Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[C@@H:3]1[NH:22][C:23]([C@@H:25]([O:27][C:28](=O)[O:29]C1C=CC([N+]([O-])=O)=CC=1)[CH3:26])=[O:24].[F:40][C:41]([F:48])([C:44]([F:47])([F:46])[F:45])[CH2:42][NH2:43]>ClCCl.C(OC(=O)C)C>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[C@@H:3]1[NH:22][C:23]([C@@H:25]([O:27][C:28](=[O:29])[NH:43][CH2:42][C:41]([F:48])([F:40])[C:44]([F:47])([F:46])[F:45])[CH3:26])=[O:24]
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](OC(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Yield: 86 %

Procedure:
0.065 g (0.12 mmol) carbonic acid 4-nitro-phenyl ester (S)-1-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester and 0.26 ml 2,2,3,3,3. pentafluoropropylamine were stirred at room temperature over night. Chromatography on silicagel with dichloromethane/ethylacetate (100-40/0-60) yielded 0.06 g (86%) (2,2,3,3,3-Pentafluoro-propyl)-carbamic acid (S)-1-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester as white foam, MS: m/e: 554.3 (M+H+), [α] 589=−4.40° (0.75% in CHCl3).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[CH:19]=[C:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:30]=1>>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[CH:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:36]([NH:35][C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)=[O:37])[CH2:22][CH2:21]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C(=C1CCNCC1)c1cccc(OCc2ccccc2)c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(OCc3ccccc3)c2)CC1
Yield: 94.8 %

Procedure:
Following the procedure in Example 1, Step 6, 4-(3-benzyloxy-benzylidene)-piperidine trifluoroacetate (550 mg, 1.4 mmol, from Step 3) and phenyl pyridin-3-ylcarbamate (331 mg, 1.55 mmol) were used to provide the title compound (530 mg). MS (APCI 10 V) AP+ 400.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.40-2.46 (m, 2H) 2.46-2.52 (m, 2H) 3.48-3.54 (m, 2H) 3.60-3.66 (m, 2H) 5.08 (s, 2H) 6.40 (s, 1H) 6.76-6.89 (m, 3H) 7.22 (t, J=8.09 Hz, 1H) 7.26-7.46 (m, 5H) 7.86-7.95 (m, J=8.36, 2.48, 1.45, 0.89 Hz, 1H) 8.16 (dd, J=4.81, 1.40 Hz, 1H) 8.58 (d, J=2.53 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]1[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(c3ccccc3)CCC2c2ccccc2C)c1
Solvent: CO
Product: Cc1ccccc1C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 64.7 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 3.5 g of methyl (2RS,5SR)-3-{3-{2-[2-(2-methylphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}phenylacetate in solution in 60 cm3 of methanol and 0.56 g of potassium hydroxide in solution in 11 cm3 of water, and after treatment and recrystallization in ethyl acetate, 2.2 g of (2RS,5SR)-3-{3-{2-[2-(2-methylphenyl)-5-phenyl-1-pyrrolidinyl]-2-oxoethyl}ureido}phenylacetic acid, melting at 133° C., are obtained.
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([C:27]([O:29]CC)=[O:28])[C:8]2[CH2:9][CH2:10][N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[C:12](=[O:17])[C:13]=2[C:14]=1[O:15][CH3:16])(=O)C.O.[OH-].[Li+].O.Cl>C(O)C>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[C:14]([O:15][CH3:16])[C:5](=[O:4])[NH:6][C:7]=2[C:27]([OH:29])=[O:28])[C:12]1=[O:17]
Reactant: CCOC(=O)c1nc(OC(C)=O)c(OC)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1c2c(c(C(=O)O)[nH]c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O

