Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](OC)[C:6]([C:11](=[O:13])C)=[C:5](OCC(OC)=O)[C:4]=1CCC(C)C>C(O)C>[CH:11](=[O:13])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(C)=O
Solvent: CCO
Product: COc1ccc(C=O)cc1
Yield: 101.1 %

Procedure:
To a liquid mixture of 11.8 g of the 4',6'dimethoxy-2'methoxycarbonylmethoxy-3'-isopentylacetophenone obtained in Production Example 5, 4.8 g of p-anisaldehyde and 50 ml of ethanol was added 150 ml of a saturated solution of potassium hydroxide in ethanol, and the mixture was stirred at room temperature overnight to effect a reaction. After the reaction, the reaction mixture was made acidic by dilute hydrochloric acid, extracted with diethyl ether and filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was recrystallized from a mixed solvent of diethyl ether and n-hexane to obtain 12.7 g (yield=81.9%) of 2'-carboxymethoxy-4,4',6'-trimethoxy-3'-isopentylchalcone in the form of a yellow prism.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([NH2:42])=[O:41])=[CH:38][CH:37]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:24]1[CH2:25][CH2:26][CH2:27][CH:22]([NH:21][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([NH:35][C:36]3[CH:44]=[CH:43][C:39]([C:40]([NH2:42])=[O:41])=[CH:38][CH:37]=3)[N:3]=2)[CH2:23]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCN(C(=O)OC(C)(C)C)C4)nc(Cl)nc32)cc1
Reactant: NC(=O)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCNC4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Temperature: 116 °C
Reaction time: 20 h
Yield: 14.4 %

Procedure:
A mixture of tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (251 mg, 0.496 mmol), 4-aminobenzamide (102 mg, 0.750 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 116° C. in a sealed tube for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give 4-(4-(piperidin-3-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (36 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:5]=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[C:22](B(O)O)[N:23]2C(OC(C)(C)C)=O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[C:22]([C:2]3[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][N:9]4[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]4)[CH:3]=3)[NH:23]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Reactant: CN1CCN(Cc2cncc(Br)c2)CC1
Product: CN1CCN(Cc2cncc(-c3cc4ccc(Cl)cc4[nH]3)c2)CC1

Procedure:
1-(5-Bromo-pyridin-3-ylmethyl)-4-methyl-piperazine and 6-chloro-1-Boc-indole-2-boronic acid are processed according to the method described in Example 91 to give 6-chloro-2-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indole. (ESI) m/z 341.1 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1>C(OCC)C>[Br:1][CH2:12][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=1)=[O:13]
Reactant: BrBr
Reactant: COc1cccc(C(C)=O)c1
Solvent: CCOCC
Product: COc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (5.32 g, 33.3 mmol) was slowly added dropwise to a solution of 1-(3-methoxyphenyl)ethanone (5.00 g, 33.3 mmol) in diethyl ether (100 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure to give the desired product as an oil quantitatively.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])[O:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[C:7]([OH:13])[CH:6]=2.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>>[Cl:1][C:2]1[C:3](=[O:14])[O:4][C:5]2[CH:6]=[C:7]([O:13][CH2:16][C:17]3([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:18][C:5](=[O:4])[C:10](=[CH2:9])[CH2:11]3)[CH:8]=[CH:9][C:10]=2[C:11]=1[CH3:12]
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1c(Cl)c(=O)oc2cc(O)ccc12
Product: C=C1CC(COc2ccc3c(C)c(Cl)c(=O)oc3c2)(c2ccccc2)OC1=O
Yield: 71 %

Procedure:
Compound 7 was prepared from 3-chloro-7-hydroxy-4-methylcoumarin and 2-bromoacetophenone according to the procedure given for 4, yield: 71%;
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]=2[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:3]=1[C:22]([O:24][CH3:25])=[O:23].[H-].[Na+].[CH2:28](I)[CH3:29]>O1CCCC1>[CH2:28]([N:7]1[C:2]([CH3:1])=[C:3]([C:22]([O:24][CH3:25])=[O:23])[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:5]2[C:10](=[O:11])[O:9][CH2:8][C:6]1=2)[CH3:29]
Reactant: CCI
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(C)=C(C(=O)OC)C(c2ccccc2C(F)(F)F)C2=C1COC2=O
Reaction time: 0.17 h

Procedure:
50 mmol of methyl 2-methyl-4-(2-trifluoromethylphenyl)-5-oxo-1,4,5,7-tetrahydrofuro-[3,4-b]pyridine-3-carboxylate are dissolved in 100 ml of anhydrous tetrahydrofuran, and 50 mmol of sodium hydride are added. After 10 minutes at room temperature, 55 mmol of ethyl iodide are added, and the mixture is boiled under reflux for 1 hour. The mixture is evaporated down, after which the residue is taken up with CH2Cl2, the solution is washed with water, dried and evaporated down, and the residue is recrystallized.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C@@H:10]([CH3:13])[C:11]#[N:12].P([O-])(OCC)(SCC)=[S:22].C(O)(C)C.C([O-])([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C@@H:10]([CH3:13])[C:11]([NH2:12])=[S:22]
Reactant: CCOP([O-])(=S)SCC
Reactant: C[C@@H](C#N)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: C[C@@H](C(N)=S)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 110 °C
Yield: 85.2 %

Procedure:
(2S,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-yl-butyronitrile (50.0 g, 180 mmol), diethyl dithiophosphate (134 mL, 719 mmol), isopropanol (50 mL) and water (40 mL) were mixed together and the mixture was heated in an oil-bath (temp. setting at 110° C.) for 3 h. After cooling to 0° C., 5% Na2CO3 aqueous solution (500 mL) was added slowly and then solid Na2CO3 (25 g) was added portionwise. The mixture was extracted with EtOAc (1 L) and the EtOAc layer was washed with sat. NaHCO3 aqueous solution, water (×2) and brine, dried over MgSO4 and evaporated under reduce pressure. The resulting solid was purified by recrystalization from isopropanol to give pure (2R,3R)-3-(2,5-difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylthiobutyrarnide (47.9 g, 85%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1([CH2:16][O:17][C:18]2[C:23]3[C:24]([O:27][CH2:28][CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[N:25][O:26][C:22]=3[CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1)=O.C(OCC)(=O)C>C(OCC)C>[OH:8][CH2:9][C:11]1([CH2:16][O:17][C:18]2[C:23]3[C:24]([O:27][CH2:28][CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)=[N:25][O:26][C:22]=3[CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)C1(COc2cccc3onc(OCC4CCN(C(=O)OC(C)(C)C)CC4)c23)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCC4(CO)CCCC4)c23)CC1
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a suspension of lithium aluminum hydride (50.7 mg, 1.34 mmol) in diethyl ether (5 mL) was added an ethereal solution (3 mL) of tert-butyl 4-{[(4-{[1-(methoxycarbonyl)cyclopentyl]methoxy}-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 51, step 2, 600 mg, 1.23 mmol) at 0° C. After being stirred for 30 min, ethyl acetate was added to the mixture. Then the mixture was washed with 2N hydrochloric acid and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 456 mg (81%) of the title compound as a white solid. The crude product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25].CN(C)C1C=CC=CC=1>>[Cl:25][C:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(c1ccc(F)cc1)N2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 2-(4-fluorophenyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (1.2 g, 4.00 mmol, 1.00 equiv), POCl3 (12.2 g, 80.26 mmol, 20.00 equiv), N,N-dimethylbenzenamine (4.9 g, 40.50 mmol, 10.00 equiv). The resulting solution was stirred for overnight at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 50 mL of water. The pH value of the aqueous solution was adjusted to 7 with sodium bicarbonate (4 mol/L). The resulting mixture was concentrated under vacuum and purified by silica gel chromatography with ethyl acetate/petroleum ether (1:40). This resulted in 0.5 g (40%) of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a white solid.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:1][NH:2][C:3]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:9])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)ONC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
The starting material is prepared as follows: tert-Butyl N-hydroxycarbamate (3.89 g, 29.2 mmol) is dissolved in 25 ml of dichloromethane and cooled to 0° C. To this is added triethylamine (3.25 g, 32.1 mmol) and acetyl chloride (2.29 g, 29.2 mmol) dropwise. The mixture is extracted with ether and the extracts are washed with aqueous 2N HCl, water, 10% sodium bicarbonate, water, dried (MgSO4) and evaporated. The resulting colorless oil is purified by silica gel chromatography (10% ethyl acetate/hexane) to give O-acetyl-N-tert-butoxycarbonylhydroxylamine as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)C1C=CC=CC=1.CS(O)(=O)=O>C(Cl)Cl.CCOCC>[CH2:21]([NH:20][C:18]([NH:17][C:15]1[S:16][C:12]2[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:10][C:9]([OH:8])=[CH:23][C:13]=2[N:14]=1)=[O:19])[CH3:22]
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(-c3ccccn3)c2s1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: CCNC(=O)Nc1nc2cc(O)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a stirred solution of 1-[5-benzyloxy-7-(2-pyridyl)-1,3-benzothiazol-2-yl]-3-ethyl-urea (76 g, 0.187 mol) in DCM (1.7 L) was added methane sulfonic acid (270 mL, 4.17 mol) dropwise over 30 min. The reaction mixture was then stirred at rt for 3 h. After the completion of reaction (by TLC), the reaction mass was concentrated under reduced pressure. EtOAc (1 L) was added to the residue and the solution poured carefully onto crushed ice. The pH of the solution was maintained to 8-9 by addition of saturated NaHCO3 solution followed by extraction with EtOAc (3×5 L). The combined organics were washed with water, brine, dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure. The residue thus obtained was stirred in Et2O (1.0 L) for 1 h at rt then filtered to obtain the desired product (57.0 g, 97%). 1H-NMR (DMSO-d6): δ 1.08 (t, J=7.20 Hz, 3H), 3.20 (m, 2H), 6.86 (br s, 1H), 7.0 (s, 1H), 7.46 (s, 2H), 7.96 (m, 1H), 8.10 (m, 1H), 8.76 (m, 1H), 9.59 (br s, 1H) and 10.41 (br s, 1H). LCMS: 315.06 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34])=O>>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[C:25]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:24]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(F)cc1F
Product: O=C(O)c1cc(-c2nc(-c3ccc(F)cc3F)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 23 %

