Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26].O>CN(C)C=O>[CH3:24][N:25]([CH3:27])/[CH:26]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)/C=C/N(C)C)cc2)CC1
Temperature: 25 °C

Procedure:
The product from Example 26A (2.14 g, 7.42 mmol) and N,N-dimethylformamide dimethylacetal (1.42 g, 11.9 mmol) in N,N-dimethylformamide (20 mL) were heated at 100° C. for 16 h. The solution was cooled to room temperature, and water (20 mL) was added over a period of 10 min. The precipitate was collected by filtration, washed with water (3×20 mL), and dried in vacuo at 50° C. for 24 h to give crude product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.11-1.21 (m, 5H), 1.43-1.55 (m, 2H), 1.63-1.82 (m, 5H), 2.22 (d, J=6.76 Hz, 2H), 2.43-2.47 (m, 1H), 2.90 (s, 3H), 3.12 (s, 3H), 4.07 (q, J=7.06 Hz, 2H), 5.79 (d, J=12.27 Hz, 1H), 7.27 (d, J=8.59 Hz, 2H), 7.67 (d, J=12.27 Hz, 1H), 7.79 (d, J=8.59 Hz, 2H): MS (ESI) m/z 344.1.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[H][H]>CO.[C].[Pd]>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH:2]([CH3:4])[CH3:1])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: [H][H]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Acetone (1.47 mL) and 10% palladium-carbon (50% wet, 186 mg) were added to piperazine-1-carboxylic acid tert-butyl ester (1.862 g) in methanol (20 mL), and the resultant mixture was stirred in a hydrogen atmosphere at room temperature for 10 hours. Acetone (1.47 mL) was added thereto, and the mixture was stirred in a hydrogen atmosphere at room temperature for 36 hours. The catalyst was filtered off. The solvent was evaporated under reduced pressure, to thereby give the title compound as an oily product (2.253 g, 98%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:13])[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:1][S:2]([N:11]1[CH2:10][CH2:9][NH:8][C:7]([CH3:13])([CH3:6])[CH2:12]1)(=[O:4])=[O:3]
Reactant: CC1(C)CNCCN1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC1(C)CN(S(C)(=O)=O)CCN1

Procedure:
A solution of 52.8 g of methanesulphonyl chloride in 100 ml of toluene is added dropwise to a mixture of 52.6 g of 2,2-dimethylpiperazine, 69.9 g of potassium carbonate and 150 ml of toluene, the internal temperature rising to about 55° C. After a stirring time of 3 hours, the insoluble fraction is filtered off with suction and the toluene solution is evaporated in vacuo. The oil which remains gradually solidifies and is recrystallised from isopropanol for purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: ClCc1ccccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
The whole of the 2-benzyloxybenzyl alcohol thus obtained was dissolved in 500 ml of tetrahydrofuran, and 85 ml of thionyl chloride were added dropwise, whilst ice-cooling, to the resulting solution. The reaction mixture was then allowed to stand overnight at room temperature, after which it was concentrated by evaporation under reduced pressure to give a dark colored oil. This product was dissolved in toluene, and the solution was decolorized by treating it with silica gel for chromatography followed by filtration. The filtrate was concentrated by evaporation under reduced pressure to give 2-benzyloxybenzyl chloride as a yellow oil, which was used in the following reaction without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-:20].[Na+]>C(O)C>[CH2:14]1[C:15]2[C:16](=[CH:10][CH:1]=[CH:2][CH:3]=2)[CH:17]=[CH:18][C:13]1=[C:5]1[CH2:6][CH2:7][CH2:8][C:11](=[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[C:4]1=[O:20]
Reactant: [OH-]
Reactant: O=C1CCCCC1
Reactant: O=Cc1ccc2ccccc2c1
Agent: [Na+]
Solvent: CCO
Product: O=C1C(=C2C=Cc3ccccc3C2)CCCC1=C1C=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(78) To a solution of the 2-naphthaldehyde (1.56 g, 10.0 mmol) and cyclohexanone (491 mg, 5.0 mmol) in 7.5 ml of ethanol was added 5 ml 40% sodium hydroxide at 0° C. After stirring for 12 hr at room temperature, the solution was filtered. The precipitate was recrystallized from ethyl acetate to afford 1.50 g (80.6%) of bright-yellow flakes: mp 179.4-180.6° C. (lit. mp 176° C., Kabli, et al., Indian J. Chem., Sect. B, 1986, 25, 152-156). 1H NMR (250 MHz) δ 8.00-7.84 (m, 10 H), 7.62-7.48 (m, 6 H), 3.07 (t, 4 H), 1.85 (p, 2 H); 13C NMR (62.7 MHz) 190.4, 137.3, 136.5, 133.7, 133.3, 130.5, 128.5, 128.1, 127.9, 127.1, 126.6, 28.6, 23.7 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:15][F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:15][F:16])[NH:13][C:12](=[S:26])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCC(CF)(c2cccc(Br)c2)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: FCC1(c2cccc(Br)c2)COCC(=S)N1
Temperature: 50 °C

Procedure:
A mixture of 5-(3-bromo-phenyl)-5-fluoromethyl-morpholin-3-one (1.52 g, 5.28 mmol) and Lawesson's reagent (2.14 g, 5.28 mmol) in 21 ml of THF was heated at 50° C. for 1 h and then evaporated. The residue was chromatographed on silica gel (cyclohexane/EtOAc=15:1) to give the title compound in the form of a colourless foam. TLC (hexane/EtOAc=3:1): Rf=0.21; HPLC: RtH2=3.49 min; 1H-NMR (400 MHz, CD3OD): 7.65 (s, 1H), 7.58 (d, 1H), 7.47 (d, 1H), 7.39 (t, 1H), 4.87 (s, 2H), 4.63 (d, 1H), 4.50 (s, 2H), 4.02 (d, 1H); MS: 304, 306 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37]>C1COCC1.CCOC(C)=O>[OH:37][CH2:36][C:35]([NH:34][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21])([CH3:39])[CH3:38]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: CC(C)(N)CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)CO)c3)n2)n1
Yield: 63 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example 1.2) (0.228 g, 0.47 mmol) by treatment with excess 2-amino-2-methyl-1-propanol in THF (10 mL) at 23° C. for 1 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.158 g, 63%) as a white solid. MS (ISP) 541.9 [(M+H)+]; mp 171° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.[OH-].[NH4+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH2:19])=[O:6]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Cl)cc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1cc(Cl)cc(Br)c1
Temperature: 25 °C

Procedure:
3-Bromo-5-chlorobenzoic acid (2.35 g, 10 mmol) was suspended in CH2Cl2 (50 mL) and stirred under argon at room temperature. Oxalyl chloride (2.53 g, 20 mmol) was added followed by DMF (10 μL), and the mixture stirred overnight. The solvents were pumped off. The residue was taken up in EtOAc and added to concentrated ammonium hydroxide (10 mL). This was stirred for thirty mins. The phases were separated and the organic phase washed 1× with brine, dried over anhydrous Na2SO4, filtered, and evaporated. The residue was crystallized from EtOAc/hexane to give the title compound as a white crystalline solid. LC-MS m/z 233.7 (M+H)+, 1.57 min (ret time); analytical HPLC shows 96.5% purity, (ret time: 12.131 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)[C:4](=O)[CH2:3]1.COP([CH2:16][C:17]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[Cl:26])=O)(=O)OC.O.[NH2:28][NH2:29]>>[Cl:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[C:17]1[N:29]=[N:28][C:4]2[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][C:5]=2[CH:16]=1
Reactant: COP(=O)(CC(=O)c1cc(Cl)ccc1Cl)OC
Reactant: NN
Reactant: CC1(C)CC(=O)C(=O)C1
Solvent: O
Product: CC1(C)Cc2cc(-c3cc(Cl)ccc3Cl)nnc2C1

