Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([OH:18])[C@H:14]2[C:19](O)=[O:20])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1CCC(N=C=NC2CCCCC2)CC1.C1C([N+]([O-])=O)=CC=C(O)C=1>C(#N)C>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:10]2[C:19](=[O:20])[C@@H:14]3[C@@H:15]([OH:18])[CH2:16][CH2:17][N:13]3[C:11]2=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(NC(=O)N2CC[C@H](O)[C@H]2C(=O)O)ccc(C#N)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC#N
Product: Cc1c(N2C(=O)[C@@H]3[C@@H](O)CCN3C2=O)ccc(C#N)c1Cl
Temperature: 25 °C
Yield: 61 %

Procedure:
To a suspension of acid 54B (210 mg, 0.649 mmol) in 15 mL of acetonitrile at rt was added DCC (134 mg, 0.649 mmol) followed by p-nitrophenol (180 mg, 1.30 mmol). The suspension was refluxed for 1 h, cooled to rt and filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/hexanes, 75:25) to afford the title compound (121 mg) as a white foam. 1H NMR (CD3OD) 1.94-2.05 (m, 1H), 2.18, 2.22 (s, 3H), 2.24-2.33 (m, 1H), 3.34-3.40 (m, 1H), 3.67-3.75 (m, 1H), 4.08, 4.16 (d, J=6.05, 1H), 4.35, 4.42 (m, 1H), 7.33, 7.38 (d, J=8.25, 1H), 7.70 (m, 1H); 13C NMR (CD3OD) 15.90, 16.11, 36.95, 37.05, 44.88, 45.06, 70.91, 70.94, 72.46, 72.90, 115.19, 115.53, 116.60, 116.66, 129.30, 129.46, 132.74, 133.03, 137.41, 137.61, 138.08, 138.37, 138.42, 138.53, 159.69, 159.97, 172.10, 172.43; HPLC a) column: Phenomenex LUNA C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 2.32 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.15 min retention time (100%); HPLC c) column: Daicel Chiralcel OD 4.6×250 mm, Isocratic 25% Isopropanol/Hexanes, 30 min, 1 mL/min, UV detection at 220 nm, 17.65 min retention time (99%); MS (ES) m/z 306 [M+H]+.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[C:4]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[N:13][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:16]=1I)([CH3:7])([CH3:6])[CH3:5].C(OCC)(=O)C.[Cl-].[NH4+]>CN(C=O)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:4]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[N:13][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:16]=1[C:1]#[C:2][CH3:3])([CH3:7])([CH3:6])[CH3:5]
Reactant: C#CC
Reactant: CC(C)(C)OC(=O)Nc1cnc(-c2ccccc2)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC#Cc1cc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Propyne (0.60 mL, 11.4 mmol) was condensed in a pressure tube at −78° C. A solution of (4-iodo-6-phenylpyridin-3-yl)carbamic acid tert-butyl ester (900 mg, 2.27 mmol) in 2 mL of DMF, 6 mL of triethylamine, dichlorobis(triphenylphosphine)palladium (II) (80.2 mg, 0.114 mmol), and CuI (43.0 mg, 0.227 mmol) were added, the tube was sealed, and the mixture was stirred at room temperature overnight. The mixture was cooled to −78° C., the sealed tube was opened, and 20 mL of ethyl acetate and 10 mL of saturated aqueous ammonium chloride solution were added. The phases were separated and the aqueous layer was extracted with three 10 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified on SiO2 (0 to 40% ethyl acetate in hexanes, gradient) to give 670 mg of (6-phenyl-4-prop-1-ynylpyridin-3-yl)carbamic acid tert-butyl ester (96% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:32])[C:17]([C:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:34][C:35]#[N:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH3:32])[C:17]([C:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:34][C:35]#[N:36]
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(O)c(Br)c2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(OCC#N)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 95.5 %

