Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:27]I>O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 73.4 mg) was added to a solution of N-[2-(1-t-butoxycarbonylpiperidin-4-yl)phenyl]methanesulfonamide (650 mg) in tetrahydrofuran (50 mL) and the mixture was stirred at room temperature for 1 h. Methyl iodide (260 mg) was added and the mixture was stirred at room temperature for 36 h. The solvent was evaporated under reduced pressure, and the residue was partitioned between water and ethyl acetate (100 mL). The organic layer was separated, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as colorless solid (662 mg), δH (CDCl3) 1.48 (9H, s), 1.73 (2H, m), 1.88 (2H, m), 2.84 (2H, m), 2.97 (3H, s), 3.25 (3H, s), 3.33 (1H, m), 4.13 (2H, m), 7.21-7.36 (4H, m). m/e (ES+) 369 (MH+).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.CN.CO>CO>[NH2:3][O:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1
Reactant: NC(=O)c1ccc(CON2C(=O)c3ccccc3C2=O)nc1
Agent: CN
Solvent: CO
Product: NOCc1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a suspension of 292 mg of 6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}nicotinamide in 4.4 ml of methanol was added 0.2 ml of a 40% methyl amine/methanol solution, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated, ethyl acetate was added thereto, and the precipitated crystal was separated by filtration and then concentrated under reduced pressure to obtain 146 mg of 6-[(aminooxy)methyl]nicotinamide.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[C:18]([CH3:24])[N:17]=3)=[CH:13][C:12]=2[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.C(O)(=O)C.[Na]>CO.Cl.CCOCC>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[N:17]=[C:18]([CH3:24])[C:19]([CH2:20][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)=[CH:22][CH:23]=3)=[CH:13][C:12]=2[CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CNC1
Reactant: Cc1nc(-c2cc3cc(Cc4ccccc4)ccc3o2)ccc1C=O
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: Cc1nc(-c2cc3cc(Cc4ccccc4)ccc3o2)ccc1CN1CC(C(=O)O)C1
Temperature: 24 °C
Reaction time: 1 h

Procedure:
A suspension of 6-(5-benzylbenzofuran-2-yl)-2-methylnicotinaldehyde (160 mg, 489 μmol) and 3-azetidinecarboxylic acid (49.4 mg, 489 μmol) in MeOH (8 mL) and glacial acetic acid (44.0 mg, 733 μmol) was stirred at 24° C. for 1 h, treated with sodium borocyanohydride (15.4 mg, 244 μmol), and stirred for 2 h. The mixture was diluted with 30 mL of 1M HCl in Et2O and evaporated. Purification of the residue by RP-HPLC to give title compound as an off-white solid [hS1P1 EC50=420 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (s, 2H), 7.55-7.53 (m, 2H), 7.43 (s, 1H), 7.28-7.18 (m, 6H), 4.04 (s, 2H), 3.59 (s, 2H), 3.45-3.23 (m, 8H). MS (ESI) m/z: Calculated: 412.5; Observed: 413.3 (M++1).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([NH:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12]>CN(C=O)C>[F:10][C:8]1[CH:9]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[NH:14][CH2:15][CH2:16][O:17][C:6]=2[CH:7]=1
Reactant: O=S(=O)(NCCO)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)NCCOc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (260 mg, 6.49 mmol) was added to a solution of 2,4-difluoro-N-(2-hydroxyethyl)benzenesulfonamide (0.7 g, 2.95 mmol) in DMF (100 mL) and the mixture stirred at RT for 48 hours. The solvent was removed in vacuo, iced water (200 mL) added and the mixture extracted into ethyl acetate. The combined organic extracts were washed with brine (40 mL), dried (MgSO4), filtered and reduced in vacuo to give a white solid which was chromatographed on silica, eluting with 20-70% ethyl acetate in isohexane, to give the desired compound as a white solid (0.18 g). 1H NMR δ (CDCl3): 3.65-3.70 (m, 2H), 4.25-4.27 (m, 2H), 4.69 (t, 1H), 6.86-6.94 (m, 2H), 7.82-7.86 (m, 1H); m/z 216 (M−H)−
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)(=O)=O.[CH3:23][N:24](C=O)C>C([O-])(O)=O.[Na+].[C-]#N.[Zn+2].[C-]#N>[C:23]([C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)#[N:24]
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc2c1CCCC2
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Product: COC(=O)c1cc(C#N)cc2c1CCCC2
Yield: 73 %