Procedure:
light yellow crystalline solid. MS (EI): 294.2 (MH+). Prepared from 4,4-dimethyl-cyclopentane-1,2-dione, [2-(2,5-Dichloro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH:13]=[O:14].[Cl-].[NH4+]>CCOCC.O1CCCC1.O>[C:1]1([CH:13]2[O:14][CH:9]([OH:15])[CH2:10][CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCCC=O
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1CCCC(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
136.1 ml of a 3 M solution of phenyl magnesium bromide in ether was added, drop by drop, to a solution of 37.1 g of 4A in 375 ml of tetrahydrofuran at -60°±10° C. The mixture was allowed to warm (over a two-hour period) to room temperature. Then 75 ml of a saturated solution of ammonium chloride in water was added, the temperature of the mixture being held at 0°-5° C. The mixture was stirred for 15 minutes, then the supernatant oil was decanted, dried (MgSO4), and stripped of solvent. The residue was passed through a short column of silica gel using ethyl acetate as eluent. The eluate was stripped of solvent, and the residue was chromatographed (high pressure liquid) over silica gel, using as eluents one liter each, in sequence, of six mixtures of ethyl acetate and hexane, varying in content from 30% to 75% ethyl acetate, followed by two liters of ethyl acetate alone. Fractions 7 through 12 (in order of increasing polarity) were combined and stripped of solvent. The resulting solid was recrystallized from hexane to give tetrahydro-6-phenyl-2H-pyran-2-ol (as a mixture of diastereomers) (4B), as a solid, m.p.: 64.5°-71° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:48]1([S:54][CH2:55]Cl)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH2:55][S:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: ClCSc1ccccc1
Product: CCCCc1nn(CSc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 17 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with chloromethyl phenyl sulfide was carried out as described in Example 3, Step A, except that only 5 equivalents of the alkylating agent was used. After work-up, the residue was flash chromatographed over silica gel (25 mL for 0.162 mole, gradient elution using 0.25-1.0% MeOH/CH2Cl2) to give the desired material as a colorless oil in 17% yield, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) m/e 740 (M+1)+.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([NH:17][S:18]([CH2:21][C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:19])=[N:11][C:10]=1[C:29]([NH:31][CH3:32])=[O:30])C1C=CC=CC=1>[Pd].C(OCC)(=O)C.CO>[CH3:32][NH:31][C:29]([C:10]1[N:11]=[C:12]([NH:17][S:18]([CH2:21][C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)(=[O:19])=[O:20])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=1[OH:8])=[O:30]
Reactant: CNC(=O)c1nc(NS(=O)(=O)Cc2cccc(C)c2)n(C)c(=O)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)c1nc(NS(=O)(=O)Cc2cccc(C)c2)n(C)c(=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
Palladium on carbon 10% (20 mg, 18.8 μmol) was added to a round-bottomed flask containing a solution of 5-(benzyloxy)-N,1-dimethyl-6-oxo-2-(m-tolylmethylsulfonamido)-1,6-dihydro-pyrimidine-4-carboxamide (0.07 g, 153 μmol) in ethyl acetate (5 ml) and MeOH (5 ml). The resulting mixture was degassed by nitrogen, evacuated and purged with hydrogen. The mixture was stirred at room temperature under an atmosphere of hydrogen for one hour, filtered and evaporated to dryness under reduced pressure. The residue was washed with hexane and DCM, and crystallized from MeOH/Et2O to give the title compound as an off-white solid (0.03 g; 53%). LCMS m/z=367 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:20]Br.C1(C)C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[BrH:20].[Br:20][C:10]1[NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: Fc1ccc(-c2nc[nH]c2-c2ccc(F)cc2)cc1
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Br
Product: Fc1ccc(-c2nc(Br)[nH]c2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Yield: 179.8 %

Procedure:
A suspension of 4,5-bis(4-fluorophenyl)-1H-imidazole (25.6 g, 0.1 mol) in chloroform (100 ml) was cooled in an ice bath and treated dropwise with bromine (16.0 g, 0.1 mol) in 50 ml of chloroform. The mixture was stirred in the ice bath for one hour and then at room temperature until no starting material was evidenced by tlc (toluene-ethyl acetate, 6:4). The reaction mixture was filtered and the resulting solid was washed with diethyl ether and dried in vacuo to yield 37.4 g (90%) of the title compound, m.p. 270°-272°.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: CS(=O)c1ncc2cc(Br)c(=O)n(C3CCCC3)c2n1
Reactant: Nc1ccccn1
Product: O=c1c(Br)cc2cnc(Nc3ccccn3)nc2n1C1CCCC1
Yield: 37 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one and 2-aminopyridine were reacted according to the procedure outlined in Example 37 to provide 6-bromo-8-cyclopentyl-2-(pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one in 37% yield. mp: 273˜275° C. Anal. Calc'd for C17H16BrN5O.0.1H2O: C, 52.62; H, 4.21; N, 18.05. Found: C, 52.23; H, 4.10; N, 17.91. M++1: Calc'd: 386.05, Found 385.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9](Cl)=[CH:10][C:11]([C:13]1[C:14]([Cl:24])=[N:15][C:16]([Cl:23])=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:12]>O1CCOCC1>[NH:1]([C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:10][C:11]([C:13]1[C:14]([Cl:24])=[N:15][C:16]([Cl:23])=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(C=C(Cl)Cl)c1c(C(F)(F)F)cc(Cl)nc1Cl
Solvent: C1COCCO1
Product: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A solution of aniline (18.4 mL, 202 mmol) in TEA (28.2 mL, 202 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one (22.9 g, 67.4 mmol) in dioxane (220 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was treated with 10% HCI and extracted with Et2O (3×). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrate in vacuo. Silica gel flash chromatography of the residue using 6:1 Hex:EtOAc gave 3,3-dianilino-1-[2,6 dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one as an off-white solid (13.10 g, 43%): 1H-NMR (d6-DMSO, 300 MHz) δ12.24 (br s, 1H), 9.20 (br s, 1H), 7.95 (s, 1H), 7.12-7.42 (m, 1H), 4.82 (s, 1H); Rf=0.60 (6:1 Hex:EtOAc).
Reaction SMILES: CO[C:3]1[C:4](=[O:14])[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:10]=2[C:11](=[O:13])[CH:12]=1.[Cl-].[Ce+3].[Cl-].[Cl-].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[NH:19]([C:3]1[C:4](=[O:14])[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:10]=2[C:11](=[O:13])[CH:12]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC1=CC(=O)c2ncccc2C1=O
Reactant: Nc1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCO
Product: O=C1C(Nc2ccccc2)=CC(=O)c2ncccc21
Yield: 16 %

