Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][NH2:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](Cl)=[O:42])=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][NH:25][C:41](=[O:42])[CH2:40][C:37]1[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC1(C)OCCn2c1nc(C(=O)NN)c(OCc1ccccc1)c2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OCCn2c1nc(C(=O)NNC(=O)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To stirred solution of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbohydrazide (0.170 g, 0.49 mmol) and Et3N (0.14 mL, 1 mmol) in CH2Cl2 (10 mL) was added 2-(4-fluorophenyl)acetyl chloride (69 mL, 0.5 mmol) and the mixture stirred 2 h at room temperature. The reaction mixture was purified by preparative HPLC on a C18 column using water/MeOH containing 0.1% TFA as eluent to afford the title compound (0.078 g, 33% yield) as a white solid. 1HNMR (500 MHz, CDCl3) δ: 9.97 (1H, d, J=7.0 Hz), 8.42 (1H, d, J=6.7 Hz), 7.54 (2H, d, J=6.7 Hz), 7.35-7.27 (5H, m), 7.05 (2H, t, J=8.6 Hz), 5.36 (2H, s), 4.04-3.98 (4H, m), 3.64 (2H, s), 1.60 (6H, s). HRMS (M+H) calcd for C25H26N4O5F: 481.1887. found: 481.1866.
Reaction SMILES: I.[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=N)SC.[CH3:19][NH:20][CH2:21][CH2:22][NH2:23].[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(O)C.CO>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[CH3:19][N:20]1[CH2:21][CH2:22][NH:23][C:9]1=[N:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNCCN
Reactant: CSC(=N)Nc1ccccc1-c1ccccc1
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: CN1CCNC1=Nc1ccccc1-c1ccccc1

Procedure:
A mixture of 1-(2-biphenylyl)-2-methyl-2-thiopseudourea hydriodide (5.6 g) and N-methylethylenediamine (3.3 g) in ethanol (70 ml) was heated under reflux for 48 hours. Removal of the solvent gave an oil which was dissolved in methanol (25 ml) and treated with fumaric acid (1.7 g) to give 2-(1-methyl-2-imidazolidinylideneamino)biphenyl fumarate (m.p. 168°-169° C.) which was recrystallised from a 1:1 mixture of methanol and ether.
Reaction SMILES: [CH2:1]([C:3]([OH:18])([CH2:6][CH2:7]/[CH:8]=[C:9](\[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)/[CH3:10])[CH2:4][CH3:5])[CH3:2].Br[CH2:20][C:21]1[CH:22]=[C:23]([C:31](OC)=[O:32])[C:24](=[CH:29][CH:30]=1)[C:25](OC)=[O:26]>>[OH:32][CH2:31][C:23]1[CH:22]=[C:21]([CH:30]=[CH:29][C:24]=1[CH2:25][OH:26])[CH2:20][O:17][C:13]1[CH:12]=[C:11](/[C:9](/[CH3:10])=[CH:8]\[CH2:7][CH2:6][C:3]([CH2:4][CH3:5])([OH:18])[CH2:1][CH3:2])[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CBr)cc1C(=O)OC
Reactant: CCC(O)(CC)CC/C=C(/C)c1cccc(O)c1
Product: CCC(O)(CC)CC/C=C(/C)c1cccc(OCc2ccc(CO)c(CO)c2)c1
Yield: 0.1 %

Procedure:
In a manner similar to Example 64(d), by reacting 234 mg (0.95 mmol) of (Z)-3-ethyl-7-(3-hydroxyphenyl)oct-6-en-3-ol with 356 mg (1.24 mmol) of dimethyl 4-bromomethylphthalate, .398 mg (92%) of expected product are obtained in the form of an oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH3:31])[N:25]=1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[N:25]=3)[CH3:31])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: CNc1cccc(OC)n1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: COc1cccc(N(C)C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)n1

