Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:30][O:31][C:32](=[O:38])[CH2:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH2:10][CH2:11][CH2:12][C@H:3]4[NH:2][S:34]([CH2:33][C:32]([O:31][CH3:30])=[O:38])(=[O:36])=[O:35])[N:17]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Reactant: COC(=O)CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N[C@@H]1CCCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Yield: 58.2 %

Procedure:
Prepared using General Procedure 6: To a stirring solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 3 (0.15 g, 0.37 mmol) in DCM (5 mL) were added TEA (76 μL, 0.55 mmol) and methyl-2-(chlorosulfonyl)acetate (76 mg, 0.44 mmol). Additional TEA and methyl-2-(chlorosulfonyl)acetate were added to drive the reaction to completion over 24 h. The crude reaction mixture was partitioned between DCM and saturated NaHCO3. The organic layer was dried over Na2SO4, concentrated, and purified by column chromatography (EA/hexanes) to give 0.11 g (57%) of (R)-methyl 2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl)acetate INT-14. LCMS-ESI (m/z) calculated for C25H26N4O6S: 510.6; found 511.1 [M+H]+, tR=3.73 min. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 8.01-7.93 (m, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.00 (d, J=8.4 Hz, 1H), 4.81 (dq, J=18.3, 5.9 Hz, 2H), 4.25-4.00 (m, 2H), 3.83 (s, 3H), 3.20 (dt, J=18.1, 5.9 Hz, 1H), 3.12-2.97 (m, 1H), 2.22-2.01 (m, 2H), 2.02-1.83 (m, 2H), 1.48 (d, J=6.1 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[C:12]1([CH3:26])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23].C(O)(C)C>N1C=CC=CC=1>[NH2:25][C:24]1[N:3]2[N:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[C:20]([C:13]2[C:12]([CH3:26])=[CH:17][C:16]([CH3:18])=[CH:15][C:14]=2[CH3:19])[C:21]=1[C:22]#[N:23]
Reactant: Cc1cc(C)c(C=C(C#N)C#N)c(C)c1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn2c(N)c(C#N)c(-c3c(C)cc(C)cc3C)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 155 mg (1 mmol) of 3-amino-4-carbethoxypyrazole and 196 mg (1 mmol) of (mesitylmethylene)malononitrile (Intermediate 3) in 3 mL of anhydrous pyridine was stirred at reflux under air for 3 days and then cooled and concentrated in vacuo. Because LC-MS indicated the presence of considerable dihydro intermediate, 112 mg (0.49 mmol) of 2,3-dichloro-5,6-cyano-1,4-benzoquinone (DDQ) and 3 mL of isopropanol were added to the residue, and the mixture was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (elution with 2% methanol in dichloromethane) to give the title compound as an orange solid. LC-MS 350 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:24]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:21]1[CH:28]=[C:27]([CH:26]=[C:23]([CH3:24])[CH:22]=1)[CH2:29][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(OCc2cc(C)cc(C)c2)c1
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxyphenyl)acetate (3 g, 16.6 mmol) in DMF (20 ml) was added potassium carbonate (2.99 g, 21.6 mmol) at room temperature followed by drop wise addition of 3,5-Dimethylbenzyl bromide (3.30 g, 16.6 mmol). The reaction mixture was stirred for 16 hours and taken in ethyl acetate, washed with water (2×), brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:24][CH:21]3[CH2:22][CH2:23][O:18][CH2:19][CH2:20]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: OC1CCOCC1
Product: CC(C)(C)OC(=O)N1Cc2ccc(OC3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and tetrahydro-4H-pyran-4-ol. White solid. MS (m/e): 264.1 ([M+H-Me2C═CH2]+, 100%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-])=O)[CH:21]=2)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O.[H][H]>[C].[Pd]>[NH2:27][C:22]1[CH:21]=[C:20]([C:11]([C:6]2[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([NH2:1])[CH:5]=2)([C:12]([F:13])([F:14])[F:15])[C:16]([F:17])([F:18])[F:19])[CH:25]=[CH:24][C:23]=1[OH:26]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(c2ccc(O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: [Pd]
Product: Nc1cc(C(c2ccc(O)c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1O

Procedure:
At present, bis(3-amino-4-hydroxyphenyl) compounds, especially 2,2-bis(3-amino-4-hydroxyphenyl)hexafluoropropane are important as materials for producing heat-resistant polymers, etc. A method mentioned below is known for producing bis(3-amino-4-hydroxyphenyl) compounds, which, however, is problematic in the following points. Japanese Patent Application Laid-Open (JP-A) No. Hei-6-211752 discloses a method of catalytic hydrogenation reduction of bis(3-nitro-4-hydroxyphenyl)hexafluoropropane with a catalyst of palladium-carbon under high-pressure hydrogen. In this method, the purity of 2,2-bis(3-amino-4-hydroxyphenyl)hexafluoropropane produced in the reaction mixture is 97%, and after the catalyst is removed through filtration, the mixture is poured into water for crystallization to obtain a dark gray product. This is recrystallized from a mixture of ethyl acetate and n-hexane to obtain the intended product, 2,2-bis(3-amino-4-hydroxyphenyl)hexafluoropropane. In this method, the starting compound is catalytically reduced with high-pressure hydrogen at a high temperature, and the method requires a pressure reactor (e.g., autoclave). Therefore, the method could neither be economical nor advantageous in view of the complicated operations it requires. In addition, the crude product obtained in the method contains coloring components that are difficult to remove, which brings about another problem that the post treatment of the product is not easy.
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].I[CH2:37][CH2:38][CH3:39]>CN(C=O)C>[F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[N:6]([CH2:37][CH2:38][CH3:39])[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)c(-c2ccc(F)cc2)s1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(CC2CCCCN2C(=O)c2nc(C)sc2-c2ccc(F)cc2)nc2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E35 (150 mg, 0.32 mmol) was added slowly to an ice-cooled slurry of sodium hydride (26 mg, 0.64 mmol, 60% dispersion in mineral oil) in DMF (10 ml). After stirring for a further 0.5 h, 1-iodopropane (60 mg, 0.35 mmol) was added. The mixture was stirred at room temperature for 16 h then partitioned between water and ethyl acetate. The organic phase was washed with water, brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 50-100% ethyl acetate-pentane then 0-5% methanol-ethyl acetate) afforded the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23](Cl)=[O:24])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][OH:31].N1C=CC=CC=1>O1CCCC1>[OH:31][CH2:30][C:29]1[CH:28]=[C:27]([NH:26][C:23](=[O:24])[CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:17]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)Cl)c1
Reactant: Nc1cccc(CO)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2cccc(CO)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 10.5 g of 3-(tetradecyloxy)benzeneacetyl chloride in 110 ml of tetrahydrofuran is added a solution of m-aminobenzyl alcohol in 110 ml of tetrahydrofuran containing 9.05 g of pyridine followed by stirring at ambient temperature for 4 hours and storing in a refrigerator over the weekend. The solvent is evaporated and the residue is poured into water and extracted with tetrahydrofuran:ether. The organic layer is washed with dilute hydrochloric acid, dried and filtered through a pad of magnesium silicate. The filtrate is evaporated and the residue purified by high pressure liquid chromatography using 2:1 hexane:ethyl acetate to give 3.6 g of the desired product as a white powder, m.p. 108°-110° C. and 5.B g of a white powder, m.p. 86°-90° C. found to be 3-(tetradecyloxy)-[3-[[[3-(tetradecyloxy)phenyl]acetyl]amino]phenyl]benzeneacetic acid methyl ester.
Reaction SMILES: [C:1]([C:3]([CH3:34])([CH3:33])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13]3[C:16]([C:27]([O:29]CC)=O)=[N:17][N:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:12]=3[C:11]2=[O:32])=[CH:6][CH:5]=1)#[N:2].[NH3:35]>C(O)CO>[C:1]([C:3]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13]3[C:16]([C:27]([NH2:35])=[O:29])=[N:17][N:18]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[C:12]=3[C:11]2=[O:32])=[CH:6][CH:5]=1)([CH3:33])[CH3:34])#[N:2]
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(C(C)(C)C#N)cc1)C2=O
Reactant: N
Solvent: OCCO
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(C(C)(C)C#N)cc2)CC3)cc1
Temperature: 80 °C
Yield: 88 %

Procedure:
Ethyl 6-[4-(cyano-dimethyl-methyl)phenyl]-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboylate (0.38 g, 0.83 mmol) obtained in Example 96 was placed in a sealed tube containing 10% ammonia in ethylene glycol (3 mL) and heated 80° C. for 2 h. The reaction was cooled, quenched with H2O, extracted with EtOAc, and dried (MgSO4). Recrystallization from CH2Cl2/Hexanes afforded 0.31 g (88%) of the title amide. High Resolution Mass Spec (M+H)+. for C24H24N5O3 430.1898.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[N+:12]([O-])([OH:14])=[O:13].C(=O)([O-])O.[Na+]>>[N+:12]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][C:5]=1[OH:9])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 7.5 g of 3-trifluoromethylphenol, 9 ml of 70% nitric acid was added dropwise at room temperature and the reaction mixture was stirred for one hour. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate twice. The combined organic layers washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.56 g of 2-nitro-5-trifluoromethylphenol.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[C:18]([Cl:19])=[CH:17][C:16]3[C:20]4[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][C:21]=4[C:22]([CH3:25])([CH3:24])[O:23][C:15]=3[C:11]=2[C:12](=[O:14])[CH:13]=1)=[O:7])CCC.O>C(O)(=O)C.Cl>[C:6]([C:8]1[O:9][C:10]2[C:18]([Cl:19])=[CH:17][C:16]3[C:20]4[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][C:21]=4[C:22]([CH3:25])([CH3:24])[O:23][C:15]=3[C:11]=2[C:12](=[O:14])[CH:13]=1)([OH:7])=[O:5]
Reactant: CCCCOC(=O)c1cc(=O)c2c3c(cc(Cl)c2o1)-c1ccc(S(=O)(=O)O)cc1C(C)(C)O3
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)Oc2c(cc(Cl)c3oc(C(=O)O)cc(=O)c23)-c2ccc(S(=O)(=O)O)cc21

Procedure:
1.0 gm (2 millimols) of 2-(n-butoxycarbonyl)-4-oxo-6,6-dimethyl-8-sulfo-12-chloro-4H,6H-[2]-benzopyrano-[3,4-f]-[1]-benzopyran (see Example 11) was heated for 1 hour in a mixture of 12 ml of acetic acid and 5 ml of concentrated hydrochloric acid. Then, the reaction mixture was evaporated to dryness, and the residue was recrystallized from methanol. 0.5 gm (53% of theory) of the compound named in the heading, m.p. 257°-259° C, was obtained (with 2 mols of water of crystallization).
Reaction SMILES: Cl[C:2]1[CH:14]=[C:6]2[N:7]([CH:11]3[CH2:13][CH2:12]3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:15])[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH2:34][OH:35])[CH:20]=[CH:21][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1>>[CH:11]1([N:7]2[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:15])[N:3]=[C:2]([O:35][CH2:34][C:19]4[CH:20]=[CH:21][C:22]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=5)=[C:17]([F:16])[CH:18]=4)[CH:14]=[C:6]23)[CH2:13][CH2:12]1
Reactant: OCc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1
Reactant: O=c1nc(Cl)cc2n1CCCN2C1CC1
Product: O=c1nc(OCc2ccc(Oc3cccc(C(F)(F)F)c3)c(F)c2)cc2n1CCCN2C1CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-cyclopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (3-fluoro-4-(3-(trifluoromethyl)phenoxy)phenyl) methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([OH:22])(=O)[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].P(Cl)(Cl)Cl>>[C:13]([NH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=2)[OH:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:22])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]
Reactant: COC(=O)c1cc(N)ccc1N
Reactant: O=C(O)c1ccccc1O
Solvent: ClP(Cl)Cl
Product: COC(=O)c1cc(NC(=O)c2ccccc2O)ccc1NC(=O)c1ccccc1O
Yield: 54 %

Procedure:
By the procedure similar to that described in Example 15, methyl 2,5-diaminobenzoate was condensed with salicylic acid with the aid of phosphorus trichloride to obtain methyl 2,5-bis(salicylamido)-benzoate (Yield; 54%). The product was confirmed to be identical to that obtained in Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH3:22]I>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH3:22])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Reactant: CI
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Yield: 58.8 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.11 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 25 mg of lithium hydride and 440 mg of methyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 554 mg of 2-[(4-chlorophenyl)imino]-2,3-dihydro-3-methyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (59%, recrystallized from a mixture of ether and hexane).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[C:8]=1[C:28]#[N:29]>>[NH2:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:20])([F:21])[F:22])=[CH:14][C:13]=2[Cl:23])[N:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[C:8]=1[C:28](=[O:2])[NH2:29]
Reactant: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: O=S(=O)(O)O
Product: NC(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reaction time: 1 h

Procedure:
To stirred 80% sulphuric acid (22 ml) was added 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.98 g) at 80° C. After 1 hour, the cooled solution was poured onto ice and extracted with dichloromethane (3×). The combined extracts were washed with water, dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo to give a white solid. This solid was recrystallized from ethyl acetate-petroleum ether to give 5-amino-4-carbamoyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.5 g), m.p. 169°-171° C. in the form of white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24]([O:28]C)=[N:23][CH:22]=[CH:21]3)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1.O>[N:11]1([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[NH:23][CH:22]=[CH:21]3)(=[O:17])=[O:16])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: COc1nccc2cc(S(=O)(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]ccc2cc(S(=O)(=O)N3CCCNCC3)ccc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
110 mg of 6-(4-tert-butoxycarbonyl-1,4-diazepan-1-ylsulfonyl)-1-methoxyisoquinoline was dissolved in 2 mL of 1,4-dioxane and 1.5 mL of water. 4 mL of a 4 M hydrochloric acid-dioxane solution was added dropwise thereto, and the mixture was then stirred at 90° C. for 16 hours. After the completion of reaction, the reaction solvent was distilled off. The obtained residue was dissolved in 5 mL of methanol, and 5 mL of ethyl acetate was then added with vigorous stirring. The deposited white crystal was collected by filtration and dried under reduced pressure to obtain 64 mg of the compound of interest as a white crystal (72%).
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH:24](OC)[O:25]C)[C:19]=2[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])=[O:30])[N:9]=[N:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[F:45][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH:24]=[O:25])[C:19]=2[C:29](=[O:30])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[N:9]=[N:8]1
Reactant: COC(Cc1noc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=CCc1noc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Combine [5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2,2-dimethoxy-ethyl)-isoxazol-4-yl]-(2-chloro-phenyl)-methanone (1 eq) in acetone/H2O (4:1) and p-toluenesulfonic acid (1 eq) with stirring. Attach a reflux condensor and stir overnight in a 60° C. oil bath. Neutralize with saturated aqueous NaHCO3, extract with ethyl acetate, dry over MgSO4, filter, and concentrate under vacuum. 1H NMR (CDCl3): δ 9.84 (s, 1H), 7.83 (s, 1H), 7.56-7.09 (m, 11H), 5.43 (s, 2H), 4.09 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=O)[CH3:9])[CH:3]=1.[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])([CH3:14])([CH3:13])[CH3:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH:8]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)[CH3:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)c1cc(C)ccn1
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnc(C(C)NCCCCNC(=O)OC(C)(C)C)c1

Procedure:
Using General Procedure B: To a stirred solution of 1-(4-methyl-pyridin-2-yl)-ethanone (Sundberg, R J et al. J. Am. Chem. Soc. 1969, 91, 658-668) and (4-amino-butyl)-carbamic acid tert-butyl ester in CH2Cl2 was added NaBH(OAc)3 to give {4-[1-(4-methyl-pyridin-2-yl)-ethylamino]-butyl}-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.35 (d, 3H, J=6.6 Hz), 1.42 (s, 9H), 1.46-1.49 (m, 4H), 1.80 (br, 1H), 2.34 (s, 3H), 2.40-2.51 (m, 2H), 3.06-3.09 (m, 2H), 3.78 (q, 1H, J=6.6 Hz), 4.89 (br, 1H), 6.96 (d, 1H, J=5.1 Hz), 7.08 (s, 1H), 8.39 (d, 1H, J=5.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27]CC)=[O:26])=[CH:17][C:16]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[O:1][C:13]1[C:12]([Cl:11])=[CH:30][C:16]2[CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]([C:21]([F:23])([F:24])[F:22])[O:20][C:15]=2[CH:14]=1)([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccc(C(=O)O)c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 3-hydroxybenzoic acid and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4. (Note: In the step similar to step 3, an additional equivalent of potassium carbonate was added.) mp 288.1-289.2° C. 1H NMR (acetone-d6/300 MHz) 7.92 (m, 2H), 7.75 (s, 1H), 7.68 (d, 1H, J=1.4 Hz), 7.62 (t, 1H, J=7.9 Hz), 7.41 (m, 1H), 6.72 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz)-79.4 (d, J=6.5 Hz) ESHRMS m/z 413.0027 (M−H, Calc'd 413.0040). Anal. Calc'd for C18H10ClF3O6: C, 52.13; H, 2.43; Cl, 8.55. Found: C, 51.88; H, 2.48; Cl, 8.65.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11])[CH:2]=[CH2:3].[SH:12][CH:13]([CH3:17])[CH:14]([OH:16])[CH3:15]>>[OH:16][CH:14]([CH3:15])[CH:13]([CH3:17])[S:12][CH2:3][CH2:2][CH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11]
Reactant: CC(O)C(C)S
Reactant: C=CCc1cccc(C)c1O
Product: Cc1cccc(CCCSC(C)C(C)O)c1O

Procedure:
In the same manner as in Synthetic example 1, 2-allyl-6-methylphenol and 3-mercapto-2-butanol were reacted to obtain 2-[3-(2-hydroxy-1-methylpropylthio)propyl]-6-methylphenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:16][N:17]1[CH2:22][C:21]([CH3:24])([CH3:23])[O:20][CH2:19][CH:18]1[C:25](O)=[O:26].C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:25]([CH:18]3[CH2:19][O:20][C:21]([CH3:23])([CH3:24])[CH2:22][N:17]3[CH3:16])=[O:26])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CN1CC(C)(C)OCC1C(=O)O
Reactant: Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 61 %

Procedure:
The desired compound was prepared according to Method B from 6-chloro-9H-β-carboline-8-ylamine and 4,6,6-trimethyl-morpholine-3-carboxylic acid in 61% yield. 1H-NMR (DMSO-d6, 300 MHz) δ 1.15 (s, 3H), 1.39 (s, 3H), 1.98 (d, 1H), 2.26 (s, 3H), 2.72 (d, 1H), 2.80 (dd, 1H), 3.79(m, 2H), 7.91 (s, 1H), 8.03-8.08 (m, 2H), 8.22 (d, 1H), 8.97 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.33 min. MS (M+H+): 373.2.