Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14]
Reactant: NCC(=O)N1CCOCC1
Reactant: O=Cc1ccccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CN=Cc1ccccc1F)N1CCOCC1

Procedure:
D 4-[2-(2-Fluorobenzylidaneamino)acetyl]morpholine can be prepared as described in Example 2D, but from 5.3 cm3 of 2-fluorobenzaldehyde, 9.1 g of 4-(2-aminoacetyl)morpholine hydrochloride, 6 g of 4 Å seive and 7 cm3 of triethylamine in 150 cm3 of dichloromethane. After treatment, there are obtained 12 g of 4-[2-(2-fluorobenzylideneamino)acetyl]morpholine in the form of an oil used as is in the subsequent syntheses.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C(N(CC)CC)C>CS(C)=O>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])([O-:18])=[O:17]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CCCN1c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 80.4 %

Procedure:
There were dissolved, in 25 ml of dimethyl sulfoxide, 1 g of L-proline and 1.23 g of 1-fluoro-2-nitrobenzene, then 1.65 ml of triethylamine was added to the resulting solution and the mixture was stirred with heating at 60° C. for 16 hours. The reaction solution was cooled to room temperature then poured into ice water and washed with ether. The aqueous phase was acidified with hydrochloric acid and extracted with ether. After washing the organic phase with water, the phase was dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was treated by silica gel column chromatography, followed by elution with methanol/chloroform (1/49) to give 1.65 g (yield: 80.3%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH2:27][CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]=2[O:24][CH2:25][CH2:26][CH2:27]3)=[O:35])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc2c1OCCC2
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCC3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Chroman-8-carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:17]([O:24][C:25]([C:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH2:17]([O:24][C:25]([C:27]1([NH:32][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]#[N:16])=[CH:5][CH:4]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: NC1(C(=O)OCc2ccccc2)CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1-c1ccc(CNC2(C(=O)OCc3ccccc3)CCCC2)cc1
Temperature: 0 °C

Procedure:
A mixture of 2.72 g (10 mmol) of 4-bromomethyl-2'-cyano-biphenyl, 2.63 g (12 mmol) of 1-aminocyclopentane-carboxylic acid benzyl ester, 3.4 ml (20 mmol) of Hunig base and 10 ml of N,N-dimethylformamide is heated to 130°-140° (bath temperature) for 2 hours while stirring. After cooling, the reaction mixture is poured onto 50 ml of ice/water. Extraction using ethyl acetate yields the crude N-(1-benzyloxycarbonylcyclopentyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-amine, which forms a hydrochloride melting between 180° and 182° (ethanol/diethyl ether).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][CH:7]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[C:17](=[O:18])[C:16](=[O:19])[C:15]=3[NH:20][C@@H:21]([CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:22][NH:23]C(=O)CCC[Si](C)(C)C)[CH2:9]2)[CH2:3][CH2:2]1.[ClH:46]>O1CCOCC1.CO>[ClH:46].[NH2:23][CH2:22][C@@H:21]([NH:20][C:15]1[C:16](=[O:19])[C:17](=[O:18])[C:14]=1[N:10]1[CH2:11][CH2:12][CH2:13][CH:8]([CH:7]([O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:9]1)[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C[Si](C)(C)CCCC(=O)NC[C@H](CC1CCCCC1)Nc1c(N2CCCC(C(OCCC3CC3)c3ccccc3)C2)c(=O)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC[C@H](CC1CCCCC1)Nc1c(N2CCCC(C(OCCC3CC3)c3ccccc3)C2)c(=O)c1=O
Reaction time: 1.5 h
Yield: 99 %

