Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1OS(C(F)(F)F)(=O)=O)=[O:2].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.O.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>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[C:4]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)[CH:5]=1
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C=O)c(-c2cccs2)c1
Temperature: 95 °C
Yield: 89.5 %

Procedure:
Ex-34B: A solution of trifluoro-methanesulfonic acid 2-formyl-5-methoxy-phenyl ester (Ex-34A, 1.6 g, 5.63 mmol) in 1,4-dioxane (15 mL) was stirred at room temperature under nitrogen for 5 min. Thiophene-2-boronic acid (1.08 g, 8.44 mmol), tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.56 mmol) and a potassium phosphate (2.2 g, 10.36 mmol) were then added and the resulting mixture was heated to 95° C. under nitrogen overnight. Upon cooling to room temperature the reaction was diluted with EtOAc (25 mL) and water (25 mL) and the layers were cut. The organic phase was concentrated under reduced pressure. Silica gel chromatography (hexane/ethyl acetate, 4:1) gave 1.1 g (90%) of the desired 4-methoxy-2-thiophen-2-yl-benzaldehyde product. 1H-NMR (300 MHz, CDCl3): 10.06 (s, 1H), 8.03 (m, 1H), 7.45 (m, 1H), 7.14 (m, 1H), 7.09 (m, 1H), 7.00 (m, 2H), 3.91 (s, 3H).
Reaction SMILES: [NH:1](/[C:8](=[C:17]1\[C:18](=[O:30])[NH:19][C:20]2[C:25]\1=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[NH:1](/[C:8](=[C:17]1\[C:18](=[O:30])[NH:19][C:20]2[C:25]\1=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:31](=[O:33])[CH3:32])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OC)/C(=C(/Nc1ccccc1)c1cccc(CN)c1)C(=O)N2
Reactant: CC(=O)OC(C)=O
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccccc1)c1cccc(CNC(C)=O)c1)C(=O)N2

Procedure:
Prepared from 3-(Z)-[1-anilino-1-(3-aminomethyl-phenyl)-methylidene]-5,6-dimethoxy-2-indolinone and acetic anhydride
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2].[CH3:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[CH3:24].C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[C:9]([O:25][C:20]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([CH3:17])[CH:19]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2]
Reactant: Cc1ccc(O)cc1C
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1cccc(Oc2ccc(C)c(C)c2)c1[N+](=O)[O-]

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g), 3,4-dimethylphenol (5.5 g.), anhydrous potassium carbonate (8.5 g.) and cupric oxide (1 g.) was treated in a similar manner to the above to give the captioned compound (3.65 g.). bp 190° to 196° C./0.8 mmHg.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]4)=[N:13][C:14]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:16]=3[O:17][CH3:18])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:39]1([NH2:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[NH2:45]>C1(C)C=CC=CC=1.O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:45][CH:40]1[CH2:41][CH2:42][CH2:43][CH2:44][CH:39]1[NH:46][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12]([NH:25][C@@H:26]4[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]4)=[N:13][C:14]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:16]=3[O:17][CH3:18])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCC1N
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2c(Cl)cccc2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2c(NC3CCCCC3N)cccc2s1
Temperature: 25 °C

Procedure:
tert-Butyl (3R)-3-[[5-(4-chloro-1,3-benzothiazol-2-yl)-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (200 mg, 0.36 mmol, 1.00 equiv), cyclohexane-1,2-diamine (112.9 mg, 0.99 mmol, 3.00 equiv), NaOBu-t (63.4 mg, 0.66 mmol, 2.00 equiv), tris(dibenzylideneacetone)dipalladium (30.2 mg, 0.03 mmol, 0.10 equiv) and O-biphenyl(t-Bu)2P (11.8 mg, 0.04 mmol, 0.12 equiv) in toluene (12.0 mL) were dissolved in dioxane (2 mL) and heated to reflux for 18 h. The mixture was cooled to room temperature and concentrated. The crude product was purified by flash chromatography on silica gel, eluting with a mixture of 6-50% ethyl acetate in petroleum ether (15:1-2:1) to provide the title compound as a yellow solid. MS, m/z:[M+H]+ (ESI): 639.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=3)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[C:36]2[CH:35]=[C:34]3[O:37][CH2:38][O:39][C:33]3=[CH:32][C:31]=2[N:30]=[CH:29][N:28]=1>CN(C=O)C.CCOC(C)=O>[O:37]1[C:34]2=[CH:35][C:36]3[C:27]([O:23][C:20]4[CH:21]=[CH:22][C:17]([C:12]5[C:13](=[O:16])[N:14]([CH3:15])[C:9]([NH:8][C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[N:10][CH:11]=5)=[N:18][CH:19]=4)=[N:28][CH:29]=[N:30][C:31]=3[CH:32]=[C:33]2[O:39][CH2:38]1
Reactant: Clc1ncnc2cc3c(cc12)OCO3
Reactant: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(O)cn2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(Oc3ncnc4cc5c(cc34)OCO5)cn2)c1=O
Temperature: 25 °C
Yield: 113.4 %

