Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:12]=[CH:11][NH:10][C:5]2=[N+:6]([O-])[C:7]=1[CH3:8].C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:20]>>[Br:1][C:2]1[C:3]([Cl:20])=[C:4]2[N:12]=[CH:11][NH:10][C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(Br)cc2nc[nH]c2[n+]1[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2[nH]cnc2c(Cl)c1Br
Temperature: 0 °C

Procedure:
A solution of 6-bromo-5-methyl-3H-imidazo[4,5-b]pyridine 4-oxide (1.00 equivalent) in POCl3 (excess) is stirred at 80° C. for 16 hours. The reaction mixture is concentrated in vacuo to give the crude material that is poured into ice-water. The resulting aqueous solution is neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product. The product is purified by trituration or flash column chromatography if further purification is necessary.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[N:13]([CH3:17])[C:12]3=[CH:18][C:19]([C:21]([NH2:23])=O)=[N:20][N:11]3[C:10](=[O:24])[C:9]=2[CH:8]=1>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[N:13]([CH3:17])[C:12]3=[CH:18][C:19]([C:21]#[N:23])=[N:20][N:11]3[C:10](=[O:24])[C:9]=2[CH:8]=1
Reactant: COc1ccc2c(c1)c(=O)n1nc(C(N)=O)cc1n2C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)c(=O)n1nc(C#N)cc1n2C
Temperature: 50 °C

Procedure:
Thionyl chloride (1.5 ml) is added slowly, with stirring to 50 ml of dimethylformamide at 0° C. To this solution is added 2.9 g of 4,9-dihydro-7-methoxy-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide and the mixture is stirred and heated at 50° C. for 18 hrs, then evaporated at reduced pressure. The residue is stirred with 600 ml of ice water and the resulting solid 4,9-dihydro-7-methoxy-4-methyl-9-oxo-pyrazolo-[5,1-b]quinazoline-2-carbonitrile is collected by filtration, washed with water and dried; mp 316°-320° C. after crystallization from dimethylformamide/ethanol.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[NH4+].[Cl-]>C1COCC1.[Zn]>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:2][C:3]1=[O:11]
Reactant: O=C1Nc2ncccc2C1(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: O=C1Cc2cccnc2N1
Reaction time: 2 h

Procedure:
A solution of 3,3-dibromo-7-azaoxindole (2.0 g, 7.2 mmol) in THF (50 mL) is stirred at room temperature and a saturated aqueous solution of NH4Cl is added. Activated zinc powder is added and the reaction mixture is stirred for 2 h. The zinc is removed by filtration through a pad of diatomaceous earth and the organic layer is separated. The aqueous layer is extracted with THF (10 mL) and the combined organic layers are dried over anhydrous MgSO4, filtered and evaporated. The residue is slurried in 10:1 CHCl3:MeOH (15 mL) and filtered through a pad of silica gel and the filtrate is evaporated. The residue is triturated with water and the solid is collected by filtration and dried under vacuum to give 7-azaoxindole, 0.668g (70%). 1H NMR (DMSO-d6) δ10.94 (s, 1H), 8.02 (d, 1H, J=5.2 Hz), 7.52 (d, 1H, J=6.8 Hz), 6.90 (dd, 1H, J=6.8, 5.2 Hz), 3.53 (s, 2H). MS(AP−ve) 133 (100) (M−H)
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[N:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:18].OCCCN1N=CC2C(=CC(OC)=C(OC)C=2)C1=O.[CH:38](Cl)(Cl)[Cl:39].C(OCC)C>>[Cl:39][CH2:38][CH2:2][CH2:3][N:4]1[N:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:18]
Reactant: ClC(Cl)Cl
Reactant: COc1cc2cnn(CCO)c(=O)c2cc1OC
Agent: COc1cc2cnn(CCCO)c(=O)c2cc1OC
Solvent: CCOCC
Product: COc1cc2cnn(CCCCl)c(=O)c2cc1OC

Procedure:
Working as described in Example 2 but replacing 2-(2-hydroxyethyl)-6,7-dimethoxy-1(2H)-phthalazinone with an equivalent amount of 2-(3-hydroxypropyl)-6,7-dimethoxy-1(2H)-phthalazinone obtained as described in Example 12, 2-(3- chloropropyl)-6,7-dimethoxy-1(2H)-phthalazinone is obtained (m.p. 185°-187° C., from chloroform/ethyl ether).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=1>>[O:9]=[C:7]1[N:24]2[CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=[CH:20][C:19]2=[N:1][C:2]2[S:3][C:4]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:5][C:6]1=2
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1N
Reactant: O=C(O)c1ccc(Cl)nc1
Product: O=C(O)c1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Yield: 6.2 %

