Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH:44]1CC[S:46](=[O:50])(=[O:49])[CH2:45]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH:14]3[CH2:44][CH2:45][S:46](=[O:50])(=[O:49])[CH2:15]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: O=S1(=O)CCC(Br)C1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(C3CCS(=O)(=O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromo-tetrahydro-thiophene 1,1-di oxide and isolated as white solid. MS (m/e): 401.3 (MH+).
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]([C@H:17]2[O:19][C@@H:18]2[C:20](O)=[O:21])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[N:24]1C(=O)C[CH2:26][C:25]1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.C(N)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([NH:24][C:20]([C@@H:18]1[C@@H:17]([C:15](=[O:16])[NH:14][CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:19]1)=[O:21])[CH3:26]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)[C@H]1O[C@@H]1C(=O)NC(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@H]1O[C@@H]1C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S, 3S)-3-diphenylmethylcarbamoyloxirane-2-carboxylic acid (1.80 g, 6.05 mmol.) and N-hydroxysuccinimide (696 mg, 6.05 mmol) in methylene chloride (10 mL) was added a solution of N,N'-dicyclohexylcarbodiimide (1.25 g, 6.05 mmol.) in methylene chloride (7 mL) under chilling with ice. The mixture was stirred for 30 minutes at room temperature. To the mixture was then added under chilling with ice a solution of ethylamine hydrochloride (493 mg, 6.05 mmol.) and triethylamine (0.84 mL, 6.05 mmol) in methylene chloride (7 mL). The resulting mixture was stirred overnight at 5° C. The solvent was distilled off under reduced pressure, and N,N'-dicyclohexylurea (DC-Urea) was removed by filtration after addition of ethyl acetate (10 mL). The solution was washed successively with water, 0.5N hydrochloric acid, an aqueous sodium hydrogen carbonate saturated solution, and an aqueous sodium chloride saturated solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (chloroform/methanol=1/0 to 50/1), to give the desired compound as a white crystalline powdery product (928 mg, yield: 47%).
Reaction SMILES: Cl.[CH:2]([N:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]([CH3:8])[CH3:7])([CH3:4])[CH3:3].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[O:20]=[C:15]1[CH2:16][CH2:17][C:18](=[O:19])[N:14]1[O:11][C:10](=[O:12])[CH2:9][N:5]([CH:6]([CH3:7])[CH3:8])[CH:2]([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)N(CC(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)N(CC(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.82 g (19.5 mMol) diisopropylamino-acetic acid hydrochloride (3), in 50 ml DMF, was added to 2.24 g (19.5 mMol) N-hydroxysuccinimide and 8.04 g (39 nMol) dicyclohexylcarbodiimide. The reaction mixture was stirred for 16 h at RT. The residue was filtered and the filtrate was evaporated in vacuum to dryness. After dissolving the residue in CH2Cl2, the solution was washed with NaHCO3, dried (sodium sulphate) and the solvent evaporated. The compound was then recrystallised from diisopropylether.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[I:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([OH:18])[CH:9]=1.[CH2:19](Br)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C=O)C>[I:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)cc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A suspension of caesium carbonate (35.2 g, 108 mmol), methyl 4-iodo-2-hydroxybenzoate (25 g, 90 mmol), phenethyl bromide (16 ml, 117 mmol) in DMF (500 ml) is stirred for 10 hours at room temperature. Caesium carbonate (20 g, 61.4 mmol) and phenethyl bromide (8.5 ml, 61.4 mmol) are added to the suspension. The organic phase is acidified at room temperature with a 2N hydrochloric acid solution to pH 5. The desired product is extracted by addition of ethyl ether. The organic phase is washed with water, dried with magnesium sulfate and concentrated using a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:14][C:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([Cl:26])=[CH:21][CH:22]=2)[N:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:16]=1[C:33]1[O:34][CH:35]=[CH:36][N:37]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][CH2:14][C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([Cl:26])=[CH:21][CH:22]=3)[N:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:16]=2[C:33]2[O:34][CH:35]=[CH:36][N:37]=2)=[O:7])=[CH:4][N:3]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=c1c(CBr)c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A 