Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.Br.[Br:18][CH2:19][CH2:20][CH2:21][NH2:22]>C(#N)C>[Br:18][CH2:19][CH2:20][CH2:21][NH:22][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: NCCCBr
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1cc(NCCCBr)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.3 %

Procedure:
A solution of 2,4,6-trichloropyrimidine (100 g, 545 mmol) in acetonitrile (2000 mL) was added triethylamine (166 g, 1636 mmol) at 0° C., The reaction mixture was stirred for 5 min at rt, then 3-bromopropan-1-amine hydrobromide (119 g, 545 mmol) was added portionwise. The reaction mixture was stirred for 1 h at rt, and filtered to provide a clear solution. Purification via FC afforded the title compound as a white solid (47 g, 30% yield).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([Si:8]([CH2:12][CH3:13])([CH2:10][CH3:11])Cl)[CH3:7].Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.CC1C=CC(C)=CC=1>[CH2:1]([O:5][Si:8]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCCCO
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccc(C)cc1
Product: CCCCO[Si](CC)(CC)CC

Procedure:
0.1 moles of n-butanol, 0.15 moles of triethylchlorosilane and 0.0005 moles of triethylbenzyl ammonium chloride in 50 ml of p-xylene were heated under reflux (80°-110° C.). When the evolution of HCl had ceased, the product was worked up by fractional distillation at reduced pressure.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[O:3]1.C(O)(=O)C>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:19])[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[O:3]1
Reactant: Cc1cccnc1C1=CC(C)(C)Oc2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccnc1C1CC(C)(C)Oc2ccccc21
Yield: 46.8 %

Procedure:
2.97 g of 2,2-dimethyl-4-(3-methyl-2-pyridyl)-2H-1-benzopyran were dissolved in 50 ml of ethanol and shaken at room temperature under a hydrogen atmosphere with 10% palladium-on-charcoal in the presence of 0.5 ml of acetic acid. After 24 hours the catalyst was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. There were obtained 1.4 g of 3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl)-2H-1-benzopyran together with mixed fractions containing this compound and starting material. The procedure described above was carried out on the mixed fractions to give 675 mg of 3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl)-2H-1-benzopyran which was recrystallized from t-butyl methyl ether and then melted at 100°-102° C.
Reaction SMILES: [Br:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:13].ClCCl.[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>>[Br:1][C:2]1[C:8]([C:9]([F:10])([F:11])[F:12])=[CH:7][C:5]([N:6]=[C:17]=[S:18])=[CH:4][C:3]=1[Cl:13]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Cl)c(Br)c(C(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)c1cc(N=C=S)cc(Cl)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-bromo-3-chloro-5-(trifluoromethyl)aniline (15 g, 54.7 mmol, Eq: 1.00) in dichloromethane (13.2 g, 10.0 ml, 155 mmol, Eq: 25.3) at 0, was added 1,1′-thiocarbonyldiimidazole (11.7 g, 65.6 mmol, Eq: 1.2) The reaction was gradually warmed to room temperature and stirred overnight. The reaction was concentrated and chromatographed (220 g Redisep, 5 to 15% dichloromethane/hexane) to give 13.84 g (80%) pale yellow oil.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH:34]([CH:37]1[NH:42][CH2:41][CH2:40][NH:39][C:38]1=[O:43])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[CH3:35][CH:34]([CH:37]1[N:42]([CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[CH2:41][CH2:40][NH:39][C:38]1=[O:43])[CH3:36]
Reactant: CC(C)C1NCCNC1=O
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)C1C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (250 mg, 0.473 mmol, Intermediate B), 3-isopropylpiperazin-2-one (67.3 mg, 0.473 mmol, ChemBridge, San Diego, Calif.), and potassium carbonate (196 mg, 1.419 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (3.15 mL) was heated to 120° C. for 30 min After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). After concentration of the filtrate, the crude residue was purified by reverse-phase HPLC, (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient), two peaks were collected and each was partitioned between CH2Cl2 and saturated aqueous NaHCO3, the organic layers were dried (Na2SO4), filtered and concentrated to give 4 isomeric products
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.CCOCC>CN(C=O)C.C([O-])(O)=O.[Na+]>[N:10]1([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCCCl
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-chlorobutyrate (0.5 g, 3.32 mmol) in DMF (2 mL), piperidine (0.98 mL, 9.96 mmol), triethylamine (1.4 mL, 9.96 mmol) and a catalytic amount of KI were added and the resulting solution was refluxed overnight. After cooling at room temperature the solution was diluted with a saturated solution of NaHCO3 (10 mL) and extracts with Et2O (3×10 mL). The collected organic extracts were dried over Na2SO4, filtered and evaporated under vacuum to give the ethyl 4-piperidin-1-ylbutanoate as an oily residue (0.6 g, 3 mmol) pure enough for the next step. To a solution of the ester in dioxane (5 mL), few drops of 37% HCl were added and the solution was refluxed overnight. After cooling at room temperature the solvent was evaporated under vacuum and the residue was dried overnight in oven at 60° C. in vacuo. The crude 4-piperidin-1-ylbutanoic acid was dissolved in CH3OH (4 mL) and NaHCO3 (0.5 g, 6 mmol) was added. After stirring for 2 h, the precipitate was filtered off and the mother liquors concentrated to afford the intermediate sodium 4-piperidin-1-ylbutanoate (0.55 g, 2.84 mmol) as a colourless oil. 1H-NMR (DMSO-d6) δ 3.35 (m, 2H), 2.80 (m, 2H), 2.70 (m, 2H), 2.15 (t, 2H, J=3 Hz), 1.95 (m, 2H), 1.75 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccc(N)cc1-c1ccccc1
Yield: 99.2 %

