Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[N:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:10]([NH:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][NH:1][C:27]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:17]=[CH:18][CH:19]=[CH:20]2)=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: NCc1cccc(NCc2ccccc2)c1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCc1cccc(NCc2ccccc2)c1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
(3-Aminomethyl-phenyl)-benzylamine (62 mg, 0.29 mmol), quinoline-6-carboxylic acid (52 mg, 0.30 mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (182 mg, 0.41 mmol) and triethylamine (114 μl, 0.81 mmol) were dissolved in N,N-dimethylformamide (0.5 mL), and the solution was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (73 mg, 0.198 mmol, 73%) was obtained as a white solid.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>C(Cl)Cl>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in methylene chloride (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in metylene chloride was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 159.8 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:20][O:19][C:18]([NH2:21])=[N:17]4)[C:4]=2[CH:3]=1)=[CH:14][C:13]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:12][CH:11]=3.F[C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1.N1C=CC=C(B(O)O)C=1>>[F:8][C:6]1[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:20][O:19][C:18]([NH2:21])=[N:17]4)[C:4]=2[CH:3]=[C:2]([C:35]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[N:7]=1)=[CH:14][C:13]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:12][CH:11]=3
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1cccnc1F
Agent: OB(O)c1cccnc1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(-c2cccnc2)nc1F

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA1 above, but using (S)-3-chloro-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared as described as in Method BB33), 2-fluoropyridin-3-ylboronic acid and 3-pyridylboronic acid
Reaction SMILES: [C:1]1([CH3:12])[C:2]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7].[OH-].[Ca+2:14].[OH-]>>[C:1]1([CH3:12])[C:2]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7].[Ca+2:14].[C:1]1([CH3:12])[C:2]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:3][CH:4]=[CH:5][C:6]=1[OH:7]
Reactant: Cc1c(O)cccc1S(=O)(=O)O
Agent: [Ca+2]
Agent: [OH-]
Product: Cc1c(O)cccc1S(=O)(=O)[O-]

Procedure:
To 1000 g of 10% cresol sulfonic acid aqueous solution stirred at room temperature, 30 g of calcium hydroxide was added. The stirring was continued while measuring the pH value. At the time when the pH value reached 6, approximately, filtration was done by using a 0.4 μm glass filter to remove the insoluble components, so as to obtain a calcium cresolsulfonate aqueous solution.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@@H:5]2[CH2:4]1.Cl[C:13]1[N:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][CH2:2][C@@H:3]1[CH2:11][N:6]2[CH2:7][CH2:8][N:9]([C:13]3[N:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)[CH2:10][C@@H:5]2[CH2:4]1
Reactant: Fc1cnc(Cl)nc1
Reactant: OC[C@H]1C[C@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Yield: 43.5 %

Procedure:
A mixture of 1.38 g (8.84 mmol) of (7S,8aS)-7-hydroxymethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine, 1.30 g (9.87 mmol) of 2-chloro-5-fluoropyrimidine (Dunaiskis, A. et al., Org. Prep. Proc. Int., 1995, 27, 600-602), and 2.85 g (26.9 mmol) of sodium carbonate and 90 mL of water was heated at 95° C. for 16 hours. The solution was cooled and extracted with chloroform (2×), the combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 9:1 chloroform:methanol gave 0.97 g (43%) of the title compound. Mp 123-124° C. m/z (MH+) 253. 13C NMR (CDCl3): δ 30.9, 37.1, 43.8, 48.8, 51.3, 57.5, 62.6, 67.2, 144.9, 145.2, 149.9, 153.2, 158.8.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[C:22]([O:28][CH3:29])[CH:21]=1.C[O-].[Na+].Cl>CO.O>[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:15]/[C:14](=[O:16])[C:13]2[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:22]([O:28][CH3:29])[CH:21]=1
Reactant: COC(=O)c1ccc(C=O)c(OC)c1
Reactant: CC(=O)c1cccnc1Nc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.8 %

