Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([N:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][C:24]([OH:26])=[O:25])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:33][C:34]([NH2:36])=[NH:35])=[N:11][CH:10]=1.Cl.NC(N)=N.[C:42](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)C1C=CC=CC=1)([CH3:45])([CH3:44])[CH3:43]>COCCOC>[C:42]([O:25][C:24](=[O:26])[CH2:23][N:22]([S:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:33][C:34]([NH2:36])=[NH:35])=[CH:17][CH:16]=1)(=[O:20])=[O:21])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:45])([CH3:44])[CH3:43]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)c3ccccc3)cc12
Reactant: CC(C)(C)OC(=O)CN(c1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: N=C(N)N
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Product: CC(C)(C)OC(=O)CN(c1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 13.3 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-phenylglycine trifluoroacetate ##STR16## NaH (32 mg, 80% dispersion by wt in mineral oil, 1.07 mmol) was added in one portion to a stirred suspension of guanidine hydrochloride (164 mg, 1.71 mmol) in DME (5.0 mL) and the mixture was heated at 60° C. under N2 for 30 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-phenylglycine t-butyl ester (200 mg, 0.43 mmol) was added and the mixture heated at 95° C. for 6 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880N3 (97:3:0.3 to 95:5:0.5) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-phenylglycine t-butyl ester (28 mg, 0.057 mmol) as a yellow resin.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C@H:12]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([C:31]#[N:32])=[N:25][C:26]=3Cl)[O:14][C@@H:13]1[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:10])[CH3:9].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)[CH2:46][NH2:47])=[CH:41][CH:40]=1>C(#N)C>[C:8]([O:11][C@H:12]1[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([C:31]#[N:32])=[N:25][C:26]=3[NH:47][CH2:46][CH:45]([C:42]2[CH:43]=[CH:44][C:39]([Cl:38])=[CH:40][CH:41]=2)[C:48]2[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=2)[O:14][C@@H:13]1[CH2:33][O:34][C:35](=[O:37])[CH3:36])(=[O:10])[CH3:9]
Reactant: NCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 16 h
Yield: 91.7 %

Procedure:
Triethylamine (0.2 ml, 1.14 mmol) was added to a stirred solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (500 mg, 1.14 mmol) (Preparation 45) and 2,2-bis(4-chlorophenyl)ethanamine (919 mg, 1.2 mmol) (J. Am. Chem. Soc., 1983, 105 (10), 3138) in acetonitrile (5 ml) at room temperature. The reaction mixture was stirred for 16 hours. The solvent was then removed under reduced pressure and the residue was dissolved in dichloromethane (20 ml). The solution was washed with water (10 ml) and saturated sodium chloride solution (10 ml), dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:(99:1 by volume) increasing in polarity to dichloromethane:methanol (98.5:1.5 by volume). The solvent was removed under reduced pressure to give the title compound (698 mg) as a foam.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH:7]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:24])[N:16]([CH2:18][CH:19](OC)[O:20]C)[CH3:17])=[N:11][N:10]=2)[CH3:8])=[CH:4][CH:3]=1.Cl>O>[CH3:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH:7]([C:9]2[S:13][C:12]([N:14]3[CH:19]([OH:20])[CH2:18][N:16]([CH3:17])[C:15]3=[O:24])=[N:11][N:10]=2)[CH3:8])=[CH:4][CH:3]=1
Reactant: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccc(C)cc2)s1)OC
Agent: Cl
Solvent: O
Product: Cc1ccc(OC(C)c2nnc(N3C(=O)N(C)CC3O)s2)cc1
Yield: 104 %

Procedure:
A mixture containing 3.5 grams of the 3-[5-[1-(4-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-(2,2-dimethoxyethyl)urea (prepared above), 150 milliliters of water and 1.5 milliliters of concentrated hydrochloric acid (HCl) was refluxed for 25 minutes, then cooled with formation of an oil. The oil was extracted with chloroform, and the chloroform extract was dried over magnesium sulfate (MgSO4), filtered and topped on a roto-vac at 70° C. to yield 3.2 grams of an orange oil. It was dissolved in diethylether and heated with formation of crystals which were filtered off and dried in a vacuum oven at 70° C. to 1.8 grams of ivory crystals of [5-[1-(4-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-4-hydroxy-2-imidazolidinone, (melting point 126°-128° C.).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]Cl>[I-].[Na+]>[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: ClCc1ccccn1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccn2)CCCC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.4 %