5 mL round-bottomed flask was charged with 6-chloronicotinamide (14 mg, 0.091 mmol), sodium hydride (60% suspension in mineral oil, 5.0 mg, 0.013 mmol) and DMF (1 mL) to give a slightly white suspension. This mixture was stirred at 50° C. for 15 min. During this time, the reaction mixture became more cloudy and difficult to stir. The reaction mixture was cooled to room temperature. A solution of 3-(bromomethyl)-7-chloro-2-(oxazol-2-yl)-1-phenylquinolin-4(1H)-one (38 mg, 0.091 mmol) in DMF (1 mL) was added dropwise to the room temperature reaction mixture. The reaction was stirred at 50° C. over 1 hr. LC/MS at this time suggested formation of the desired product. The reaction mixture was allowed to cool gradually to room temperature, then it was stirred at room temperature overnight. The reaction was quenched via addition of 1 mL water slowly. The quenched reaction mixture was then partitioned between 20 mL ethyl acetate and 20 mL water. The organic phase was dried (MgSO4), filtered, then concentrated over silica gel. The silica gel supported crude product was loaded onto a 40 gram silica gel column. Flash chromatography (75% ethyl acetate-hexanes ramped to 100% ethyl acetate) was used to partially purify the desired product 6-chloro-N-(7-chloro-2-(oxazol-2-yl)-4-oxo-1-phenyl-1,4-dihydroquinolin-3-ylmethyl)nicotinamide from the side product 6-chloro-N,N-bis((7-chloro-2-(oxazol-2-yl)-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methyl)nicotinamide. Homogeneous fractions were concentrated to provide 6-chloro-N-(7-chloro-2-(oxazol-2-yl)-4-oxo-1-phenyl-1,4-dihydroquinolin-3-ylmethyl)nicotin-amide as 1 mg (2% yield) of a white solid. 1H NMR (chloroform-d) δ ppm 8.75 (d, J=2.4 Hz, 1H) 8.42 (d, J=8.6 Hz, 1H) 7.99 (dd, J=8.2, 2.7 Hz, 1H) 7.68 (bs, 1H), 7.58 (s, 1H), 7.45 (m, 3H), 7.39 (dd, J=8.5, 2.0 Hz, 1H) 7.34 (d, J=8.2 Hz, 1H) 7.28 (m, 2H) 7.13 (s, 1H) 6.85 (d, J=2.0 Hz, 1H) 4.47 (d, J=5.5 Hz, 2H). MS calcd. for C25H16C12N4O3 [(M+H)+] 490.1, obsd. 490.9.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O.[OH-].[Ca+2].[OH-].[H][H]>>[OH:12][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: [H][H]
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
As shown in the drawing, a glucose-water feed solution at 10 is mixed with an alkaline promotor material at 11 such as calcium hydroxide. The resulting mixture is pressurized and passed with hydrogen from 12 through preheater 14 to fixed-bed catalytic reactor 16 for hydrogenation reaction to produce mainly sorbitol. The promotor material added at 11 should be sufficient to control pH of feedstream to range of 7-14 to prevent leaching damage to the catalyst in reactor 16. The catalyst is preferably a reduced and stabilized nickel on silica-alumina support, and usually contains 50-66 W % nickel. Catalyst particle size of 0.060 to 0.250 inch can be used. The reaction conditions which can be used in reactor 16 are 130°-180° C. temperature, 500-2000 psig hydrogen partial pressure, and 0.5-3.5 Vf/hr/Vc space velocity to achieve at least about 90 W % conversion of the glucose feed to sorbitol solution.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([NH2:12])[C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:13].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=2)=O)=O)=[CH:17][CH:16]=1>CO>[CH3:1][N:2]1[C:6]2=[CH:7][C:8]3[N:12]=[C:21]([C:18]4[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=4)[C:23]([C:25]4[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=4)=[N:11][C:9]=3[CH:10]=[C:5]2[N:4]=[C:3]1[CH3:13]
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Cc1nc2cc(N)c(N)cc2n1C
Solvent: CO
Product: Cc1nc2cc3nc(-c4ccc(Br)cc4)c(-c4ccc(Br)cc4)nc3cc2n1C
Temperature: 25 °C

Procedure:
To a solution of 1,2-dimethyl-5,6-diaminobenzoimidazole in methanol was added 4,4′-dibromo-benzil. The reaction mixture was refluxed for 3 h and cooled to room temperature. The precipitate which formed was filtered and recrystallized from n-butyl alcohol to give the title quinoxaline.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([OH:17])=[O:16].[OH:18][CH:19]1[CH:24]([OH:25])[CH:23]([OH:26])[CH:22]([CH2:27][OH:28])[O:21][C:20]1=[O:29]>CO>[OH:21][CH:22]([CH:23]([OH:26])[CH:24]([OH:25])[CH:19]([OH:18])[CH2:20][OH:29])[C:27]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:28]