Procedure:
A mixture of the 2-phenyl-4-nitrobenzoic acid methyl ester prepared in Example 210A (48.4 g, 188 mmol), palladium (10%) on carbon (2.1 g), and ammonium formate (59.4 g, 941 mmol) in methanol (500 mL) was refluxed for 3 hours. The solvent was removed in vacuo, and the residue was desolved in a miminum amount of hot methanol (about 30 mL). To this solution was added chloroform and ether (1/1 ratio, 400 mL), and the mixture was filtered through a plug of silica gel (80 g) and rinsed with chloroform. The filtrate was concentrated in vacuo to give pure 2-phenyl-4-aminobenzoic acid methyl ester (42.4 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.80 (d, 1H), 7.40-7.25 (m, 5H), 6.65 (dd, 1H), 6.57 (d, 1H), 3.60 (s 3H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=4)[N:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:44][C@@H:45]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:46]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:47].C(N(C(C)C)CC)(C)C>C1COCC1.C(Cl)Cl.C(Cl)CCl>[CH2:49]([NH:48][C:46]([C@@H:45]([NH:44][C:28]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:31])[F:1])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=[CH:26]2)=[O:29])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:47])[CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCNC(=O)[C@@H](N)c1ccccc1
Reactant: O=C(O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCNC(=O)[C@@H](NC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
2-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (F-1a2, 1.2 g, 2.53 mM), EDC (0.79 g, 6.34 mM), HOBT (0.86 g, 6.34 mM) and (S)-2-amino-N-pentyl-2-phenyl-acetamide hydrochloride (0.78 g, 3.05 mM,) were combined and dissolved in THF (12.5 mL). The mixture was treated with diisopropylethylamine (2.20 mL, 13 mM) and stirred at room temperature for 16 h. The mixture was diluted with CH2Cl2 and washed with water. The CH2Cl2 fraction was dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography, eluting with 30% acetone in hexanes to give 1.36 g of (S)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (pentylcarbamoyl-phenyl-methyl)amide as an amorphous solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:12]1[CH2:17][CH2:16][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)OC1C=CC=CC=1)#[N:2].[CH3:44][CH:45]([S-:47])[CH3:46].[Na+]>C1COCC1>[C:1]([N:3]=[C:4]([N:12]1[CH2:13][CH2:14][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][CH2:17]1)[S:47][CH:45]([CH3:46])[CH3:44])#[N:2]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=NC#N)Oc2ccccc2)CC1
Reactant: CC(C)[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=NC#N)SC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a stirred solution of phenyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate (20 mg, 0.035 mmol) in THF (1 mL) was added sodium 2-propanethiolate (6.8 mg, 0.07 mmol). The resulting mixture was stirred at ambient temperature for 30 minutes before evaporation of the solvent. The crude product was then purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford isopropyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carbimidothioate as a white solid (14 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J=7.5 Hz, 1H), 7.45-7.40 (m, 2H), 7.32-7.24 (m, 4H), 7.21-7.14 (m, 2H), 4.39-4.26 (m, 3H), 3.53 (br, 4H), 2.65 (s, 3H), 2.33-2.05 (m, 4H), 1.99-1.85 (m, 13H), 1.38 (d, J=6.4 Hz, 6H). HRMS m/z (M+H)+ calcd: 555.3270, obsd: 555.3274.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([N:26]=[C:27]=[O:28])=[C:18]([F:29])[CH:17]=1.Cl>C1(C)C=CC=CC=1.CN(C)C=O.O>[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:20][C:19]([NH:26][C:27](=[O:28])[NH:1]/[C:2](/[C:9]([F:10])([F:11])[F:12])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:18]([F:29])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C(\NC(=O)Nc1cc(OC(C)C)c(Cl)cc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.0 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 10 ml of absolute toluene is added dropwise while stirring at 0° C. during 15 minutes to a suspension of 0.24 g of a 55% sodium hydride dispersion in 20 ml of absolute dimethylformamide and the mixture is stirred at 0° C. for 15 minutes. The reaction mixture is subsequently cooled to -30° C. and treated with a solution of 1.26 g of 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate in 10 ml of absolute toluene. The temperature rises rapidly to -10° C. and the reaction mixture is thereafter stirred at room temperature for 2 hours. The reaction mixture is poured into a solution of 3 ml of 2N hydrochloric acid and 500 ml of water and the aqueous mixture is extracted twice with 100 ml of ethyl acetate each time, and the organic phases are washed twice with 50 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether/n-hexane. Via ethyl 3-[3-(4-chloro-2-fluoro-5 -isopropoxyphenyl)ureido]-4,4,4-trifluorocrotonate (m.p. 144°-146° C.), which is not isolated, there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 195°-197° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]1([C:12](Cl)=[O:13])[CH2:11][CH2:10]1>>[F:1][C:2]1[CH:3]=[C:4]([O:8][C:12]([CH:9]2[CH2:11][CH2:10]2)=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1
Reactant: O=C(Cl)C1CC1
Product: O=C(Oc1cccc(F)c1)C1CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To 31.4 parts of 3-fluorophenol were added dropwise 29.3 parts of cyclopropanecarbonyl chloride at 80° C. Upon completion, the whole was stirred for 1 hour at 80° C. The reaction mixture was distilled, yielding 49.7 parts (98%) of (3-fluorophenyl)cyclopropanecarboxylate; bp. 75°-85° C. at 0.5 mm. pressure (intermediate 86).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.[Pd]>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=C1CCCCc2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCCCc2ccccc21
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A solution of ethyl (6,7,8,9-tetrahydro-5-benzocycloheptenylidene)acetate (0.550 g) in ethyl acetate (10 ml) was added with 10% palladium/carbon (0.055 g), and the mixture was stirred for 3 hours under a hydrogen flow. The reaction mixture was filtered through Celite, and then the solvent of the filtrate was concentrated under reduced pressure to obtain the title compound (0.551 g, yield: 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([CH3:19])[C:14]([O:16]CC)=[O:15])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH:13]([CH3:19])[C:14]([OH:16])=[O:15])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(C)Cc1cccc(OCc2c(C)cccc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(CC(C)C(=O)O)c1
Reaction time: 3 h

