Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[CH2:8]1[O:18][C:17]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=2[O:9]1.N1CCCCC1.CC(O)=O>C(O)(C)C>[CH2:8]1[O:18][C:17]2[CH:16]=[CH:15][C:12]([CH:13]=[C:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[CH:11][C:10]=2[O:9]1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc2c(c1)OCO2)C(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.1 %

Procedure:
A mixture of pentane-2,4-dione (20.0 g, 200 mmol), 3,4-methylenedioxybenzaldehyde (32.2 g, 200 mmol), piperidine (1.98 mL, 20.0 mmol), and HOAc (1.20 mL, 20.0 mmol) in 200 mL of isopropanol were stirred at room temperature for 3 days (no precipitate). The solvent was remove in vacuo, and the crude product was heated to 50-70° C. under reduced pressure for 0.5 hours (no solids). The crude product was chromatographed on 900 g of silica packed with 10% EtOAc-hexane. The column was eluted with increasing amounts of EtOAc (10% to 30%, 2.5%/2 L change) to give 19.1 g (41%) of the desired product as a yellow solid: mp 79-80° C. The product was used in the next step after spectral characterization.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[N:4]([CH3:13])[C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:11])(=[O:12])[N:4]([CH3:13])[C:3]=1[C:14](=[O:16])[NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1
Reactant: Nc1nccs1
Reactant: COC(=O)C1=C(O)c2ccsc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2ccsc2S1(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.25 g. of 4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno[3,2-e]1,2-thiazine-1,1-dioxide is heated under reflux for 17 hours with 0.14 g. of 2-aminothiazole in 28 ml. of absolute xylene, while passing a stream of nitrogen through the said mixture. The mixture is cooled to room temperature and crystallization of the product is initiated by scratching. The product is kept overnight in the cold. The precipitate crystals are removed by filtration under suction and recrystallized from ethanol, whereby 4-hydroxy-2-methyl-3-(2-thiazolylcarbamoyl)-2H-thieno[3,2-e]1,2-thiazine-1,1-dioxide having a melting point of 226°-227° (with decomposition) is obtained.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2([O:21][CH3:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C(Cl)Cl>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([C:15]2([O:21][CH3:22])[CH2:20][CH2:19][N:18]([S:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[Cl:23])(=[O:32])=[O:31])[CH2:17][CH2:16]2)=[O:14])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COC1(C(=O)Nc2ccc(C(C)(C)C)cc2)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1(C(=O)Nc2ccc(C(C)(C)C)cc2)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 25.5 mg (0.078 mmol) 4-Methoxy-piperidine-4-carboxylic acid (4-tert-butyl-phenyl)-amide, hydrochloride, 21.4 mg (0.1 mmol) 2-chlorobenzenesulfonyl chloride and 39.4 mg (0.39 mmol) NEt3 in 1.5 mL DCM was stirred for 16 h at room temperature. The mixture was concentrated and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 20.2 mg (56%) of the title compound as light yellow oil. MS (m/e): 465.2 [(M+H)+].
Reaction SMILES: C([NH:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9](=[O:18])[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:12][C:7]=2[C:6]=1[CH2:21][CH2:22][CH3:23])(=O)C.Cl>C(O)C.O>[NH2:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9](=[O:18])[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:12][C:7]=2[C:6]=1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1c(NC(C)=O)ccc2c(=O)cc(C(=O)OCC)oc12
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCc1c(N)ccc2c(=O)cc(C(=O)OCC)oc12
Yield: 55.3 %

Procedure:
A solution of the amide of step (d) (10 g) in ethanol (300 ml), containing concentrated hydrochloric acid (5 ml), was refluxed for 8 hours. The reaction mixture was diluted with water and extracted into ethyl acetate. The extract was washed with water, dried and the solvent was evaporated to leave a dark brown semisolid. This was chromatographed on a silica gel column, using ether as eluant to give 4.8 g of the required product whose structure was confirmed by mass and NMR spectral evidence; mp 84°-87° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.O>C(O)(=O)C>[OH:9][C:4]1[CH:3]=[C:2]([N:1]2[C:13](=[O:14])[C:12]3[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]2=[O:15])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1cc(N)cc(O)c1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(O)cc(N2C(=O)c3ccccc3C2=O)c1
Yield: 80.6 %

Procedure:
36.0 g (292 mmol) 3-amino-5-methylphenol and 73.5 g (496 mmol) phthalic acid anhydride were heated for 2 h to boiling under reflux in 280 ml glacial acetic acid. Water was added, it was heated for a short time, allowed to cool and filtered. 59.6 g (80%) 2-(3-hydroxy-5-methyl-phenyl)-isoindole-1,3-dione of Fp 174°-175° C. was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:2].C([Mg]Br)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:22]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[CH:10]=2)[NH:14][CH:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc2[nH]cc(Cc3ccccc3)c2c1
Temperature: 0 °C
Yield: 32.3 %

