Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(N)(C)CSC.C1(=O)OC(=O)C2=CC=CC=C12.[CH3:19][C:20]([NH:25][C:26](=[O:36])[C:27]1[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:29]([OH:31])=O)([CH3:24])[CH2:21][S:22][CH3:23].C(=O)([O-])O.[Na+].ClC(OC)=O.[CH3:47][C:48]1[CH:54]=[C:53]([C:55]([F:64])([C:60]([F:63])([F:62])[F:61])[C:56]([F:59])([F:58])[F:57])[CH:52]=[CH:51][C:49]=1[NH2:50].Cl>ClCCCl.C(N(CC)CC)C>[CH3:24][C:20]([NH:25][C:26]([C:27]1[C:28]([C:29]([NH:50][C:49]2[CH:51]=[CH:52][C:53]([C:55]([F:64])([C:56]([F:57])([F:58])[F:59])[C:60]([F:61])([F:62])[F:63])=[CH:54][C:48]=2[CH3:47])=[O:31])=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:36])([CH3:19])[CH2:21][S:22][CH3:23]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N
Reactant: CSCC(C)(C)NC(=O)c1ccccc1C(=O)O
Agent: COC(=O)Cl
Agent: CSCC(C)(C)N
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CSCC(C)(C)NC(=O)c1ccccc1C(=O)Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A mixture of 2-methyl-1-methylthio-2-propanamine (11.61 g) and triethylamine (1.97 g) was added dropwise to a mixture of phthalic anhydride (14.42 g) and 1,2-dichloroethane (58 mL) at 50° C. The resulting mixture was stirred at the same temperature for 30 minutes to prepare N-[1,1-dimethyl-2-(methylthio)ethyl]phthalamic acid. Aqueous sodium hydrogencarbonate solution (9.81 g/101 mL) was added dropwise to this mixture at 40° C. and then methyl chloroformate (11.04 g) was added dropwise thereto at the same temperature. After completion of the dropwise addition, the reaction mixture was stirred at 50° C. for 1 hour and the organic layer was separated to prepare a solution of N-[1,1-dimethyl-2-(methylthio)ethyl]isophthalimide in 1,2-dichloroethane. This solution was added dropwise to a mixture of 2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoro-methyl)ethyl]aniline (25.45 g), concentrated hydrochloric acid (0.49 g) and 1,2-dichloroethane (14.4 mL) at 60° C., and then stirred at 65° C. for 30 minutes. The reaction mixture was cooled and then neutralized with an aqueous sodium hydrogencarbonate solution, after which the organic layer was separated. The organic layer obtained was concentrated under reduced pressure, and the crystals precipitated were filtered, washed with water and then dried to obtain 47.06 g (yield 92%) of the title compound.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][C:14]1[S:15][C@@H:16]2[C@@H:33]([CH2:34][CH3:35])[C:32](=[O:36])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl.C1COCC1.CCOC(C)=O>[CH3:12][S:13]([C:14]1[S:15][C@@H:16]2[C@@H:33]([CH2:34][CH3:35])[C:32](=[O:36])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)=[O:20])=[O:6]
Reactant: CC[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC)S[C@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(C)=O)S[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 85% m-chloroperoxy benzoic acid (53 mg, 0.26 mmol) in CH2Cl2 (1 ml) is added dropwise over a few minutes to an ice-cold, stirring solution of p-nitrobenzyl (5R,6S)-2-methylthio-6-ethyl-pen-2-em-3-carboxylate (94 mg, 0.25 mmol) in anhydrous THF (2 ml). The resulting solution is stirred an additional 30 minutes at 0°, then diluted with EtOAc and washed with H2O, 5% aqueous NaHCO3, H2O, and brine. The organic phase is dried with MgSO4, filtered, and evaporated in vacuo to provide the title compound as a mixture of sulfoxide isomers.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22]>>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][C:10]([C:5]12[CH2:6][CH2:7][C:2]([NH:1][CH2:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[C:28]#[N:29])=[O:22])([CH2:9][CH2:8]1)[CH2:3][CH2:4]2)=[O:11]
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Reactant: NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Product: N#C[C@@H]1CCCN1C(=O)CNC12CCC(C(=O)OC3CCCCO3)(CC1)CC2
Yield: 67.8 %