Procedure:
The N—((S)-2-(2-(3-((2-cyclopropylethoxy)(phenyl)methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)-3-cyclohexylpropyl)-4-(trimethylsilyl)butanamide (12.3 mg, 0.02 mmol) was dissolved in dioxane (1 mL) and treated with 4M HCl in dioxane (0.5 mL, 2.0 mmol). The solution was allowed to stir for 1.5 h before evaporation of solvent. The residual oil was redissolved in methanol and evaporated under reduced pressure to afford 3-((S)-1-amino-3-cyclohexylpropan-2-ylamino)-4-(3-((2-cyclopropylethoxy)(phenyl)methyl)piperidin-1-yl)cyclobut-3-ene-1,2-dione hydrochloride as an oil (10 mg, >99%). MS ESI+ve m/z 494 (M+1).
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:21](O)(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>N1C=CC=CC=1>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][C:21]([C@@:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3])=[O:29])([OH:28])=[O:27]
Reactant: O=C(O)CCCCC(=O)O
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: c1ccncc1
Product: Nc1nc2c(ncn2[C@]2(C(=O)CCCCC(=O)O)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 500 mg of guanosine in anhydrous pyridine was added adipic acid (5 mol eq) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPDC) (1.0 mol eq.). The mixture was allowed to stir at room temperature for 18 h, then the solvent was removed in vacuo. The residue was added to 100 mL of ice-cooled water and the aqueous layer adjusted to pH 3.0 and then extracted three times with 60 mL of ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on a silica gel column and eluted with a mixture of chloroform-ethanol, whereupon the eluate was evaporated in vacuo.
Reaction SMILES: O.[C:2]1(=[O:8])O[C:5](=[O:6])[CH:4]=[CH:3]1.[CH2:9]([NH2:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].P(=O)(O)(O)O>C1(C)C(C)=CC=CC=1>[CH2:9]([N:21]1[C:5](=[O:6])[CH:4]=[CH:3][C:2]1=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCN
Reactant: O=C1C=CC(=O)O1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCCN1C(=O)C=CC1=O
Temperature: 215 °C

Procedure:
A glass flask having an inner volume of 3 liters was fitted with a thermometer, a stirrer, and a water separator. In this reactor, 240 g of a solution containing 120 g of maleic anhydride in xylene was placed. Then, a solution containing 220 g of dodecylamine in 1880 g of xylene was added gradually and piecemeal over a period of 120 minutes at 40° C. to the reactor. After the addition was completed, the mixture in the reactor and 65.4 g of orthophosphoric acid (purity 89% by weight) added thereto were heated at 215° C. for 1 hour under 4.4 kg/cm2.G to effect reaction. The resultant reaction mixture was cooled to 30° C., washed with 400 ml of water, and separated into a water layer and a xylene layer. The xylene layer was separated by filtration to effect removal of insolubles. The xylene layer was distilled to expel xylene. Consequently, there was obtained 258 g of slightly impure N-dodecyl maleimide. This product was found to have purity of 85.3% by weight, indicating the yield to be 69.9 mol% based on dodecylamine.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[O:6][CH2:5][CH2:4][O:3]1.[CH3:13][I:14]>C1(C)C=CC=CC=1>[I-:14].[CH3:13][N+:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:2]2([CH3:1])[O:3][CH2:4][CH2:5][O:6]2)[CH:8]=1
Reactant: CI
Reactant: CC1(c2cccnc2)OCCO1
Solvent: Cc1ccccc1
Product: C[n+]1cccc(C2(C)OCCO2)c1
Product: [I-]
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A 3-l. three-necked flask, equipped with mechanical stirrer, reflux condenser and thermometer was charged under nitrogen with 155 g of 3-(2-methyl-1,3-dioxolan-2-yl)pyridine and 1.2 l of toluene. 272 g of methyl iodide was added. The mixture was stirred and heated at 53° (internal temp.) for 32 hours and then let stand at room temperature overnight. The precipitate was collected by filtration, washed with 500 ml of toluene, 500 ml of hexane and dried (r.t., 0.1 mm, const. weight) to yield 286.2 g (99.3%) of 1-methyl-3-(2-methyl-1,3-dioxolan-2-yl)pyridinium iodide as light yellow crystals, m.p. 185.5°-187° (sinters at 167°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:34])[CH:5]=[C:6]([Cl:33])[C:7]=1[CH2:8][C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28]CC2CC2)[CH:19]=1)[O:10][C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:33][C:6]1[CH:5]=[N+:4]([O-:34])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([OH:28])[CH:19]=1)[O:10][C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12]
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)c1cccs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(O)c1)c1cccs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.6 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide (180 mg, 0.339 mmol) (Compound 21), prepared as previously described in Example 5, Scheme 5, Table 3, was treated with trifluoroacetic acid (TFA) (4 mL, 51.9 mmol), and the resulting solution was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with CH2Cl2 (40 mL) and washed with water (3×40 mL). The organic layer was died over Na2SO4 and evaporated to dryness. The residue was purified by chromatography on SiO2 (CH2Cl2:AcOEt=3:2) to afford (S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-hydroxyphenyl)-2-(thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide (83) (67 mg, 0.141 mmol, 41.4% yield, MS/ESI+474.99 [MH]+)
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.Cl>[CH3:11][O:10][C:9]1[C:2]([O:1][CH2:21][O:22][CH3:23])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: COCCl
Reactant: COc1cccc(C=O)c1O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1c(C=O)cccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
2-Hydroxy-3-methoxybenzaldehyde (90 mg, 0.59 mmol) was placed in a 20 mL reaction vessel, and dissolved in 1.8 mL of dry dichloromethane. To the solution were added N,N-diisopropylethylamine (0.30 mL, 1.7 mmol), 4-dimethylaminopyridine (9 mg, 0.07 mmol), and chloromethyl methyl ether (112 μL, 1.48 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with 30 mL of ethyl acetate and 7 mL of 1N HCl, and extracted. The extract was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a pale yellow oil (93.4 mg, 80%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[S:13][C:12]([NH2:14])=[N:11][C:10]=1[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:8].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21].CCCCCC>ClCCl>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([N:14]=[C:20]=[O:21])[S:13][C:9]=1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:8]
Reactant: Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C=Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
Compound 186 (200 mg, 0.737 mmol) was suspended in dichloromethane (15 mL), and carbonyldiimidazole (179 mg, 1.11 mmol) was added thereto at room temperature, followed by stirring at room temperature for 2 hours. Hexane (7.5 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration to afford the entitled Compound y (133 mg, 61%) as a brown solid.
Reaction SMILES: [N:1]#[C:2]Br.C([O-])([O-])=O.[Na+].[Na+].[CH3:10][NH2:11].[CH3:12][CH2:13][O:14][CH2:15][CH3:16]>>[O:14]1[CH2:15][CH2:16][CH2:12][C@@H:13]1[CH2:10][NH:11][C:2]#[N:1]
Reactant: CN
Reactant: N#CBr
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CNC[C@H]1CCCO1
Reaction time: 1.5 h

