Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[C:18]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1.O>CN(C)C=O>[N:41]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[C:18]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:33][CH3:34])[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCCl)c(OC)cc12
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCn3ccnc3)c(OC)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Propyl 3-[7-(3-chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate (compound 325) (110 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare a solution. Potassium carbonate (317 mg) and imidazole (78 mg) were added to the solution, and the mixture was stirred at 60° C. overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (97 mg, yield 82%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:14]1[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])[CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 475 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 9.05-6.65 (m, 9H), 4.80-2.75 (m, 5H), 1.70-0.65 (m, 8H).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1[C@@H:36]1[CH2:46][CH2:45][C@@H:44]([O:47][Si:48]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[C@H:37]1O>O1CCCC1>[Cl:8][C@H:37]1[C:38]2[C:39](=[N:40][CH:41]=[CH:42][CH:43]=2)[C@H:44]([O:47][Si:48]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[CH2:45][CH2:46][C@H:36]1[C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[F:28]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](O)c2cccnc21)(C(C)C)C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@@H](Cl)c2cccnc21)(C(C)C)C(C)C
Reaction time: 0.08 h
Yield: 82.9 %

Procedure:
In an oven-dried 250 mL round-bottom flask was suspended NCS (0.751 g, 5.62 mmol) in tetrahydrofuran (15 mL). Triphenylphosphine (1.475 g, 5.62 mmol) was added. After stirring under nitrogen for 5 min, (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (1.007 g, 2.250 mmol) was added in one portion to the gray suspension. The resulting reddish suspension was stirred at room temperature. The solids gradually dissolved to give a tan solution. After 5 h, LCMS indicated complete conversion. Tetrahydrofuran was removed in vacuo and the remaining red oil was directly purified by ISCO (240 g silica column) up to 60% ethyl acetate/hexane. Pure ethyl acetate eluted the non polar component and the product was eluted by 10% methanol (with 2.0M NH4OH) in Methylene chloride. The product fractions were combined and re-purified by FCC up to 50% Ethyl acetate/hexane to afford the desired product as a colorless oil (869 mg, 83%).
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[C:7]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:8]=[CH:9][C:10]=2[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:5][C:4]1=[O:45]>[Ni].C(O)C>[C:31]1([CH2:30][CH2:29][O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:14]([CH2:13][CH2:12][C:10]2[CH:9]=[CH:8][C:7]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:6]3[C:11]=2[CH2:3][C:4](=[O:45])[NH:5]3)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CSC1C(=O)Nc2c(OCc3ccccc3)ccc(CCN(CCCCCCOCCc3ccccc3)Cc3ccccc3)c21
Agent: [Ni]
Solvent: CCO
Product: O=C1Cc2c(CCN(CCCCCCOCCc3ccccc3)Cc3ccccc3)ccc(OCc3ccccc3)c2N1

Procedure:
Raney nickel (1.5 g) was added to a solution of the compound from step d) (2.1 g) in dry ethanol (60 ml). The mixture was heated to reflux for 1 hour, the catalyst was removed by filtration and the filtrate evaporated under reduced pressure. Trituration with ether gave an off-white solid which was purified by reverse phase HPLC (SiO2) using methanol:chloroform as eluant. Recrystallisation from isopropyl alcohol gave the subtitled compound as a buff coloured solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: ClCCNCCCl
Reactant: Nc1ccc2c(c1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: c1cc2c(cc1N1CCNCC1)OCCO2
Yield: 30.3 %

Procedure:
A solution of 1,4-benzodioxan-6-amine (2.00 g, 13.2 mmol), bis-(2-choroethyl)amine hydrochloride (3.54 g, 19.8 mmol), and potassium carbonate (1.83 g, 13.2 mmol) in of 20 mL chlorobenzene is heated to reflux for 24 hours. The dark brown reaction mixture is then partitioned between 3N NaOH and methylene chloride. The organic layer is separated, dried over Mg2SO4, filtered and concentrated. Purification by flash column chromatography (8% methanol/methylene chloride on silica) provides 0.88 g (30%) of the desired 1-(1,4-benzodioxan-6-yl)piperazine as a white solid (m.p. 138° C., TLC Rf 0.37 with 10% methanol/methylene chloride).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][NH:17][C:16](=[O:19])[C:15]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)[CH2:23][CH2:24]N(C)C.C([Li])CCC.C(I)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([CH2:23][CH3:24])([CH3:20])[C:16]([OH:19])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)[nH][nH]c1=O
Reactant: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1(C)C(O)=NN=C1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 255 mg (0.9 mmol) of 1-tert-butoxycarbonyl-4-(4-methyl-(1H)-pyrazol-3-one-5-yl)piperidine (from Piperidine 15, Step C) and 0.155 mL (1.0 mmol) of freshly distilled tetramethylethylene diamine in 3 mL of THF at −78° C. was treated with 0.8 mL (2.0 mmol) of 2.5 M n-butyl lithium in hexanes (J. Med. Chem. 1996, 39, 3920–3928). After stirring for 15 minutes at −78° C., the reaction was warmed to 0° C. for 15 minutes. Upon recooling to −78° C., 0.11 mL (1.3 mmol) of ethyliodide was added. After warming to rt and stirring for 19 hours, the reaction was cooled to 0° C. and quenched with 1 N HCl. The reaction mixture was partitioned between 100 mL of EtOAc and 100 mL of 1 N HCl. After separating phases, the organic layer washed with 100 mL of brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 99:1 v/v CH2Cl2/MeOH, 98:2 v/v CH2Cl2/MeOH and 97:3 v/v CH2Cl2/MeOH as the gradient to afford the title compound as a white solid: RF: 0.40 (19:1 v/v CH2Cl2/MeOH); 1H-NMR (500 MHz) δ 0.73 (t, J=7.4, 3H), 1.26 (s, 3H), 1.47 (s, 9H), 1.59–1.85 (m, 6H), 2.38 (m, 1H), 2.76–2.81 (m, 2H), 4.16–4.21 (m, 2H), 8.61 (br s, 1H).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:15]2[N:19]([CH3:20])[N:18]=[C:17]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[N:16]=2)[CH:10]=[CH:11][C:12]=1[CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[OH:46]>O>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[C:17]1[N:16]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][O:46][C:37]3[CH:38]=[CH:39][C:40]([C:42]([F:43])([F:44])[F:45])=[CH:41][C:36]=3[F:35])=[C:7]([Cl:6])[CH:8]=2)[N:19]([CH3:20])[N:18]=1
Reactant: Oc1ccc(C(F)(F)F)cc1F
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(C(F)(F)F)cc2F)c(Cl)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
To 100 ml of N,N-dimethylformamide are added 5-(3-chloro-4-chloromethylphenyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (1.60 g) and potassium carbonate (0.60 g) and 2-fluoro-4-trifluoromethyl phenol (0.80 g) is added thereto at room temperature with stirring, which is stirred at 70° C. for 3 hours. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 1.62 g of desired compound (refractive index: 1.6010).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C1C=CC2N(O)N=[N:19]C=2C=1.N>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:19])=[O:7]
Reactant: COc1cccc(C(=O)O)c1C
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C(N)=O)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.5 %