Procedure:
From 5.0 g (0.02 mol) of 2-amino-5-phenyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966) and 3.2 g (0.02 mol) of 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company), following the procedure of Example 3, there is obtained 0.4 g of 4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno [2,3-d]pyrimidine-7-carboxylic acid; mp 387°-392° C. after recrystallization from pyridine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:22]([C:25]3[C:33]4[O:32][C:31]([F:35])([F:34])[O:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH3:21])[CH:17]=[CH:16][C:15]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].CI.[ClH:42]>C(O)(C)C>[ClH:42].[CH3:21][N:20]([C:18]1[CH:17]=[CH:16][C:15]([O:36][CH3:37])=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=1)[S:22]([C:25]1[C:33]2[O:32][C:31]([F:35])([F:34])[O:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: COc1ccc(N(C)S(=O)(=O)c2cccc3c2OC(F)(F)O3)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CC(C)O
Product: COc1ccc(N(C)S(=O)(=O)c2cccc3c2OC(F)(F)O3)cc1N1CCNCC1

Procedure:
The compound was prepared by reaction of 4-{5-[(2,2-difluorobenzo[1,3]dioxole-4-sulfonyl)-methyl-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester with sodium hydride and methyliodide by analogy to Preparation Example 3, and subsequent deprotection of the tert.butoxycarbonyl group with hydrochloric acid in isopropanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:32][C:31]1[C:23]([F:22])=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[CH:25]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OCc1ccccc1
Reactant: Oc1ccc2[nH]ccc2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCc1ccccc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A mixture of 6-benzyloxy-4-chloro-7-methoxyquinazoline (0.88 g, 2.9 mmol), (EP1153920 production examples 28-30), 4-fluoro-5-hydroxyindole (0.53 g, 3.5 mmol) and potassium carbonate (0.607 g, 4.39 mmol) in DMF (18 ml) was stirred at 95° C. for 2 hours. After cooling, the mixture was filtered and the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and ethyl acetate to give 6-benzyloxy-4-(4-fluoroindol-5-yloxy)-7-methoxyquinazoline (0.8 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:15][NH:16][CH3:17]>C1COCC1.Cl>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:16]([CH3:17])[CH3:15])=[O:5]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CNC
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1Cl

Procedure:
2-chloro-4-nitrobenzoyl chloride Compound 13a1 (7.08 g, 32.2 mmol) and dimethylamine hydrochloride (2.62 g, 32.2 mmol) were combined in THF (50 mL) at 0° C. TEA (8.97 mL, 64.4 mmol) was added and the mixture was heated at reflux for 18 hrs. When the reaction was complete, the mixture was diluted with 1N HCl and extracted with EtOAc. The product was isolated by flash chromatography (30-50% EtOAc/hexane gradient) to provide 2-chloro-N,N-dimethyl-4-nitro-benzamide Compound 13a2 (3.05 g) as a tan solid. MS 229 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[O:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:26]=[CH:27][C:22]([NH:1][C:2]3[CH:14]=[C:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:23][CH:24]=2)[CH2:29][CH2:30]1
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccc(N2CCOCC2)cc1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-phenylbenzoate 94 mg were added 4-(4-bromophenyl)morpholine 0.21 g, cesium carbonate 0.23 g, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg at room temperature, and it was stirred at 110° C. for 6 hours. After the reaction mixture was cooled to room temperature, palladium acetate 1.6 mg, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg were added, and it was stirred at 110° C. for 12 hours. After the reaction mixture was cooled to room temperature, 4-(4-bromophenyl)morpholine 0.21 g, cesium carbonate 0.23 g, palladium acetate 1.6 mg, tris(dibenzylideneacetone)dipalladium(0) 3.2 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8.3 mg were added, and it was stirred at 110° C. for 4 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(4-morpholinoanilino)-4-phenylbenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1>CO.[Pd]>[NH2:9][C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=1
Reactant: COc1ncc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: COc1ncc(N)cn1
Reaction time: 18 h
Yield: 99.5 %

Procedure:
To 0.342 g (2.20 mmol) of the above nitro compound in MeOH (20 mL) was added 0.30 g of 10% Pd/C and the mixture was stirred under hydrogen (25 in/Hg) for 18 hrs. The reaction mixture was filtered through celite, and concentrated, to give 0.274 g (100% yield) of 5-amino-2-methoxypyrimidine as a colorless oil: 1H NMR (DMSO-d6) δ 8.05 (s, 2H), 3.94 (s, 3H); LCMS (APCI+) m/z: 126 (MH+, 100%).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[F:16])[N:3]=1.[CH2:17]([CH:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCCC1>[CH2:17]([CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[F:16])[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: c1ccc(CC2CCCN2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCCC2Cc2ccccc2)nc(-c2ccncc2F)cc1=O
Yield: 79.6 %