Procedure:
2-(4-Fluoro-phenylamino)-5-(5-hydroxy-pyridin-2-yl)-3-methyl-3H-pyrimidin-4-one (2.18 g, 7 mmol) was dissolved in dry DMF (30 ml) to which was added 60% NaH (774 mg, 19.3 mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 8-Chloro-[1,3]dioxolo[4,5-g]quinazoline (2.08 g, 6.7 mmol) in dry DMF (40 ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give crude title compound and further purification to yield product (3.68 g, 90%). 1HNMR (400 MHz, DMSO): 9.18 (s, 1H), 8.60 (m, 3H), 8.45 (d, 1H), 7.84 (s, 1H), 7.82 (m, 1H), 7.55 (m, 3H), 7.21 (m, 2H), 4.15 (s, 2H). LC/MS Calcd for (M+H)+485.4. found 485.9.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[N:9]#[C:10][NH2:11].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[F:5][C:4]([F:7])([F:6])[C:3]1[O:8][C:10]([NH2:11])=[N:9][CH:2]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: N#CN
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: Nc1ncc(C(F)(F)F)o1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 6 %

Procedure:
5-Trifluoromethyl-oxazol-2-ylamine: The 5-trifluoromethyl-oxazol-2-ylamine, off-white solid and MS: m/e=152.0 (M+), is obtained using the following procedure: To a solution of 21.6 ml (39.4 g, 0.2 mol) of 97% 3-bromo-1,1,1-trifluoroacetone in 40 ml of tert-butanol are added 12.6 g (0.3 mol, 1.5 equiv.) of cyanamide. A slight exotherm is observed. After stirring for 10 min, 19.7 g (0.24 mol, 1.2 equiv.) of finely powdered sodium acetate were added with vigorous stirring and the suspension is heated for 30 min at 65° C., refluxed for 2 h and then allowed to cool. The mixture is poured into a well stirred mixture of 200 ml of ethyl acetate and 100 ml of water. The pH of the aqueous phase is set to ca. 8-9 with 5% sodium bicarbonate solution. The org. phase is separated. The aqueous phase is extracted with 50 ml ethyl acetate. The combined organic phases were washed twice with 20 ml of water and concentrated in vacuo. The residue, 40.2 g, viscous light orange oil, is then purified by flash chromatography on silica gel using a 2:1 mixture of methylene chloride and ethyl acetate as eluent. The fractions containing the desired compound (6.08 g, light yellow oil) and containing more polar impurities were concentrated and repurified by flash chromatography on silica gel using a 98:2 mixture of methylene chloride and methanol as eluant. One obtains 1.83 g (0.012 mol, 6%) of 5-trifluoromethyl-oxazol-2-ylamine.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:24])[CH:12]=2)[C:7]1=[O:25].Cl.CCOC(C)=O.[CH2:34](O)[CH2:35][CH2:36]C>>[CH2:2]([O:3][C:4]([C:5]1[N:6]=[C:7]([OH:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([O:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])=[CH:10][CH:9]=2)=[O:26])[CH2:34][CH2:35][CH3:36]
Reactant: COC(=O)CN1C(=O)c2ccc(Oc3c(C)cccc3C)cc2C1=O
Reactant: CCCCO
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(O)c2ccc(Oc3c(C)cccc3C)cc2c1O
Temperature: 70 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
Sodium (1 eq) was dissolved in n-butanol (1.6 mL/mmol) with stirring at 70° C. Subsequently, the temperature was raised to 95° C. before a solution of [5-(2,6-Dimethyl-phenoxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetic acid methyl ester (0.5 eq) in hot n-butanol (2.3 mL/mmol) was added in one portion with stirring. Stirring was continued at 95° C. for 3 h before the mixture was concentrated in vacuo. To the residue was added 2 N hydrochloric acid (1.3 eq) and EtOAc (ca. 4-fold volume) and the mixture was stirred vigorously for 45 min. Subsequently, the solid component was sucked off, washed with water and dried in vacuo before it was suspended in EtOAc (ca. 20 mL/g) and the mixture was refluxed with stirring for 2 h. After cooling to ambient temperature the solid component was sucked off, washed with EtOAc and dried in vacuo to give the title compound as an off-white solid (yield: 43%); MS-(+)-ion: M+1=382.5.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]2[S:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][C:15]=2[N:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:12][C:13]2[C:14]3[S:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][C:15]=3[N:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: O=C=NCc1ccc(F)cc1
Reactant: CCOC(=O)n1nc(N)c2sc(C(=O)OC)cc21
Solvent: ClCCl
Product: CCOC(=O)n1nc(NC(=O)NCc2ccc(F)cc2)c2sc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 59.5 %