Reactant: O=C1OC(CO)C(O)C(O)C1O
Reactant: NCCOCCOCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO
Temperature: 25 °C

Procedure:
172 mg of sodium carbonate are added to a solution of 450 mg of [2-(2-aminoethoxy)ethoxy]acetic acid and 318 mg of 3,4,5-trihydroxy-6-hydroxymethyltetrahydropyran-2-one in 10 ml of methanol, and the mixture is stirred at room temperature until the reaction has gone to completion. The reaction solution is filtered and concentrated. The residue is taken up in water and acetonitrile (1/1), resulting in the formation of 2 phases. The aqueous phase is concentrated and contains 20:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-:16])[C:5]2[CH:6]=[CH:7][C:8](=[O:15])[N:9]([CH2:12][CH:13]=C)[C:10]=2[CH:11]=1.O.I([O-])(=O)(=O)=[O:19].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:19])=[N+:4]([O-:16])[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)ccc2c1cc(F)c[n+]2[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=CCn1c(=O)ccc2c1cc(F)c[n+]2[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Fluoro-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one 5-oxide (340 mg, 1.544 mmol) was stirred in 1,4-dioxane (16 mL) and water (8 mL) was added, followed by sodium periodate (990 mg, 2.3 eq.) and osmium tetroxide (1 mL of 4% aqueous solution). The mixture was stirred at room temperature for 3 hours. The solvents were evaporated under reduced pressure (water bath temperature 30° C.) to a volume of ca. 10 mL, and the residue was extracted with 20% methanol in DCM (v:v, 3×50 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give (7-fluoro-5-oxido-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde largely as its methyl hemiacetal) as a tan foam (327 mg). LCMS showed major peaks for the aldehyde hydrate (32%) and the methyl hemiacetal (64%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.Br[C:17]1[CH:30]=[CH:29][C:20]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1>>[N:23]1([C:21]([C:20]2[CH:19]=[CH:18][C:17]([NH:1][C:2]3[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:3]=3)=[CH:30][CH:29]=2)=[O:22])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C(c1ccc(Br)cc1)N1CCOCC1
Reactant: NC(=O)c1cn(-c2ccccc2)nc1N
Product: NC(=O)c1cn(-c2ccccc2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1

Procedure:
3-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-1-phenyl-1H-pyrazole-4-carboxamide was prepared according to the general procedure in Example 1 Step 4 using 3-amino-1-phenyl-1H-pyrazole-4-carboxamide (52 mg, 0.257 mmol) and 4-(4-bromobenzoyl)morpholine (69.5 mg, 0.257 mmol) as the starting materials.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[C:33]=2[Cl:42])[CH2:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[ClH:42].[Cl:42][C:33]1[C:34]([C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:16]([CH2:17][CH:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:15][CH2:14][CH2:13][O:12][C:8]1[CH:7]=[C:6]([NH:5][CH2:4][C:3]([OH:43])=[O:2])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CNc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirring solution of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamino)-acetic acid methyl ester in THF (6 ml) and water (2 ml) was added lithium hydroxide monohydrate (20 mg, 0.47 mmol) and the mixture was stirred at room temperature for 6 hours. The reaction mixture was acidified with 1 M aqueous HCl (0.5 mL). The aqueous mixture was concentrated in vacuo and the crude material was dissolved in EtOAc. The ethyl acetate solution was washed with brine (1×), dried over sodium sulfate, and filtered. The organic layer was concentrated, and the crude amine was treated with 1 M HCl (Et2O). The resulting precipitate was dried under vacuum to afford the title compound as a solid. MS(ES) m/e 597.4 (M+).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH:25]([C:28]1[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][C:34](O)=[O:35])=[CH:30][CH:29]=1)([CH3:27])[CH3:26].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([CH:32]=[CH:33][C:34]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:35])=[CH:37][CH:38]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)c1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(C(C)C)cc1
Yield: 97.8 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 4-i-propylcinnamic acid (2.7 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.5 g, 98%) as an oily product.
