Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCCC1=O.[C:8]([NH:12][C:13]1[C:22]([F:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15](F)[N:14]=1)([CH3:11])([CH3:10])[CH3:9].[CH3:25][C:26]([NH2:33])([CH3:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[C:8]([NH:12][C:13]1[C:22]([F:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([NH:33][C:26]([CH3:32])([CH3:25])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:14]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)c1cc(F)c(NC(C)(C)C)nc1F
Reactant: CC(C)(C)CC(C)(C)N
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(F)c(NC(C)(C)C)nc1NC(C)(C)CC(C)(C)C
Temperature: 140 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
To 7 ml N-methylpyrrolidone were added 2.44 g of methyl 6-t-butylamino-2,5-difluoronicotinate and 4.0 g of 1,1,3,3-tetramethylbutylamine, and the mixture was stirred at 140° C. for 16 hours and allowed to cool. After adding 50 ml of chloroform, the mixture was washed three times with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The brown oily residue was subjected to column chromatography (silica gel, 40 g; eluent: chloroform:n-hexane, 1:1) to obtain 2.90 g of the title compound as a colorless oily residue.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Cl:8][C:9]1[CH:16]=[CH:15]C(CCl)=[CH:11][CH:10]=1.CN([CH:20]=[O:21])C>>[Cl:8][C:9]1[CH:16]=[CH:15][C:2]([CH2:1][N:3]2[CH2:6][CH2:7][C:20](=[O:21])[CH2:5][CH2:4]2)=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: ClCc1ccc(Cl)cc1
Reactant: CN(C)C=O
Product: O=C1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-piperidine trifluoroacetate obtained from step (iv) (853 mg, 4.0 mmol) in DMF was added triethylamine (2.66 mL, 19.2 mmol), followed by 4-chlorobenzyl chloride (753 mg, 4.8 mmol) and the reaction mixture was stirred overnight at room temperature. The volatiles were removed in vacuo, residue was dissolved in ethylacetate, washed with water (H2O), organic layer was dried over sodium sulphate (Na2SO4), filtered and concentrated. The residue was purified by silica gel flash chromatography to give the subtitled compound (350 mg).
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]=[CH2:4].[CH3:17][C:18]([OH:22])(C)[CH:19]=C.C(OC)(=O)CC(C)=O>>[CH3:1][C:2]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:3][CH2:4][CH2:17][C:18](=[O:22])[CH3:19].[CH3:9][C:8](=[CH:7][CH2:6][CH2:5][C:2](=[O:16])[CH3:1])[CH3:15]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)C
Reactant: C=CC(C)(C)O
Agent: COC(=O)CC(C)=O
Product: CC(=O)CCC=C(C)C
Product: CC(=O)CCC=C(C)CCCC(C)CCCC(C)C
Temperature: 165 °C

Procedure:
A mixture of 637 g of 3,7,11-trimethyl-dodec-1-en-3-ol (86% pure), 8.6 g of Al isopropylate and 60 g of 3-methyl-but-1-en-3-ol was heated to 165° C. in the apparatus described in Example 12, and 471 g of methyl acetoacetate and 159 g of 3-methyl-but-1-en-3-ol were added dropwise in the course of 5 hours, whilst keeping the temperature at the 2nd theoretical plate of the column at about 90°-100° C. by appropriate adjustment of the reflux ratio. After a further 2 hours' reaction at 165° C., the mixture was worked up by distillation. 598 g of 6,10,14-trimethyl-pentadec-5-en-2-one and 161 g of 2-methyl-hept-2-en-6-one were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][N:6]=[CH:5]2.[Cl:12][C:13]1[S:14][C:15]([C:18](=O)[CH:19]=O)=[CH:16][CH:17]=1>C(O)C>[Cl:12][C:13]1[S:14][C:15]([C:18]2[CH:19]=[N:1][C:2]3[CH:3]=[C:4]4[CH:5]=[N:6][NH:7][C:8]4=[CH:9][C:10]=3[N:11]=2)=[CH:16][CH:17]=1.[Cl:12][C:13]1[S:14][C:15]([C:18]2[CH:19]=[N:11][C:10]3[CH:9]=[C:8]4[NH:7][N:6]=[CH:5][C:4]4=[CH:3][C:2]=3[N:1]=2)=[CH:16][CH:17]=1
Reactant: Nc1cc2cn[nH]c2cc1N
Reactant: O=CC(=O)c1ccc(Cl)s1
Solvent: CCO
Product: Clc1ccc(-c2cnc3cc4[nH]ncc4cc3n2)s1
