Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:32])([O:28][CH2:29][CH2:30]Br)([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2].[CH3:33][N:34]([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[P:1]([O-:32])([O:28][CH2:29][CH2:30][N+:34]([CH3:36])([CH3:35])[CH3:33])([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)OCCCOP(=O)([O-])OCCBr
Reactant: CN(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCNC(=O)OCCCOP(=O)([O-])OCC[N+](C)(C)C
Temperature: 60 °C

Procedure:
The entire amount of the phosphate ester obtained in Example 3 is dissolved in 70 ml of toluene containing 14 g of trimethylamine under anhydrous state and heated at 60° C. for 48 hours. The reaction mixture is concentrated to dryness under reduced pressure, and the residue is dissolved in 40 ml of methanol, vigorously stirred in the presence of 2.7 g of silver carbonate and heated under reflux for 1 hour. After filtration, the filtrate is evaporated to dryness, and the product is separated and purified by silica gel chromatography [eluent: chloroform-methanol-water (65:25:4)] and crystallized from chloroform-acetone. By this procedure is obtained 0.9 g of the above-indicated compound as colorless crystalline powder.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:12]1(=[O:26])[N:16]([CH2:17][C:18]([NH2:20])=[S:19])[C:15](=[O:21])[C:14]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:13]12>C(O)(C)C>[C:15]1(=[O:21])[N:16]([CH2:17][C:18]2[S:19][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:20]=2)[C:12](=[O:26])[C:13]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:14]12
Reactant: O=C1c2ccccc2CC1Br
Reactant: NC(=S)CN1C(=O)c2ccccc2C1=O
Solvent: CC(C)O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2c(s1)Cc1ccccc1-2
Yield: 50.3 %

Procedure:
In 100 ml of isopropanol, 1.64 g of 2-bromo-1-indanone was dissolved. Then, 2.0 g of phthalimidothioacetamide was added, followed by heating under reflux for 6 hours. The precipitate thus formed was collected by filtration and then distributed between chloroform and a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed successively with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was then evaporated, whereby 1.3 g of 2-phthalimidomethyl-8H-indeno[1,2-d]thiazole was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]3[C:14]([CH3:18])=[C:15]([CH3:17])[S:16][C:10]=3[N:9]([CH2:19][C:20]([O:22]CC)=[O:21])[C:8]2=[O:25])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[C:20]([CH2:19][N:9]1[C:10]2[S:16][C:15]([CH3:17])=[C:14]([CH3:18])[C:11]=2[C:12](=[O:13])[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=2)[C:8]1=[O:25])([OH:22])=[O:21]
Reactant: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)cc2)c(=O)c2c(C)c(C)sc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1sc2c(c1C)c(=O)n(Cc1ccc(Cl)cc1)c(=O)n2CC(=O)O
Yield: 61 %

Procedure:
A 0.7 g quantity of 3-(4-chlorobenzyl)-1-ethoxycarbonylmethyl-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H, 3H)-dione (Compound IV-1) prepared in Reference Example 5 was dissolved in 30 ml of methanol. To the solution was added 0.3 g of sodium hydroxide dissolved in 2 ml of water. The mixture was allowed to react at 60° C. for 30 minutes, and then the reaction mixture was concentrated. Diluted hydrochloric acid was added thereto with ice-cooling to acidify the resulting solution. The solution was filtrated and the separated crystals were recrystallized from methanol, giving 0.4 g of 1-carboxymethyl-3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H, 3H)-dione having m.p. of 173° to 176° C. in a yield of 61%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:10](OC(OCC)OCC)C>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:9]=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc(F)cnc1N
Solvent: O=CO
Product: Fc1cnc2[nH]cnc2c1
Temperature: 100 °C
Yield: 36 %

Procedure:
A stirred mixture of 5-fluoropyridine-2,3-diamine (1.13 g) from Step 1 of this Example, formic acid (0.5 mL), and triethylorthoformate (15 mL) was heated at 100° C. for 1 h. The reaction mixture was cooled to rt, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with 100% DCM to 10% MeOH in DCM to afford 6-fluoro-3H-imidazo[4,5-b]pyridine (760 mg, 36% over two steps) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 13.09 (br s, 1H), 8.49 (s, 1H), 8.37 (s, 1H), 7.97 (d, J=7.9 Hz, 1H). LCMS (ESI) m/z 138 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH:5]=[N:6][CH:7]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2N(C3C=CC=CC=3)C3C=CC=CC=3N=2)=[CH:26][CH:25]=1>>[CH:29]1[C:28]2[C:27](=[CH:30][CH:11]=[CH:10][CH:22]=2)[CH:26]=[CH:25][C:24]=1[C:26]1[C:25]2[C:24](=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:29]([C:2]2[CH:3]=[C:4]([C:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]4[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=4[N:9]=3)[CH:5]=[N:6][CH:7]=2)=[C:28]2[C:27]=1[CH:30]=[CH:14][CH:13]=[CH:18]2
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: Brc1cncc(-c2nc3ccccc3n2-c2ccccc2)c1
Product: c1ccc(-n2c(-c3cncc(-c4c5ccccc5c(-c5ccc6ccccc6c5)c5ccccc45)c3)nc3ccccc32)cc1

