Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][C:16]1[C:20]([CH3:21])=[C:19]([NH2:22])[O:18][N:17]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:15][C:16]1[C:20]([CH3:21])=[C:19]([NH:22][S:11]([C:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[S:6][C:2]=2[CH3:1])(=[O:13])=[O:12])[O:18][N:17]=1
Reactant: Cc1noc(N)c1C
Reactant: Cc1sc2ccccc2c1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1noc(NS(=O)(=O)c2c(C)sc3ccccc23)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methylbenzo[b]thiophene-3-sulfonyl chloride (1.7 mmoles, 0.41 g) was added to a solution of 3,4-dimethyl-5-aminoisoxazole (0.75 mmoles, 84 mg), 4-dimethylaminopyridine (DMAP; 50 mg) and pyridine (5 ml) at ambient temperature. After 24 h, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with 2% HCl (3×50 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect a brown-orange solid, which was dissolved in a solution of methanol (10 ml) and NaOH (60 mg). The solution was stirred 1 h at ambient temperature, then the methanol was evaporated and the resulting residue was diluted with 2% HCl (50 ml), and extracted with ethyl acetate (75 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect a tan solid. Recrystallization from chloroform and hexanes resulted in 93 mg (38%) of N-(3,4-dimethyl-5-isoxazolyl)-2-methylbenzo[b]thiophene-3-sulfonamide as light yellow crystals, m.p. 174-176° C.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-]1C=CC=C1.[Fe+2:11].[Al+3].[Cl-].[Cl-].[Cl-].[C:16]1([CH3:24])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:16]1([CH3:24])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1.[CH:1]1([Fe+:11])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: [Fe+2]
Reactant: c1cc[cH-]c1
Agent: [Zr+4]
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1cc(C)cc(C)c1
Product: [Fe+]C1C=CC=C1

Procedure:
In accordance with the procedure of Example 4, 10 g (0.043 mol) of ZrCl4 are added at 60° C. under argon over the course of 1 hour and 10 minutes to a stirred mixture of 60 ml of mesitylene, 8 g (0.043 mol) of ferrocene and 5.7 g (0.043 mol) of sublimed AlCl3. Working up is effected as in Example 4, affording 20.1 g (83.4% of theory) of crude (η6 -mesitylene)-η5 -(cyclopentadienyl)-iron(II) tetrapnenylborate.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[CH3:13][N:14]([CH2:16][CH2:17][NH2:18])[CH3:15]>>[CH3:13][N:14]([CH3:15])[CH2:16][CH2:17][NH:18][C:9]([C:5]1[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[CH3:8])=[O:11]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: CN(C)CCN
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Yield: 52 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (0.5 g, 2.99 mmol) was reacted with dimethylaminoethylamine (0.32 mL) to give 0.37 g (52% yield) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylamino-ethyl)-amide by using General Amidation Procedure 1, 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.84 (br s, 1H, NH), 9.52 (s, 1H, CHO), 7.47 (m, 1H, NH), 3.3 (m, 2H, CH2), 2.55 (m, 2H, CH2), 2.35 (s, 3H, CH3), 2.29 (s, 6H, 2×CH3), 2.30 (s, 3H, CH3). MS m/z 266 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]3[N:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16](=[O:19])[NH:17][N:18]=2)=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH3:24]>CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]3[N:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16](=[O:19])[NH:17][N:18]=2)=[CH:8][C:3]=1[C:4]([NH2:24])=[O:5]
Reactant: COC(=O)c1cc(Cc2n[nH]c(=O)c3cccnc23)ccc1F
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(Cc2n[nH]c(=O)c3cccnc23)ccc1F
Temperature: 25 °C

