Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([OH:19])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:30][N:31]1CCOC[CH2:32]1.CNC.C1COCC1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:30][N:31]([CH3:32])[C:17]([C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])=[O:19]
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 87 %

Procedure:
(2S)-1-{[(Phenylmethyl)oxy]carbonyl}-2-piperidinecarboxylic acid (2.0 g, 7.595 mmol) and HOBt (1.231 g, 9.114 mmol) were dissolved in CH2Cl2 (40 mL), and 4-methylmorpholine (2.5 mL, 22.78 mmol), 2.0 M solution of dimethyl amine in THF (4.55 mL, 9.114 mmol), and EDCI (1.750 g, 9.114 mmol) were added. This solution was stirred overnight, and was then washed with 1 N HCl (25 mL) and the aqueous layer was extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-100% ethyl acetate/hexanes) to provide phenylmethyl (2S)-2-[(dimethylamino)carbonyl]-1-piperidinecarboxylate (1.919 g, 87%). LCMS: (M+H)+: 291.1.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:26])[C:6]([C:27]([O:29]CC)=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(=O)C>C(O)C.[OH-].[K+].O>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:19]5[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CCN(C)CC4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CC1
Yield: 50.4 %

Procedure:
A suspension of 0.85 g of 1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-8-(4-methyl-1-pip-erazinyl)-4 -oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 12 cm3 of ethanol, 5 cm3 of 2 N aqueous potassium hydroxide solution and 7 cm3 of water is heated at a temperature close to 80° C. for 1 hour. After adding 5.8 cm3 of a 10% aqueous solution of acetic acid, the precipitate obtained is drained and washed with 3 times 5 cm3 of water. After recrystallizing twice from a mixture of 7.5 cm3 of ethanol and 7.5 cm3 of dimethylformamide each time, 0.4 g of 1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 250° C.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:8]=1N.N([O-])=O.[Na+].[OH-].[Na+].[C-:21]#[N:22]>O>[Cl:6][C:7]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:8]=1[C:21]#[N:22]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: [C-]#N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: N#Cc1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Conc. H2SO4 (1.365 L) and water (4.5 L) were charged into a suitable round bottom flak and the solution was cooled to 0° C. 2,3-Dichloroaniline (650 g, 4.012 moles) was added to the above solution and the reaction mixture was cooled and maintained at 0° C. A saturated solution of sodium nitrite (332.22 g, 4.815 moles) was added dropwise to the reaction while maintaining the temperature below 5° C. The reaction mixture was stirred at 0-5° C. for 1 hr and neutralised with sodium hydroxide at 0-5° C. The neutral solution was added dropwise to the cyanide solution [Cyanide solution obtained by mixing Cu(one)CN (365 g, 4.10 moles), NaCN (340 g 6.93 moles) and water (1.0 L)] at 65° C., under vigorous stirring for a period of 15 mins. The reaction mixture was warmed to 70° C. and stirred for another 15 mins. The 2,3-dichlorobenzonitrile so formed was extracted using ethylacetate (2.0 L). The organic layer was died over sodium sulfate and stripped to give a semi-solid mass of 2,3-dichlorobenzonitile (C6H3Cl2CN).
Reaction SMILES: C1(C(=O)CC(OC(C)(C)C)=O)CC1.[O-]CC.[Mg+2].[O-]CC.[CH3:21][C:22]1[C:30]([O:31][CH2:32][CH3:33])=[C:29]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].C(Cl)(=O)C([Cl:41])=O>C(OCC)C>[CH3:21][C:22]1[C:30]([O:31][CH2:32][CH3:33])=[C:29]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:28]=[CH:27][C:23]=1[C:24]([Cl:41])=[O:25]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: CC(C)(C)OC(=O)CC(=O)C1CC1
Agent: CC[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CCOc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 3-cyclopropyl-3-oxopropionate (9.2 g) in ethyl ether (200 mL) was added magnesium ethoxide (5.7 g). The reaction mixture was heated at reflux for 1 hour. After cooling back to room temperature, a solution of 2-methyl-3-ethoxy-4-methylsulfonylbenzoyl chloride (13.8 g), which was prepared from 2-methyl-3-ethoxy-4-methylsulfonylbenzoic acid (the preparation of which is described in U.S. Pat. No. 5,329,041 which is incorporated herein by reference) and oxalyl chloride, in ethyl ether (50 mL) was added over a period of 15 minutes. After stirring overnight at room temperature, the reaction mixture was poured over ice-water (100 mL), and the phases were separated. The ether layer was dried over magnesium sulfate and then concentrated in vacuo to afford 17 g of the crude product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=2)[CH:12]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]2
Reactant: COc1ccc2cc(-c3cc(F)c(OC)cc3F)ccc2c1
Agent: BrB(Br)Br
Product: Oc1ccc2cc(-c3cc(F)c(O)cc3F)ccc2c1

Procedure:
The title compound was prepared by 2-(2,5-difluoro-4-methoxyphenyl)-6-methoxynaphthalene (1.5 g, 5.0 mmol) with boron tribromide (25 mL of 1.0 M solution in CH2Cl2, 25 mmol) according to method D to yield 1.28 g (94%) of a yellowish solid: mp 217-219° C.; 1H NMR (DMSO-d6): δ 6.90 (1H, dd, J=11.87 Hz, J=7.51 Hz), 7.10-7.15 (2H, m), 7.45 (1H, dd, J=11.87, J=7.61 Hz), 7.53-7.55 (1H, m), 7.74 (1H, d, J=8.65 Hz), 7.92 (1H, s), 9.85 (1H, s), 10.50 (1H, s); MS (ESI) m/z271 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH2:13][CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:3]1=[O:23].[CH3:24][N:25]([CH:27](OC)OC)[CH3:26]>CN(C=O)C>[CH3:24][N:25]([CH3:27])[CH:26]=[CH:8][C:7]1[N:2]([CH3:1])[C:3](=[O:23])[N:4]([CH2:13][CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:5](=[O:12])[C:6]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1c([N+](=O)[O-])c(=O)n(CCCOC2CCCCO2)c(=O)n1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1c([N+](=O)[O-])c(=O)n(CCCOC2CCCCO2)c(=O)n1C
Temperature: 95 °C
Yield: 73 %

Procedure:
To a solution of 1,6-dimethyl-5-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrimidine-2,4(1H,3H)-dione (980 mg, 3 mmol) in DMF (2 mL) was added DMF-DMA (5 mL). The reaction was heated at 95° C. for 15 h, cooled to RT and concentrated to a residue which was dissolved in EA (20 mL). The mixture was washed with aq. 1N LiCl (3×10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (2:1) to give 6-(2-(dimethylamino)vinyl)-1-methyl-5-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl) pyrimidine-2,4(1H,3H)-dione (840 mg, 73% yield) as a yellow oil. LCMS: MH+ 383 and TR=1.308 min.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([NH2:12])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]#[N:23])=[O:16]>>[C:10]([C:5]12[CH2:4][CH2:3][C:2]([NH:1][CH2:14][C:15]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[C:22]#[N:23])=[O:16])([CH2:9][CH2:8]1)[CH2:7][CH2:6]2)(=[O:11])[NH2:12]
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Reactant: NC(=O)C12CCC(N)(CC1)CC2
Product: N#C[C@@H]1CCCN1C(=O)CNC12CCC(C(N)=O)(CC1)CC2
Yield: 59.5 %

Procedure:
Using 4-aminobicyclo[2.2.2]octane-1-carboxamide (50.0 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (56.9 mg), the same procedure was followed as in Example 1 to give (2S)-1-[[(4-carbamoylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (47.5 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:21]([O-])=O)=[C:12]([CH:20]=2)[CH:13]=[CH:14][C:15](OCC)=[O:16])[CH2:4][CH2:3]1>[Pd].C(O)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:20]=[C:12]3[C:11](=[CH:10][CH:9]=2)[NH:21][C:15](=[O:16])[CH2:14][CH2:13]3)[CH2:4][CH2:3]1
Reactant: CCOC(=O)C=Cc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1CCc2cc(N3CCC(O)CC3)ccc2N1
Temperature: 50 °C
Reaction time: 14 h
Yield: 47.5 %

Procedure:
A suspension of 5.2 g of ethyl 5-(4-hydroxypiperidino)-2-nitrocinnamate and 1 g of 5% palladium on carbon in 50 ml of acetic acid was stirred under a hydrogen atmosphere at 50° C. for 14 hr. The catalyst was filtrated off and the filtrate was concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography and recrystallized from ethanol to give 1.9 g of 6-(4-hydroxypiperidino)-3,4-dihydrocarbostyril.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=2[F:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:2].O1CCCC1>CO.[C].[Pd]>[CH2:28]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=2[F:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:29]
Reactant: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.3 %

Procedure:
To a solution of 1-(3-diethylaminopropyl)-3-[4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]urea (547 mg, 1.35 mmol) in methanol (40 ml)-tetrahydrofuran (20 ml) was added 10% palladium carbon (200 mg), followed by stirring under a hydrogen atmosphere at room temperature for 12 hrs. The catalyst was filtered and washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=10:1) to provide the titled compound (316 mg, 62.3%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[F:16].[OH-].[Na+].CCO.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[F:16]
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=O)Nc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Ethyl 2-(4-chloro-3-fluorophenylamino)-2-oxoacetate (4.18 g, 0.017 mol) to a solution of NaOH (1.361 g, 0.0340 mol) in mixture 50 ml EtOH and 50 ml water was added and the resulting mixture was stirred at RT for 6 h. The mixture was acidified with 2N HCl to pH 4-5 at 0° C. The precipitate was filtered, washed with water and dried on the air to afford 2-(4-chloro-3-fluorophenylamino)-2-oxoacetic acid (3′) (2 g, 55.2%) as a white solid. LC-MS (APCI+) m/z: calcd for C8H5ClFNO3: 216.99. found: 217 (M+H+).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:28]([O:33][CH2:34][CH3:35])(=[O:32])[C:29]#[C:30][CH3:31].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>O1CCCC1>[CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:30]([CH2:29][C:28]([O:33][CH2:34][CH3:35])=[O:32])[CH2:31][N:13]=1)=[CH:8]2
Reactant: CC#CC(=O)OCC
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccc4C(F)(F)F)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57 %

Procedure:
A mixture of 7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indole-2-carbothioamide (2.65 g), ethyl but-2-ynoate (1.5 mL), tributylphosphine (1.6 mL), toluene (30 mL) and tetrahydrofuran (20 mL) was stirred for 2.5 hr at room temperature. The reaction solution was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-4:6) to give the title compound (1.92 g, yield: 57%) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20]C=O)[S:18][CH:19]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH2:20])[S:18][CH:19]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.5 %

Procedure:
A mixture of 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (15.0 g) and conc. hydrochloric acid (9.5 g) in methanol (75 ml) was stirred at ambient temperature for 2.5 hours. Water (100 ml) was added to the reaction mixture and the solution was adjusted to pH 3.0 with 10% aqueous solution of sodium hydroxide under stirring. The precipitates were collected by filtration, washed with water and diisopropyl ether and dried to give 2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl) acetic acid (syn isomer) (12.7 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>O1CCCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:26]([NH:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=3)=[O:27])=[N:13][CH:14]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)nc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ambient solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.350 g, 1.59 mmol) in tetrahydrofuran (4 mL) was added 3-trifluoromethylphenyl isocyanate (1.59 mmol). The solution was stirred at room temperature for 1 hour and was then concentrated under reduced pressure. The solid was washed with diethyl ether (2 mL) and air-dried to give the title compound MS (ESI) m/z 408 [M+H]+.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]12[CH2:8][OH:9].[OH-:10].[Na+]>S(=O)(=O)(O)O.O1CCOCC1.O>[OH:10][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:1]
Reactant: [OH-]
Reactant: OCC12CCCCC1O2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCC1(O)CCCCC1O

Procedure:
A stirred mixture of 10.6 g of 1,2-epoxycyclohexanemethanol and 8 drops of concentrated sulfuric acid in 100 ml of p-dioxane and 100 ml of water was heated at 60°-70° for 18 hours. The reaction mixture was neutralized with sodium hydroxide, and evaporated under reduced pressure to a viscous residue. The residue was taken up in methanol and dried with sodium sulfate. The mixture was filtered and the filtrate evaporated under reduced pressure to a residue. The residue was distilled to give 10.8 g of 1,2-dihydroxycyclohexanemethanol; bp 170°-240°/0.02 mm. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]=[O:23].[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].CCN(CC)CC>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:17][CH2:18][O:19][Si:28]([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29])[CH3:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]=[O:23]
Reactant: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCO[Si](C)(C)C(C)(C)C)c1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.8 %

Procedure:
To a solution of 2-(4-bromo-3-formyl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile (9) (400 mg, 1.06 mmol) in THF (anhydrous, 30 mL) were added TBDMS-Cl (193 mg, 1.28 mmol) and Et3N (0.178 mL, 1.28 mmol). The solution was stirred at room temperature for 2 days. The solution was filtered and concentrated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 2.5%-20% EtOAc/hexanes gradient, to afford 420 mg (81% yield) of the title compound. 1H NMR 400 MHz (CDCl3) δ 10.4 (s, 1H), 7.83 (s, 1H), 7.76-7.68 (m, 2H), 7.40-7.33 (m, 1H), 6.30 (br s, 1H), 3.62 (br s, 2H), 3.48 (s, 2H), 3.02 (s, 3H), 0.89 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:27])=[CH:29][CH:30]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(C2CCOCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1sc(C2CCOCC2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.4 %

Procedure:
To a mixture of 4-({cyclohexyl[2-ethyl-5-(tetrahydro-2H-pyran-4-yl)thiophen-3-yl]methyl}amino)benzoic acid (250 mg) synthesized in Example 268 (5), ethyl 3-(methylamino)propanoate (92.1 mg), 1-hydroxybenzotriazole monohydrate (108 mg) and triethylamine (98 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate) to give a colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 4 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (160 mg, 53%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)([C:10]2[N:11]=[CH:12][N:13]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[OH:9])=[CH:4][C:3]=1F.[CH3:42][N:43](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C:8]([OH:9])([C:10]2[N:11]=[CH:12][N:13]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[C:5]2[CH:6]=[CH:7][C:2]([C:42]#[N:43])=[CH:3][CH:4]=2)=[CH:35][CH:36]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Br)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(O)(c2ccc(Cl)cc2)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(4-Bromo-3-fluoro-phenyl)-(4-chloro-phenyl)-(1-trityl-1H-imidazol-4-yl)-methanol (0.360 g, 0.578 mmol) and Zn(CN)2 (0.045 g, 0.405 mmol) was stirred in anhydrous DMF (8 mL). The solution was purged with Ar for 10 min, degassed under high vacuum for 5 min, then tetrakis(triphenylphosphine)palladium(0) (0.067 mg, 0.057 mmol) was added and the mixture stirred overnight at 80° C. under Ar. Subsequent additions of Zn(CN)2 and tetrakis(triphenylphosphine)palladium(0) were added to drive the reaction to completion. The reaction was diluted with EtOAc and extracted with satd. NaHCO3 solution, water and brine, dried (MgSO4), concentrated and purified using SiO2 chromatography (0.5% MeOH/CH2Cl2) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:13][CH3:14])=[CH:10]/[CH:11]=O)=[CH:5][CH:4]=1.[C:15]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH3:18])=[O:16]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:18][O:17][C:15](=[O:16])/[CH:19]=[CH:11]/[CH:10]=[C:9](/[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)\[CH2:13][CH3:14]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC/C(=C\C=O)c1ccc(OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1

Procedure:
As described in Example 99, (E)-3-(4-methoxyphenyl)-2-pentenal (7.1 g) was treated with (carbomethoxymethylene)triphenylphosphorane (14 g) in carbon tetrachloride (70 mL) and dichloromethane (15 mL) overnight at room temperature. The ester was isolated in the normal fashion to afford 8 g of (E,E)-5-(4-methoxyphenyl)-2,4-heptadienoic acid methyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:16][C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:17]([Cl:16])=[O:19]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Fc1cccc(Nc2ccccc2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N(c1ccccc1)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
2,3-Difluoro-N-phenylaniline (100 mg, 0.487 mmol) and triphosgene (159 mg, 0.536 mmol) were dissolved in CH2Cl2 (1 mL). The solution was cooled in an ice bath, and pyridine (79 μL, 0.975 mmol) was added slowly. Upon complete addition, the reaction was warmed to room temperature and stirred for 1 h. Then, it was cooled in an ice bath and quenched by the slow addition of H2O (1 mL). The reaction mixture was extracted with H2O (5 mL) and CH2Cl2 (5 mL). The aqueous layer was extracted again with CH2Cl2 (5 mL). The organic layers were combined and washed once with H2O (10 mL), dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to yield the title compound as a light brown oil (114.7 mg).