Procedure:
A solution of methyl 3-trifluoromethylsulfonyloxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (2.08 g, 6.15 mmol), zinc cyanide (0.81 g, 6.89 mmol) and tetrakistriphenylphosphine palladium (0.56 g, 0.48 mmol) in DMF (8 mL) was stirred at 120° C. for 1 h. The mixture was diluted with saturated NaHCO3, extracted with EtOAc, dried (MgSO4), filtered, and concentrated. Following column chromatography methyl-3-cyano-5,6,7,8-tetrahydro-1-naphthalenecarboxylate was obtained as a white solid (960 mg, 73%). 1H NMR (CDCl3) δ 7.94 (s, 1H), 7.49 (s, 1H), 3.90 (s, 3H), 3.11 (s, 2H), 2.84 (s, 2H), 1.81 (m, 4H); MS m/z 216.1 (M+H), 214.1 (M−H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:25]([OH:26])=[C:24]([O:27][CH3:28])[C:23]([O:29][CH3:30])=[CH:22][C:21]=1[CH3:31].N(S([O-])(=O)=O)(S([O-])(=O)=[O:35])[O].[K+].[K+].O.CO>CN(C)C=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:25](=[O:26])[C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[C:22](=[O:35])[C:21]=1[CH3:31]
Reactant: COc1cc(C)c(CCCCCCCCCCCCCCCCCCO)c(O)c1OC
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCO)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1080 h
Yield: 60.1 %

Procedure:
6-(18-Hydroxyoctadecyl)-2,3-dimethoxy-5-methylphenol (0.5 g), prepared by deacetylating the above 18-acetoxy compound in the same manner as in Reference Example 3, is dissolved in dimethylformamide (1 l) followed by addition of potassium nitrosodisulfonate (13 g), water (700 ml), methanol (100 ml) and potassium-dihydrogen phosfate (1 g). The mixture is stirred at room temperature for 45 days. The product is extracted in a conventional manner and recrystallized from hexane to give yellow needles of 6-(18-hydroxyoctadecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (I, n=18, 0.31 g). m.p. 81° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5]2.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][N:17]=1>O1CCOCC1.O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:16]1[N:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][N:17]=1)[CH:6]=[CH:5]2
Reactant: OB(O)c1ccc2cc(O)ccc2c1
Reactant: O=C(O)c1cnc(Cl)nc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cnc(-c2ccc3cc(O)ccc3c2)nc1
Temperature: 120 °C

Procedure:
Followed procedure described in Step 1 of Example 7 starting from 6-hydroxynaphthalen-2-ylboronic acid and 2-chloropyrimidine-5-carboxylic acid with modifications: the solvent was dioxane/water (6/1), and the reaction was heated to 120° C. by microwave for 0.5 h. Purified by prep-HPLC. 1H-NMR (DMSO-d6 500 MHz): 13.70 (brs, 1H), 10.12 (s, 1H), 9.29 (s, 2H), 8.97 (s, 1H), 8.42-8.44 (d, J=9.0 Hz, 1H), 8.00-8.01 (d, J=8.5 Hz, 1H), 7.82-7.84 (d, J=9.0 Hz, 1H), 7.20 (s, 1H), 7.15-7.18 (dd, J=2.0, 9.0 Hz, 2H). MS (ESI): m/z=267.0 [M+1]+.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:14])=[C:7]([C:11]([OH:13])=O)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].[OH:15][C:16]1[C:25]([CH2:26][CH3:27])=[CH:24][C:19]([C:20]([NH:22]O)=[NH:21])=[CH:18][C:17]=1[CH2:28][CH3:29]>>[CH2:28]([C:17]1[CH:18]=[C:19]([C:20]2[N:22]=[C:11]([C:7]3[S:8][C:9]([CH3:10])=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]=3[CH3:14])[O:13][N:21]=2)[CH:24]=[C:25]([CH2:26][CH3:27])[C:16]=1[OH:15])[CH3:29]
Reactant: CCc1cc(C(=N)NO)cc(CC)c1O
Reactant: Cc1sc(C(=O)O)c(C)c1CC(C)C
Product: CCc1cc(-c2noc(-c3sc(C)c(CC(C)C)c3C)n2)cc(CC)c1O