Procedure:
A 0° C. suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (1.50 g, 6.17 mmol), potassium carbonate (2.60 g, 18.8 mmol), and catalytic amount of sodium iodide (ca. 10 mg), was treated with 2-picolyl chloride hydrochloride (1.10 g, 6.70 mmol). The cold bath was removed and the reaction stirred at ambient temperature 72 hours. The reaction was poured into H2O (100 mL) and the mixture extracted four times with ethyl acetate. The combined organic layers were washed four times with H2O, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (elution with 70% then 80% then 85% EtOAc in hexanes) to afford 1.70 g (82%) of the 9-[(2-pyridyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as an oil which solidified on standing. 1H NMR (CDCl3) δ 8.52 (br s, 1H), 7.54-7.47 (m, 1H), 7.34-7.26 (m, 2H), 7.18-7.11 (m, 2H), 6.67 (d, J=7.8 Hz, 1H), 5.34 (s, 2H), 3.99 (s, 3H), 2.87 (t, 2H, J=6.0 Hz), 2.50 (t, 2H, J=6.3 Hz), and 2.20-2.13 (m, 2H). IR (CHCl3, cm−1) 3010, 2953, 1725, 1654, 1463, 1446, 1288 and 1121. MS (ES) m/e 335 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[N+:10]1([O-:20])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>O>[N+:6]([C:13]1[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[N+:10]([O-:20])=[CH:11][CH:12]=1)([O-:9])=[O:7]
Reactant: [O-][n+]1cccc2c1CCCC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])c2c1CCCC2
Temperature: 25 °C

Procedure:
A stirred mixture of sulphuric acid (200 ml) and nitric acid (200 ml) was treated with 5,6,7,8-tetrahydroquinoline N-oxide (47 g, 315 mmol), heated at 60°-80° for 3h, cooled to room temperature, poured onto ice (1 Kg), diluted with water (1 1), and extracted with dichloromethane (3×500 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give the product (48 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH:13]2[CH2:18][C:17]3([C:26]4[C:21](=[CH:22][C:23](Br)=[CH:24][CH:25]=4)[NH:20][CH2:19]3)[CH2:16][CH2:15][N:14]2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)#[N:39].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.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:1][C:2]1[CH:3]=[C:4]([N:9]([CH:13]2[CH2:18][C:17]3([C:26]4[C:21](=[CH:22][C:23]([C:44]5[CH:43]=[CH:42][CH:41]=[C:40]([C:38]#[N:39])[CH:45]=5)=[CH:24][CH:25]=4)[NH:20][CH2:19]3)[CH2:16][CH2:15][N:14]2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC(=O)N(c1ccc(F)c(Cl)c1)C1CC2(CCN1C(=O)OCc1ccccc1)CNc1cc(Br)ccc12
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1cccc(-c2ccc3c(c2)NCC32CCN(C(=O)OCc3ccccc3)C(N(C(N)=O)c3ccc(F)c(Cl)c3)C2)c1
Temperature: 90 °C
Yield: 35.9 %

Procedure:
To a solution of crude 1-(3-chloro-4-fluorophenyl)ureido-6-bromo-1′-benzyloxycarbonyl-spiro[indoline-3,4′-piperidine] (˜0.27 mmol) and Pd(PPh3)4 (0.011 g, 0.030 mmol, 10 mol %) in degassed toluene (5 mL) was added a solution of 3-cyanophenylboronic acid (0.067 g, 0.46 mmol, 1.7 eq.), aqueous Na2CO3 (2.5 mL of a 2N solution, 5 mmol), and EtOH (2.5 mL). The resulting mixture was heated at 90° C. for 16 h then partitioned between EtOAc (20 mL) and 10% aqueous NaHCO3 (20 mL). The organic phase was separated and washed with 10% aqueous NaHCO3 (3×10 mL) and saturated brine (10 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude residue was purified by flash column chromatography by eluting 10-20% EtOAc/hexane to give 1-(3-chloro-4-fluorophenyl)ureido-6-(3-cyanophenyl)-1′-benzyloxycarbonyl-spiro[indoline-3,4′-piperidine] as a yellowish oil (0.057 g, 0.097 mmol, 36%). 1H NMR (300 MHz, CD3OD): δ 7.23 to 8.31 (m, 15H), 5.27 (s, 2H), 4.32 (d, 2H), 4.21 (s, 2H), 3.17 (m, 2H), 1.98 (m, 2H), 1.82 (m, 2H).
Reaction SMILES: [C:1](=[O:3])=[O:2].C([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=O.C(OC)(=O)CCCCC([O-])=O>>[CH3:6][CH:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:1]([OH:3])=[O:2]
Reactant: O=C=O
Reactant: COC(=O)CCCCC=O
Agent: COC(=O)CCCCC(=O)[O-]
Product: CC(CCC(=O)O)C(=O)O
Yield: 96 %