Procedure:
A solution of EXAMPLE 462A (1 g, 3.2 mmol) in 7N ammonia in methanol (5 ml) was heated at 70° C. overnight, and cooled to room temperature. The solid was collected by filtration, washed with methanol and dried to provide the title compound. MS (DCI/NH3) m/z 299 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C[Si](C)(C)N[Si](C)(C)C.COC(O[CH:24]1[O:38][C@H:37]([CH3:39])[C@@H:31]([O:32][C:33]([O:35][CH3:36])=[O:34])[C@H:25]1[O:26][C:27]([O:29][CH3:30])=[O:28])=O.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])O.[Na+]>S([O-])([O-])(=O)=O.[NH4+].[NH4+].ClCCl.O.C(#N)C>[CH3:30][O:29][C:27]([O:26][C@@H:25]1[C@H:31]([O:32][C:33]([O:35][CH3:36])=[O:34])[C@@H:37]([CH3:39])[O:38][C@H:24]1[N:6]1[CH:7]=[C:2]([F:1])[C:3]([NH2:9])=[N:4][C:5]1=[O:8])=[O:28]
Reactant: Nc1nc(=O)[nH]cc1F
Reactant: COC(=O)OC1O[C@H](C)[C@@H](OC(=O)OC)[C@H]1OC(=O)OC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COC(=O)O[C@@H]1[C@H](OC(=O)OC)[C@@H](C)O[C@H]1n1cc(F)c(N)nc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.1 %

Procedure:
11.6 g (0.090 mole) of 5-fluorocytosine, 19 ml of hexamethyldisilazane and 24 ml of acetonitrile were mixed, and 0.2 g of ammonium sulfate was added to the mixture, which was refluxed for 1 hr. After cooling the reaction mixture to room temperature, 72 ml of acetonitrile was added thereto, followed by subjecting the resulting mixture to distillation to remove about 60 ml of the solvent. The resulting solution was cooled to room temperature, mixed with 27.7 g (0.090 mole) of the compound obtained in Example 1 and 72 ml of acetonitrile, and the resulting mixture was cooled to 20° C. After adding 16.3 ml (0.090 mole) of trimethylsilyl trifluoromethanesulfonate dropwise thereto at 25° C., the reaction mixture was stirred at room temperature overnight, cooled to 10° C., mixed with 45.4 g of sodium hydrogen carbonate, and stirred for 30 min. 9.8 g of water and 72 ml of dichloromethane were added dropwise thereto, the resulting solution was stirred for 2 hrs, filtered, and the isolated solid was washed with 72 ml of dichloromethane. The filtrate was washed with 120 ml of 4% sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under a reduced pressure, to obtain 35.8 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][CH:14]([OH:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3>ClC(Cl)Cl.[O-2].[O-2].[Mn+4]>[O:22]=[C:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[CH2:2][OH:1])=[CH:13]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(O)CC[C@@]43C)[C@@H]1CC[C@@H]2CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2CO
Yield: 96.6 %

Procedure:
A solution of 17β-(hydroxymethyl)androst-4-ene-3-ol (27 g, 0.089 mol) in 1200 ml trichloromethane was treated with activated manganese dioxide (66 g). After 3 hours the mixture was filtered. Concentration afforded 26 g (96%) of 3-oxo-17β-(hydroxymethyl)-4-androstene (m.p. 151° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:16][CH:17]=[CH2:18])(C(OC)=O)[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH2:16][CH:17]=[CH2:18])[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C=CCC1(C(=O)OC)Oc2c(OC)cccc2C1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: C=CCC1Oc2c(OC)cccc2C1=O
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Methyl 7-methoxy-3-oxo-2-(2-propenyl)-2,3-dihydrobenzofuran-2-carboxylate (18.42 g) and concentrated sulfuric acid (2 ml) were dissolved in t-butyl alcohol (150 ml) and the solution was refluxed for 22.5 hours. After cooling the reaction solution to room temperature, the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and then washed with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate by filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (solvent:hexane/ethyl acetate=4/1) using silica gel to obtain the desired compound (11.39 g, yield: 79%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[NH:24][C:23](=[O:26])[C:22]([CH3:27])=[CH:21]2>CC(C)=O>[CH2:1]([O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[NH:24][C:23](=[O:26])[C:22]([CH3:27])=[CH:21]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2cccc(O)c2[nH]c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc2cccc(OCc3ccccc3)c2[nH]c1=O