Procedure:
4-Fluorobenzylisocyanate (0.130 ml, 1.02 mmol) was added to a solution of 1-ethyl 5-methyl 3-amino-1H-thieno[3,2-c]pyrazole-1,5-dicarboxylate (85 mg, 0.32 mmol) in anhydrous dichloromethane (5 ml). After stirring for 96 h at room temperature, the solvent was removed under reduced pressure, and the residue purified by chromatography over silica gel (eluent dichloromethane 50; methyl alcohol 0.5; 6% aqueous ammonia 0.1) to yield 80 mg of the title compound as a white solid. Chromatographic method A, Rt 6.11, [M+H]+ 621.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=C(C=C)[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.C[N+]1([O-])CC[O:20]CC1.Cl.[CH3:25][C:26]([CH3:28])=[O:27]>O.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:25]([CH:26]([OH:27])[CH2:28][OH:20])[CH:7]=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Reactant: C=Cc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Solvent: O
Product: COC(=O)c1cc(C(O)CO)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 46 h

Procedure:
3-Nitro-5-vinylbenzoic acid methyl ester (2.02 g, 9.76 mmol) was dissolved in a mixture of acetone and water (200 ml, 9:1), and, after cooling to 0° C., OsO4 (60 mg, 0.24 mmol) was added followed by N-methylmorpholine-N-oxide (2.34 g, 20.0 mmol). After stirring for 46 h at room temperature, an aqueous solution of Na2S2O5 (3.7 g) in water (150 ml) was added and the solution was acidified with dilute aqueous HCl. The volume of the solution was reduced to 150 ml by evaporation and the residue was extracted with ethyl acetate (3×100 ml). The combined organic phases were evaporated and the residue was purified by column chromatography on silica gel using ethyl acetate as the eluent. Yield: 1.60 g (60%).
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2=NNC(c3ccccc3)C2)cc1
Agent: [Pd]
Product: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Yield: 76.4 %

Procedure:
The procedure of Example 18 is followed except that 2 parts of 5% palladium on barium sulfate are used in lieu of the palladium on alumina Example 18. Following a 21/2 hour of reflux, unreacted 3,5-diphenyl-2-pyrazoline is found to amount to 2.4%, and a 76.4% yield of 3,5-diphenylpyrazole, melting at 198° - 201° C. is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH:10][CH:11]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>CS(C)=O>[OH:10][CH:11]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(CCNCC(O)COc2ccccc2)cc1
Solvent: CS(C)=O
Product: CCOC(=O)CCCOc1ccc(CCNCC(O)COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
525 mg of ethyl 4-bromobutyrate were added to a solution of 574 mg of p-[2-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenol and 300 mg of potassium t-butylate in 10 ml of dimethylsulfoxide and the mixture was stirred at room temperature under argon for 6 hours. The solvent was evaporated in vacuo and the residue was chromatographed on 75 g of silica gel. Uitlizing chloroform/n-propanol/saturate ammonia (500:10:1), there were obtained 600 mg of pure, amorphous ethyl 4-[p-[2-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenoxy]butyrate, ε221 =17510.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9]([NH2:18])([C:15]([OH:17])=[O:16])[CH2:10]2)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](=O)([O:42]N1C(=O)CCC1=O)[O:27][CH2:28][CH:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2>C(#N)C.O>[C:26]([CH:10]1[C:11]2[C:6](=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1([NH2:18])[C:15]([OH:17])=[O:16])([O:27][CH2:28][CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:42]
Reactant: CC(C)Oc1cccc2c1CCC(N)(C(=O)O)C2
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.7 %

