Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH2:13](O)[CH2:14][CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)C1(OCCCO1)C(=O)N2
Yield: 73.6 %

Procedure:
A mixture of 5-methylisatin (8.00 g, 49.6 mmol), 1,3 propanediol (10.89 mL, 149 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (1.89 g, 9.92 mmol, 0.2 eq) in benzene (940 mL) was heated to reflux under a Dean Stark Trap for 17.5 hr. The reaction mixture was concentrated. The residue was taken up in EtOAc (300 mL) and washed with sat. aq. NaHCO3 (2×) and concentrated. The crude product was purified on Biotage KP silica gel eluting with 60/40 Pet ether/EtOAc to give the title compound as a yellow solid (8.0 g., 74% yield). NMR (300 Mz, DMSO-d6): consistent.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O-:10])=[O:9].[Na+].Br[C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[CH2:23][CH:24]4[NH:28][CH:27]([C:16]=3[C:15]=2[C:14]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]4>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[CH2:23][CH:24]4[NH:28][CH:27]([C:16]=3[C:15]=2[C:14]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]4)(=[O:10])=[O:9]
Reactant: Cc1ccccc1S(=O)[O-]
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cc1ccccc1S(=O)(=O)c1ccc2c(c1C(=O)OC(C)(C)C)c1c(n2C)CC2CCC1N2
Yield: 17 %

Procedure:
Intermediate 19 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(2-methylphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (45 mg, 17%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.18 (dd, J=7.4, 1.5 Hz, 1H), 7.95 (dd, J=7.8, 1.8 Hz, 1H), 7.16-7.71 (m, 5H), 5.24 (br s, 1H), 4.70 (br s, 1H), 3.60 (s, 3H), 3.38 (br s, 1H), 2.50 (d, J=15.9 Hz, 1H), 2.49 (s, 3H), 2.26-2.47 (m, 1H), 2.13-2.26 (m, 1H), 1.88-1.99 (m, 1H), 1.59-1.67 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [S:1]1[CH2:4][CH:3]([O:5][N:6]=[C:7]([C:30]2[N:31]=[C:32]([NH:35]C=O)[S:33][CH:34]=2)[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[O:26])=[C:15]([CH2:18][N+:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH2:2]1.Cl>CO>[S:1]1[CH2:2][CH:3]([O:5][N:6]=[C:7]([C:30]2[N:31]=[C:32]([NH2:35])[S:33][CH:34]=2)[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[O:26])=[C:15]([CH2:18][N+:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH2:4]1
Reactant: O=CNc1nc(C(=NOC2CSC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)cs1
Agent: Cl
Solvent: CO
Product: Nc1nc(C(=NOC2CSC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
A mixture of 7-[2-(3-thietanyloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.1 g) and conc. hydrochloric acid (0.8 g) in methanol (80 ml) was stirred at room temperature for 3 hours. Methanol was evaporated in vacuo and the residue was pulverized with isopropyl ether. The solid was dissolved in water (50 ml) and the solution was adjusted to pH 2.0 with 10% hydrochloric acid. The insoluble substance was filtered off. The filtrate was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark: prepared by Mitsubishi Chemical Industries) and eluted with 10% aqueous solution of isopropyl alcohol. The fractions containing the object compound were concentrated and lyophilized to give 7-[2-(3-thietanyloxyimino)-2-(2-aminothiazol-4-yl)-acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (0.45 g).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH3:13])=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([C:3]1[S:4][C:5]([CH3:13])=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1nc(CC)sc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc(C(=O)O)c(C)s1
Yield: 11.6 %

