Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:30])[C@@H:10]([CH2:14][C:15]([N:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:12][CH3:13])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH:28]1[C:29]2[N:17]([C:15](=[O:16])[CH2:14][C@@H:10]([CH2:11][CH2:12][CH3:13])[C:9]([OH:30])=[O:8])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1
Reactant: CCC[C@H](CC(=O)n1c2ccccc2c2ccccc21)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC[C@H](CC(=O)n1c2ccccc2c2ccccc21)C(=O)O
Reaction time: 3 h
Yield: 84.4 %

Procedure:
A stirred solution of (2R)-2-(2-carbazol-9-yl-2-oxo-ethyl) -pentanoic acid benzyl ester (4.50 g, 11.26 mmol) in EtOAc (60 ml) was treated with 10% Pd on carbon (˜400 mg) and the reaction mixture was then placed under an atmosphere of hydrogen. After 1 h further 10% Pd on carbon (˜300 mg) was added and the reaction mixture was placed under hydrogen, with stirring, for a further 3 h after which the reaction mixture was filtered through a celite pad and concentrated to give the sub-title compound (2.94 g, 84%) as a white solid which also contained carbazole: 1H NMR (400 MHz, CDCl3) δ 0.92-1.04 (3H, m), 1.32-2.00 (4H, m), 3.19-3.34 (2H, m), 3.58-3.70 (1H, m), 7.30-7.53 (4H, m), 8.00-8.30 (4H, m).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]([CH2:23][CH3:24])[S:21][C:20](=[O:25])[NH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[Cl:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][CH2:27][N:19]1[N:18]=[C:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH3:7])[CH:10]=2)[CH:22]([CH2:23][CH3:24])[S:21][C:20]1=[O:25].[ClH:26]
Reactant: CN(C)CCCCl
Reactant: CCC1SC(=O)NN=C1c1ccc(OC)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCC1SC(=O)N(CCCN(C)C)N=C1c1ccc(OC)c(OC)c1
Product: Cl
Reaction time: 0.5 h

Procedure:
0.6 g of potassium tert-butylate is added to a solution of 1.5 g of 5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one [obtainable by reacting 1-(3,4-dimethoxyphenyl)-2-bromobutan-1-one with methyl hydrazinethioformate] in 30 ml of dimethylformamide (DMF), and the mixture is stirred for 30 minutes. A solution of 3-chloropropyldimethylamine in toluene is then added and the mixture is boiled for three hours. The solvent is removed in vacuo, and the mixture is worked up as usual to give 3-dimethylaminopropyl-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 175° (hydrochloride).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](C)[C:5](=O)OC(C)(C)C.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17]([Cl:19])=[O:18].N1C=CC=CC=1>C(OCC)(=O)C>[ClH:19].[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17]([O:1][CH2:2][CH2:3][NH:4][CH3:5])=[O:18]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CNCCOC(=O)c1ccc(F)c(F)c1
Product: Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.6 %

