Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[Br:12][C:13]1[CH:18]=C[C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=1.O>CO>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C:8]([CH:18]=1)=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:20][N:19]=2
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: N#CCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Brc1ccc2noc(-c3ccccc3)c2c1
Temperature: 50 °C
Yield: 55.2 %

Procedure:
Phenylacetonitrile (8.1 g, 69 m mol) was added to a room temperature solution of potassium hydroxide (85%) (74 g, 1.1 mol) in methanol (150 ml). To this was added 4-bromo-1-nitrobenzene (12.7 g, 63 m mol) suspended in methanol (130 ml). An exotherm was noted and the reaction was maintained at 50° C. for 5 hrs. After cooling to room temperature, water (400 ml) was added. The precipitate was collected and washed with water. The crude product (13.15 g) was crystallized from hot methanol (200 ml) to yield yellow needles (9.52 g, mp 113°-116° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[CH:16][N:17]=[C:4]2[N:3]=1.C(O)(=O)C.CO>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:15]=[CH:16][N:17]=[C:4]2[N:3]=1
Reactant: Clc1nc2ncnn2c(Cl)c1-c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Clc1nc2ncnn2cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.5 g 5,7-dichloro-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidine, 0.22 mL glacial acetic acid, 0.5 mL methanol, 3 mL THF and 366 mg of Zn/Cu pair were stirred for 3 h at ambient temperature. The mixture was filtered through celite, evaporated to dryness and the residue was purified on silica gel (dichloromethane/ethyl acetate) to yield the desired product.
Reaction SMILES: [S:1]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:4])(=[O:3])[NH2:2].Br[C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[N:25]([CH:39]([CH3:41])[CH3:40])[CH:26]=[C:27]([C:28]3[CH:36]=[C:35]4[C:31]([CH2:32][CH2:33][N:34]4[CH3:37])=[CH:30][C:29]=3[F:38])[C:20]=12.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[F:38][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][C:28]=1[C:27]1[C:20]3[C:21](=[N:22][CH:23]=[CH:24][C:19]=3[NH:2][S:1]([CH:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]3)(=[O:4])=[O:3])[N:25]([CH:39]([CH3:40])[CH3:41])[CH:26]=1)[N:34]([CH3:37])[CH2:33][CH2:32]2
Reactant: CC(C)(C)OC(=O)N1CCC(S(N)(=O)=O)CC1
Reactant: CC(C)n1cc(-c2cc3c(cc2F)CCN3C)c2c(Br)ccnc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc3c(cc2F)CCN3C)c2c(NS(=O)(=O)C3CCN(C(=O)OC(C)(C)C)CC3)ccnc21
Temperature: 130 °C
Yield: 94.4 %

Procedure:
A microwave vial was charged with tert-butyl 4-sulfamoylpiperidine-1-carboxylate (331 mg, 1.252 mmol), 4-bromo-3-(5-fluoro-1-methylindolin-6-yl)-1-isopropyl-1H-pyrrolo[2,3-b]pyridine (D37) (324 mg, 0.834 mmol), Pd2(dba)3 (76 mg, 0.083 mmol), xantphos (97 mg, 0.167 mmol) and cesium carbonate (816 mg, 2.503 mmol). This was suspended in 1,4-dioxane (7 mL) and degassed under nitrogen atmosphere for 10 mins before subjected to microwave heating at 130° C. for 30 mins. The reaction mixture was filtered through celite (washing with ethyl acetate). The filtrate was removed in vacuo to give a residue which was purified using chromatography on silica (eluted with 0-20% ethyl acetate/DCM) to afford the title compound (450 mg). LCMS (A): m/z (M+H)+ 572, C29H38FN5O4S requires 571 (acidic).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:19][C:8]2[C:9]3[CH:10]=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][C:14]=3[S:15][C:7]=2[C:6]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:19][C:8]2[C:9]3[CH:10]=[CH:11][C:12]([C:16](=[O:18])[NH:46][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:13][C:14]=3[S:15][C:7]=2[C:6]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:4]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)O)ccc12
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)NCc3ccccc3)ccc12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 14.3 %