Procedure:
A mixture of ethyl 3-(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (217 g, 0.48 mol), lithium hydroxide monohydrate (70.7 g, 1.67 mol), and water (320 mL) in ethanol (1.8 L) was sonicated for 20 minutes. The reaction mixture was cooled in an ice-water bath and treated with hydrochloric acid (425 mL, 3 M). The resultant light yellow solid was filtered, washed successively with water (1 L), a 3:2 v/v mixture of water and ethanol (500 mL), MTBE (750 mL), and air dried. The yellow solid was dissolved in anhydrous DMF (700 mL) and concentrated under vacuum. The procedure was repeated twice to remove residual water. The yellow solid was triturated with MTBE, filtered, and stored under vacuum overnight to afford the title acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.C(#N)C.C[Si]([CH:20]=[N+:21]=[N-:22])(C)C.C(OCC)C>C1COCC1>[N+:21](=[CH:20][C:10](=[O:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[N-:22]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC#N
Product: COc1cccc(CC(=O)C=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under an argon atmosphere, 3-methoxyphenylacetyl chloride (81) (952 mg, 5.16 mmol) was dissolved in THF (2.5 mL) and acetonitrile (2.5 mL) and cooled to 0° C. To this was slowly added a solution of trimethylsilyldiazomethane in diethyl ether (2.0 M, 5.00 mL, 10.0 mmol), which was stirred overnight (15 hours) after warming up to room temperature. After concentrating under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/diethyl ether=3/2) to give 1-diazo-3-(3-methoxyphenyl)propan-2-one (82) as a pale yellow oily substance (650 mg, 3.42 mmol, 66.3%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.C([Li])CCC.[CH:20]([O:23][C:24]1[C:25](=O)[C:26](=[O:32])[C:27]=1[O:28]C(C)C)([CH3:22])[CH3:21]>O1CCCC1>[CH:20]([O:23][C:24]1[C:27](=[O:28])[C:26](=[O:32])[C:25]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([CH3:22])[CH3:21]
Reactant: Cc1ccc(-c2ccccc2Br)cc1
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 60.1 %

Procedure:
To a solution of 2-bromo-4'-methylbiphenyl (9.0 g; obtainable as described in Example 3 (a) and in Gomberg and Pernert, J. Am. Chem. Soc. (1926) Vol 48 p 1373) in tetrahydrofuran (60 ml) was added butyllithium (2.5M in hexanes, 15.3 ml) dropwise at -70° C. under a nitrogen atmosphere over a period of 3 minutes. The mixture was stirred for 10 minutes at -70° C. then added to a solution of 3,4-diisopropoxycyclobut-3-ene-1,2-dione (7.6 g) in tetrahydrofuran (100 ml) at -70° C. under nitrogen over a period of 1 minute. The solution obtained was stirred for an additional 30 minutes at -70° C. then quenched with trifluoroacetic anhydride (6.4 ml), followed by saturated aqueous ammonium chloride (40 ml). The resulting mixture was allowed to warm to ambient temperature, then partitioned between diethyl ether (300 ml) and aqueous sodium bicarbonate (5%, 300 ml). The aqueous layer was re-extracted with diethyl ether (200 ml) and the combined organic layers were washed with brine, dried over magnesium sulphate, and evaporated to give a yellow oily solid which was purified by flash chromatography on silica gel (eluting with 10% rising to 20% ethyl acetate in petroleum ether (b.p. 60°-80° C.)) to give the intermediate compound 3-isopropoxy-4-(4'-methylbiphenyl-2-yl)cyclobut-3-ene-1,2-dione as a yellow solid (6.7 g), substantially identical to the product of Example 1(b). The above method is described in Reed et al, Journal of Organic Chemistry (1988) Vol.53, p 2477.
Reaction SMILES: [ClH:1].N[C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[C:4]=1[C:13]([OH:15])=[O:14].Cl.N([O-])=O.[Na+]>O>[Cl:1][C:3]1[CH:12]=[CH:11][C:6]2[O:7][CH2:8][CH2:9][O:10][C:5]=2[C:4]=1[C:13]([OH:15])=[O:14]
Reactant: Nc1ccc2c(c1C(=O)O)OCCO2
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(Cl)ccc2c1OCCO2
Reaction time: 1 h
Yield: 74.4 %