Procedure:
A solution of 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.24 g, 1.0 mmol), (2RS)-2-benzyl-pyrrolidine (0.20 g, 1.2 mmol) and triethylamine (0.3 g, 3.0 mmol) in tetrahydrofuran (4 ml) was stirred for 5 hours at 40° C. The solution was partitioned between water and ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform/ethyl acetate=3/2) to afford 2-((2RS)-2-benzyl-pyrrolidin-1-yl)-6-(3-fluoro-pyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.29 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:12]=3[NH:11][C:10]=2[CH:20]=1)=[O:5])[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[CH:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:15][CH2:16][C:17]([CH3:19])([CH3:18])[C:12]=3[NH:11][C:10]=2[CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c3c([nH]c2c1)C(C)(C)CCC3
Reactant: CCCCCCCCBr
Product: CCCCCCCCC1CCC(C)(C)c2[nH]c3cc(C(=O)OCC)ccc3c21
Yield: 103.2 %

Procedure:
Using the procedure of Example 9, 4.8 g of the ethyl ester from Example 6 was alkylated with 4.38 g of 1-bromooctane to provide 5,6,7,8-tetrahydro-6,6-dimethyl-9-octyl-9H-dibenzo[b,d]pyrrole-3-carboxylic acid ethyl ester (7.0 g;100%) as a yellow oil after purification on a small pad of silica gel.
Reaction SMILES: [CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19](C(F)(F)F)=[O:20])[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:25].[Na+].Cl>O1CCOCC1>[CH:1]1([C@H:7]2[N:12]3[CH:13]=[C:14]([C:19]([OH:25])=[O:20])[C:15]4[CH:16]=[CH:17][CH:18]=[C:10]([C:11]=43)[O:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1cn2c3c(cccc13)OC[C@H]2C1CCCCC1)C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1cn2c3c(cccc13)OC[C@H]2C1CCCCC1

Procedure:
To a solution of (R)-3-cyclohexyl-6-trifluoromethylcarbonyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine (628 mg, 1.86 mmol) in 1,4-dioxane (20 ml) was added 4 N NaOH (5.0 ml). The mixture was refluxed for 42 h, then acidified to pH 1 using 5 N hydrochloric acid and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane, and combined organic layers were washed with brine, dried over Na2SO4 and concentrated to afford (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (572 mg). The title compound was prepared following the method of Example 7, using (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid amide (prepared from (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid) instead of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboxylic acid amide. EsIMS: m/z 411.0 [M+H]+; [α]D22−30.7° (c=1.50 mg/ml in chloroform)
Reaction SMILES: [C:1]([CH2:24][C:25](=O)[CH2:26][C:27](=[O:49])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[BH4-].[Na+].[OH2:53]>>[C:1]([CH:24]([OH:53])[CH2:25][CH2:26][C:27](=[O:49])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)CC(=O)CC(=O)CCCCCCCCCCC/C=C\CCCCCCCC
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)CCC(O)C(=O)CCCCCCCCCCC/C=C\CCCCCCCC

Procedure:
A triacylglycerol containing oil having an EOE content of at least 50% based on total triacylglycerol composition can be chemically synthesized using 1,3 dihydroxyacetone and free erucic and oleic fatty acids as starting materials. Oils chemically synthesized as described herein have EOE contents of 80% or greater, and preferably greater than 90%. In the first step, 1,3 dihydroxyacetone dimer and erucic acid can be reacted in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine to form 1,3 dierucoylpropanone. The ketone group of 1,3 dierucoylpropanone can be reduced using, for example, sodium borohydride and water to form 1,3 dierucoylpropanol. EOE can be produced by reacting 1,3 dierucoylpropanol and oleic acid in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine to form 1,3 dierucoyl 2-oleoyl propane.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])=[O:16])([O:3][CH3:4])=[O:2].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:16])([O:3][CH3:4])=[O:2]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)CCCCCCCCCCC(=O)Nc1ccccc1O
Product: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCC(=O)OC

Procedure:
When (44) and 4-bromobutyronitrile are reacted under the conditions of step (A), above, (45) is obtained as a waxy solid. Conversely, reacting (44) with ethyl 4-bromobutyrate as in step (A) yields (8).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH:12]([CH3:14])[CH3:13])[C@@:7]([CH2:16][CH2:17][OH:18])([OH:15])[CH2:6][CH2:5]2.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:18][CH2:17][CH2:16][C@:7]2([OH:15])[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[C@H:8]2[CH:12]([CH3:13])[CH3:14])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CC(C)[C@@H]1c2ccc(F)cc2CC[C@@]1(O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC[C@]2(O)CCc3cc(F)ccc3[C@H]2C(C)C)cc1
Temperature: 0 °C
Yield: 84.5 %