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) were added 3,4-difluorobenzoyl chloride (1.77 g) and pyridine (0.97 mL). After stirring at room temperature for 3 days, ethyl acetate (80 mL) was added to the reaction mixture. The mixture was washed with water (20 mL), a saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 4 hrs, the mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate (15 mL), and dried under reduced pressure at 60° C. to give the title compound (2.05 g) as a white solid. 1H-NMR (DMSO-d6): 2.62 (3H, s), 3.32 (2H, m), 4.53 (2H, t, J=5.0 Hz), 7.64 (1H, m), 8.00 (1H, m), 8.25 (1H, m), 9.25 (2H, bs).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH3:9])=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[OH:61][C:54]1[C:53]([CH2:52][NH:51][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:58]([CH3:59])[CH:57]=[C:56]([CH3:60])[N:55]=1
Reactant: Cc1ccc(OC(C)c2ccc(C(=O)O)cc2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(OC(C)c2ccc(C(=O)NCc3c(C)cc(C)nc3O)cc2)cc1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
A mixture of 4-(1-(p-tolyloxy)ethyl)benzoic acid (30 mg, 0.12 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (67 mg, 0.18 mmol), triethylamine (0.1 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (22 mg, 0.14 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was washed with water (30 mL), dried over sodium, filtered, and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(p-tolyloxy)ethyl)benzamide as a white solid (26 mg, 56%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[NH:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:14])[CH:11]=2)[CH2:6]1.CS(C)=O.N1C=CC=CC=1.[CH3:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([C:43](Cl)=[O:44])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:14][C:43]([C:31]3[C:32]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:42])[F:41])=[CH:35][CH:34]=4)=[C:27]([CH3:26])[CH:28]=[CH:29][CH:30]=3)=[O:44])[CH:11]=2)[CH2:6]1)=[O:15]
Reactant: COC(=O)N[C@@H]1Cc2ccc(N)cc2C1
Reactant: Cc1cccc(C(=O)Cl)c1-c1ccc(C(F)(F)F)cc1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N[C@@H]1Cc2ccc(NC(=O)c3cccc(C)c3-c3ccc(C(F)(F)F)cc3)cc2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice bath cooled solution of (R)-(5-aminoindan-2-yl)-carbamic acid methyl ester (9.5 g, 46.1 mmol) prepared as described in example 12 ([α]D=−26.29 (c=9.87 mg/mL, DMSO); mp 144-145° C.) and pyridine (4.48 mL, 55.5 mmol) in 200 mL of methylene chloride is added 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid chloride (80.5 mL of a 0.63 M solution in methylene chloride, 50.7 mmol). The reaction is stirred for 15 minutes at room temperature. The mixture is washed with 1N HCl, bicarbonate and brine. The organic layer is dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The product is purified by crystallization from ethyl acetate/hexanes (1:2) to give (R)-6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid (2-methoxycarbonylaminoindan-5-yl)-amide (the compound of example 13(i)) as a crystalline solid, mp 112-114° C. MS (ES+), m/z469 (M+1); [α]D=−12.85° (c=11.36 mg/ml DMSO).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:38]1[CH:43]=[CH:42][N:41]=[CH:40][N:39]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[C:24]([N+:34]([O-])=O)=[N:25][N:26](C3CCCCO3)[CH:27]=2)=[CH:12][C:11]=1[F:37])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[NH2:34][C:24]1[C:23]([C@H:19]2[CH2:20][CH2:21][CH2:22][C@@H:18]2[O:17][C:13]2[C:14]([CH3:16])=[CH:15][C:10]([S:7]([NH:6][C:38]3[CH:43]=[CH:42][N:41]=[CH:40][N:39]=3)(=[O:9])=[O:8])=[C:11]([F:37])[CH:12]=2)=[CH:27][NH:26][N:25]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCC[C@@H]3c3cn(C4CCCCO4)nc3[N+](=O)[O-])cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1c[nH]nc1N
Yield: 81.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclopentyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (101 mg, 0.185 mmol) prepared in Example 85c, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol (1.0 mL), to yield the title compound (65 mg, 76%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:20](Cl)[CH:21]=[CH2:22].[CH2:24](OCC=C)[CH:25]=[CH2:26]>C(C(C)=O)C.C1(C)C=CC=CC=1.CS(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:26][CH:25]=[CH2:24])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1)[CH:21]=[CH2:22]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=CCCl
Reactant: C=CCOCC=C
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C(C)(C)c2ccc(OCC=C)cc2)cc1
Temperature: 37.5 °C
Reaction time: 12 h

Procedure:
Bisphenol A diallyl ether was synthesized as described in U.S. Pat. No. 4,740,330. In a four-necked reactor, equipped with a condenser, stirrer, thermometer with temperature controller, and an addition funnel, were added 800 mL of bis-(2-methoxy ethyl)ether(diglyme), 400 mL of dimethyl sulfoxide (DMSO), 228 g (1 mole) bisphenol-A, and 284 g (4 moles) of 85% KOH at ambient temperature (˜25° C.). The mixture was stirred and heated to 35-40° C., and the addition of 304 g (4 moles) of allyl chloride was begun. This reaction was exothermic and was controlled at less than 45° C. by controlling the allyl chloride addition rate. The allyl chloride was added over a 4-hour period, and the reaction was continued at 45° C. for an additional 12 hours to convert the bisphenol-A into diallyl ether. The reaction mixture was cooled to ambient temperature and filtered to remove salts formed in the reaction. The filtrate was mixed with 1000 mL of 50:50 (volume:volume) methyl ethyl ketone-toluene mixture and washed four times with 200 mL portions of water. The solvents were removed from the diallyl product by rotary evaporation first at 50-60° C. and 120 mmHg and then at 120-130° C. at 10 mmHg until gas chromatography (GC) showed all the diglyme and DMSO had disappeared. The yield was 235 g (76% yield) of a light yellow product, bis A diallyl ether, with greater than 95% purity as determined by GC.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[NH2:20].C([O:23]CC)C>>[OH2:23].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[NH2:20])=[O:23].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[NH2:20])=[O:23]
Reactant: CCOCC
Reactant: Cc1cc(C)c(N)c(CSc2nc3ccccc3[nH]2)c1
Product: Cc1cc(C)c(N)c(CS(=O)c2nc3ccccc3[nH]2)c1
Product: O

Procedure:
The title compound was prepared by the method of Example 3 using 950 mg of the title product of Example 29 instead of the title product of Example 2. Trituration with diethylether gave 434 mg of the title compound. Analysis. Calc'd. for C16H17N3OS*½ H2O: C, 62.23; H, 5.88; N, 13.63; S, 10.40. Found: C, 62.39; H, 5.72; N, 13.50; S, 10.65.
Reaction SMILES: O.Cl[C:3](Cl)(Cl)[CH2:4][CH:5](Cl)OCC.[N+]([O-])(O)=O.[CH3:16][C:17]1[CH:21]=[C:20]([CH3:22])[N:19]([C:23]([NH2:25])=[NH:24])[N:18]=1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].ClC(Cl)=CC=O>C(COC)OC.[N+]([O-])(O)=O.CC1C=C(C)N(C(N)=N)N=1>[F:26][C:27]([F:35])([F:36])[C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[O:34][C:3]1[CH:4]=[CH:5][N:25]=[C:23]([N:19]2[C:20]([CH3:22])=[CH:21][C:17]([CH3:16])=[N:18]2)[N:24]=1
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCOC(Cl)CC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: O=CC=C(Cl)Cl
Agent: [K+]
Solvent: COCCOC
Solvent: O=[N+]([O-])O
Solvent: O
Product: Cc1cc(C)n(-c2nccc(Oc3cccc(C(F)(F)F)c3)n2)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
Water (20 mmoles) is added to a solution of 1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25 ml). The mixture is stirred for 2 h at 90° C. The resulting mixture is slowly added to a mixture consisting of a 3,5-dimethylpyrazole-1-carboxamidine nitrate (10 mmoles), 3-trifluoromethylphenol (10 mmoles), potassium carbonate (60 mmoles) and dimethoxyethane (50 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein solution is completed additional 3,5-dimethylpyrazole-1-carboxamidine nitrate (0.5 mmoles) is added. The reaction mixture is stirred for 10 hours under reflux and subsequently cooled down to ambient temperature, filtered through silica, and the organic phase is concentrated in vacuo. The residue is purified by chromatography on SiO2 (ethyl acetate) to give 2,2 g of a yellow solid. The solid was washed with petrol ether (50 ml) to yield 1,75 g (52%) of colorless crystals having a melting point of 101-102° C.
Reaction SMILES: Cl.[O:2]=[S:3]1(=[O:25])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]2[CH2:22][CH2:23][CH2:24][CH:5]2[NH:4]1.CO[CH:28]1[CH2:32][CH2:31][CH:30](OC)O1.O.CC(O)=O>C(Cl)CCl>[N:21]1([CH2:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[O:13][C:10]2[CH:11]=[CH:12][C:7]3[N:6]4[CH2:22][CH2:23][CH2:24][CH:5]4[NH:4][S:3](=[O:2])(=[O:25])[C:8]=3[CH:9]=2)[CH:28]=[CH:32][CH:31]=[CH:30]1
Reactant: NCc1cccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)c1
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: O=S1(=O)NC2CCCN2c2ccc(Oc3cccc(Cn4cccc4)c3)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
200 mg (0.58 mmol) of the product obtained in Example 1, in the form of the free amine, and 105 μl (0.81 mmol) of 2,5-dimethoxytetrahydrofuran are added to a two-phase mixture of 2.5 ml of water, 0.95 ml of AcOH and 2.85 ml of dichloro-1,2-ethane. The mixture is stirred at 80° C. for 2 hours, allowed to return to ambient temperature and extracted with CH2Cl2. The organic phase is washed with saturated aqueous NaCl solution and dried over MgSO4. The expected product is purified by chromatography on a silica column (CH2Cl2/heptane 75/25).
Reaction SMILES: FC1C=CC=CC=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61][C:62]1[CH:63]=[C:64](N=C=S)[CH:65]=[CH:66][CH:67]=1>>[F:61][C:62]1[CH:67]=[C:66]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:15][CH:16]=2)[CH:65]=[CH:64][CH:63]=1
Reactant: Fc1cccc(N=C=S)c1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 258 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 3-fluorophenyl isothiocyanate. The compound of example 258 was used directly without isolation for the preparation of compound of example 259.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH:7]=[CH2:8])(=O)[CH:2]=[CH2:3].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14]CCC>>[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:9])[CH:7]=[CH2:8]
Reactant: CCCCCCCCO
Reactant: C=CC(=O)OC(=O)C=C
Product: C=CC(=O)OCCCCCCCC
Reaction time: 4 h
Yield: 81.3 %

