Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1.[NH:12]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:13]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(C(F)(F)F)cc2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
4-(Trifluoromethyl)iodobenzene (145 μl, 1.0 mmol), tert-butyl (3R)-pyrrolidin-3-ylcarbamate (0.22 g, 1.2 mmol), potassium phosphate (0.43 g, 2.0 mmol), ethylene glycol (0.11 mL, 2.0 mmol), copper(I) iodide (19 mg, 0.10 mmol) and 2-propanol (1 mL) were charged in a threaded test tube, and the mixture was stirred overnight at 80° C. The solvent was evaporated, and the residue was worked-up according to a conventional method. The obtained crude product was purified by silica gel column chromatography (15% mixed solvent of ethyl acetate/hexane) to give the title compound (0.07 g, 0.21 mmol, 21%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH2:14]Br>CN(C=O)C>[C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=O)cc1
Reactant: BrCBr
Solvent: CN(C)C=O
Product: C=Cc1ccc(OC(C)=O)cc1
Reaction time: 1 h

Procedure:
Then a mixture obtained by mixing 32.8 g of p-acetoxybenzaldehyde (PABA) (0.2 mol) and 52.15 g of dibromomethane (0.3 mol) in 85 g of anhydrous DMF was dropping for 1 hour keeping the internal temperature at 50° C. Then agitation was continued for 40 minutes under the same temperature.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][OH:21]>[Na]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([O:21][CH3:20])[N:15]=[C:14]([NH2:19])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N)n2)cc1
Agent: [Na]
Product: COc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(N)n1
Temperature: 150 °C
Reaction time: 9 h
Yield: 94 %

Procedure:
0.27 g (0.0009 mol) of 4-amino-N-(2-amino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide was dissolved in a solution of 0.23 g of sodium in 20 ml of methanol and stirred in an autoclave at 150° C. for 9 hours. The solvent was distilled off, the residue was added to water and the pH value was adjusted to 4-5 with 1N HCl. The precipitate which thereby separated was filtered off under suction, washed with water and dried. The crystals obtained were triturated in 20 ml of methanol, again filtered off and dried in a high vacuum. There was obtained 0.25 g (94%) of 4-amino-N-(2-amino-6-methoxy-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.: >250° C. (dec.).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[CH:8](=[C:2]1/[C:1](=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3]/1)\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCCC/C1=C\c1ccccc1
Temperature: 98 °C
Yield: 32.8 %