Procedure:
A mixture of 1-(2-phenylamino-pyridin-3-yl)-ethanone (833 mg, 3.92 mmol) in methanol (16.5 mL) at 25° C. was treated with 4-formyl-3-methoxy-benzoic acid methyl ester (508 mg, 2.61 mmol) and sodium methoxide in methanol (4.37M, 1.2 mL, 5.23 mmol). The reaction was stirred at 25° C. for 48 h. At this time, the reaction was diluted with water (100 mL), neutralized with a 1N aqueous hydrochloric acid solution, and extracted with methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate filtered and concentrated in vacuo. Flash chromatography (40 g silica column, 10-50% ethyl acetate/hexanes) afforded 3-methoxy-4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (880 mg, 86.8%) as a red solid. ES+-HRMS m/e calcd for C23H20N2O4 [M+H+] 389.1496. Found 389.1494.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH:8]([CH2:14][CH3:15])[C:9]([O:11]CC)=[O:10])=[CH:5][C:4]=1[CH2:18][C:19](=[O:29])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28].[OH-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH:8]([CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[CH:5][C:4]=1[CH2:18][C:19](=[O:29])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CC(=O)Nc2ccc(Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(Cc1ccc(OC)c(CC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.27 g of ethyl 2-(4-methoxy-3-{2-oxo-2-[2,4-dichloroanilino]ethyl}benzyl)butanoate was dissolved in 10 ml ethanol, and 1 ml of 5 N sodium hydroxide was added. After stirring the reaction solution at room temperature for 24 hours, water was added thereto and the aqueous layer was extracted with diethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 2-(4-methoxy-3-{2-oxo-2-[2,4-dichloroanilino]ethyl}benzyl)butanoic acid as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH:20]2[C:21](=O)[O:22][C:23](=[O:24])[CH:19]2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH2:9]1.[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:22])[N:33]([CH2:32][C:31]3[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:30]=3[O:29][CH3:28])[C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COc1ccc2[nH]c3c(c2c1)C1C(=O)OC(=O)C1C(c1ccccc1Cl)C3
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)c3c(-c4ccccc4Cl)cc4[nH]c5ccc(OC)cc5c4c3C2=O)c(OC)c1

Procedure:
To a solution of anhydride (286) (2.80 g, 7.42 mmol) prepared as described in example 296 in glacial acetic acid (70 mL) was added 2,4-dimethoxybenzylamine (1.67 mL, 11.1 mmol). The resulting solution was heated at reflux for 6 hours before being partially concentrated under reduced pressure and diluted with water to precipitate an orange solid, which was collected by filtration, washed with water and dried in vacuo. This crude material was then dissolved in p-dioxane and aromatized according to the procedure for example 79, before being chromatographed on silica eluting with ethyl acetate/hexane (1:1). Crystallisation from methanol then gave carbazole (287) (1.46 g, 37%) as a yellow powder, mp 224–226° C. 1H NMR δ [(CD3)2SO] 12.02 (br s, 1H), 8.45 (d, J=2.6 Hz, 1H), 7.62 (s, 1H), 7.58 (m, 2H), 7.53–7.42 (m, 3H), 7.25 (dd, J=8.8, 2.6 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.57 (d, J=2.3 Hz, 1H), 6.45 (dd, J=8.4, 2.3 Hz, 1H), 4.68 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H). Found: C, 68.22; H, 4.37; N, 5.29. C30H23ClN2O5 requires: C, 68.38; H, 4.40; N, 5.32.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C([Li])CCC.[O:15]1[C:19]2([CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.[C:30]1([Se:36]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:30]1([Se:36][C:22]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:24][C:19]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:20][CH2:21]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Br[Se]c1ccccc1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1([Se]c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of diisopropylethyl amine (5.59 g, 55.30 mmol) in anhydrous tetrahydrofuran (150 mL) was added a solution of butyllithium (1.6 M in hexanes, 34.5 mL, 55.30 mmol) at 0° C. The reaction solution was stirred at the same temperature for 1 hour, then added a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (10.80 g, 50.00 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. The reaction mixture was stirred at the same temperature for 1 h then added phenylselenium bromide (11.90 g, 50.70 mmol). The mixture was continued to stir at −78° C. for 5 hour, then at ambient temperature for 16 hour. The reaction was quenched with saturated sodium hydrogencarbonate (200 mL), diluted with ethyl acetate (200 mL), saturated ammonium chloride (3×150 mL), brine (3×100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10%) to afford the title compound as a viscous liquid (14.10 g, 76%): 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=7.6 Hz, 1H), 7.37-7.32 (m, 1H), 7.26 (dd, J=7.0, 7.0 Hz, 2H), 4.05 (dd, J=7.1 Hz, 2H), 3.90 (d, J=3.4 Hz, 4H), 2.20-2.12 (m, 2H), 2.00-1.88 (m, 2H), 1.82-1.70 (m, 2H), 1.57-1.46 (m, 2H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: COC1C=CC(C[N:8]([C:31]2[S:35][N:34]=[CH:33][N:32]=2)[S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[N:17][NH:16][C:15]3=[O:30])(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:18]1[C:19]2[C:14](=[CH:13][C:12]([S:9]([NH:8][C:31]3[S:35][N:34]=[CH:33][N:32]=3)(=[O:10])=[O:11])=[CH:21][CH:20]=2)[C:15](=[O:30])[NH:16][N:17]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccccc4OC)n[nH]c(=O)c3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 24 h
Yield: 21.9 %

