Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[OH:21])[C:7]3[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: c1cc(C2CO2)ccn1
Reactant: CN1CCc2[nH]c3cc(C(F)(F)F)ccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3ccc(C(F)(F)F)cc3n2CC(O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 3.937 mmol) in DMF (5 mL) was added NaH (472 mg, 11.81 mmol) in portions at 0° C. After stirring the reaction mixture at 0° C. for 15 min, a solution of 4-(oxiran-2-yl)pyridine (714 mg, 5.90 mmol) in DMF (1 mL) was dropwise added into the reaction mixture at the same temperature and stirring was continued at RT overnight. The progress of reaction was monitored by TLC, LCMS and NMR. After consumption of starting material, ice water was added into the reaction mixture and the product was extracted with EtOAc (3×50 mL). The organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography to yield 2-(2-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.54 (d, 2H), 7.5 (s, 1H), 7.37 (d, 1H), 7.3 (d, 1H), 7.18 (d, 2H), 4.78 (m, 1H), 4.17 (m, 2H), 3.5 (m, 2H), 2.8 (m, 1H), 2.7 (m, 2H), 2.63 (m, 1H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers 65a and 65b.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[CH3:7].I.[PH2](O)=O.C=O.[C:14](O)(=O)[CH3:15]>>[CH3:5][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([CH3:7])[C:14]=1[CH3:15]
Reactant: CC(=O)O
Reactant: Cc1cc[nH]c1C
Agent: C=O
Agent: I
Agent: O=[PH2]O
Product: Cc1[nH]c(C)c(C)c1C
Yield: 51 %

Procedure:
As in Example 58, using 2,3-dimethyl-pyrrole (2 g), acetic acid (50 ml), hydriodic acid (50 ml), hypophosphorous acid (5 ml) and paraformaldehyde (1.2 g). Yield 51%, m.p. 105°-107°. Anal. Found: C, 77.81; H, 10.32; N, 11.45.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:10]=3[N:11]=2)[CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2oc(N3CCOCC3)nc2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2oc(N3CCOCC3)nc2c1
Yield: 30.7 %

Procedure:
A solution of 2-morpholino-5-nitrobenzo[d]oxazole (130 mg, 0.52 mmol) in ethanol/water 1:1 v/v (10 mL) was treated with sodium dithionite (182 mg, 1.04 mmol) at room temperature and then refluxed for 16 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and evaporated to afford 35 mg (30%) of the title compound.
Reaction SMILES: B.[NH2:2][C:3]1[C:11]([CH3:12])=[CH:10][C:9]([I:13])=[CH:8][C:4]=1[C:5](O)=[O:6].O.[OH-].[Na+]>C1COCC1>[NH2:2][C:3]1[C:11]([CH3:12])=[CH:10][C:9]([I:13])=[CH:8][C:4]=1[CH2:5][OH:6]
Reactant: Cc1cc(I)cc(C(=O)O)c1N
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(I)cc(CO)c1N
Reaction time: 0.5 h

Procedure:
A solution of borane in THF (270 cm3 of a 1M solution) was added over 0.5 hours to a stirred suspension of 2-amino-5-iodo-3-methylbenzoic acid (18.48 g) in THF (400 cm3) at 0°. After stirring at 0° for 0.5 hours, the reaction mixture was warmed to 50° for a further 3 hours. After cooling in an ice-bath, water (25 cm3) was cautiously added dropwise with stirring, the resulting mixture was treated with an aqueous 10% solution of sodium hydroxide (100 cm3), and stirring was continued for a further 24 hours. Volatile material was then removed in vacuo and the residue was partitioned between water (100 cm3) and chloroform (200 cm3). The aqueous phase was re-extracted with chloroform (2×200 cm3), and the combined and dried (MgSO4) organic extracts were evaporated in vacuo to give an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform. Combination and evaporation of appropriate fractions afforded the title compound, m.p. 101°-103° (14.22 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@H:12]([OH:21])[CH:11]=[CH:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:21][C@@H:12]1[CH:11]=[CH:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C:18]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][CH2:7]3)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)C=C[C@@H]12
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](OC(C)=O)C=C[C@@H]12

