Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].[Br:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1F.[F-].[K+]>>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:12][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[Br:14]
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: [F-]
Agent: [K+]
Product: O=Cc1ccc(OC(F)F)c(Oc2ccc([N+](=O)[O-])cc2Br)c1

Procedure:
According to other embodiments, the present invention provides methods of preparing N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfoneamide-dibenzo[b,d]furan-1-carboxamide comprising the steps of: (a) reacting 4-difluoromethoxy-3-hydroxybenzaldehyde with 2-bromo-1-fluoro-4-nitrobenzene in a first solvent comprising potassium fluoride to produce 4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde; (b) cyclizing 4-difluoromethoxy-3-(4-nitro-2-bromophenoxy)benzaldehyde in a second solvent comprising a catalyst to produce 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran; (c) oxidizing 4-difluoromethoxy-8-nitro-1-formyl dibenzofuran in a third solvent comprising an oxidizing agent to produce 4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid; (d) reacting 4-difluoromethoxy-8-nitrobenzo[b,d]furan-1-carboxylic acid in a fourth solvent comprising an inorganic acid halide, 4-amino-3,5-dichloropyridine and a first base, wherein N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide is produced; (e) reducing N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide in the presence of a reducing agent to produce N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide; and (f) reacting N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide in a fifth solvent comprising methanesulfonyl chloride and a second base to produce N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(methanesulfonamide) dibenzo[b,d]furan-1-carboxamide.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([CH3:29])[N:24]=2)[CH2:19][CH2:18]1)C(=O)OC(C)(C)C>ClCCl>[CH3:8][NH:9][CH:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([CH3:29])[N:24]=2)[CH2:21][CH2:22]1
Reactant: Cc1cncc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCN(c2cncc(C)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (2 ml) was added at 0° C. to a solution of tert-butyl methyl(1-(6-methylpyrazin-2-yl)piperidin-4-yl)carbamate (250 mg, 0.816 mmol, 1 eq) in dichloromethane (10 ml) and the reaction mixture was stirred for 2 h at room temperature. Concentration under reduced pressure was then carried out. The crude product so obtained was used in the next stage without being purified further.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:26])[CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]3[CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]3[N:27]=[CH:28][CH:29]=[CH:30][C:9]=3[NH:8][C:7](=[O:31])[C:6]=2[CH:32]=1.[C:33](#N)C>>[CH2:24]([N:21]([CH2:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][N:14]1[CH2:13][C:12]([N:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:32][C:6]=2[C:7](=[O:31])[NH:8][C:9]2[CH:30]=[CH:29][C:28]([CH3:33])=[N:27][C:10]1=2)=[O:26])[CH2:22][CH3:23])[CH3:25]
Reactant: CC#N
Reactant: CCN(CC)CC1CCCCN1CC(=O)N1c2ccc(Cl)cc2C(=O)Nc2cccnc21
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2ccc(C)nc21

Procedure:
8-Chloro-11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one of m.p. 186° to 188° C. (acetonitrile using active charcoal);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CC(C)(C)C(=O)Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C(C)(C)C)nc23)CC1
Yield: 484.3 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.067 mL (0.048 mMol) 2,2-dimethylpropanoyl chloride, 0.067 gm (48%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH:25]([CH2:28][OH:29])[CH2:26][OH:27])[CH:20]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH:25]([CH2:26][OH:27])[CH2:28][OH:29])[C:20]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1C(CO)CO
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1C(CO)CO