Procedure:
Six grams of 6-methoxyquinoline-5,8-quinone were dissolved in 500 ml of absolute ethanol and 9 g of cerium chloride were added. After the reaction was stirred, 3.3 g of aniline were added. The reaction mixture was refluxed for several hours, then it was stirred overnight at room temperature. The ethanol was evaporated to dryness and partitioned between chloroform and an aqueous sodium chloride solution. The chloroform layer was washed with an aqueous sodium chloride solution, dried with sodium sulfate, and then evaporated. The product was crystallized from absolute ethanol and weighed 3 g (16% yield). It had a melting point of about 182°-184° and the mass spectrum indicated the expected molecular ion at m/e=250.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([CH:19]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]([O:22]CC)=[O:21])=[O:18])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(O)C.[OH-].[K+].Cl>C1COCC1.O>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([CH:19]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]([OH:22])=[O:21])=[O:18])=[CH:12][CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)Nc1ccc(CP(=O)(OCC)OCC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)C(Cc2ccccc2)C(=O)O)cc1)OCC
Temperature: 0 °C
Reaction time: 15 h
Yield: 94.2 %

Procedure:
To an ice-cooled and stirred solution of ethyl 2-(p-diethoxyphosphorylmethylphenylaminocarbonyl)-3-phenylpropionate (6.0 g) in THF (30 ml)-ethanol (10 ml) was added dropwise a solution of KOH (0.9 g) in water (10 ml). After stirring at 4° C.-room temperature for 15 hours, the reaction mixture was acidified with 1N HCl, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried (MgSO4). The organic solvent was evaporated off to yield 2-(p-diethoxyphosphorylmethylphenylaminocarbonyl)-3-phenylpropionic acid (5.3 g, 94%) as crystals. Recrystallization from ethyl acetate-hexane gave pale yellow needles having melting point of 160° to 161° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[CH:16]1[CH2:18][CH2:17]1.[H-].[Na+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]=1[CH:16]1[CH2:17][CH2:18]1
Reactant: ClCc1ccccc1
Reactant: COC(=O)Cc1c(C2CC2)[nH]c2ccc(OC)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C2CC2)n(Cc2ccccc2)c2ccc(OC)cc12
Reaction time: 0.5 h
Yield: 4 %

Procedure:
A solution of 3.8 g (146 mmol) of 2-cyclopropyl-5-methoxyl-1H-indole-3-acetic acid methyl ester in 50 mL of DMF was treated with 0.59 g (0146 mol) of 60% NaH/mineral oil, stirred 0.5 hour, and 1.69 mL (146 mmol) of benzyl chloride added. After 20 hours, the reaction mixture was diluted with water, extracted with EtOAc, the EtOAc solution was washed four times with water and dried over Na2SO4. After concentrating at reduced pressure, the product was purified by chromatography on silica, eluting with a gradient, 5% EtOAc/toluene→15% EtOAc/toluene, to give 2.05 g (40% yield) of 2-cyclopropyl-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid methyl ester as an oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[C:25]([CH2:27]Cl)[N:26]=2)[CH:23]=1.C(N(CC)CC)C>C(O)CO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH:24]=[C:25]([CH2:27][N:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=4)[CH2:14][CH2:13]3)[N:26]=2)[CH:23]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: FC(F)(F)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)nc1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A mixture of 1-(5-trifluoromethylpyridin-2-yl)piperazine (0.4803 g), 6-chloro-2-(chloromethyl) imidazo[1,2-a]pyridine (Example 4, Step 1; 0.4177 g), triethylamine (0.231 g), and ethylene glycol (1 mL) is stirred at 80° C. for 70 min. after which additional 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (0.072 g) is added; thirty minutes later another portion (0.0517 g) is added. After stirring for a total of 2 h, the mixture is cooled and partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. Chromatography on silica gel using methanol/dichloromethane (4/96) and crystallization from ethyl ether/hexane gives 0.549 g of the title compound; mp 81-82° C.; MS m/z 395; IR (mineral oil) 1617, 1332, 1328, 1112, 1082 cm-1. 1H NMR (CDCl3) δ2.68, 3.69, 3.77, 6.62, 7.14, 7.52, 7.55, 7.61, 8.14, 8.38.