Procedure:
200 mg. of 3-methoxy-1,3,5(10),15-estratetraen-17α-ol is agitated for 3 hours in 2.5 ml. of pyridine with 0.5 ml. of acetic anhydride. After the product has been worked up as described in Example 4 and purified by preparative layer chromatography (eluent: hexane/ethyl acetate = 7 : 3), 170 mg. of 17α-acetoxy-3-methoxy-1,3,5(10),15-estratetraene is isolated as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=2[C:13]1=[O:22].C1(NC2CCCCC2)CCCCC1.[Cl:36]Cl>ClC(Cl)=C(Cl)Cl>[Cl:36][C:6]1[C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]([N:12]2[C:13](=[O:22])[C:14]3[CH2:21][CH2:20][CH2:19][CH2:18][C:15]=3[C:16]2=[O:17])=[C:2]([F:1])[CH:7]=1
Reactant: ClCl
Reactant: CC(C)Oc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClC(Cl)=C(Cl)Cl
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl

Procedure:
N-(2-Fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (II: R=isopropyl) (1 g) and dicyclohexylamine (0.01 g) were dissolved in tetrachloroethylene (20 ml), and chlorine (1 ml) was introduced therein at room temperature. The resultant solution was stirred at the room temperature for 2 hours. The reaction mixture was extracted with methylene chloride, and the extract was concentrated. The residue was purified by silica gel chromatography using a mixture of n-hexane and ethyl acetate as an eluent to give 0.9 g of N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (I: R=isopropyl). M.P., 81°-82° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.[C:14]([C:16]1[CH:17]=[C:18]([C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][N:39]=2)[C:33]([O:35][CH3:36])=[O:34])[CH:19]=[CH:20][C:21]=1OS(C(F)(F)F)(=O)=O)#[N:15].[CH:40]([Si:43]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[N:44]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45]1)([CH3:42])[CH3:41]>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.O>[C:14]([C:16]1[CH:17]=[C:18]([C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][N:39]=2)[C:33]([O:35][CH3:36])=[O:34])[CH:19]=[CH:20][C:21]=1[C:46]1[CH:47]=[CH:48][N:44]([Si:43]([CH:52]([CH3:54])[CH3:53])([CH:55]([CH3:57])[CH3:56])[CH:40]([CH3:41])[CH3:42])[CH:45]=1)#[N:15]
Reactant: COC(=O)c1ccnc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c2)c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccnc(-c2ccc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)c(C#N)c2)c1
Temperature: 130 °C
Yield: 5.2 %

Procedure:
58 mg of tetrakis(triphenylphosphine)palladium and 208 mg of potassium carbonate were added to a toluene (10 ml) solution of 386 mg of methyl 2-(3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)isonicotinate and 534 mg of 1-(triisopropylsilyl)pyrrole-3-boronic acid, then this was irradiated with microwaves and heated at 130° C. in a nitrogen atmosphere for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 70:30) to obtain 24 mg of methyl 2-{3-cyano-4-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]phenyl}isonicotinate. (2) 24 mg of this compound was dissolved in 1 ml of THF, and 63 μL of 1 M tetrabutylammonium fluoride/THF solution was added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10 to 70:30) to obtain 6 mg of methyl 2-[3-cyano-4-(1H-pyrrol-3-yl)phenyl]isonicotinate. (3) 6 mg of this compound was dissolved in a mixture of 0.5 ml of methanol and 0.5 ml of THF, and 22 μl of aqueous 1 M sodium hydroxide solution was added, followed by heating at 60° C. for 2 hours. The reaction liquid was cooled, and the solvent was removed under reduced pressure. Water was added to the residue, followed by neutralization with 1 M hydrochloric acid. The precipitated crystal was collected by filtration and washed with a mixture of ethanol and water to obtain 1.5 mg of 2-[3-cyano-4-(1H-pyrrol-3-yl)phenyl]isonicotinic acid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[C:9]([CH2:15][O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:8]=1.C(N(CC)C(C)C)(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][S:2]([O:14][CH2:13][C:11]1[CH:10]=[C:9]([CH2:15][O:16][CH2:17][C:18]([F:21])([F:19])[F:20])[N:8]=[C:7]([Cl:6])[N:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(COCC(F)(F)F)nc(Cl)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCc1cc(COCC(F)(F)F)nc(Cl)n1
Reaction time: 0.17 h
Yield: 103.3 %