Product: Clc1ccc(-c2cnc3cc4cn[nH]c4cc3n2)s1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a mixture of 5,6-diaminoindazole (0.5 g) in 30 ml absolute ethanol is added slowly a solution of 2-chloro-5-glyoxyloylthiophene (0.72 g) and 20 ml ethanol. The resulting mixture is stirred at room temperature for 4.5 hours. The yellow solid which forms is filtered off, washed with ethanol then with hexane and air dried overnight.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[C:4]([CH2:7][C:8]([OH:10])=[O:9])[CH:3]=1.[CH:11](OCC)(OCC)[O:12]CC.O>C(O)(C(F)(F)F)=O>[CH:11]([C:5]1[NH:6][C:2]([CH3:1])=[CH:3][C:4]=1[CH2:7][C:8]([OH:10])=[O:9])=[O:12]
Reactant: CCOC(OCC)OCC
Reactant: Cc1cc(CC(=O)O)c[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(CC(=O)O)c(C=O)[nH]1
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a solution of (5-methyl-1H-pyrrol-3-yl)-acetic acid (8.2 mmol) in TFA (6 mL) at 0° C. was added triethyl orthoformate (6 mL), it was then at 0° C. for 10 mins and at rt for 0.5 hours. The reaction was poured into water, extracted with ethyl acetate, dried and concentrated. The residue was purified on a silica gel column to give 1.15 g (84%) of (2-formyl-5-methyl-1H-pyrrol-3-yl) acetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([OH:21])=[O:20])[C:3]=1[Cl:22].C(C1NC=CN=1)(C1NC=CN=1)=O.C(=O)=O.[CH2:38](O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:20])[C:3]=1[Cl:22]
Reactant: OCc1ccccc1
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)O)c(Cl)c(N)c2F)c1F
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: O=C=O
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Cl)c(N)c2F)c1F
Temperature: 90 °C
Yield: 78 %

Procedure:
To a solution of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinic acid (prepared by the methods described in U.S. Pat. No. 7,314,849 B2; 100 milligrams (mg), 0.29 millimoles (mmol)) in tetrahydrofuran (THF; 1 milliliter (mL)) was added carbonyl diimidazole (51 mg, 0.32 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes (min) when carbon dioxide (CO2) evolution ceased. Benzyl alcohol (62 mg, 0.58 mmol) was added, and the reaction mixture was heated in a benchtop microwave at 90° C. for 20 min The reaction mixture was purified by silica gel chromatography (applied directly to an Isco 40 gram (g) RediSep® column eluting with 0-100% diethyl ether (Et2O) in hexanes) to yield a white solid (147 mg, 78%): mp 132-133° C., 1H NMR (400 MHz, DMSO-d6) δ 7.50-7.33 (m, 6H), 7.29 (dd, J=8.5, 7.1 Hz, 1H), 7.13 (s, 2H), 5.37 (s, 2H), 3.92 (s, 3H); ESIMS m/z 439 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:20]=[N:21][CH:22]=2)[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:6]([C:8]([OH:10])=O)[CH:7]=1.[CH3:23][C:24]1([CH3:32])[O:28][C@H:27]([CH2:29]NO)[CH2:26][O:25]1.CCN=C=NCCCN(C)C.C1C=CC2[N:52]([OH:53])N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:32][C:24]1([CH3:23])[O:28][C@@H:27]([CH2:29][O:53][NH:52][C:8]([C:6]2[CH:7]=[C:2]([F:1])[C:3]3[N:4]([CH:20]=[N:21][CH:22]=3)[C:5]=2[NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[O:10])[CH2:26][O:25]1
Reactant: O=C(O)c1cc(F)c2cncn2c1Nc1ccc(I)cc1F
Reactant: On1nnc2ccccc21
Reactant: CC1(C)OC[C@@H](CNO)O1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@H](CONC(=O)c2cc(F)c3cncn3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.1 %

Procedure:
8-Fluoro-5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (235 mg, 0.57 mmol), O—(((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (92 mg, 0.62 mmol), EDCI (120 mg, 0.62 mmol), HOBt (84 mg, 0.62 mmol) and DIPEA (0.1 mL, 0.62 mmol) were dissolved in DMF (10 mL) and the reaction mixture stirred at room temperature for 72 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried with MgSO4 and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (298 mg, 97%). LCMS (Method B): RT=3.34 min, [M+H]+=545.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70](=[O:72])[CH3:71])=[CH:66][C:65]=1[O:73][CH3:74]>>[C:70]([C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:65]([O:73][CH3:74])[CH:66]=1)(=[O:72])[CH3:71]
