Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=2[CH3:15])[C:5]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][CH:3]=1.C1[C:29]2[CH:28]=[CH:27][C:26]([O:30]B(OO)OO)=[CH:25][C:24]1=2.[C:36](=O)(O)[O-:37].[Na+]>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>[O:30]1[C:26]2[CH:27]=[CH:28][C:29]([C:2]3[N:6]([C:7]4[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=4[CH3:15])[C:5]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][CH:3]=3)=[CH:24][C:25]=2[O:37][CH2:36]1
Reactant: CCOC(=O)CCc1ccc(Br)n1-c1ccc(C#N)cc1C
Reactant: O=C([O-])O
Reactant: OOB(OO)Oc1ccc2c(c1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: CCOC(=O)CCc1ccc(-c2ccc3c(c2)OCO3)n1-c1ccc(C#N)cc1C
Yield: 115.1 %

Procedure:
To a suspension of ethyl 3-(5-bromo-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (400 mg, 0.665 mmol), 3,4-methylenedioxylphenylboric acid (143 mg, 0.864 mmol), sodium bicarbonate (560 mg, 5.32 mmol) in solvent (4 mL) was added Pd(PPh3)4 (60 mg, 0.199 mmol). The reaction was degassed and heated to reflux for 5 h. TLC showed that the reaction was completed. Water (4 mL) was added and the mixture was extracted with ethyl acetate (5 mL×3). The combined organic layers were dried with magnesium sulfate, filtered and evaporated to obtain a brown oil, which was purified by silica gel column chromatography to afford ethyl 3-(5-(benzo[d][1,3]dioxol-5-yl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate as a colorless oil (308 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]=[O:10].[CH3:12][C:13](=[CH2:16])[CH2:14][OH:15]>CC1C=CC(S(O)(=O)=O)=CC=1.CCCCCCC>[CH3:3][C:2](=[CH2:1])[CH2:6][O:10][CH:9]([O:15][CH2:14][C:13]([CH3:12])=[CH2:16])[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]([CH3:7])[C:2]1([CH3:11])[CH3:1]
Reactant: CC1=CCC(CC=O)C1(C)C
Reactant: C=C(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Product: C=C(C)COC(CC1CC=C(C)C1(C)C)OCC(=C)C
Yield: 186.9 %