Procedure:
Using 2-tetrahydropyranyl 4-aminobicyclo[2,2,2]octane-1-carboxylate (90.0 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (70.0 mg), the same procedure was followed as in Example 1 to obtain (2S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonylbicyclo[2,2,2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (85.2 mg).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH:3]([C:30]1[CH:35]=[CH:34][N+:33]([O-])=[CH:32][CH:31]=1)[O:4][C:5]1[C:14]([N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.C[Si]([C:43]#[N:44])(C)C.CN(C)C(Cl)=O.C(=O)(O)[O-].[Na+]>ClCCl.O>[C:43]([C:34]1[CH:35]=[C:30]([CH:3]([O:4][C:5]2[C:14]([N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[S:16]([CH2:19][CH2:20][CH3:21])(=[O:18])=[O:17])=[N:13][C:12]3[C:7]([N:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:2]([F:38])([F:37])[F:1])[CH:31]=[CH:32][N:33]=1)#[N:44]
Reactant: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1cc[n+]([O-])cc1)C(F)(F)F
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1nc2ccccc2nc1OC(c1ccnc(C#N)c1)C(F)(F)F
Yield: 102.1 %

Procedure:
Compound B4 (210 mg, 0.367 mmol) obtained in Step 1 was dissolved in dichloromethane (4 mL). To the solution were added trimethylsilyl cyanide (0.25 mL, 1.8 mmol) and dimethylcarbamoyl chloride (0.17 mL, 1.8 mmol), and the mixture was refluxed for 24 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give Compound B5 (218 mg, 100% yield).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=3)=[CH:14][CH:13]=2)=[O:30])=[CH:32][CH:33]=1
Reactant: NCc1ccc(-c2ccnc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(-c2ccnc(C(F)(F)F)c2)cc1)c1ccc(-c2cnccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)methanamine 28-3 (16 mg, 0.063 mmol), 4-(pyrazin-2-yl)benzoic acid 18-3 (13 mg, 0.065 mmol), and HATU (26 mg, 0.068 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield 4-(pyrazin-2-yl)-N-(4-(2-(trifluoromethyl)pyridin-4-yl)benzyl)benzamide 28 as a solid. MS m/z 435.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CO>C1COCC1.CCOC(C)=O>[F:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=Cc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Reactant: C1COCCN1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(F)cccc1F
Temperature: 25 °C
Yield: 10.3 %

Procedure:
To a mixture of 2,6-difluoro-N-[3-(5-formyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (75.0 mg, 0.20 mmol) in anhydrous THF (5 ml) stirring at ambient temperature was successively added 3 Å molecular sieves, morpholine (35 μL, 0.40 mmol) and triacetoxy sodiumborohydride (127 mg, 0.60 mmol). The mixture was stirred for 4 h, MeOH (3 ml) added and then the mixture reduced in vacuo. The residue was taken up in EtOAc, washed with water and brine, dried (MgSO4), reduced in vacuo and then purified through preparative LC/MS to give 2,6-difluoro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (9 mg, 10%) as a white solid. (LC/MS: Rt 1.90, [M+H]+ 439.09).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18]([OH:20])=O)[CH:8]=[CH:9]2)[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O:28][P:29]([CH2:34][O:35][NH2:36])([O:31]CC)=[O:30])C>>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18](=[O:20])[NH:36][O:35][CH2:34][P:29]([OH:31])([OH:30])=[O:28])[CH:8]=[CH:9]2)[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOP(=O)(CON)OCC
Reactant: CCOC(=O)c1c2ccc(CC(=O)O)ccc-2c(C(=O)OCC)c1N
Product: CCOC(=O)c1c2ccc(CC(=O)NOCP(=O)(O)O)ccc-2c(C(=O)OCC)c1N

Procedure:
In an analogous manner to that described in Example 26, from diethyl 2-amino-6-carboxymethyl-azulene-1,3-dicarboxylate and phosphonomethoxyamine (L. Maier, Phosphorus, Sulfur, and Silicon 1993, Vol. 76, 119-122) the title compound is obtained as an amorphous powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@H:12]([CH:17]([CH3:19])C)C(OC)=O)[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.NCCC[C:25]([O:27][CH3:28])=[O:26]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH2:12][CH2:17][CH2:19][C:25]([O:27][CH3:28])=[O:26])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCN
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(Br)cc2C1=O
Agent: Cl
Product: COC(=O)CCCN1Cc2ccc(Br)cc2C1=O

Procedure:
The compound of example 347 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and methyl 4-aminobutanoate hydrochloride.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH:5][CH2:6][CH2:7][S:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:4].B1([O-])O[O:20]1.O.O.O.O.[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[ClH:1].[CH3:4][CH:3]([NH:5][CH2:6][CH2:7][S:8]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:20])[CH3:2]
Reactant: CC(C)NCCSc1cccc2ccccc12
Reactant: [O-]B1OO1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)NCCS(=O)c1cccc2ccccc12
Yield: 8.6 %