Procedure:
8 g of ethyl 2-ethyl-5-methyl-1,3-thiazole-4-carboxylate was dissolved in 10 ml ethanol. 2 ml of 5N sodium hydroxide was added, followed by heating under reflux for 1 hour. The reaction solution was ice-cooled and neutralized with 2N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evapoarated, to give 0.8 g of 2-ethyl-5-methyl-1,3-thiazole-4-carboxylic acid.
Reaction SMILES: [N:1]1[C:2]([CH2:10]O)=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>ClCCl>[Br:32][CH2:10][C:2]1[N:1]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1nc2ccccn2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1nc2ccccn2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a brown suspension of [1,2,4]triazolo[1,5-a]pyridin-2-ylmethanol (870 mg, 5.83 mmol) and triphenylphosphine polymer bound (2.94 g, 8.75 mmol) in dichloromethane (18 mL) was slowly added carbon tetrabromide (2.9 g, 8.75 mmol) at 0-5° C. The ice bath was removed after 5 min and the reaction mixture was stirred at RT overnight. The solvent was evaporated, the brown residue was suspended in ethyl acetate (100 mL) and the organic phase was washed with water (3×50 mL) and brine (1×50 mL). The aqueous layers were back-extracted with ethyl acetate (1×100 mL) and the combined organic layer was dried over MgSO4 and concentrated in vacuo to give the product as colorless waxy solid (1.35 g with 90% purity, 5.7 mmol, 98.2%) which was used without further purification for the next step.
Reaction SMILES: C([C@@]1(O)[C@@H](CO)O[C@@](C(=O)C)([N:11]2[C:21]3[N:20]=[C:18]([NH2:19])[NH:17][C:15](=[O:16])[C:14]=3[N:13]=[CH:12]2)[C@]1(C(=O)C)O)(=O)C.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(Cl)C1C=CC=CC=1.Cl>C(#N)C>[CH2:30]([N:13]1[C:14]2[C:15](=[O:16])[NH:17][C:18]([NH2:19])=[N:20][C:21]=2[N:11]=[CH:12]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(=O)[C@@]1(O)[C@@](O)(C(C)=O)[C@@H](CO)O[C@@]1(C(C)=O)n1cnc2c(=O)[nH]c(N)nc21
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: ClCc1ccccc1
Solvent: CC#N
Product: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
Triacetylguanosine (0.756 g, 1.85 mmols) was suspended in 6 ml of acetonitrile, and 0.28 ml (1.25 equivalents) of benzyl bromide and 0.27 ml (1.25 equivalents) of benzyl chloride were added to the suspension. The mixture was reacted at 50° C. for 24 hours and at 60° for 23 hours. The temperature was returned to room temperature, and 1.58 ml (10.1 equivalents) of conc. hydrochloric acid were added thereto. The resulting mixture was reacted for 3 hours. After 40 minutes of the reaction, the solid was precipitated. Fifteen milliliters of methanol were added thereto, and the slurry was stirred for 1.5 hours, and then filtered. The crystals were washed twice with 5 ml of methanol, and dried at 50° C. under reduced pressure for 4 hours to give 0.468 g of 7-benzylguanine crystals in a yield of 80.5%.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7](=[C:10]([C:25]#[N:26])[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23])[N:12]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27]C(C)([O-])C.[K+].CI.C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl.CCOCC>[C:1]([C:5]1[NH:6][C:7](=[C:10]([C:25]#[N:26])[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]([CH3:27])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23])[N:12]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)NCCCNc1nccc(C(C#N)=C2NC(C(C)(C)C)=CS2)n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCCN(C)c1nccc(C(C#N)=C2NC(C(C)(C)C)=CS2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.4 %