Procedure:
To a stirred mixture of cyanogen bromide (2.2 g, 20.8 mmol) and anhydrous Na2CO3 (4.2 g, 39.6 mmol) in dry ether (30 mL) cooled between −20 and −10° C. was added (R)-tetrahydro-furan-2-yl)-methylamine (Aldrich) (2.0 g, 19.8 mmol) over 10 minutes. Stirring was continued for an additional 1.5 hours at −20 to −10° C. Then the mixture was filtered and concentrated to provide 2.21 g of the title product. MS (ESI) m/z 127 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([SH:22])[N:14]=[C:13]2[CH2:23][CH2:24][CH3:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([S:22][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:14]=[C:13]2[CH2:23][CH2:24][CH3:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCOC(=O)CCCCCBr
Reactant: CCCc1nc(S)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Product: CCCc1nc(SCCCCCC(=O)OCC)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2

Procedure:
The operation is carried out as in Stage 7 of Example 1 starting with the product obtained in Stage 6 of Example 1 and ethyl 6-bromo-hexanoate instead of ethyl 4-bromocyclohexaneacetate.
Reaction SMILES: [Li].[CH:2](/Cl)=[CH:3]\[CH3:4].C(/[Li])=C\C.[C:10]1([C:16](=[O:21])[C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CCCCCC.CCOCC>[C:10]1([C:16](/[CH:2]=[CH:3]/[CH3:4])([OH:21])[C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C/C=C/Cl
Reactant: COC(=O)C(=O)c1ccccc1
Agent: Cl
Agent: [Li]
Agent: [Li]/C=C/C
Solvent: CCOCC
Solvent: CCCCCC
Product: C/C=C/C(O)(C(=O)OC)c1ccccc1
Reaction time: 1 h

