Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([OH:8])=O.[C:18]([O-])(=[O:20])[CH3:19].[Na+]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([O:8][C:18](=[O:20])[CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[CH:9]=1)=[O:17]
Reactant: COC(=O)C(=Cc1ccc(F)cc1)CC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(OC(C)=O)c2cc(F)ccc2c1
Yield: 49.9 %

Procedure:
To a solution of 2-(4-fluoro-benzylidene)-succinic acid 1-methyl ester (2 g, 8.4 mmol) in acetic anhydride (10 mL) was added sodium acetate (0.83 g, 10.1 mmol). After being heated at reflux for 6 hours, the mixture was concentrated in vacuo. The residue was dissolved in 1 N hydrochloric acid (20 mL). The aqueous solution was extracted with ethyl acetate (15 mL×3). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (10-20% ethyl acetate in petroleum ether) to afford 4-acetoxy-6-fluoro-naphthalene-2-carboxylic acid methyl ester (1.1 g, 50%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.52 (s, 1H), 8.00 (dd, J=9.09, 5.56 Hz, 1H), 7.89 (s, 1H), 7.50 (dd, J=9.85, 2.53 Hz, 1H), 7.37 (td, J=8.59, 2.53 Hz, 1H), 3.99 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][C:37](=[O:68])[NH:38][CH:39]([C:43]([N:45]1[CH:51]([C:52]2[NH:53][C:54]([C:57]3[CH:66]=[CH:65][C:64]4[C:59](=[CH:60][CH:61]=[C:62](Br)[CH:63]=4)[CH:58]=3)=[CH:55][N:56]=2)[CH2:50][C:47]2([CH2:49][CH2:48]2)[CH2:46]1)=[O:44])[CH:40]([CH3:42])[CH3:41].C([O-])([O-])=O.[K+].[K+]>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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:62]3[CH:61]=[CH:60][C:59]4[C:64](=[CH:65][CH:66]=[C:57]([C:54]5[NH:53][C:52]([CH:51]6[CH2:50][C:47]7([CH2:48][CH2:49]7)[CH2:46][N:45]6[C:43](=[O:44])[CH:39]([NH:38][C:37]([O:36][CH3:35])=[O:68])[CH:40]([CH3:42])[CH3:41])=[N:56][CH:55]=5)[CH:58]=4)[CH:63]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
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+]
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 68.4 %

Procedure:
4-Cyano-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.990 g, 2.13 mmol), (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (1.007 g, 1.92 mmol), Pd(PPh3)4 (222 mg, 0.192 mmol) and K2CO3 (2.0 M in H2O, 2.1 mL, 4.2 mmol) were combined in 1,2-dimethoxymethane. The mixture was degassed for 10 min with bubbling N2 then heated to reflux for 4 h then cooled. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine before being dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (EtOAc, then 2% MeOH/DCM, then 4% MeOH/DCM) to provide the title compound (1.028 g, 68%).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH3:10][Si:11]([CH3:16])([CH3:15])[CH2:12]CO.P([O-])([O-])([O-])=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH2:10][Si:11]([CH3:16])([CH3:15])[CH3:12])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: C[Si](C)(C)CCO
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCC(=O)CC(=O)OCC[Si](C)(C)C

Procedure:
1.26 ml (10.0 mmol) of methyl 3-oxovalerate, 2.87 ml (20.0 mmol) of 2-trimethylsilylethanol and 122 mg (1.0 mmol) of 4-dimethylaminopyridine were heated under reflux in 20 ml of toluene overnight. A phosphate buffer solution was added to the obtained reaction liquid. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous salt solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH3:12])=[O:10].C(=O)(O)[O-].[Na+].[CH3:18][S:19][CH2:20]Cl.NC(N)=O>CC(C)=O>[CH3:12][N:11]([CH2:18][S:19][CH3:20])[C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:10]
Reactant: CSCCl
Reactant: CNC(=O)Nc1ccccc1F
Agent: NC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CSCN(C)C(=O)Nc1ccccc1F
Reaction time: 2 h

Procedure:
To a stirred slurry of 16.8 g. (0.1 mol) of N-(2-fluorophenyl)-N'-methyl urea, dissolved in 500 ml. of acetone containing 9.24 g. (0.11 mol) of sodium bicarbonate was added 10.6 g. ((0.11 mol) of chloromethyl methyl sulfide. The resulting mixture was stirred for 2 hours at a gentle reflux. The precipitated solid was removed by filtration. The filtrate was evaporated to give a clear oil. Crystallization from benzene gave 7.1 g. of the original urea. The filtrate from this crystallization was evaporated and the residue crystallized from diethylether to give 3.4 g. of a crystalline solid product, melting point 81°-82°C. Analysis calculated for C10H13FN2OS: S, 14.03%; F, 8.32%. Found: S, 14.02%; F, 8.43%. The infrared spectrum showed strong adsorption at 3.0, 6.9, 7.3 and 13.0μ. The NMR spectra was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:21]=[CH:20][C:16]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:21]=[CH:20][C:16]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: Clc1ccnc2ccccc12
Product: CN(C)c1ccc(-c2cc(Cl)c3ccccc3n2)cc1

