Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][NH:27][CH2:28][C:29]1[S:30][CH:31]=[C:32]([CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[N:33]=1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([N:27]([CH3:26])[CH2:28][C:29]3[S:30][CH:31]=[C:32]([CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[N:33]=3)=[O:23])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1
Reactant: CNCc1nc(CN2CCCC2)cs1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3nc(CN4CCCC4)cs3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), N-methyl-1-[4-(pyrrolidin-1-ylmethyl)-1,3-thiazol-2-yl]methanamine (30 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). A portion of the crude product was purified using prep method D to afford the title compound.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].C1(C)C=CC(S([NH:21][NH2:22])(=O)=O)=CC=1.[OH-].[Na+].[O-2].[Al+3].[O-2].[O-2].[Al+3]>>[N+:21](=[C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3])=[N-:22]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Al+3]
Agent: [Na+]
Agent: [O-2]
Product: [N-]=[N+]=C1C(=O)Nc2ccccc21

Procedure:
Once the desired isatin has been obtained, the corresponding 3-diazoindol-2(3H)-one is prepared in accordance with known procedures. See, for example, J. M. Michowski, Tetrahedron Letters, 1773 (1967) and M. P. Cava, et al., J. Am. Chem. Soc., 80, 2257 (1958). The appropriate isatin compound is treated with p-toluenesulfonylhydrazine. The resulting hydrazone then is treated with a base such as aqueous sodium hydroxide or aluminum oxide to give the desired 3-diazoindol-2(3H)-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[CH:24]=[C:25](O)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:28]=[C:27]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Oc1cccc(F)c1
Product: N#Cc1ccc(N(CCOc2cccc(F)c2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 3-fluorophenol: MS (APCI) m/z 407 (M+1).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[C:12]([CH3:26])[CH:11]=1.S(OCC)(O[CH2:31][CH3:32])(=O)=O>O.C(O)(=O)C.CCOCC>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([O:21][CH2:31][CH3:32])=[O:20])=[C:12]([CH3:26])[CH:11]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1ccc(Nc2ccccc2C(=O)O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1Nc1ccc(OC)cc1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Dimethylformamide (250 ml) was added to sodium hydride (obtained from 4.80 g of 50% oil dispersion after washing and drying) and the mixture cooled to 0°-5° C. 2-(4-Methoxy-2-methylphenylamino)benzoic acid (25.7 g) was then added, and the mixture was stirred at room temperature for 45 minutes and then cooled to 0°-5° C. To the latter mixture was added 13 ml of diethyl sulfate, and the reaction mixture was stirred overnight at room temperature and poured into a mixture of ether, acetic acid, water and ice. The mixture was extracted with ether and the ether extracts washed with 1N potassium hydroxide and dried over anhydrous magnesium sulfate. Removal of the ether and crystallization of the residue from isopropyl alcohol gave 12.2 g of ethyl 2-(4-methoxy-2-methylphenylamino)benzoate as a pale yellow solid, m.p. 42°-43° C.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[O:48]1[CH2:53][CH2:52][CH:51]([NH2:54])[CH2:50][CH2:49]1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([NH:54][CH:51]4[CH2:52][CH2:53][O:48][CH2:49][CH2:50]4)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: NC1CCOCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC2CCOCC2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with tetrahydro-pyran-4-ylamine (Matrix Scientific) to give the title compound. HR-MS (ES, m/z) calculated for C40H51Cl2N6O4 [(M+H)+] 749.3344, observed 749.3343.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=3)=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1.Cl>C(Cl)(Cl)Cl.O.C(O)C>[Cl:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([S:33]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)(=[O:34])=[O:35])=[CH:31][CH:32]=3)=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ncnc3cc(Cl)ccc23)cc1
Reactant: CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CN1CCN(S(=O)(=O)c2ccc(Nc3ncnc4cc(Cl)ccc34)cc2)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
N-Methylpiperazine (1.0 g, 0.01 mole) was dissolved in chloroform (50 ml). Sodium carbonate (10 g) was dissolved in water (50 ml). The solutions were combined and cooled to 10° C. 4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride (3.85 g, 0.01 mole) was added in portions to the vigorously stirred solution. Stirring was continued for one hour. The chloroform layer was separated, dried and evaporated. The resulting gummy solid was redissolved in chloroform and chromatographed on an alumina column. Elution with chloroform gave a first band which was discarded. The second band was obtained as a low melting solid, which was converted to the hydrochloride by dissolving in ethanol and adding ethereal hydrogen chloride to give the title compound as the sesquihydrochloride (650 mg) m.p. 237°-239° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([C@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:22]2)=[O:20])[C:6]([C:9]([O-:11])=[O:10])=[N:7][CH:8]=1.[OH-].[Na+].O.C(OCC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([C@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([F:30])([F:28])[F:29])[CH2:23][CH2:22]2)=[O:20])[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1
Reactant: COc1cnc(C(=O)[O-])c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)m ethoxy)picolinate (170 mg, 0.37 mmol, EXAMPLE 31 Step 3) in tetrahydrofuran was added 2 N aq. sodium hydroxide (0.5 mL, 1.00 mmol) at room temperature. After being stirred at room temperature for 24 h, water and diethylether were added to the mixture. The aqueous layer was washed with diethylether and acidified with 2 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo to afford 151 mg (95%) of the title compound as an oil. The residual oil was used for the next step without further purification.