Procedure:
3-Methoxy-2-methylbenzoic acid (5.0 g, 30 mmol) in CH2Cl2 (90 ml) and DMF (90 ml) was treated with HOBt (4.06 g, 30 mmol) and WSCDI (5.75 g, 30 mmol) and the resulting mixture stirred at RT for 20 min. After cooling to 0° C. ammonia (2H in EtOH, 30 ml, 60 mmol) was added and the mixture stirred for a further 2 h. The mixture was filtered, the solvent was removed from the filtrate. The crude material was taken up in CH2Cl2 and washed with water and brine and dried (Na2SO4), which gave a white solid (2.9 g) on isolation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(C(C)C)C(C)C)C.Cl[C:33]1[N:38]=[C:37]([S:39][C:40]#[N:41])[C:36]([N+:42]([O-:44])=[O:43])=[CH:35][N:34]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:20]([C:17]([C:13]1[CH:12]=[C:11]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:33]3[N:38]=[C:37]([S:39][C:40]#[N:41])[C:36]([N+:42]([O-:44])=[O:43])=[CH:35][N:34]=3)[CH:3]=2)=[O:22])[CH:16]=[CH:15][CH:14]=1)([CH3:19])[CH3:18])#[N:21]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
To a solution of N-(3-amino-4-methylphenyl)-3-(1-cyano-1-methylethyl)benzamide (1.00 g, 3.41 mmol) in tetrahydrofuran (15 mL) were added N-ethyl-N-isopropylpropane-2-amine (893 μL, 5.11 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (812 mg, 3.75 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (1.41 g, 88%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.Br[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C(OCC)(=O)C>C1COCC1>[O:3]1[CH2:8][CH2:7][CH:6]([O:9][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:5][CH2:4]1
Reactant: OC1CCOCC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(COC2CCOCC2)cc1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil; 490 mg, 12.2 mmol) in THF (10 mL) was added a solution of tetrahydro-2H-pyran-4-ol (1.20 g, 12.2 mmol) in THF (2 mL) at rt. The reaction mixture was stirred at it for several minutes and then heated to reflux for 15 min. After cooling to rt, 4-(bromomethyl)benzonitrile (2.00 g, 10.2 mmol) was added, and the reaction mixture was stirred at it over night. Ethyl acetate was added and the mixture was washed with water. The organic layer was dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 7:3) to afford the title compound (1.57 g, 71%): 1H NMR (400 MHz, CDCl3) δ 7.53 (d, 2H), 7.45 (d, 2H), 4.61 (s, 2H), 4.00-3.92 (m, 2H), 3.65-3.58 (m, 1H), 3.49-3.41 (m, 2H), 1.99-1.92 (m, 2H), 1.72-1.62 (m, 2H); ES-MS m/z 218, HPLC RT (Method D) 1.86 min.
Reaction SMILES: [Mg].II.Br[C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH3:10].[CH3:11][O:12][CH2:13][CH2:14][CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O.Cl>C(OCC)C.BrC1SC=CC=1C>[CH3:11][O:12][CH2:13][CH2:14][CH2:15][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccsc1Br
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: COCCCc1sccc1C
Temperature: 30 °C

Procedure:
Magnesium turnings (365 mg, 15.0 mmol, 1.5 equiv.) were suspended in 15 ml dry diethyl ether. A crystal of iodine and a few drops of 2-bromo-3-methylthiophene in 10 ml ether were added till the reaction started (3 min. with heating to 30° C.). The remaining solution of 2-bromo-3-methylthiophene (total 2.44 g, 10.0 mmol, 1.0 equiv.) was added dropwise to maintain the reaction at reflux. The reaction mixture was refluxed for 30 min. Toluene-4-sulfonic acid 3-methoxy-propyl ester (2.13 g, 12.0 mmol, 1.2 equiv.) dissolved in 5 ml diethyl ether was added dropwise and the yellow solution was refluxed again for 2 hours. The brown suspension was cooled, acidified with 1N HCl and extracted twice with ethyl acetate. The combined organics were washed with KHSO4/K2SO4 and brine, dried over Na2SO4, filtered, evaporated and chromatographed on a 50 g Silicagel cartridge with heptane and than MTBE-heptane 1:9 as solvent to give 2-(3-methoxy-propyl)-3-methyl-thiophene, 410 mg, m/e 170.0 (MH+) by GC/MS.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[CH3:20][NH:21][CH3:22]>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[N:21]([CH3:22])[CH3:20]
Reactant: Clc1cccc(Cl)c1Cn1cnc2c(Cl)ncnc21
Reactant: CNC
Solvent: CO
Product: CN(C)c1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Yield: 79 %

Procedure:
6-Chloro-9-(2,6-dichlorobenzyl)purine 627 mg, 2.2 g of 20% methanolic dimethylamine and 50 ml of methanol were treated in the same manner as Example 2. By the above procedure there was obtained 504 mg (yield 79%) of 9-(2,6-dichlorobenzyl)-6-dimethylaminopurine as colorless needles, m.p. 174°-175° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[C:10]([C:14]1[CH:15]=[C:16]([NH2:34])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)[CH:20]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>C1COCC1>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:34][C:16]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)[CH:20]=2)[N:18]=[C:14]([C:10]([CH3:12])([CH3:13])[CH3:11])[CH:15]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CN3CCC(F)(F)CC3)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CN3CCC(F)(F)CC3)c2)n1
Reaction time: 3 h
Yield: 72 %