Procedure:
A 2 liter 3 neck flask equipped with a Dean-Stark trap, condenser, thermometer, mechanical agitator, and nitrogen inlet and outlet was charged with 392.5 g of 2,2,3-trimethylcyclopent-3-en-1-yl acetaldehyde at a purity of 88.9% (2.30 moles), 415 g of 2-methyl-2-propen-1-ol (5.64 moles), 0.2 g of p-TSA and 1 liter of heptane. The contents were brought to reflux and 43 ml of water were collected. The batch was cooled and washed with 2×250 ml of 10% sodium hydroxide. The batch was dried (MgSO4), filtered and concentrated in vacuo to yield 671 g of crude 2,2,3-trimethylcyclopent-3-en-1-yl acetaldehyde bis-(2-methyl-2-propenyl) acetal. BP 88° C./1.0 mmHg; 1H-NMR (300 MHz), δ 0.76 (3H, s), 0.98 (3H, s), 1.58 (1H, m), 1.61 (3H, s), 1.76 (6H, s), 1.86-2.0 (3H, m), 2.31 (1H, br s), 3.88-4.04 (4H, m), 4.65 (1H, m), 4.87 (2H, s), 4.89 (2H, s), 5.22 (1H, s); 13C-NMR (75 MHz), δ 12.74, 19.87, 19.91, 25.71, 33.98, 35.88, 46.20, 47.10, 69.00, 69.72, 102.28, 112.27, 112.35, 122.36, 142.84, 148.98; IR (Neat), 1130, 1000 cm-1 ; MS (m/e), 206 (M+ -72), 108 (Base); The crude acetal, with 3 g of citric acid added, was distilled through a 10" saddle packed column at a pressure of 115 mmHg. A total of 185.6 g of lights was distilled out between 68°-115° C. The batch was now heated under nitrogen at 160° C. for 3 hours. The batch was now distilled to afford 320.1 g of purified product (74% yield). BP 81° C./0.4 mmHg; 1H-NMR (300 MHz), δ 0.88 (3H, s), 0.96 (3H, s), 1.59 (3H, s), 1.71 (3H, s), 1.9-2.4 (5H, m), 2.65 (1H, m), 4.71 (1H, s), 4.76 (1H, s), 5.24 (1H, s), 9.49 (1H, d, J=5.43 Hz); 13C-NMR (75 MHz), δ 12.64, 20.26, 22.67, 26.34, 34.19, 37.57, 47.24, 50.47, 52.29, 113.20, 121.39, 143.01, 149.47, 205.82; IR (Neat), 3080, 3050, 2950, 2715, 1730, 1655 cm-1 ; MS (m/e), 206 (M+), 108 (Base);
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]([NH2:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ncccc1F
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1ncccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of (5-fluoro-2-nitro-phenyl)-(3-fluoropyridin-2-yl)amine (93 mg, 0.370 mmol) in EtOAc (10 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (10 mg) and was stirred at RT under a hydrogen atmosphere for 3 h. The mixture was then filtered through a phase separator and the filtrate was concentrated in vacuo to afford the title compound as a brown solid (81 mg, 99%). LCMS (Method C): RT 1.70 min [M+H]+ 222.18.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7](/[C:11](=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:18][CH3:19])/[C:12]([O:14]CC)=[O:13])[CH:8]=[CH:9][CH:10]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7](/[C:11](=[C:17](\[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)/[CH2:18][CH3:19])/[C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)/C(=C(\CC)c1ccccc1)c1cccc(OCOC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC/C(=C(\C(=O)O)c1cccc(OCOC)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
To a solution of 2a (195 mg, 0.573 mmol) in MeOH (6 ml) was added 2N NaOH (3 ml) and the mixture was stirred at 80° C. for 15 h. After cooling, 2 N HCl (3 ml) was added drop wise under ice cooling, and the whole was extracted with AcOEt, the organic layer was washed with brine, dried over Na2SO4, then concentrated. The residual solid was triturated with hexanes to give 3a (69%). 3a: colorless powder; 1H-NMR (CDCl3) δ 1.04 (3H, t, J=7.5 Hz), 2.83 (2H, t, J=7.5 Hz), 3.34 (3H, s), 4.93 (2H, s), 6.68 (1H, m), 6.73 (1H, d, J=7.6 Hz), 6.77 (2H, dd, J=2.5, 7.8 Hz), 7.01-7.07 (3H, m), 7.10-7.18 (3H, m).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:25][C:26]1[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1.O>C1(C)C=CC=CC=1>[Br:25][C:26]1[S:30][C:29]([CH:31]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=Cc1ccc(Br)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
4.2 g (12.5 mmol, 1.2 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 2.0 g (10.4 mmol, 1.0 eq) of 5-bromothiophene-2-carbaldehyde in 15 mL of toluene. The reaction mixture is stirred for 1 hour at 80° C. The reaction is stopped by adding 20 ml of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (80/20 heptane/ethyl acetate). 2.1 g of methyl 3-(5-bromothiophen-2-yl)acrylate are obtained. Yield=82%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]([CH3:26])[CH3:25])=[C:17]([NH:27][CH:28]3[CH2:33][CH2:32][N:31](CC4C=CC=CC=4)[CH2:30][CH2:29]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CO.C([O-])=O.[NH4+]>[Pd].O>[C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]([CH3:26])[CH3:25])=[C:17]([NH:27][CH:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)n1cnc2c(NC3CCN(Cc4ccccc4)CC3)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)n1cnc2c(NC3CCNCC3)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc21