Reaction SMILES: CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.[CH2:17]([O:22][C:23](=[O:32])[C:24]1[C:29](I)=[CH:28][N:27]=[C:26]([NH2:31])[CH:25]=1)[CH2:18][CH2:19][CH2:20][CH3:21].[N:33]1([S:39]([C:42]2[CH:47]=[CH:46][C:45]([SH:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Cu](I)I>[CH2:17]([O:22][C:23](=[O:32])[C:24]1[C:29]([S:48][C:45]2[CH:44]=[CH:43][C:42]([S:39]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)(=[O:40])=[O:41])=[CH:47][CH:46]=2)=[CH:28][N:27]=[C:26]([NH2:31])[CH:25]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Reactant: CCCCCOC(=O)c1cc(N)ncc1I
Agent: I[Cu]I
Agent: CC(C)(C)[O-]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: Cc1ccccc1
Product: CCCCCOC(=O)c1cc(N)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
Copper iodide (26 mg, 0.14 mmol) and neocuproine (29 mg, 0.14 mmol) were added to a stirred mixture of 2-amino-5-iodo-isonicotinic acid pentyl ester (450 mg, 1.35 mmol), 4-(piperidine-1-sulfonyl)-benzenethiol (449 mg, 1.49 mmol) and sodium t-butoxide (195 mg, 2.025 mmol) in toluene (10 ml) and the reaction was heated to reflux overnight. The reaction was cooled to room temperature, solids filtered off through celite and the filtrate concentrated under reduced pressure onto silica. The residue was purified by flash column chromatography using ethyl acetate 2/3 hexane as eluent to afford 2-amino-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-isonicotinic acid pentyl ester as an orange solid (348 mg, 56%). 1H NMR (CDCl3): (1H, s, py); 7.51 (2H, d, Ar); 7.10 (2H, d, Ar); 6.80 (1H, s, py); 4.92 (2H, br s, NH2); 4.14 (2H, t, OCH2); 2.90 (4H, m, 2×CH2N pip); 1.53 (6H, m, OCH2CH2, 2×CH2 pip); 1.46 (2H, m, CH2 pip); 1.24 (4H, m, OCH2CH2CH2CH2CH3); 0.80 (3H, t, CH2CH3).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([C@@H:33]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:34][CH2:35][N:36]([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH:20]=2)=[CH:12][CH:11]=1)(C)(C)C.[ClH:50]>O1CCOCC1>[ClH:50].[ClH:50].[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:21]([C@@H:33]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:34][CH2:35][N:36]([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH:20]=2)=[CH:12][CH:11]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1OCc1ccccc1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCN)cc2)ccc1OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-butyl{2-[4-(2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}ethoxy)phenyl]ethyl}carbamate (Preparation 41, 3.4 g, 5.1 mmol) was dissolved in dioxan (20 ml) and treated with hydrochloric acid (4M in dioxan, 26 ml). After stirring for 4 hours at room temperature the solvent was removed in vacuo. The residue was azeotroped twice from dichloromethane to yield the title compound as a brown solid, 3.
Reaction SMILES: Cl.[C:2]1([N:8]2[C:12]3[C:13]4[S:17][C:16]([NH:18]C(=O)C)=[N:15][C:14]=4[CH2:22][CH2:23][C:11]=3[CH:10]=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O>[C:2]1([N:8]2[C:12]3[C:13]4[S:17][C:16]([NH2:18])=[N:15][C:14]=4[CH2:22][CH2:23][C:11]=3[CH:10]=[N:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1nc2c(s1)-c1c(cnn1-c1ccccc1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2c(s1)-c1c(cnn1-c1ccccc1)CC2
Temperature: 25 °C

Procedure:
650 ml 37% hydrochloric acid are placed in 650 ml of water and 99 g (0.27 mol) N-(1-phenyl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl)-acetamide (prepared analogously to Example 1) are dissolved therein. The solution is refluxed for 2 hours with stirring. After cooling to ambient temperature the mixture is carefully made basic (pH 10-11) with sodium hydroxide solution. The precipitate formed is suction filtered and stirred out with methanol. Yield: 66 g (m.p.: 307-308° C.)