Procedure:
According to another embodiment of the invention, the olefin acid anhydrides are reacted with alcohols to give high yields of the acrylate esters at room temperature. In particular, acrylic anhydride has been reacted with a series of alcohols ranging from C-1 to C-18 to give high yields of the acrylate esters at room temperature. The synthesis of acrylate esters by the reaction of alcohols with acrylic anhydride were found to proceed essentially to completion at room temperature to yield only the desired acrylate esters. The following mechanism is proposed for this reaction: ##STR3## No significant competing reactions were observed, such as the Michael addition reactions that often accompany the production of acrylate esters under reflux conditions. The following are representative of this embodiment: (1) the reaction of n-butyl alcohol with acrylic anhydride was completed in 3.5 hours and yielded 91.2% of n-butyl acrylate; (2) the reaction of n-octyl alcohol with acrylic anhydride was completed in 4 hours to obtain an 81.3% yield of n-octyl acrylate; and (3) the reaction of cis-12,13-epoxy-cis-9-octadecenol with acrylic anhydride was completed in 55 hours to give an 88.4% yield of cis-12, 13-epoxy-cis-9-octadecenyl acrylate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7](NN)[N:6]=[C:5]([F:12])[C:4]=1[F:13].C(OCC)C.CCCCCC.C(OCC)C>O.S([O-])([O-])(=O)=O.[Cu+2]>[OH:1][CH2:2][C:3]1[C:8]([F:9])=[CH:7][N:6]=[C:5]([F:12])[C:4]=1[F:13]
Reactant: NNc1nc(F)c(F)c(CO)c1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: OCc1c(F)cnc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
To a suspension of 0.7 g (0.0036 mole) of (4-hydroxymethyl-2,3,5-trifluoropyridin-6-yl)hydrazine (from Example 6) in 25 ml of distilled water was added a solution of 2.5 g (0.016 mole) of copper (II) sulfate during a 1.5 hour period. Nitrogen evolution continued while the reaction mixture was stirred at ambient temperature for two hours and while it refluxed for an additional two hours. After being cooled, the reaction mixture was extracted with diethyl ether. This extract was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, leaving a brown oil. This oil was passed through a short column of silica gel using a mixture of diethyl ether and hexane (50/50) as eluant. The appropriate fractions were combined and the solvent evaporated under reduced pressure, yielding 0.3 g of 4-hydroxymethyl-2,3,5-trifluoropyridine as a yellow oil. The structure and nmr spectra for this compound are set forth in Table 1C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH3:16])([C:13](O)=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>CC(C)=O.O>[CH3:1][N:2]([CH3:17])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH3:16])([C:13]([N:31]=[N+:32]=[N-:33])=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C(=O)N1CC2CC(C)(C(=O)O)CC2C1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C(=O)N1CC2CC(C)(C(=O)N=[N+]=[N-])CC2C1
Yield: 62.8 %

Procedure:
Upon cooling by an ice-water bath, 2-dimethylcarbamoyl-5-methyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 12c (1.0 g, 4.2 mmol) was dissolved in 25 mL of acetone with stirring, followed by dropwise addition of a solution of triethylamine (463.5 mg, 4.58 mmol) and ethyl chloroformate (497 mg, 4.58 mmol) in 10 mL of acetone at −5° C. The reaction mixture was reacted for 15 minutes at −5° C. followed by addition of a solution of sodium azide (546 mg, 8.4 mmol) in 10 mL of water. Then the reaction mixture was stirred for another 30 minutes at −5° C., and quenched with 25 mL of water and extracted with ethyl acetate (50 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude compound 2-dimethylcarbamoyl-5-methyl-hexahydro-cyclopenta[c]pyrrole-5-carbonylazide 12d (700 mg) as a yellow oil.
Reaction SMILES: Br.O=[C:3]1[CH:12]([CH2:13][C:14]([O:16]C)=O)[CH2:11][CH2:10][C:9]2[CH:8]=[N:7][CH:6]=[CH:5][C:4]1=2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:14](=[O:16])[CH2:13][CH:12]3[C:3]([C:4]4[CH:5]=[CH:6][N:7]=[CH:8][C:9]=4[CH2:10][CH2:11]3)=[N:26]2)=[CH:21][CH:20]=1
Reactant: COC(=O)CC1CCc2cnccc2C1=O
Reactant: NNc1ccc(Cl)cc1
Agent: Br
Product: O=C1CC2CCc3cnccc3C2=NN1c1ccc(Cl)cc1