Procedure:
Almost the same procedure as step (2) in Synthesis Example 1 was carried out except that corresponding 2-(5-bromopyridine-3-yl)-1-phenyl-1H-benzimidazole was used instead of 2-(4-bromophenyl-phenyl-1H-benzimidazole, resultantly obtaining an aimed compound (Compound (4-6) (yield: 36%). As a result of MS analysis, it was recognized that m/e=573 for aimed substance's molecular weight of 573.22.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28]([O:30]C)=[O:29])[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28]([OH:30])=[O:29])[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CC(=O)CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC2CCC(=O)CC2C(=O)O)OC1(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.6 %

Procedure:
A solution of 4-benzyl-5-(2-methoxycarbonyl-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.81 g, 3.94 mmol) in dry tetrahydrofuran (24 ml) was treated with 1M aqueous lithium hydroxide solution (8 ml 7.88 mM). The resulting mixture was stirred at room temperature for 6 hours then diluted with ethyl acetate, washed with a 1:1 mixture of brine and 1 M hydrochloric acid, dried (anhydrous magnesium sulfate) and concentrated in vacuo to give 4-benzyl-5-(2-carboxy-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.66 g, 95%) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4].[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:10])[CH:9]=1)=[O:4]
Reactant: C[O-]
Reactant: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(I)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirred solution of 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl) ethanone (68 g, 201 mmol, 1.0 equivalent) in dry methanol (400 mL) under nitrogen, was added a solution of sodium methoxide in methanol (4.37 M, 54 mL, 235 mmol, 1.2 equivalents) over 10 minutes. The resulting mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the crude was then partitioned between water and tert-butylmethyl ether. The organic phase was separated, washed two times with water, saturated sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (48 g, 96%) as a colorless solid, that was used directly without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH2:8]([Mg]Br)[CH3:9].C(Br)C.[Mg].[Cl-].[NH4+]>C(OCC)C>[NH:2]=[C:1]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CC[Mg]Br
Reactant: COC(=O)CC#N
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Product: CCC(=N)CC(=O)OC

Procedure:
Methyl cyanoacetate (99 g.) was added to a stirred solution of ethyl magnesium bromide [prepared by the method well known in the art, from ethyl bromide (328 g.) and magnesium (71 g.)] in diethyl ether, at such a rate that vigorous reflux was maintained. The mixture was then heated at reflux for 40 hours and then treated with a saturated aqueous solution of ammonium chloride (3000 ml.). The ethereal layer was separated off and the aqueous layer was extracted with diethyl ether. The combined ethereal layers were dried over sodium sulphate, the solvent was removed in vacuo, and the residue distilled under reduced pressure to give methyl 3-iminovalerate (33 g.), b.p. 100°-120° C./20 mm Hg.
Reaction SMILES: [CH2:1]([C:14]1[CH:15]=[C:16](C(OC)=O)[NH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(O)CO.[OH-].[K+]>O>[CH2:1]([C:14]1[CH:15]=[CH:16][NH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCCCCCCCCCCCCc1cc[nH]c1
Temperature: 190 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
Into a mixture of 9.50 g (30.9 mmol) of methyl 4-tridecylpyrrole-2-carboxylate obtained in Synthesis Example 3,200 ml of ethylene glycol and 10 ml of water, was added 20 g of potassium hydroxide and the mixture was heated at 190° C. under stirring for 5 hours. After cooling, the mixture was added with water and extracted with ethyl acetate. The organic layer was collected, washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by a silica-gel column chromatography (eluent: ethyl acetate/hexane=1/5) to obtain 7.50 g of 3-tridecylpyrrole. The yield was 97% and the melting point was 32.5° to 33.5° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>>[CH2:49]([O:48][C:46](=[O:47])[CH2:45][NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:42])([CH3:41])[CH3:43])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:6][CH2:7]1)[CH3:50]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CNC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 146, (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with ethyl bromoacetate (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O4 [(M+H)+] 708.3078, observed 708.3076.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[C:9]=1[C:17]([OH:19])=O.CC[N:22](CC)CC>C(Cl)Cl>[Br:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[C:9]=1[C:17]([NH2:22])=[O:19]
Reactant: O=C(O)c1c(Br)ccc2c1OCO2
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1c(Br)ccc2c1OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (6.13 mmol) was added to a solution of the acid (5-bromobenzo[1,3]dioxole-4-carboxylic acid) (3.25 mmol) in anhyd CH2Cl2 (30 ml) and the stirred mixture was refluxed for 2 h. Then the mixture was concentrated to dryness under reduced pressure. To this residue was added a solution of amine from step g (2.45 mmol) in anhyd CH2Cl2 (15 ml) and anhyd Et3N (3.67 mmol) and the mixture was stirred overnight at room temperature. The mixture was concentrated to dryness and diluted with CH2Cl2, then washed with 10% HCl, aq NaHCO3 solution and brine. The residue was dissolved in chloroform and subjected to flash chromatography to provide 5-bromobenzo[1,3]dioxole-4-carboxamide), N-(5-(biphenyl[1,1′]-4-yl)-6,7-dimethoxynaphthalen-1-yl) (1H NMR (CDCl3) δ 3.66 (s, 3H), 4.04 (s, 3H), 6.16 (s, 2H), 7.47-7.50 (m, 10H), 7.70-7-74 (m, 6H)).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][C:15]=1[O:23][CH3:24].[CH2:25]1[O:35][C:34]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=2[O:26]1>>[O:35]1[C:34]2[CH:33]=[CH:32][C:29](/[CH:30]=[C:20](/[C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:15]([O:23][CH3:24])[CH:16]=3)\[C:21]#[N:22])=[CH:28][C:27]=2[O:26][CH2:25]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1cc(CC#N)ccc1OCCCCCCCCCCCO
Product: COc1cc(/C(C#N)=C/c2ccc3c(c2)OCO3)ccc1OCCCCCCCCCCCO
Yield: 72 %