Reaction SMILES: CO[CH:3]=[C:4]1[C:9](=[O:10])[O:8][C:7]([CH3:12])([CH3:11])[O:6][C:5]1=[O:13].[CH2:14]([SH:16])[CH3:15]>C(O)C>[CH2:14]([S:16][CH:3]=[C:4]1[C:5](=[O:13])[O:6][C:7]([CH3:11])([CH3:12])[O:8][C:9]1=[O:10])[CH3:15]
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: CCS
Solvent: CCO
Product: CCSC=C1C(=O)OC(C)(C)OC1=O
Yield: 60.8 %

Procedure:
5-(Methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (7 g, 38 mmole), described by Bihlmayer et al., supra, was suspended in ethanol (70 ml). The suspension was stirred vigorously while being subjected to the addition of ethanethiol (12.85 g, 200 mmole). The mixture was heated at reflux until all the starting material had been consumed, as indicated by thin layer chromatography (silica gel plates, 30% ethyl acetate in hexane). The volatile portion of the reaction mixture was removed by distillation under reduced pressure. The residue was purified by high pressure liquid chromatography (HPLC, 20% ethyl acetate in hexane, v/v). The purest fractions were combined. The solvent was removed under reduced pressure. The residue was crystallized to give 5.0 g of the title compound; mp 52°-54° C.; NMR (CDCl3) δ 1.45 (t, 3H), 1.7 (s, 6H), 3.02 (q, 2H), 9.0 (s, 1H); IR (CHCl3) 1720, 1700 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[O:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[C:10]2[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(/C=C/C(=O)O)cc2)c2ccc(O)c(Cl)c2)CC(C)(C)O1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of Ethyl (2E)-3-{4-[(3-chloro-4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-propenoate (131) (0.32 g, 0.70 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Upon concentration and adding hexanes, the title compound 132 was obtained as a white powder (0.255 g, 85%). mp 118-121° C. 1H NMR (400 MHz, DMSO-d6): δ 1.10 (s, 6H), 1.12 (s, 6H), 2.11 (s, 2H), 2.13 (s, 2H), 6.47 (d, J=15.9 Hz, 1H), 6.85-7.00 (m, 2H), 7.08 (d, J=1.8 Hz, 1H), 7.19 (d, J=8.2 Hz, 2H), 7.54 (d, J=15.9 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 10.15 (s, 1H), 12.36 (s, 1H). LCMS (ESI): m/z 425 (M−H)−. Anal. Calcd for C25H27ClO4.0.2H2O: C, 69.74; H, 6.41; Found: C, 69.82; H, 6.56.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:19]=[C:18](F)[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])[N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li][N:29]([CH3:31])[CH3:30]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:19]=[C:18]([N:29]([CH3:31])[CH3:30])[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])[N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]N(C)C
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1Nc1cc(F)ccc1C(=O)O
Solvent: C1CCOC1
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1Nc1cc(N(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a solution of 2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-fluorobenzoic acid (Example 248, 35 mg, 0.09 mmol) in THF (1 mL) at −40° C. was added LiNMe2 (0.19 mL, 1 M in hexanes) under nitrogen. The mixture was then stirred at this temperature for 30 min, and then gradually warmed to rt over a 4 h period. The pH of the solution was adjusted to pH 5, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by HPLC using gradient elution from 10 to 80% acetonitrile in water to afford 5.7 mg (15%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 9.55 (s, 1H), 7.73 (d, 1H), 7.22-7.35 (m, 4H), 6.44 (d, 1H), 6.18 (dd, 1H), 6.15 (s, 1H), 3.00 (s, 6H), 2.04 (s, 3H), 1.32 (s, 9H). ES-MS m/z 393.2 (MH30 ); HPLC RT (min) 2.84.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=1[CH3:32]>>[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])=[CH:27][C:26]=1[CH3:32]
Reactant: COc1ccc(N)cc1C
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Cl)cc3)c2)o1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1C

Procedure:
N-(4-Methoxy-3-methylphenyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carbonyl chloride and 4-methoxy-3-methylaniline using method K. NMR; δH [2H6]—DMSO 10.14,(1H, b), 8.05,(2H, d), 7.90,(1H, dd), 7.57-7.55,(5H, m), 6.92,(1H, d), 3.77,(3H, s), 2.57,(3H, s), 2.33,(3H, s), 2.16,(3H, s). LCMS; retention time 3.53 min, MH+ 414.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]1=[NH:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc2ccccc2[nH]1
Product: N=c1n(Cc2ccccc2)c2ccccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 2-aminobenzimidazole and benzyl bromide by Procedure A. The title product was isolated by filtration and washed with acetonitrile and water to give the title compound as the hydrobromide salt (solid, mp>300° C.). MS(ES+) m/z 314 ([M+1]+, 100).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]#[C:31][C:32]([CH3:35])([OH:34])[CH3:33])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]#[C:31][C:32]([OH:34])([CH3:33])[CH3:35])=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cc1nc(Cl)ccc1C#CC(C)(C)O
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1C#CC(C)(C)O

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.32 mmol) and 4-(6-chloro-2-methylpyridin-3-yl)-2-methylbut-3-yn-2-ol (67 mg, 0.32 mmol) as starting materials.