Procedure:
5-(2-Cyanophenyl)indole (2.3 mmole, 0.50 g) was dissolved in 3 ml THF, cooled to 0° C. Ethyl magnesium bromide (2.41 mmoles, 1.21 ml of 2.0M solution in ether) was added dropwise. Benzyl bromide (94.6 mmole, 0.80 g) was added dropwise to the solution. The reaction was refluxed for 24 hours and poured into aqueous ammonium chloride and ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated. The intermediate was chromatographed over silica gel eluted with 10% ethyl acetate in hexane to yield 229 mg of 3-benzyl-5-(2-cyanophenyl)indole.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:9]([C:13]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[O:30])[C:20]2[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=2)[N:14]=1)[CH:10]([CH3:12])[CH3:11])[C:5](=[O:8])[CH:6]=[CH2:7].C(OC(=O)NCCN(C(=O)C=C)C(C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:23]([N:22]1[C:21](=[O:30])[C:20]2[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=2)[N:14]=[C:13]1[CH:9]([N:4]1[C:5](=[O:8])[CH2:6][CH2:7][NH:1][CH2:2][CH2:3]1)[CH:10]([CH3:12])[CH3:11])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=CC(=O)N(CCN)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Agent: C=CC(=O)N(CCNC(=O)OC(C)(C)C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O

Procedure:
N-(2-Amino-ethyl)—N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-acrylamide: (2-{Acryloyl-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-amino}-ethyl)-carbamic acid tert-butyl ester (300 mg, 0.56 mmol) was treated with 50% TFA in CH2Cl2 (3 mL at room temperature. After 2 h the mixture was concentrated under vacuum, redissolved in CH2Cl2, washed with 10% NaHCO3, brine, dried and concentrated to give the title compound (240 mg) as a white solid: MS (ES) m/e 439.2 (M+H)+.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:38]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Cl:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:42]=1[C:48]1[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:38][NH:54][C:51]2[CH:50]=[CH:49][C:48]([C:42]3[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:41]=3[Cl:40])=[CH:53][CH:52]=2)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Reactant: Nc1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (4.9 g, 22.9 mmol) was added to a DCE solution (37 mL) of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate, prepared as in Example 6, (4.1 g, 11.5 mmol), 2′,4′-dichloro-[1,1′-biphenyl]-4-amine, prepared as in example x (3.0 g, 12.6 mmol), and AcOH (2.6 mL, 45.8 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C.C(Cl)Cl>[CH:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([Cl:24])=[O:14])=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCC2CCCCC2)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 21-3 (0.307 g, 1.1 mmol) and DMF (1 drop) in methylene chloride (3 ml) under nitrogen cooled in an ice-bath was added dropwise a solution of oxalyl chloride (0.113 ml, 1.3 mmol) in methylene chloride (1 ml). The resulting solution was stirred 1 h with ice-bath cooling, 1 h at ambient temperature, then was evaporated at reduced pressure to give crude 4-(cyclohexylmethyloxy)-3-nitrobenzoyl chloride as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.[CH3:20][CH:21]([CH2:30][CH3:31])[C:22](=O)[CH2:23][C:24](OCC)=[O:25].[O-]CC.[Na+].C(O)C.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>CN(C=O)C.O1CCCC1.C(=O)=O.ClCCl.CO.C(OCC)(=O)C.CCOCC>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]1[C:23]([CH2:24][OH:25])=[C:22]([C@H:21]([CH3:20])[CH2:30][CH3:31])[O:6][N:5]=1
Reactant: ON=Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)CC(=O)C(C)CC
Agent: CC(C)C[Al+]CC(C)C
Agent: CC[O-]
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC[C@@H](C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Temperature: 25 °C
Yield: 3.2 %