Procedure:
N-(4-methoxybenzyl)-1-(2-methoxyphenyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (65.0 mg, 0.121 mmol) was dissolved in DCM (1.21 mL) and then TFA (46.7 μl, 0.607 mmol) was added. After 1 d at rt, LCMS showed mainly product. The reaction was quenched with 1 mL of saturated aqueous NaHCO3 and was concentrated. Chromatography was performed using reverse phase Isolera through a pre-packed C18 column (12 g), eluting with a gradient of 0% to 60% MeCN with 1% TFA in water with 1% TFA. Fractions containing the product were combined and concentrated. White solid precipitated out of the water. The solid was filtered off with an aid of water and dried to afford 1-(2-methoxyphenyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (11 mg, 21.8% yield). m/z (ESI) 416.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18].N1C=CC=CC=1.[CH2:25]([CH:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28](Cl)=[O:29])[CH3:26]>C(Cl)(Cl)Cl>[CH2:25]([CH:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28]([O:18][C:10]1[CH2:11][C:12]([CH3:16])([CH3:17])[CH2:13][C:14](=[O:15])[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:29])[CH3:26]
Reactant: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)c(C)c1
Reactant: CCCCC(CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCC(CC)C(=O)OC1=C(c2ccc(C)cc2C)C(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
A solution of 1.50 g (6.14 mmol) of 2-(2',4'-dimethylphenyl)-5,5-dimethyl-1,3-cyclohexanedione in 10 ml of chloroform was cooled in ice and 1.94 g (24.56 mmol) of pyridine added followed by 2.00 g (12.28 mmol) of 2-ethylhexanoyl chloride. The mixture was stirred for 2 hrs. at room temperature, then refluxed for 12 hrs. The mixture was worked up exactly as described in Example I above to give 1.58 g of a slightly yellow, viscous oil. This material was chromatographed through 75 g of silica gel (0.063-0.2 mm) using a gradient ranging from 98:2 to 90:10 hexane-ethyl acetate. The chromatography gave 1.15 g (51%) of 3-(2-ethylhexanoyloxy)-5,5-dimethyl-2-(2',4'-dimethylphenyl)-2-cyclohexenone as a clear colorless oil which showed one spot on a thin layer chromatogram (70:30 hexane-ethyl acetate) at Rf=0.52.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Cl[C:12](=[O:17])[C:13]([O:15][CH3:16])=[O:14].C(OC(CCCCCC(=O)C(OC)=O)=O)(C)(C)C>[Zn]>[C:7]([O:6][C:4]([CH2:3][CH2:2][C:12](=[O:17])[C:13]([O:15][CH3:16])=[O:14])=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)OC(=O)CCBr
Agent: COC(=O)C(=O)CCCCCC(=O)OC(C)(C)C
Agent: [Zn]
Product: COC(=O)C(=O)CCC(=O)OC(C)(C)C
Yield: 72 %

Procedure:
3-Bromopropanoic acid, tert-butyl ester (2.2 g, 10.6 mmol), activated zinc (1.25 g in 25 ml of THF) and methyl chlorooxoacetate (1.4 ml, 11.4 mmol) were reacted by the same procedure as described in Example 1 for the preparation of methyl 7-tert-butyoxycarbonyl-2-oxoheptanoate to give the crude title material (1.65 g) as a colorless liquid which is used directly in next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([C:13](O)=[O:14])=[C:6]2[O:16][CH:17]([CH3:19])[CH3:18].[CH3:20][NH2:21].[OH-].[NH4+]>>[CH3:20][NH:21][C:13]([C:7]1[N:8]([CH3:12])[C:9]2[C:5]([C:6]=1[O:16][CH:17]([CH3:19])[CH3:18])=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:14]
Reactant: CN
Reactant: COc1ccc2c(c1)c(OC(C)C)c(C(=O)O)n2C
Agent: [NH4+]
Agent: [OH-]
Product: CNC(=O)c1c(OC(C)C)c2cc(OC)ccc2n1C
Yield: 45 %

Procedure:
Prepared from 5-methoxy-1-methyl-3-(1-methylethoxy)-1H-indole-2-carboxylic acid by the procedure of Example 1 with 40% aqueous methylamine solution substituted for ammonium hydroxide. Yield 45% after recrystallization from hexane; mp 85°-86° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[S:9])[NH2:8])=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:19])[CH2:14][CH:15](Br)[CH:16]=O)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:19])[CH2:14][C:15]1[S:9][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:8][CH:16]=1)[CH3:11]
Reactant: CCOC(=O)CC(Br)C=O
Reactant: NC(=S)c1ccncc1
Solvent: CCO
Product: CCOC(=O)Cc1cnc(-c2ccncc2)s1