Procedure:
1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2,6-dicarboxylic acid 2-methyl ester (49 mg, 0.13 mmol) and carbonyldiimidazole (25 mg, 0.15 mmol) were dissolved in THF (6 ml). After stirring for 1.5 hr at 60° C., the reaction was cooled to RT. Benzylamine (30 μl, 0.27 mmol, 2.1 equiv) was added and stirred for 3 hr. Removal of solvent followed by column chromatography yielded 9mg (15%) of 6-benzylcarbamoyl-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester.
Reaction SMILES: Cl[C:2]1[C:6]([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[N:5][S:4][N:3]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][OH:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[CH2:24][O:25][C:2]1[C:6]([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[N:5][S:4][N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCC1CCCN1Cc1ccccc1
Reactant: Clc1nsnc1-n1ccnc1
Product: c1ccc(CN2CCCC2COc2nsnc2-n2ccnc2)cc1

Procedure:
Following the procedures of Example 1, the title compound is prepared from 3-chloro-4-(1H-imidazol-1-yl)-1,2,5-thiadiazole and 1-benzyl-2-(hydroxymethyl)pyrrolidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=1.[CH3:9][O-:10].[Na+]>CO>[CH3:9][O:10][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=1
Reactant: C[O-]
Reactant: Nc1nccc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(N)n1

Procedure:
A solution of 4-chloro-pyrimidin-2-ylamine (10 g, 77 mmol) in methanol (400 mL) under argon, was treated with a solution of sodium methoxide in methanol (25.7%, 51.59 mL, 0.232 mol) whereupon a cream yellow solution was obtained. The reaction was heated at reflux for 3 hours to give a clear yellow green solution. On cooling the volatiles were removed in vacuo and the residue taken up in 100 mL EtOAc and washed with 100 mL water. The organic phase was dried, filtered and concentrated in vacuo to give the title compound as a white solid (9.12 g).
Reaction SMILES: [NH:1]([C:8]1[C:13]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][N:11]=[C:10]([Cl:22])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C>[NH:1]([C:8]1[C:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][N:11]=[C:10]([Cl:22])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(C#Cc2ccccc2)c(Nc2ccccc2)n1
Solvent: CCOC(C)=O
Product: Clc1ncc(CCc2ccccc2)c(Nc2ccccc2)n1
Reaction time: 20 h
Yield: 17.3 %

Procedure:
4-Anilino-2-chloro-5-(2-phenylethynyl)pyrimidine (Method 72; 400 mg) was dissolved in ethyl acetate (100 ml) and the solution was purged with nitrogen. 5% Rhodium on carbon (50 mg) was added and the mixture was hydrogenated at standard temperature and pressure (STP) for 20 hours. A further portion of 5% rhodium on carbon catalyst (50 mg) was added and the solution was hydrogenated at STP for a further 3 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by bond elute chromatography, eluting with 0-10% ethyl acetate in isohexane, to give the product (70 mg). NMR (CDCl3): 2.8 (t, 2H), 3.0 (t, 2H), 6.25 (s, 1H), 7.1 (m, 1H), 7.15-7.4 (m, 9H), 7.95 (s, 1H); MS (MH+): 310, 312.
Reaction SMILES: [OH:1][C:2]([CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])([CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[C:3](O)=[O:4].O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:46]([O:53][NH2:54])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:46]([O:53][NH:54][C:3](=[O:4])[C:2]([OH:1])([CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: COc1ccc(S(=O)(=O)CC(O)(CS(=O)(=O)c2ccc(-c3ccccc3)cc2)C(=O)O)cc1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(S(=O)(=O)CC(O)(CS(=O)(=O)c2ccc(-c3ccccc3)cc2)C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-phenylbenzenesulfonyl)propionic acid (0.6 g, 1.2 mmol) in 50 mL of methylene chloride is added 1-hydroxybenzotriazole monohydrate (0.185 g, 1.36 mmol), O-benzylhydroxylamine hydrochloride (0.218 g, 1.36 nmol), diisopropylethylamine (0.177 g, 1.36 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.262 g, 1.36 mmol), in that order. The clear, colorless solution is stirred overnight at ambient temperature. Methylene chloride is removed under reduced pressure and the residue is partitioned between ethyl acetate and water. The organic phase is washed with several portions of 1N HCl and then with aqueous potassium bicarbonate. It is dried over magnesium sulfate, filtered, concentrated, and chromatographed on silica gel. Elution with 1:1 ethyl acetate:hexanes affords the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].C(N)(=[S:13])C>CN(C)C=O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4](=[S:13])[NH2:5]
Reactant: N#Cc1cc(F)ccc1F
Reactant: CC(N)=S
Solvent: CN(C)C=O
Product: NC(=S)c1cc(F)ccc1F
Temperature: 100 °C
Reaction time: 48 h
Yield: 86.7 %