Procedure:
To a stirred solution of Ethyl 3-(3-(2,6-dimethylbenzyloxy)phenyl)-2-methylpropanoate (Step C, 1.61 g, 4.9 mmol) in absolute ethanol (25 ml) was added 1N NaOH (10 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified to pH 3.5-4.0 by 1N HCl, and concentrated. The residue was taken into chloroform and washed with 0.1N HCl, brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 95:5 spiked with acetic acid) to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[CH2:16]1[S:20](=O)[CH2:19][CH2:18][CH2:17]1.C(OC(C)C)(C)C.[F:29][C:30]([F:53])([S:49]([O-:52])(=[O:51])=[O:50])[CH:31]([O:36][C:37]([C:39]12[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][CH:41]([CH2:42]3)[CH2:40]1)[CH2:46]2)=[O:38])[C:32]([F:35])([F:34])[F:33].[Na+]>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[C:39]12([C:37]([O:36][CH:31]([C:32]([F:35])([F:33])[F:34])[C:30]([F:29])([F:53])[S:49]([O-:52])(=[O:50])=[O:51])=[O:38])[CH2:40][CH:41]3[CH2:47][CH:45]([CH2:44][CH:43]([CH2:42]3)[CH2:48]1)[CH2:46]2.[SH+:20]1[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=S1CCCC1
Agent: COCCOc1cccc2ccccc12
Agent: CS(=O)(=O)O
Agent: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: CC(C)OC(C)C
Product: C1CC[SH+]C1
Reaction time: 8 h