Procedure:
To suspension of N-[3-({4-[(4-tert-butyl-1,3-thiazol-2(3H)-ylidene)(cyano)methyl]pyrimidin-2-yl}amino)propyl]acetamide (290 mg, 0.68 mmol) in THF (7 ml) were added potassium tert-butoxide (91 mg, 0.81 mmol) and methyl iodide (0.085 mL, 1.35 mmol). The resulting mixture was stirred 2 h at rt. LC/MS analysis showed the presence two peaks with the same mass in a proportion of 7:3. The THF was evaporated and the residue was taken up in water and extracted with EtOAc (3×). The combined organic layer was washed with brine, dried with MgSO4 and the solvent was evaporated under reduced pressure to give a gummy residue which was the mixture of to compounds of the same mass. It was taken up in DCM and an excess TFA then ether were added to the solution. As no precipitation occurred, the solution was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 93 mg of the title compound as a TFA salt pyrimidine (yellow solid, Y=27.3%).
Reaction SMILES: [NH:1]([C:5]1[N:16]=[C:8]2[C:9]3[C:14]([CH2:15][N:7]2[N:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:2]([NH2:4])=S.[OH:17]O.Cl>[OH-].[Na+]>[NH:1]([C:5]1[N:16]=[C:8]2[C:9]3[C:14]([CH2:15][N:7]2[N:6]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:2]([NH2:4])=[O:17]
Reactant: NC(=S)Nc1nc2n(n1)Cc1ccccc1-2
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)Nc1nc2n(n1)Cc1ccccc1-2
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
2-Thioureido-5H-s-triazolo[5,1-a]isoindole (1.15 g, 0.005 mole) is suspended in 20 ml of 2% aqueous sodium hydroxide and 2.3 ml of 36% H2O2 (0.024 mole) is added at 40°-45° C. After 15 minutes, the mixture is heated for 5 minutes at 80° C then, after cooling and neutralizing with dilute hydrochloric acid, the resulting solid precipitate is recovered by filtration and is purified by crystallization from 60% ethanol. Yield 0.83 g; m.p. 261°-3° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[S:8][CH2:9][CH2:10][O:11][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].B1(C=C)OB([CH:24]=[CH2:25])OB(C=C)O1.C1C=CN=CC=1.O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:24]([C:2]1[N:7]=[N:6][C:5]2[S:8][CH2:9][CH2:10][O:11][C:4]=2[CH:3]=1)=[CH2:25]
Reactant: Clc1cc2c(nn1)SCCO2
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1cc2c(nn1)SCCO2
Temperature: 96 °C
Yield: 71.2 %

Procedure:
A solution of 3-chloro-6,7-dihydro[1,4]oxathiino[3,2-c]pyridazine (450 mg, 2.4 mmol) in dimethoxyethane (12 ml) was treated with tetrakis(triphenylphosphine)palladium (0) (61 mg), potassium carbonate (313 mg), 2,4,6-trivinylcyclotriboroxane pyridine complex (375 mg) and water (1.5 ml). The mixture was heated at 96° C., overnight. The mixture was evaporated to dryness, treated with aqueous sodium bicarbonate solution, extracted (4×) with DCM, dried (sodium sulphate), evaporated and chromatographed on silica gel (50 g), eluting with 1:1 ethyl acetate-hexane, affording a solid (200 mg, 46%), containing slightly impure product.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:30]=[CH:29][C:10]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([CH2:27][C:26](=[O:28])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[O:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]=1[O:31][CH3:32])([CH3:6])([CH3:5])[CH3:4].[CH:33](OCC)=[O:34]>C1COCC1>[C:3]([C:7]1[CH:30]=[CH:29][C:10]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([C:27](=[CH:33][OH:34])[C:26](=[O:28])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[O:19]3)[CH2:17][CH2:18]2)=[O:12])=[CH:9][C:8]=1[O:31][CH3:32])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC=O
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2ccccc2O3)ccc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2C(=O)C3=CO)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
NaH (57 mg, 1.4 mmol) was added in small portions to a mixture of 1′-(4-tert-butyl-3-methoxy-benzoyl)spiro[chromane-2,4′-piperidine]-4-one (250 mg, 0.61 mmol) in THF (2.5 mL) at 25° C. A solution of ethyl formate (74 μL, 0.90 mmol) in THF (0.5 mL) was added and the mixture was allowed to stir at 25° C. for 3 h before it was quenched with 0.5M aqueous HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 1′-(4-tert-butyl-3-methoxybenzoyl)-3-(hydroxymethylene)spiro[chroman-2,4′-piperidin]-4-one (50 mg, 19%) as an orange oil. ESI-MS m/z calc. 435.2. found 436.2 (M+1)+; Retention time: 1.87 minutes (3 min run).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([CH2:14][NH:15]CC1C=CC=CC=1)([OH:13])[CH2:4][NH:5]CC1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:5][CH2:4][C:3]([CH2:14][NH2:15])([OH:13])[C:2]([F:24])([F:23])[F:1]
Reactant: OC(CNCc1ccccc1)(CNCc1ccccc1)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NCC(O)(CN)C(F)(F)F
Yield: 126.6 %

Procedure:
A solution of 1,1,1-trifluoro-3-[(phenylmethyl)amino]-2-{[(phenylmethyl)amino]methyl}-2-propanol (8.15 g, 24.1 mmol) in ethanol (200 ml) was stirred under a hydrogen atmosphere over Pearlman's catalyst (500 mg) for 24 hours. The catalyst was filtered off and the filtrate concentrated under reduced pressure. The residue was redissolved in methanol and concentrated under reduced pressure to give an oil (4.825 g). This oil was redissolved in ethanol (200 ml) and stirred under a hydrogen atmosphere over Pearlman's catalyst (500 mg) for 24 hours. The catalyst was filtered off and the filtrate concentrated under reduced pressure to give the title compound (3.07 g) as an oil.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH:11]([CH2:13]O)[OH:12]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:2]1([CH:1]2[O:9][CH2:10][CH:11]([OH:12])[CH2:13][O:8]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OC1COC(c2ccccc2)OC1
Temperature: 0 °C
Yield: 21.1 %

Procedure:
A mixture of about 184 g of glycerol, about 212.03 g of benzaldehyde and about 3.6 g of p-toluenesulfonic acid was refluxed for about 5 hours, using a Dean-Stark trap. The mixture was then cooled at about 0° C. for about 17 hours and the solid collected and dissolved in about 1200 ml of warm toluene containing about one gram of sodium methoxide. This solution was washed with about 600 ml of dilute (about 1%) dibasic sodium phosphate and dried. Dilution with petroleum ether gave a solid which was recrystallized from toluene-petroleum ether, giving about 76 g of the desired title compound as a white solid.
Reaction SMILES: [I-].[K+].[F:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[F:11])[NH2:7].C(N(CC)C(C)C)(C)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([NH:41][C:42](=[O:45])[CH2:43]Cl)[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O.C(OCC)(=O)C.O>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([NH:41][C:42](=[O:45])[CH2:43][NH:7][C:6]3[CH:8]=[CH:9][C:10]([F:11])=[C:4]([F:3])[CH:5]=3)[CH:35]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)c(NC(=O)CCl)c2)CC1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)c(NC(=O)CNc3ccc(F)c(F)c3)c2)CC1
Temperature: 90 °C

Procedure:
Potassium iodide (10 mg), 3,4-difluoroaniline (0.4 ml), N,N-diisopropyl ethylamine (0.9 ml) and 4-[4-chloro-3-(2-chloro-acetylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (500 mg) were combined in N,N-dimethylformamide (10 ml) and heated at 90° C. for 24 hr. After cooling to room temperature, the reaction was poured into ethyl acetate/water. The organic layer was separated, washed with water (×3) and brine, dried (MgSO4) and concentrated. Purification of the residue by silica gel chromatography (eluting ethyl acetate/iso-hexane (1:2 to 1:1) gave the subtitle product (360 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>Cl.O>[F:13][C:12]([F:15])([F:14])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc(Nc2ccnc3c(C(F)(F)F)cccc23)cc1
Temperature: 90 °C
Yield: 96.6 %

Procedure:
23.16 Grams (0.1 mole) of 4-chloro-8-trifluoromethyl quinoline were dissolved in 22 milliliters of concentrated hydrochloric acid and 150 milliliters of water and the solution was added in a stream to a vigorously stirred solution of 13.7 grams (0.1 mole) of p-aminobenzoic acid in 150 milliliters of water at 60° C. The mixture was heated at 90° C. for 2 hours, cooled, and the solid collected and recrystallized from ethanol to give 32.1 grams (83%) of the title compound as the hydrochloride monohydrate, melting point 262°-265° C.(d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=1.Cl[C:22]1[CH:32]=[C:26]2[N:27]([CH3:31])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[N:10]=1)[CH2:19][O:20][C:22]1[CH:32]=[C:26]2[N:27]([CH3:31])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=1
Reactant: OCc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(C(F)(F)F)n3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluoro-4-((6-(trifluoromethyl)pyridine-2-yl)oxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]2=[O:17])=[N:6][CH:7]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N12CCN(CC1)CC2>ClCCl>[CH3:16][C:11]1([CH3:15])[CH2:10][C:9](=[O:17])[N:8]([C:5]2[N:6]=[CH:7][C:2]([O:1][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:3][N:4]=2)[C:13](=[O:14])[CH2:12]1
Reactant: CC1(C)CC(=O)N(c2ncc(O)cn2)C(=O)C1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CN(C(=O)Oc1cnc(N2C(=O)CC(C)(C)CC2=O)nc1)c1ccccc1