Procedure:
Pyridine-4-thioamide (1.38 g, 0.01 mole) and 3-bromo-4-oxobutyric acid ethyl ester (3.1 g., 0.015 mole) in ethanol (50 ml) are heated at reflux for six hours. After cooling the solvent is evaporated and the residue is neutralized with sodium bicarbonate solution and then extracted with chloroform (300 ml.). The chloroform solution is washed with water, dried with (MgSO4) and evaporated to yield crude 2-(4-pyridyl)-thiazole-5-acetic acid ethyl ester. Purification is carried out by dissolving in acetone and adding petroleum ether to induce crystallization. When this ester intermediate is treated with methanol solution saturated with ammonia gas (25 ml./g. of ester) for 3 days at room temperature 2-(4-pyridyl)thiazol-5-ylacetamide is obtained after partial evaporation of the methanol. Purification is carried out by recrystallization from ethanol. When the amide is treated according to the procedure in Example 1, there is obtained 3-hydroxy-4-[2-(4-pyridyl)thiazol-5-yl]-3-pyrroline-2,5-dione.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH:14][C:15]1[S:16](=[O:39])[NH:17][C:18]2[CH:24]=[C:23]([O:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)([O:12][CH3:13])=[O:11].C(OCC)(=O)C>N1C=CC=CC=1.O>[C:1]([N:17]1[C:18]2[CH:24]=[C:23]([O:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=[C:15]([NH:14][C:10]([O:12][CH3:13])=[O:11])[S:16]1=[O:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)NC1=Nc2ccc(OS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2NS1=O
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)NC1=Nc2ccc(OS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2N(C(=O)c2ccccc2)S1=O
Temperature: 0 °C

Procedure:
1 Milliliter of benzoyl chloride was added dropwise, while stirring and cooling with an ice mixture, to a solution of 1.4 g of 3-carbomethoxyamino-7-(3-trifluoromethyl-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine-S-oxide in 20 ml of pyridine. After the mixture has been stirred for 2 hours at 0° C, 1 ml of benzoyl chloride was added once more. After another hour of stirring at 0° C, the reaction mixture was diluted with water. It was then shaken with ethyl acetate, and the extract was washed with saturated sodium chloride solution. After evaporation of the solvent, the residue was isolated by trituration with methanol and filtration. 1-Benzoyl-3-carbomethoxyamino-7-(3-trifluoromethyl-phenylsulfonyloxy)-1H-2,1,4-benzothiadiazine-S-oxide was obtained in a yield of 1.1 g.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][S:7](=[O:11])(=[O:10])[N:6]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1)=[O:4].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][S:7]1(=[O:10])=[O:11])#[N:20]
Reactant: COC(=O)C1CCS(=O)(=O)N1Cc1cccc(C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(CN2C(C(=O)O)CCS2(=O)=O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a stirred solution of 2-(3-cyano-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid methyl ester (6.0 g, 20.4 mmol) in a tetrahydrofuran-water mixture (4:1, 50 mL), lithium hydroxide monohydrate (2.5 g, 59.6 mmol) was added at room temperature and stirred at this temperature for 4 h. Then tetrahydrofuran was removed from the reaction mixture under reduced pressure. The residual reaction mixture was cooled to 0° C. and 1N hydrochloric acid was added to make the pH˜2. The acidified reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water (2×50 mL) followed by brine (50 mL) and then dried over sodium sulfate and concentrated under reduced pressure to provide 2-(3-cyano-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (5.2 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([OH:19])=O)[CH:3]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.C([O-])(=O)C.[NH4+].O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([NH2:22])=[O:19])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Reaction time: 12 h

Procedure:
6-Chloro-3-[(2-fluoro-4-iodophenyl)amino]pyridazine-4-carboxylic acid (144 mg, 0.37 mmol.) and 1,1′-carbonylbis(1H-imidazole) (119 mg, 0.73 mmol) were suspended in N,N-dimethylformamide (1.00 ml). The mixture was stirred over night (12 hr). Solid ammonium acetate (31 mg, 0.40 mmol) then added. The reaction was stirred for another 5 h. Water (0.5 mL) was then added into the mixture. The desired product was precipitated and was collected by vacuum filtration. LC/MS [7.39 min; 393 (M+1)].
Reaction SMILES: CC1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH3:7])N=1.IC1N[N:23]=[C:22](C)[C:21]=1C.IC1NC(C)=NC=1C>>[CH3:21][C:22]1[C:5]([CH3:7])=[C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])[NH:3][N:23]=1
Reactant: Cc1n[nH]c(I)c1C
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1ccc(C)c(-c2[nH]nc(C)c2C)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except 5-iodo-3,4-dimethyl-1H-pyrazole (compound 59.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 245 (M+H)+.