Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]#[C:11][C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:18])([CH3:17])[CH:9]=[C:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C#CCC(C)(C)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C=C=CC(=O)O)c1ccc(Cl)cc1

Procedure:
16 g of the product of Step B is dissolved in a minimum amount of ethanol and the solution added to 96 ml of 20% aqueous sodium hydroxide. Under a nitrogen atmosphere, the mixture is heated to 110° for 6 hours while permitting most of the ethanol to distill off. After cooling, the mixture is acidified to PH2 with conc. hydrochloric acid, the title product recovered by filtration, and refined by crystallization from petroleum ether, m.p. 64° - 67°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][N:9]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:11]=1[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH:11]1[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccsc2)CN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1c1ccsc1
Temperature: 40 °C
Yield: 71 %

Procedure:
A solution of the product from step b) (6.69 g, 20.4 mmol) was dissolved in EtOH (37 ml) and treated with 10% Pd/C (Wet Degussa type, 13.4 g) and heated to 40° C. for 2 days under H2 (1 atm). Next, the Pd/C was removed by filtration through celite, replaced with fresh 10% Pd/C (13.4 g) and the reaction was continued for two more days. The Pd/C was removed by filtration through celite and the EtOH was evaporated in vacuo to provide the subtitle compound (4.78 g, 71%). MS calculated for C19H23NO2S+H 330, observed 330.
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][C@H:9]1[CH2:14][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C@H:12]([CH3:23])[CH2:11][N:10]1[C@H:24]([C:32]1[CH:44]=[CH:43][C:35]([C:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1.CI>CCCCC>[CH3:8][C@H:9]1[CH2:14][N:13]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C@H:12]([CH3:23])[CH2:11][N:10]1[C@H:24]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:37])=[CH:43][CH:44]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:4])[CH:26]=1
Reactant: C1CCOC1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CI
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Sodium hydride (60% dispersion in oil, 400 mg (240 mg NaH, 10 mmol)) was washed with pentane (2×7 mL), then tetrahydrofuran (10 mL) added as supernatant. 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (Example 1, 1.007 g, 2.0 mmol) was dissolved in the stirred suspension, and when effervescence had subsided, methyl iodide (249 μL, 568 mg, 4 mmol) was added. The reaction mixture was sealed under nitrogen and stirred for 6 h at ambient temperature. The reaction mixture was evaporated to dryness, and the residue partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was separated, the aqueous portion extracted with ethyl acetate (2×10 mL) and the combined organic extracts dried over anhydrous sodium sulfate. The organic solution was evaporated to a pale yellow gum, which on trituration and sonication with pentane yielded 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide as a flocculent white solid (0.798 g, 77% after drying at room temperature and 5 mm Hg). Calc. for C32H40FN3O2 0.25 H2O: C, 73.60; H, 7.82; N, 8.05; F, 3.64. Found C, 73.58; H, 7.70; N, 8.04; F, 3.84%. 1H NMR (CDCl3, 300 MHz); δ 1.09 (d, J=6.2 Hz, 6H, superimposed on br m, 3H); 1.21 (br m, 3H); 1.99 (m, 2H); 2.57 (br m, 2H); 2.66 (m, 3H); 3.15 (d, J=13.3 Hz, 1H); 3.27 (br m, 2H); 3.54 (br m, 2H); 3.78 (s, 3H); 3.84 (d, J=13 Hz, 1H); 5.10 (s, 1H); 6.76 (s, 1H); 6.70 (d, J=8.1 Hz, 2H); 6.96 (t, J=8.2 Hz, 2H); 7.26 (m, 5H); 7.46 (d, J=7.8 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])[CH2:6][CH2:5]2.C[Si](C)(C)[O:15][C:16](O)(O)[CH2:17][CH2:18]O[Si](C)(C)C>C(Cl)Cl>[CH2:16]1[O:15][C:7]2([CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[CH2:8]2)[O:12][CH:17]1[CH3:18]
Reactant: C[Si](C)(C)OCCC(O)(O)O[Si](C)(C)C
Reactant: O=C1CCc2cc(Br)ccc2C1
Solvent: ClCCl
Product: CC1COC2(CCc3cc(Br)ccc3C2)O1