Procedure:
Benzyl bromide (1.28 mL) is added to a suspension of potassium carbonate (2.98 g) in a solution of 8-hydroxy-3-methyl-1H-quinolin-2-one (1.26 g) in acetone (36 mL) at room temperature. The reaction mixture is refluxed for 18 hours, filtered, evaporated and purified by flash column chromatography on silica gel, eluting with 2% methanol in dichloromethane.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:16]=[C:15]([CH3:17])[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][C:28]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:27][N:26]=1.ClCCl>COCCOC.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].ClC1N=C(C)N=C2C=1N=CN2C1CCCCO1.FC1C(B(O)O)=CC(COCC2C=CC(OC)=CC=2)=CN=1.ClCCl>[F:24][C:25]1[C:30]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:29][C:28]([CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)=[CH:27][N:26]=1
Reactant: COc1ccc(COCc2cnc(F)c(B(O)O)c2)cc1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(COCc2cnc(F)c(-c3nc(C)nc4c3ncn4C3CCCCO3)c2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
6-Chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (38.7 mg, 0.153 mmol), 2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-ylboronic acid (51.2 mg, 0.176 mmol), potassium carbonate (87.8 mg, 0.635 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (21.0 mg, 0.0257 mmol) were suspended in DME (1.0 mL) and water (0.30 mL). The flask was fitted with a reflux condenser and placed in a preheated oil bath (100° C.), stirred under nitrogen for 2 hours, and cooled to room temperature. In a separate flask, 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (933 mg, 3.69 mmol), 2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-ylboronic acid (1.338 g, 4.597 mmol), potassium carbonate (2.096 g, 1.517 μmol), and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (360.9 mg, 0.4419 mmol) were suspended in DME (15 mL) and water (4.0 mL). Nitrogen was bubbled through the suspension for about 30 seconds, and then the flask was fitted with a reflux condenser and placed in a preheated oil bath (100° C.) and stirred under nitrogen, After 1 hour and 45 minutes, the reaction was cooled to room temperature. At this point, both reactions were combined, and the aqueous phase was removed via pipette. Then, the combined reactions were filtered through a Celite® (diatomaceous earth) pad, which was washed with DCM and MeOH. The filtrate was concentrated and treated with Et2O. No precipitate was observed, so this was concentrated and the residue was purified on a silica gel filter (about 3 inches, 50:1 DCM/2N ammonia in MeOH to 25:1 DCM/2N ammonia in MeOH to 10:1 DCM/2N ammonia in MeOH). Note: Product elutes with 50:1 DCM/2N ammonia. The fractions with product were collected, concentrated, and dried under high vacuum overnight to give 6-(2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1.688 g, 69% purity, 68% yield). MS (ESI pos. ion) m/z 464 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1)[CH2:9][CH2:10][CH3:11].[O-:25][C:26]#[N:27].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:8]([N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:26]([NH2:27])=[O:25])[CH:19]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCn1cccc1Cc1cccc(N)c1
Reactant: N#C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1cccc1Cc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of 3.5 ml (45 mmol) of trifluoroacetic acid in 25 ml of benzene was added dropwise to a suspension of 5 g (21 mmol) of 1-butyl-2-(3'-aminobenzyl)pyrrole and 2.85 g (43 mmol) of sodium cyanate in 250 ml of benzene. The reaction mixture was stirred at room temperature for 1 hour further and then poured into 600 ml of saturated sodium carbonate solution. The organic phase was separated and the aqueous phase extracted with ethyl acetate (3×300 ml). The combined extracts were washed with water (2×250 ml), dried and evaporated under reduced pressure. The residue was purified by column chromatography on 300 g of silica gel, using hexane-ethyl acetate (30:70) as eluant, thus obtaining 3.82 g (65%) of the title compound, 1-butyl-2-(3'-ureidobenzyl)pyrrole, which was recrystallized from acetone-hexane.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1>O1CCCC1>[N:5]1[CH:4]=[CH:3][C:2]([C:1]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)=[O:9])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccncc1
Reactant: c1ccc2c(c1)CCNC2
Solvent: C1CCOC1
Product: O=C(c1ccncc1)N1CCc2ccccc2C1
Reaction time: 0.5 h