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(1,3-dihydroxypropan-2-yl)indolin-5-yl)cyclopropanecarboxamide (40.3 mg, 0.0711 mmol as the trifluoracetic acid salt) was dissolved in toluene (1 mL). To the resulting solution was added 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (35 mg, 0.14 mmol). The resulting suspension was heated at 100 CC in an oil bath for 10 minutes. The crude product was then evaporated to dryness, dissolved in a 1 mL of NA-dimethylformamide and purified by purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(1,3-dihydroxypropan-2-yl)-1H-indol-5-yl)cyclopropanecarbox amide. ESI-MS m/z calc. 450.2, found 451.5 (M+1)+. Retention time of 1.59 minutes.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1.P(Cl)(Cl)([Cl:23])=O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=2)[N:5]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1ccc2nc(C(=O)OCC)cc(O)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCc1ccc2nc(C(=O)OCC)cc(Cl)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
126 parts of ethyl 4-hydroxy-6-n-butylquinoline-2-carboxylate, prepared as described in Example 2, and 213 parts of phosphorus oxychloride were stirred together. After the exothermic reaction had subsided the dark-coloured mixture was stored for 1 hour at room temperature then cooled to 0°C, diluted with 75 parts of ethanol to improve its mobility and subsequently added dropwise to 500 parts of ice and 1500 parts of water. The aqueous mixture was neutralised to pH 7 - 8 by addition of sodium carbonate when 133.2 parts of a light brown coloured crystalline solid separated out and were collected by filtration and dried. This material was purified by recrystillisation from about 380 parts of acetone (with carbon treatment) and yielded 100.8 gm. of ethyl 4-chloro-6-n-butylquinoline-2-carboxylate which was isolated as pale grey needles, m.pt. 58°- 58.5°C. An additional 27.5 parts of less pure product, m.pt. 54.5°-56°C, was obtained by dilution of the acetone mother-liquor with water.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[CH3:2].[NH2:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19].C([BH3-])#N.[Na+]>>[CH2:1]([O:3][C:4]([CH:5]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:19])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:16])[CH3:2]
Reactant: CCOC(=O)C(=O)CCc1ccccc1Cl
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)C(CCc1ccccc1Cl)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in Example 26, ethyl-2-oxo-4-(2-chlorophenyl)butyrate and L-alanyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-[1-ethoxycarbonyl-3-(2-chlorophenyl)-propyl]-L-alanyl-L-proline. The mass spectrum shows a peak at 411, (M+1), and a strong peak at 392, (M-18).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12]1[C:13](=O)[C:14](=[O:19])[C:15]=1[O:16]CC)[CH3:10]>C(O)C>[CH2:9]([O:11][C:12]1[C:15](=[O:16])[C:14](=[O:19])[C:13]=1[NH:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:10]
Reactant: Nc1cccnc1O
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccnc2O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
A mixture of 1.82 g (16.5 mmol, 1 eq) of 3-aminopyridin-2-ol and 3.6 ml (24.8 mmol, 1.5 eq) of 3,4-diethoxycyclobut-3-ene-1,2-dione (3.6 ml, 24.8 mmol) in solution in 87 ml of ethanol was stirred at ambient temperature for 16 hours and then heated at 50° C. for 3 days with formation of a precipitate. Ethanol was added in order to promote the fall of the precipitate, which was filtered off, washed with diethyl ether and dried under vacuum at 45° C. 3.47 g of 3-ethoxy-4-(2-hydroxypyridin-3-ylamino)cyclobut-3-ene-1,2-dione were obtained in the form of a brown solid. Yield=90%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.Cl.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17]N.B(F)(F)F.CCOCC>C(O)(=O)C>[F:9][C:10]([F:19])([F:20])[C:11]1[C:12]2[NH:17][C:4]3[CH2:3][CH2:2][NH:1][CH2:6][C:5]=3[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: NNc1ccccc1C(F)(F)F
Reactant: O=C1CCNCC1
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc2c3c([nH]c12)CCNC3
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 4-piperidone.HCl (1.36 g, 10.0 mmol) and 2-trifluoromethylphenylhydrazine.HCl (2.13 g, 10.0 mmol) in acetic acid (50 mL) was added the 1.0 M borontrifluoride etherate (2.46 mL, 20.0 mmol) and the reaction stirred at 90° C. for 8 hours and then allowed to cool. The mixture was concentrated in vacuo and ethanol (ca 20 mL) added and then cooled to 0° C., the solid was filtered off and the mother liquor was concentrated in vacuo and water (adjusted to pH 14 with 2M NaOH) added to the residue. The solid was filtered off and washed with water and dried under high vacuum.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:29]1(B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC>[C:29]1([C:14]2[N:15]=[C:11]([C:10]3[C:2]([CH3:1])=[N:3][N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=34)[S:12][C:13]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1C1=CCCCC1
Yield: 95.8 %

