Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3]C=1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:36]=[C:35]([C:37]([O:39][CH3:40])=[O:38])[CH:34]=[CH:33][C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)=[O:24]>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:33]=[CH:34][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:36][C:21]=2[NH:20][C:13]([CH:10]2[CH2:9][CH2:8][N:7]([CH:4]([CH3:3])[CH3:5])[CH2:12][CH2:11]2)=[O:15])=[N:27][CH:28]=1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(N)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)C2CCN(C(C)C)CC2)c1

Procedure:
Using a similar procedure to that described in Example 275, 1-(4-pyridinyl)piperidin-4-ylcarboxylic acid (2.0 g, 9.7 mmol), thionyl chloride (1.4 m L, 19 mmol), and 2-amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide (2.8 g, 9.2 mmol) afforded, after purification by column chromatography (SiO2: 5 to 10% [2.0 N ammonia in methanol]:methylene chloride), 0.40 g (9%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:16])[CH2:4][CH2:5][CH:6]([N+:13]([O-:15])=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:17]=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][N:2]1[CH2:17][C:6]([N+:13]([O-:15])=[O:14])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH:3]1[CH3:16]
Reactant: C=O
Reactant: CNC(C)CCC(c1ccccc1)[N+](=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1CCC(c2ccccc2)([N+](=O)[O-])CN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a suspension of 138 mg (0.621 mmol) Methyl-(1-methyl-4-nitro-4-phenyl-butyl)-amine in 2.2 ml dioxane under argon at room temperature, was added 49.8 ul (0.683 mmol) formaldehyde (37% in water). The mixture was stirred at room temperature for 30 minutes and then at 65° C. for 4.5 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. Sodium sulfate was added. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on silica (Eluent: heptane/ethyl acetate 0 to 20%) to provide 76 mg (52%) of the title compound as a colorless oil. MS (m/e): 235.3 (M+H).
Reaction SMILES: Cl[CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5].[C:10]([O-:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].[K+]>C(P(CCCCCCCC)CCCCCCCC)CCCCCCC>[C:10]([O:15][CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)[O-]
Reactant: CO[Si](CCl)(OC)OC
Agent: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Agent: [K+]
Product: C=C(C)C(=O)OC[Si](OC)(OC)OC
Temperature: 90 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
170.7 g (1 mol) of chloromethyltrimethoxysilane, 11.1 g (0.03 mol) of tri-n-octylphosphine and 0.1 g (0.05 mol % based on silane) of phenothiazine are placed in a reaction vessel at 90° C. and 130.4 g (1.05 mol) of potassium methacrylate are added a little at a time over a period of 1 hour. After stirring at 90° C. for another 1 hour, the reaction is complete. After filtration from the potassium chloride formed, the product is distilled by means of a short-path evaporator, giving 209.3 g (95%) of methacryloxymethyl-trimethoxysilane having a purity of 98.8%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH3:11][NH:12][CH3:13]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([N:12]([CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ncc(Br)cn1
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
The 5-Bromo-pyrimidine-2-carbonyl chloride (55 g, 250 mmol) was dissolved in tetrahydrofuran (828 ml) and dimethyl-amine (2M solution in tetrahydrofuran) (373 ml, 745 mmol) was added portionwise at room temperature. The reaction was stirred at room temperature under nitrogen for 16 hours, after which time, LCMS indicated completion. The mixture was diluted with ethyl acetate (500 ml) and washed with H2O (500 ml). The water layer was further extracted with CH2Cl2 (5×500 ml), all organics combined, and dried over magnesium sulfate. The filtrate was concentrated in vacuo and then suspended in methyl-t-butylether (650 ml). The solution was then heated to reflux. The hot solution was allowed to cool overnight to afford pink crystals. The crystals were filtered and washed with cold methyl-t-butylether (100 ml) the solid was dried in a vacuum oven at 55° C. for 12 hours to afford the title compound 5-bromo-N,N-dimethylpyrimidine-2-carboxamide (SM-2: 44 g, 77%) as a pink solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:32])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=4[CH3:31])[CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][I:34]>CN(C=O)C>[I-:34].[CH3:33][N+:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:32])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=4[CH3:31])[CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: Cc1ccc(C)c(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCCCC4)cc3)c2)c1
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(-c2cccc(/C=C/C(=O)Nc3ccc(C[N+]4(C)CCCCC4)cc3)c2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.4 %