Procedure:
The title compound, MS: m/e=282 (M+), was prepared from 4-chloro-quinoline and 4-bromo-N,N-dimethylaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1.CC1(C)O[C:18](=[O:19])[CH2:17][C:15](=[O:16])[O:14]1>O>[CH3:1][O:2][C:3]1[CH:10]=[C:7]2[C:6](=[CH:5][CH:4]=1)[O:11][C:18](=[O:19])[C:17]([C:15]([OH:16])=[O:14])=[CH:8]2
Reactant: COc1ccc(O)c(C=O)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: COc1ccc2oc(=O)c(C(=O)O)cc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
5-methoxy-salicylaldehyde (211.1 mg, 1.39 mmol) and Meldrum's acid (200 mg, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 241.1 mg of 6-methoxy-3-carboxy-coumarin in a 79% yield.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH2:13]([O:15][P:16]([CH2:21][CH2:22][NH2:23])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]>C(O)C>[CH2:18]([O:17][P:16]([CH2:21][CH2:22][NH:23][C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])(=[O:20])[O:15][CH2:13][CH3:14])[CH3:19]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCOP(=O)(CCN)OCC
Solvent: CCO
Product: CCOc1c(NCCP(=O)(OCC)OCC)c(=O)c1=O

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (4.00 g, 23.5 mmol) in ethanol (100 mL) was added 2-aminoethylphosphonic acid diethyl ester (5.43 g, 30.0 mmol) in ethanol (100 mL) over a 1 hour period. After leaving overnight the reaction mixture was preadsorbed onto silica gel and purified by flash chromatography (5.5 cm diameter, gradient elution with 2.5-10% isopropanol in dichloromethane) to yield [2-[(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]ethyl]phosphonic acid diethyl ester as an oil which solidifies on standing (3.98 g, 55%, mp 66°-68° C.); IR (KBr, cm-1): 3400, 3180, 1800, 1700, 1600; MS (+FAB): 306 (MH+, 100), 278 (14), 137 (14), 109 (35); 1H NMR (CDCl3, 400 MHz): δ 6.58, 6.46 (br s, NH), 4.75 (br m, 2H), 4.21- 4.07 (m, 4H), 4.00, 3.75 (br m, 2H), 2.08 (d of t, J=17.5 and 6.5 Hz, 2H), 1.46 (br m, 3H), 1.35 (t, J=7 Hz, 6H).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=1)[C:14]#[N:15].[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=1)#[CH:18]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:27][C:26]([F:28])([F:29])[O:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])[CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: C#Cc1cccc(OC(F)(F)F)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cncc(C#Cc2cccc(OC(F)(F)F)c2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 14.7 %

Procedure:
Add triethylamine (1.73 mL, 12.28 mmol), copper (I) iodide (34.0 mg, 0.180 mmol) and bis(triphenylphosphine)palladium (II) dichloride (107.7 mg, 0.150 mmol) to a solution of 5-bromonicotinonitrile (562.2 mg, 3.07 mmol) and 1-ethynyl -3-trifluoromethoxybenzene, (prepared as described in PREPARATION 28), (571.4 mg, 3.07 mmol) in ethyl acetate (3 mL). Stir in a sealed tube at 50° C. for 18 h, concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 100:50 hexanes:ethyl acetate, to give the title compound (130 mg, 15%).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:13]=[C:12]([N:14]2[C:22]3[C:17](=[C:18]([N:23]4[CH:27]=[C:26]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[N:25]=[CH:24]4)[CH:19]=[CH:20][CH:21]=3)[C:16]([CH:34]([CH3:36])[CH3:35])=[N:15]2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[OH-:37].[Na+].OO.O>CS(C)=O>[C:1]([NH:5][C:6]1[CH:13]=[C:12]([N:14]2[C:22]3[C:17](=[C:18]([N:23]4[CH:27]=[C:26]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[N:25]=[CH:24]4)[CH:19]=[CH:20][CH:21]=3)[C:16]([CH:34]([CH3:36])[CH3:35])=[N:15]2)[CH:11]=[CH:10][C:7]=1[C:8]([NH2:9])=[O:37])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NC(C)(C)C)c2)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(NC(C)(C)C)c2)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of compound (1b) in DMSO (4.41 mL) were added 4N aqueous sodium hydroxide solution (160 μL) and 30% aqueous hydrogen peroxide solution (60 μL), and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, water was poured into the reaction solution, and the precipitated solid was collected by filtration to obtain compound (1) (150 mg, yield 96%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][C@@H:19]([CH3:23])[CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:24](I)([CH3:26])[CH3:25]>CC#N.CCOC(C)=O>[CH:24]([N:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:16])[CH2:18][CH:19]1[CH3:23])([CH3:26])[CH3:25]
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(C(=O)OCc2ccccc2)CC1C
Temperature: 25 °C