Procedure:
Into an inert 100 gallon reactor, there is drawn 29.3 kg of cyclohexanone from a grounded drum on a weight scale. The reactor is vented with nitrogen and then 28.5 kg of benzaldehyde is added. Then 125 liters of deionized water is metered into the above mixture. The vessel is closed and `reinerted` with nitrogen. To the resulting reactor contents there is added, from a grounded drum on a weight scale, a 50 percent (w/v) solution of sodium hydroxide in water solution, (10.6 kg), while stirring the mixture. The resulting mixture is stirred and heated to reflux (about 98° C.). under an atmosphere of nitrogen. The mixture is held at reflux temperature for about three hours and then stirred and cooled overnight. The resulting cooled reaction mixture is extracted once with a 198 liter batch of methylene chloride, separating the aqueous layer, and then again with 132 liters of methylene chloride, neutralizing and discarding the aqueous layer. The combined methylene chloride liquid layers are washed with 284 liters of water and then with 284 liters of water containing 50 ml of acetic acid. After aqueous layer separation, the methylene chloride liquid layer is dried over sodium sulfate with stirring. The resulting dried methylene chloride layer is concentrated to an oil using 35° C. jacket water temperature and jet vacuum procedures. The (E)-2-(benzylidene)cyclohexanone is crystallized by dissolving the oily residue in 60 liters of Skellysolve® B and seeding with authentic material and cooling the vessel overnight by circulating a cooled water/methanol mixture through the reactor jacket. The pale yellow crystals are collected on a 24-inch filter, washed with Skellysolve® B, and recrystallized from 75 gallons of Skellysolve® B by heating to 50° C. to effect dissolution and then cooling the tank contents to 0° C. Alternatively, we have used isopropanol in this crystallization step with approximately equal effectiveness in terms of quality of the crystalline intermediate (E)-2-(benzylidene)cyclohexanone. The crystalline intermediate is dried in a vacuum oven at room temperature to give about 16.4 kg (33 percent yield) of the (E)-2-(benzylidene)cyclohexanone, m.p. 47°-54° C. (Lit. m.p. 54° C.). TLC analysis (silica gel GF; 5 percent ethyl acetate in Skellysolve® B developer) indicates the presence of a small amount of a less polar impurity, identified as ##STR10## on the basis of isolation and melting point.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Br[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31]>O>[CH3:1][O:2][C:3]([CH2:4][N:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:29][C:30]([OH:32])=[O:31])[C:6]1=[O:15])=[O:16]
Reactant: COC(=O)CN1Cc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1Cc2ccccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid methyl ester (9.5 g, 29.3 mmol) and K2CO3 (2.5 eq, 10.31 g, 73.3 mmol) in a round bottom flask are treated with dry DMF. Tert-Butyl bromoacetate (1.02 eq, 4.2 ml, 30 mmol) is added dropwise via syringe under argon. The reaction suspension is stirred at RT for one hour. The reaction mixture is diluted with distilled water and extracted with EtOAc (3×). The separated organic layer is dried over MgSO4, filtered and the solvent concentrated in vacuo. The title compound is obtained as brown viscous oil crystallizing on standing. [M+H]+ 335.
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C(O)C.[I-:29].[K+]>O>[I-:29].[CH3:1][CH:2]([N+:14]([CH3:16])([CH3:15])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13]
Reactant: CC1=CCCC(C)(C)C1/C=C/C(C)N(C)C
Reactant: ClCc1ccc(Cl)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1=CCCC(C)(C)C1/C=C/C(C)[N+](C)(C)Cc1ccc(Cl)cc1
Yield: 131.7 %

Procedure:
A mixture of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2-(trans)propenyl]dimethylamine (2.2 g), α,4-dichlorotoluene (0.8 g) and ethanol (30 cc) was refluxed for 1 hour, and thereto were added water (100 cc) and potassium iodide (5.0 g). The reaction mixture was extracted with chloroform, and the chloroform layer was dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol to give crystals (3.1 g) of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethyl(4-chlorobenzyl)ammonium iodide.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>C(O)(=O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]2=[O:16])=[CH:5][CH:4]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1Nc1ccc(Br)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
To a stirred solution of (4-bromophenyl)hydrazine hydrochloride (0.5 g, 2.2 mmol) in glacial acetic acid (8 mL) was added phthalic anhydride (0.398 g, 2.690 mmol), and the reaction mixture was stirred at 130° C. for 1 h under a nitrogen atmosphere. The reaction mixture was quenched with satd aq. NaHCO3 solution and filtered to give a solid. Purification by column chromatography (SiO2, 0-10% EtOAc in petroleum ether) afforded the title compound as a solid (60 mg, 84%): mp 205-206° C.; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.99 (m, 4H), 7.32 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H); ESIMS m/z 314.95 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][C@:5]1([CH3:37])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26]C(=O)OC(C)(C)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36].[ClH:40]>O1CCOCC1>[ClH:40].[NH2:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:16]([C:7]3[C:6](=[O:36])[C@@:5]([CH2:4][CH2:3][C:2]([CH3:1])([CH3:38])[CH3:39])([CH3:37])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:17][S:18](=[O:35])(=[O:34])[C:19]=2[CH:25]=1
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 93 %