Procedure:
(2Z)-3-(1,3-benzodioxol-5-yl)-2-{4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}prop-2-enenitrile is prepared starting from {4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}acetonitrile and commercial 3,4-(methylenedioxy)benzaldehyde according the same procedure following for example 1 in 72% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: C1COCC1.[OH-].[Na+].C([O:10][C:11](=[O:46])[C:12]([CH3:45])=[CH:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21](=[O:43])[NH:22][C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([O:40][CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:29]=3[F:42])[N:27]=2)=[CH:16][C:15]=1[F:44])C.Cl>CO>[F:44][C:15]1[CH:16]=[C:17]([C:21](=[O:43])[NH:22][C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([O:40][CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:29]=3[F:42])[N:27]=2)[CH:18]=[C:19]([F:20])[C:14]=1[CH:13]=[C:12]([CH3:45])[C:11]([OH:46])=[O:10]
Reactant: CCCCCC(OC)c1cccc(-c2csc(NC(=O)c3cc(F)c(C=C(C)C(=O)OCC)c(F)c3)n2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCC(OC)c1cccc(-c2csc(NC(=O)c3cc(F)c(C=C(C)C(=O)O)c(F)c3)n2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a mixture of THF (2 mL), methanol (2 mL), and 2N sodium hydroxide aqueous solution of 3-(2,6-difluoro-4-{4-[2-fluoro-3-(1-methyloxyhexyl)phenyl]thiazol-2-ylcarbamoyl}phenyl}-2-methylacrylic acid ethyl ester (500 mg) was stirred at room temperature for 3 h. The reaction mixture was acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate to obtain the compoumd (B1) 370 mg.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1.[CH3:19][O:20][C:21](Cl)=[O:22]>CN(C=O)C>[CH3:19][O:20][C:21]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:22]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Yield: 85 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3-adamantanediol and 12 mmole of pyridine were dissolved in 10 mL of DMF. To the mixture, 11 mmole of methoxycarbonyl chloride was added dropwise with stirring at room temperature. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3-adamantanediol was 99% and 1-methoxycarbonyloxy-3-adamantanol (yield 85%) was formed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:23][C:22]1[CH:21]=[CH:20][C:4]([O:5][C:6]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=3)=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:25]=1[F:24]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CNc1cc(-c2cccnc2Oc2ccc(Cl)c(N)c2)ccn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CNc1cc(-c2cccnc2Oc2ccc(Cl)c(NC(=O)c3cc(C(F)(F)F)ccc3F)c2)ccn1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
In a sealed tube, [2-(3-Amino-4-chloro-phenoxy)-[3,4′]bipyridinyl-2′-yl]-methyl-amine (300 mg, 0.918 mmol) and 2-Fluoro-5-trifluoromethyl-benzoyl chloride (0.180 mL, 1.19 mmol) were dissolved in 2.0 mL chloroform. The solution was heated to 75° C. and stirred for 48 h. The reaction was then cooled to RT, quenched with triethylamine (0.128 mL, 0.918 mmol), and concentrated in vacuo to yield the title compound as a crude light yellow solid. MS m/z (M+H)+=517; Calc'd 516.87 for C25H17ClF4N4O2.
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:7][C:6]=1[OH:21])=[O:4].C(Cl)(Cl)Cl.CO>CO>[CH:3]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7][C:6]=1[OH:21])=[O:4]
Reactant: CCOC(=O)CCCCOc1ccc(C=O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=Cc1ccc(OCCCCC(=O)O)cc1O
Yield: 97.7 %