Procedure:
In DMF (6 ml) was dissolved (E)-N-[4—(piperidino-methyl)phenyl]-3—(2,5-dimethylphenyl)cinnamamide (0.60 g), and to the mixture was added methyl iodide (0.60 g). The mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give (E)-1-methyl-1-[4—(3—(2,5-dimethylphenyl)cinnamamido)benzyl]-piperidinium iodide (Compound 76) (0.66 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1Cl.SC1SC2C=C(C#N)C=CC=2N=1.[Cl:23][C:24]1[S:25]C2C=CC(Cl)=CC=2N=1>>[Cl:23][C:24]1[S:25][C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[N:1]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: N#Cc1ccc(N)c(Cl)c1
Agent: N#Cc1ccc2nc(S)sc2c1
Product: N#Cc1ccc2nc(Cl)sc2c1
Temperature: 120 °C

Procedure:
The title compound was prepared from 4-amino-3-chlorobenzonitrile via 2-mercapto-1,3-benzothiazole-6-carbonitrile as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 120° C. for 12 h.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][CH2:9][CH2:10][N:11]1[C:18]2[N:14]([N:15]=[CH:16][CH:17]=2)[CH:13]=[CH:12]1>C(O)=O>[CH:5]([NH:8][CH2:9][CH2:10][N:11]1[C:18]2[N:14]([N:15]=[CH:16][CH:17]=2)[CH:13]=[CH:12]1)=[O:7]
Reactant: NCCn1ccn2nccc12
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNCCn1ccn2nccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of acetic anhydride (19.5 ml) and formic acid (15.7 ml) was stirred at room temperature for 45 minutes. The mixture was cooled at 5° C. and 1-(2-aminoethyl)-1H-imidazo[1,2-b]pyrazole was added thereto. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was evaporated and the residue was subjected to column chromatography on silica gel using a mixture of ethyl acetate and methanol (9:1) as eluent. Fractions containing the object compound were combined and evaporated to give 1-(2-formylaminoethyl)-1H-imidazo[1,2-b]pyrazole (7 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(CC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-tert-butoxycarbonyl-4-(4-fluorobenzyl)piperidine (39.9 g) was added 4N-hydrogen chloride in ethyl acetate (100 ml), and the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and to the concentrate was added diethyl ether. The resulting precipitates were collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the titled compound (30.1 g).
Reaction SMILES: C(N)(C)(C)C.[Br:6]N1C(=O)CCC1=O.[CH3:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=2)[N:16]=1>C1(C)C=CC=CC=1.CCCCCC>[Br:6][C:19]1[C:18]([OH:25])=[C:17]2[C:22]([CH:23]=[CH:24][C:15]([CH3:14])=[N:16]2)=[CH:21][CH:20]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CC(C)(C)N
Product: Cc1ccc2ccc(Br)c(O)c2n1
Temperature: -70 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
The protocol was established from works by: D. E. Pearson et al. J. Org. Chem. 1967, 2358-2360. tert-butylamine (3.23 ml, 30.78 mmol) is stirred under argon in 100 ml of toluene for 2 hours at ambient temperature in the presence of an activated 4 Å molecular sieve (10 g). After cooling to −70° C., N-bromosuccinimide (5.48 g; 30.78 mmol) and 2-methyl-8-hydroxyquinoline (5.00 g; 30.78 mmol) are added in succession. The mixture is slowly brought to ambient temperature (approximately 4 hours). The reaction medium is filtered and the molecular sieve is washed with diethyl ether (20 ml). The filtrate is washed in water (3×50 ml), dried over anhydrous Na2SO4 and the organic phase is concentrated