Procedure:
A solution of Example 49F (1.91 g, 3.45 mmol) in 4 M hydrochloric acid in 1,4-dioxane (30 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give 1.58 g (93%) of the title compound. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.38 (td, J=12.87, 3.68 Hz, 1 H) 0.78 m, 10 H) 1.59 (s, 3 H) 2.08 m, 1 H) 2.23 (td, J=12.78, 4.60 Hz, 1 H) 7.07 m, 2 H) 7.53 m, 2 H) 7.77 m, 2 H) 8.16 (d, J=7.72 Hz, 1 H) 13.58 (s, 1 H); MS (ESI+) m/z 454 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].CC(O)=O.[Cl:8][C:9]1[C:14]([CH:15]=O)=[C:13]([Cl:17])[N:12]=[C:11]([S:18][CH3:19])[N:10]=1>CCO>[Cl:8][C:9]1[C:14]([CH:15]=[N:2][OH:3])=[C:13]([Cl:17])[N:12]=[C:11]([S:18][CH3:19])[N:10]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CSc1nc(Cl)c(C=NO)c(Cl)n1
Temperature: 70 °C
Yield: 39.9 %

Procedure:
To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 mL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50° C. for about 1 hour, 60° C. for about 30 minutes and 70° C. for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80%). LC-MS m/z 238 (M+H)+1.57 minute, 1.65 minute; 1H-NMR (CDCl3) δ 2.62, 2.65 (3 H), 7.53, 8.30 (1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([O:21][C:24]2[CH:23]=[CH:22][C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=2)=[O:20])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(=O)O)c2c3c(n(C)c12)C(=O)N(C)CC3
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3c(n(C)c12)C(=O)N(C)CC3

Procedure:
A solution of 8-methoxy-2,9-dimethyl-1-oxo-1,2,3,4-tetrahydro-β-carboline-5-carboxylic acid (from step 5) (1 mmol), p-nitrophenol (1.5 mmol), EDCI (1.5 mmol) and DMAP (0.1 mmol) in dry THF was stirred at r.t. for 18 h. Minimum water was then added and the precipitated p-nitrophenylester was filtered and washed with water and dried (50-60%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC>O1CCCC1>[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](=[O:14])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccncc1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cc1ccncc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 4-methylpyridine (74.4 g) and ethyl 4-fluorobenzoate (134.4 g) in dry tetrahydrofuran (600 ml) was added a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.6 l) dropwise with ice cooling. The mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture was added hexane (12.2 l) and the separated solid was collected, washed with hexane and dried. The obtained solid was dissolved in 3N-hydrochloric acid (800 ml) and the solution was neutralized with an aqueous saturated sodium bicarbonate solution. The separated solid was collected, washed with water and dried to give 1-(4-fluorophenyl)-2-(pyridin-4-yl)ethan-1-one (148 g).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[NH:32]([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:32]([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35])=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: OCCNCCO
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(CCO)CCO

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and diethanolamine. Elementary analysis: as C32H53O4N
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.[N:38]1([C:45](=O)[CH2:46]Cl)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:45][CH2:46][O:37][C:36]2[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:3][C:2]=2[F:1])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(CCl)N1CCCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCCCC3)c(F)c2)c1
Yield: 35.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azepan-1-yl-2-chloroethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.5 mg) was obtained.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (4.91 g, 16.56 mmol) and triphenylphosphine (6.52 g, 24.85 mmol) in methylene chloride (41 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (5.01 g, 28.16 mmol) in small portions. The reaction mixture color changed from light yellow to a darker yellow then to brown. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The brown reaction mixture was then treated with 2-aminothiazole (4.98 g, 49.69 mmol). The resulting reaction mixture was stirred at 25° C. for 19 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining black residue was diluted with a 10% aqueous hydrochloric acid solution (400 mL) and then extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate then 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (4.49 g, 72%) as a white solid: mp 216-217° C.; EI-HRMS m/e calcd for C18H22N2O3S2(M+) 378.1072, found 378.1071.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][N:10]=[C:9]2[CH:13]=O)=[CH:4][CH:3]=1.C(OP([CH2:23][C:24]([O:26]CC)=[O:25])(OCC)=O)C.[H-].[Na+].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[N:11][N:10]=[C:9]2/[CH:13]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:6][CH:7]=1
Reactant: O=Cc1nncn1-c1ccc(F)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1nncn1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A mixture of 4-(4-fluorophenyl)-4H-1,2,4-triazole-3-carbaldehyde (3.83 g), ethyl diethylphosphonoacetate (5.60 g), sodium hydride (60% in oil, 0.88 g) and tetrahydrofuran (130 ml) was stirred at 0° C. for 1 hr. The reaction mixture was poured into an aqueous dilute hydrochloric acid solution and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in a 6N aqueous hydrochloric acid solution (100 ml) and stirred for 2 hrs. with heating under reflux. Disodium hydrogen phosphate was added to neutralize the reaction mixture. The precipitated solids were collected by filtration, washed with water and dried to give (2E)-3-[4-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl]acrylic acid (3.60 g, yield 76%) as pale-yellow crystals. melting point: 226-229° C. (recrystallized from ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=O)[NH:12][C:13]4[N:14]([N:16]=[CH:17][C:18]=4[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:11]1[C:10]2[CH:9]=[N:8][C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=3[C:15]=2[N:14]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:13]2[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn2c1[nH]c(=O)c1cnc3c(cnn3CC)c12
Product: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12