Procedure:
10 g (71.9 mmol) of 2,5-difluorobenzonitrile and 16.2 g (215.7 mmol; 3 equivalents) of thioacetamide are dissolved in 80 ml of dimethylformamide containing 10% hydrochloric acid. The reaction mixture is maintained under stirring at 100° C. for 48 hours. After returning to ambient temperature, the reaction mixture is poured onto ice and insoluble material is filtered out. The mother liquors are extracted with 3 times 80 ml of ethyl acetate and the organic phases are washed with twice 50 ml of water. The organic phases are combined, dried over sodium sulphate and the solvents are evaporated under reduced pressure. The residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane mixture 1:2) and 10.8 g (yield=87%) of 2,5-difluorobenzenecarbothioamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]=[C:11]=[O:12])=[C:4]([F:13])[CH:3]=1.[OH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]2[CH2:15][OH:14])=[O:12])=[C:4]([F:13])[CH:3]=1
Reactant: OCC1CCCCN1
Reactant: COc1cc(N=C=O)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)N2CCCCC2CO)c(F)cc1Cl
Reaction time: 2 h
Yield: 79.6 %

Procedure:
10.1 g (0.05 mol) of 4-chloro-2-fluoro-5-methoxyphenyl isocyanate are dissolved in 50 ml of toluene, and 5.8 g (0.05 mol) of 2-hydroxymethylpiperidine, dissolved in 20 ml of toluene, are added dropwise at RT(1). The mixture is stirred for 2 hours at 20°-25° C. and cooled in and ice bath, and the precipitate which has been deposited is filtered off with suction. 12.6 g (79% of theory) of 1-[N-(4-chlor-2-fluor-5-methoxyphenyl)-carbamoyl]-2-hydroxymethylpiperidine are obtained after drying in the form of colorless crystals, melting point 176°-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CCCCCCCBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5-bromosalicylaldehyde (5.00 g) and potassium carbonate (10.3 g) in N,N-dimethylformamide (50 ml) was added heptyl bromide (4.10 ml), and the mixture was stirred at room temperature for 1.5 hr, and further at 50° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (7.61 g) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29]Cl>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:27][O:28][CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 70 °C
Yield: 56 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (31 mg, 0.23 mmol) and chloromethyl methyl ether (26 μL, 0.34 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 70° C. for 2 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using 20-30% hexanes/ethyl acetate afforded 19 mg (54%) of 3-(2-Pyridyl)-5-(3-cyano-5-(methoxymethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.24 (d, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.91 (t, 1H), 7.56 (s, 1H), 7.49 (m, 1H), 5.31 (s, 2H), 3.52 (s, 3H).
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].[CH:6]1[CH:11]=[CH:10][C:9]([CH2:12]Br)=[CH:8][CH:7]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].[CH2:12]([O:5][CH2:4][C:2]1[CH:8]=[CH:7][CH:6]=[CH:11][CH:1]=1)[C:9]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: BrCc1ccccc1
Agent: OC[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a mixture of (R)-glycidol (25 g, 0.337 mol) and BnBr (60.2 mL, 0.506 mol) in anhydrous DMF (1 L) was slowly added NaH (16.2 g of 60% oil dispersion, 0.405 mol) at 0° C. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was concentrated in vacuo. After aqueous work-up (CH2Cl2) and chromatography, 44.8 g of the benzyl ether was obtained: [α]25D -1.6° (c 0.63, CHCl3). 1H NMR (CDCl3): δ2.60 (1H, dd, J=2.5, 5.0), 2.79 (1H, dd, J=4.4, 5.0), 3.17 (1H, m), 3.43 (1H, dd, J=5.7, 11.5), 3.75 (1H, dd, J=3.0, 11.5), 4.57 (2H, AB q, J=11.9), 7.32-7.34 (5H, m). 13C NMR (CDCl3): δ44.3, 50.8, 70.8, 73.3, 127.7, 128.4, 137.8. HRMS (EI) calcd for C10H12O2 164.0837, found 164.0803.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][C:18]1C=CC=CC=1)=[O:16].NC1[S:26][C:27]([CH3:30])=[CH:28][N:29]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][C:18]1[S:26][C:27]([CH3:30])=[CH:28][N:29]=1)=[O:16]
Reactant: Cc1cnc(N)s1
Reactant: CN1C(C(=O)Nc2ccccc2)=C(O)c2ccccc2S1(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1cnc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)s1
Yield: 23.7 %