Procedure:
2 N aqueous NaOH (10 mL) was added to ethyl 5-(4-formyl-3-hydroxyphenoxy)valerate (1.5 g, mw 266.3, 5.8 mmol; prepared as in Example 16) dissolved in methanol (20 mL) and the solution stirred at 25° C. for 1 hour, at which point TLC (CHCl3 -methanol, 99:1) indicated the reaction was complete. Methanol was removed under reduced pressure and the reaction diluted with water (50 mL), washed with ethyl acetate (3×15 mL, discarded), acidified to pH 4 with 6 N aqueous HCl, and extracted with ethyl acetate (4×25 mL). The combined organic extracts were washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated to yield 1.35 g (98%) of a white solid. A portion of the solid was purified by flash chromatography on silica (CHCl3 -methanol, 45:1) and recrystallized from boiling ethyl acetate-hexane to provide NMR and TLC (Rf origin) pure title product; 1H NMR (500 MHz, CDCl3, 294 K) δ 11.47 (s), 9.71 (s), 7.42 (d, J=8.6; 1H), 6.53 (dd, J=2.3, 8.6; 1H), 6.41 (d, J=2.3; 1H), 4.04 (t, J=5.8; 2H), 2.46 (t, J=7.0; 2H), 1.86 (m; 4H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)[CH2:6][CH2:5]1
Reactant: N#Cc1ccc(N2CCN(CCO)CC2)cc1C(F)(F)F
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(N2CCN(CCBr)CC2)cc1C(F)(F)F
Reaction time: 1.5 h
Yield: 50.6 %

Procedure:
To a solution of alcohol 30a (35 mg, 0.12 mmol) in dichloromethane (4 mL) at 0° C. were added potassium carbonate (71 mg, 0.51 mmol), triphenylphosphine (88 mg, 0.34 mmol), and carbon tetrabromide (112 mg, 0.35 mmol). The solution was allowed to return at room temperature and was stirred for 90 min. The resulting solution was diluted with dichloromethane (25 mL), washed with a 10% sodium bicarbonate solution and filtered over a cotton plug. Purification of the resulting crude product by flash chromatography using ethyl acetate/hexane (7:3) as an eluant gave the desired compound 31a (22 mg, 60%). 1H NMR (400 MHz, Acetone-d6) δ: 2.71 (t, 4H, J=5.12 Hz), 2.82 (m, 2H), 3.56 (m, 6H), 7.27 (dd, 1H, J1=6.23 Hz, J2=2.61 Hz), 7.35 (d, 1H, J=2.53 Hz), 7.78 (d, 1H, J=8.84 Hz).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[CH3:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=1>C(O)C>[CH3:9][C:10]1[N:15]=[C:14]([C:16]([NH2:17])=[O:2])[CH:13]=[C:12]([C:18]([F:21])([F:19])[F:20])[CH:11]=1
Reactant: Cc1cc(C(F)(F)F)cc(C#N)n1
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)cc(C(N)=O)n1
Reaction time: 12 h
Yield: 84.3 %

Procedure:
To 10 ml of ethanol were added 0.86 g of sodium bicarbonate and 0.71 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.8 g of 6-methyl-4-trifluoromethylpyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 12 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.74 g of 6-methyl-4-trifluoromethylpyridine-2-carboxamide=oxime.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].C(O)(C)C>O1CCCC1>[CH3:3][CH:2]([CH2:4][C:5]([OH:7])=[O:6])[C:1]([OH:9])=[O:8]
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(CC(=O)O)C(=O)O
Temperature: 85 °C

Procedure:
In a 20 ml-volume Schlenk's tube were charged 65.0 mg (0.5 mmole) of itaconic acid and 14.91 mg (0.01 mmole) of [RuH((-)-BINAP)2 ]PF6, and 2.5 ml of tetrahydrofuran (THF) and 2.5 ml (32.7 mmole) of isopropyl alcohol were added thereto. The mixture was heated at reflux in an oil bath at 85° C. for 24 hours. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 20 ml of a 1M sodium hydroxide aqueous solution and washed three times with each 10 ml portions of chloroform. The aqueous layer was adjusted to a pH of 1 with concentrated hydrochloric acid and then extracted three times with each 10 ml portions of diethyl ether. The combined ether layer was dried over magnesium sulfate, and the solvent was removed to give 47 to 60 mg of methylsuccinic acid as a white solid.