Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[N:15]([CH3:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:28][C:29](OC)([O:31]C)[CH3:30]>CN(C=O)C>[CH3:24][N:12]([CH2:13][C:14]1[N:15]([CH3:23])[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]1[CH:6]=[N:7][C:2]([NH:1][CH2:28][C:29](=[O:31])[CH3:30])=[CH:3][CH:4]=1
Reactant: COC(C)(CBr)OC
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2cc3ccccc3n2C)cn1
Reaction time: 18 h
Yield: 9.6 %

Procedure:
To a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.12 g, 0.32 mmol), from Example 1, in DMF (1 mL) was added NaH (14 mg. 60% dispersion in oil, 0.35 mmol) and 1-bromo-2,2-dimethoxy-propane (0.05 mL, 0.37 mmol). After 18 h at RT, the reaction was complete by TLC analysis. The solvent was removed under vacuum and the residue was purified by reverse phase preparative HPLC (YMC CombiPrep® ODS-A, 10% to 90% CH3CN/H2O+0.1% TFA) to give the title compound (11.6 mg) as a pale yellow oil: 1H NMR (400 MHz, MeOH-d4, 2:1 mixture of rotamers, minor rotamer in italics) δ 9.28 and 9.22 (s, 1 H), 8.60 and 8.52 (s, 1 H). 8.25 and 8.15 (d, 1 H), 7.68 (d, J=16 Hz, 1 H), 7.50 (m, 1 H), 7.35 (m, 3 H), 7.15 (m, 1 H), 7.02 (m, 1 H), 6.55 and 6.25 (s, 1 H), 5.05 and 4.95 (s, 2 H), 3.72 and 3.68 (s, 3 H), 3.50 and 3.48 (s, 3 H), 3.35 (s, 2 H), 3.15 and 3.10 (s, 3 H). MS (ES+) m/e 376.3 (M+H)+. Unreacted (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (68 mg) was also recovered.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C([Li])CCC.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH2:28][CH2:29][C:30](OC)=[O:31])(=[O:21])=[O:20])=[CH:15][CH:14]=1>O1CCCC1.CCCCCC>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([CH2:34][CH2:35][CH2:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH2:28][CH2:29][C:30]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[O:31])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Reactant: CC(C)(C)CO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 0.378 g of 2,2-dimethylpropanol in 3 ml tetrahydrofuran is added 0.003 ml of 2.5M n-butyllithium in hexane. To this solution is added 0.332 g methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate and the mixture is refluxed for 20 h. The reaction is quenched by addition of 3 ml of saturated ammonium chloride solution. It is then extracted with methylene chloride (3×10 ml). The combined organic extracts are dried, filtered and evaporated to dryness to give a clear oil which is purified by preparative thin layer chromatography to obtain 2,2-dimethylpropyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[NH2:27][C:28]1[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[NH2:27][C:28]1[CH:33]=[C:32]([O:34][C:2]2[N:3]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=2[CH2:8][CH3:9])[CH:31]=[CH:30][N:29]=1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Cl
Reactant: Nc1cc(O)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1ccnc(N)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (200 mg), 2-amino-4-pyridinol (118 mg), cesium carbonate (348 mg), and N-methylpyrrolidone (2 mL) was stirred at 120° C. for 3 hours. The reactant was purified by silica gel column chromatography (eluent; chloroform:methanol=95:5-80:20, NH2 type: eluent; chloroform:methanol=99:1-98:2) and then washed with ethyl acetate to obtain 5-[(2-aminopyridin-4-yl)oxy]-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (104 mg) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21]>C(O)(C)C>[CH3:22][C:19]([NH:18][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:16]=1)([CH3:23])[CH2:20][OH:21]
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: CC(C)(N)CO
Solvent: CC(C)O
Product: CC(C)(CO)Nc1nc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C

Procedure:
A mixture containing 12 g (0.05 mole) of 2 phenyl-4-chloroquinazoline, 4.5 g (0.05 mole) of 2-amino-2-methyl-1-propanol and 150 ml of isopropanol was refluxed for 4 hrs and filtered. The reaction mixture cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. The semi-solid residue was recrystallized with water to give 2.2 g of the title compound, m.p. 136°-138° C.
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:9])[CH3:8])[C:4](=O)[CH3:5])O.[NH2:10][CH:11](C(O)=O)[CH2:12][CH2:13][CH3:14]>C(O)CCC>[C:7]([C:3]1[NH:1][C:11]([CH2:12][CH2:13][CH3:14])=[N:10][C:4]=1[CH3:5])(=[O:9])[CH3:8]
Reactant: CCCC(N)C(=O)O
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: CCCCO
Product: CCCc1nc(C)c(C(C)=O)[nH]1
Yield: 48.5 %

Procedure:
To 40 g (0.309 moles) of 3-oximino-2,4-pentanedione dissolved in 200 ml of n-butanol was added 39.92 g (0.341 moles) of d,l-norvaline. The resulting mixture was brought to reflux, while stirring rapidly under nitrogen with an oil bath. After 19.3 h the reaction mixture was cooled, and then suction filtered. The residue was washed with ethyl acetate (100 ml) and the combined filtrates concentrated in vacuo. The resulting oil was dissolved in ethyl acetate (200 ml) and extracted with three 50 ml portions of 5% aqueous sodium hydroxide solution. Removal of the solvent in vacuo gave 0.15 moles (55.7% yield based on recovered d,l-norvaline) of 5-acetyl-4-methyl-2-propylimidazole.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC(C)C)(C)C.[CH:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(Br)C#C>CCCCCC.O1CCCC1>[CH2:3]([C:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]#[CH:1]
Reactant: [Li]CCCC
Reactant: O=C(O)C1CCCCC1
Agent: C#CCBr
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C#CCC1(C(=O)O)CCCCC1
Temperature: -20 °C

Procedure:
300 cm3 of dry tetrahydrofuran (THF) and 267 cm3 of 1.47 M solution of butyl-lithium in hexane were introduced into a 1 liter three-necked flask, which was kept under a nitrogen atmosphere. 40 g of anhydrous diisopropylamine and then 25.6 g (0.2 mole) of cyclohexylcarboxylic acid, dissolved in 50 cm3 of THF, were added to the mixture, which had been cooled to -20° C. The mixture was heated at 60° C. for 2 hours. 23.6 g of propargyl bromide were then added to the solution which had been cooled to -70° C. When the mixture had warmed to ambient temperature, it was concentrated under reduced pressure and the resulting product was taken up in water. The aqueous solution was washed with hexane and then treated with dilute hydrochloric acid. The expected 1-propargyl-1-cyclohexyl-carboxylic acid, which was in the form of a colourless liquid, was extracted with ether and then distilled in vacuo.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[CH:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:30]3[CH:31]=[N:32][N:33]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:34]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: CC(c1c(Cl)cccc1Cl)c1c[nH]c2ncc(Br)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(c1c(Cl)cccc1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Temperature: 100 °C

Procedure:
To a stirred mixture of 5-bromo-3-[1-(2,6-dichlorophenyl)ethyl]-1H-pyrrolo[2,3-b]-pyridine (10.00 mg, 0.027 mmol), 4-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine hydrochloride (11.00 mg, 0.035 mmol), potassium carbonate (15.00 mg, 0.11 mmol) in DME (2.0 mL) and H2O (0.40 mL) was added (1,1′-bis-(diphenylphosphino)ferrocene)palladium dichloride (0.84 mg, 0.0011 mmol) under nitrogen atmosphere. The resulting mixture was refluxed at 100° C. for 90 min. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography (eluent: 8% MeOH in DCM) to give desired product. 1H NMR (400 MHz, CD3OD): δ=1.92 (d, J=7.1 Hz, 3H), 1.98-2.21 (m, 4H), 2.76-2.91 (m, 2H), 3.19-3.32 (m, 2H), 4.30-4.44 (m, 1H), 5.27-5.40 (m, 1H), 7.20-7.51 (m, 5H), 7.59 (s, 1H), 7.89 (s, 1H), 8.34 (d, J=2.0 Hz, 1H). MS (ES+): m/z 440.06, 442.06 [MH+]. HPLC: tR=2.46 min (ZQ3, polar—5 min)
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([C:19]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[O:20])[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:18]=[C:17]([C:19]([N:21]4[CH2:26][CH2:25][N:24]([S:39]([C:35]5[CH:36]=[CH:37][CH:38]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:34]=5)(=[O:41])=[O:40])[CH2:23][CH2:22]4)=[O:20])[CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(c1cccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccc(S(=O)(=O)N2CCN(C(=O)c3cccc(-c4ccc(Oc5ccc(F)cc5)cc4)n3)CC2)c1
Yield: 84 %

