS(=O)(=O)c1sccc1S(=O)(=O)N=C=O

Procedure:
A suspension of 3.3 g of the N-(n-butylamino carbonyl) derivative of (XXV) in 75 ml of xylene containing 0.5 g of DABCO was heated to 125°-130° and a solution of 1.8 ml of liquid phosgene in 2 ml of xylene was added. The mixture was heated at reflux for an additional 1.5 hour, cooled under nitrogen, and concentrated to dryness in vacuo. A sample of the crude product displayed a characteristic sulfonyl isocyanate band in the IR at 2200 cm-1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C@@:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[O:12])[C:4](=[O:26])[CH:3]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:46]=[CH:47][C:48]=1B1OC(C)(C)C(C)(C)O1)[O:31][CH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH2:35][CH2:34]1.C(N)(=O)CCC>>[F:27][C:28]1[CH:29]=[C:30]([O:31][CH2:32][C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH2:35][CH2:34]2)[CH:46]=[CH:47][C:48]=1[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C@@:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[O:12])[C:4](=[O:26])[CH:3]=1
Reactant: CC1(C)OB(c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2F)OC1(C)C
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NO[C@@H]1CCCCO1)S(C)(=O)=O
Agent: CCCC(N)=O
Product: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O

Procedure:
The title compound (366 mg, 65.5 mmol) was prepared from (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-[(2R)-tetrahydro-2H-pyran-2-yloxy]butanamide (0.410 g, 8.23 mmol) and (+/−)-2-[(trans-4-{[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclohexyl)oxy]tetrahydro-2H-pyran (0.358 g, 8.23 mmol) by a procedure analogous to that described for (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{[cis-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-Netrahydro-2H-pyran-2-yloxy)butanamide Example 8, Step E. LCMS m/z 677.8 (M−1)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][N:28]=1)[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15].[Li+].[BH4-]>C1COCC1.CO>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([CH2:12][N:13]([CH2:26][C:27]2[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][N:28]=2)[S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])=[C:4]([CH2:3][OH:2])[CH:9]=1)#[N:11]
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(C)cc1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cnc(CN(Cc2ccc(C#N)cc2CO)S(=O)(=O)c2ccccc2[N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
To a solution of 5-cyano-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(2-nitro-benzenesulfonyl)-amino]-methyl}-benzoic acid methyl ester (0.83 g, 1.68 mmol) dissolved in THF (30 mL) and MeOH (10 mL), LiBH4 (0.37 g, 16.8 mmol) was slowly added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and redissolved in CH2Cl2 (50 mL). Water (50 mL) was added and the resulting mixture was extracted with CH2Cl2 (4×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give crude N-(4-cyano-2-hydroxymethyl-benzyl)-N-(3,5-dimethyl-pyridin-2-ylmethyl)-2-nitro-benzene-sulfonamide (0.82 g, 78%) as a yellow foam. 1H NMR (CDCl3) δ 2.16 (s, 3H), 2.25 (s, 3H), 4.58 (s, 2H), 4.67 (s, 2H), 4.76 (br s, 1H), 4.88 (s, 2H), 7.10 (s, 1H), 7.36 (m, 2H), 7.50 (m, 1H), 7.65-7.72 (m, 3H), 7.80 (s, 1H), 7.89 (d, 1H, J=7.5 Hz).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][N:35]=1)[C:31]#[N:32].Cl.C(OCC)(=O)C>C(OCC)C>[ClH:27].[C:31]([C:30]1[CH:33]=[CH:34][N:35]=[C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=2)[CH:29]=1)#[N:32]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1cc(C#N)ccn1

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloroisonicotinonitrile as starting materials and by operations similar to those of Example 303-3 and Example 303-4 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(OCC)=O>C(Cl)Cl.C1COCC1>[CH:6]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])=[O:5]
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: CCOC=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=CNCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
{3-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (81 mg, 0.18 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed in vacuo. To the residue were added THF (5 mL), triethylamine (0.12 mL, 0.90 mmol), and ethyl formate (5 mL), and the resulting mixture was refluxed for 4 days. The mixture was concentrated to dryness, and the residue was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 46 mg of the title compound as an off-white solid. MS: (+) m/z 381.37 (M+1).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([OH:38])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>ClCCl>[CH:22](=[O:38])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCC/C=C/CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCC/C=C/C=O
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To a stirred suspension of 60.6 g (0.161 mol) pyridinium dichromate in 100 mL of dichloromethane was added 25.7 g (0.107 mol) of trans-2-hexadecenol. After 4 h at 25° C., the mixture was filtered (through Celite diatomaceous earth) and the resulting brown solution refiltered through Florisil, an activated magnesium silicate in the form of hard, porous, stable, white granules that are free from dusting sold by Floridin Co. The colorless solution obtained was concentrated in vacuo to 21.8 g (86%) of a white solid. Distillation (90-100° C./0.40-0.45 torr) provided 19.1 g (75%) of pure trans-2-hexadecenal as a white waxy solid. IR (thin film as melt) 2920, 2850, 1695, 1465, 975 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 9.53 (d, 1, J=6.7 Hz, CHO), 6.88 (overlapping dt. 1, J=15.7, 6.7 Hz, OHCCH=), 1.53 (m, 2CH2CH3), 1.1-1.2 (m, 20, CH2CH2CH2), 0.90 (t, 3, J=7 Hz, CH2CH3). Rf (15% ethyl acetate:hexanes): trans-2-hexadecenol, 0.19 trans-2-hexadecenal, 0.44. MS(FD) m/e 238 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].[C-:18]#[N:19].[Na+].C(OCC)(=O)C>CS(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:18]#[N:19])=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: Cc1cc(CBr)ccc1NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(CC#N)ccc1NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
The compound (155.1 mg) obtained in Example 519 was dissolved in dimethyl sulfoxide (5 ml). To the solution, sodium cyanide (127 mg) was added and the mixture was heated at 50° C. under stirring for 10 min. To the resulting reaction mixture, ethyl acetate was added and the organic layer was washed with water twice, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 77.7 mg of the titled compound (yield, 61%).