Procedure:
The crude product was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and and 2-methoxy-6-methylaminopyridine. The reaction mixture was evaporated to dryness, dissolved in dichloromethane (100 ml) and extracted with a aqueous phosphate buffer, pH 7. The aqueous phase was extracted with dichloromethane (100 ml×2) and the combined organic phases were dryed and evaporated to dryness. The product was subjected to flash chromatography, ethyl acetate/heptane (1:7) to give the titlew product (86%, white crystals). HPLC-MS m/z=420.4 (M+1), Rt: 5.23 min.
Reaction SMILES: I[C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C(N(CC)CC)C.O1CCCC1.[Cu]I.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:3]([NH2:12])=[N:4][CH:5]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(C(F)(F)F)cc1I
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc(C(F)(F)F)cnc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
3-Iodo-5-trifluoromethyl-pyridin-2-ylamine (52.5 g, 180 mmol) was dissolved in a mixture of triethylamine (76 mL) and tetrahydrofuran (300 mL) and the solution was degassed and purged with nitrogen. Trimethylsilyl acetylene (38 mL, 270 mmol), copper(I) iodide (0.7 g, 3.6 mmol) and bis(triphenylphosphino) palladium (II) chloride (2.53 g, 3.6 mmol) were added. The mixture was degassed and purged with nitrogen one more time. The mixture was stirred at ambient temperature for 16 h and a solution containing a white precipitate resulted. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 15%-35% ethyl acetate in hexanes) to afford 5-trifluoromethyl-3-trimethylsilanylethynyl-pyridin-2-ylamine (43.8 g, 92%) as a yellow solid: LC/MS m/e calcd for C11H13F3N2Si [M+H]+ 259.32, observed 258.9.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:26][C:25]3[CH:27]=[CH:28][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: COc1ccc(N)cc1
Solvent: CCOCC
Product: COc1ccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 4-methoxy-aniline (Aldrich) according to the method described in Example 94. Melting Point: 105-107° C. (diethylether
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[N:7]=[C:8]2[N:13]([CH:14]=1)[CH2:12][C@H:11]([OH:15])[CH2:10][O:9]2)([O-:5])=[O:4].Br[CH2:17][C:18]1[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1>CN(C=O)C>[Cl:24][C:21]1[N:20]=[N:19][C:18]([CH2:17][O:15][C@@H:11]2[CH2:10][O:9][C:8]3=[N:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][N:13]3[CH2:12]2)=[CH:23][CH:22]=1
Reactant: Clc1ccc(CBr)nn1
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(Cl)nn1)C2
Temperature: -42 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Sodium hydride (60% w/w, 0.30 g, 7.6 mmol) was added to a solution of (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol (0.89 g, 4.8 mmol) in DMF (20 mL) at 0° C. The resultant solution was cooled to −42° C. and a solution of 3-(bromomethyl)-6-chloropyridazine (1.05 g, 5.1 mmol) in DMF (5 mL) was added. The mixture was stirred at −42° C. for 1 h and then quenched with ice. EtOAc (200 mL) was added, the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel, initially eluting with hexanes/EtOAc (1:1) to remove unreacted 3-(bromomethyl)-6-chloropyridazine and then EtOAc to give the title compound (0.84 g, 56%) as a white solid. APCI MS m/z 312.6 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.02 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 4.97 (d, J=13.2 Hz, 1H), 4.94 (d, J=13.2 Hz, 1H), 4.69 (dt, J=12.0, 2.6 Hz, 1H), 4.50 (d, J=12.1 Hz, 1H), 4.30-4.39 (m, 2H), 4.25 (dd, J=13.5, 3.3 Hz, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]([NH2:22])=O)=[CH:15][CH:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:20]([NH2:22])=[S:39])=[CH:15][CH:14]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Solvent: Cc1ccccc1
Product: NC(=S)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1

Procedure:
2.0 g (0.0052 mol) of the compound from Example II and 1.3 g (0.0031 mol) of Lawesson's reagent were heated at the boiling point with 15 ml of toluene under an argon atmosphere for 3 hours. The mixture was then separated by column chromatography (silica gel 60, toluene/tetrahydrofuran 100:5). A slightly yellowish product which could be recrystallised from diisopropyl ether was obtained (Rf =0.45).
Reaction SMILES: [F-:1].[K+].[N+]([C:6]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:7]=1[C:8]([NH:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9])([O-])=O.C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:6]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:7]=1[C:8]([NH:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9]
Reactant: C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)O
Temperature: 175 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A mixture of spray-dried KF (410 mg, 7.06 mmol), intermediate 11 (200 mg, 0.706 mmol) and catalytic amount of 18-crown-6 in dry DMSO (5 mL) was stirred at 170-180° C. for 30 min. Work-up of the reaction mixture as described in example 1 gave the product as a pale brown color solid (117 mg, 65%), mp 136-138° C. 1H NMR (400 MHz, DMSO-d6): 812.74 (1H, br s), 8.96 (1H, d, J=7.2 Hz), 8.21 (1H, d, J=9.6 Hz), 8.16 (1H, d, J=8.4 Hz), 7.82 (1H, t, J=7.6 Hz), 4.42 (1H, pentet, J=7.0 Hz), 1.38 (3H, d, J=7.2 Hz); LC-MS (negative ion mode): m/z 255 (M−H)−.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]12[CH2:17][CH:13]([CH2:14][CH2:15][CH2:16]1)[CH:12]1[CH2:18][CH:9]2[CH2:10][CH2:11]1)(O)=[O:6]>C1C=CC=CC=1>[Cl:3][C:5]([C:8]12[CH2:17][CH:13]([CH2:14][CH2:15][CH2:16]1)[CH:12]1[CH2:18][CH:9]2[CH2:10][CH2:11]1)=[O:6]
Reactant: O=C(O)C12CCCC(C1)C1CCC2C1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)C12CCCC(C1)C1CCC2C1
Yield: 92 %