Procedure:
1.0 gm (3 millimols) of 4-hydroxy-2-methyl-N-phenyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were refluxed with 1.15 gm (10 millimols) of 2-amino-5-methyl-thiazole and 0.1 gm of p-toluenesulfonic acid in 250 ml of xylene for 72 hours. After cooling, the reaction mixture was washed with 2N hydrochloric acid and with water, dried and evaporated in vacuo. The residue was purified column-chromatographically (Merck-silica gel 60; particle size: 0.2-0.5 mm; eluant: chloroform/ethanol, 95:5), yielding 0.25 gm (24% of theory) of 4-hydroxy-2-methyl-N-(5-methy-2-thiazolyl)-2H-1,2-benzothiazine-3-caboxamide-1,1-dioxide.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[C:18]([N:20]=[C:21]=[O:22])[CH:17]=[CH:16][C:15]=1[CH2:23][N:24]1[C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[CH2:26][O:25]1.C(OCC)C>O1CCCC1>[Cl:13][C:14]1[CH:19]=[C:18]([NH:20][C:21]([N:4]([O:3][CH3:2])[CH3:5])=[O:22])[CH:17]=[CH:16][C:15]=1[CH2:23][N:24]1[C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[CH2:26][O:25]1
Reactant: CNOC
Reactant: CC1(C)CON(Cc2ccc(N=C=O)cc2Cl)C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Nc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
A stirred solution of 2.0 grams (0.02 mole) of O,N-dimethylhydroxylamine hydrochloride in 25 ml of dry tetrahydrofuran was cooled to -30° C. and 2.0 grams (0.02 mole) of triethylamine in 25 ml of dry tetrahydrofuran was added. The reaction mixture was stirred for 20 minutes and 5.6 grams (0.02 mole) of 2-(2-chloro-4-isocyanatophenyl)methyl-4,4-dimethyl-3-isoxazolidinone in 75 ml of dry tetrahydrofuran was added dropwise. The reaction mixture temperature was maintained at -30° C. throughout the addition. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature as it stirred for 16 hours. The reaction mixture was heated under reflux for one hour then cooled to ambient temperature. The reaction mixture was placed in a separatory funnel and 20 ml of diethyl ether was added. The mixture was washed with three portions of 50 ml each of water, then dried with sodium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual oil. The oil was crystallized from heptane/ethyl acetate to give 4.2 grams of 2-(2-chloro-4-[(N-methoxy-N-methylamino)carbonylamino]phenyl)methyl-4,4-dimethyl-3-isoxazolidinone; m.p. 93°-95° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:2].[CH3:23][Si](C)(C)N[Si](C)(C)C.[K].CI>C1COCC1>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:6]1[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:23])[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC(=O)Cc1cc2ccccc2n1C(=O)OC(C)(C)C
Agent: [K]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1cc2ccccc2n1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
tert-Butyl 2-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (3.0 g, 9.9 mmol) was added to anhydrous THF (29 mL) and cooled to −78° C. A 0.5M solution of potassium hexamethyldisilazane (20 mL, 9.9 mmol) was added slowly such that the internal temperature stayed below −60° C. Stirring was continued for 1 h at −78° C. Methyl iodide (727 μL, 11.7 mmol) was added to the mixture. The mixture was stirred for 30 minutes at room temperature. The mixture was quenched with sat. aq. ammonium chloride and partitioned between water and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over Na7SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethylacetate/hexane=1/9) to give tert-butyl 2-(1-ethoxy-1-oxopropan-2-yl)-1H-indole-1-carboxylate (2.8 g, 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].C[O-].[Na+].[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20].Cl>C(OCC)C.C(OCC)(=O)C>[F:10][C:6]1[CH:5]=[C:4]([C:11](=[O:13])[CH2:12][C:19](=[O:20])[C:18]([F:25])([F:24])[F:17])[CH:3]=[C:2]([F:1])[C:7]=1[S:8][CH3:9]
Reactant: CSc1c(F)cc(C(C)=O)cc1F
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CSc1c(F)cc(C(=O)CC(=O)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-[3,5-difluoro-4-(methylthio)phenyl]ethanone (4.84 g, 23.9 mmol) was dissolved in diethyl ether (200 mL). Sodium methoxide (24 mL of 25% in methanol, 30 mmol) was added and stirred 10 min at ambient temperature. Ethyl trifluoroacetate (3.79 g, 23.9 mmol) was added. The solution was stirred for 1 hour then aqueous hydrochloric acid was added (100 mL, 1 M). The layers were separated and the organic layer collected. The organic layer was washed with water (2×100 mL), saturated ammonium chloride (2×200 mL) and dried over sodium sulfate. The solvent was removed in vacuo to afford a yellow oil. The 1-[3,5-difluoro-4-(methylthio)phenyl]-4,4,4-trifluorobutane-1,3-dione was isolated by crystallization from ethyl acetate and hexanes (5.50 g, 77%). 1H NMR (CDCl3/300 MHz) 7.49 (m, 2H), 6.50 (s, 1H), 2.62 (s, 3H). ESHRMS m/z 297.0012 (M+H+, Calcd 297.0009). Anal. Calcd for C11H7F5O2S: C, 44.30; H, 2.37. Found: C, 44.36; H, 2.26.
Reaction SMILES: O=C(C1C=CC=CC=1)C[O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:7]=1.NC1C=C(C=CC=1)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[F:15][C:14]([F:16])([F:17])[C:13]([NH:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([OH:19])=[O:4])=[O:18]
Reactant: O=C(COC(=O)c1cccc(NC(=O)C(F)(F)F)c1)c1ccccc1
Agent: Nc1cccc(C(=O)O)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cccc(NC(=O)C(F)(F)F)c1