Procedure:
Using ethyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (220 mg, 0.5 mmol) produced in Example 15(i), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (620 mg, 3.0 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (72 mg, 0.088 mmol), cesium carbonate (620 mg, 1.9 mmol), water (0.5 mL) and 1,2-dimethoxyethane (15 mL) as starting materials and in the same manner as in Example 13(iii), the title compound (176 mg, 95%) was obtained as a yellow solid.
Reaction SMILES: CS[C:3](=[N:12][C:13]#[N:14])[NH:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Br:11])[CH:10]=1.[C:15]1([S:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOCC>N1C=CC=CC=1>[Br:11][C:9]1[CH:10]=[C:5]([NH:4][C:3]([NH:12][C:13]#[N:14])=[N:24][CH2:23][CH2:22][S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[N:7][CH:8]=1
Reactant: CSC(=NC#N)Nc1cncc(Br)c1
Reactant: NCCSc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: N#CNC(=NCCSc1ccccc1)Nc1cncc(Br)c1

Procedure:
S-Methyl N-(5-bromo-3-pyridyl)-N'-cyanoisothiourea (650 mg) and 2-phenylthioethylamine (740 mg) in pyridine (0.5 ml) were heated to 50° C. for 5 hours. To the resulting clear solution was added ether (10 ml), and the desired pure compound was collected by filtration and washed with ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[C:11]1([C:17]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:25]3[C@@H:21]([CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24]3)[C:20](=[O:33])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Ce+3].[Cl-].[Cl-].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:11]1([C:17]2([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@@H:25]3[C@@H:21]([CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24]3)[C@@:20]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])([OH:33])[CH2:19][CH2:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@H]2C1
Reactant: COc1ccccc1[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
A suspension of 2-methoxyphenylmagnesium bromide (prepared from 75.3 g of 2-bromoanisole and 9.8 g of magnesium) in 100 cm3 of dry tetrahydrofuran is added dropwise at room temperature with stirring to a suspension of 20 g of (3aS,7aS)-7,7-diphenyl-2-(tert-butoxycarbonyl)perhydroisoindol-4-one and 31.6 g of anhydrous cerium chloride in 250 cm3 of dry tetrahydrofuran. The reaction mixture is stirred at room temperature for 24 hours, treated with 400 cm3 of a saturated aqueous ammonium chloride solution, diluted with 200 cm3 of ethyl acetate, washed with 300 cm3 of water (twice) and then with 300 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (particle size 0.04-0.06 mm, diameter of 5.8 cm, height 26.5 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 100 cm3 fractions. Fractions 9 to 29 are combined and concentrated to dryness under reduced pressure (2.7 kPa). There are obtained 17.82 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-(tert-butoxycarbonyl)perhydroisoindol-4-ol in the form of a white foam.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C@H:9]2[O:13][C:12](=[O:14])[NH:11][C@@H:10]2[C:15]2[CH:20]=[CH:19]C=[C:17]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[CH:6]=[CH:7][CH:8]=1.BrC1C=C([C@@H]2[C@@H](C3C=CC=CC=3)OC(=O)N2)C=C[N:31]=1.C1(C#C)C=CC=CC=1>>[C:5]1([C@H:9]2[O:13][C:12](=[O:14])[NH:11][C@@H:10]2[C:15]2[CH:20]=[CH:19][N:31]=[C:17]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[CH:4]=[CH:3][CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Reactant: O=C1N[C@H](c2ccnc(Br)c2)[C@@H](c2ccccc2)O1
Solvent: C#Cc1ccccc1
Product: O=C1N[C@H](c2ccnc(C#Cc3ccccc3)c2)[C@@H](c2ccccc2)O1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with (4R,5R)-4-(2-bromopyridin-4-yl)-5-phenyloxazolidin-2-one and phenylacetylene. 1H-NMR (CDCl3, 500 MHz) δ 8.64 (d, J=4.9, 1H), 7.60 (m, 2H), 7.50 (m, 1H), 7.45 (m, 3H), 7.40 (m, 3H), 7.34 (m, 2H), 7.17 (dd, J=5.2, 1.5, 1H), 6.73 (bs, 1H), 5.25 (d, J=7.3, 1H), 4.82 (d, J=7.3, 1H). 13C-NMR (CDCl3, 126 MHz) δ 158.8, 151.0, 148.1, 144.6, 136.7, 132.2, 129.7, 129.4, 129.3, 128.6, 126.2, 124.4, 121.9, 120.2, 90.5, 88.2, 85.4, 63.7. Mass spec.: 341.2 (MH)+.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26](Cl)=[O:27].C(N(CC)C(C)C)(C)C>>[CH3:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)=[O:27]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Yield: 88 %