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:27]=[CH:26][C:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:24][C:18]=1[O:19][CH2:20][C:21](O)=[O:22])[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][CH:49]=1)[C:42]([O:44][CH2:45]C)=[O:43].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>CN(C=O)C>[CH2:1]([N:8]([CH2:16][C:17]1[CH:27]=[CH:26][C:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:24][C:18]=1[O:19][CH2:20][C:21]([NH:38][C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][CH:49]=1)[C:42]([O:44][CH3:45])=[O:43])=[O:22])[C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)N(Cc1ccccc1)Cc1ccc(-c2cccc3ccccc23)cc1OCC(=O)Nc1cccc(C(=O)OC)c1
Reaction time: 5 h

Procedure:
A room temperature solution of Example 21A (50 mg, 0.10 mmol) in DMF (1.0 mL) was treated with ethyl 3-aminobenzoate (20 μL, 0.13 mmol), HOBT (23 mg, 0.14 mmol), EDCI (29 mg, 0.15 mmol), and Et3N (21 μL, 0.15 mmol), stirred for 5 hours, and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2:5 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([OH:11])=O)[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]([CH2:35][CH2:36][NH2:37])#[N:34].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:33]([CH2:35][CH2:36][NH:37][C:9]([C:7]1[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4][C:3]([CH2:19][F:20])([CH2:2][F:1])[CH:8]=1)=[O:11])#[N:34]
Reactant: O=C(O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reactant: N#CCCN
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCCNC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C

Procedure:
To a mixture of 30 mg of 2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran-4-carboxylic acid and 2 ml of tetrahydrofuran was added 28 mg of 1,1'-carbonyldiimidazole with stirring under ice-cooling and the mixture was stirred for 1 hour. Then, 0.10 ml of 2-cyanoethylamine was added therein, and the resultant mixture was stirred under ice-cooling for 1 hour and subsequently at room temperature for 12 hours. An aqueous potassium carbonate solution was added therein and the reaction solution was extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled. The resultant residue was recrystallized by a mixed solvent of ethyl acetate and hexane to obtain 26.6 mg of N-(2-cyanoethyl)-2,2-bis(fluoromethyl)-6-nitro-2H-1-benzopyran-4-carboxamide with a melting point of 173°-174° C.
Reaction SMILES: ClC1C=CC(C(F)(F)F)=CC=1OC1C=C(C=CC=1)C(O)=O.S(Cl)(Cl)=O.CS(N)(=O)=O.[CH3:31][S:32]([NH:35][C:36](=[O:58])[C:37]1[CH:42]=[C:41]([O:43][C:44]2[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][C:45]=2[Cl:54])[CH:40]=[CH:39][C:38]=1[N+]([O-])=O)(=[O:34])=[O:33]>C(OCCCC)(=O)C.N1C=CC=CC=1>[CH3:31][S:32]([NH:35][C:36](=[O:58])[C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([O:43][C:44]2[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][C:45]=2[Cl:54])[CH:42]=1)(=[O:33])=[O:34]
Reactant: CS(=O)(=O)NC(=O)c1cc(Oc2cc(C(F)(F)F)ccc2Cl)ccc1[N+](=O)[O-]
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cccc(Oc2cc(C(F)(F)F)ccc2Cl)c1
Solvent: CCCCOC(C)=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)NC(=O)c1cccc(Oc2cc(C(F)(F)F)ccc2Cl)c1

Procedure:
The acid from (b) (0.8 g) was treated with thionyl chloride followed by methanesulphonamide and pyridine as described in paragraph (d) above for compound 32. The product was recrystallised from a mixture of ether and petroleum (b.p. 40°-60°) to give compound 31 with a melting point of 132°-133°.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13]CC)(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:16](#[N:18])[CH3:17].O>C1(C)C=CC=CC=1>[C:5]([CH2:17][C:16]#[N:18])(=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC#N
Reactant: CCOC(=O)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
To a suspension of sodium ethoxide (34.0 g. 0.500 mole) in dry toluene (200 mL were added ethyl benzoate (71.4 mL, 0.500 mole) and dry acetonitrile (32 mL, 0.60 mole). The mixture was mechanically stirred under nitrogen at 105°-110° C. for 29 hours, during which time it became quite viscous. After cooling to room temperature, water (300 mL) was added and the mixture was washed with ethyl ether (2×100 mL). The aqueous layer was then acidified to pH 5-6 with con. aq. HCl (required 30-35 mL) and the resulting crystalline precipitate was collected by suction filtration, washed twice with water, and air-dried. This subtitled material (49.23 g, 68%, m.p. 72°-73°) was sufficiently pure to be used in further transformations (lit., m.p. 80°-81°, Long, R. S., J. Am. Chem. Soc., (1947), 69, p. 990. 1NMR (CDCl3, δ) 7.95 (dd, 2H, J=7, 2 Hz, o-aryl), 7.6 (m, 3H, aryl), 4.1 (s, 2H, CH2). This benzoyl acetonitrile intermediate is also now commercially available but we prepared ours as above.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])[CH3:2].[CH3:10][C:11](OC(C)=O)=[O:12]>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:6][C:11](=[O:12])[CH3:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccc(N)c1
