Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:15][N:14]=1>CN(C)P(=O)(N(C)C)N(C)C>[O:11]1[CH2:10][CH:9]1[CH2:7][O:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:15][N:14]=1
Reactant: Oc1cc(-c2ccccc2)on1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: c1ccc(-c2cc(OCC3CO3)no2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.6 %

Procedure:
10.28 g of anhydrous potassium carbonate and 6.89 g of epichlorohydrin were added to a solution of 10.00 g of 3-hydroxy-5-phenylisoxazole in 50 ml of hexamethylphosphoric triamide, and the mixture was stirred at room temperature for 24 hours. At the end of this time, insoluble materials were removed by filtration from the reaction mixture, and 200 ml of ethyl acetate were added thereto. The mixture was then washed twice, each time with 200 ml of a 10% w/v aqueous solution of sodium chloride. The organic layer was then dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, eluted with a 4:1 by volume mixture of cyclohexane and ethyl acetate, to give 11.00 g (yield 82%) of the title compound as colorless needles, melting at 98°-99° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].[CH3:18]I>CN(C=O)C>[CH3:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCc1cc2ccccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
To a solution of methyl 3-(1H-indol-2-yl)propanoate (800 mg, 3.94 mmol) in dry DMF (10 mL) was added NaH (300 mg, 7.50 mmol) at 0° C. After 15 min, MeI (0.40 mL, 6.40 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (50 mL) and extracted with EA (50 mL×3). The combined organic phase was dried over sodium sulfate, filtered, and concentrated. Purification via flash chromatography then afforded the title compound (332 mg, 1.299 mmol, 85% purity, 33% yield). LCMS: rt=3.17 min, [M+H+]=218.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(CC)C(C)C)(C)C.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([C@@H:33]1[CH2:37][S:36][CH2:35][N:34]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:32])[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([O:18][C:19]([NH:21][C@H:22]([C:23]([O:25][CH2:2][C:3]#[N:4])=[O:24])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([C@@H:33]1[CH2:37][S:36][CH2:35][N:34]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:32])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C)C(=O)O
Reactant: N#CCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
Bromoacetonitrile (57 μl, 0.845 mmol) and N,N-diisopropylethylamine (147 μl, 0.845 mmol) were added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-6-((R)-3-(tert-butoxycarbonyl)thiazolidine-4-carboxamido)hexanoic acid (Compound tk82) (130 mg, 0.282 mmol) in acetonitrile (5 ml), and the reaction solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure using an evaporator, and the residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (R)-tert-butyl 4-(((S)-5-((tert-butoxycarbonyl)amino)-6-(cyanomethoxy)-6-oxohexyl)carbamoyl)thiazolidine-3-carboxylate (Compound tk83) (140 mg, 99%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.C(OC([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:3][C:4]([CH3:13])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1cc(Cl)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Yield: 47.3 %

Procedure:
4,7-Dichloro-2-methylquinoline (De, D., Byers L. D., Krogstad, D. J. J. Heterocyclic Chem. 1997, 34, 315) (453 mg, 2.1 mmol) and 1-tert-butoxycarbonylpiperazine (2.05 g, 11.0 mmol) are reacted according to method A. The Boc group is cleaved with trifluoroacetic acid (5 mL) in CH2Cl2 (5 mL) giving 0.26 g of the piperazine.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([CH:8]1[CH2:9][N:10]([C:20](=[O:21])[CH2:19][CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CNC2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N1CC(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
A solution of 3-benzylazetidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-phenylpropionyl chloride (421.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing the ethyl 1-(3-benzylazetidin-1-yl)-3-phenylpropan-1-one are collected and the solvent is removed in vacuo to give 432 mg of colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].O>ClCCl>[CH3:16][N:12]1[C:13](=[O:15])[C:14]2[C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][C:40](=[O:42])[CH3:41])=[C:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[S:8][C:9]=2[N:10]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:11]1=[O:17]
Reactant: CC(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCN)c(Cc3cccc4ccccc34)sc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCSc1c(Cc2cccc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reaction time: 8 h