Procedure:
Lithium ribbon (1.0% Na content) 6.9 g., 1.0 g. at.) was cut into strips (1.0 cm.=0.089 g.), degreased in hexane and cut into thin strips into ether (200 ml.) under helium. The reaction flask was equipped with dry-ice condenser and trans-propenyl chloride (25.5 g., 0.30 mole) was introduced dropwise during 60 minutes to the rapidly stirred suspension. The reaction was exothermic and was controlled by the addition of the halide. After addition the mixture was stirred for an additional 60 minutes. The trans-propenyllithium slurry was subsequently siphoned (in spurts during 30 minutes by He.pressure) into a stirred solution containing methyl phenylglyoxylate (55.0 g., 0.3 mole) in ether which was cooled to -78°. After 30 minutes of additional stirring, the reaction was warmed to -10° and poured onto 30 ml. of concentrated HCl and ca. 200 g. of ice. The ether layer was separated and the aqueous layer was further extracted with 3×50 ml. of ether. All ether layers were combined and dried over Drierite for 18 hours. After the solvent was stripped, the crude product weighting 58.1 g. (94%) was obtained which on distillation afforded 35 g. (57%) of pure material, b.p. 100° (0.05 mm.).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12](O)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:21].C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([Cl:21])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCOC(=O)c1nc(O)c2sccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1nc(Cl)c2sccc2c1O
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 143.5 %

Procedure:
A mixture of 4,7-dihydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (267 mg, 1 mmol), POCl3 (217 mg, 1.4 mmol), and toluene (4 ml) was heated in a microwave oven at 140° C. for 15 min. The same procedure was repeated with a second batch. Both batches were combined, conc. aqueous NaHCO3 (40 ml) and EtOAc (40 ml) were added and the mixture was stirred vigorously for 45 min. The organic layer was then separated, dried over MgSO4 and concentrated in vacuo to give a tan solid (410 mg). Purification by flash column chromatography on silica gel using CH2Cl2:EtOAc=9:1 as the eluent yielded the title compound as a tan solid (297 mg, first major fraction). MS-(−)-ion: M−1=284.3.
Reaction SMILES: [CH:1]1[CH:13]=[CH:12][C:11]2[C:14](=[O:17])[CH2:15][CH2:16][N:9]3[C:10]=2[C:2]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=13.C([Li])CCC.[CH:23](=[O:26])[CH2:24][CH3:25].[Cl-].[NH4+]>O1CCCC1>[OH:26][CH:23]([C:15]1[C:14](=[O:17])[C:11]2[CH:12]=[CH:13][CH:1]=[C:2]3[C:10]=2[N:9]([CH:16]=1)[C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]3=1)[CH2:24][CH3:25]
Reactant: O=C1CCn2c3ccccc3c3cccc1c32
Reactant: CCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cn2c3ccccc3c3cccc(c1=O)c32
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5,6-dihydro-4H-pyrido[3,2,1-jk]carbazole-4-one (800 mg) prepared by the procedure described in J.O.C., 24, 324 (1959) was dissolved in anhydrous tetrahydrofuran (30 ml). n-butyl lithium (solution in hexane, 3 ml) was added dropwise to the solution cooled in an acetone-dry ice bath, and the mixture was stirred for 30 minutes. Propionaldehyde (0.29 ml) dissolved in anhydrous tetrahydrofuran (15 ml) was gradually added dropwise to the solution cooled in an acetone-dry ice bath, and the mixture was stirred for 90 minutes. Saturated aqueous solution of ammonium chloride of an adequate amount was added to the reaction mixture, and the mixture was heated to room temperature, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=4:1) to obtain the title compound as a diastereomer (450 mg, 45%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=[O:12])=[CH:5][NH:6]2.[H-].[Na+].[CH2:15](I)[CH3:16]>CN(C=O)C.ClCCl>[CH2:15]([N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[C:4]([CH:11]=[O:12])=[CH:5]1)[CH3:16]
Reactant: CCI
Reactant: Cc1cccc2[nH]cc(C=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1cc(C=O)c2c(C)cccc21
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of 4-methyl-1H-indole-3-carbaldehyde (150 mg. 0.942 mmol) in dry DMF (1 mL) was added NaH (26 mg, 1.08 mmol) in 3 portions. When the evolution of gas was complete, the reaction vial was sealed and agitated for 5 m, after which time ethyl iodide (0.086 mL, 1.1 mmol) was added and agitation was continued overnight. The mixture was diluted with dichloromethane (10 mL), washed with water (2×5 mL), and brine (5 mL), dried and concentrated. This mixture was purified by flash chromatography using a gradient of ethyl acetate/hexane to provide 1-ethyl-4-methyl-1H-indole-3-carbaldehyde (111 mg, 63%). This intermediate (371 mg, 2 mmol) was dissolved in THF (3 mL) and NaBH4 (38 mg, 5 mmol) was added followed by 3 drops of water. The reaction mixture was agitated for 4 h then added to a saturated solution of NaHCO3 (10 mL). This mixture was stirred for 1 h and the intermediate, (1-ethyl-4-methyl-1H-indol-3-yl)-methanol was isolated by filtration and dried (330 mg, 88% yield). This intermediate was then convened to the title compound using methods similar to those described in Example 31. LCMS (ESMS): m/z 420 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCC=Cc1ccco1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: O=C(O)CCCCCCCCc1ccco1
Yield: 93.6 %

