Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:16]=[CH:15][S:14][C:9]=3[NH:10][C:11](=[O:13])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19]I.O>CN(C)C=O>[CH3:19][O:13][C:11]1[N:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:16]=[CH:15][S:14][C:9]=2[N:10]=1
Reactant: O=c1nc(-c2ccccc2)c2ccsc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2)c2ccsc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 4.0 g of 4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 80 ml of dimethylformamide is added 0.8 g of 63% sodium hydride. The mixture is stirred at 60°C for 1 hour. The mixture is cooled to room temperature and 4.97 g of methyl iodide in 15 ml of dimethylformamide is added dropwise thereto at 10°C. The mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into water and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel, using chloroform as an eluent. From the first fraction, 2-methoxy-4-phenylthieno[2,3-d]pyrimidine is obtained as crystals having a melting point of 160° - 161.5°C (after recrystallization from ethanol). From the second fraction, 1-methyl-4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one is obtained as crystals having a melting point of 256° - 257.5°C (after recrystallization from ethanol). From the third fraction, 3-methyl-4-phenyl-3H-thieno[2,3-d]pyrimidin-2-one is obtained as crystal having a melting point of 175° - 181°C (after recrystallization from ethanol).
Reaction SMILES: C[Si](C)(C)[Br:3].[OH:6][CH2:7][C@@H:8]1[CH:23]=[C:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[NH:16][CH:15]=3)[N:10]([CH3:11])[CH2:9]1.N>CS(C)=O>[Br:3][C:15]1[NH:16][C:17]2[C:24]3[C:14]=1[CH2:13][C@@H:12]1[C:22]([C:21]=3[CH:20]=[CH:19][CH:18]=2)=[CH:23][C@@H:8]([CH2:7][OH:6])[CH2:9][N:10]1[CH3:11]
Reactant: C[Si](C)(C)Br
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Agent: N
Solvent: CS(C)=O
Product: CN1C[C@H](CO)C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2 g of trimethylbromosilane are portionwise added to 20 ml of dimethylsulfoxide and the reaction mixture is stirred at room temperature for 15 minutes, then a solution containing 1 g of lysergol in 15 ml of dimethylsulfoxide is added. After stirring for 20 minutes, the mixture is poured onto 150 ml of ice-water and the pH is adjusted to 8-9 by adding aqueous ammonia. The mixture is extracted 3 times with 30 ml of dichloromethane each. The combined organic phase is washed 3 times with 20 ml of 10% sodium chloride solution each, dried over sodium sulfate, filtered and the filtrate is evaporated under reduced pressure to give the title compound in a yield of 0.8 g (0.00277 mole, 70.5%),
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[O:19][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Product: CCOC(=O)CCCOc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1

Procedure:
In a similar manner to example 33, a mixture of 3-(1,4-dihydroindeno-[1,2-c]pyrazol-3-yl)phenol (0.20 g) was reacted with ethyl 4-bromobutyrate (0.16 g) to give ethyl 4-[3-(1,4-dihydroindeno-[1,2-c]pyrazol-3-yl)phenoxy]butyrate, m.p. 142-148° C.
Reaction SMILES: C[O:2][C:3](OC)([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8]/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)=[C:14]([O:24][CH3:25])[CH:13]=2)/[C:6]1=[O:26]>Cl>[CH3:25][O:24][C:14]1[CH:13]=[C:12](/[CH:11]=[C:7]2/[C:6](=[O:26])[N:5]([CH2:4][C:3](=[O:2])[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH2:10][CH2:9][CH2:8]/2)[CH:17]=[CH:16][C:15]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1
Reactant: COc1cc(/C=C2\CCCN(CC(OC)(OC)c3ccncc3)C2=O)ccc1-n1cnc(C)c1
Agent: Cl
Product: COc1cc(/C=C2\CCCN(CC(=O)c3ccncc3)C2=O)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
Concentrated hydrochloric acid (10 mL) was added to 1-(2,2-dimethoxy-2-pyridin-4-ylethyl)-3-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}piperidin-2-one (580 mg), and the mixture was stirred at 50° C. for four hours. After confirming that the raw materials disappeared, the reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate were added to the resulting residue, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH, elution solvent: heptane:ethyl acetate=1:2) to obtain 346.2 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CCCCCC>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)Cn1c(CN2CCNCC2)cc2cnc(C#N)nc21
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)Cn1c(CN2CCN(Cc3ccc(F)cc3)CC2)cc2cnc(C#N)nc21
Temperature: 50 °C
Yield: 90.5 %

