Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([CH:7]=[O:8])=[C:5]([Br:9])[NH:4][N:3]=1.[CH:10]([O:12][CH2:13][CH3:14])=[CH2:11].Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:6]([CH:7]=[O:8])=[C:5]([Br:9])[N:4]([CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[N:3]=1
Reactant: C=COCC
Reactant: O=Cc1c(Br)n[nH]c1Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(C)n1nc(Br)c(C=O)c1Br
Temperature: 20 °C
Reaction time: 15 h
Yield: 92.7 %

Procedure:
1 g (3.94 mmol) of 3,5-dibromo-1H-pyrazole-4-carboxaldehyde, 1.5 mL (16 mmol) of ethyl vinyl ether and 3 drops of concentrated 12 N hydrochloric acid are introduced with stirring into 30 mL of toluene at a temperature in the region of 20° C. The reaction mixture is stirred for 15 hours at a temperature in the region of 20° C., followed by addition of 1.5 mL (16 mmol) of ethyl vinyl ether, and stirring is continued for 15 hours at a temperature in the region of 20° C. The reaction mixture is then diluted with 20 mL of toluene and washed with twice 30 mL of saturated sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.19 g of 3,5-dibromo-1-(1-ethoxyethyl)-1H-pyrazole-4-carboxaldehyde in the form of a yellow oil. 1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 1.10 (t, J=7.5 Hz: 3H); 1.64 (d, J=6.5 Hz: 3H); 3.31 (mt: 1H); 3.51 (mt: 1H); 5.88 (q, J=6.5 Hz: 1H); 9.73 (s: 1H).
Reaction SMILES: C([O:10][C:11](=[O:55])[C@H:12]([C@@H:24]([CH3:54])[O:25][C:26](=[O:53])[C@H:27]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)[N:28]([C:30](=[O:43])[C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH3:29])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])C(C1C=CC=CC=1)=O>[Zn].C(O)(=O)C>[C:39]([O:38][C:36]([N:32]1[CH2:33][CH2:34][CH2:35][C@H:31]1[C:30]([N:28]([CH3:29])[C@H:27]([C:26]([O:25][C@H:24]([CH3:54])[C@@H:12]([C:11]([OH:55])=[O:10])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:53])[CH2:44][C:45]1[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=1)=[O:43])=[O:37])([CH3:40])([CH3:41])[CH3:42]
Reactant: COc1ccc(C[C@@H](C(=O)O[C@H](C)[C@H](NC(=O)OCc2ccccc2)C(=O)OCC(=O)c2ccccc2)N(C)C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(C[C@@H](C(=O)O[C@H](C)[C@H](NC(=O)OCc2ccccc2)C(=O)O)N(C)C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1

Procedure:
2.80 g (3.68 mmol) of (12 ) were stirred with 1.8 g of zinc powder in 20 ml of 90% strength aqueous acetic acid at RT for 4 h; undissolved zinc was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between EA and 1N KHSO4. The combined organic phases were dried (MgSO4) and concentrated under reduced pressure. The remaining resin was evaporated with toluene 3 times under reduced pressure. It was then taken up in 10 ml of 1N KHCO3, the solution was extracted twice with ether, and the ether phases were back-extracted twice with H2O. EA was added to the combined aqueous phases, which were acidified with 1N KHSO4 while cooling. The mixture was extracted twice more with EA, and the combined organic solutions were dried (MgSO4) and evaporated under reduced pressure. Yield: 2.25 g (3.5 mmol, 95%).
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[C:14]2[S:18][C:17](=[S:19])[N:16]([CH2:20][C:21]([OH:23])=[O:22])[C:15]2=[O:24])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](O)[CH3:26].Cl>O1CCOCC1>[NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[C:14]2[S:18][C:17](=[S:19])[N:16]([CH2:20][C:21]([O:23][CH2:25][CH3:26])=[O:22])[C:15]2=[O:24])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN1C(=O)C(=Cc2csc(Nc3ccccc3)n2)SC1=S
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CN1C(=O)C(=Cc2csc(Nc3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 30, the desired compound was prepared from 1 g of 5-(2-anilinothiazol-4-ylmethylene)rhodanine-3-acetic acid, 2 g of ethanol and 10 ml of a 4N dioxane solution of hydrogen chloride. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[N:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25]CC5C=CC=CC=5)=[N:23][CH:24]=4)=[CH:15][N:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[C].[Pd].CO>[CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[N:14]=[CH:15][C:16]([C:19]4[CH:20]=[CH:21][C:22](=[O:25])[NH:23][CH:24]=4)=[CH:17][N:18]=3)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc(-c3cnc(OC4CCN(C5CCCC5)CC4)nc3)cn2)cc1
Agent: [Pd]
Solvent: CO
Product: O=c1ccc(-c2cnc(OC3CCN(C4CCCC4)CC3)nc2)c[nH]1

Procedure:
10% palladium-carbon (700 mg) was added to a methanol solution (30 ml) of 2-(cyclopentylpiperidin-4-yloxy)-5-(2-benzyloxypyridin-5-yl)pyrimidine (2.22 g), and stirred in a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered to remove palladium-carbon, and the filtrate was concentrated under reduced pressure to obtain the entitled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:22])[CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[OH:12])=[CH:6][CH:7]=1
Reactant: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C(O)CCC(O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolved the product from Example 39A (3.64 g, 10.05 mmol) in ethanol (67 mL) and added sodium borohydride (0.837 g, 22.11 mmol) portionwise. After stirring for 1 h at room temperature, the mixture was filtered through celite and washed with methanol and ethyl acetate and the filtrate concentrated to a solid. The solid was dissolved in ethyl acetate (200 mL) and extracted with 1N aq. HCl (200 mL), then brine and the organic layer dried and concentrated to a colorless oil (3.68 g, 100%) that was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[F:33][C:21]([F:20])([F:32])[C:22]1[CH:23]=[C:24]([S:28]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][C:6]3[CH:16]=[CH:17][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=3)[N:14]=2)(=[O:29])=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: O=S(=O)(Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-trifluoromethyl-phenoxymethyl)-pyridin-2-ylamine (0.08 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.081 g) as a light yellow gum (0.114 g). MS (ESI−): 475.0 ([M−H]−).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][CH2:25][NH2:26])[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:26][CH2:25][CH2:24][CH2:23][O:19][N+:20]([O-:22])=[O:21])#[N:2]
Reactant: NCCCO[N+](=O)[O-]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCCCO[N+](=O)[O-])c1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.5 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3-nitroxypropylamine nitrate (0.53 g, 2.9 mmol) and sodium methoxide (0.22 g, 4.1 mmol) were added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (60:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.27 g, 1.08 mmol, yield: 41%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.O[CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:30]4[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CCCCCCN1CCC(O)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(OC)cc4)sc4cc(OC)ccc34)cc2)CC1
Yield: 50.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (895 mg, 2.30 mmol), 4-hydroxy-1-hexylpiperidine (850 mg, 4.59 mmol), triphenylphosphine (1.20 g, 4.59 mmol), and DEAD (4.59 mmol) were converted to product by the procedure of Example 1 to give 653 mg of the title compound. Yield: 51%. MS(FD) 557(M+). EA calculated for C34H39NO4S: C, 73.21; H, 7.05; N, 2.51. Found: C, 73.46; H, 7.26; N, 2.57.
Reaction SMILES: [NH2:1][NH2:2].[OH-].[Na+].[CH2:5]([O:12][C@H:13]([C@H:16]([C@@H:25]([C@@H:34]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:35])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:14]=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO.O1CCCC1>[NH:1]([C:14]([C@@H:13]([C@H:16]([C@@H:25]([C@@H:34]([CH2:36][O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[OH:35])[O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:12][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:15])[NH2:2]
Reactant: O=C[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NNC(=O)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 50 °C
Reaction time: 168 h

Procedure:
1.77 g (55.5 mmoles) of anhydrous hydrazine (which has been twice distilled over NaOH) are dissolved in 3 ml of absolute methanol and the solution is cooled in an ice bath. While stirring 3.0 g (5.55 mmoles) of 2,3,4,6-tetra-O-benzyl-D-glucose dissolved in 15 ml of absolute tetra-hydrofuran were added dropwise. After a few minutes the ice bath is removed and the solution is heated to 50° C. At this temperature the mixture is stirred for 7 days in closed flasks. Following this the excess hydrazine is drawn off with the solvent at room temperature in a rotary evaporator. For removal of the last traces of hydrazine the substance is dried for 48 hours with an oil pump running. A colorless viscous sirup remained, yield: 3.05 g (100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:19]([F:21])[F:20])=[N:8][N:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Na+]>C(O)C>[C:15]([N:9]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH:19]([F:21])[F:20])=[N:8]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1c(C(F)F)nn(C(C)(C)C)c1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1nc(C(F)F)c(C(=O)O)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
N-tert-Butyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid ethyl ester (2.48 g, 7.9 mmol) in ethanol (15 ml) was admixed gradually with an 8N aqueous sodium hydroxide solution (3.0 ml) and stirred at room temperature for 3 h. The solvent was removed by rotary evaporation; the residue was taken up in water (40 ml) and extracted with diethyl ether (20 ml). Acidification to pH 1 with 6M HCl was followed by extraction with ethyl acetate (3×30 ml). The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed by rotary evaporation. N-tert-Butyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid (2.15 g, 7.52 mmol, 94%) was isolated as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:12](=[O:27])[N:13]([CH2:17][C:18]([NH:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:19])[CH:14]=[CH:15][CH:16]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:10][C:11]1[C:12](=[O:27])[N:13]([CH2:17][C:18]([NH:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: CCC(CC)CNC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: CCC(CC)CNC(=O)Cn1cccc(N)c1=O
Reaction time: 2.5 h

Procedure:
5.22 g of benzyl-1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl-carbamate (2.4, ˜11.2 mmol) are dissolved under nitrogen atmosphere in 60 mL of methanol. To this solution, 500 mg of Pd/C (10%) are added and stirred under hydrogen atmosphere at atmosphere pressure for 2.5 h. The catalysis is separated by filtration over silica gel, before the solvent is removed in vacuo. Dark oil is obtained and it is suitable for further processing without further purification.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16](Br)[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:19]([O:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[O:24][CH2:25][CH2:26][NH2:27])[CH3:20].[I-].[K+].C1OCCOCCOCCOCCOCCOC1>O1CCOCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16]([NH:27][CH2:26][CH2:25][O:24][C:23]3[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=3[O:21][CH2:19][CH3:20])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(CC(C)Br)cc(C#N)c21
Reactant: CCOc1ccccc1OCCN
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOc1ccccc1OCCNC(C)Cc1cc(C#N)c2c(c1)CCN2C(C)=O
Yield: 27.9 %

Procedure:
To a solution of 1-acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (300 mg) and 2-(2-ethoxyphenoxy)ethylamine (391 mg) in dioxane (4 ml) were added potassium iodide (17 mg) and 18-crown-6 (26 mg), and the mixture was reacted in a sealed tube at 180° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel using a mixture of methylene chloride and methanol (40/1) as eluent to give 111 mg of 1-acetyl-5-[2-[2-(2-ethoxyphenoxy)ethylamino] propyl]indoline-7-carbonitrile as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)CO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2([C:19]([OH:21])=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C2CCN(Cc3ccccc3)CC2)CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: O=C(O)C1(C2CCN(Cc3ccccc3)CC2)CCCC1

Procedure:
Ethyl 1-(1-benzylpiperidin-4-yl)cyclopentanecarboxylate was reacted with potassium hydroxide in ethylene glycol under heating to obtain 1-(1-benzylpiperidin-4-yl)cyclopentanecarboxylic acid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@H:12]1[O:16][C:15](=[O:17])[NH:14][C@@H:13]1[CH3:18].[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1>C1COCC1>[F:30][C:29]([F:31])([F:32])[C:27]1[CH:28]=[C:23]([CH:24]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=1)[CH2:22][N:14]1[C@H:13]([CH3:18])[C@@H:12]([C:3]2[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=2[I:1])[O:16][C:15]1=[O:17]
Reactant: C[C@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)ccc1I
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
(4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 12, 1.451 g, 3.910 mmol) was dissolved in anhydrous THF (30 mL) and cooled in an ice bath. Sodium hydride (60% w/w in mineral oil, 172 mg, 4.301 mmol) was added into the reaction mixture all in once. The reaction was stirred cold (ice bath) for 30 min followed by addition of 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (1.078 mL, 1.80 mg, 5.865 mmol). The crude mixture was cooled (ice bath) and quenched adding by NH4Cl (aq, sat.) when reaction time was 5 hours. Reaction crude was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to an oil. The oil was purified by flash chromatography (SiO2, Biotage 40+M cartridge, EtOAc/hexanes) to afford (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=596.98; found=598.05 (M+1)+. 132.6 mg of unreacted starting material was also recovered.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=2)[CH:7]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(#N)C>[N:16]1([C:2]2[N:3]=[CH:4][C:5]3[N:6]([C:8]([S:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=3)[CH:7]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: C1CNCCN1
Reactant: FC(F)(F)Sc1cnc2cnc(Cl)cn12
Solvent: CC#N
Product: FC(F)(F)Sc1cnc2cnc(N3CCNCC3)cn12

Procedure:
6-Chloro-3-trifluoromethylthioimidazo[1,2-a]pyrazine from Step A is reacted with piperazine (2 g) in efluxing acetonitrile for 24 hours. The mixture is cooled, concentrated under vacuum, and the esidue partitioned between dilute sodium hydroxide and chloroform. The chloroform extract is dried over sodium sulfate, filtered and concentrated under vacuum to the crude base which is purified by chromatography on silica gel and converted to 6-(1-piperazinyl)-3-trifluoromethylthioimidazo[1,2-a]pyrazine hydrochloride with ethanolic hydrogen chloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]1([C:22]2[C:31]([OH:32])=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:32][C:31]1[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: Oc1cc2ccccc2nc1-c1ccccc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3ccccc3)c2cc1OC
Temperature: 145 °C
Reaction time: 7 h
Yield: 67.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (222 mg), 2-phenylquinolin-3-ol (107 mg), and 4-dimethylaminopyridine (340 mg) were suspended in o-dichlorobenzene (11 ml), and the suspension was stirred at 145° C. for 7 hr. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (134 mg, yield 68%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[C:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([N:36]4[CH2:35][CH2:34][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:38][CH2:37]4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 1-Boc-piperazine (Aldrich, Cat. No. 343536). LCMS (M+H)+: m/z=509.3.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]3[NH:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[N:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:27][C:28]1[O:32][C:31]([CH3:33])=[N:30][CH:29]=1>CN(C)C=O>[CH3:33][C:31]1[O:32][C:28]([CH2:27][N:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=[C:15]2[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:13][CH2:12]2)=[CH:29][N:30]=1
Reactant: Cc1ncc(CBr)o1
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ccccc32)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 26 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole in 282 parts of N,N-dimethylformamide there were added 4.8 parts of a dispersion of sodium hydride in mineral oil (50%) under a nitrogen atmosphere. After stirring for 1 hour, there was added portionwise a solution of 15 parts of 5-(bromomethyl)-2-methyloxazole in 47 parts of N,N-dimethylformamide, while cooling in an ice-bath (<20° C.). The whole was stirred for 18 hours and allowed to warm to room temperature. The oily layer was separated and discarded. The N,N-dimethylformamide layer was poured into water and the whole was extracted with 4-methyl-2-pentanone (3×). The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 90:10). The eluent of the desired fraction was evaporated and the residue was successively crystallized from 2,2'-oxybispropane and acetonitrile, yielding 14.31 parts (42.0%) of 1-[(2-methyl-5-oxazolyl)methyl]-2-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-1H-benzimidazole; mp. 108.6° C. (comp. 1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.[CH3:34][N:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36](Cl)=[O:37]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:36]([N:35]([CH3:34])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:37])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(OC(=O)N(C)c2ccccc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 100 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 25.4 mg, 0.0564 mmol) and N-methyl-N-phenylcarbamoyl chloride (20.4 mg, 0.120 mmol) was dissolved in pyridine (1 mL), and stirred for 2 hours at 100° C. The reaction mixture was concentrated, and then the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (28.7 mg) as a pale yellow amorphous product. (Yield 87%)