Procedure:
To a solution of 2,6-dichlorobenzaldehyde oxime (26.4 g, 139 mmol) in DMF (70 mL) at 5° C. was added solid N-chlorosuccinimide (18.6 g, 139 mmol) in portions. The mixture was allowed to stir and warm to ambient temperature (with occasional cooling when warming was noted) over approximately 1.5 hour and then poured into ether. The organic layer containing the crude imidoyl chloride was washed twice with water followed by brine, dried over magnesium sulfate and concentrated. To a separate solution of ethyl 4-methyl-3-oxohexanoate (28.8 g, 167 mmol) in tetrahydrofuran (50 mL) at 0° C. was added a 21 wt % solution of sodium ethoxide in ethanol (62.3 mL, 167 mmol) quickly. The above imidoyl chloride was added dropwise in tetrahydrofuran (100 mL). The solution was allowed to stir while warming to ambient temperature overnight. The mixture was then poured into ether, washed twice with water followed by brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 1.25% acetone in hexanes) to afford an oil which was dissolved in tetrahydrofuran (75 mL) at 0° C. Then a 1.5 M solution of diisobutylaluminum hydride in toluene (100 mL, 150 mmol) was added slowly. The solution was allowed to warm slightly while stirring for approximately 2.5 hours and then was re-cooled to 0° C. and stirred for 1.5 hours. Then approximately 20 mL of Rochelle's salt was added carefully followed by ethyl acetate and the mixture was stirred overnight. Then the layers were separated and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 20% ethyl acetate in hexanes) to afford a white solid. The enantiomers were resolved by supercritical fluid chromatography (Chiralpak AD, 10% methanol in supercritical carbon dioxide) and the resulting solid was taken up with dichloromethane, dried over magnesium sulfate and concentrated to afford {3-(2,6-dichlorophenyl)-5-[(1R)-1-methylpropyl]-4-isoxazolyl}methanol (1.35 g, 6%) 1H-NMR (400 MHz, DMSO-d6) δ 7.61-7.51 (m, 3H), 4.85 (t, J=5 Hz, 1H), 4.20-4.06 (m, 2H), 3.15-3.10 (m, 1H), 1.69-1.62 (m, 2H), 1.29 (d, J=7 Hz, 3H), 0.79 (t, J=7 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[O:9])=[CH:24][CH:25]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OCCNC(=O)c2ccc(C(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(C(=O)NCCOc2ccc(C(=O)O)cc2)cc1
Yield: 82 %

Procedure:
Methyl 4-[2-(4-isopropylbenzamido)ethoxy]benzoate (102.42 g) was dissolved in 1 liter of ethanol with heating. A solution of 14.4 g of sodium hydroxide in 200 ml of water was added to the above ethanolic solution and the mixture was heated to reflux for 2 hours. The reaction solution was concentrated in vacuo, 1 liter of ice water was added to the residue, the mixture was neutralized with 10% hydrochloric acid, crystals separated out therefrom were collected by filtration, washed with water, dried and recrystallized from ethanol to give 80.5 g (yield: 82%) of crystalline product. M.p. 202°-203° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:16])=[C:12]([CH:15]=2)[C:13]#[N:14])[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1>C(Cl)Cl.CO>[CH3:16][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:30][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:22]4[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]4)=[CH:32][CH:31]=3)[N:7]=2)=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1ccc(-c2nc(Cl)ncc2C)cc1C#N
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-c2nc(Nc3ccc(CN4CCN(C)CC4)cc3)ncc2C)cc1C#N
Yield: 93 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 5-(2-chloro-5-methylpyrimidin-4-yl)-2-methylbenzonitrile and 4-((4-methylpiperazin-1-yl)methyl)aniline in 93% yield (yellow solid). After flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.31 (s, 1H), 7.88 (d, 1H, J=1.7 Hz), 7.76 (dd, 1H, J=8.0, 1.9 Hz), 7.55 (d, 2H, J=8.6 Hz), 7.43 (d, 1H, J=7.9 Hz), 7.25 (d, 2H, J: not calculated due to overlapping peaks), 3.45 (s, 2H), 2.62 (s, 3H), 2.45 (bs, 8H), 2.26 (s, 3H), 2.25 (s, 3H); MS (ESI): 413.5 [M+H]+, 207.4 [M+2H]2+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[C:5]2[SH:16].F[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[C:5]2[S:16][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: O=C(O)Cc1cc(S)c2cc(F)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Sc2cc(CC(=O)O)cc3ccc(F)cc23)cc1
Temperature: 100 °C
Yield: 74.6 %

Procedure:
To a solution of (6-fluoro-4-mercapto-naphthalen-2-yl)-acetic acid (30 mg, 0.127 mmol) in N,N-dimethylformamide (2 mL), was added 1-fluoro-4-methanesulfonyl-benzene (43.4 mg, 0.25 mmol) and potassium carbonate (35 mg, 0.25 mmol) under a nitrogen atmosphere. After being heated under microwave conditions (100° C., 30 minutes), the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (0-20% methanol in dichloromethane) to afford [6-fluoro-4-(4-methanesulfonyl-phenylsulfanyl)-naphthalen-2-yl]-acetic acid (37.0 mg, 74.6%) as an off-white powder. 1H NMR (400 MHz, CDCl3) δ ppm 7.86-7.93 (m, 4H), 7.69-7.74 (m, 2H), 7.34 (td, J=8.53, 2.65 Hz, 1H), 7.08-7.15 (m, 2H), 3.85 (s, 2H), 3.01 (s, 3H); MS cald. for C19H15FO4S2 390, obsd. (ESI+) [(M+H)+] 391.
Reaction SMILES: Cl[CH:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].Cl.[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:41]=1[O:42][CH3:43])[CH2:38][NH:37][CH2:36][CH2:35]2>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:7]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:28][N:37]2[CH2:36][CH2:35][C:34]3[C:39](=[CH:40][C:41]([O:42][CH3:43])=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:38]2)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(C(C#N)(CCCCC(C)Cl)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Product: COc1ccc(C(C#N)(CCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 51.6 %