to yield a solid which is brought to reflux in 100 ml of hexane for 1 hour. After 24 hours at ambient temperature, the precipitate is filtered and dried under vacuum to yield 7-bromo-2-methyl-8-hydroxyquinoline in the form of a white powder (4.85 g; 20.47 mmol, yield=67%). NMR-1H (250 MHz, CDCl3) δ, ppm: 8.00 (d, 3J (H, H)=8.5 Hz, 1H); 7.52 (d, 3J (H, H)=9.0 Hz, 1H); 7.31 (d, 3J (H, H)=8.5 Hz, 1H); 7.16 (d, 3J (H, H)=9.0 Hz, 1H); 2.72 (s, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 157.9; 149.2; 137.7; 136.2; 130.1; 125.4; 122.9; 118.2; 103.9; 24.8. MS (CID, NH3): m/z=238 (MH+). Analysis (%) for C10H8BrNO: calculated C, 50.45; H, 3.39; N, 5.88. found C, 50.02; H, 3.37; N, 6.12.
Reaction SMILES: [SH:1][C:2]([CH3:17])([CH3:16])[CH2:3][S:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:14][OH:15])[CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:26][S:27](=O)(SC)=O>C(O)C.ClCCl>[CH3:16][C:2]([S:1][S:27][CH3:26])([CH3:17])[CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[C:8]([CH2:14][OH:15])[CH:7]=1
Reactant: CSS(C)(=O)=O
Reactant: CC(C)(S)CSCc1cc(CO)cc(CO)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CSSC(C)(C)CSCc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
(5-((2-mercapto-2-methylpropylthio)methyl)-1,3-phenylene)dimethanol (0.120 g, 0.440 mmol) was dissolved in ethanol (5 mL) and 1.0 M potassium phosphate buffer (pH 7) (5.00 mL) and cooled in an ice bath (a ppt formed but it was ignored). S-methyl methanesulfonothioate (0.083 mL, 0.881 mmol) was added and the mixture stirred overnight with gradual (over 30 minutes) warming to room temperature. The reaction was diluted with dichloromethane and the organic layer was removed, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was dissolved in dichloromethane and loaded onto a 500 micron ptlc plate and developed with 66% ethyl acetate in hexane. The band corresponding to the product was scraped, filtered using ethyl acetate, and concentrated to give (5-((2-methyl-2-(methyldisulfanyl)propylthio)methyl)-1,3-phenylene)dimethanol (0.091 g, 0.286 mmol, 64.9% yield). 1H NMR (400 Hz, CDCl3): δ 7.27 (s, 3H), 4.71 (s, 4H), 3.78 (s, 2H), 2.77 (s, 2H), 2.41 (s, 3H), 1.94 (br s, 2H), 1.38 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 141.6, 139.0, 126.7, 124.2, 65.0, 51.8, 44.0, 38.2, 26.7, 25.3; MS (m/z), expected: 341.5, found 341.1 (M+Na). See FIG. 30.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1C=CC=CC=1>[CH2:1]([N:8]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: c1ccc(Cn2nnc(-c3ccccc3)c2-c2ccccc2)cc1

Procedure:
Benzyl azide (0.400 g, 3.00 mmol), diphenylacetylene (0.588 g, 3.30 mmol), Cp*RuCl(PPh3)2 (25 mg, 0.031 mmol). Solvent, benzene; reaction temperature, 80° C.; reaction time, 2 hours; yield, 0.75 g (80%). EI-MS: m/z 312 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:19]([NH2:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)=O)=[N:6][CH:7]=1.[CH3:21][NH:22][S:23](Cl)(=[O:25])=[O:24].[BH4-].[Na+]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:10]3[CH:11]=[CH:12][C:13]4[C:18](=[N:17][CH:16]=[CH:15][CH:14]=4)[C:19]=3[NH:20][S:23](=[O:25])(=[O:24])[N:22]2[CH3:21])=[N:6][CH:7]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2ccc(F)cn2)ccc2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccc(F)cn2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 6.9 %