Procedure:
Prepared according to Method E from 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol), 3,3-dimethylbutanoyl chloride (0.167 mL, 1.2 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) to give 0.347 g of the title compound as a white solid, mp 74–75° C.;
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:21][CH2:20]1)=[O:4].[C:32](Cl)(=[O:35])[CH2:33][CH3:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:32](=[O:35])[CH2:33][CH3:34])[C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:21][CH2:20]1)=[O:4]
Reactant: CCC(=O)Cl
Reactant: CNC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(=O)N(C)C(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Yield: 12 %

Procedure:
A mixture of 2.22 g of N-methyl-2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide, 1.39 g of propionyl chloride, 2.53 g of triethylamine and 50 ml of toluene is refluxed for 2.5 days with stirring. The mixture is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, successively. The ethyl acetate solution is dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:ethyl acetate=3:1). 0.30 g of N-methyl-N-propionyl-2-{2-[2-(4-(3-fluorophenyl)piperazine-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide is obtained as an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1C(C)C
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (1.25 g) and 37% formalin (0.83 mL) in the same manner as in Example 1 was dissolved in chloroform (7 mL), and triethylamine (1.25 mL) and 3-cyano-5-isopropyl-4-methoxybenzoyl chloride (710 mg) were added to the solution, and then the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (1.02 g) as a yellow oily substance.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([S:13][CH2:14][CH2:15][CH2:16][S:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([N+:27]([O-:29])=[O:28])=[CH:25][N:26]=3)[N:23]=2)[CH:9]=[CH:8][N:7]=1>CO>[CH3:1][O:2][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([S:13][CH2:14][CH2:15][CH2:16][S:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([N+:27]([O-:29])=[O:28])=[CH:25][N:26]=3)[N:23]=2)[CH:9]=[CH:8][N:7]=1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1nccc(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)c1C
Temperature: 25 °C

Procedure:
A solution of sodium methanolate (0.69 ml of a 30% strength solution) is added to a suspension of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)-propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine (1.23 g, 3 mmol) in methanol (75 ml). After heating under reflux for 16 h and cooling to room temperature the solvent is evaporated in vacuo. The residue is chromatographed (silica, toluene/dioxane 5:1) and crystallized from diisopropylether/ethyl acetate to give the title compound as off-white crystals, 0.34 g (28 %). M.p. 107-110° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][O:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 13.1 %

Procedure:
A mixture of methyl thiosalicylate (0.56 g, 3.4 mmol), 2-cyano-6-methoxypyridine (0.45 g, 3.4 mmol), triethylamine (0.70 ml, 5.0 mmol) and toluene (50 ml) was refluxed for 48 hrs as described in Example 1. The reaction mixture was concentrated under reduced pressure and recrystallized from ethanol to give the titled compound (0.12 g, 13%) as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20][C:21]1[CH:33]=[C:32]([CH2:34][S:35]([NH:38][CH3:39])(=[O:37])=[O:36])[CH:31]=[CH:30][C:22]=1[NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18][N:23]([C:22]1[CH:30]=[CH:31][C:32]([CH2:34][S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[CH:33][C:21]=1[Br:20])[C:24](=[O:29])[C:25]([F:26])([F:28])[F:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNS(=O)(=O)Cc1ccc(NC(=O)C(F)(F)F)c(Br)c1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Product: CNS(=O)(=O)Cc1ccc(N(CC=C[C@H]2CCCN2C(=O)OCc2ccccc2)C(=O)C(F)(F)F)c(Br)c1
Yield: 44 %

Procedure:
(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene and 2-bromo-4-methylaminosulfonylmethyl-N-trifluoroacetylaniline were used. Column chromatography using elution with 4% acetone in methylene chloride afforded the title compound as a white foam (44%): FAB LRMS (m/z, relative intensity) 620 ([MH+ with 81Br], 618 ([MH+ with 79Br], 98), 576 (50), 574 (63), 512 (17), 484 (33).