Procedure:
5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (51 mg) and triethylamine (100 μl) were dissolved in dichloromethane (2 ml) and acetyl chloride (25 μl) was added. The reaction was stirred overnight, then water was added and the phases were separated. The aqueous phase was extracted with dichloromethane, then the organic phases were combined, dried, filtered and evaporated. Purification by HPLC (ethanol:dichloromethane 1-10: 99-90) gave the title compound (36 mg).
Reaction SMILES: C([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=O)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1C[C@H](OCC)[C@H](Nc2nc(CC)c(-c3ccc(Cl)cc3Cl)nc2CC)C1

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting ethyl chloroformate and making non-critical variations provided the title compound as an oil:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]([CH2:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28](=O)[CH3:29])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:22][CH2:23][C@H:24]([N:27]([CH2:28][CH3:29])[CH2:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:25][CH2:26]2)=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)N(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of LiAlH4 (74 mg, 1.95 mmol) and THF (10 ml) at 0° under Argon, a solution of trans-N-[4-(4-benzyloxy-phenyl)-cyclohexyl]-N-(3-phenyl-propyl)-acetamide (0.43 g, 0.97 mmol) in THF (10 ml) was added. The suspension was stirred for 2 h at RT and for 1 h at reflux. After cooling to 0°, H2O (0.4 ml) was carefully added, followed by 15% NaOH (0.4 ml) and H2O (0.4 ml). The precipitate was removed by filtration and the filtrate dried over Na2SO4, and evaporated. The residue was purified by chromatography over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2—MeOH 95:5 to give trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-ethyl-(3-phenyl-propyl)-amine (0.11 g, 26%) as a colorless oil. MS: m/e=328.5 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:2]2[C:3]3[S:22][CH2:21][CH2:20][C:4]=3[N:5]=[C:6]([N:8]3[CH2:9][CH2:10][N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:12][CH2:13]3)[N:7]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Reactant: Nc1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc(Nc2nc(N3CCN(c4ccccc4)CC3)nc3c2SCC3)c1

Procedure:
0.320 g (0.96 mmol) of 4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (V), 1.0 mL (9.5 mmol) of 3-chlorophenylamine, and 0.33 mL (1.92 mmol) of diisopropylethylamine are combined and the mixture is reacted for 0.5 hours at 130° C. in the microwave. Then the reaction mixture is combined with ethyl acetate and acidically extracted. The organic phase is dried and evaporated to dryness. The residue is to combined with acetonitrile, water, and trifluoroacetic acid. The phase containing the product I is purified by chromatography through an RP column by HPLC (column: Microsorb, RP-C18, 300 Å, 10 μm, 21.4*250 mm, eluant: acetonitrile+0.1% formic acid (A), water+0.13% formic acid (B)).
Reaction SMILES: [N:1]1([CH2:7][C:8](=[CH2:12])[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Br:48])[CH:43]=1>C1COCC1.CN(C=O)C.O>[Br:48][C:44]1[CH:43]=[C:42]([NH:41][C:32]2[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([NH:28][C:9](=[O:11])[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[CH2:12])[CH:30]=3)[N:35]=[CH:34][C:33]=2[C:39]#[N:40])[CH:47]=[CH:46][CH:45]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: C=C(CN1CCOCC1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=C(CN1CCOCC1)C(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Reaction time: 0.17 h
Yield: 23 %