Procedure:
Add to a solution of trans-{4-[6-(1-benzyl-piperidin-4-ylamino)-9-isopropyl-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (8b, 1 g, 1 mmol) and methanol (40 ml), a suspension of palladium black (0.25 g) in a little water. Then add a solution of ammonium formate (0.4 mg, 6.4 mmol) and 10 ml of water, and reflux overnight. Filter the reaction through Celite® and concentrate the filtrate to dryness. Dissolve the residue in methylene chloride (50 ml), extracted with water, and filter through Celite® to remove a milky white precipitate. Separate the organic layer, wash with brine, dry over sodium sulfate, filter and concentrate the filtrate to dryness. Purify the residue on a 40 gram silica gel column (Biotage) using DCM/methanol (4:1) to give 0.8 grams of trans-{4-[9-isopropyl-6-(piperidin-4-ylamino)-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (9b).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=CC=1)[NH:7]C=[CH:5]2.C([O-])([O-])=O.[K+].[K+].IC.[CH3:19][N:20]1[C:24](=O)[CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[CH3:19][N:20]1[C:24]2[C:23](=[CH:5][C:4]([C:8]#[N:7])=[CH:3][CH:2]=2)[CH:22]=[CH:21]1
Reactant: CN1CCCC1=O
Reactant: Brc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1ccc2cc(C#N)ccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of 5-bromoindole (500 mg; 2.55 mmol) and cuprous cyanide (342 mg; 3.83 mmol) in NMP (10 mL) was heated under microwave irradiations to 100° C. for 30 minutes then at 200° C. for 30 minutes. The reaction mixture was partitioned with water and DCM and the organic layer was washed with brine and concentrated in vacuo to give a pink solid. Purification by silica column chromatography (DCM) gave a white solid. It was dissolved in DMF (5 mL) and K2CO3 (704 mg; 5.10 mmol) and iodomethane (543 mg; 3.83 mmol) were successively added. The reaction mixture was stirred at RT for 3 days and then partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give a slightly yellow oil which crystallized upon standing to give the title compound as an off-white solid (80 mg, 70%). LC/MS (Method A): 156.9 (M+H)+.
Reaction SMILES: C12CCCC1CC=C2.[CH3:9][O:10][C:11]([CH2:13][CH2:14][CH:15]=[CH:16][C:17]1[CH2:24][C@H:23]2[C@H:19]([CH2:20][C@@H:21]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[C@H:22]2/[CH:25]=[CH:26]/[C:27](=[O:34])[CH:28]([F:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH:18]=1)=[O:12].[BH4-].[Na+]>CO>[CH3:9][O:10][C:11]([CH2:13][CH2:14][CH:15]=[CH:16][C:17]1[CH2:24][C@H:23]2[C@H:19]([CH2:20][C@@H:21]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)[C@H:22]2/[CH:25]=[CH:26]/[CH:27]([OH:34])[CH:28]([F:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH:18]=1)=[O:12]
Reactant: CCCCC(F)C(=O)/C=C/[C@H]1[C@H]2CC(C=CCCC(=O)OC)=C[C@H]2C[C@H]1OC1CCCCO1
Agent: C1=CC2CCCC2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCC(F)C(O)/C=C/[C@H]1[C@H]2CC(C=CCCC(=O)OC)=C[C@H]2C[C@H]1OC1CCCCO1
Reaction time: 0.5 h

Procedure:
(1S,5S,6S,7R)-3-[4-Methoxycarbonyl-1(EZ)-butenyl]-6-[4(RS)-fluoro-3-oxo-(E )-1-octenyl]-7-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene bicyclo[3.3.0]oct-2-ene (5) (0.088g) was dissolved in methanol. Into the solution, sodium borohydride (0.008 g) was added at 0° C. and the mixture was stirred for 30 minutes. The reaction mixture was treated by a usual manner to give (1S,5S,6S,7R)-3-[4-methoxycarbonyl-1(EZ)-butenyl]-6-[4(RS)-fluoro-3(R S)-hydroxy-(E)-1-octenyl]-7-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene (5") as a colorless oily product. Yield: 0.089 g
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].[N+:15]([O-])([O-:17])=[O:16].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: N#Cc1cc([N+](=O)[O-])ccc1-c1ccccc1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
2-Cyanobiphenyl (0.111 moles, 20.0 g) and ammonium nitrate (10.0 grams) were added to 250 ml chloroform. Trifluoroacetic anhydride (80 ml) was added. The reaction mixture was stirred until the ammonium nitrate was dissolved. The reaction mixture was added to 300 ml of ice water. The organic layer was separated, dried over sodium sulfate, and concentrated im vacuo to yield 23.5 g of 2-Cyano-4-nitrobiphenyl. (MS)
Reaction SMILES: [NH2:1][CH2:2][C:3]#[N:4].[Cl:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7](Cl)=[O:8]>C(Cl)Cl>[Cl:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([NH:4][CH2:3][C:2]#[N:1])=[O:8]
Reactant: N#CCN
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: ClCCl
Product: N#CCNC(=O)C(Cl)c1ccccc1
Yield: 79.6 %