Procedure:
The ketone group of the tetralone is first protected as a ketal. Preferably, ketalization is afforded by slowly adding 1,3-bis-trimethylsilyloxy propandiol to a solution of trifluromethanesulfonate in methylene chloride. Temperatures from about -70° C. to about -60° C. are employed using standard cooling procedures. For example, 6-bromo-2-tetralone is slowly added to a solution of 1,3-bis-trimethylsilyloxy propandiol and trifluromethanesulfonate in methylene chloride to yield 6-bromo-2-tetralone propylene ketal.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:6].C([C:28]1[C:29]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)#N>>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:2]([NH:1][C:39]3[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:29]=4[N:35]=[CH:36][N:37]=3)[CH:3]=2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Oc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Oc3ccc(O)cc3)ncnc2n1
Yield: 49 %

Procedure:
The product of Example 37C was reacted with the product of Example 9B using the procedure of Example 37D substituting the product of Example 9B for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (42 mg, 49%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.66 (s, 3 H) 6.75 (d, J=8.82 Hz, 2 H) 6.89 (t, J=8.27 Hz, 3 H) 7.53 (d, J=8.82 Hz, 3 H) 7.75 (d, J=9.19 Hz, 2 H) 7.86 (dd, J=8.64, 1.65 Hz, 1 H) 8.18 (d, J=1.47 Hz, 1 H) 8.61 (s, 1 H) 8.77 (d, J=8.46 Hz, 1 H) 9.39 (s, 1 H) 10.00 (s, 1 H) 10.30 (s, 1 H); MS (ESI+) m/z 542/544 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].Cl>C(Cl)Cl>[CH3:15][S:16]([O:4][CH2:3][C@H:2]([CH3:1])[CH2:5][CH2:6][O:7][S:16]([CH3:15])(=[O:18])=[O:17])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO)CCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](CCOS(C)(=O)=O)COS(C)(=O)=O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-methylbutane-1,4-diol (30 g, 0.29 mol) in DCM (600 mL) was added triethylamine (100 mL, 0.72 mol). The solution was cooled to −20° C., and methanesulfonyl chloride (49 mL, 0.63 mol) was added dropwise over 30 min with vigorous stirring. The resulting mixture was stirred for additional 1 h while the temperature was maintained between −20 and −15° C. The mixture was allowed to warm to 0° C. and then poured into cold 1N HCl solution (100 mL). The organic layer was separated, and aqueous phase was extracted with DCM (100 mL). The combined organic extracts were washed with sat'd NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting product (75.9 g, quant) was used directly for the next step. 1H NMR (400 MHz, CDCl3): δ 4.41-4.24 (m, 2H), 4.12 (dq, 2H), 3.02 (d, 6H), 2.13 (td, 1H), 1.95 (td, 1H), 1.80-1.65 (m, 1H), 1.07 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][CH:21]([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[F:20][CH:21]([F:32])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:31])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(OC(F)F)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2ccc(OC(F)F)cc2)cc1

Procedure:
47.5 mg of solid white 3-{4-[3-(4-difluoromethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-difluoromethoxyphenyl isocyanate.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[S:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1.O[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[S:13]1[CH2:16][CH:15]([O:17][N:19]2[C:20](=[O:29])[C:21]3=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]3[C:23]2=[O:24])[CH2:14]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OC1CSC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CSC1
Temperature: 40 °C
Reaction time: 12 h
Yield: 38.5 %

Procedure:
Diethyl azodicarboxylate (4.3 g) was added all at once to a stirred mixture of 3-thietanol (2.0 g), N-hydroxyphthalimide (3.6 g) and triphenylphosphine (5.8 g) in dry tetrahydrofuran (100 ml) at room temperature. The temperature of the reaction mixture was raised to 40° C. The mixture became clear solution and was stirred for 12 hours at room temperature. Tetrahydrofuran was evaporated in vacuo and the residue was dissolved in ethyl acetate (50 ml). The insoluble substance was filtered off. The filtrate was washed three times with a saturated aqueous solution of sodium bicarbonate (50 ml) and with a saturated aqueous solution of sodium chloride (50 ml), dried over magnesium sulfate and evaporated. The residue was dissolved in methylene chloride (50 ml), subjected to column chromatography on silica gel and eluted with methylene chloride. The fractions containing the object compound were collected and evaporated in vacuo to give N-(3-thietanyloxy)phthalimide (2.0 g).
Reaction SMILES: S(N1CCC[C@@H]1C(Cl)=O)(C1C=CC(C)=CC=1)(=O)=O.[C:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27](C(=O)[C@H]3CCCN3S(C3C=CC(C)=CC=3)(=O)=O)[CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Agent: Cc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)Cl)cc1
Product: c1ccc(-c2c[nH]c3ccccc23)cc1
Temperature: -40 °C
Yield: 207.5 %

Procedure:
By following the procedure of Example 1 substantially faithfully while using N-tosyl-D-prolyl chloride in the place of benzoyl chloride and changing the reaction temperature during the course of cooling to -40° C., 3.88 g of 3-phenyl-1-(N-tosyl-D-prolyl)indole (48.2%) having a melting point of 148-149° C. was obtained from 3.50 g of 3-phenylindole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([C:11]2[N:12]=[N:13][NH:14][N:15]=2)[CH2:9][CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:37][CH3:38]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([C:11]2[N:12]=[N:13][N:14]([CH2:37][CH3:38])[N:15]=2)[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(c1ccc(Cl)cc1)(c1nn[nH]n1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1nnc(C(CC)(c2ccc(Cl)cc2)n2ccc3c(NS(C)(=O)=O)cccc32)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of the product from Step B (65 mg, 0.151 mmol), K2CO3 (41.7 mg, 0.302 mmol) and iodoethane (30.8 mg 0.181 mmol) in DMF (1 mL) was stirred at 80° C. overnight. The volatile was evaporated. The residue was extracted with ethyl acetate (50 mL). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (5/1 to 1/1, v/v) to afford the title compound as a yellow solid. LC/MS m/z=459.0 [M+H]+.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C:16]([CH3:21])([CH2:19][OH:20])[CH2:17]O)[C:9]=2[N:10]=[CH:11][N:12]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>CCCCCC.C1COCC1>[Cl:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C:16]3([CH3:21])[CH2:19][O:20][CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CC(CO)(CO)n1ccc2c(Cl)ncnc21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(n2ccc3c(Cl)ncnc32)COC1
Temperature: -50 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
n-BuLi (6.6 mL of a 2.5 M solution in hexane, 16.5 mmol) was added to a solution of 2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropane-1,3-diol (Preparation 217, 3.63 g, 15.0 mmol), in THF (80 mL) at −78° C. The reaction mixture was allowed to warm to −50° C. in 2 hours and TsCl (3.15 mg, 16.5 mmol) in THF (20 mL) was added to the reaction. The reaction was allowed to warm to 0° C. in 3 hours and additional n-BuLi (6.6 mL of a 2.5 M solution in hexane solution, 16.5 mmol) was slowly added to the reaction mixture. The mixture was stirred for 1 hour at 0° C. and stirred at 60° C. for 16 hours. After cooling to room temperature, the reaction was quenched by 50 mL of saturated aqueous NH4Cl solution and 100 mL of water, and the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude residue was purified by column chromatogranhy on silica gel (gradient of EtOAc:heptane 20:80 to 70:30) to give a solid in 55% yield, 1.87 mg.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)(=[O:7])[CH3:6]>C1(C)C=CC=CC=1>[C:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:3])=[O:13])=[CH:10][CH:9]=1)(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C(=O)Cl)cc1

Procedure:
120 mmol of thionyl chloride are added to 600 mmol of 4-acetylbenzoic acid in 150 ml of toluene. The reaction mixture is heated at reflux for 3 hours and then cooled. The solvent is evaporated off. The product is used without any other treatment.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][O:6][CH:7]([O:12][CH3:13])[CH2:8][CH2:9][CH2:10]Cl.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:5][O:6][CH:7]([O:12][CH3:13])[CH2:8][CH2:9][CH2:10][N:1]1[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: COC(CCCCl)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCCN1CCC1)OC

Procedure:
A mixture of azetidine (2.0 g, 35.0 mmol), 4-chlorobutanal dimethylacetal (5.88 g, 39.0 mmol) and K2CO3 (5.38 g, 39.0 mmol), in anhydrous DMF (100ml), was stirred at room temperature for 72 h. Water (50 ml) was added and the mixture extracted with EtOAc (3×150 ml). The combined extracts were washed with H2O (3×50ml), dried (Na2SO4) and evaporated. The crude product was purified by distillation (1.2 g). δ (360 MHz, CDCl3) 1.35-1.42 (2H, m, CH2), 1.57-1.64 (2H, m, CH2), 2.00-2.40 (2H, m, CH2), 2.36 (2H, t, J=9.0 Hz, CH2), 3.15 (4H, m, t, J=7.0 Hz, 2 of CH2), 3.33 (6H, s, 2 of OMe), 4.35 (1H, t, J=5.7 Hz, CH).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[OH:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[NH:16][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: Nc1cccc(O)c1
Solvent: ClCCl
Product: Cc1cccc(Nc2cc(Nc3cccc(O)c3)ncn2)c1
Temperature: 140 °C
Yield: 39 %

Procedure:
A mixture of 4-chloro-6-(3'-methylanilino)pyrimidine (9.56 g) and 3-aminophenol (5.22 g) was stirred and heated at 140° C. for 3 hours. The product so obtained was dissolved in methylene chloride and a few drops of methanol, and chromatographed on silica using a mixture of methylene chloride and methanol, increasing in polarity from pure methylene chloride to a 19:1 mixture of methylene chloride and methanol as eluent. The product so obtained was recrystallised from a mixture of ethyl acetate and hexane to give 4-(3'-hydroxyanilino)-6-(3'-methylanilino)pyrimidine in 39% yield, m.p. 188°-189° C.;
Reaction SMILES: [F:1][C:2]([C:11]1[CH:12]=[CH:13][C:14]([O:19][CH3:20])=[C:15]([CH:18]=1)[CH:16]=O)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[ClH:21].Cl.FC1C=CC(C(F)(F)F)=CC=1C[NH:27][C@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][C@H:29]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[ClH:21].[ClH:21].[C:34]1([C@H:29]2[C@@H:28]([NH:27][CH2:16][C:15]3[CH:18]=[C:11]([C:2]([F:1])([C:3]([F:6])([F:5])[F:4])[C:7]([F:9])([F:8])[F:10])[CH:12]=[CH:13][C:14]=3[O:19][CH3:20])[CH2:33][CH2:32][CH2:31][NH:30]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Fc1ccc(C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C=O
Agent: Cl
Product: COc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 1 and Compound 17 in the same manner of Compound 2.
Reaction SMILES: CN(C)C=O.S([O:11][CH3:12])(OC)(=O)=O.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[NH:21][C:22]([NH:24][C:25](=[NH:28])[NH:26][CH3:27])=O.C(N(CC)CC)C.[CH3:36][S:37]([OH:40])(=[O:39])=[O:38]>C(#N)C>[CH3:36][S:37]([OH:40])(=[O:39])=[O:38].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[N:21]1[CH:22]=[N:24][C:25]([NH:26][CH3:27])=[N:28][C:12]1=[O:11]
Reactant: CNC(=N)NC(=O)Nc1c(C)cccc1C
Reactant: COS(=O)(=O)OC
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1
Temperature: 10 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To 29.2 grams (0.4 mole) of N,N-dimethylformamide, heated to 50°-60° C., are added dropwise 50.5 grams (0.4 mole) of dimethyl sulfate while maintaining the temperature between 50° and 60° C. After the addition, the reaction mixture is heated at 70°-80° C. for four hours. The reaction mixture is diluted with acetonitrile (150 milliliters) and cooled to approximately 10° C. in an ice water bath. Then 44.0 grams (0.2 mole) of 1-(2', 6'-dimethylphenyl)-3-methylamidinourea are added on one portion followed by the dropwise addition of 80.8 grams (0.8 mole) of triethylamine while keeping the temperature below 25° C. The reaction mixture is allowed to come to ambient temperature and stirred for one hour. The solvent is removed in vacuo and the residue diluted with water and the pH adjusted to 10 with ten percent (10%) aqueous sodium hydroxide. The aqueous layer is extracted with chloroform (3 times with 200 milliliters each time) and the combined extracts dried (MgSO4) and concentrated in vacuo. The residual solid is taken up in boiling acetonitrile (350 milliliters) and concentrated to approximately two-thirds of its volume on a steam bath. The hot solution is treated with 21.0 grams (0.22 mole) of methanesulfonic acid and on cooling a white crystalline solid deposits, which is filtered, washed with cold acetonitrile and vacuum dried at 80° C. for one hour to yield 60.6 grams (93%) of 1-(2', 6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one methanesulfonate, m.p. 264°-266° C. dec.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[O:26]1CCCC1>>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:1][CH2:2][CH2:3][OH:26])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (5 g, 12.5 mmol) in tetrahydrofuran (60 mL) was added BH3 THF (25 mL, 1 mol/L, 25 mmol) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Then NaOH (3 mol/L, 10 mL) and H2O2 (15 mL) were added to the above mixture. When the reaction was over, the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by column chromatography to give (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (2.5 g, 40%). 1H NMR: (400 MHz, CDCl3): δ=1.48 (t, 3H), 1.53 (m, 1H), 1.73 (m, 1H), 1.93-1.98 (m, 2H), 2.17-2.28 (m, 3H), 3.57 (t, 2H), 5.59 (m, 1H), 6.72 (m, 2H), 7.20 (m, 2H), 7.25-7.37 (m, 5H).
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>>[N:9]1([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Oc1cccnc1Br
Reactant: C1CCNC1
Agent: Cl
Product: Oc1cccnc1N1CCCC1
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
2-bromopyridin-3-ol (200 mg, 1.15 mmol) and pyrrolidine (184 mg, 2.58 mmol) were added in a reaction tube, followed by reacting in microwave at 120° C. for 20 minutes. The reaction mixture was added with 1 M HCl solution to neutralized, and extracted with ethyl acetate and dichloromethane. The obtained organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 2-(pyrrolidin-1-yl)pyridin-3-ol (78 mg, 41%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6](Cl)[C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)=[CH:2]1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:16][CH2:15]1.OC1CCN(C/C=C/COC2C=CC=CC=2[N+]([O-])=O)CC1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:18][CH2:19]2)=[CH:2]1
Reactant: O=[N+]([O-])c1ccccc1OC/C=C\CN1CCC(O)CC1
Reactant: ClC(c1ccsc1)c1ccsc1
Agent: O=[N+]([O-])c1ccccc1OC/C=C/CN1CCC(O)CC1
Product: O=[N+]([O-])c1ccccc1OC/C=C\CN1CCC(OC(c2ccsc2)c2ccsc2)CC1