Procedure:
68 ml of thionyl chloride was added dropwise to 46.0 g (0.24 mole) of 1-carboxytricyclo[4.3.1.12,5 ]undecane dissolved in 200 ml of benzene at room temperature. The resulting mixture was refluxed for 1.5 hours, and excess thionyl chloride and benzene were distilled off under reduced pressure. The residue obtained was fractionally distilled under reduced pressure to afford 47.0 g (yield: 92%) of 1-chlorocarbonyltricyclo[4.3.1.12,5 ]undecane having a boiling point of 101° C. (1 mmHg).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)(Cl)Cl>[CH2:28]([NH:34][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCN
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 71.3 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -11° C. and -12° C. during 20 minutes. After stirring for 5 minutes, 8.9 g (0.088 mol) of hexylamine dissolved in 80 ml of dried chloroform are dropped to the above solution at -12° C. during 35 minutes. The reaction mixture is stirred at the same temperature for 1 hour and then let to stand under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 16.4 g (71.3%) of the named product as yellow crystals after recrystallization from ethanol, m.p.: 116°-118° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[CH3:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])=[O:8]>O>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=1[C:7](=[O:8])[CH2:6][CH:2]([OH:3])[C:1]([OH:5])=[O:4]
Reactant: COc1ccc(OC)c(C(C)=O)c1
Reactant: O=CC(=O)O
Solvent: O
Product: COc1ccc(OC)c(C(=O)CC(O)C(=O)O)c1

Procedure:
22.2 g of glyoxylic acid, 50 wt.% in water, are heated under reduced pressure until about 80% of the water present has been eliminated; then, after cooling, 54 g of 2,5-dimethoxyacetophenone are added, i.e., an excess of 100% over theoretical.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)[NH2:2].[CH2:13]([CH2:15][CH2:16][CH2:17][C:18](CC([O-])=O)=[O:19])[CH3:14]>>[O:19]=[C:18]1[N:1]([C:3]2[CH:4]=[C:5]([S:9]([OH:12])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=2)[N:2]=[C:16]([CH2:15][CH2:13][CH3:14])[CH2:17]1
Reactant: CCCCCC(=O)CC(=O)[O-]
Reactant: NNc1cccc(S(=O)(=O)O)c1
Product: CCCC1=NN(c2cccc(S(=O)(=O)O)c2)C(=O)C1

Procedure:
From the reaction of 3-hydrazinobenzenesulfonic acid and ethylbutyrylacetate, 3-(4,5-Dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzenesulfonic acid is obtained. Subsequent reaction with 2-ethylaniline yields 3-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-y 1)-benzenesulfonic acid, Mp 258.6° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35](F)=[CH:34][CH:33]=2)[C:25]([O:27][CH2:28]C)=[O:26])=[CH:19][CH:18]=1.[Cl:39]C1C=CC=CC=1C=O>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccc(C)cc3)oc2C)cc1)NCc1ccc(F)cc1
Product: COC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1ccccc1Cl

Procedure:
In the same manner as in Example 7, 466.5 mg of the title compound was obtained as colorless oil from 609.3 mg of Referential Compound 3 and 230 μL of 2-chlorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10]Cl.[C-:12]#[N:13].[K+].COC(C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][C:12]#[N:13]
Reactant: [C-]#N
Reactant: Cc1cc(CCl)c(Cl)cc1Cl
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: Cc1cc(CC#N)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
To a solution of 1,5-dichloro-2-chloromethyl-4-methylbenzene (CAS #101349-87-5, 5.22 g) in dimethyl sulfoxide (20 ml) was added potassium cyanide (1.36 g) and the reaction solution was stirred at room temperature for 6 hours. Potassium cyanide (0.68 g) was added to the reaction solution and the solution was further stirred at room temperature overnight. To the reaction solution were added ice-cold water and tert-butyl methyl ether and the organic layer was separated. The water layer was re-extracted by the tert-butyl methyl ether. The combined organic layer was sequentially washed with water (twice) and brine. After drying over anhydrous magnesium sulfate, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: Walcogel™ C-200; elution solvent:heptane:ethyl acetate 49:1→19:1) to obtain the title compound (1.88 g). The property values of the obtained compound are as follows; 1H-NMR (CDCl3) δ (ppm): 2.38 (s, 3H), 3.78 (s, 2H), 7.38 (s, 1H), 7.43 (s, 1H).
Reaction SMILES: C([N:8]1[C@@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:20])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:20][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[NH:8]1
Reactant: CCCCC(=O)[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCC(=O)[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(ethyl propionyl)piperidine. (1.8 g, 6.01 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 75 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(ethyl propionyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occured. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 121.1-122.0° C.; 1H NMR (300 MHz) δ9.44 (s, 2H), 5.68 (m, 2H), 4.19 (s, 1H), 3.56 (s, 1H), 2.2-1.2 (m, 17H), 0.88 (t, 3H); 13C NMR (75 MHz) δ137.1 (s), 122.8 (s), 48.34 (s), 47.94 (s), 31.4 (s), 28.8 (s), 28.4 (s), 27.9 (s), 22.4 (s), 17.6 (s), 17.1 (s), 13.97 (s) ppm. FT-IR (neat): 3435, 3192, 2924, 1586, 1431, 1030, 673. Elemental Analysis. for C13H26NCl: C, 67.34%; H, 11.33%; N, 6.04%. Found: C, 67.44%; H, 11.23%; N, 5.98%.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[CH:9][C:10]1[S:14][CH:13]=[CH:12][CH:11]=1)=O)C.[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21](=[NH:23])[NH2:22])[CH3:17]>C(O)C>[CH2:16]([O:18][C:19]([C:20]1[CH:8]([CH2:9][C:10]2[S:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:19]([O:18][CH2:16][CH3:17])=[O:24])=[C:5]([CH3:4])[NH:23][C:21]=1[NH2:22])=[O:24])[CH3:17]
Reactant: CCOC(=O)CC(=N)N
Reactant: CCOC(=O)CC(=O)C=Cc1cccs1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1Cc1cccs1
Yield: 73 %