Procedure:
256 g of 8-ethyl-5,8-dihydro-5-oxo-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester are refluxed in 1 liter of phosphorus oxychloride for 24 hours. The excess phosphorus oxychloride is decomposed by pouring the solution on ice and the crystallized 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]-pyrimidine-3-carboxylic acid, ethyl ester is filtered off, yield 245 g (91%); m.p. 170°-172° (butyl alcohol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:43])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]1([C:34]2[CH:33]=[C:32]([C:28]3[CH:27]=[C:26]([C:24]4[CH2:23][C:22](=[O:43])[NH:21][C:9]5[CH:10]=[C:11]([C:17]([F:20])([F:18])[F:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=5[N:7]=4)[CH:31]=[CH:30][CH:29]=3)[CH:37]=[CH:36][N:35]=2)[CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CCCC4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C4CCCC4)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopentyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M273) (360 mg, 0.589 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (198 mg, 68%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:15][C:16]1[CH:20]=[CH:19][NH:18][N:17]=1>C(O)(=O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[NH:2][C:1]([NH:15][C:16]1[CH:20]=[CH:19][NH:18][N:17]=1)=[CH:3]2
Reactant: Nc1cc[nH]n1
Reactant: COc1ccc(C(=O)O)c(CC#N)c1
Solvent: CC(=O)O
Product: COc1ccc2c(=O)[nH]c(Nc3cc[nH]n3)cc2c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
2-Cyanomethyl-4-methoxy-benzoic acid (1.91 g, 0.01 mol), 3-amino-pyrazole (1 g, 0.01 mol) and acetic acid (15 ml) were sealed in a bottle (20 ml). The mixture was heated at 130° C. for 20 minutes under microwave irradiation. The mixture was concentrated and the residue was dissolved in 5 ml MeOH. The solution was added dropwise to 200 ml water. After stirred for 1 hour, solid was collected and dried to give product (2.24 g, 82% yield). LC-MS:
Reaction SMILES: O1CCCC1.[C:6]1([C:12]2[N:13]=[C:14]([C:23]3[CH:24]([CH2:28][C:29]4[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=4)[C:32]([OH:34])=O)[CH2:25][CH2:26][CH:27]=3)[O:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.ClC(OCC)=O.[NH3:44]>C(N(CC)CC)C>[C:6]1([C:12]2[N:13]=[C:14]([C:23]3[CH:24]([CH2:28][C:29]4[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=4)[C:32]([NH2:44])=[O:34])[CH2:25][CH2:26][CH:27]=3)[O:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N
Reactant: O=C(O)c1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran solution (10 ml) of 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}benzoic acid (0.30 g) and triethylamine (0.15 ml) was added ethyl chloroformate (0.15 ml) at 0° C. The solution was stirred for 30 minutes at the same temperature. Then aqueous ammonia (10 ml) was added to the solution. After stirred for 6 hours at 0° C., the solution was partitioned between ethyl acetate and water. The organic layer was washed with water, 1N hydrochloric acid, water and brine. After dried over MgSO4, the solvent was evaporated in vacuo to afford 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}benzamide (0.24 g).