Procedure:
7-(2,2-Dimethyl-propyl)-6-piperazin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.4 mmol) and 1-bromomethyl-4-fluoro-benzene (0.6 mmol) is dissolved in DMF (5 ml) and potassium carbonate (0.6 mmol) is added to the solution. The reaction mixture is heated at 50° C. for 3 h. After the mixture is diluted with AcOEt, the organic layer is washed with brine, dried over magnesium sulfate and filtrated. AcOEt is evaporated and the residue is purified by reverse phase HPLC. The product is obtained in 90.5% yield. Rf=0.32 (n-hexane:AcOEt=1:5).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[O:22]1[C:27]2[CH:28]=[CH:29][C:30](B(O)O)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1>>[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]4[CH2:14][CH2:13][CH2:12][C@H:11]4[CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:9])=[C:4]([F:21])[CH:3]=3)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Product: O=C(c1ccc(-c2ccc3c(c2)OCCO3)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2,3-Dihydro-1,4-benzodioxin-6-yl boronic acid. MS (M+H) 411.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].C[Si](O[C:18]#[N:19])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(Cl)Cl.O1CCCC1.[I-].[Zn+2].[I-]>[NH2:19][CH2:18][CH:6]([C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[OH:7]
Reactant: C[Si](C)(C)OC#N
Reactant: COc1ccc(C=O)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C(O)CN)cc1OC
Temperature: 25 °C

Procedure:
3,4-dimethoxybenzaldehyde (2.00 g, 12.04 mM) and trimethylsilyl cyanate (1.57 g, 15.04 mM) were dissolved in dry methylene chloride (1 ml). While stirring at room temperature, zinc iodide (8.5 mg) was carefully added and the mixture was stirred for 2 hours. Next, the solution was dropwise added to a solution of lithium aluminum hydride (1.10 g, 28.88 mM) in dried tetrahydrofuran (120 ml) cooled to 0° C., then the reaction temperature was gradually warmed to room temperature and the mixture was stirred for 1 hour. Water (2 ml) was carefully added while cooling the reaction solution in an ice bath, the mixture was stirred for 1 hour, then the solution was filtered through Celite. The filtrate was dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo to obtain a crude product (2.37 g) as a yellow solid. The crude product thus obtained had a sufficient purity even without purification, so could be used for the next reaction as it was.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:17])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>C(Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:17][C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nn2cccc(Br)c2c1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nn2cccc(Br)c2c1-c1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-3-phenyl-pyrazolo[1,5-a]pyridin-2-ylamine (0.295 g 1 eq) was dissolved in DCM (3 mL) at 5° C. and Et3N (356 μL) was added followed by the cyclopropane carbonyl chloride (234 μL). The reaction mixture was then allowed to warm to room temperature. The solvent was removed in vacuo the residue was treated with 7 M methanolic ammonia solution (5 mL) and stirred at room temp for 1 h to hydrolyse any bis-acylated product. The solvent was removed in vacuo and the residue was re-dissolved in DCM and washed with water and brine. The organics were passed through a hydrophobic frit and concentrated in vacuo. Purification by preparative HPLC
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@@H:7]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:13][C@H:14]([OH:17])[CH2:15][Cl:16])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)[C@@H](NC(OC(C)(C)C)=O)CCCCNC[C@@H](O)CCl)(C)(C)C.ClC(OCC1C=CC=CC=1)=O.C(N(CC)CC)C>>[C:1]([O:5][C:6](=[O:36])[C@@H:7]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:13][C@@H:14]([OH:17])[CH2:15][Cl:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN(C[C@H](O)CCl)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@@H](CCCCNC[C@@H](O)CCl)C(=O)OC(C)(C)C
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN(C[C@@H](O)CCl)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Yield: 85 %