Procedure:
According to the methodology described in Example 7, compound 6 (100 mg, 0.24 mmol), 3-methylsulfonylbenzenesulfonyl chloride (60 mg, 0.24 mmol), DIEA (0.1 mL, 0.7 mmol) and DCM (5 mL) were reacted to give compound 8 in 84% yield (LC/MS (m/z+H)=596; 1H NMR (CDCl3) δ ppm: 6.8-8.5 (m, 15H); 4.0 (m, 4H); 3.3 (m, 4H); 3.2 (s, 3H)).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:3]1=[O:25].Br[CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:27]([N:7]1[C:6]2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:3](=[O:25])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCBr
Reactant: CCOP(=O)(CCCCCn1c(=O)c2[nH]cnc2n(C)c1=O)OCC
Product: CCCCn1cnc2c1c(=O)n(CCCCCP(=O)(OCC)OCC)c(=O)n2C

Procedure:
The title substance was prepared from 0.008 mol of diethyl [5-(3-methyl-xanthin-1-yl)pentyl]phosphonate and 0.01 mol of 1-bromobutane analogously to Example 46.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9](N)=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1.N([O-])=[O:14].[Na+]>O.S(=O)(=O)(O)O.[Cl-].[Na+].O>[N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9]([OH:14])=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(-n2ncnn2)cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-n2ncnn2)cc1
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
A suspension of 4-tetrazol-2-yl-phenylamine (5.4 g) in water (42 ml ) and conc sulphuric acid (10 ml) was added slowly to a solution of sodium nitrite (2.3 g) in water (8.5 ml) at 5°. The resulting green solution was stirred at this temperature for ca. 30 min, treated with a mixture of water (50 ml) and conc. sulphuric acid (67 ml) and heated to 120° for 1 h. Water (170 ml) was added, the reaction mixture cooled, saturated with brine (100 ml) and extracted with dichloromethane (3×100 ml), dried (Na2SO4) and evaporated to give the title compound as an orange solid (1.6 g).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH:8]=[O:9].[C:10]([Mg]Br)([CH3:12])=[CH2:11].[Cl-].[NH4+]>C1COCC1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH:8]([OH:9])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)[Mg]Br
Reactant: O=CC1CC2CCC1C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)C(O)C1CC2CCC1C2
Temperature: 25 °C

Procedure:
Bicyclo[2.2.1]heptane-2-carbaldehyde (47 g, 378 mmol) in THF (25 ml) was added dropwise to isopropenylmagnesium bromide (0.5 molar in THF, 860 ml, 430 mmol) at −78° C. (slurry at this temperature) under nitrogen over 2 hours. The reaction was slowly warmed up to room temperature and stirred over the week-end. After cooling into an ice-water bath, a saturated aqueous ammonium chloride solution (500 ml) was added (slowly early on) to the reaction. The phases were vigorously stirred and separated. The organic phase was washed with more ammonium chloride solution (300 ml) and brine (300 ml). Each aqueous phase was re-extracted with diethyl ether (300 ml). Combined extracts were dried over sodium sulfate. The product was purified by fractional distillation through a 20-cm Widmer column.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH:15]=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH:17][NH2:18].CC([O-])=O.[Na+].C(OC(C)C)(=O)C>O.C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH:15]=[N:18][OH:17])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ncc(C=O)cc2C)ccn1
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)OC(C)C
Product: Cc1cc(-c2ncc(C=NO)cc2C)ccn1