Procedure:
58 g of 6-amino-1,4-benzodioxane-5-carboxylic acid hydrochloride and 116 ml of water were introduced in a 500 ml balloon flask provided with a stirrer, a thermometer and a dropping funnel. 28 ml of hydrochloric acid (d=1.18) were added and the mixture was cooled to a temperature of from 0°-5° C. A solution of 17.5 g of sodium nitrite in 38 ml of water was added at a temperature within the 0°-5° C. range. The mixture was stirred for one hour. 20 g of cuprous chloride and 75 ml of hydrochloric acid were added. The mixture was allowed to stand overnight and then filtered. The solid was washed with water, dried at 50° C. and purified by treatment with carbon black in alkaline solution (200 ml of water and 25 ml of 36° Be' caustic soda lye) and then 25 ml of hydrochloric acid was added. 40 g of 6 -chloro-1,4-benzodioxane-5-carboxylic acid were obtained (M.P. 162° C.; yield: 74%).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](SC)[N:14]=2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OOS([O-])=O.[K+].[NH2:28][CH2:29][CH2:30][N:31]1[C:35]([CH3:37])([CH3:36])[C:34](=[O:38])[NH:33][C:32]1=[O:39].C(N(C(C)C)CC)(C)C>CC(C)=O.O.CC(O)C>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:28][CH2:29][CH2:30][N:31]3[C:35]([CH3:36])([CH3:37])[C:34](=[O:38])[NH:33][C:32]3=[O:39])[N:14]=2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: CSc1ncc(Cl)c(-c2nnc(Cc3ccccc3)s2)n1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Cl)c(-c2nnc(Cc3ccccc3)s2)n1
Temperature: 170 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
4-(5-Benzyl-1,3,4-thiadiazol-2-yl)-5-chloro-2-(methylthio)pyrimidine (0.190 g, 0.57 mmols) was dissolved in 75 mL acetone. Oxone (1.05 g, 1.7 mmol) was dissolved in 75 mL H2O and added to the acetone solution. This mixture was allowed to stir for 5 h. The acetone was removed under vacuum, the resulting precipitate was obtained by filtration. LC/MS analysis indicates a mixture of both sulfoxide and sulfone. This solid mixture was dried briefly in a vacuum oven. This material was charged to a microwave reaction vessel along with 1-(2-aminoethyl)-5,5-dimethyl-imidazolidine-2,4-dione (0.194 g, 1.1 mmol) and diisopropyl ethylamine (0.20 mL, 1.1 mmol) and 15 mL IPA. This reaction was heated under microwave conditions to 170° C. for 1200 s. Upon cooling 0.236 g (90% yield) of product was obtained by filtration. MS (M+H)+ 458.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][C:3]=1[F:20].[C:21]([Si](C)(C)C)#[CH:22].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:21]([C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][C:3]=1[F:20])#[CH:22]
Reactant: C#C[Si](C)(C)C
Reactant: C[C@@H](COc1ccc(Br)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C#Cc1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
Under nitrogen, a mixture of tert-butyl [(1S)-2-(4-bromo-3-fluorophenoxy)-1-methylethyl]carbamate (23.3 g), ethynyl(trimethyl)silane (13.1 g), bis(triphenylphosphine)palladium(II) dichloride (4.70 g), cuprous iodide (1.27 g), triethylamine (14.0 mL), and toluene (20 mL) was stirred at 100° C. overnight. The precipitate was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (200 mL), and tetrabutylammonium fluoride (1.0 M solution in THF, 201 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hr. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and washed with hexane to give the title compound (12.2 g) as a light brown solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH2:2]2.[CH:8]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]2[CH2:15][OH:16].[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH:19]=[CH:18]1>>[C:1]12([CH2:15][OH:16])[CH2:7][CH:4]([CH2:3][CH2:2]1)[CH2:5][CH2:6]2.[CH:8]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[CH:10]=[CH:9]2.[C:20]1(=[O:21])[O:22][C:17](=[O:23])[CH:18]=[CH:19]1
Reactant: OCC1CC2CCC1C2
Agent: C1=CC2CCC1C2
Agent: O=C1C=CC(=O)O1
Product: OCC12CCC(CC1)C2