Procedure:
50 g (406 mmol) of isonicotinic acid are dissolved under an argon atmosphere in 1000 ml of tetrahydrofuran and 25 g of N,N'-carbonyldiimidazole are added while stirring, the mixture is stirred for half an hour, a further 25 g of N,N'-carbonyldiimidazole are added, the mixture is stirred for a further half hour and 15 g of N,N'-carbonyldiimidazole are added. Stirring is continued for 1 h 30 min, 51.39 g (385.8 mmol) of 1,2,3,4-tetrahydroisoquinoline dissolved in a few millilitres of tetrahydrofuran are introduced slowly into the mixture, which has become clear, and the mixture is stirred overnight at room temperature. The solvent is then evaporated off, the oily residue taken up with approiximately 700 ml of dichloromethane, and the solution obtained washed twice with saturated sodium bicarbonate solution and thereafter twice with water and dried over magnesium sulphate. 87.48 g of an orange-coloured oil, which solidifies slowly in the cold, are obtained.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[CH3:36][O:37][C:38]([CH3:47])([CH3:46])[CH2:39][N:40]1[CH:44]=[CH:43][C:42]([NH2:45])=[N:41]1>C1C=CC=CC=1.CN(C=O)C.C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=2)[C:8]([NH:45][C:42]2[CH:43]=[CH:44][N:40]([CH2:39][C:38]([O:37][CH3:36])([CH3:46])[CH3:47])[N:41]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1cccc([C@@H](CC2CCCC2)C(=O)O)c1
Reactant: COC(C)(C)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2cccc(S(C)(=O)=O)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a stirred solution of (R)-3-cyclopentyl-2-(3-methylsulfonyl-phenyl)-propionic acid (prepared in Example 134, 200 mg, 0.65 mmol) in benzene (10 mL) was added oxalyl chloride (123 mg, 0.97 mmol) and DMF (1 drop) and the reaction was stirred at 25° C. for 3 h. The reaction was concentrated under reduced pressure and the residue was dissolved into methylene chloride (10 mL) under a nitrogen atmosphere. To this stirred solution was added N,N′-diisopropylethylamine (125 mg, 0.97 mmol) and 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared in Example 94, 130 mg, 0.84 mmol). The reaction was stirred at 25° C. for 18 h and then diluted with methylene chloride (30 mL). The methylene chloride was washed with water, 2 N aqueous hydrochloric acid solution, saturated sodium bicarbonate and saturated sodium chloride solution and then dried over magnesium sulfate. Filtration and concentration afforded the crude product which was purified by flash column chromatography (Biotage 40S Flash Column; 70% ethyl acetate/hexanes) to yield (R)-3-cyclopentyl-2-(3-methanesulfonyl-phenyl)-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (157 mg, 55%) as a white solid: ES-HRMS m/e calcd for C23H33N3O4S (M+H)+ 448.2265, observed 448.2265; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.10 (m, 2H, CH2), 1.35-1.80 (m, 8H, 4×CH2), 2.13 (m, 1H, CH), 3.13 (s, 3H, OCH3), 3.21 (s, 3H, SO2CH3), 3.94 (m, 1H, ArCHCO), 3.96 (s, 2H, NCH2), 6.46 (d, J=2.1 Hz, 1H, Ar), 7.47 (d, J=2.1 Hz, 1H, Ar), 7.61 (t, J=7.7 Hz, 1H, Ar), 7.73 (d, J=7.7 Hz, 1H, Ar), 7.82 (d, J=7.7 Hz, 1H, Ar), 7.94 (s, 1H, Ar), 10.79 (s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][CH2:23][O:24]C)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1onc(-c2nonc2NCCCO)n1-c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of 4-(3-bromo-4-fluorophenyl)-3-{4-[(3-methoxypropyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one (6.3 g, 14 mmol) in dichloromethane (60 mL) at −78° C. was treated with 1 M boron tribromide in dichloromethane (28 mL, 28 mmol) and stirred at 25° C. for 2 h. The reaction mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate (100 mL). The aqueous layer was separated and extracted with dichloromethane (2×150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude off-white solid. This material was purified on silica gel to give the desired product (4.0 g, 73%) as a white solid. LCMS for C13H12BrFN5O4 (M+H)+: m/z=400.0, 402.0. 1H NMR (400 MHz, DMSO-d6): δ 8.07 (dd, J=6.2, 2.5 Hz, 1H), 7.72-7.68 (m, 1H), 7.59 (dd, J=8.8, 8.6 Hz, 1H), 6.54 (t, J=5.7 Hz, 1H), 4.60 (t, J=5.1 Hz, 1H), 3.48-3.43 (m, 2H), 3.32-3.26 (m, 2H), 1.74-1.67 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([O:14][CH3:15])=[O:13])=[C:9]([CH3:16])[CH:8]=[CH:7]2.[CH3:17][O-:18].[Na+].N1C=CC=CC=1.Cl>CO.O.[Cu](I)I>[CH3:17][O:18][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([O:14][CH3:15])=[O:13])=[C:9]([CH3:16])[CH:8]=[CH:7]2
Reactant: COC(=O)c1c(C)ccc2cccc(Br)c12
Reactant: C[O-]
Agent: I[Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1c(C)ccc2cccc(OC)c12
Yield: 40 %