Procedure:
In a similar fashion using route 27 general procedure 70, 7-[(5-fluoropyridin-2-yl)carbonyl]-8-aminoquinoline (Intermediate 373) (648 mg, 2.4 mmol), N-methylsulfamoyl chloride (Intermediate 213) (942 mg, 7.2 mmol) and NaBH4 (92 mg, 2.4 mmol) in pyridine (10 ml) gave the title compound (57 mg, 2.2%) after purification by preparative HPLC (acidic conditions).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.I([O-])(=O)(=O)=[O:19].[Na+]>CO.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:19]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)C=CC=CCSc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)C=CC=CCS(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Yield: 76.4 %

Procedure:
To a solution of 6-(4-chlorophenylsulfanyl)-hexa-2,4-dienoic acid methyl ester (0.396 g, 1.47 mmol) in methanol (20 mL) was added dropwise at 0° C. a solution of sodium metaperiodate (0.37 g, 1.72 mmol) in distilled water (10 mL). The mixture was allowed to warm to 20° C., then heated at reflux for 5 hours. The solution was concentrated under reduced pressure to give an oil that was dissolved in ethyl acetate (20 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (10 mL), distilled water (10 mL), then with brine. The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (2:8 ethyl acetate:40-60° C. petroleum ether). The resulting powder was recrystallised from ethylacetate/40-60° C. petroleum ether to give the title compound (0.32 g, 77%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[O:16][CH3:17]>C(O)C.C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][N:2]([CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[O:16][CH3:17])[CH3:3]
Reactant: CNC
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(CN(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a solution of dimethyl amine (0.9 mL of a 5.6 M solution in ethanol) in THF (20 mL), a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (500 mg, 2.06 mmol) was added. The mixture was stirred at rt for 35 min before it was diluted with water (150 mL) and sat. aq. Na2CO3-solution (50 mL) and extracted with EA (70 mL). The org. extract was separated, dried over Na2SO4, filtered, evaporated and dried to give methyl 4-dimethylaminomethyl-3-methoxy-benzoate as a colourless oil (420 mg). LC-MS: tR=0.61 min, [M+1]+=224.04.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:11][C@H:10]2[OH:22])=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.[C:28](Cl)(=[O:30])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+].[O:38]1CC[CH2:40][CH2:39]1>C(N(CC)CC)C>[C:28]([O:22][C@H:10]1[C@@H:9]([NH:8][C:6](=[O:7])[C:5]2[CH:23]=[C:24]([Cl:25])[C:2]([NH:1][C:39](=[O:38])[CH3:40])=[CH:3][C:4]=2[O:26][CH3:27])[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:11]1)(=[O:30])[CH3:29]
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(Cc2ccccn2)C[C@H]1O
Reactant: CC(=O)Cl
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N[C@H]1CCN(Cc2ccccn2)C[C@H]1OC(C)=O
Reaction time: 18 h

Procedure:
To a stirred and cooled (ice-bath) solution of 6.64 parts of cis-4-amino-5-chloro-N-[3-hydroxy-1-(2-pyridinylmethyl)-4-piperidinyl]-2-methoxybenzamide in 68 parts of tetrahydrofuran were added 1.95 parts of N,N-diethylethanamine. Then there was added dropwise a solution of 1.41 parts of acetyl chloride in 27 parts of tetrahydrofuran at about 0° C. Upon completion, the mixture was allowed to reach slowly room temperature and stirring was continued for 18 hours at this temperature. Sodium carbonate was added and the whole was evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by HPLC using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was suspended in petroleumether. The product was filtered off and dried, yielding 2.03 parts of cis-4-[[4-(acetylamino)-5-chloro-2methoxybenzoyl]amino]-1-(2-pyridinylmethyl)-3-piperidinol acetate (ester); mp. 179.4° C. (compound 229).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]#[CH:11])[C:3]=1[N+:12]([O-])=O.O.O.[Sn](Cl)Cl>CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]#[CH:11])[C:3]=1[NH2:12]
Reactant: C#CCOc1cccc(F)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOc1cccc(F)c1N
Yield: 38.5 %

