Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=3[N+:22]([O-:24])=[O:23])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C(OC([N:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][OH:40])=O)(C)(C)C.[H-].[Na+].[Cl-:43].[NH4+]>CN(C=O)C>[ClH:43].[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:40][CH2:39][C@@H:35]4[CH2:36][CH2:37][CH2:38][NH:34]4)[CH:18]=[CH:17][C:16]=3[N+:22]([O-:24])=[O:23])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: [Cl-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC[C@@H]2CCCN2)ccc1[N+](=O)[O-]
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide (3.0 g) and (S)-(−)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol (2.54 g) in DMF (45 ml) was added sodium hydride (1.34 g of a 60% dispersion in oil) portion-wise (ice bath cooling). The reaction was stirred for 24 hours at room temperature under an atmosphere of argon. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution (200 ml) and the resulting precipitate was collected by filtration, dissolved in methanol (10 ml) and 4N HCl in dioxane (5 ml) added. The reaction mixture was stirred at room temperature for 16 hours, concentrated and re-precipitated from methanol/ethyl acetate to yield N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitro-5-[(2S)-pyrrolidin-2-ylmethoxy]benzamide hydrochloride salt (2.25 g) as a yellow solid which was used without further purification; Mass Spectrum: M+H+ 439.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[CH:7]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH3:12])[N:10]=2)[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nc2ccc(I)cn12
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nc2ccc(I)cn2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-iodo[1,2,4]triazolo[4,3-α]pyridin-3(2H)-one (Intermediate 13, 360 mg, 1.379 mmol) in anhydrous dimethylformamide (DMF, 4 mL) was added sequentially cesium carbonate (1.35 g, 4.14 mmol) and iodomethane (0.52 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate, and the precipitated solids were removed by filtration. The filtrate was washed with saturated aqueous brine, dried (magnesium sulfate), and concentrated to dryness under reduced pressure. The residue was purified by preparative thin layer chromatography (silica gel, 3% methanol/dichloromethane) to afford the title compound. LC/MS 257.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:17])=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9](OCC)=[O:10].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:17])=[C:8]([CH2:9][OH:10])[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cccc(OCc2c(C)cccc2C)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cccc(CO)c1C
Reaction time: 4 h

Procedure:
To a solution of Ethyl 3-(2,6-dimethylbenzyloxy)-2-methylbenzoate (Step B, 5.94 g, 19.93 mmol) in dry THF (35 ml) was added drop wise LiAlH4 (1M in THF, 0.832 g, 21.92 mmol) at 0° C. under argon. The reaction mixture was stirred for 4 hours or until all the starting material is consumed, then quenched slowly with 0.1N HCl at 0° C., and EtOAc (20 ml) was added to the reaction mixture. The reaction mixture was filtered and precipitate was washed with EtOAc (25 ml×2). The combined organic layer was washed with 0.1N HCl, brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)[C@H:13]([OH:25])[C:14]([C:16]1([C:22](O)=[O:23])[CH2:20][CH2:19][CH2:18][CH:17]1[NH2:21])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([O:44][C:45](=[O:65])[C@H:46]([CH2:48][CH2:49][CH2:50][NH:51][C:52](=[NH:64])[NH:53][C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:44][C:45](=[O:65])[C@H:46]([CH2:48][CH2:49][CH2:50][NH:51][C:52](=[NH:64])[NH:53][C:54]([O:56][CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)=[O:55])[NH:47][C:22]([C:16]1([C:14](=[O:15])[C@@H:13]([OH:25])[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH:17]1[NH2:21])=[O:23])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CS(=O)(=O)c1ccc(C[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C(=O)C2(C(=O)O)CCCC2N)cc1
Reactant: N=C(NCCC[C@H](N)C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Product: CS(=O)(=O)c1ccc(C[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C(=O)C2(C(=O)N[C@@H](CCCNC(=N)NC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)CCCC2N)cc1
Yield: 30 %