Procedure:
According to the method described for the preparation of 13a, 12b (2.93 g, 7.42 mmol) was reacted with benzyl chloroformate (1.60 g, 9.38 mmol) and triethylamine (1.50 g, 14.81 mmol) to obtain 13b (3.35 g, 85%) as a colorless oil: 1H NMR δ 1.24-1.82 (m, 6H), 1.44 (s, 9H) 1.45 (s, 9H), 3.15-3.64 (m, 6H), 3.92 (m, 1H), 4.00 (m, 1H), 5.12 (m, 2H), 7.25-7.40 (m, 5H); 13C NMR δ 24.0, 28.3, 28.8, 32.5, 42.4, 51.3, 52.3, 55.7, 68.4, 71.0, 71.1, 80.4, 82.5, 129.0, 129.1, 129.6, 138.0, 158.1, 158.4, 173.7; HRMS m/z calcd for C26H42ClN2O7 529.2681, found 529.2691. Anal. calcd. for C26H41ClN2O7: C 59.03, H 7.81, N 5.29. Found: C 58.88, H 7.83, N 5.23. [α]23D−1.7°(c 0.98, CH3OH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][OH:12])=[O:5])[CH3:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[Si:18]([O:12][CH2:11][C:10]1[S:9][CH:8]=[N:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1ncsc1CO
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncsc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
4-Ethoxycarbonyl-5-hydroxymethylthiazole (282 mg) was dissolved in 5 ml of DMF, 123 mg of imidazole and 250 mg of t-butyldimethylsilyl chloride were added to the solution in an argon atmosphere under ice cooling, and the mixture was stirred at room temperature for 1.5 hr. Brine was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give 374 mg of 5-t-butyldimethylsilyloxymethyl-4-ethoxycarbonylthiazole.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:34]1[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:41])[F:40])=[CH:38][C:33]=1[F:32])=[N:3][CH:4]=[CH:5]2)(=[O:14])=[O:13]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1F
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: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4F)nccc3c2)c(OC)c1
Temperature: 90 °C
Yield: 85.5 %

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO; 0.250 g, 0.525 mmol), (2-fluoro-4-(trifluoromethyl)phenyl)boronic acid (0.164 g, 0.788 mmol), Pd(PPh3)4 (0.061 g, 0.053 mmol), and potassium carbonate (0.363 g, 2.63 mmol). Dioxane (2.63 mL) and Water (0.875 mL) were added, the vial was flushed with argon and sealed, and heated in a microwave reactor at 90° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 50% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.271 g, 0.449 mmol, 85% yield) as a white solid. N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (35 mg, 0.058 mmol) was dissolved in 1 mL of DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, dissolved in methanol, and passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford 1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.92 (br. s., 1H), 8.77 (d, J=5.7 Hz, 1H), 8.62 (d, J=1.6 Hz, 1H), 8.24 (d, J=5.6 Hz, 1H), 7.99-7.91 (m, 2H), 7.89-7.77 (m, 3H), 7.27 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H). m/z (ESI) 454.1 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]1[C:13]([O:15][C:16](=[O:17])[C:7]1=[CH:6]2)=[O:14].Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]1[C:13]([O:15][C:16](=[O:17])[C:7]1=[CH:6]2)=[O:14]
Reactant: COc1ccc2cc3c(cc2c1)C(=O)OC3=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1OC(=O)c2cc3cc(O)ccc3cc21

Procedure:
6-Methoxy-2,3-naphthalenedicarboxylic anhydride (4.0 g) and pyridine hydrochloride (8.0 g) were fused at 240° for 0.5 hr. in a nitrogen atmosphere. The flask contents were cooled, washed (water) and filtered to give a crude sample of 6-hydroxy-2,3-naphthalenedicarboxylic anhydride (m.p. 266°) which was used without purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]1[C:17]1[O:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(C(O)=O)CCSC.N>CS(O)(=O)=O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]1[C:17]1[O:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3Cc3ccccc3)o2)cc1
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Agent: N
Product: Oc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3Cc3ccccc3)o2)cc1

Procedure:
A solution of 19.6 g of 2-[1-benzyl-4-(trifluoromethyl)-imidazol-2-yl]-5-(4-methoxyphenyl)-furan and 8.1 g of D,L-methionine in 110 ml of methanesulphonic acid is stirred under nitrogen for 20 hours at 100°. After cooling, the reaction mixture is poured onto ice, the pH is adjusted to 8 with concentrated ammonia and the mixture is extracted several times with methylene chloride. Washing with water, drying and concentration by evaporation of the organic phase yield the crystalline 2-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-5-(4-hydroxyphenyl)-furan which is used as such in the next step.
Reaction SMILES: P(Br)(Br)Br.[CH3:5][C:6]1[N+:11]([O-])=[C:10]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:9]2=[C:8]([N+:18]([O-:20])=[O:19])[C:7]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:5][C:6]1[N:11]=[C:10]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:9]2=[C:8]([N+:18]([O-:20])=[O:19])[C:7]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c([N+](=O)[O-])c2c([n+]([O-])c1C)CCCCC2
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2c(c1[N+](=O)[O-])CCCCC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
Phosphorus tribromide (3.51 g, 12.5 mmol) was dissolved in ethyl acetate (12.0 ml) to which was subsequently added dropwise ethyl acetate solution (10.0 ml) of ethyl 2-methyl-4-nitro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate N-oxide (1.47 g, 5.00 mmol) at room temperature, and the resulting mixture was stirred at the same temperature for 10 minutes and then at 80° C. for 15 minutes. After cooling, the reaction solution was poured into ice water, mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, and the thus obtained organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain the title compound (1.36 g, 97.9%) as pale brown oil.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.BrN1C(=O)CCC1=O.[N-:29]=[N+:30]=[N-:31].[Na+].C(Cl)Cl>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>[N:29]([C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[N+:30]=[N-:31]
Reactant: Cc1cccc(-c2cccc(C(=O)OC(C)(C)C)c2)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc(-c2cccc(N=[N+]=[N-])c2)c1
Temperature: 80 °C
Yield: 89.1 %