Procedure:
To a solution of 1-fluoro-2-nitro-3-prop-2-ynyloxy-benzene (460 mg) in EtOAc (50 mL), was added tin(II) chloride dihydrate with stirring. After 6 hours the mixture was diluted with EtOAc and washed 3 times with brine. The organic layer was dried with sodium sulfate, concentrated and the residue purified by silica gel chromatography to afford 150 mg of 2-fluoro-6-prop-2-ynyloxy-phenylamine: 1H NMR (300 MHz, CDCl3) δ 6.9-6.7 (m, 3H), 4.8 (s, 2H), 4.0 (bs, 2H), 2.6 (s, 1H).
Reaction SMILES: C([N:4]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])(=O)C.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C.O>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[C:8]2[NH:4][C:5](=[O:18])[N:6]([C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[F:17])[C:7]2=[O:9])=[CH:22][CH:21]=1
Reactant: CC(=O)N1CC(=O)N(c2cc(F)ccc2F)C1=O
Reactant: Cc1ccc(C=O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C=C2NC(=O)N(c3cc(F)ccc3F)C2=O)cc1
Yield: 89.2 %

Procedure:
N-acetyl-3-(2,5-difluorophenyl)imidazolidine-2,4-dione (2.1 g, 8.2 mmol), 4-methylbenzaldehyde (1.05 g, 8.7 mmol) and triethylamine (1.7 g, 16.5 mmol) were heated under reflux in DMF (20 mL) for 4 hours. The solution was cooled diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine (saturated), dried (over MgSO4), filtered and concentrated to give 2.3 grams of 5-(4-methylbenzylidene)-3-(2,5-difluorophenyl)imidazolidine-2,4-dione, m.p. 218°-224° C.
Reaction SMILES: [CH:1]1([CH2:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)(O)=[O:9].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([CH2:6][NH:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: NCC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCC1CCCC1)c1ccc2[nH]ccc2c1
Yield: 79.5 %

Procedure:
A solution of cyclopentylmethylamine (2.66 g), 5-carboxyindole (4.76 g), 4-(dimethylamino)pyridine (3.60 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.67 g) in dichloromethane (60 ml) was stirred for 12 hours under an atmosphere of nitrogen. The amber solution was diluted with dichloromethane (150 ml), washed successively with 10% (w/v) aqueous sodium carbonate, 10% (v/v) hydrochloric acid, water, and brine, dried (MgSO4), and evaporated. The residual amber oil was purified by flash chromatography on silica gel (700 ml), eluting with 1:3 v/v ethyl acetate:chloroform, to yield 5-(N-cyclopentylmethylcarbamoyl)indole (A) (5.17 g, 80%) as a white crystalline solid; mp 110°-112° C.; NMR (80 MHz, CDCl3): 1.0-2.4(broad m, 9H, cyclopentyl), 3.4(dd, 2H, CH2N), 6.2(broad, 1H, NH), 6.6(m, 1H, H3 -indole), 7.3(t, 1H, H2 -indole), 7.4(d, 1H, H7 -indole), 8.5(broad, 1H, CONH).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]([O:31]CC)=[O:30].[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC(=O)OCC)ccc3c2)oc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(Cl)c(OCC(=O)O)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 4 of Example 6, ethyl 2-{[1-chloro-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetate (0.477 g, 1.03 mmol) was hydrolyzed with potassium hydroxide (0.175 g, 3.12 mmol) in THF (10 mL) and water (10 mL). The title compound was obtained as a light yellow solid (0.249 g), mp 142-143° C. Mass spectrum (+ESI, [M+H]+) m/z 437. 1HNMR (500 MHz, DMSO-d6): δ13.0-13.5 (br, 1H), 8.5 (s, 1H), 8.25 (d, 1H, J=8.7 Hz), 8.1 (d, 1H, J=9.0 Hz), 8.05 (t, 2H, J=10.3 Hz), 7.75 (d,1H, J=8.0 Hz), 7.55 (d, 1H, J=9.2 Hz), 7.4-7.45 (m, 2H), 5.05 (s, 2H), 2.75 (t, 2H, J=7.2 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.75 ppm (t, 3H J=7.3 Hz). Elemental Analysis for C25H21ClO5: Calculated: C, 68.73; H, 4.84; N, 0.00. Found: C, 68.56; H, 4.60; N, 0.08.