Procedure:
By working in a way similar to that described in example 1 and using 1-[(2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-(4-methylsulfonyl-phenyl)-butanoyl]-amino-1-cyclopentanecarboxylic acid (0.4 g; 0.00077 moles), prepared as described in example 15, and Nω -benzyloxycarbonyl-L-arginine benzyl ester (0.614 g; 0.00154 moles) as starting compounds, Nα -[1-[(2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4(4-methylsulfonyl-phenyl)-butanoyl]-amino-1-cyclopentanecarbonyl]-Nω -benzyloxycarbonyl-L-arginine benzyl ester was obtained (0.207 g; 30% yield).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([O:11][CH:12]=[CH:13][C:14](Cl)=[O:15])[CH3:10]>N1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:14](=[O:15])[CH:13]=[CH:12][O:11][CH2:9][CH3:10]
Reactant: Nc1ccccc1F
Reactant: CCOC=CC(=O)Cl
Solvent: c1ccncc1
Product: CCOC=CC(=O)Nc1ccccc1F
Yield: 17.7 %

Procedure:
A solution of 2-fluoroaniline (ex. Aldrich) (3 g) in pyridine (20 ml) was treated at 0° with 3-ethoxyacryloyl chloride (3.64 g) (Prepared according to Paul et al, U..S. Pat. No. 2,768,174, (1956)). After 30 minutes at 0°-10° the reaction mixture was partitioned between ether and water and worked-up in conventional fashion. Chromatography on silica (ether : hexane, 1:1) gave N-(2-fluorophenyl)-3-ethoxyacrylamide (1 g). The latter was added in portions to conc. sulphuric acid (15 ml) at room temperature. After stirring overnight the mixture was poured onto ice-water. The resultant cream precipitate was collected and dried in vacuo to give 2-hydroxy-8-fluoroquinoline. This was converted to 2-chloro-8-fluoroquinoline by anlogy with Example IV.
Reaction SMILES: [CH2:1]([SH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N([C:25]([CH3:29])([CH3:28])C#N)=NC(C)(C)C#N.[CH2:30]([O:33][CH2:34][C:35]([CH2:46][O:47][CH2:48][CH:49]=[CH2:50])([CH2:41][O:42][CH2:43][CH:44]=[CH2:45])[CH2:36][O:37][CH2:38][CH:39]=[CH2:40])[CH:31]=[CH2:32]>>[CH2:1]([S:17][CH2:50][CH2:49][CH2:48][O:47][CH2:46][C:35]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:29][CH2:25][CH3:28])([CH2:41][O:42][CH2:43][CH2:44][CH2:45][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:34][O:33][CH2:30][CH2:31][CH2:32][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCOCC(COCC=C)(COCC=C)COCC=C
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: CCCCCCCCCCCCCCCCS
Product: CCCCCCCCCCCCCCCCSCCCOCC(COCCCSCCCCCCCCCCCCCCCC)(COCCCSCCCCCCCCCCCCCCCC)COCCCSCCCCCCCCCCCCCCCC
Temperature: 80 °C