Procedure:
Partially dissolved 1.26 g (7.37 mmol) 2-morpholin-4-ylmethyl-2-propenoic acid in 40 ml THF and chilled to 0° C. under N2. Added 810 μl (7.37 mmol) N-methylmorpholine and 950 μl (7.37 mmol) isobutyl chloroformate. After stirring 10 minutes, added a solution of 1.00 g (2.95 mmol) 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 2.5 ml DMF and 20 ml THF. Stripped solvent at 2 hours, slurried residue with water, collected solids, and dried in vacuo. Recrystallized from ethyl acetate and dried in vacuo, giving 334 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=492, 494.3.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([N+:27]([O-])=O)[C:21]=1[Cl:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO.O>[NH2:27][C:22]1[C:21]([Cl:30])=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:25]([Cl:26])=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc([N+](=O)[O-])c1Cl)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(N)c1Cl)(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
To a stirred mixture of 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-nitrobenzene (433 mg), ferric chloride hexahydrate (17.5 mg) and activated carbon (17.5 mg) in a mixture of methanol (2.78 ml) and water (0.69 ml) was added hydrazine monohydrate (0.135 ml) dropwise at 60-70° C. After the addition was finished, the mixture was refluxed for half an hour. The mixture was allowed to cool and filtered. The filtrate was concentrated in vacuo. The residue was extracted with dichloromethane and the organic phase was dried over anhydrous magnesium sulfate. After being filtered, the filtrate was concentrated in vacuo and the resulting residue was washed with n-hexane to give 3-amino-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichlorobenzene (348 mg) as a white mass.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[F:54][C:55]([F:73])([F:72])[C:56]1[CH:57]=[C:58]([NH:62]C2C=CC=CC=2C(O)=O)[CH:59]=[CH:60][CH:61]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[F:54][C:55]([F:72])([F:73])[C:56]1[CH:57]=[C:58]([NH:62][C:29]2[CH:30]=[CH:31][CH:2]=[CH:3][C:4]=2[C:5]([NH:7][CH:8]([C:10]2[N:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[N:12][CH:11]=2)[CH3:9])=[O:6])[CH:59]=[CH:60][CH:61]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: O=C(O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3Nc3cccc(C(F)(F)F)c3)nn2)cc(OC)c1OC
Yield: 80 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid (240 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave 2-{[3-(trifluoromethyl)phenyl]amino}-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (297 mg, 80%) as a yellow solid. MS m/z 568 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[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][NH:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=1.[OH-].[K+].C(O)C.Cl>O>[CH3:30][Si:2]([CH3:1])([CH3:29])[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][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A solution of 14.1 g. ethyl 4-[14-(trimethylsilyl)tetradecylamino]benzoate and 6.4 g. 85% potassium hydroxide in 150 ml. 95% ethanol was heated at 75° for 5 hr. The reaction was diluted with 300 ml. water and adjusted to pH 3.5 with concentrated hydrochloric acid. The precipitate was filtered, dried, and crystallized from acetone to yield a white solid, m.p. 105°-107° C.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=[O:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Na+]>C1COCC1>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][O:43][Si:44]([C:47]([CH3:48])([CH3:50])[CH3:49])([CH3:45])[CH3:46])[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][OH:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccccc1CO
Reaction time: 1 h
Yield: 89 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-[(7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-(2-formylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D60, 27.7 mg, 0.0356 mmol) was suspended in dry THF (1.5 mL) before adding sodium borohydride (3 mg, 0.078 mmol) and stirring for 1 hour. Added more sodium borohydride (3 mg, 0.078 mmol) and left stirring for a further 1 and ½ hours. Reaction quenched with water, diluted with EtOAc. Organic layer washed with water, dried (MgSO4). Filtered. Solvent evaporated to afford the title compound as an off white solid in 89% yield. Used crude in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[C:10]([C:18]([CH3:20])=[CH2:19])[N:9]=2)=[CH:4][CH:3]=1.[BH4-].C([N+](CC)(CC)CC)C.C([O-])(O)=[O:32].[Na+]>CO.COCCOC.O>[OH:32][C:18]([C:10]1[CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1)([CH3:20])[CH3:19]
Reactant: O=C([O-])O
Reactant: C=C(C)c1cc(C(=O)OC)cc(-c2ccc(C)cc2)n1
Agent: CC[N+](CC)(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(C)cc2)nc(C(C)(C)O)c1
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(4-methylphenyl)-6-(prop-1-en-2-yl)pyridine-4-carboxylate (191 mg, 0.71 mmol) in methanol (3.6 mL) and DME (3.6 mL) was added cobalt(II)mesotetraphenylporphine (2.4 mg, 3.6 mop. After 30 min, tetraethylammonium borohydride (170 mg, 1.17 mmol) was added in 3 portions over 1 h. Saturated aqueous NaHCO3 was added. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 90% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (165 mg). MS 286.1 (M+1).
Reaction SMILES: [BH4-].[Na+].O1CCCC1.[CH2:8]([N:11]([CH2:27][CH2:28][CH3:29])[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[C:15]([CH:22]=[CH:23][N+:24]([O-])=O)[CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[CH2:9][CH3:10].Cl>C(O)(C)C.C(N(CC)CC)C>[CH2:27]([N:11]([CH2:8][CH2:9][CH3:10])[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[C:15]([CH2:22][CH2:23][NH2:24])[CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[CH2:28][CH3:29]
Reactant: CCCN(CCC)C1CCc2cccc(C=C[N+](=O)[O-])c2C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc(CCN)c2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
820 mg (20.4 mmol) of sodium borohydride were initially introduced into 30 ml of absolute tetrahydrofuran at 0° C. under nitrogen. 3.24 ml (25.8 mmol) of boron trifluoride diethyl ether complex were added dropwise at this temperature, and the mixture was subsequently stirred for 15 minutes at room temperature. A solution of 1.3 g (4.3 mmol) of 2-dipropylamino-8-(2-nitro-ethenyl)-1,2,3,4-tetrahydronaphthalene and 10 ml of absolute tetrahydrofuran was then added dropwise, and the mixture was then stirred for 5.5 h under reflux. After cooling to room temperature, 55 ml of ice water were carefully added dropwise, and the mixture was then acidified using 55 ml of 1N hydrochloric acid. The mixture was subsequently stirred for 2 h at +80°-+85° C. The cooled aqueous phase was washed twice with 35 ml of ether, then adjusted to pH 12 using 5 molar sodium hydroxide solution, and the product was extracted with methylene chloride. The extract was dried over sodium sulphate and evaporated. The product was obtained by subsequent chromatography over silica gel 60, 40-63 μm, using isopropanol/triethylamine, 95:5.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:22])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][OH:21])[N:18]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.C(Cl)Cl.CC(C)=O>[CH2:23]([O:21][CH2:20][CH2:19][C:17]1[N:18]=[C:14]([NH:13][S:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=2[CH3:22])(=[O:11])=[O:12])[S:15][CH:16]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCO)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCOCc2ccccc2)cs1
Reaction time: 0.25 h