Procedure:
9.2 g (0.10 m) aminoacetonitrile and 19.0 g (0.11 m) α-chlorophenylacetyl chloride are heated to reflux in methylene chloride for 4 hours. The reaction mixture is filtered and the solvent is removed. The residual solid is recrystallized from benzene to give 16.7 g (80% yield) of the title compound, which has a melting point of 73°-4° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:41])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:36]([O:38]CC)=[O:37])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:41])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:36]([OH:38])=[O:37])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(OCCOC)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(=O)O)ncc(-c3cccc(NC(=O)OCc4ccccc4)c3C)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.5 %

Procedure:
To a solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylate (0.299 g, 0.540 mmol) in tetrahydrofuran (15 mL) and methanol (5 mL) at room temperature was added a solution of lithium hydroxide hydrate (0.091 g, 2.160 mmol) in water (2 mL). The resulting mixture was stirred at room temperature for 1.5 hr, and then concentrated under vacuum to almost dryness. To the residue was added water (8 mL), and the mixture was neutralized with 1N HCl to pH 4-5. The insoluble product (0.237 g, 0.451 mmol, 83% yield) was collected as a beige solid by suction filtration and dried over Drierite under vacuum.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4](C(OCC)=O)[CH2:5][C:6]1[S:7][C:8]([NH:11][C:12]([NH2:14])=[S:13])=[N:9][N:10]=1.Cl>[OH-].[Na+]>[NH:11]([C:8]1[S:7][C:6]([CH2:5][CH2:4][C:3]([OH:20])=[O:2])=[N:10][N:9]=1)[C:12]([NH2:14])=[S:13]
Reactant: CCOC(=O)C(Cc1nnc(NC(N)=S)s1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=S)Nc1nnc(CCC(=O)O)s1

Procedure:
Carbethoxy-3-(5-thioureido-[1,3,4]thiadiazol-2-yl)-propionic acid methyl ester (0.675 g, 2.91 mmol) is suspended in 2M NaOH (8 ml) and the reaction is stirred at reflux for 3.5 hours. When cool, the solution is acidified to pH 3 with 6M HCl and the titled compound is removed by filtration and dried.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[F:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>O1CCCC1>[F:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([OH:19])[CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[CH:16][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nnnc1CC(O)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution of 1,5-dimethyltetrazole (0.98 g, 10.0 mmoles) in tetrahydrofuran (20 mL) at -30° C. was added n-butyl lithium (4.7 mL of 2.14M solution, 10.0 mmoles). After stirring for 0.25 hour, the solution was cooled to -50° C. and 4,4'-difluorobenzophenone (1.74 g, 8.0 mmoles) was added. After stirring for 1 hr at -50° C. and 1 hour at -10° C., the reaction was quenched with 1N hydrochloric acid. The mixture was extracted with methylene chloride, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with 40% (v/v) ethyl acetate in hexane to give 2.0 g of the title compound; m.p.=116°-118° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]([CH3:23])[CH:19]=[CH:20][C:21]#[N:22].C(N(CC)CC)C>O1CCOCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([C:20](=[CH:19][N:18]([CH3:23])[CH3:17])[C:21]#[N:22])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=CC#N
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C=C(C#N)C(=O)c1cccc(Oc2ccccc2)c1
Reaction time: 8 h
Yield: 36.2 %

Procedure:
A mixture of 3-phenoxybenzoyl chloride (6.9 g), 3-dimethylaminoacrylonitrile (2 g) and triethylamine (4 g) in dry dioxan (50 ml) was refluxed for 6 hours under a nitrogen atmosphere. After standing at room temperature overnight, the dioxan was evaporated in vacuo and dichloromethane added to the residue. The extracts were washed with water, 2N NaOH, brine and finally dried over MgSO4. After filtration and evaporation of the dichloromethane, the residue was purified on a silica gel column using 5% methanol-dichloromethane as eluant to give the title compound (2.2 g, 36%) as a white solid of m.p. 80°-82 C. (identical to that described in Example 46).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O-2].[O-2].[O-2].[Al+3].[Al+3]>>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Agent: [Al+3]
Agent: [O-2]
Product: C=CCCCCCCC=CCCCCCCCC