Procedure:
A mixture N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-N-methyl-1-benzofuran-3-carboxamide (1.60 g, 3.25 mmol), prepared in the previous step, bromoacetonitrile (272 μL, 3.90 mmol) and potassium carbonate (2.25 g, 16.3 mmol) in 25 mL of DMF was stirred under nitrogen at room temperature for 23 h. The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-2-butyl-N-methyl-1-benzofuran-3-carboxamide (1.65 g, 95%) as a brown foam, MS (ESI) m/z 531 [M+H]+. Elemental Analysis for C29H27BrN2O3. Calc'd: C, 65.54; H, 5.12; N, 5.27. Found: C, 65.37; H, 5.14; N, 5.21.
Reaction SMILES: [CH2:1](B(O)O)[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[C:15]1[CH:33]=[CH:32][C:18]2[N:19]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[C:28]([O:30][CH3:31])=[O:29])[O:21][C:17]=2[CH:16]=1.O1CCCC1>C1(C)C=CC=CC=1>[CH2:1]([C:15]1[CH:33]=[CH:32][C:18]2[N:19]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[C:28]([O:30][CH3:31])=[O:29])[O:21][C:17]=2[CH:16]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CB(O)O
Reactant: COC(=O)[C@@H]1CCCCN1c1nc2ccc(Br)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCCN1c1nc2ccc(CC(C)C)cc2o1
Temperature: 80 °C
Yield: 13.6 %

Procedure:
Isobutyl boronic acid (475 mg), potassium carbonate (644 mg) and tetrakis triphenylphosphine palladium (269 mg) were added sequentially to a solution of methyl (2S)-1-(6-bromo-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (790 mg) [see Preparation 40] in toluene:tetrahydrofuran, 60:40 by volume, (20 ml) under nitrogen. The reaction mixture was then heated to 80° C. for 20 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between water and dichloromethane. The organic layer was separated and washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 80:20, by volume, hexane:ethyl acetate to afford methyl (2S)-1-(6-isobutyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (100 mg) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:13][CH2:14]1)=[O:21])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.75 g (5.84 mmol) trans-[4-(5-Hydroxy pentyl)-cyclohexyl)-methyl-carbamic acid tert-butyl ester and 0.5 ml (6.42 mmol) of methanesulfonyl chloride in 20 ml CH2Cl2 was added, under cooling with an ice bath, 1.56 ml (11.7 mmol) of Et3N. The mixture was stirred for 3 h at RT. The reaction-mixture was then partitioned between ether/1N HCl and water. The ether-solution was concentrated in vacuo to yield 2.12 g (96%) of clean trans-Methansulfonic acid 5[-4-(tert-butoxy carbonyl-methyl-amino)-cyclohexyl)-pentylester.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][NH2:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:24][NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(NCc3ccc(Cl)c(Cl)c3)c2cc1OCC

Procedure:
In the manner of Example 61 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3,4-dichlorobenzylamine gave the tide compound as a tan solid, mp 163-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CN(C)C=O.[N+:14]([C:17]1[O:21][C:20]([CH:22]=[CH:23][C:24]2[N:33]=[C:32](Cl)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>O>[N+:14]([C:17]1[O:21][C:20]([CH:22]=[CH:23][C:24]2[N:33]=[C:32]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc(Cl)c3ccccc3n2)o1
Reactant: Nc1ccccc1O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Nc3ccccc3O)c3ccccc3n2)o1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
An Erlenmeyer flask equipped with magnetic stirrer and oil bath for heating was charged with 5.0 g (0.046 mole) of o-aminophenol and 100 ml of dimethylformamide. The charge was stirred to dissolve o-aminophenol and 6.0 g (0.02 mole) of 2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline (IV) added. The reaction mixture was reacted at 80° to 90°C for 2 hours to form an orange precipitate; 100 ml of water was added to the warm mixture which was then allowed to cool and placed overnight in a refrigerator to crystallize. The solids were collected, washed with methanol and dried to obtain 7.5 g of brown-tan solid which melted 224°-6°C with decomposition. A solution of the product in 100 ml of dimethylformamide was treated with activated carbon and filtered. A first portion of 75 ml of methanol was added to the warm filtrate then an additional 25 ml portion. Cooling and scratching gave 5.5 g of orange crystals of the purified product which melted at 230°-1°C with decomposition.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[O:8][CH2:9][C:10]3[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=3[CH:12]([C:13](O)=[O:14])[C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23]>>[CH:32]([C:28]1[CH:29]=[CH:30][CH:31]=[C:25]([CH:22]([CH3:24])[CH3:23])[C:26]=1[NH:27][C:13]([CH:12]1[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[CH2:9][O:8][C:7]2[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]1=2)=[O:14])([CH3:34])[CH3:33]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)C1c2ccccc2COc2ccc([N+](=O)[O-])cc21
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1c2ccccc2COc2ccc([N+](=O)[O-])cc21
Yield: 45.3 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.18 g of 6,11-dihydro-2-nitrodibenz[b,e]oxepin-11-carboxylic acid obtained in Example 62 (Compound AA) in place of Compound A and 0.73 g of 2,6-diisopropylaniline in place of aniline to obtain 0.83 g of Compound 46.
Reaction SMILES: C1(CC2CCCC[N:9]2[CH2:14][CH:15]([C:17]2C=CC=C(Br)C=2)[CH3:16])CCCCC1.[CH2:24]([Li])[CH2:25][CH2:26][CH3:27]>C(OCC)C>[CH3:27][C:26]1[CH:16]=[C:15]([CH:17]=[CH:24][CH:25]=1)[C:14]#[N:9]
Reactant: [Li]CCCC
Reactant: CC(CN1CCCCC1CC1CCCCC1)c1cccc(Br)c1
Solvent: CCOCC
Product: Cc1cccc(C#N)c1
Yield: 212 %