Procedure:
This compound was synthesized from 9-(2-furyl)-8-nonenoic acid (0.89 g, 4 mmol) by a hydrogenation reaction using Pd/BaSO4 (90 mg). Crystallization (petroleum ether) afforded the product (0.84 g, 93%) as white crystals (mp 31°-32° C.); IR: 3450-2500, 1720 cm-1 ; 1H-NMR: 1.30 (m, 8H), 1.63 (m, 4H), 2.35 (t, 2H), 2.60 (t, 2H), 5.95 (s, 1H), 6.27 (s, 1H), 7.28 (s, 1H), 9. 85 (bs, 1H). Anal. Calcd. for C13H20O3 : C, 69.61, H, 8.99%; Found: C, 69.42, H, 9.04%.
Reaction SMILES: C([CH:4]([CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[C:5]([CH3:9])(O)[CH:6]=[CH2:7])(C)=C.CN1C[CH2:24][CH2:23][C:22]1=O.[OH2:27]>>[CH3:9][C:5](=[CH:4][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:17])[CH3:18])[CH2:6][CH2:7][CH2:22][C:23](=[O:27])[CH3:24]
Reactant: CN1CCCC1=O
Reactant: C=CC(C)(O)C(CC=C(C)CCC=C(C)C)C(=C)C
Reactant: O
Product: CC(=O)CCCC(C)=CCC=C(C)CCC=C(C)C
Temperature: 190 °C
Yield: 73 %

Procedure:
In a nitrogen atmosphere, a mixture of 500 g of 4-isopropenyl-3,7,11-trimethyl-1,6,10-dodecatrien-3-ol (purity 89.61%) and 500 g of N-methylpyrrolidone was heated at 190° C. for 4 hours. The reaction mixture was cooled, poured into a container of water and the resulting aqueous solution was extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulphate. The ethereal extract was distilled under reduced pressure to remove the ether and low-boiling fractions, and the residue was distilled in vacuo to obtain 6,10,14-trimethyl-6,9,13-pentadecatrien-2-one (yield 73%) as a distillate at bp. 121-123° C. / 0.17 mm Hg.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[S:20][C:19]([CH:21]([CH2:25][C:26]#[N:27])[CH2:22][C:23]#[N:24])=[N:18][CH:17]=3)[C:10]=2[CH:9]=[CH:8]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[S:20][C:19]([CH:21]([CH2:25][C:26]#[N:27])[CH2:22][C:23]#[N:24])=[N:18][CH:17]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnc(C(CC#N)CC#N)s3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(CC#N)c1ncc(-c2ncnc3[nH]ccc23)s1
Reaction time: 4 h
Yield: 61.8 %

Procedure:
A solution of 3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]pentanedinitrile (14 mg, 0.033 mmol) in DCM (3 mL) containing TFA (0.6 mL) was stirred for 4 hours. The mixture was then concentrated and the residue was redissolved in methanol (2 mL) to which ethylenediamine (0.4 mL) was then added. After 1 hour reaction time, the product was purified by preparative-HPLC/MS (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (6 mg, 62%).