Procedure:
Potassium carbonate (11.2 g) was added to a solution of (S)-1-benzyloxycarbonyl-3-methylpiperazine (D19)(10.18 g) in CH3CN (60 ml), followed by isopropyl iodide (11.3 ml) and the mixture was heated at reflux overnight. The reaction mixture was then allowed to cool to rt and the inorganics were filtered off. The filtrate was evaporated to give an oil which was taken up in EtOAc (100 ml) and washed with water (2×50 ml). The EtOAc layer was dried (MgSO4) and concentrated to give the title compound (D26) as an oil (8 g). LCMS electrospray (+ve) 277 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:46]2[N:45]=[C:44]([CH2:47][N:48]3C(=O)C4=CC=CC=C4C3=O)[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1)=[O:37])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7].O.NN>C(O)C>[NH2:48][CH2:47][C:44]1[NH:43][C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([C:36]([NH:35][C:34]3[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=4[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[O:23])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])=[O:37])[C:46]=2[N:45]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CN3C(=O)c4ccccc4C3=O)nc12
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CN)nc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(2-phthalimidomethyl-1 H-benzimidazol-4-yl)carbonylaminobenzamide (383 mg) in ethanol (5 ml) was added hydrazine monohydrate (19 mg) at ambient temperature and the solution was stirred at 60° C. for 1 hour. The reaction mixture was stirred in an ice water bath for 2 hours and the precipitate was filtered off. The filtrate was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (chloroform-methanol-ammonia solution (28%)=160:32:1) to give 4-(2-aminomethyl-1 H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) as a powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[N:4]=[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)[N:4]=4)[CH2:23][CH2:22]3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2nccc(CCl)n2)cc(OC)c1OC
Product: COc1cc(-c2nccc(CN3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)n2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl) pyrimidine (300 mg) and piperazine (44 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19]1([CH:25]([CH3:29])[C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:2]1([CH2:1][C@H:8]2[CH2:12][O:11][C:10](=[O:13])[N:9]2[C:26](=[O:27])[CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:29])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)Cl)c1ccccc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Reaction time: 0.83 h

Procedure:
A mixture of (4S)-(-)-4-benzyl-2-oxazolidinone (3.903 g, 22.0 mmol) in THF (23 ml) is cooled at -78° and butyl lithium (1.6M in hexane, 14.7 ml, 23.5 mmol) is added. The mixture is stirred for 50 min and then the portion of 2-phenylpropionic acid chloride (XL) from above, in THF (8 ml) is added dropwise to the mixture. The mixture is stirred for 1 hr at -78° and then allowed to warm to 20-25°. Saturated aqueous sodium bicarbonate solution (100 ml) is added and the phases separated. The aqueous phase is washed with ether and the combined organic phases are then washed several times with saturated aqueous sodium bicarbonate followed by a saline wash. The organic phase is dried over magnesium sulfate and concentrated. The resulting diastereomers are separated on silica gel eluting with ethyl acetate/hexane (7/93) followed by ethyl acetate/hexane (12/88). The appropriate fractions are pooled and concentrated to give (4S)-4-(phenylmethyl)-3-(2-phenylpropionyl)-2-oxazolidinone (XLI, Isomer I, less polar isomer), NMR (CDCl3) 1.55, 2.79, 3.35, 4.09, 4.58, 5.12 and 7.30 δ; and (4S)-4-(phenylmethyl)-3-(2-phenylpropionyl)-2-oxazolidinone (XLII, Isomer II, more polar isomer), NMR (CDCl3) δ 1.52, 2.58, 3.09, 4.08, 4.19, 4.75, 5.11, 6.95 and 7.31 δ.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([O:19][CH3:20])[CH:11]=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=2)=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: COc1cc(F)ccc1B(O)O
Product: COc1cc(F)ccc1-c1cc[n+]([O-])cc1
Yield: 87.4 %