Procedure:
A solution of methanesulfonyl chloride (0.13 mL, 1.64 mmol) in DCM (2 mL) was cooled at −30° C. (2-Chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)methanol (0.35 g, 1.36 mmol) and N,N-diisopropylethylamine (0.45 mL, 2.73 mmol) in DCM (15 mL) were added. The mixture was stirred for 10 min. Brine (50%, 50 mL) was added. The organic phase was isolated using a phase separator containing sodium sulfate. The solvents were evaporated to give the title compound 0.47 g (quant).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=2[F:24])[NH2:20])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([NH:20][S:39]([C:33]3[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])(=[O:41])=[O:40])[CH:21]=[CH:22][C:23]=2[F:24])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cc(N)ccc2F)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1nc(-c2cc(NS(=O)(=O)c3c(F)cccc3F)ccc2F)c(-c2ccnc(Cl)n2)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluoroaniline (7.4 g, 20.4 mmol) in DCM (200 mL) was added pyridine (4.85 g, 61.3 mmol) and cooled to 0° C. 2,6-Difluorobenzene-1-sulfonyl chloride (4.76 g, 22.5 mmol) in DCM (10 mL) was added dropwise to the mixture. The reaction was stirred at rt overnight. Then the reaction was washed with water (200 mL), and extracted with DCM (2×100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:EtOAc 5:1) to afford the title compound of Step E (2.3 g, 7.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (d, J=5.3 Hz, 1H), 7.62-7.75 (m, 1H), 7.20-7.32 (m, 5H), 6.92 (d, J=5.3 Hz, 1H), 1.40 (s, 9H). m/z (ES+): 539 [M+H]+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]3[OH:17])[CH2:7][CH2:6]2)[O:4]CC1.Cl.O.[OH-].[Na+]>O1CCOCC1>[OH:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[N:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1
Reactant: O[C@@H]1CCCC[C@H]1N1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCN([C@@H]2CCCC[C@H]2O)CC1
Temperature: 105 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A solution of (+/−)-trans-2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-cyclohexanol (1.50 g, 6.25 mmol) in dioxane (45 ml) was treated with 5N hydrogen chloride (10 ml). The mixture was warmed to 105° C. and stirred for 4 h. After cooling to room temperature, water (9 ml) was added to the mixture, which was then basified to pH 14 by slow addition of 5N sodium hydroxide. The mixture was then extracted three times with ethyl acetate and the combined organic extracts were dried with anhydrous sodium sulphate and concentrated. The residual oil was purified by flash chromatography on silica gel, eluting with methanol 0–5% in dichloromethane. (+/−)-trans-1-(2-Hydroxy-cyclohexyl)-piperidin-4-one (0.830 g, 68%) was obtained as a white solid, MS (ISP): m/e=198.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:15](O)=[O:16])[CH:5]=[CH:4][C:3]1=2.CC(C)(C)C(Cl)=O.[Cl-].[Li+].[CH3:33][CH:34]([C@@H:36]1[C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:39][C:38](=[O:53])[NH:37]1)[CH3:35]>C1COCC1.C(N(CC)CC)C>[CH3:35][CH:34]([C@@H:36]1[C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:39][C:38](=[O:53])[N:37]1[C:15](=[O:16])[C@@H:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:23])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:33]
Reactant: CCCCCC(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(C)[C@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC[C@@H](C(=O)N1C(=O)OC(c2ccccc2)(c2ccccc2)[C@H]1C(C)C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -30 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
2.0 g of (RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanoic acid were dissolved in 30 ml of THF and cooled to −30° C. To the cooled mixture, were added successively, 2.3 ml of triethylamine and 780 μl of trimethylacetyl chloride. The mixture was kept at −30° C. for two hours. 308 mg of lithium chloride were added followed by 978 mg of (R)-4-(1-methylethyl)-5,5-diphenyloxazolidin-2-one (Hintermann T., Seebach D., Helv. Chim. Acta, 1998, 81, 2093). The mixture was allowed to warm to room temperature and was kept at that temperature for 18 hours. The reaction mixture was quenched by the addition of one portion of 30 ml of a saturated aqueous ammonium chloride solution. The resulting mixture was extracted with three portions of 30 ml of ether. The combined organic extracts were washed with two portions of 30 ml of 1N hydrochloric solution, one portion of 30 ml of water and one portion of 30 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and the solvent evaporated. The residual yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes to 20% ethyl acetate/hexanes, dry pack), yielding 1.8 g of the titled compound and 0.8 g of the starting acid, 1H NMR (CDCl3): 7.40-7.20 (m, 6H), 7.15-6.95 (m, 6H), 6.77 (dd, J=8.2, 2.0 Hz, 1H), 5.26 (d, J=3.4 Hz, 1H), 4.92 (dd, J=8.8, 6.2 Hz, 1H), 2.15 (m, 1H), 1.97 (m, 1H), 1.70 (m, 1H), 1.58 (br. s, 4H), 1.35-1.25 (m, 6H), 1.23 (s, 3H), 1.20 (s, 3H), 1.17 (s, 3H), 1.03 (s, 3H), 0.92 (d, J=7.0 Hz, 3H), 0.85 (t, J=6.8 Hz, 3H), 0.80 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:7]1([NH:6][CH2:2][C:3]([NH2:5])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccccc1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)CNc1ccccc1
Yield: 9.6 %