Product: CCc1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Ethylaniline (2 g, 0.016 mol) was added slowly in portion into neat Ac2O (8 ml) at 0° C. After removed ice bath and the reaction was stirred at room temperature for 2 hour. The solvent was removed in vacuo and extracted with EtOAc, washed with water and brine, dried over Na2SO4. Concentrated to get crude N-(3-ethylphenyl)acetamide as light yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][C:7]=1[C:30]([F:33])([F:32])[F:31])=O)C.[BH4-].[Na+]>CO>[OH:3][CH2:4][C:6]1[O:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][C:7]=1[C:30]([F:32])([F:31])[F:33]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nc(C(F)(F)F)c(C(=O)OCC)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nc(C(F)(F)F)c(CO)o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-{2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoylamino}-4-trifluoromethyl-oxazole-5-carboxylic acid ethyl ester (150 mg, 0.31 mmol) and sodium borohydride (150 mg, 3.947 mmol) in 3 ml methanol was stirred at room temperature for 10 min. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated and the residue was purified by preparative HPLC to give the title compound as a white solid. APCl M+1=436.1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1.[Li][CH2:18]CCC.CI.[Cl-].[NH4+].N>C(OCC)C>[CH3:18][C:12]1[Se:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:15])[F:16])=[CH:9][CH:8]=2)=[CH:14][CH:13]=1
Reactant: [Li]CCCC
Reactant: FC(F)(F)Oc1ccc(-c2ccc[se]2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: Cc1ccc(-c2ccc(OC(F)(F)F)cc2)[se]1
Temperature: -70 °C
Reaction time: 24 h

Procedure:
8.6 g (29.5 mmol) of 2-(4-trifluoromethoxyphenyl)selenophene are initially introduced in 50 ml of diethyl ether, and 25.0 ml (39.8 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 25 min and subsequently cooled to −70° C. 7.4 ml (0.12 mol) of methyl iodide are added in one portion, and the mixture is warmed to RT and stirred for 24 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added, and the batch is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed successively with water, 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1→10:1). The further purification is carried out by recrystallisation from n-heptane. 2-Methyl-5-(4-trifluoromethoxyphenyl)selenophene is obtained as a colourless solid (m.p. 122° C.).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[S:17][C:16]2[S:15](=[O:19])(=[O:18])[N:14]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:13][CH:12]([OH:26])[C:11]=2[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:4][C:2]([NH:5][S:6]([C:9]1[S:17][C:16]2[S:15](=[O:19])(=[O:18])[N:14]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:13][C:12](=[O:26])[C:11]=2[CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: COCCCCN1CC(O)c2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COCCCCN1CC(=O)c2cc(S(=O)(=O)NC(C)(C)C)sc2S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a solution of the product from Step A (9.5 g, 0.022 mol) in acetone (20 mL) at -10° C. was added freshly prepared Jones reagent (10 mL) and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated and saturated aqueous sodium bicarbonate was added until the pH of the solution was 6. The aqueous mixture was extracted with ethyl acetate (4×50 mL). The combined extracts were washed with brine (2×10 mL), dried (MgSO4) and evaporated to provide a yellow solid (7.5 g, 78%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[NH2:10])=[O:4].[OH-].[Na+]>CO>[NH2:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:20])([F:21])[F:19])=[CH:15][CH:16]=2)[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2ccc(OC(F)(F)F)cc2)noc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Yield: 75.7 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl-5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylate (6.0 g, 19.85 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (4.32 g, 15.02 mmol, 76%) was obtained.