Procedure:
Upon heataing a solution of 12.2 g of (2-thenylidene)acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 4 hours, 2-amino-6-methyl-4-(2-thenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 170°C (ethanol) is obtained.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21]O.O>S(=O)(=O)(O)O.C1C=CC=CC=1>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][CH2:21][CH2:20][CH:19]([CH3:23])[CH3:18])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC(C)CCO
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(C)CCOC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Yield: 85.3 %

Procedure:
A mixture of 2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran-5-yl methanesulphonate (13g, 0.05 mole), 3-methyl-1-butanol (4.4g, 0.05 mole) and concentrated sulphuric acid (4 drops) in benzene (50 ml) was heated at reflux under a Dean and Stark trap until 0.9 ml water (0.05 mole) had been eliminated. The reaction mixture was cooled, washed with dilute aqueous sodium hydroxide solution and with water (twice) and dried over sodium sulphate. The benzene was then distilled off under reduced pressure to give 2,3-dihydro-3,3-dimethyl-2-(3-methylbutoxy)-5-benzofuranyl methanesulphonate as a yellow oil (14 g, 86% yield) which slowly solidified (melting point 35°-38° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.[CH3:10][NH:11][CH2:12][CH2:13][CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:10])[C:7](=[O:9])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOCC(=O)O
Reactant: CNCCCO
Product: COCCOCC(=O)N(C)CCCO

Procedure:
By using 1.4 mL of (2-methoxyethoxy)acetic acid and 1.0 g of 3-(methylamino)propan-1-ol as starting materials, the reaction similar to Preparation Example 16 was performed, thereby obtaining 2.19 g of N-(3-hydroxypropyl)-2-(2-methoxyethoxy)-N-methylacetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[N:14]=[N:15][C:16]([Cl:20])=[C:17](Cl)[N:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:12][C:13]1[N:14]=[N:15][C:16]([Cl:20])=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[N:18]=1
Reactant: Clc1nnc(Cl)c(Cl)n1
Reactant: CP(C)(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CP(C)(=O)c1ccc(Nc2nc(Cl)nnc2Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-amino-dimethylphenylphosphine oxide (1.6 mmol) and 3,5,6-trichloro-1,2,4-triazine (1.6 mmol) in CH2Cl2, is added triethylamine (2 mmol). The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:21]3[O:22]C(=O)[CH:24]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[N:25]=3)[CH:12]=[N:13][C:14]=2[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:6][C:7]=1[Cl:8]>O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([O:15][CH2:16][C:17]([F:19])([F:20])[F:18])=[N:13][CH:12]=[C:11]([CH:10]=2)[C:21]([NH:25][CH2:24][C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])=[O:22])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1OC(c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)c(Cl)c3)c2)=NC1C(=O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCC(=O)C(F)(F)F)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Yield: 56.3 %

Procedure:
A suspension of 3.00 g 2-[5-(3,4-dichloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-4-(2,2,2-trifluoro-acetyl)-4H-oxazol-5-one in 15 ml water and 15 ml dioxan was heated to reflux for 1 h. The resulting slightly turbid solution was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=9:1 to 1:1. The product fractions were concentrated and the residue was taken up in dichloromethane whereby crystallization occurred. The solid was collected by filtration and washed with little dichloromethane to yield 1.60 g of the title compound as white solid. m.p.: 122-124° C. MS (EI): 474 (M+).