Procedure:
The procedure of Example 3 is repeated using 4.3 g of α-(5-chlorohexyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 4.25 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 3.05 g of the desired product as a golden gum.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13]([NH2:18])(=[O:17])[CH:14]([CH3:16])[CH3:15]>>[C:13]([NH:18][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1)(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: CC(C)C(N)=O
Product: COC(=O)c1cc(C)nc(NC(=O)C(C)C)n1
Yield: 88 %

Procedure:
The title compound is prepared in 88% yield (1.1 g, a yellow solid) from methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1.0 g, 5.4 mmol) and isobutyramide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([OH:13])=O.F[P-](F)(F)(F)(F)F.[N:21]1([O:30][C:31](N(C)C)=[N+](C)C)[C:25]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[CH3:31][O:30][N:21]([CH3:25])[C:11]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:13]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)[nH]c2ccccc12
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1[nH]c2ccccc2c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
A mixture of 3-methyl-1H-indole-2-carboxylic acid (from Matrix Scientific, 1.0 g, 5.7 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.3 g, 11 mmol) and triethylamine (4.0 mL, 28 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 10 minutes. N,O-Dimethylhydroxylamine hydrochloride (0.84 g, 8.6 mmol) was added and the resulting suspension was stirred at room temperature over the weekend. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-30% EtOAc/hexane) to give the desired product (1.1 g, 88%). LCMS calculated for C12H15N2O2(M+H)+: m/z=219.1. Found: 219.1.
Reaction SMILES: C1(C=[N:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)C=CC=CC=1.Br[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: C(=NCC1CCNCC1)c1ccccc1
Reactant: COc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(CCN2CCC(CN)CC2)cc1

Procedure:
To a stirred solution of N-[phenylmethylidene]-1-(piperidin-4-yl)methanamine (compound iii; 0.158 moles; 31.9 g), prepared as described in WO2004/101548 in absolute ethanol (70 ml), 1-(2-bromoethyl)-4-methoxybenzene (compound iv; 0.237 moles; 32.7 g) and potassium carbonate were added.
Reaction SMILES: C([O:3][P:4](Cl)[O:5]CC)C.[CH2:9]([Mg]Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.Cl>C(OCC)C>[CH2:9]([PH:4](=[O:3])[OH:5])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CCOP(Cl)OCC
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=[PH](O)CCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Diethylchlorophosphite (15.6 g,0.1 mol) in 100 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenethylmagnesium chloride (100 mL, 0.1 mol, 1.0 M in THF) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and stirred at room temperature overnight. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. The liquid was stirred as 15 mL of water was added followed by 0.5 mL of concentrated hydrochloric acid. An exothermic reaction was observed and stirring continued for 15 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. The clear liquid was brought up in sodium hydroxide (40 mL, 2.0 M NaOH), stirred for 1 hour and washed once with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give phenethylphosphinic acid (1,R=CH2CH2Ph, R1=H)(9.8 g, 58%) as a clear light yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[Mg].[F:8][C:9]([F:19])([F:18])[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>O1CCCC1>[F:8][C:9]([F:18])([F:19])[C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: C=CCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCC(O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-bromopent-1-ene (6.0 g, 40 mmol) and magnesium (1.44 g, 59.2 mmol) in tetrahydrofuran (40 mL) was stirred at 0° C. for 30 minutes. 4-(Trifluoromethyl)benzaldehyde (4.6 g, 26 mmol) was added drop-wise, and the reaction mixture was stirred at room temperature for 4 hours, then quenched by addition of water (30 mL). After extraction with ethyl acetate (3×15 mL), the combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product as a yellow oil. This was used without additional purification. Yield: 2.6 g, 11 mmol, 42%. 1H NMR (400 MHz, CDCl3) δ 7.58-7.64 (m, 2H), 7.44-7.50 (m, 2H), 5.72-5.84 (m, 1H), 4.93-5.04 (m, 2H), 4.73-4.79 (m, 1H), 2.05-2.13 (m, 2H), 1.64-1.85 (m, 2H), 1.47-1.60 (m, 1H), 1.34-1.47 (m, 1H).