Procedure:
2,6-Diethyl-4-[5-(4-isobutyl-3,5-dimethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenol is prepared from 4-isobutyl-3,5-dimethyl-thiophene-2-carboxylic acid and 4,N-dihydroxy-3,5-diethyl-benzamidine in analogy to Example 21; LC-MS: tR=1.24 min, [M+1]=385.28.
Reaction SMILES: [CH2:1]([C:3]1([CH3:22])[CH:8]([CH3:9])[CH:7]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][C:5]([CH2:20][CH3:21])([CH3:19])[NH:4]1)[CH3:2].Cl.[CH2:24]1[O:26][CH2:25]1>CO>[OH:26][CH2:25][CH2:24][N:4]1[C:5]([CH2:20][CH3:21])([CH3:19])[CH2:6][CH:7]([NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:22]
Reactant: CCC1(C)CC(NC(=O)c2ccccc2)C(C)C(C)(CC)N1
Reactant: C1CO1
Agent: Cl
Solvent: CO
Product: CCC1(C)CC(NC(=O)c2ccccc2)C(C)C(C)(CC)N1CCO
Temperature: 130 °C

Procedure:
30.3 g of 2,6-diethyl-2,3,6-trimethyl-4-benzamidopiperidine (compound no. 9), 200 ml of methanol and 2 ml of concentrated hydrochloric acid are introduced into an autoclave. About 9 g of ethyleneoxide are added, and the contents of the autoclave are heated to 130° C. for 30 hours. After cooling, the contents of the autoclave are purified by filtration, and the methanol is evaporated. Crystallization of the residue from toluene yields 1-β-hydroxyethyl-2,6-diethyl-2,3,6-trimethyl-4-benzamidopiperidine (compound no. 27); m.p. 212°-214° C. If, instead of 30.3 g of 2,6-diethyl-2,3,6-trimethyl-4-benzamidopiperidine an equimolar amount of N,N'-diacetyl-N,N'-bis-(2,6-diethyl-2,3,6-trimethyl-4-piperidyl)-hexamethylene-1,6-diamine (compound no. 22), 12 g instead of 9 g of ethyleneoxide are used and otherwise the procedure described above is followed, N,N'-diacetyl-N,N'-bis-(1-β-hydroxyethyl-2,6-diethyl-2,3,6-trimethyl-4-piperidyl)-hexamethylene-1,6-diamine (compound no. 28) is obtained as a yellowish viscous resin.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([OH:37])=[C:13]2[C:18](=[CH:19][N:20]=1)[N:17](CC1C=CC=CC=1)[C:16](=[O:28])[C:15]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[CH:14]2)=[O:10])C.[OH-].[Na+].CO>C1COCC1>[CH2:15]([N:20]1[CH:19]=[C:18]2[C:13](=[CH:14][CH:15]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:16](=[O:28])[NH:17]2)[C:12]([OH:37])=[C:11]1[C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:38])=[O:10])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)CCCNC(=O)c1ncc2c(cc(-c3cccc(OC)c3)c(=O)n2Cc2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(C2C=C3C(=CN(Cc4ccccc4)C(C(=O)NCCCC(=O)O)=C3O)NC2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 132.5 %

Procedure:
A mixture of 4-{[1-benzyl-5-hydroxy-3-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carbonyl]-amino}-butyric acid ethyl ester (38 mg, 0.074 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washes several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 24 mg of the title compound as a yellow solid. MS: (+) m/z 488.40 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[CH:9][CH:8]=1)=[O:5].C1C(=O)N(Br)C(=O)C1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C([O-])(O)=O.[Na+]>C1COCC1.C1(P([Pd](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC=CC=1.CCO>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)=[CH:16][C:17]=2[CH3:18])=[CH:11][CH:12]=1)=[O:5]
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccsc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2cccnc2)sc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-difluoro-N-(4-(3-methylthiophen-2-yl)phenyl)benzamide (A, 1.3 mmol) in THF (5 mL) was added NBS (1.5 mmol) and solution was stirred at rt for 2 h. Pyridin-3-ylboronic acid (1.5 mmol), bis(triphenylphosphino)palladium dichloride (0.05 mmol) and NaHCO3 (3 mmol) was added followed by EtOH (2 mL), toluene (5 mL) and water (5 mL). The mixture was heated at 110° C. for 1 h. The organic layer was separated, concentrated and purified by flash chromatography to give 2,6-difluoro-N-(4-(3-methyl-5-(pyridin-3-yl)thiophen-2-yl)phenyl)benzamide (B, 50 mg) as white solids. 1H-NMR (CD3OD) □ 8.8 (br, 1H), 8.4 (m, 1H), 8.0 (m, 1H), 7.7 (m, 2H), 7.4-7.6 (m, 6H), 7.1 (t, 2H, J=8), 2.38 (s, 3H) ppm; ESMS calcd for C23H16F2N2OS: 406.1. Found: 407.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11](=[O:14])([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:14][C:11]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[N+:8]([O-:10])=[O:9])([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1Oc1ccccc1[N+](=O)[O-]
Yield: 41.7 %