Procedure:
A compound having general Formula 4, exemplified by 3-(2,2,2-Trifluoro-acetylamino)-benzoic acid 2-oxo-2-phenyl-ethyl ester (Compound 4; FIG. 1) can be prepared as follows. A solution of 3-aminobenzoic acid (137 mg, 1.0 mmol) in dichloromethane is treated with trifluoroacetic anhydride (420 mg, 2.0 mmol). The reaction mixture is stirred until no further reaction occurs. The reaction mixture is concentrated to give 3-(2,2,2-Trifluoro-acetylamino)-benzoic acid. A solution of 3-(2,2,2-Trifluoro-acetylamino)-benzoic acid (233 mg, 1.0 mmol) and 2-hydroxyacetophenone (136 mg, 1.0 mmol) in dimethylformamide and diisopropylethylamine (260 mg, 2.0 mmol) is treated with HBTU (379 mg, 1.0 mmol). The reaction mixture is stirred until no further reaction occurs. The reaction is poured into ethyl acetate and water. The organic phase is collected, dried and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](F)[C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>CO>[NH2:19][C:11]1[C:10]([N+:16]([O-:18])=[O:17])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][N:12]=1
Reactant: N
Reactant: O=[N+]([O-])c1c(OCc2ccccc2)ccnc1F
Solvent: CO
Product: Nc1nccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.73 g of 4-benzyloxy-2-fluoro-3-nitropyridine (starting material M3) are dissolved in 10 ml of a 5M solution of ammonia in methanol and stirred at ambient temperature for 16 hours. The solvent is distilled off and the residue is chromatographed on silica gel (dichloromethane/petroleum ether 4:1+1% triethylamine). Concentration of the pure fractions and drying in vacuo gives 0.51 g of the title compound as a yellow solid of m.p. 145–147° C. The mass spectrum shows the molecular peak MH+ at 246.0 Da.