Procedure:
A 250 ml three-necked flask equipped with a magnetic stirrer, a condenser and a nitrogen inlet tube was first purged with nitrogen 107 grams of n-hexadecyl mercaptan (0.417 mole) was then charged and heated to 80° C. To the heated and stirred n-hexadecyl mercaptan, a solution of 0.2 gram of 2,2'-azobis(isobutyronitrile) in 29.64 grams (0.1 mole) of pure pentaerythritol tetraallyl ether was added dropwise over a 15-minute period. One-half hour after this addition was completed, 0.1 gram of 2,2'-azobis(isobutyronitrile) was added. Two more 0.1 gram additions of 2,2'-azobis-(isobutyronitrile) were made at half-hour intervals. After the last addition, the reaction was held at 80° C. for an additional hour. The crude product was recrystallized three times in 300 ml. of hexane yielding 57 grams of a white solid having a melting point of 55°-57° C. The elemental analysis found: C - 73.4%, H - 11.9%, S(total) - 10.0%, and S(mercapto) - 3 ppm. Calculated for C98H164S2 ; C - 73.12%, H-12.43%, S(total) - 9.64% and S(mercapto) - 4 ppm.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:18]#N)[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.Cl.[OH2:39]>C(Cl)Cl>[Cl:21][C:6]1[C:7]([CH3:20])=[C:8]([CH:18]=[O:39])[C:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cc(F)cc(F)c1
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1c(Cl)cc(C(C)O)c(-c2cc(F)cc(F)c2)c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a mixture of 6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carbonitrile (2.43 g, 7.95 mmol) in methylene chloride (50 mL) was added 1.0 M diisobutylaluminum hydride in hexane (19.9 mL, 19.9 mmol) at −78° C. The reaction was warmed to rt over 2 h with stirring. 5.0 M Hydrogen chloride in water (70 mL) was added slowly, and stirring was continued for 1 h. The resultant mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated to dry. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexanes, to give the desired product (2.4 g, 97%). LCMS calculated for C16H12ClF2O (M-OH)+: m/z=293.1; Found: 293.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10]C(=O)O[C:7](=[O:12])[C:6]=2[CH:13]=1.[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1>CS(C)=O.CCOC(C)=O>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:13][C:6]=1[C:7]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:18][CH2:17]1)=[O:12]
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1ccc(O)cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step 2): A mixture of 6-hydroxy-1,2-dihydro-4H-3,1-benzoxazin-2,4-dione (360 mg, 2 mmol) and 4-aminomethyl-1-diphenylmethylpiperidine (420 mg, 1.5 mmol) in DMSO (5 ml) was stirred for 3 hours at room temperature. The reaction mixture was diluted with AcOEt and washed twice with brine. The organic layer was dried over MgSO4 and evaporated, and then the residue was purified by column chromatography on silica gel to give 2-amino-5-hydroxy-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide, 520 mg (63%).
Reaction SMILES: ClC1C=CC(C[C:7]2[C:16]([C:17]([NH2:19])=[O:18])=[C:15]([OH:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:13]=3)[N:8]=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43][CH2:44]Cl)=[CH:39][CH:38]=1.Cl[CH2:47][Cl:48]>CN(C=O)C>[Cl:48][C:47]1[CH:14]=[CH:13][C:12]([CH2:21][NH:19][C:17]([C:16]2[C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:13]=3)[N:8]([CH2:44][S:43][C:40]3[CH:39]=[CH:38][C:37]([Cl:36])=[CH:42][CH:41]=3)[CH:7]=2)=[O:18])=[CH:11][CH:10]=1
Reactant: NC(=O)c1c(Cc2ccc(Cl)cc2)nc2ccc(CN3CCOCC3)cc2c1O
Reactant: ClCSc1ccc(Cl)cc1
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CSc2ccc(Cl)cc2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 105 °C

Procedure:
A suspension of N-(4-chlorobenzyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.25 gm) from Preparation No. 40 and cesium carbonate (0.39 gm) in DMF (3 mL) is treated with chloromethyl 4-chlorophenyl sulfide (0.13 mL). The mixture is tightly capped and heated to 105° C. for 2 hrs. The reaction mixture is allowed to cool to room temperature, diluted with dichloromethane (50 mL), washed with water (2×10 mL), brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 1% to 3% methanol in dichloromethane and then by trituration with ethyl acetate to afford 0.26 gm of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][C:12]2=[O:21])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:30][CH2:31][C:32](Cl)=[O:33].O>C1COCC1>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:21])[C:11]2=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:32](=[O:33])[CH:31]=[CH2:30])[CH:10]=2)[CH2:6][O:7]1
Reactant: O=C(Cl)CCBr
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Temperature: 45 °C
Yield: 89.3 %