Procedure:
To a 5-L four-necked flask equipped with an overhead stirrer, and a thermocouple was charged with 2′,3-dimethyl-[2,4′-bipyridine]-5-carbaldehyde (34d, 1120 mmol), hydrochloro hydroxyamine (34e, 140.1 g, 2016 mmol), and ethanol (1600 mL). The mixture was stirred at 23° C. for 2 h before the addition of NaOAc (183.8 g, 2240 mmol, 2 eq) and iso-propyl acetate (2 L)/water (2 L). The aqueous layer was back-extracted with iso-propyl acetate (2 L) after the layer separation. The combined organic layers were concentrated to almost dryness to afford the crude 2′,3-dimethyl-[2,4′-bipyridine]-5-carbaldehyde oxime (34f) as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[OH:28][CH2:29][CH2:30][CH2:31][NH:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1>CN(C=O)C>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:32]([CH2:31][CH2:30][CH2:29][OH:28])[CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:35][CH2:34]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCCO)CC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCO)C2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole with tert-butyl 4-[(3-hydroxypropyl)amino]-piperidine-1-carboxylate (Yokoyama et al., Bioorg. Med. Chem. 2008, 16, 7968) in DMF gave tert-butyl 4-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)amino]-1-piperidinecarboxylate: 1H NMR (DMSO-d6) (rotamers) δ 7.99 and 7.90 (2d, J=8.4, 8.5 Hz, 1H), 7.78 and 7.70 (2t, JHF=52.9, 52.3 Hz, 1H), 7.42 and 7.37 (2t, J=8.3 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.71-4.64 and 4.58-4.47 (2m, 2H), 4.13-4.04 (m, 2H), 3.98 and 3.97 (2s, 3H), 3.79 and 3.69 (2br m, 8H), 3.60-3.46 (m, 4H), 2.82-2.79 (m, 2H), 1.79-1.62 (m, 6H), 1.42 (br s, 9H); Anal. Calcd. for C24H40F2N8O5: C, 56.3; H, 6.5; N, 18.1. Found: C, 56.4; H, 6.7; N, 18.0%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[C:14](=N)(OCC)[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:15]([C:14]1[NH:12][C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[N:1]=1)[CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: CCCCC(=N)OCC
Agent: Cl
Product: CCCCc1nc2c(C(=O)OC)cccc2[nH]1
Yield: 87.3 %

Procedure:
Using the procedure of Step A of Example 1, 2.5 g of methyl 2,3-diaminobenzoate [J. Chem. Soc., Vol. 117 (1920) p 775 and CAN. J. Chem., Vol. 55 (1977), p. 1653 to 1657] and 2.73 g of ethyl pentanimidoate hydrochloride [J.A.C.S., Vol. 64, p. 1827 (1942)] were reacted to obtain 3.05 g of the desired product which after crystallization from essence G melted at approximately 85° C. The analytical sample was obtained by two successive crystallizations of 280 mg of product from isopropyl ether to obtain 100 mg of the product melting at 97° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C@H:5]1[CH2:8][C@@H:7]([OH:9])[CH2:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)([O-:32])=[O:31].C1(C)C=CC=CC=1>C1COCC1.N(C(OCC)=O)=NC(OCC)=O>[CH3:1][O:2][C:3]([CH2:4][C@H:5]1[CH2:8][C@H:7]([O:9][C:37](=[O:38])[C:36]2[CH:35]=[CH:34][C:33]([N+:30]([O-:32])=[O:31])=[CH:41][CH:40]=2)[CH2:6]1)=[O:10]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C[C@H]1C[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of cis-(3-hydroxy-cyclobutyl)-acetic acid methyl ester (570 mg, 3.96 mmol), triphenylphosphine (2.08 g, 7.92 mmol), and 4-nitrobenzoic acid (1.32 g, 7.92 mmol) in dry THF (50 mL), 40% diethyl azodicarboxylate in toluene (1.42 mL, 7.92 mmol) is added at room temperature. The mixture is stirred at room temperature for 15 hours. The solvent is removed under reduced pressure, and the obtained residue is purified by silica gel column chromatography to give trans-4-nitro-benzoic acid 3-methoxycarbonylmethyl-cyclobutyl ester (558 mg, 48%); TLC (hexane/AcOEt, 3:1) Rf 0.31, 1H NMR (400 MHz, chloroform-d) δ ppm 2.28-2.35 (m, 2H), 2.44-2.51 (m, 2H), 2.56 (d, 2H), 2.82-2.87 (m, 1H), 3.69 (s, 3H), 5.33-5.40 (m, 1H). 8.18-8.30 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH3:13]I>O>[CH3:13][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
To a suspension of p-nitrothiophenol (20 g, 0.129 mol) in water (150 mL) was added an aqueous solution of sodium hydroxide (75 mL, 2 N) at room temperature. After the mixture was stirred for 15 minutes and cooled to 10° C., methyl iodide (57 g, 25 mL, 0.401 mol) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The resulting mixture was extracted with diethyl ether (100 mL×3). The organic layers were combined, washed with water (200 mL) and brine (200 mL), dried over calcium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford 11 g of 1-(methylsulfanyl)-4-nitrobenzene as a yellow solid.
Reaction SMILES: [CH2:1]([C:19]([OH:62])([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]/[CH:52]=[CH:53]\[CH2:54]/[CH:55]=[CH:56]\[CH2:57][CH2:58][CH2:59][CH2:60]C)[CH:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:21][CH2:22]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[CH3:64][N:65]([CH3:72])[CH2:66][CH2:67][CH2:68][C:69]([OH:71])=[O:70].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:64][N:65]([CH3:72])[CH2:66][CH2:67][CH2:68][C:69]([O:71][CH2:22][CH2:21][CH:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:19]([OH:62])([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:70]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCCC(O)(CCCCCCCC/C=C\C/C=C\CCCCC)C(CCO)OCCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CN(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(CCOC(=O)CCCN(C)C)C(O)(CCCCCCCC/C=C\C/C=C\CCCCC)CCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 64 h
Yield: 74.8 %