Procedure:
In 10 g of Eaton's reagent (Aldrich, diphosphorus pentoxide/methanesulfonic acid solution) was dispersed 5.0 g (0.024 mol) of 1-(2-methoxyethoxy)naphthalene in Reference Synthesis Example 3. With stirring, 5.1 g (0.049 mol) of tetramethylene sulfoxide was added dropwise to the dispersion. The solution was matured overnight at room temperature and combined with 30 g of water and 30 g of diisopropyl ether, from which a water layer was separated. The water layer was again washed with 30 g of diisopropyl ether. This aqueous solution was combined with an aqueous solution of sodium 1,1,3,3,3-pentafluoro-2-(adamantane-1-carbonyloxy)propanesulfonate (corresponding to 0.007 mol) synthesized according to the formulation described in JP-A 2007-145797, after which extraction was effected twice with 50 g of dichloromethane. The organic layer was washed with water, and the solvent was distilled off in vacuum. The residue was poured into isopropyl ether for crystallization, filtered and dried, obtaining the target compound. White crystal, 7.9 g, yield 94%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([C:26]([CH3:28])=[O:27])[CH:24]=[CH:25][C:20]=2[S:19][C:18]2[N:29]=[CH:30][CH:31]=[N:32][C:17]1=2.[C:33](Cl)(=[O:35])[CH3:34]>O1CCCC1.CCCCCC.C(OCC)(=O)C.O>[CH3:13][O:14][CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([C:26](=[O:27])[CH2:28][C:33](=[O:35])[CH3:34])[CH:24]=[CH:25][C:20]=2[S:19][C:18]2[N:29]=[CH:30][CH:31]=[N:32][C:17]1=2
Reactant: COCN1c2cc(C(C)=O)ccc2Sc2nccnc21
Reactant: CC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: O
Product: COCN1c2cc(C(=O)CC(C)=O)ccc2Sc2nccnc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 18.3 %