Reactant: COc1cc(C(C)=O)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 37.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.43 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.21 g, 0.89 mmol), then reacted with 1-(4-amino-3-methoxyphenyl)ethanone (Bionet) (0.11 g, 0.67 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-acetyl-2-methoxy-phenyl)-amide as a light yellow solid (Yield 0.098 g, 37%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH:18][C:19]2[C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][N:22]=[C:21]([Cl:30])[N:20]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.O>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH:18][C:19]2[C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=[C:21]([Cl:30])[N:20]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1NCC1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cnc(Cl)nc1NCC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.9 %

Procedure:
To a solution of ethyl 4-((1-(benzyloxycarbonyl)piperidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylate (808 mg, 1.86 mmol) in THF (10 mL), aq. 1N NaOH (10 mL, 10.0 mmol) was added. The mixture was stirred at room temperature for 18 h. It was acidified to pH 1-2 with 6N HCl. Water and EtOAc were added. The organic phase was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give 4-((1-(benzyloxycarbonyl)piperidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylic acid (745 mg).
Reaction SMILES: C([NH:8][CH2:9][C:10]#[C:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(OC(C)(C)C)=O.[ClH:22].O1CCOCC1>C1COCC1>[ClH:22].[NH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#CCN)cc1
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of methyl 4-(N-Boc-3-aminoprop-1-ynyl)benzoate (3.40 g, 11.7 mmol) in THF (25 ml) was added 4M HCl/dioxane (25 ml, 100 mmol). The reaction mixture was stirred for 1 h. The formed precipitate was collected, washed with diethyl ether (200 ml) and dried in vacuo providing methyl 4-(3-aminoprop-1-ynyl)benzoate hydrochloride (2.46 g) as white solid. Alternatively, the N-Boc protected amine can be dissolved in methanol instead of THF. In this case the solvent was removed in vacuo and the precipitate was washed with diethyl ether.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[NH:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>C1(C)C=CC=CC=1>[N:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH:20][C:16]=1[N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: NCC1CCN(c2nc3ccccc3[nH]2)CC1

Procedure:
45 g of 4-aminomethylpiperidine are placed 500 ml of anhydrous toluene in the presence of 55 g of potassium carbonate and of 50 g of 2-chlorobenzimidazole. The mixture is subjected to reflux overnight. Aver evaporation and crystallization of the oily residue, the expected product is obtained after washing with dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:18]=[CH2:19])[C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH:20]1([C:23]([CH:25]2[CH2:27][CH2:26]2)=O)[CH2:22][CH2:21]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:18]=[CH2:19])[C@@H:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[NH:10][CH:23]([CH:25]2[CH2:27][CH2:26]2)[CH:20]2[CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C1CC1)C1CC1
Reactant: C=C[C@H](c1cccc(Cl)c1)[C@H](N)c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C=C[C@H](c1cccc(Cl)c1)[C@H](NC(C1CC1)C1CC1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 2.0 g (6.84 mmol) of (1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine (Example 115, Step E), dicyclopropyl ketone (7.54 mL, 68.4 mmol), and acetic acid (1.96 mL, 34.2 mmol) in methanol (25.0 mL) was added sodium cyanoborohydride (1.44 mL, 27.4 mmol) at rt. The resulting mixture was stirred at 50° C. for 2 days. Acetic acid (1.5 ml) and sodium cyanoborohydride (0.6 g) were added again and heating was continued overnight. 200 ml of ethyl acetate was added, and the organic layer was washed consecutively with K2CO3 solution and sat. NaCl solution, dried over K2CO3, filtered and the filtrate was concentrated under reduced pressure at 60° C. The mixture was purified by flash chromatography on silica gel (eluent: DCM/MeOH, 95/5) to give the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1ccc(OC2CCNCC2)cc1