Procedure:
The cleavage in stage (c) is advantageously carried out in the presence of molecular oxygen or a gas which contains molecular oxygen and an inert gas, such as nitrogen, carbon dioxide, argon or steam. A molar ratio of formylvaleric esters to molecular oxygen of from 1:0.05 to 1:3, in particular from 1:0.2 to 1:1.5, e.g., from 1:0.25 to 1:1.25, is advantageously used. This increases the catalyst life and in particular the yield of pentenoic esters. The presence of molecular oxygen was not indicated since methyl 5-formylvalerate is oxidized to monomethyl adipate in a yield of 96% by molecular oxygen at as low as 50° C., as disclosed in European Patent 131,860, and it was therefore to be expected that 4- and 3-formylvaleric esters would be oxidized in a similar manner to give 2-methylglutaric acid and 3-ethylsuccinic esters.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[CH2:19][O:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:12])=[CH:6][CH:5]=1.[CH:27](O)=O.[OH-].[Na+]>C=O.O>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:27])[CH2:15][CH:14]2[CH2:19][O:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=CO
Reactant: O=C(Nc1ccc(Cl)cc1)N1CCNCC1COc1cccnc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1CCN(C(=O)Nc2ccc(Cl)cc2)C(COc2cccnc2)C1
Reaction time: 16 h
Yield: 7 %

Procedure:
N-(4-chlorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide dihydrochloride (prepared as described in Example 7) (141 mg, 0.335 mmol) was dissolved in formaldehyde (37% aqueous solution, 1 mL) and formic acid (1 mL) and heated to 60° C. After 16 h, the reaction mixture was brought to pH 12 with 1 N NaOH in water and was extracted with CH2Cl2 (3×10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by HPLC (5 to 30% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL) and treated with 4M HCl in 1,4-dioxane. The mixture was concentrated under reduced pressure, yielding 10.3 mg (7%) of the desired product as a white solid. LC-MS: RT=4.48 min, [M+H]+=361.1.
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>CN(C1C=CN=CC=1)C.ClCCl.CCOC(C)=O>[C:26]([O:1][C:2]([CH3:18])([CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])[CH3:17])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C)(O)CCOc1cccc([N+](=O)[O-])c1C#N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)(C)CCOc1cccc([N+](=O)[O-])c1C#N
Reaction time: 8 h
Yield: 47 %

Procedure:
To a solution of 2-(3-hydroxy-3-methylbutoxy)-6-nitrobenzonitrile (Example 231d) (250 mg, 1 mmol), triethylamine (3 equiv.), and DMAP (0.1 equiv.) in dry dichloromethane (20 mL) was added dropwise acetyl chloride (1.5 equiv.) at 0° C. under nitrogen. The reaction mixture was then stirred at 0° C.—room temperature overnight. The reaction was diluted with EtOAc, washed with brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 20% EtOAc in hexanes to give the title compound (137 mg, 47%). MS 293 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]([OH:24])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].OC1C=CC=CC=1C1(C#N)CCNCC1.[CH3:41][S:42]([NH2:45])(=[O:44])=[O:43].CCN=C=NCCCN(C)C.Cl>C1COCC1.C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[ClH:25].[CH3:41][S:42]([NH:45][C:22](=[O:24])[CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:44])=[O:43]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2CCC(=O)O)CC1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)NC(=O)CCc1ccccc1C1CCNCC1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
Acid 3-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)propanoic acid obtained in step 1 of representative example 8 (40 mg, 0.12 mmol) and methane sulfonamide (17 mg, 0.18 mmol) were dissolved in THF/CH2Cl2 (0.5 mL/1.0 mL). DMAP (22 mg, 0.18 mmol) and EDC.HCl (35 mg, 0.18 mmol) were added and the reaction was stirred at 23° C. overnight. Water was added to the reaction mixture and was extracted with EtOAc (2×10 mL). The organic layers were dried over Na2SO4 and concentrated.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[S:21]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=1)([CH3:20])(=[O:23])=[O:22]
Reactant: N#Cc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
A 16.1 g (0.1 mol) quantity of 4-(3hydroxypropyl)benzonitrile was admixed with 27.8 ml (0.2 mol) of triethylamine and 300 ml of methylene chloride. To the mixture was added 15.5 ml (0.2 mol) of methanesulfonyl chloride at 0° C. The reaction mixture was stirred at room temperature for 12 hours and then concentrated. The concentrate was diluted with 500 ml of benzene, and washed with saturated aqueous solution of sodium chloride. The washed dilution was dried over Na2SO4 and concentrated, giving 24.0 g (yield 100%) of crude 4-(3-mesyloxypropyl)benzonitrile in the form of an oil.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH:37]5[CH2:42][CH2:41][CH2:40][CH2:39][O:38]5)[CH:33]=[CH:32][C:31]=4[F:43])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH:37]5[CH2:42][CH2:41][CH2:40][CH2:39][O:38]5)[CH:33]=[CH:32][C:31]=4[F:43])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(COc2cnc(-c3cc(OC4CCCCO4)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)Cc1cc(OCc2cccc(C(CC(=O)O)C3CC3)c2)cnc1-c1cc(OC2CCCCO2)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((6-(2-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-5-neopentylpyridin-3-yl)oxy)methyl)phenyl)propanoate (84.1 mg) in ethanol (2.85 mL) was added 2N aqueous sodium hydroxide (357 μl) solution, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was cooled to 0° C., neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (52.8 mg) as a white amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29]([OH:31])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([O:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36])[CH3:33].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:27])[CH3:28])[C:21]([C:29]([N:40]2[CH2:39][CH2:38][N:37]([C:35]([O:34][CH2:32][CH3:33])=[O:36])[CH2:42][CH2:41]2)=[O:31])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Reactant: CCOC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCOC(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCCN(C(=O)OC(C)(C)C)CC4)ccc3n2C(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.2 %

Procedure:
To a mixture of 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid (144 mg) and 4-ethoxy carbonyl piperazine (1 eq., 53 mg) in acetonitrile (5 ml) was added N-hydroxybenzotriazole (0.2 eq., 9 mg). The mixture was stirred 5 min before the addition of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (1.1 eq., 77 mg). The mixture was stirred two days at room temperature. The mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel (19:1 EtOAc/MeOH) to afford the product as an off-white powder (195 mg, 89%). MS (m/z): 570.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](O)=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.S(Cl)(Cl)=O.[CH3:36][S-:37].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](=[O:15])[S:37][CH3:36])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Reactant: C[S-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CSC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Yield: 9.4 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (30 mg, 0.066 mmol) was treated with thionylchloride (1.5 mL) and stirred at reflux for 2 h. The mixture was concentrated under reduced pressure. The intermediate was treated with benzene (3×) and the benzene was evaporated to remove water. Then, the obtained mixture was dissolved in benzene (1.5 mL) and sodium methanethiolate (32.5 mg, 0.46 mmol) was added. The reaction mixture was stirred at reflux for 5 h. The mixture was diluted with dichloromethane and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product (example B-68) was purified by pTLC (1:1 EE/PE) to give 3 mg of a white solid (yield 9%). Result of LC/MS MH+: 482.76; 1H NMR (CDCl3): 2.33 (t, 3H), 7.19 (t, 1H), 7.33-7.55 (m, 6H), 8.23 (s, 1H)
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[CH2:16]([NH2:19])[CH2:17][CH3:18]>C1C=CC=CC=1.CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:19][CH2:16][CH2:17][CH3:18])[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: CCCN
Solvent: c1ccccc1
Solvent: CO
Product: CCCNC(C)=C1C(=O)OC(=O)C(C(C)=O)=C1O

Procedure:
To a boiling solution of 4.2 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of benzene/methanol is added 1.2 g. (0.02 m.). of n-propylamine and the resulting mixture is refluxed overnight. The reaction mixture is concentrated, filtered and the solid treated with water to give pure 5-acetyl-4-hydroxy-3-[1-(n-propylamino)-ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 145° -148° C.
Reaction SMILES: [CH2:1]([S:3]([CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([F:32])[N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)=[O:4])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>>[CH2:1]([S:3]([CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([F:32])[N:11]([C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)(=[O:41])=[O:4])[CH3:2]
Reactant: CCS(=O)CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCS(=O)(=O)CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
Using the same technique as for the starting material of Example 50, but using two equivalents of 3-chloroperbenzoic acid, there was obtained 4-(3-ethanesulphonylpropyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.35 (t, 3H); 2.09 (quintet, 2H); 2.58 (t, 2H); 2.84 (q, 4H); 6.29 (s, 1H); 7.0-7.4 (m, 15H).
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH3:31])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=3)=[CH:14][C:13]=2[CH3:31])[CH2:10][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-phenyl}-acetate (Compound 80, 75.0 mg, 0.18 mmol) in ethanol (3 mL) and tetrahydrofiran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 30.0 mg (40%) of the title compound.