Procedure:
4-Chloropyridine-N-oxide (305 mg, 2.35 mmol), 4-fluoro-2-methoxyphenylboronic acid (1.0 g, 8.8 mmol) were reacted according to the procedure of Example 39 (step a) to provide the title compound (450 mg, 87%) as a purple solid: 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J=7.2 Hz, 2H), 7.45 (d, J=7.2 Hz, 2H), 7.31 (d, J=6.5 Hz, 1H), 6.80-6.71 (m, 2H), 3.85 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[C:30]2[N:31]=[CH:32][N:33]([CH3:34])[C:29]=2[CH:28]=[CH:27][N:26]=1>>[CH3:34][N:33]1[C:29]2[CH:28]=[CH:27][N:26]=[C:25]([NH:2][C:3]3[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=3)[CH2:6][NH:7][C:8]3[C:17]4[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][N:9]=3)[C:30]=2[N:31]=[CH:32]1
Reactant: Cn1cnc2c(Cl)nccc21
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Agent: Cl
Product: Cn1cnc2c(Nc3cccc(CNc4ncnc5c(C(N)=O)cccc45)c3)nccc21
Reaction time: 10 h

Procedure:
The title compound was prepared according to Example 549 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 4-Chloro-1-methyl-1H-imidazo[4,5-c]pyridine. Reaction conditions: 120° C. in the microwave for 10 h:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1>C1COCC1.CCOCC>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:16][CH:17]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: O=C(O)c1ccc(Br)nc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(Br)nc4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.4 %

Procedure:
To a solution of 6-bromonicotinic acid (0.16 g, 0.78 mmol) in dry THF (5 ml) was added under an atmosphere of argon 1,1′-carbonyldiimidazole (0.13 g, 0.78 mmol) and the reaction mixture stirred at room temperature for 5 h. To the reaction mixture was added 2-(4-aminophenyl)-6-methoxybenzothiazole (0.2 g, 0.78 mmol) over 2 mins, stirring continued at room temperature for 1 h, then heated under reflux for 18 h. After cooling to room temperature, the reaction mixture was diluted with Et2O (30 ml) and the precipitate was collected by filtration, washed with Et2O (50 ml) and dried under high vacuum to give the title compound (0.101 g, 29%) as an orange solid.
Reaction SMILES: [CH:1]#[C:2][C@@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:9][C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1]
Reactant: C#C[C@@H](O)CCCCC
Reactant: C1=COCCC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: C#C[C@H](CCCCC)OC1CCCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (3S)-1-octyn-3-ol (63 g., 0.5 mole) and dihydropyran (63 g., 0.75 mole) is cooled to 5° in an ice bath and stirred while concentrated sulfuric acid (0.5 ml.) is added dropwise. The resulting solution is allowed to warm to room temperature and stand for 24 hours. The solution is then treated with solid anhydrous sodium carbonate, filtered, and distilled to yield (3S)-3-(2-tetrahydropyranyloxy)-1-octyne.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[C:3]1=[O:16].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:3]1=[O:16]
Reactant: CN1CCCN(CC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCCN(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 1012.6 %

Procedure:
To a solution of 0.090 g (0.39 mmol) of tert-butyl (3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)acetate from step B above in 4 mL of anhydrous dichloromethane was added 1 mL of TFA. The resulting mixture was stirred at ambient temperature for 6 h then evaporated to dryness in vacuo to afford the title compound as an off-white gum (0.68 g, 99%). LC-MS: m/z (ES) 173 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([C:32]#[CH:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]O)=[CH:38][CH:37]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:34][C:35]([F:44])([F:45])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40][O:30][C:29](=[O:31])[CH2:28][C@@H:27]([C:32]#[CH:33])[NH:26][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]3)[CH2:19]2)=[O:25])=[CH:38][CH:37]=1
Reactant: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C#C[C@H](CC(=O)OCc1ccc(C(F)(F)F)cc1)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 0 °C

Procedure:
To a mixture of N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)ethynyl-β-alanine (0.63 g), 4-(trifluoromethyl)benzyl alcohol (0.23 ml) and N,N-dimethylaminopyridine (18 mg) in dichloromethane (7 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.32 g) under stirring at 0° C. After stirring at ambient temperature for overnight, the solution was evaporated in vacuo. The residue was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaHCO3 solution, water and brine, and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with (CHCl3:MeOH=100:1) to give N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine 4-trifluoromethylbenzyl ester (0.71 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:13])=[O:12]
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Product: O=C(O)c1ccc(Cl)c(S(=O)(=O)N2CCCCC2)c1
Yield: 89 %

Procedure:
Compound 3.2 was prepared from 4-chloro-3-chlorosulfonyl-benzoic acid 2.2 and piperidine a1 in 89% yield according to general method B. MS (M−1)=302.