Procedure:
A mixture of racemic 5-isopropoxy-2-aminotetraline-2-carboxylic acid (3.48 g, 5.98 mmole theoretical), triethylamine (1.10 ml, 7.89 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 2.62 g, 7.77 mmole) in acetonitrile (30 ml) and water (30 ml) was stirred at room temperature for one day. TLC analysis of the reaction indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (500 mg) was added and the mixture was stirred at room temperature for another day. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH˜3 with 10% aqueous citric acid solution, and the white emulsion extracted three times with methylene chloride. The combined organic layers were washed with water, brine, dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 1→2→5→8% methanol/methylene chloride) to give racemic Fmoc-5-isopropoxy-2-aminotetraline-2-carboxylic acid (0.50 g, 18% yield over 2 steps) as a white solid. HRMS (FAB): C29H30NO5 (M+H) calc. 472.2124; observed: 472.2117.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:26]1([N:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccccc2)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.5 g), triethylamine (4.2 cc) and N-phenylpiperazine (4.8 cc) in toluene (80 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (30 cc), 2-[3-(4-phenyl-1-piperazinyl)propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (5.7 g) is obtained, m.p. 126° C.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11](=[O:40])[N:12]([CH3:39])[CH:13]=[C:14]([CH2:19][CH2:20][O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]=1[C:16]([OH:18])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN=C=NCCCN(C)C.[Cl:75][C:76]1[CH:77]=[C:78]([CH:81]=[CH:82][CH:83]=1)[CH2:79][NH2:80]>CN(C)C=O.O>[C:1]([O:9][C:10]1[C:11](=[O:40])[N:12]([CH3:39])[CH:13]=[C:14]([CH2:19][CH2:20][O:21][Si:22]([C:35]([CH3:36])([CH3:38])[CH3:37])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:15]=1[C:16](=[O:18])[NH:80][CH2:79][C:78]1[CH:81]=[CH:82][CH:83]=[C:76]([Cl:75])[CH:77]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cccc(Cl)c1
Reactant: Cn1cc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C(=O)O)c(OC(=O)c2ccccc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C(=O)NCc2cccc(Cl)c2)c(OC(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzoyloxy-5-[2-(tert-butyldiphenylsilanyloxy)ethyl]-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (0.956 g) in dimethylformamide (10 ml) were added 1-hydroxybenzotriazole hydrate (HOBT) (0.395 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, (WSC) (0.495 g) and 3-chlorobenzylamine (0.274 ml) and the mixture was stirred at room temperature for 2 hr. Water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under,reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give 5-[2-(tert-butyldiphenylsilanyloxy)ethyl]-4-(3-chlorobenzylcarbamoyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl benzoate (0.615 g). This compound was dissolved in tetrahydrofuran (20 ml), and acetic acid (0.259 ml) and tetrabutylammonium fluoride (0.474 g) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to give 4-(3-chlorobenzylcarbamoyl)-5-(2-hydroxyethyl)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl benzoate (0.213 g).
Reaction SMILES: [F:1][CH:2]1[CH2:8][CH:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5][N:4]([C:19](OC(C)(C)C)=O)[CH2:3]1.Cl.[F-].[K+].Cl[C:30]1[N:34](C)[N:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37]>CO.CS(C)=O.O>[F:1][CH:2]1[CH2:8][CH:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH2:6][CH2:5][N:4]([C:19]2[N:33]([CH3:32])[N:34]=[CH:30][C:31]=2[N+:36]([O-:38])=[O:37])[CH2:3]1
Reactant: COc1ccc(COC2CCN(C(=O)OC(C)(C)C)CC(F)C2)cc1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: COc1ccc(COC2CCN(c3c([N+](=O)[O-])cnn3C)CC(F)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-fluoro-5-(4-methoxybenzyloxy)azepane-1-carboxylate (740 mg, 0.21 mmol) in MeOH (5 mL) was added HCl (4 M in 1,4-dioxane, 5.3 mL, 21 mmol) and the solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the residue was dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7 N ammonia in MeOH. The solvents were removed under reduced pressure to afford a yellow oil. To a solution of this oil in dry DMSO (15 mL) was added potassium fluoride (0.32 g, 8.4 mmol) and 5-chloro-1-methyl-4-nitro-1H-pyrazole (372 mg, 2.31 mmol) and the mixture was heated at 65° C. for 16 hr. After cooling to room temperature, the mixture was diluted with water (300 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (3×50 mL) and the solvent was removed under reduced pressure. Purification via silica gel column chromatography (20-100% EtOAc/isohexane) gave 3-fluoro-5-(4-methoxybenzyloxy)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as a yellow oil (300 g, 55% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.33-7.23 (m, 3H), 6.89-6.86 (m, 2H), 4.82-4.66 (m, 2H), 4.49-3.93 (m, 1H), 3.81 (s, 3H), 3.30-2.99 (m, 4H), 2.95-2.74 (m, 4H), 2.35-2.03 (m, 2H), 1.98-1.83 (m, 2H).
Reaction SMILES: ClC1C=[C:4](C(F)(F)F)[CH:5]=[CH:6][C:7]=1[NH2:8].[F:13][C:14]1[CH:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][C:19]=1[NH2:20].C#N.[CH:27](=O)C(C)C>O>[F:13][C:14]1[CH:15]=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:18][C:19]=1[NH:20][CH:6]([CH:5]([CH3:27])[CH3:4])[C:7]#[N:8]
Reactant: CC(C)C=O
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1F
Agent: C#N
Solvent: O
Product: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1F

Procedure:
Following the procedure of Example 1, each of 3-chloro-4-aminobenzotrifluoride and 3-fluoro-4-aminobenzotrifluoride is reacted with hydrogen cyanide and isobutyraldehyde, in a neat, initially water-free system, to give the respective nitrile, 2-(2-chloro-4-trifluoro-methylphenylamino)-3-methylbutyronitrile and 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutyronitrile.