Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH2:8]([Mg]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[CH2:8]([CH:3]1[CH2:4][O:5][CH2:6][CH2:7][N:2]1[OH:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: ON1CCOCC1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCOCC1Cc1ccccc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxymorpholine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of benzylmagnesium chloride (2.0 M in tetrahydrofuran, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 25% diethyl ether in hexanes to give the title compound (0.326 g, 34%) as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17](/[CH:21]=[CH:22]/[CH2:23][OH:24])[CH:18]=[CH:19][CH:20]=1>[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17](/[CH:21]=[CH:22]/[CH:23]=[O:24])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(/C=C/CO)c1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(/C=C/C=O)c1

Procedure:
According to the method described for Reference Example 34, (E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-propen-1-ol was subjected to oxidation with activated manganese dioxide to give (E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-propen-1-al. Recrystallization from ethyl acetate--hexane gave colorless prisms, m.p.103°-104° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O.C(COC)OC>O.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.CCO>[C:19]([NH:18][C:16]1[S:17][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([O:8][C:6]3[CH:5]=[C:4]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[N:3]=[C:2]([C:40]4[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=4)[N:7]=3)[C:14]=2[N:15]=1)(=[O:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(C4=CCN(C(=O)OC(C)(C)C)CC4)n3)cccc2s1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzo[d]thiazol-2-yl}-acetamide (279 mg, 0.6 mmol, Example 7(d)), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (309 mg, 1.0 mmol, ChemShop), PdCl2(PPh3)2 (42 mg, 0.06 mmol, Aldrich), Na2CO3.H2O (74 mg, 0.6 mmol), dimethoxyethane (0.7 mL), H2O (0.3 mL) and EtOH (0.2 mL) was heated in a microwave synthesizer at 120° C. with stirring for 10 min. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2×30 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (30% EtOAc/hexane) to give the title compound. MS (ESI, pos. ion) m/z: 612 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([CH3:25])=[CH:18][CH:19]=[CH:20][C:21]([O:23]C)=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[CH:16][C:17]([CH3:25])=[CH:18][CH:19]=[CH:20][C:21]([OH:23])=[O:22])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C=CC=C(C)C=Cc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C=Cc1ccc(OCc2ccccc2)cc1)=CC=CC(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.7 %

Procedure:
A mixture of methyl 7-(4-benzyloxyphenyl)-5-methyl-hepta-2,4,6-trienoate (3.2 g, 9.7 mmol) and potassium hydroxide (1.1 g, 19.4 mmol) in 200 ml of ethanol and 10 ml of water was stirred under nitrogen at room temperature for 48 hrs. The mixture was then concentrated on rotary evaporator and water (250 ml) was added. The solution was extracted with 30 ml of ethyl acetate; the aqueous layer was acidified with 10N HCl to pH 3. The yellow precipitate formed was extracted into ethyl acetate, washed with 30 ml of water, dried (magnesium sulfate) and concentrated on rotary evaporator to give a yellow powder, which was triturated with ethyl acetate to give 1.7 g of the product as yellow powder, mp: 210° C. (sublimed).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])O[C:3]1=[O:4].[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.C1(C)C(C)=CC=CC=1>O>[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[N:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:3]1=[O:4]
Reactant: Nc1ccncc1
Reactant: CC1CC(=O)OC1=O
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1CC(=O)N(c2ccncc2)C1=O
Reaction time: 3.5 h

Procedure:
The starting material is prepared as follows: The mixture of 28.5 g of 2-methylsuccinic anhydride, 23.5 g of 4-aminopyridine and 350 ml of xylene is refluxed on a water separator while stirring for 3.5 hours. The hot solution is decanted from some gummy residue, cooled, filtered, the residue suspended in 100 ml of boiling isopropanol and filtered off again, to yield the 3-methyl-1-(4-pyridyl)-pyrrolidin-2,5-dione melting at 119°-120°.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1>C(#N)C>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([NH:5][CH2:4][CH2:3][N:9]3[CH2:8][CH2:7][CH2:6][CH2:15][CH:10]3[CH2:11][CH3:12])=[CH:7][CH:8]=[N:9]2)=[CH:14][CH:13]=1
Reactant: ClCCNc1ccnc2cc(Cl)ccc12
Agent: Cl
Solvent: CC#N
Product: CCC1CCCCN1CCNc1ccnc2cc(Cl)ccc12

Procedure:
1.52 g from N-(2-chloroethyl)-7-chloro-4-quinolinamine hydrochloride; colourless crystals from acetonitrile, m.p.: 115°-117° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[CH2:39][CH2:40][CH2:41][C:42](OCC)=[O:43]>C1COCC1>[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[CH2:39][CH2:40][CH2:41][C:42](=[O:43])[CH2:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CCOC(=O)CCCc1ncccn1
Reactant: CS(=O)(=O)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 2-[4-(methylsulfonyl)piperazin-1-yl]-5-(2,2,2-trifluoroethoxy)pyrimidine (8.05 g, 23.6 mmol) in THF (175 mL) at −78° C. was added LHMDS (47.2 mL, 47.2 mmol) dropwise and the reaction stirred for 15 minutes. A solution of ethyl 4-pyrimidin-2-ylbutanoate (5.5 g, 28.3 mmol) in THF (50 mL) was then added at −78° C., warmed to −20° C. and stirred for 2 hours. The reaction was then quenched by addition of a saturated solution of NH4Cl (250 mL), extracted twice with EtOAc (2×250 mL), combined organics were washed with brine (250 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid. This was then purified by flash chromatography (silica gel, 50% EtOAc/hexanes) to give 5-pyrimidin-2-yl-1-({4-[5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl]piperazin-1-yl}sulfonyl)pentan-2-one as an off white solid (9.47 g, 19.4 mmol, 82%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C)[CH:36]=[O:37]>>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:23][CH2:24][N:25]([CH2:11][CH2:10][CH2:9][CH2:14][CH2:13][CH2:12][O:37][CH2:36][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(F)(F)F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: O=C(N(CCCCCCOCCc1ccccc1)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(F)(F)F
Temperature: 70 °C

Procedure:
A solution of N-[2-[3,4-Bis(phenylmethoxy)phenyl]ethyl]-2,2,2-trifluoroacetamide (11 g) in dry dimethylformamide (30 ml) was added dropwise to a stirred suspension of sodium hydride (0.615 g) in dry dimethylformamide (20 ml) in (a) nitrogen atmosphere. The mixture was heated at 70° C. for 1 hour and then cooled to room temperature.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[O-][Si]([O-])=O.[Mg+2]>ClCCl>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21](=[O:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(=O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
A suspension of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (600 mg, 1.07 mmol), pyridinium dichromate (610 mg, 1.61 mmol) and Florisil (3 g) in dichloromethane (10 ml) was stirred at room temperature for 1.5 hours, then ultrasonicated for 2.5 hours. The solvent was distilled off under reduced pressure and the resulting residue was diluted with diethyl ether and filtered through Celite. The solvent was distilled off under reduced pressure and the resulting residue was purified by column chromatography (hexane:ethyl acetate=15:1) to give the title compound as a colorless solid (343 mg, 57%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C:8]([C:10]1[S:11][C:12]([S:41][CH3:42])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=S)=[CH:26][C:25]=3[CH3:40])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[NH3:44]>CO.[Hg]=O>[C:1]([O:5][C:6](=[O:43])[NH:7][C:8]([C:10]1[S:11][C:12]([S:41][CH3:42])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:44])=[N:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:26][C:25]=3[CH3:40])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)=[NH:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCCNC(=S)Nc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1
Reactant: N
Agent: O=[Hg]
Solvent: CO
Product: CCCCCCN=C(N)Nc1ccc(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
({4-[4′-(3-Hexyl-thioureido)-2′-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (33 mg, 0.14 mmol. Example 136: step a) was dissolved into ammonia in methanol (2.0 M, 4 mL). To this was added mercury (II) oxide (33.9 mg, 0.16 mmol) and the reaction stirred at RT for 2 hours. Additional mercury (II) oxide (154 mg, 0.08 mmol) was added and the reaction was heated to 40° C. overnight. The reaction was filtered with 0.2 μM disk and washed with EtOAc followed by removal of solvents in vacuo that yielded the title compound which was used without further purification (30 mg). ESI-MS (m/z): Calcd. for C31H41N5O4S3: 644.2 (M+1); found: 644.1.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:35][CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][CH:36]([F:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: FC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC(F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.56 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 442 [M+H]
Reaction SMILES: [F:1][C:2]1C=CC=CC=1[C@]12COC[C@H]1CSC(NC(=O)C1C=CC=CC=1)=N2.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([O:41][CH3:42])=[O:40])=[N:37][CH:38]=1.O>CN(C)C=O>[F:1][CH2:2][O:32][C:33]1[N:34]=[CH:35][C:36]([C:39]([O:41][CH3:42])=[O:40])=[N:37][CH:38]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3F)COC[C@H]2CS1)c1ccccc1
Reactant: COC(=O)c1cnc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(OCF)cn1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
Fluoromethyl toluene-4-sulfonate (Journal of Labelled Compounds & Radiopharmaceuticals, 46 (6), 555-566; 2003) (344 mg) and cesium carbonate (824 mg) were added to a solution of methyl 5-hydroxypyrazine-2-carboxylate (130 mg) in N,N-dimethylformamide (2.0 mL). The reaction solution was stirred at 70° C. for five hours and 30 minutes and then cooled to room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (18.0 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([CH2:18][OH:19])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][O:19][C:2]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:17][CH2:16]1
Reactant: OCC1CC1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) and cyclopropyl-methanol. The crude material was purified by flash chromatography to yield the title compound as a white solid. MS (m/e): 269.1 ([M−H]−, 100%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11]C)=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[CH:6]=[N:5]1.Br.O>C(O)(=O)C>[F:22][C:2]([F:1])([F:21])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([OH:11])=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)[CH:6]=[N:5]1
Reactant: COc1c(-c2ccc(SC)cc2)cnn(CC(F)(F)F)c1=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(-c2cnn(CC(F)(F)F)c(=O)c2O)cc1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of 2-(2,2,2-Trifluoroethyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (2 g, 6.1 mmol) and hydrobromic acid (40% in water, 20 mL) in acetic acid (40 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and water (50 mL) was added. The crystals formed were filtered, washed with water and 5% ethyl acetate in hexanes, and dried to constant weight. The product was obtained as a white solid (yield: 1.75 g, 91%). 1H NMR (300 MHz, CDCl3) δ 2.54 (s, 3H), 4.82 (q, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.65 (d, J=9 Hz, 2H), 7.73 (br s, 1H), 8.00 (s, 1H). MS (DCI) m/z 317 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[S:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C([Li])CCC.[C:25](=[O:27])=[O:26]>C1COCC1>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:25]([OH:27])=[O:26])=[CH:10][CH:9]=2)[C:5]([S:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:6]1
Reactant: O=C=O
Reactant: CN1CCC(Sc2cn(C)c3ccc(Br)cc23)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(Sc2cn(C)c3ccc(C(=O)O)cc23)CC1
Reaction time: 1 h

Procedure:
A solution of 5-bromo-1-methyl-3-[(1-methylpiperidin-4-yl)thio]-1H-indole (19 g, prepared in Example 58) in THF (100 ml) is treated at -78° C. with a solution of butyllithium (31.5 ml, 2.5M in hexane). After 1 hour at this temperature, carbon dioxide is passed into the solution until it is saturated. After one hour, the reaction mixture is left to return to room temperature. The solvent is evaporated off and the residue is taken up with ether to give 1-methyl-3-[(1-methylpiperidin-4-yl)thio]-1H-indole-5-carboxylic acid (22.8 g) in the form of a yellow solid, which is used for the next step without purification.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:6]([OH:8])=[O:7].[C:13]([O-])(O)=O.[Na+]>CO>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:4]=[C:3]([Br:2])[CH:11]=[C:10]([I:12])[CH:9]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methanol (40 mL) was added to a 250 mL round bottom flask followed by 60 mL of a solution saturated with anhydrous hydrochloric acid. 3-bromo-5-iodobenzoic acid (Aldrich)(5.02 g, 0.015 mole) was then added and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into chilled saturated NaHCO3 solution (700 mL). The mixture was extracted 3× with methylene chloride (100 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuum to yield methyl-5-bromo-3-iodobenzoate (5.08 g) as a pink solid. MP=55-57° C. MS and NMR were consistent with the desired structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH2:12][C:13]([OH:15])=O)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:16]([NH-:19])[CH2:17][CH3:18]>>[CH2:16]([NH:19][C:13](=[O:15])[CH2:12][C:10]1[O:9][C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH:11]=1)[CH2:17][CH3:18]
Reactant: CCC[NH-]
Reactant: COc1cccc2cc(CC(=O)O)oc12
Product: CCCNC(=O)Cc1cc2cccc(OC)c2o1
Yield: 75 %

Procedure:
Following the procedure of Example 1 Part B, but using 1.19 g of 7-methoxy-3-benzofuranacetic acid and 0.53 g of n-propylamide in place of cyclopropylmethylamine, and heating to 48° for 19 hours, there was obtained 1.07 g (96%) of N-(n-propyl)-7-methoxy-3-benzofuranacetamide as a solid. NMR spectrum (200 mHz in CDCl3): δ0.8 (t, J=7 Hz, 3H), 1.4 (m, 2H), 3.15 (q, J=6 Hz, 2H), 3.63 (s, 2H), 4.0 (s, 3H), 5.5-5.7 (broad s, 1H), 6.85 (d/d, J=7.0/0.5 Hz, 1H) 7.1-7.3 (m, 2H) and 7.61 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[N:12]=1.C1COCC1.[OH-].[Na+]>CCO>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:20])=[O:2])[O:9][CH:10]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2N)co1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccccc1-c1coc(CCCCC(=O)O)n1

Procedure:
Combine 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (2.5 g, 9.1 mmol) with THF (3 mL), EtOH (3 mL) and 1N NaOH (15 mL) and stir until hydrolysis is complete. Concentrate the mixture, dilute the residue with water and adjust the pH to 2.5-3.5 with aq HCl. Extract the mixture with EtOAc and dry the extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (EtOAc) to allow for recovery of 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid (2.03 g, 86%). MS (ES): (M+1)+ 261.1 m/z.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:26](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[CH3:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3[nH]cnc23)CC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 107.3 %

Procedure:
4-(2-Chloro-9H-purin-6-yl)piperazine-1-carboxylic acid t-butyl ester (6.62 g) was dissolved in N,N-dimethylformamide (66 mL), methyl iodide (1.34 mL) and anhydrous potassium carbonate (3.51 g) were added to this solution cooled in an ice bath. After stirring the reaction solution at room temperature for five hours, 1 N hydrochloric acid (5 mL) and water (200 mL) were added to this reaction solution, which was then extracted using ethyl acetate. The obtained organic layer was washed sequentially with water and then saturated brine, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to give the title compound as a solid (7.40 g).
Reaction SMILES: CS[CH2:3][C@@H:4](C(O)=O)[NH:5]C(=O)C.[CH2:12]([S:14][CH2:15][C@@H:16]([C:21]([OH:23])=O)[NH:17][C:18](=[O:20])[CH3:19])[CH3:13]>>[CH2:4]([NH:5][C:21](=[O:23])[C@H:16]([CH2:15][S:14][CH2:12][CH3:13])[NH:17][C:18](=[O:20])[CH3:19])[CH3:3]
Reactant: CCSC[C@H](NC(C)=O)C(=O)O
Reactant: CSC[C@H](NC(C)=O)C(=O)O
Product: CCNC(=O)[C@H](CSCC)NC(C)=O

Procedure:
S-Ethyl-N-acetyl-L-cysteine ethylamide was synthesized in exactly the same manner as described in Example 14 except that the S-methyl-N-acetyl-L-cysteine used in that example was replaced by S-ethyl-N-acetyl-L-cysteine.