Procedure:
To a solution of (14Z,17Z)-4-((9Z,12Z)-octadeca-9,12-dienyl)-3-((9Z,12Z)-octadeca-9,12-dienyloxy)tricosa-14,17-diene-1,4-diol (450 mg, 0.52 mmol), 4-(dimethylamino)butanoic acid hydrochloride (105 mg, 0.62 mmol), EDCI hydrochloride (120 mg, 0.62 mmol), DIPEA (225 μL, 1.3 mmol) in anhydrous dichloromethane (10 mL) was added DMAP (5 mg). The solution was stirred at room temperature under nitrogen for 64 hours. Upon completion, the solution was concentrated in vacuo to dryness and purified by column chromatography on silica gel 60 (eluted with 1:1 hexanes/Ethyl acetate) to afford (13Z,16Z)-4-hydroxy-4-((9Z,12Z)-octadeca-9,12-dienyl)-3-((9Z,12Z)-octadeca-9,12-dienyloxy)docosa-13,16-dienyl 4-(dimethylamino)butanoate as a colorless oil (375 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 5.43-5.29 (m, 12H), 4.31-4.11 (m, 2H), 3.60-5.29 (m, 2H), 3.27-3.22 (m, 1H), 2.78 (t, 6H, J=6.4 Hz), 2.39-2.28 (m, 3H), 2.24 (s, 6H), 2.09-2.02 (m, 12H), 1.91-1.72 (m, 4H), 1.61-1.23 (m, 60H), 0.90 (t, 9H, J=7.0 Hz).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][C:8]=1[CH3:15].[CH:16](=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[OH:26][CH:16]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][C:8]=1[CH3:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCC=O
Reactant: Cc1cc(CO)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCC(O)c1ccc(CO)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 8.3 mL, 20.7 mmol) was added dropwise to a solution of 4-bromo-3-methylbenzyl alcohol (1.90 g, 9.44 mmol, from Step A) in tetrahydrofuran (25 mL) at −78° C. After 1 h, n-decanal (2.95 g, 18.89 mmol) was added and the reaction allowed to warm to 0° C. After 30 min, the reaction was quenched with water (25 mL) and diluted with ethyl acetate (25 mL). The organic layer was washed with sat'd sodium chloride (30 mL), dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with 25% ethyl acetate/hexane gave 1.69 g (6.07 mmol, 64%) of product: 1H NMR (500 MHz): δ 7.45 (d, J=8.0 Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.14 (s, 1H), 4.88-4.94 (m, 1H), 4.64 (s, 2H), 2.34 (s, 3H), 1.22-1.80 (m, 16H), 0.87 (t, J=7.0 Hz, 3H).