Procedure:
A solution of 46.0 g of 1-benzyl-4-(p-trifluoromethylphenoxy)piperidine, the free base of Part (a), in 250 ml. of 95% ethanol is treated with 6.0 g of 10% palladium-on-charcoal catalyst and is shaken with hydrogen gas at 50° C. until the theoretical amount of hydrogen is absorbed. The suspension is cooled, filtered, and the solvent is removed. The residual oil is fractionally distilled under reduced pressure and the fraction which boils at 74°-76° C/0.05 mm is collected. The collected oil crystallizes on standing to give a solid of 4-(p-trifluoromethylphenoxy)piperidine.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:14][CH2:15][C@@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C:18]([OH:20])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:29](I)[CH3:30]>O.CO>[CH2:7]([O:14][CH2:15][C@@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][C:18]([O:20][CH2:29][CH3:30])=[O:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of cesium carbonate (3.53 g, 10.9 mmol) in water (22 ml) was added to an ice-cooled solution of (3S)-4-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]butanoic acid (3.36 g, 10.9 mmol) in methanol (70 ml) and water (7 ml), and the reaction stirred for 20 minutes. The mixture was concentrated under reduced pressure and azeotroped with N,N-dimethylformamide and dichloromethane. The residual oil was dissolved in N,N-dimethylformamide (70 ml), ethyl iodide (1.64 g, 10.9 mmol) added, and the reaction stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure, suspended in ethyl acetate (300 ml), washed with water (4×), brine, then dried (MgSO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using hexane:ethyl acetate (85:15) to afford the title compound as a pale yellow oil, 2.86 g; 1H NMR (CDCl3, 400 MHz) δ: 1.26 (t, 3H), 1.45 (s, 9H), 2.65 (d, 2H), 3.58 (m, 2H), 4.17 (m, 3H), 4.55 (s, 2H), 5.20 (bs, 1H), 7.36 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[O:21].C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>O>[CH3:36][C:35]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[O:21])=[CH:18][C:17]=1[O:16][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][CH3:15])[N:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNc1cc(-c2cccnc2Cl)ncn1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(-c2cccnc2Oc2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc2C)ncn1
Temperature: 125 °C

Procedure:
[6-(2-Chloro-pyridin-3-yl)-pyrimidin-4-yl]-methyl-amine (55 mg, 0.25 mmol), 3-hydroxy-4-methyl-N-(3-trifluoromethyl-phenyl)-benzamide (81 mg, 0.27 mmol), Cs2CO3 (162 mg, 0.50 mmol) and DMSO (0.8 mL) were combined. The mixture was heated overnight at 125° C. in a sealed tube. The resulting mixture was cooled to RT, diluted with water and extracted with EtOAc. The aqueous layer was neutralized (pH˜7) with TFA and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield the title compound. MS m/z=480 [M+1]+. Calc'd for C25H20F3N5O2: 479.47.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]#[C:6][CH2:7][OH:8].[N:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])=[N+:10]=[N-:11].[CH3:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>C1COCC1.N1C=CC=CC=1>[CH3:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:1][CH2:2][C:3]#[C:4][C:5]#[C:6][CH2:7][O:8][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:9]=[N+:10]=[N-:11])=[O:23])=[O:37]
Reactant: [N-]=[N+]=NCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: OCC#CC#CCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)OCC#CC#CCOC(=O)CCCCCCCCCCN=[N+]=[N-]
Reaction time: 3 h
Yield: 39.9 %

Procedure:
In a glass reaction vessel, 400 milligrams (3.75 mmol) HOCH2C≡C—C≡CCH2OH prepared in Step 1, was dissolved in a mixture of 25 milliliters THF and 1 milliliters pyridine. To this stirred solution was added 1.0 gram (4.1 mmol) N3(CH2)10C(O)Cl prepared in Step 2, and 950 μL (4.1 mmol) CH3(CH2)10C(O)Cl. The resulting mixture was stirred for 3 h, concentrated, dissolved into hexanes and filtered to remove the salts. The filtrate was concentrated and purified using column chromatography eluting with 10% by volume of ethyl acetate in hexanes to yield 750 milligrams CH3(CH2)10C(O)OCH2C≡C—C≡CCH2OC(O)(CH2)10N3. In a glass reaction vessel, 280 milligrams (0.56 mmol) CH3(CH2)10C(O)OCH2C≡C—C≡CCH2OC(O)(CH2)10N3 was dissolved in 1 milliliters water and 8 milliliters THF. To this solution, 350 milligrams (1.3 mmol) triphenylphosphine was added. After 20 h of stirring, hydrogen chloride gas was bubbled through the mixture for 30 seconds. The resulting solid was filtered and washed with diethyl ether to yield 150 milligrams CH3(CH2)10C(O)OCH2C≡C—C≡CCH2OC(O)(CH2)10NH3Cl.
Reaction SMILES: Br[C:2]1[N:3]([CH3:20])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][N:6]2[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[Cl:19].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([Li])CCC.[CH3:40][CH2:41][CH2:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46]>O1CCCC1>[Cl:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[N:6]1[CH2:7][CH2:8][CH2:9][C:10]2=[C:2]([C:43]([OH:47])([CH2:44][CH2:45][CH3:46])[CH2:42][CH2:41][CH3:40])[N:3]([CH3:20])[N:4]=[C:5]12
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(Cl)c1
Reactant: CCCC(=O)CCC
Agent: [Li]CCCC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1CCOC1
Product: CCCC(O)(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
3-Bromo-7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (122 mg) and a crystal of 1,10-phenanthroline were dissolved in 3 mL of dry tetrahydrofuran and the solution was chilled to −78° C. under an atmosphere of argon. Then n-butyllithium (2.0 M in cyclohexane) was added until the dark color of the organolithium/phenanthroline complex persisted. An additional 0.17 mL of the butyllithium solution then was added. After 10 min, a solution of 4-heptanone (42.6 mg) in 1 mL tetrahydrofuran was added via syringe. The reaction mixture was allowed to stir at −78° C. for 15 min, then was allowed to warm to 0° C. After quenching with aqueous ammonium chloride, the reaction mixture was partitioned between ethyl acetate and brine. The ethyl acetate was dried with magnesium sulfate and concentrated on the rotary evaporator. The residue was chromatographed on silica gel eluting with 9:1 hexane/acetone to provide 76.0 mg of 4-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo-[3,4-b]pyridin-3-yl]heptan-4-ol, which was recrystallized from hexane, mp 129-130° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.[Li]CCCC.[C:12]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1C[O:29]CC1>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:29])([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: c1cocn1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: C1CCOC1
Agent: B
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ncco2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of oxazole (1 g, 14 mmol) in anhydrous THF (10 ml) was added borane. THF complex (14 ml, 1M in THF, 14 mmol) and the mixture stirred for 1 h, after which time the reaction was cooled to −78° C. and nBuLi (9 ml, 1.6 M in hexanes, 14 mmol) added dropwise and the reaction stirred for a further 1 h. A solution of Boc-piperidone (3.2g, 16 mmol) in THF (10 ml) is then added, the reaction stirred for a further 4 h at −78° C. before allowing the reaction to reach room temperature overnight. The solvent is then evaporated, the residue redissolved in EtOAc, washed with saturated ammonium chloride solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc:Heptane 3:7) affords the title product (1.9 g, 44%) as a colourless gum, contaminated with an unknown byproduct. MS: 269.2 (MH+)