Procedure:
The procedure of Example 39 (a) was repeated except for using di(3-thienyl)methyl chloride and 4-hydroxy-1-[4-(2-nitrophenoxy)-2(Z)-butenyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine to give oily 4-di(3-thienyl)methoxy-1-[4-(2-nitrophenoxy)-2(Z)-butenyl]piperidine.
Reaction SMILES: CN(CCO)C.[CH2:7]([Li:11])[CH2:8][CH2:9][CH3:10].[C:12]1([C:18]2C=CC=C[N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC>[Li:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:19]=1
Reactant: c1ccc(-c2ccccn2)cc1
Reactant: [Li]CCCC
Agent: CN(C)CCO
Solvent: CCCCCC
Product: [Li]c1cccc(-c2ccccc2)n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A hexane (70 ml) solution of N,N-dimethylaminoethanol (12.0 ml, 118.5 mmol) was dropwise added to a hexane solution of n-butyllithium (150 ml, 1.58 M, 237.0 mmol) at 5° C. while 30 minutes. Next, a hexane (10 ml) solution of 2-phenylpyridine (8.5 ml, 59.3 mmol) was dropwise added to the mixture at 5° C. while 20 minutes. A hexane solution of 2-lithio-6-phenylpyridine was prepared by the mixture stirred at 5° C. for 1 hour additionally.