Procedure:
Prepared according to the method described in Example 1 from methyl 5,6,7,8-tetrahydro-5-oxoisoquinoline-6-acetate hydrobromide and 4-chlorophenylhydrazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[Cl:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]>>[Cl:10][C:11]1[CH:18]=[C:17]([S:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]
Reactant: COc1ccccc1S
Reactant: O=Cc1ccc(F)cc1Cl
Product: COc1ccccc1Sc1ccc(C=O)c(Cl)c1

Procedure:
The target product (5.50 g) was obtained as a colorless oil by reacting 2-methoxybenzenethiol (2.80 g) and 2-chloro-4-fluorobenzaldehyde (3.17 g) based on the same experiment operations as in Reference Example 1 of WO 03029205 pamphlet.
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([SH:10])[CH2:2]1.CI.[O-][CH2:15]C.[Na+]>C(O)C>[CH3:15][S:10][CH:3]1[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2]1
Reactant: CC1CCC(C(C)C)C(S)C1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSC1CC(C)CCC1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Menthane-3-thiol (3.5 g., 20 mmole), methyl iodide (3.5 g., 25 mmole) and sodium ethoxide in ethanol (25 ml. of 0.8 M solution) were mixed together and stirred at room temperature for 21/2 hours. The ethanol was then removed and water was added to the residue, which was extracted with ether. The ether extracts were dried (MgSO4) and the solvent was removed. The residue was eluted with 40/60 petroleum ether down a silica column and the product was distilled to give p-menth-3-yl methyl sulphide b.p. 83°-5°/0.05 mm.
Reaction SMILES: C1COCC1.[C:6]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][C:11]=1[Cl:21])([CH3:9])([CH3:8])[CH3:7].C1N=CN(C(N2C=NC=C2)=O)C=1.C(C1C=CC(OCC([NH:46][CH2:47][C:48]2[CH:57]=[CH:56][C:51]3[NH:52][C:53](=[O:55])[NH:54][C:50]=3[CH:49]=2)=O)=CC=1)(C)(C)C>C(N(CC)CC)C>[C:6]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([NH:46][CH2:47][C:48]2[CH:57]=[CH:56][C:51]3[NH:52][C:53](=[O:55])[NH:54][C:50]=3[CH:49]=2)=[O:18])=[CH:12][C:11]=1[Cl:21])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(OCC(=O)NCc2ccc3[nH]c(=O)[nH]c3c2)cc1
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc3[nH]c(=O)[nH]c3c2)cc1Cl
Reaction time: 2 h
Yield: 10.9 %

Procedure:
To a THF (3.0 ml) solution of the compound of 4A (109 mg, 0.45 mmol) was added CDI (73 mg, 0.45 mmol) at room temperature and the mixture was stirred for 2 hours followed by the additional stirring for 10 hours after the injection of triethylamine (0.3 ml) and the amine compound of Example 1 (156 mg, 0.5 mmol). The resulting precipitate was removed by filtration, followed by evaporation under reduced pressure to give the crude residue which was purified through silica gel column chromatography eluting with DCM/MeOH (9:1) to furnish the title compound as a white solid (19 mg, 11%). 1H NMR (CDCl3): δ 1.40 (9H, s), 4.29 (2H, d, J=5.9 Hz), 4.53 (2H, s), 6.78-6.92 (4H, m), 7.01 (1H, d, J=2.6 Hz), 7.37 (1H, d, J=8.5 Hz), 8.61 (1H, bt, J=6.6 Hz), 10.55, 1H, bs), 10.57 (1H, bs). MS (ESI) m/z 388 (M+H)+.