Procedure:
A solution of 3-[[[3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]phenol (100 mg, 0.23 mmol), 1-bromo-2-nitrobenzene (52.4 mg, 0.26 mmol), copper(I) trifluoromethanesulfonate benzene complex (3 mg, 2.5 mol %) and cesium carbonate (100 mg, 0.31 mmol) in toluene (1 mL) and ethyl acetate (1 mL) was heated at 95° C. in a sealed vial for 4 d. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 50% to 90% acetonitrile in water to afford 14.1 mg (11%) of the desired 2-nitrophenyl ether product as an orange oil. HRMS calcd. for C24H20F7N2O5: 549.1260 [M+H]+, found: 549.1235. 1H NMR (CDCl3) δ 3.63 (dd, 1H), 3.84 (dd, 1H), 4.35-4.42 (m, 1H), 4.64 (s, 2H), 5.90 (tt, 1H), 6.47-6.67 (m, 3H), 6.98-7.50 (m, 8H), 7.97 (d, 1H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]([C:14]1C=C(C)C=C(C(C)(C)C)[C:15]=1[OH:25])(C)(C)C.C(Cl)(=O)C=C.Cl>O.N1C=CC=CC=1.CC(N(C)C)=O>[C:15]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:25])[CH:14]=[CH2:10]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C(O)CCCCCO
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: C=CC(=O)OCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A mixture of 6-hydroxyhexanoic acid (10 g), 2,6-di-tert-butyl-4-methylphenol (0.5 g), and dimethylacetamide (57 mL) was cooled to 0° C. Acryloyl chloride (17.2 g) was then added dropwise. After stirring for 3.5 hrs, pyridine (12 mL) and water (12 mL) were slowly added. After stirring for another 2 hrs, the solution was acidified with dilute HCl and extracted with ethyl acetate. The combined organic layer was washed with water, dried, filtered, and concentrated to afford 6-acryloyloxyhexanoic acid. 1H NMR (CDCl3, 500 MHz) δ 1.46 (m, 2H), 1.70 (m, 4H), 2.37 (t, J=7.3 Hz, 2H), 4.17 (t, J=6.4 Hz, 2H), 5.82 (d, J=10.4 Hz, 1H), 6.12 (dd, J=17.3, 10.5 Hz, 1H), 6.39 (d, J=17.3 Hz, 1H), 11.59 (br, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][N:20]=[N:19][CH:18]=2)[CH2:8][NH:9]C(=O)OC(C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][N:20]=[N:19][CH:18]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCC(c1ccccc1)c1ccnnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(c1ccccc1)c1ccnnc1

Procedure:
A solution of tert-butyl (2-phenyl-2-(pyridazin-4-yl)ethyl)carbamate (120 mg, 0.40 mmol) in DCM (2 ml) and TFA(2 ml) was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was diluted with sat.aq Na2CO3 to adjust pH=9-10, then, extracted with AcOEt (3×30 ml), the combined organic layer was washed with brine, dried over Na2SO4 and concentrated to get the 2-phenyl-2-(pyridazin-4-yl)ethanamine(crude 80 mg), which was used for next step directly.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:7][CH:8]([CH3:12])[C:9](O)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH:1]1([O:6][C:9](=[O:10])[CH:8]([SH:7])[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: CC(S)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CC(S)C(=O)OC1CCCC1