Procedure:
4-[4-(2,4-Difluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (66 mg, 23%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-2′,4′-difluoroacetophenone (available from Matrix Scientific) using the procedure described for the preparation of Example 18. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J=1.4 Hz, 2H), 8.10-8.35 (m, 4H), 7.21-7.33 (m, 3H), 7.77 (t, J=7.5 Hz, 1H), 7.64 (t, J=7.7 Hz, 1H), 7.23-7.50 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[C:42]3[C:37]([CH:38]=[CH:39][CH:40]=[N:41]3)=[CH:36][CH:35]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[C:42]3[C:37]([CH2:38][CH2:39][CH2:40][NH:41]3)=[CH:36][CH:35]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3cccnc3c2)C1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3c(c2)NCCC3)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
A solution of 116 mg (0.20 mmol) of tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(quinolin-7-ylmethoxy)-piperidine-1-carboxylate in 1.5 ml of methanol was treated with 24 mg (0.1 mmol) of nickel(II) chloride hexahydrate and 30 mg (0.8 mmol) of sodium borohydride. The dark suspension was stirred at 0° C. for 1 hour and at room temperature for a further hour. For the working-up, the mixture was partitioned between 20 ml of ether and 5 ml of aqueous saturated ammonium chloride solution and then the organic phase was separated. The aqueous phase was extracted three times with 20 ml of ether each time. The combined ether phases were dried over magnesium sulphate and finally the solvent was distilled off under reduced pressure. The crude product (150 mg) was purified by chromatography on silica gel with a 1:1 mixture of ethyl acetate and hexane as the eluent. There were obtained 70 mg (60% of theory) of tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylate as a light yellow resin; MS: 587 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C@:14]12([CH3:24])[C:20]([CH3:22])([CH3:21])[CH:17]([CH2:18][CH2:19]1)[CH2:16][CH:15]2[NH2:23].N1C=CC=CC=1>O>[C@:14]12([CH3:24])[C:20]([CH3:21])([CH3:22])[C@@H:17]([CH2:18][CH2:19]1)[CH2:16][C@@H:15]2[NH:23][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: CC1(C)C2CC[C@@]1(C)C(N)C2
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)[C@H]2CC[C@@]1(C)[C@@H](NC(=O)c1cnc3ccccc3n1)C2
Yield: 50.3 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), (R)-(+)-bornylamine (138 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 140 mg (50%) of (150):
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]([F:47])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:32]OS(C(F)(F)F)(=O)=O>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:32][C:31]([F:47])([F:30])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:15]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)CCCCCC1
Reactant: O=S(=O)(OCC(F)(F)c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCC(F)(F)c3ccccc3)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.7 %