Procedure:
Into 20 ml of ice-cooled solution of 1.27 ml of diisopropylamine in dry tetrahydrofuran was dropped in a nitrogen atmosphere 5.5 ml of a 1.6 M solution of n-butyllithium in hexane. After stirring for 10 minutes, the reaction mixture was cooled to −78° C. Next, 5 ml of a solution of 2.0 g of (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methyl ketone in dry tetrahydrofuran was added thereto and the mixture was stirred for 30 minutes. After further dropping 700 mg of acetyl chloride thereinto, the reaction mixture was brought back to room temperature. Then the reaction mixture was distributed into water and ethyl acetate and the organic layer was extracted, washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with toluene/acetone) to thereby give 420 mg of the title compound as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:7](CC=C)=[C:6](I)[CH:5]=[C:4]([CH:12]([OH:14])[CH3:13])[N:3]=1.[PH2](O)=O.C(N(CC)CC)C.[CH2:25]1C[O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[N:3]=[C:4]([CH:12]([OH:14])[CH3:13])[CH:5]=[C:6]2[CH:26]([CH3:25])[CH2:27][O:28][C:7]=12
Reactant: C=CCc1c(I)cc(C(C)O)nc1Cl
Reactant: C1CCOC1
Agent: O=[PH2]O
Solvent: CCN(CC)CC
Product: CC(O)c1cc2c(c(Cl)n1)OCC2C
Yield: 97 %

Procedure:
A solution of 2-chloro-3-(1-propen-3-yl)-4-iodo-6-(1-hydroxyethyl)-pyridine (1.06 g, 3.14 mmol) in THF (5 mL) is treated with 50% hypophosphorous acid (2.13 g, 15.73 mmol), triethylamine (1.75 g, 17.33 mmol), and 2,2'-azobis(2-methylpropino-nitrile) (AIBN; 192 mg, 1.23 mmol). The solution is stirred at reflux for 2 hours. The solution is allowed to cool and concentrated in vacuo. Sat'd NaHCO3 is added, and the mixture is extracted 3× EtOAc. The organics are dried over MgSO4, and concentrated in vacuo. The crude light yellow oil is chromatographed (SiO2, hexane/ethyl acetate, 2:1) to yield 650 mg (97%) of 7-chloro-2,3-dihydro-5-(1-hydroxyethyl)-3-methyl-furo[2,3-c]pyridine, mp 67-68° C.
Reaction SMILES: Br.[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=O.[N+:13]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([NH2:25])=[C:18]([NH2:26])[CH:17]=1)([O-:15])=[O:14]>CS(C)=O>[Cl:12][C:7]1[CH:6]=[C:5]([C:3]2[CH:2]=[N:26][C:18]3[C:19](=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=3)[N:25]=2)[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1N
Agent: Br
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc2ncc(-c3ccc(Cl)c(Cl)c3)nc2cc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 24 h

Procedure:
48% aqueous HBr (8.8 M) (3.4 ml, 30 mmol) was slowly added to a stirred solution of 3,4-dichloroacetophenone (1.89 g, 10 mmol) in DMSO (17 ml). The solution was stirred in an open flask at 55° C. for 24 hours. The solution was poured onto ice, the solid product was filtered, washed with water, and redissolved in ethanol (18 ml). 4,5-Dinitro-1,2-phenylene-diamine (890 mg, 4.5 mmol) was added and the mixture was heated to reflux for 4 hours.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C1(C2[O:17]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:17]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncccn1
Solvent: ClCCl
Product: CS(=O)c1ncccn1

Procedure:
The methylsulfanyl-pyrimidine compound of formula (83) is reacted with an oxidising agent, preferably 3-phenyl-2-(phenylsulfonyl)oxaziridine, in an organic solvent, preferably dichloromethane, at room temperature. The product of formula (84), a methanesulfinyl-pyrimidine derivative, is isolated by conventional means, and preferably reacted in the next step without further purification. The product of formula (84) may, however, be additionally purified by means of chromatography or recrystallisation.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].Cl[CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[N:9]([CH2:29][C:30]2[N:31]=[C:32]([CH3:35])[S:33][CH:34]=2)[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Reactant: Cc1nc(CCl)cs1
Product: Cc1nc(Cn2c(=O)n(O)c(=O)c3oc4ccccc4c32)cs1

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with 4-(chloromethyl)-2-methyl-1,3-thiazole and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 2.59 (s, 3H); 5.54 (s, 2H); 7.38 (dd, J=8 Hz, 1H); 7.44 (s, 1H); 7.62 (dd, J=8 Hz, 1H); 7.81 (d, J=8 Hz, 1H); 7.87 (d, J=8 Hz, 1H); Ret. time=2.01 min., m/z=330.0.