Procedure:
2,2,2-Trichloroethyl chloroformate (0.077 mL, 0.57 mmol) was added to a solution of Intermediate 12c (200 mg, 0.57 mmol) and DIPEA (0.31 mL, 1.81 mmol) in THF (5 mL), and the mixture stirred for 3 h. The mixture was then partitioned between water (10 mL) and EtOAc (3×15 mL), and the combined organic extracts dried (Na2SO4). The solvent was evaporated and the residue triturated under pentane and filtered to give the title compound as a yellow solid (215 mg, 72%). LCMS (Method 1): Rt 2.89 min, m/z 523/525 [MH+]
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[O:8].[NH4+:9].[OH-]>O>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([NH2:9])=[O:1]
Reactant: [NH4+]
Reactant: O=CCCCCCO
Agent: [OH-]
Solvent: O
Product: NC(=O)CCCCCO
Temperature: 90 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
5.28 Grams (45 mmols) of 6-hydroxyhexanal was charged to a 100 milliliter Schlenk flask and dissolved in 10 milliliters of deionized water by heating to 85-95° C. in a water bath. The resulting solution was charged to the Parr autoclave containing 35 milliliters of NH4OH. The reactor was placed under 400 psi air, heated to 80° C. and a 500 psi air purge was established. Reaction was allowed to proceed for 3 hours. At that time, reaction conversion was virtually complete and 6-hydroxycaproamide was formed in 35% yield.
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:23]=[O:24].Cl>O.CO>[OH:24][CH2:23][C:19]1[CH:20]=[CH:21][C:16]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:17][C:18]=1[OH:22]
Reactant: C=O
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCc1ccc(CO)c(O)c1
Yield: 19.4 %

Procedure:
(2 1) 150 g of 3-pentadecylphenol and 17.7 g of paraformaldehyde were dispersed in 300 ml of water and 150 ml of methanol, and the dispersion was stirred at 50° C. for 12 hours. The reaction mixture was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 300 ml of hexane were added to the residue to precipitate a crystal. The crystal was recovered by filtration and dried to obtain 32 g of 2-hydroxymethyl-5-pentadecylphenol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:20][N:21]1[C:25]([CH3:26])=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1>>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:23]=[N:22]1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Product: Cc1c(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)cnn1C

Procedure:
The subtitled compound (804 mg) was prepared from tert-butyl 3-(3-bromophenethoxy)propanoate [Preparation 3, Step i)] and 1 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using a similar method to that described in Example 18, Step i). MS [M+H-C4H8]+=289 (MultiMode+) 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.33-7.26 (m, 1H), 7.21-7.18 (m, 2H), 7.12 (d, 1H), 3.84 (s, 3H), 3.69 (q, 4H), 2.91 (t, 2H), 2.49 (t, 2H), 2.38 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=O)[CH:3]=1.S(Cl)([Cl:15])=O>ClC(Cl)C>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([Cl:15])=[O:12])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)n1

Procedure:
A solution of 4,5,6-trichloropyridine-2-carboxylic acid (5.20 g, 23.1 mmol) and thionyl chloride (3.0 mL) in dichloroethane (30 mL) was refluxed until the evolved gas ceased. The reaction mixture was concentrated to give 4,5,6-trichloropyridine-2-carbonyl chloride (5.60 g, 23.0 mmol), mp 60-62° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:40]([CH2:41][CH3:42])=[CH:39][N:38]=[C:37]([CH3:43])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.[C:46](O)([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[CH2:41]([C:40]1[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:44])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([O:47][CH2:46][C:48]([F:51])([F:50])[F:49])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:36][C:37]([CH3:43])=[N:38][CH:39]=1)[CH3:42]
Reactant: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(C)cc1-c1cccc(C2=Nc3cc(OCC(F)(F)F)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from [2-{3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M134) (0.29 g, 0.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (220 mg, 93%).
Reaction SMILES: [CH2:1]([NH:5][C@H:6]([C:22]([OH:24])=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH:2]([CH3:4])[CH3:3].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.Cl>[CH2:1]([N:5]([C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:6]([C:22]([OH:24])=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C(=O)c1ccccc1)[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Nα-isobutyl-Nε-benzyloxycarbonyl-L-lysine (213 mg, 0.50 mmol) in CH2Cl2 (5 mL) was added benzoyl chloride (140 mg, 1.00 mmol) and DIEA (130 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 1 h and then diluted with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography. Elution with 70% EtOAc in hexane provided Nα-isobutyl-Nα-benzoyl-Nε-benzyloxycarbonyl-L-lysine that was further hydrogenolyzed using 10% Pd/C and then treated with 9-fluorenylmethyl chloroformate instead of N-(9-fluorenylmethoxycarbonyloxy) succinimide as outlined in step D of example 38 to provide the title compound (90% yield).