Procedure:
A solution of 12.0 g (0.043 mole) of 1-methyl-N-[2-(1-naphthalenylthio)ethyl]ethanamine hydrochloride and 19.7 g (0.028 mole) of sodium perborate tetrahydrate in 500 ml of 2N sulfuric acid was stirred overnight at room temperature. The solution was poured over ice and the mixture was made alkaline with 50% sodium hydroxide and then extracted with chloroform. The chloroform layer was evaporated to give a dark-brown oil, the free base of the title compound, which crystallized at room temperature. A one gram sample was reacted with ethereal hydrogen chloride and recrystallized from methanol-diethyl ether to give 0.72 g (9.1%) of white solid, m.p. 153°-155° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1Oc1ccccc1
Yield: 70.9 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-6-phenoxy-2-phenylpyrimidin-5-yl)pentanoate (0.082 g; 0.218 mmol), sodium hydroxide 10N (0.218 mL; 2.18 mmol) in methanol (2 mL) to afford 0.056 g (68%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][O:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:20][C:21]1([F:30])[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][O:17][CH2:16][CH2:15][N:14]2[C:27]([CH:24]2[CH2:25][CH2:26][C:21]([F:30])([F:20])[CH2:22][CH2:23]2)=[O:28])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: CC(C)(C)c1cc(NC(=O)C2COCCN2)no1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(NC(=O)C2COCCN2C(=O)C2CCC(F)(F)CC2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold (0° C.) solution of morpholine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (50 mg; 0.115 mmol), 4,4-difluorocyclohexanecarboxylic acid (18.9 mg, 0.115 mmol) and N,N-diisopropylethylamine (0.052 mL; 0.3 mmol) in anhydrous acetonitrile (2 mL) is added phosphorous oxychloride (0.01 mL; 0.115 mmol). The reaction mixture is left stirring at room temperature for 18 hours. After this time, the reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by preparative LC-MS provides the title compound, m/z 400 [M+H+].
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:5][C:6]([NH:8][NH:9]C(OC(C)(C)C)=O)=[O:7].FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH:4]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1)[CH2:5][C:6]([NH:8][NH2:9])=[O:7]
Reactant: CC(C)(C)OC(=O)NNC(=O)CC(CCBr)c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NNC(=O)CC(CCBr)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl N′-[5-bromo-3-(3-trifluoromethylphenyl)pentanoyl]hydrazinecarboxylate (1.6 g) was dissolved in methylene chloride (8 mL), and trifluoroacetic acid (10 mL) was added at 0° C. The mixture was stirred at room temperature for two hours and then concentrated under reduced pressure. The resulting oil was diluted with ethyl acetate, and then washed with 1 N sodium hydroxide aqueous solution and brine and dried over magnesium sulfate. The oil after concentration under reduced pressure (990 mg) was used directly for the next reaction as a crude product.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][CH:26]([F:56])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:52])[C:37]2[CH:42]=[C:41]([CH2:43][NH:44][C:45]([C:47]([CH3:50])([CH3:49])[CH3:48])=[O:46])[CH:40]=[CH:39][C:38]=2[Cl:51])=[CH:31][C:30]=1[C:53]([OH:55])=O.[Cl:57][C:58]1[CH:59]=[C:60]([CH:62]=[CH:63][C:64]=1[F:65])[NH2:61]>C1COCC1>[F:25][CH:26]([F:56])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:52])[C:37]2[CH:42]=[C:41]([CH2:43][NH:44][C:45]([C:47]([CH3:50])([CH3:49])[CH3:48])=[O:46])[CH:40]=[CH:39][C:38]=2[Cl:51])=[CH:31][C:30]=1[C:53]([NH:61][C:60]1[CH:62]=[CH:63][C:64]([F:65])=[C:58]([Cl:57])[CH:59]=1)=[O:55]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ccc(OCC(F)F)c(C(=O)O)c2)c1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ccc(OCC(F)F)c(C(=O)Nc3ccc(F)c(Cl)c3)c2)c1
Reaction time: 0.25 h

Procedure:
HATU (43 mg, 0.11 mmol) was added to N-[4-(2,2-difluoroethyl)oxy-3-hydroxycarbonyl-phenyl]-2-chloro-5-(tert-butylcarbonylamino)methyl-benzamide (50.0 mg, 0.107 mmol) in 5.0 mL THF, followed by 52 μL TEA and the mixture was stirred for 15 min. Then 3-chloro-4-fluoroaniline (15.5 mg, 0.107 mmol) was added and it was stirred for 4 h at rt. The crude mixture was concentrated, EtOAc was added and the organic phase was washed with satd. aq. NaHCO3-solution, water and satd. NaCl-solution. The organic phase was dried with Na2SO4 and concentrated i. vac. to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4](=[O:20])[C:3]=1[C:21]#[N:22].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[C:3]([C:21]#[N:22])[C:4]2=[O:20])=[CH:14][CH:15]=1
Reactant: N#Cc1c(Cl)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Reactant: C1CNCCN1
Solvent: ClCCl
Product: N#Cc1c(N2CCNCC2)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A solution of Compound 8 (15 g, 48 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (12 g, 144 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solid was dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 17.17 g (98%) of yellow solids. 1H NMR (DMSO-d6): δ 2.8 (m, 2H), 3.0 (m, 2H), 3.6 (m, 2H), 3.7 (m, 2H), 5.45 (s, 2H), 7.1 (m, 2H), 7.3 (m, 3H), 7.4 (m, 1H), 7.6 (m, 1H), 7.90 (t, J=8.2 Hz, 1H); EIMS: 363 (M+H).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:24])([F:23])[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15](OC)=[O:16])[CH:9]=[CH:10][CH:11]=1>CO>[F:4][C:5]([F:24])([F:23])[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([NH:2][NH2:3])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: NN
Reactant: COC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 52 %