Procedure:
The mixture of 2-chloroacetamide (3.1 g), aniline (3.1 g), K2CO3 (4.5 g) and KI (1 g) in acetonitrile (50 mL) and water (10 mL) was stirred at room temperature for overnight. The solvent was evaporated to about 20 ml under vacuum and the residue was poured into water (40 mL). The solution was extracted with ethyl acetate (3×20 mL), dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 0.48 g of 2-phenylamino-acetamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[NH:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH2:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1.N=C=N.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:26][CH2:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[NH:16][CH:17]=[CH:18]3)=[O:10])[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: Nc1nc(C(=O)O)cc(-c2ccco2)n1
Reactant: NCc1ccc2[nH]ccc2c1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(C(=O)NCc2ccc3[nH]ccc3c2)cc(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
A mixture consisting of 2-amino-6-(2-furyl)pyrimidine-4-carboxylic acid (206 mg, 1.0 mmol), indole-5-methanamine (146 mg, 1.0 mmol), polymer supported carbodiimide (Argonaut Technologies, loading 1.38 mmol/g, 1.10 g, 1.5 mmol) and 1-hydroxybenzotriazole hydrate (203 mg, 1.5 mmol) in DMF (5 mL) was stirred at room temperature for 24 hr. The mixture was filtered through a pad of Celite, washing through with EtOAc. The filtrate was washed successively with H2O (10 mL), 2-M Na2CO3 (2×10 mL) and H2O (10 mL), dried (MgSO4) and concentrated in vacuo. The resulting oil was dissolved in MeOH (1.0 mL), added dropwise with stirring to H2O (2 mL) and the resulting precipitate filtered to give the title compound (198 mg, 59%) as a cream solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:34])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:33])[C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:35][CH2:36][CH2:37]Br>C(O)C>[CH3:3][O:4][C:5](=[O:34])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:33])[C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:37][CH2:36][Br:35])=[CH:12][CH:13]=1
Reactant: BrCCBr
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccc(C(C)(C)C)cc1
Yield: 42.2 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-[(2-(4-tert-butylbenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.27 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.67 g, 42%).
Reaction SMILES: [C:1]1([NH:7][C:8](=O)[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:20])=O>ClCCl>[C:1]1([N:7]=[C:8]([Cl:20])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(=O)Nc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(Cl)=Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-phenylpropionamide(7.46 g, 0.05 mol) and pyridine(13.8 g, 0.18 mol) were dissolved in dichloromethane(300 g), and the mixture was cooled to 0° C. And then phosphorus oxychloride(8.43 g, 0.05 mol) was added dropwise thereto for 2 hours, and then the mixture was stirred at room temperature (20° C.) for 2 hours to produce N-phenylpropionimidoylchloride.