Procedure:
A solution of 1-(5-hydroxy-pyrimidin-2-yl)-4,4-dimethyl-piperidine-2,6-dione (0.60 g, 2.55 mmol), N-methyl-N-phenylcarbamoyl chloride (0.48 g, 2.81 mmol) and 1,4-diazabicyclo-[2,2,2]octane (0.31 g, 2.81 mmol) in dichloromethane (25 mL) was stirred at room temperature for 15 minutes. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50), yielding the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CN(CC1SC=C(CSC[CH2:27][NH:28][C:29]2[C:33](OC)=[N:32][S:31](=[O:36])[N:30]=2)N=1)C.CN>CO>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:33]2[C:29]([NH:28][CH3:27])=[N:30][S:31](=[O:36])[N:32]=2)[N:9]=1)[CH3:1]
Reactant: COC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Agent: CN
Solvent: CO
Product: CNC1=NS(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
When a methanol suspension of 3,4-dimethoxy-1,2,5-thiaziazole 1-oxide [prepared in Example 4, Step A] is reacted with an equimolar amount of 2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine [prepared in Example 33, Step E] and the resulting 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide is treated with methylamine, the title compound is thereby produced.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[N:11]=[C:10]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]3)=[C:29]([O:39][CH3:40])[CH:28]=2)[CH:9]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:40][O:39][C:29]1[CH:28]=[C:27]([NH:26][C:10]2[CH:9]=[C:8]([CH2:7][OH:6])[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=3)[N:11]=2)[CH:32]=[CH:31][C:30]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1
Reactant: COc1cc(Nc2cc(C(C)(C)O[SiH2]C(C)(C)C)cc(Nc3ccc(OC(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(Nc2cc(CO)cc(Nc3ccc(OC(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′-(4-trifluoromethoxy-phenyl)-pyridine-2,6-diamine (50 mg, 0.083 mmol) was dissolved in 1 mL of tetrahydrofurane and tetrabutyl ammonium fluoride (44 mg, 0.17 mmol) were added. The mixture was stirred at 20° C. for 2 hours, concentrated in the rotatory evaporator and diluted with water. Extraction with ethyl acetate and purification by chromatography on amino-modified silica gel (Merck HPTLC Silica Gel 60 NH2F254S) using ethyl acetate/methanol (gradient 0 to 2% methanol) gave the pure title compound as a yellowish solid (5 mg, 10%). MS ISP (m/e): 486.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.58 (s, 1H), 7.41 (d, 2H), 7.19 (d, 1H), 7.20-7.05 (m, 3H), 6.97 (dxd, 1H), 6.83 (s, 1H), 6.78 (s broad, 1H), 6.67 (s broad, 1H), 6.40 (s, 1H), 6.33 (s, 1H), 4.59 (s, 2H), 3.67 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:21][C:22]=1[CH3:23]>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20](/[CH:24]=[CH:25]/[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:21][C:22]=3[CH3:23])=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: Cc1oc(/C=C/c2ccccc2)nc1CCl
Product: Cc1oc(/C=C/c2ccccc2)nc1COc1ccc(CCCn2ccnc2)cc1
Yield: 66 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-5-methyl-2-[(E)-2-phenylethenyl]oxazole to give 4-[4-[3-(1-imidazolyl)propyl)phenoxymethyl]-5-methyl-2-[(E)-2-phenylethenyl]oxazole. The yield was 66%. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 94-95° C.