Procedure:
To a stirred mixture of 3-(6-amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one (300 mg, 1.0 mmol) and triethylamine (0.41 ml, 3.0 mmol) in THF (10 ml), was added 3-bromopropionyl chloride (0.12 ml, 1.2 mmol). The mixture was heated at 45° C. for 2 hours, cooled to room temperature and poured into water (150 ml). The solid was filtered, washed with water and dried under vacuum to give crude product. The crude product was triturated with toluene to afforded N-[3-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-acrylamide as a bright yellow solid (315 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][Br:10])=[CH:4][C:3]=1[S:12](=[O:15])(=[O:14])[NH2:13].[CH2:16]([NH:20][C:21]([NH:23][CH3:24])=[S:22])[CH:17]([CH3:19])[CH3:18]>>[BrH:10].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:11])[CH2:9][S:22][C:21](=[N:20][CH2:16][CH:17]([CH3:19])[CH3:18])[N:23]2[CH3:24])=[CH:4][C:3]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: CNC(=S)NCC(C)C
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Product: Br
Product: CC(C)CN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1C

Procedure:
6.2 g of 4'-chloro-3'-sulfamoyl-2-bromoacetophenone and 3.0 g of 1-isobutyl-3-methylthiourea were reacted according to the prescription made in Example 23 and the colorless end product was precipitated with 200 ml of diethyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[C:5](/O)=[CH:6]/[C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)=O)[CH3:2].[CH3:19][NH:20][NH2:21]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[N:20]([CH3:19])[N:21]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[CH:6]=1)=[O:18])[CH3:2].[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:20]([CH3:19])[N:21]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)/C(O)=C/C(=O)c1ccc(Cl)c(Cl)c1
Reactant: CNN
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)n(C)n1
Product: CCOC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)nn1C

Procedure:
In analogy to the procedure described for example 4 b], (Z)-4-(3,4-dichloro-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester was reacted with methylhydrazine in ethanol under reflux conditions to give 5-(3,4-dichloro-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester as colorless crystals and 5-(3,4-dichloro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].Br[C:17]1[C:25]2[NH:24][C:23]3[CH2:26][CH2:27][N:28]([CH3:30])[CH2:29][C:22]=3[C:21]=2[CH:20]=[CH:19][CH:18]=1>C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[CH3:30][N:28]1[CH2:27][CH2:26][C:23]2[NH:24][C:25]3[C:17](/[CH:9]=[CH:8]/[C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]=2[CH2:29]1
Reactant: CN1CCc2[nH]c3c(Br)cccc3c2C1
Reactant: C=Cc1ccc(C)nc1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(/C=C/c2cccc3c4c([nH]c23)CCN(C)C4)cn1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
A mixture of bis(tri-t-butylphosphino)palladium (25.4 mg, 0.05 mmol; Aldrich), the product of Example 1B (142 mg, 1.19 mmol), sodium t-butoxide (159 mg, 1.66 mmol; Aldrich) and the product of Example 1A (200 mg, 0.66 mmol) was combined with 1,4-dioxane (6 mL). The reaction mixture was purged with nitrogen and stirred at 105° C. for 4 hours in a sealed tube. The mixture was then heated at 105° C. for another 60 hours. The reaction mixture was cooled to room temperature, filtered through a glass microfiber frit, rinsed with CH3OH (3 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 50-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 2.54 (s, 3H), 2.56 (s, 3H), 2.90 (t, J=5.8 Hz, 2H), 2.98 (t, J=5.6 Hz, 2H), 3.69 (br s, 2H), 7.02 (t, J=7.6 Hz, 1H), 7.23 (d, J=16.5 Hz, 1H), 7.29-7.33 (m, 2H), 7.40 (d, J=7.3 Hz, 1H), 7.67 (d, J=16.5 Hz, 1H), 8.02 (dd, J=8.2, 2.1 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H); MS (APCI) m/z 304 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl.C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cccc(CCl)c1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1cccc(CN2N=C(c3ccc(OC)c(OC)c3)[C@@H]3CCCC[C@@H]3C2=O)c1

Procedure:
Prepared from compound 1 and 3-methoxybenzylchloride as described for compound 78. Crystallized from methanol. M.p. 115° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[C:14]([I:15])[C:9]=2[O:8][N:7]=1)=[O:4].S(OC)(O[CH3:23])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:18][C:2]([F:17])([F:1])[C:3]([N:5]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[C:14]([I:15])[C:9]=2[O:8][N:7]=1)[CH3:23])=[O:4]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc2c(NC(=O)C(F)(F)F)noc2c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2c(N(C)C(=O)C(F)(F)F)noc2c1I
Temperature: 50 °C

Procedure:
To 2,2,2-trifluoro-N-(7-iodo-6-methylbenzo[d]isoxazol-3-yl)acetamide in acetone (5.0 mL) at RT was added dimethyl sulfate (766 mg, 6.07 mmol) and potassium carbonate (1.40 g, 10.12 mmol). The mixture was heated at 50° C. in an oil bath for 5 h, then cooled to RT, filtered through a pad of Celite and rinsed with additional acetone (2×5 mL). The filtrate was concentrated to dryness to provide 2,2,2-trifluoro-N-(7-iodo-6-methylbenzo[d]isoxazol-3-yl)-N-methylacetamide. MS (ESI, pos. ion) m/z: 385.0 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:16])[CH:13](Br)[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>C(O)CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:16])[CH:13]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(Br)C(C)Cc1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: OCCO
Product: CC(Cc1ccc(C(C)(C)C)cc1)C(C)N1CCCCC1

Procedure:
21.2 g of 3-(p-tert.butyl-phenyl)-1,2-dimethyl-propyl bromide, 17 g of piperidine and 7.5 g of ethyleneglycol are heated to 110° C. for 60 hours. After cooling, the mixture is treated with 2-N hydrochloric acid and the neutral constituent is extracted with ether. Subsequently, the hydrochloric acid solution is made alkaline with 5-N sodium hydroxide solution and extracted with ether. The combined ether extracts are washed neutral with water, dried over sodium sulphate and evaporated. By distillation there is obtained pure 1-[3-(p-tert.butyl-phenyl)-1,2-dimethyl-propyl]-piperidine (boiling point 125° C./0.005 Torr) in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[N:10]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34].C1CCN2C(=NCCC2)CC1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]([F:25])([F:35])[F:36])=[O:20])=[CH:17][CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: NCc1ccccc1C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCc1ccccc1C(F)(F)F)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Temperature: 85 °C
Yield: 21.8 %

Procedure:
The mixture of methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.280 mmol), 1-[2-(trifluoromethyl)phenyl]methanamine (0.075 g, 0.430 mmol), 1,2,4-traizole (0.004 g, 0.05 mmol) and DBU (0.009 g, 0.005 mmol) was heated at 80-90° C. in seal tube for 15 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was washed with dilute HCl and water, dried over anhydrous sodium sulphate and concentrated to afford 0.030 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 4.66-4.68 (d, J=4.2 Hz, 2H), 7.45-7.75 (m, 7H), 8.05 (s, 4H), 9.16 (br s, 1H), 12.73 (br s, 1H); MS (m/z): 489.42 (M−H)−.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1.ClC(OCC)=O.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C([N:34](CC)CC)C>>[N:26]1([NH:34][C:11](=[O:13])[CH2:10][CH2:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: CCN(CC)CC
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: c1ccccc1
Product: O=C(CCC(=O)c1ccccc1)NN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
A suspension of 17.8 grams (0.1 mole) of β-benzoyl-propionic acid (Organic Synthesis, 2:81) in 500 milliters of dry benzene is prepared and 10.5 grams of triethylamine, 15 grams of ethyl chloroformate, and 18 grams (0.2 mole) of morpholine are sequentially added. The suspension is stirred for two hours at room temperature and then filtered to remove the precipitated triethylamine hydrochloride. The mother liquor is evaporated in a small amount for filtration and the solid product which is obtained, is separated by filtration and crystallized from ethanol to provide about 15 grams of N-morpholinyl-β-benzoyl-propionamide having a melting point of 87°-89° C.