Procedure:
Into a 250 ml reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 86 grams of cyclopentanol; 25 grams of 2-mercaptopropionic acid; and 1 gram of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 8 hours. At the end of the 8 hour reflux period, the reaction mass is cooled and admixed with 200 ml diethylether followed by washing with two 100 ml volumes of 10% aqueous sodium carbonate and one 100 ml volume of water. The reaction mass is dried over anhydrous sodium sulfate and the solvent is recovered on a Buchi apparatus. The reaction mass is then micro distilled yielding the product having the structure: ##STR135##
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[CH:10]=O.O.[NH2:13][NH2:14]>>[NH:13]1[C:2]2[C:3](=[CH:4][C:5]([C:8]#[N:9])=[CH:6][CH:7]=2)[CH:10]=[N:14]1
Reactant: NN
Reactant: N#Cc1ccc(F)c(C=O)c1
Solvent: O
Product: N#Cc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
4-Fluoro-3-formylbenzenecarbonitrile (4.6 g, 30.85 mmol) was suspended in 20 mL of hydrazine mono-hydrate and the reaction mixture was stirred at room temperature for 48 hours. The title compound was isolated by filtration as a white solid, was washed with small portions of distilled water, and was dried in a vacuum (3.6 g, 81% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=[CH2:13]>>[CH3:14][C:12](=[CH:13][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[C:11]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C=C(C)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: CCOC(=O)C(C)=Cc1ccc([N+](=O)[O-])cc1
Yield: 46 %

Procedure:
The procedure described in Example 26 is repeated, but using 5.05 g (25 mmols) of 4-bromonitrobenzene and 3.43 ml (27.5 mmols) of ethyl methacrylate. After a reaction time of 8 hours at 130° C. and working up as described in Example 1, recrystallising the crude product from methanol gives 2.70 g (11.5 mmols) of ethyl α-methyl-4-nitrocinnamate in the form of yellow crystals of melting point 75° C.; yield 46% of theory (conversion figure 4600; Pd content 0.01 mol %). Analysis for C12H13NO4 (molecular weight 235.24): calculated C 61.27; H 5.57; N 5.96, found C 61.18; H 5.57; N 6.24.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:34]3[N:33]=[CH:32][N:31]=[C:29]([NH2:30])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:35][CH2:36][CH2:37][O:38][CH3:39])[C@@H:21]1[OH:40])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:59](Cl)(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[C:59]([NH:30][C:29]1[C:28]2[N:27]=[CH:26][N:25]([C:34]=2[N:33]=[CH:32][N:31]=1)[C@@H:23]1[O:24][C@H:20]([CH2:19][OH:18])[C@@H:21]([OH:40])[C@H:22]1[O:35][CH2:36][CH2:37][O:38][CH3:39])(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: COCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cnc2c(N)ncnc21
Reactant: O=C(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21

Procedure:
5′-O-t-Butyldiphenylsilyl-2′-O-(methoxyethyl)adenosine is treated with TBAF as per the procedure of Example 8 and subsequently treated with benzoyl chloride as per the procedure of Example 4 to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH:6]([C:12]([OH:14])=[O:13])[CH2:5]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:8]2[C:9]3[C:4](=[CH:3][C:2]([OH:1])=[CH:11][CH:10]=3)[CH2:5][CH:6]([C:12]([OH:14])=[O:13])[NH:7]2)=[O:24])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(O)C1Cc2cc(O)ccc2CN1
Solvent: CN(C)C=O
Product: O=C(O)C1Cc2cc(O)ccc2C(C(=O)Nc2ccc(Cl)cc2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a suspension of (D,L) 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (500 mg, 2.59 mmol) in DMF (12 mL), 4-chlorophenyl isocyanate (400 mg, 2.60 mmol) was added. The reaction mixture was stirred at room temperature overnight, and the suspension became clear solution. It was then concentrated in vacuo. The residue was dissolved in CH2Cl2, and the product was extracted with 5N NaOH. The alkaline solution was then separated, acidified with 4N HCl to pH 2-3. The cloudy mixture was extracted with EtOAc. The EtOAc solution was dried over Na2SO4, concentrated in vacuo to give the titled compound as a solid (841 mg), which was pure enough for the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:28][CH:29](Br)[CH3:30]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][N:11]([CH2:30][CH2:29][Br:28])[C:10]=1[C:18]([O:20][CH3:21])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Br)Br
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(CCBr)c(C(=O)OC)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of dimethyl 4-benzyloxy-1H-pyrazole-3,5-dicarboxylate (1.0 g, 3.45 mmol) in anhydrous DMF (20 mL) were added Cs2CO3 (1.35 g, 4.13 mmol) and dibromoethane (2.27 g, 12.1 mmol). The reaction mixture was stirred at room temperature for 2 hours and then filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using a 0-25% EtOAc/hexanes gradient elution. Collection and concentration of the appropriate fractions provided the title compound as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 7.45-7.34 (m, 5H), 5.06 (s, 2H), 4.88 (t, J=6.4 Hz, 2H), 3.86-3.79 (m, 8H).