Procedure:
Hydrazine hydrate (14 ml) is added dropwise to a solution of methyl 2-[(3-trifluoromethylphenyl)amino]-benzoate (1.463 g, 4.95 mmol) in 70 ml of methanol. The reaction solution is heated at 60° C. under an inert atmosphere for two hours and then concentrated in vacuo and chromatographed, eluting with ethyl acetate and hexane (1:1), providing 763.0 mg (52%) of a white solid, mp 134°-135° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]([NH2:21])=[O:20].[OH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](OCC)=O)=[CH:26][CH:25]=1.[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=3)=[N:21][C:19](=[O:20])[C:3]2=[C:4]([CH:16]([CH3:18])[CH3:17])[NH:5]1
Reactant: CCOC(=O)Cc1ccc(CO)cc1
Reactant: CC(C)c1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(CO)cc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 347 mg (1.0 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 777 mg (4.0 mmol) of ethyl 4-(hydroxymethyl)phenylacetate followed by 2.0 mL (5.33 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 25 mL of 5% aq. HOAc, cooled to ambient temperature, and extracted with EtOAc. The organic extract was washed twice with water and once with brine, dried (MgSO4), and chromatographed on silica gel (elution with 1:1 EtOAc-hexanes) to give, after removal of solvent, 320 mg (67%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(hydroxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white, amorphous solid. 1H NMR (300 MHz, CDCl3) d 11.46(br. s, 1H); 7.54(s, 2H); 7.42(d, 2H, J=8.1 Hz); 7.31(d, 2H, J=8.5 Hz); 4.66(s, 2H); 4.00(s, 2H); 3.47(septet, 1H, J=7.0 Hz); 1.48(d, 6H, J=7.0 Hz).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7]C2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](C=O)=[CH:33][CH:32]=1>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:31]=[CH:32][CH:33]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:19]=2[N:20]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Product: C[C@@H]1CN(Cc2ccnc3ccccc23)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting quinoline-4-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 10.68 (brs, 1H), 8.83 (d, J=4.1 Hz, 1H), 8.25-8.22 (m, 1H), 8.12-8.08 (m, 1H), 7.98 (s, 1H), 7.75-7.72 (m, 1H), 7.54 (d, J=3.3 Hz, 1H), 7.36 (d, J=3.3 Hz, 1H), 5.21 (m, 1H), 4.77 (m, 1H), 4.13-4.06 (m, 3H), 3.59-3.52 (m, 2H), 3.32 (d, J=8.7 Hz, 1H), 3.03 (d, J=9.9 Hz, 1H), 2.88-2.86 (m, 1H), 2.72-2.69 (m, 1H), 2.36-2.28 (m, 3H), 2.04-2.00 (m, 1H), 1.89-1.84 (m, 2H), 1.20 (d, J=7.1 Hz, 3H). MS: (M+H m/z 445.1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:18])=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:9])[F:10]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Solvent: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)s2)noc1C(F)(F)F
Yield: 85 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a saturated aqueous NaHCO3 solution followed by water to afford product as a pale yellow solid (88 mg, 85%). 1H NMR (CDCl3) 1.76 (m, 4 H), 1.96-2.10 (m, 4 H), 2.37 (d, J=1.3, 3 H), 2.56-2.64 (m, 6 H), 3.80 (m, 2 H), 4.48 (m, 1 H), 7.50 (d, J=4.0, 1 H), 7.57 (br, 1 H). 19F NMR −63.2. LC/MS 4.66 min, [M+1]+ 414.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)=[O:3].[CH3:12][NH:13][CH2:14][CH:15]=[O:16]>C1C=CC=CC=1>[CH3:12][N:13]([CH2:14][CH:15]=[O:16])[C:10]([NH:9][C:7]1[S:8][C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=1)=[O:11]
Reactant: CS(=O)c1nnc(N=C=O)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(S(C)=O)s1

Procedure:
A mixture of 5-methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.