Procedure:
A mixture of methyl 8-bromo-2-methylnaphthalene-1-carboxylate (Intermediate 191, 1.0 g), sodium methoxide (25% wt/solution in methanol, 5 g), copper iodide (0.37 g), and pyridine (13 ml) in methanol (13 ml) was stirred and heated at reflux for 3 days. After cooling, the mixture was diluted with water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, washed with 1M HCl and brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give methyl 8-methoxy-2-methylnaphthalene-1-carboxylate (0.33 g) as a lilac oil.
Reaction SMILES: C1(O)C=CC=CC=1.[C:8]([CH:11]([CH2:21][CH2:22][CH2:23][CH:24]([OH:37])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](C(C)(C)C)=[CH:29][CH:28]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])(=[O:10])[CH3:9]>>[C:8]([CH:11]([CH2:21][CH2:22][CH2:23][CH:24]([OH:37])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])(=[O:10])[CH3:9]
Reactant: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(C(C)(C)C)cc1
Solvent: Oc1ccccc1
Product: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccccc1

Procedure:
The synthesis of this compound is carried out by the procedure of Example 10 except that an equivalent amount of phenol is substituted for the 4-tert-butylphenol of Example 10. The title compound is obtained as a colorless viscous oil after purification by silica gel column chromatography.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:34])[S:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([NH:23][C:24](=[O:33])[C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])[CH2:21]O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[Cl:3][CH2:21][CH:20]([NH:23][C:24](=[O:33])[C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[F:32])[C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([S:7][CH:6]([F:34])[F:5])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: O=C(NC(CO)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(NC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Temperature: 45 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A portion of 0.37 g (3.1 mmol) of thionyl chloride was added to 1.20 g (2.75 mmol) of N-[1-[4'-[(difluoromethyl)thio][1,1-biphenyl]4-yl]-2-hydroxyethyl]-2,6-difluorobenzamide and 10 mL of toluene. The mixture was warmed to 45° C. for 3.25 h. An additional portion of 0.25 g (2.1 mmol) of thionyl chloride was added and the mixture was stirred for an additional 1 h. The mixture was cooled to 25° C. and the solvent removed under reduced pressure gave the product 1.18 g (96% yield) as an off-white solid. Chromatography on silica gel (eluted with ethyl acetate/hexanes, 1:2) afforded an analytical sample; m.p. 146-147° C. IR (Nujol): 3290, 1652, 1625, 1539, 1311, 1234, 1065, 1009, 818 cm31 1. 1H-NMR(CDCl3): δ3.96-4.08 (m, 2H), 5.62-5.68 (m, 1H), 6.65 (d, J=7.3 Hz, 1H), 6.86 (t, J=57 Hz, 1H), 6.95-7.02 (m, 2H), 7.30-7.48 (m, 3H), 7.50-7.67 (m, 6H).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[C:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:3]1>CO>[S:2]1[CH:6]=[CH:5][C:4]([CH:7]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:3]1
Reactant: CN1CCC(=C(c2ccsc2)c2ccsc2)CC1
Agent: Cl
Solvent: CO
Product: CN1CCC(C(c2ccsc2)c2ccsc2)CC1
Yield: 11 %

Procedure:
9.5 grams (0.03 mole) of 4-(di-3-thienyl-methylene)-N-methyl-piperidine hydrochloride were dissolved in 270 ml of methanol and hydrogenated in the presence of 9.5 grams of PdBaSO4 (9.25% Pd) at 65° C. and 5 bar. The purification was carried out by dry column chromatography on silica gel (elution agent: chloroform/methanol=95%/5% by volume) and recrystallization from chloroform/petroleum ether. M.P. of the hydrochloride 251°-253° C.; Yield: 11%.