Procedure:
Sodium hydride (95% dry, 76 mg, 3.00 mmol) was added to a stirred solution of EXAMPLE 181A (400 mg, 1.20 mmol) in THF (10 mL) at room temperature. After stirring for 15 min. the mixture was treated with benzyl bromide (226 mg, 1.32 mmol). After 2 h at 50° C. additional sodium hydride (60 mg, 2.40 mmol) and benzyl bromide (142 mg, 1.20 mmol) were added in two equal portions under a period of 2 h. The reaction was quenched by adding 1M HCl (3 mL) at room temperature. The mixture was extracted with DCM and dried (Sodium sulfate). Evaporation of the solvent gave a residue which was purified by flash chromatography on silica gel eluting with 5% acetone in DCM giving (105 mg, 0.25 mmol, 21%) which solidified on standing: MS (Ionspray, [M+H]+) m/z 322. Anal. Calcd. (found) for C19H19ClN2O3S2.0.5 CH2Cl2: C, 50.3 (50.7)%; H, 4.3 (4.1)%; N, 6.0 (5.9)%.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH3:14].[OH-].[Na+]>>[C:3]([OH:15])(=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH3:14]
Reactant: CCC=CCCCCCCCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CCC=CCCCCCCCC(=O)O

Procedure:
The 9-dodecenoic acid methyl ester is then hydrolyzed under basic conditions (reflux with an excess of dilute aqueous NaOH), followed by removal of methanol. The resulting aqueous solution is then treated with an excess of dilute HCl, and the solution is distilled to provide 9-dodecenoic acid. Estolides are then prepared according to the methods set forth in Examples 1 and 2, wherein the oleic acid is replaced with 9-dodecenoic acid.