Procedure:
The obtained reaction product was a copolymer polymerized from 5-norbornene-2-norbornylmethanol and maleic anhydride, having a weight average molecular weight of 5,570 and a polydispersity of 1.95.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].CC(C)([O-])C.[K+].Cl[C:17]1[N:22]=[C:21]2[NH:23][N:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:20]2=[CH:19][CH:18]=1>>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[C:20]2[C:21](=[N:22][C:17]([O:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:18][CH:19]=2)[NH:23][N:24]=1
Reactant: Oc1ccc(F)cc1F
Reactant: Clc1ccc2c(-c3ccccc3Cl)n[nH]c2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Fc1ccc(Oc2ccc3c(-c4ccccc4Cl)n[nH]c3n2)c(F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.4 %

Procedure:
2,4-Difluorophenol (517 mg, 4 mmol) was placed in a 10 mL microwave reactor tube under nitrogen and cooled in an ice bath. Potassium t-butoxide (4 mL of 1.0 M solution in THF) was added dropwise, and the solution was stirred for five minutes at 0° C. The reaction mixture was warmed to room temperature, and 6-chloro-3-(2-chloro-phenyl)-1H-pyrazolo[3,4-b]pyridine (350 mg, 1.33 mmol) was added in one portion. The reaction was then heated to 160° C. via microwave for nine hours. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic phase was washed with brine, followed by water, and then dried over MgSO4. The solvent was removed under reduced pressure, and the residue was eluted through a FLASH column using 0.5% MeOH in methylene chloride. Solvent was removed, and the residue was recrystallized from methylene chloride/hexanes to afford 78 mg of 3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-b]pyridine as a white solid. Mass Spec. M+H=358.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26]>>[CH2:23]([NH:27][C:28]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:17])=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 9 from N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide and n-butylisocyanate. The analytical values are summarized in Table I.
Reaction SMILES: C([O:9][C@H:10]1[CH2:15][CH:14]=[CH:13][CH2:12][C@H:11]1[C:16](OC)=[O:17])(=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.O.[OH-].[Na+]>[OH:17][CH2:16][C@H:11]1[CH2:12][CH:13]=[CH:14][CH2:15][C@H:10]1[OH:9]
Reactant: COC(=O)[C@@H]1CC=CC[C@@H]1OC(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CC=CC[C@H]1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
Methyl cis-2-benzoyloxy-cyclohex-4-enecarboxylate (6, 1.1 g, 4.19 mmol) was dissolved in THF (10 ml), and the solution added to a dispersion of lithium aluminum hydride (0.35 g, 9.15 mmol) in THF (30 ml) at -78° C. The mixture was warmed to RT and stirred for 5 hours. The reaction mixture was then cooled to -15° C., and then diluted successively with water (0.35 ml), 15% NaOH (0.35 ml), and water (1.05 ml). The precipitate was removed by filtration, washed with EtOAc, and the solvent removed under vacuum. The residual oil was purified by chromatography on silica gel (EtOAc, Rf=0.28) to yield cis 2-hydroxymethylcyclohex-4-eneol (7, 419 mg, 78%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:9](=[O:11])[C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH3:12])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)cc1
Reactant: C[C@@H](C(=O)O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)Nc1ccc(Br)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (2R)-2-(4-fluorophenyl)propanoic acid (30.79 g) and 4-bromoaniline (30.0 g) in dimethylformamide (522 g) were added sodium bicarbonate (43.9 g) and HATU (99.5 g). The mixture was stirred at room temperature overnight. Then water (1000 g) was added followed by stirring at room temperature for 1 h. The precipitated solid was collected by filtration and washed with water (500 g) and dried by 50° C. in the vacuum overnight to give 52.59 g (93.6% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[OH:13]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-:13])=[CH:8][CH:7]=[CH:6]2
Reactant: OO
Reactant: COc1ccc2ncccc2c1
Solvent: CC(=O)O
Product: COc1ccc2c(ccc[n+]2[O-])c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
6-Methoxy quinoline (15 g, 0.094 mol) was dissolved in acetic acid (97 ml) and treated with hydrogen peroxide (37 ml). The mixture was stirred to 100° C. for 2 hours. After evaporation to dryness 100 ml of water was added to the residue until a precipitate appears. Filtration and washing with water gives a yellow precipitate that is dried under vacuum to yield 13.5 g of the title compound as a light yellow solid (82%). MS (m/e): 176.3 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH3:13][C:12]1[C:11]2[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=[CH:17][C:10]=2[O:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3ccccc3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)oc2cccc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Methyl-4-phenyl-benzofuran-2-carboxylic acid tert-butyl ester was dissolved in 2 mL of TFA/dichloromethane (1:1). The solution was stirred at room temperature for 3 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 66 mg of 3-methyl-4-phenyl-benzofuran-2-carboxylic acid as white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[N:8][C:7]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[C:29](N=C(N(C)C)N(C)C)([CH3:32])([CH3:31])[CH3:30].BrCC(C)C>C(#N)C>[CH:1]1([C:4]2[N:9]=[N:8][C:7]([N:10]([CH2:30][CH:29]([CH3:32])[CH3:31])[S:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:18][CH:19]=3)(=[O:12])=[O:13])=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C3CC3)nn2)cc1
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C3CC3)nn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.8 %