Procedure:
28.5 g (0.113 mol) of [1R,2R]-(-)-2-[6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl]ethanol were dissolved in 150 ml of pyridine and treated portionwise within 30 minutes at 0° with 31.5 g (0.165 mol) of p-toluenesulphonyl chloride. After 90 minutes the reaction solution was poured into ice-water and extracted with ether. The organic phase was washed in succession with 3N hydrochloric acid, water and a saturated sodium carbonate solution. After drying over magnesium sulphate and evaporation of the solvent under reduced pressure, the remaining oily residue was recrystallized from ether/hexane, yielding 38.8 g (85%) of [1R,2R]-(-)-2-[6-fluoro-1,2,3,4-tetrahydro-2-hydroxy-1-isopropyl-2-naphthyl]ethyl p-toluenesulphonate as white crystals, m.p. 65°-67°; [α]D20 =-54.1° (c=1, methanol).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].Cl.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[OH:28]>>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH2:19][NH:18][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[F:16])=[C:21]([OH:28])[CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(CN)c(O)c1
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Agent: Cl
Product: CCOC(C(=O)NCc1ccc(C#N)cc1O)c1ccc(OC)cc1F

Procedure:
(RS)-Ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid, described in example 63.1 was coupled with 4-aminomethyl-3-hydroxy-benzonitrile hydrochloride according to general procedure B to give (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Colorless solid. MS 457.1 ([M−H]−)
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][C:17]=1[F:30].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:17]([F:30])[CH:18]=1)#[N:29]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.89 g) in tetrahydrofuran (70 ml) was added a solution of ethyl 3-oxohexanoate (5.45 g) in tetrahydrofuran (20 ml) dropwise at room temperature. After being stirred at room temperature for 1 hr, 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (5.0 g) was added to the mixture and the mixture was stirred at room temperature for 15 hr. Ethyl acetate and saturated aqueous ammonium chloride solution were added to the mixture. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (5.18 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].C[C:22](=[O:25])[CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:24][CH2:23][CH2:22][OH:25])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCC(C)=O
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Compound 5 (0.32 mL, 3.54 mmols) was mixed with 4-(3,4-dichlorophenyl)piperazine (0.58 g, 2.5 mmols) and potassium carbonate (0.78 g, 5.6 mmols) in 15 ml 2-butanone overnight at 85° C. as described in General Procedure B to yield compound 7p and was used as is for the next reaction. MS (LC/MS, ESI): 289 (M+H).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](=O)[CH3:11].[C:13]([NH:16][NH2:17])([NH2:15])=[NH:14].[ClH:18]>C(O)C.Cl>[ClH:18].[ClH:18].[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](=[N:17][NH:16][C:13]([NH2:15])=[NH:14])[CH3:11]
Reactant: N=C(N)NN
Reactant: CC(=O)c1cc2ccncc2[nH]1
Agent: Cl
Solvent: CCO
Product: CC(=NNC(=N)N)c1cc2ccncc2[nH]1
Temperature: 25 °C
Yield: 161.8 %

Procedure:
A mixture of 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanone (Example 70) (90 mg, 0.56 mmol) and aminoguanidine hydrochloride (65 mg, 0.59 mmol) in ethanol (5.6 mL) and 6 N HCl (0.47 mL) was heated under reflux for 1.5 h. The reaction mixture was cooled to room temperature and the precipitate was filtered, rinsed with ethanol and diethyl ether, and dried under vacuum at 45° C. to provide [[1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethylidene]amino]guanidine dihydrochloride (138 mg, 86%) as a white solid: mp 314-318° C. dec.; 1H NMR (300 MHz, CD3OD) δ2.50 (3H, s), 7.40 (1H, s), 8.10-8.27 (2H, m), 9.04 (1H, s); ESI MS m/z 217 [C10H12N6+H]+; HPLC (Method A) >99% (AUC), tR=9.01 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH:18]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[N:19]1>>[N:18]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[N:19]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: c1n[nH]c2c1CCCC2
Product: FC(F)(F)c1cc(-n2ncc3c2CCCC3)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (76 mg, 0.293 mmol) and 4,5,6,7-tetrahydroindazole (44 mg, 0.360 mmol) similar to Example 166 and was isolated as a white solid (25 mg, 0.072 mmol, 25% %). 1H NMR (CDCl3) 9.68 (d, J=1.2 Hz, 1H), 8.75 (m, 2H), 8.40 (s, 1H), 8.07 (s, 1H), 7.45 (ddd, J=1.2, 5.1, 9.0 Hz, 1H), 2.73 (m, 4H), 1.88 (m, 4H).