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:21]2[CH:37]=[CH:36][C:24]([O:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:23][CH:22]=2)[C:17]([NH:19][OH:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].Cl>ClCCl.CCOCC>[NH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:36]=[CH:37][C:21]([C@@H:16]([NH:15][S:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=2)(=[O:14])=[O:13])[C:17]([NH:19][OH:20])=[O:18])=[CH:22][CH:23]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)NO)c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)NO)c2ccc(OCCN)cc2)cc1
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Through a solution of 0.354 g (0.664 mmol) of the product of Example 199, tert-butyl 2-{4-[(1R)-1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(hydroxyamino)-2-oxoethyl]phenoxy}ethylcarbamate, in 10 mL of dichloromethane was bubbled hydrogen chloride gas for 10 minutes. The reaction was stoppered and let sit at room temperature for 30 minutes. The reaction was then diluted with 15 mL of ether and the resulting white precipitate was collected by filtration and dried in vacuo to give 0.283 g of (2R)-2-[4-(2-Aminoethoxy)phenyl]-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxyethanamide as a white solid. Electrospray Mass Spec 434.3 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18](=O)[CH3:19])(=[O:6])=[O:5])#[N:2].[K+].[Br-]>CO>[CH3:19][C:18]1[NH:17][C:8]2[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=2[S:4](=[O:6])(=[O:5])[C:3]=1[C:1]#[N:2]
Reactant: CC(=O)Nc1cc(C(F)(F)F)ccc1S(=O)(=O)CC#N
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: CC1=C(C#N)S(=O)(=O)c2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared by base catalyzed ring closure of N-(2-cyanomethylsulfonyl-5-trifluoromethylphenyl)-acetamide by a procedure analogous to the procedure described in EXAMPLE 1 c); white flakes (from methanol), mp 329-333° C., 1H-NMR(CD3OD) δ (ppm): 8.20-8.10 (br d, 1H), 7.78-7.62 (m, 2H), 4.88 (br, H2O+NH), 2.52 (s, 3H); 13C-NMR (DMSO-d6) δ (ppm): 156.4, 135.6, 133.1 (q, J=33 Hz), 126.6, 124.2, 123.0 (CF3, J=273 Hz), 121.9 (J=3.4 Hz), 116.2 (J=4.5 Hz), 112.4 (C≡N), 86.3 20.4; IR (KBr) ν (cm−1): 3301, 3195, 3133, 2214(C≡N), 1628, 1614, 1592, 1554, 1487, 1422, 1339, 1308, 1265, 1241, 1187, 1159, 1131, 1083, 890; MS m/e (rel. intensity): 288 (74%, M+), 224 (74%), 223 (100%), 203 (8%), 155 (9%), 69 (16%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Na].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1>CN(C)C=O>[N:13]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Clc1ccc2ccccc2n1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: c1ccc2nc(-n3cncn3)ccc2c1

Procedure:
1.64 g of 2-chloro-quinoline and 1.1 g of the sodium salt of 1H-1,2,4-triazole are reacted in 10 ml of dimethyl formamide for 20 hours at 100° C. and worked up as in Example 1 to give 1.43 g of 2-(1H-1,2,4-triazole-1-yl)-quinoline /yield 53%/