Procedure:
To a solution of N-(6-cyclopropylpyridazin-3-yl)-4-((3,5-dimethylisoxazol-4-yl)methoxy)benzenesulfonamide (51 mg, 0.127 mmol) in acetonitrile (0.1 mL) stirred at room temperature, was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.051 mL, 0.255 mmol). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.028 mL, 0.255 mmol) added. The reaction was then heated by microwaves to 150° C., for 30 minutes. After cooling the solvent was removed under a stream of nitrogen and the crude sample purified by mass directed autoprep (formic acid modifier) to give the title product (2.8 mg). LCMS (2 min, formic) Rt 1.21 min, m/z (ES+) 457 (M+H).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])=O)(C)(C)C.[OH:33][NH:34]C(C1C(COC(=O)C)CCCCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]=[CH:15][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:8]1[C:6](=[O:5])[NH:34][OH:33])[CH3:21]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)NO)cc1
Reactant: CCOC(=O)C=CC1CCCCN(S(=O)(=O)c2ccc(OC)cc2)C1C(=O)OC(C)(C)C
Product: CCOC(=O)C=CC1CCCCN(S(=O)(=O)c2ccc(OC)cc2)C1C(=O)NO

Procedure:
3-(2-Hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-azepan-3-yl)-acrylic acid ethyl ester was synthesized from 3-(2-Ethoxycarbonyl-vinyl)-1-(4-methoxybenzene sulfonyl)-azepane-2-carboxylic acid tert-butyl ester in the same manner as the procedures used for the preparation of Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-azepan-3-ylmethyl ester: MS (M+H)+ =427.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:17]=3[S:18][C:19]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:16]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:17]=3[S:18][C:19]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc2ccc(F)cc2c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2c(C(=O)O)sc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 91 (176 mg; 0.42 mmol) in acetonitrile (2 mL) was added aqueous sodium hydroxide (0.83 mL; 2N). The resulting mixture was stirred overnight at room temperature. The reaction mixture was acidified with aqueous hydrochloric acid (2N) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, decanted, and concentrated under reduced pressure. The desired product was obtained as fine needles from dichloromethane and hexanes as a greenish-yellow solid (137 mg).