Procedure:
To a mixture of 1-(3-hydroxy-4-methoxy-benzoylamino)-cycloheptanecarboxylic acid methyl ester (80 mg, 0.249 mmol) and potassium carbonate (83 mg, 0.60 mmol) in 0.5 ml of acetone and 0.5 ml of DMF was added slowly a solution of the compound of step 1 (0.22 g, 0.374 mmol) as solution in acetone. The mixture was stirred for 3 d at room temperature and then evaporated. The residue was purified by preparative RP HPLC (water/ACN gradient) to give the title compound (87 mg).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][CH:6]([C:12](OCC)=[O:13])[C:7](OCC)=[O:8].C[O-].[Na+]>CCO>[SH:3][C:2]1[N:4]=[C:7]([OH:8])[C:6]([CH3:5])=[C:12]([OH:13])[N:1]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)nc(S)nc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of thiourea (1 g, 13.14 mmol) and diethyl methylmalonate (3.4 mL, 19.71 mmol) in EtOH (15 mL), NaOMe (2.68 g, 39.41 mmol) was added portionwise. After stirring at 0° C. for 30 min, the reaction was allowed to reach rt and was stirred for another 3 h at rt. The mixture was quenched with diluted acetic acid and the solid was filtered off to yield 2-mercapto-5-methylpyrimidine-4,6-diol as a white solid which was used in the next step without further purification. LC-MS conditions A: tR=0.21 min, [M+H]+=159.11.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[NH:15][CH:16]=[N:17][C:18]=3[C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:13][C:8]=2[N:7]([CH2:26][CH3:27])[C:6]1=[O:28])[CH3:4].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:29]([N:15]1[C:14]([C:12]2[CH:11]=[CH:10][C:9]3[N:5]([CH2:3][CH3:4])[C:6](=[O:28])[N:7]([CH2:26][CH3:27])[C:8]=3[CH:13]=2)=[C:18]([C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[N:17]=[CH:16]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CCn1c(=O)n(CC)c2cc(-c3[nH]cnc3-c3cccc(C)c3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(CC)c2cc(-c3c(-c4cccc(C)c4)ncn3Cc3ccccc3)ccc21
Reaction time: 0.25 h
Yield: 21.3 %

Procedure:
To a slurry of sodium hydride (254 mg of a 60% dispersion in mineral oil, 6.4 mmol) in DMF (79 mL) was added 1,3-diethyl-5-(5-m-tolyl-3H-imidazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (prepared as described above, 2.0 gm, 5.8 mmol). The resulting mixture was stirred for 15 minutes, then benzyl bromide (0.76 mL, 6.4 mmol) was added all in one portion. The reaction was stirred for an additional 30 minutes, and was then quenched with water. The aqueous mixture was extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a yellow oil. The oil was purified by flash chromatography eluting with ethyl acetate to afford 540 mg of the title compound as the less polar constituent. MS (M+1)=437.0
Reaction SMILES: N[C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[ClH:18].C(OCC)C>O>[Cl:18][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: Cl
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F
Reaction time: 1.5 h

Procedure:
A solid mixture of 0.52 g of 3-amino-2,4,5-trifluorobenzoic acid (Example 2) and 0.33 g of sodium nitrite is added in portions to a solution of 3 g of cupric chloride in 9 ml of water and 0.5 g of a 36% aqueous solution of hydrochloric acid. The resulting mixture is allowed to stir at 15°-25° C. for 1.5 hours and then additional water (25 ml) is added. Stirring is continued another hour at 25° C. and then 20 ml of diethyl ether is added. The layers are separated and the aqueous layer extracted with 20 ml of diethyl ether. The combined organic extracts are extracted with 5 ml of a 36% aqueous solution of hydrochloric acid and then concentrated on the rotary evaporator to give 0.45 g of 3-chloro-2,4,5-trifluorobenzoic acid as a tan solid; gas chromatography (GC) (98.8%); high performance liquid chromatography (HPLC) (84.8%); (a portion of the 3-chloro- 2,4,5-trifluorobenzoic acid was recrystallized from heptanes; mp 109°-111° C.).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[C:5]#[N:6].S(Cl)([Cl:19])=O.O>N1C=CC=CC=1>[Cl:19][CH2:2][CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[C:5]#[N:6]
Reactant: N#CC(CCO)c1ccccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: N#CC(CCCl)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h

Procedure:
4-Hydroxy-2-(2-trifluoromethylphenyl) butyronitrile (2.6 g) was dissolved in pyridine (10 mL). Thionyl chloride (2.1 mL) was carefully added and the mixture was heated with stirring at 60° C. for four hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.3 g). The property values of the compound are as follows.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([CH2:23]Cl)=[CH2:22])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C(O)C>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([CH2:23][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH2:22])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: C=C(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CCO
Solvent: O
Product: C=C(CN1CCCCC1)CN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 7.0 g of 1-benzhydryl-4-(2-chloromethyl-2-propenyl)-piperazine (0.0205 mole) and 6.98 g of piperidine (0.082 mole) in 150 ml of absolute ethanol is heated until it has dissolved completely, and subjected to reflux for 3 hours. Then, it is conditioned to room temperature and the ethanol is removed by distillation. The resulting crude reaction product is treated with distilled water several times until a solid material is obtained which is then filtered and washed abundantly with water. By recrystallization from ethanol, 7.4 g crystals of 1-benzhydryl-4-(2-(1-piperidinylmethyl)-2-propenyl)-piperazine (I, R1 =benzhydryl, R2 =2-(1-piperidinylmethyl-2-propenyl) are obtained. Yield: 94%; m.p. 99°-102° C.