Procedure:
Oleyl alcohol, having about a 4/1 cis/trans ratio, is dehydrated over gamma-alumina in the presence of nitrogen to produce 1,9-octadecadiene.
Reaction SMILES: [CH3:1][Al](C)C.[O:5]1[C@@H:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:6]1[CH2:7][OH:8]>Cl>[OH:5][C@H:6]([C@H:9]([CH3:1])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][OH:8]
Reactant: C[Al](C)C
Reactant: OC[C@@H]1O[C@H]1CCc1ccccc1
Agent: Cl
Product: C[C@H](CCc1ccccc1)[C@@H](O)CO
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a 5 L 3-neck round-bottom flask equipped with a mechanical stirrer, thermocouple and nitrogen inlet was added a mixture of hexanes (IL). The vessel was cooled to 0° C. A 2.0M solution of Me3Al in hexanes (800 mL, 1.6 mol) was added, followed by a solution of epoxide 16 (120 g, 0.677 mol) in hexanes (250 mL)/CH12C12 (50 mL), maintaining the temperature below 20° C. Upon complete addition, the cloudy reaction mixture was stirred at 5° C. for 35 min. Then a solution of 10% HCl (300 mL) was added dropwise, followed by the addition of conc HCl (350 mL). The layers were separated, and the organic phase was washed with brine and dried over MgSO4. After removal of the volatiles in vacuo, the title compound (122.1 g) was obtained as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].[CH:16](Br)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCNC(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
5.0 g (26.6 mmol) N-(tert-butoxycarbonyl)-1,4-diaminobutane 5.5 g (39.8 mmol) potassium carbonate and 0.9 g (5.3 mmol) potassium iodide are placed in 50 ml DMF and 6.6 g (26.6 mmol) benzhydryl bromide are added dropwise at RT. The mixture is stirred for 12 hours at 70° C. and the suspension is filtered after cooling and the filtrate is concentrated under vacuum. The residue is taken up in 200 ml chloroform and washed with 100 ml water. The organic phase is dried over sodium sulfate and, subsequently, the solvent is removed under vacuum. The accumulated crude product is further processed without further purification: Yield 10.8 g.
Reaction SMILES: [C:1](Cl)(=[O:19])[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][CH3:18].[C:21]([NH2:25])(=[O:24])[CH:22]=[CH2:23].Cl>[Cl-].[Zn+2].[Cl-].CC(C)=O>[C:1]([NH:25][C:21](=[O:24])[CH:22]=[CH2:23])(=[O:19])[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][CH3:18]
Reactant: C=CC(N)=O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)=O
Product: C=CC(=O)NC(=O)CCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Into a 250 -mL-capacity conical flask equipped with an anhydrous calcium chloride (CaCl2) guard tube, 15.1 g 1-octadecanoyl chloride [CH3—(CH2)16—COCl] (0.005 M). 3.5 g acrylamide (CH2═CH—CO—NH2) (0.05 M), and 50 ml acetone were placed to obtained a clear solution. The solution was stirred with a magnetic needle at room temperature. Anhydrous zinc chloride (ZnCl2), 6.5 g (0.05 M), was added and the reaction mixture was stirred at room temperature. After 5-10 min of stirring, vigorous evolution of hydrogen chloride took place which ceased after about 5 min. The temperature of reaction mixture was increased to 40-50° C. It was then cooled to room temperature and poured into 500 ml cold distilled water. A white product precipitated. The product was isolated and purified by reprecipitation from acetone into cold water. The purified product was dried in a vacuum desiccator.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:7][CH:8]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:4]=[CH:5][C:6]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)=[N:7][CH:8]=4)[CH2:23][CH2:22]3)=[CH:8][N:7]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2ccc(CCl)cn2)cc(OC)c1OC
Product: COc1cc(-c2ccc(CN3CCN(Cc4ccc(-c5cc(OC)c(OC)c(OC)c5)nc4)CC3)cn2)cc(OC)c1OC

Procedure:
5-Chloromethyl-2-(3,4,5-Trimethoxyphenyl)pyridine (294 mg) and piperazine (43 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.