Procedure:
Compound 19 (2.18 g, 8.13 mmol) and N-bromosuccinimide (1.70 g, 9.50 mmol) was suspended in 60 mL of CCl4. Dibenzoyl peroxide (20 mg) was added and the mixture was refluxed for 1.5 hr. After removing the solid, the filtrate was washed with concentrated sodium bicarbonate and dried over sodium sulfate. 1H NMR showed the crude material contained 70% of monobrominated and 30% of dibrominated product. This material was dissolved in 20 mL of DMSO and sodium azide (3.70 g, 57 mmol) was added. The mixture was heated to 80° C. for 4 hr before being poured into a mixture of methylene chloride and water. The organic layer was dried and evaporated. The residue was purified by flash column chromatography (5% of ethyl acetate in hexane) to give 20 (2.14 g, 78%, two steps) as colorless oil. 1H NMR (CDCl3) δ 8.22 (s, 1H), 8.00 (d, 7.7 Hz, 1H), 7.76 (d, 8.2 Hz, 1H), 7.58 (m, 2H), 7.50 (m, 2H), 7.33 (d, 7.6 Hz, 1H), 4.43 (s, 2H), 1.62 (s, 9H). 13C NMR (CDCl3) δ 165.2, 140.5, 140.3, 135.8, 132.3, 130.7, 129.1, 128.5, 128.2, 127.8, 127.1, 126.7, 126.6, 80.9, 54.3, 27.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[C@@H:16]([OH:17])[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C=O.[C:20](O)(=O)C.C(Cl)(Cl)Cl>C(O)C.O=[Pt]=O.CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[C@@H:16]([OH:17])[CH2:15][CH2:14][CH2:13][N:12]2[CH3:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)O
Reactant: COc1ccc([C@@H]2NCCC[C@@H]2O)cc1OC
Agent: O=[Pt]=O
Agent: C=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc([C@H]2[C@@H](O)CCCN2C)cc1OC

Procedure:
A solution of cis-2-(3,4-dimethoxyphenyl)-3-piperidinol (19.0 g, 80 mmoles, described in Example 4), ethanol (200 ml), 37% aqueous formaldehyde (7.4 g, 91 mmoles) and glacial acetic acid (8.0 g, 131 mmoles) is stirred at room temperature for 2 hours. The solution is diluted to 300 ml with ethanol and hydrogenated in the presence of Adams catalyst (400 mg). The residue is subjected to chromatography on silica gel using chloroform, 5% methanol-chloroform and finally 20% methanol-chloroform. The appropriate eluates are evaporated and the residue is dissolved in acetone. Maleic acid is added, followed by ether. The precipitate is collected and crystallized from acetonitrile-ether to give the title compound as the maleate salt, mp 132°-134° C.
Reaction SMILES: C(N(CC)CC)C.N12CCN(CC1)CC2.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17].[Cl:21][C:22]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[CH:29]=[CH:28][C:23]=1[O:24][CH2:25][CH2:26][OH:27]>O1CCCC1>[Cl:21][C:22]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[CH:29]=[CH:28][C:23]=1[O:24][CH2:25][CH2:26][O:27][C:19]([NH:18][CH2:16][CH3:17])=[O:20]
Reactant: OCCOc1ccc(Oc2cccc(Cl)c2)cc1Cl
Reactant: CCN=C=O
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)OCCOc1ccc(Oc2cccc(Cl)c2)cc1Cl

Procedure:
0.1 ml of triethylamine, 15 mg of 1,4-diazabicyclo[2.2.2]octane and 1.3 g of ethyl isocyanate are added to a solution of 4.49 g of 2-[2-chloro-4-(3-chlorophenoxy)phenoxy] ethanol in 40 ml of tetrahydrofuran. The reaction mixture is heated at 55° for 18 hours, with stirring, and then evaporated to dryness in vacuo. The residue is purified by chromatography [silica gel; diethyl ether/hexane (2:3)]. This gives the title compound which melts at 73°-74° C.