Procedure:
Following a procedure similar to that described in Example 7, 18.9 g. (0.05 mole) of 2cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was reacted with 0.095 mole of n-butyl lithium in diethyl ether and the resulting lithio derivative reacted directly with 12.4 g. (0.106 mole) of 3-methylbenzonitrile to give 10.7 g. of 2-cyclohexylmethyl-1-{2-[3-(3-methylbenzoyl)phenyl]propyl}piperidine as a yellow oil.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][CH:9]([C:14](=O)[CH3:15])[C:10](OC)=[O:11])=[CH:6][CH:5]=1)#[N:2].C(=O)(O)O.[NH2:23][C:24]([NH2:26])=[NH:25].C(O)(=O)C>CO.O>[NH2:26][C:24]1[N:25]=[C:10]([OH:11])[C:9]([CH2:8][C:7]2[CH:17]=[CH:18][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=2)=[C:14]([CH3:15])[N:23]=1
Reactant: COC(=O)C(Cc1ccc(CC#N)cc1)C(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(N)nc(O)c1Cc1ccc(CC#N)cc1
Temperature: 30 °C

Procedure:
A stirred mixture of the crude product from step (i) and guanidine carbonate (36.7 g, 0.20 mol) in methanol (389 g) was heated under reflux for 7 hours. The mixture was cooled to 30° C., diluted with water (222 g), and the pH of the solution was adjusted to pH 6.5 with acetic acid. After the mixture was cooled to 5° C., the resulting precipitate was collected by filtration, washed with methanol twice (167 g, 333 g), and dried under reduced pressure to give the subtitle compound as a solid, 32.6 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][C:12]([CH:17]([CH3:19])[CH3:18])=[C:13]([CH2:15][OH:16])[N:14]=1)=[O:8]>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][C:12]([CH:17]([CH3:19])[CH3:18])=[C:13]([CH:15]=[O:16])[N:14]=1)=[O:8]
Reactant: CC(C)c1sc(NC(=O)NCc2cccc(F)c2)nc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)c1sc(NC(=O)NCc2cccc(F)c2)nc1C=O

Procedure:
1-(3-Fluorobenzyl)-3-(4-(hydroxymethyl)-5-isopropylthiazol-2-yl)urea (32 mg, 0.1 mmol) was oxidized with MnO2 (87 mg, 1.0 mmol) in CH2Cl2 (5 mL). Filtration and evaporation afforded 1-(3-fluorobenzyl)-3-(4-formyl-5-isopropylthiazol-2-yl)urea. 1H NMR (400 MHz, CDCl3): δ 9.83 (s, 1H), 7.60 (s, 1H, br), 7.27 (m, 1H), 7.12 (d, 1H), 7.06 (d, 1H), 6.93 (td, 1H), 4.48 (d, 2H), 3.80 (m, 1H), 1.42 (d, 6H). MS (ES+): M/Z 322 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[NH:29][CH2:30][C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=3[CH3:21])[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cc1cccc(NCc2nnn(C)n2)c1C
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2cccc(C)c2C)[C@H]1O
Yield: 47 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (300 mg, 1.07 mmol) obtained in step 1 of example 2 and N-(2,3-dimethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (253 mg, yield: 47%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C=O>>[C:1]1([C:7]2[CH:11]=[C:10]([C:12](=[O:17])[CH:13]([CH2:24][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:14]([CH3:15])[CH3:16])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: CC(C)CC(=O)c1cc(-c2ccccc2)no1
Agent: C=O
Agent: Cl
Product: CC(C)C(CN1CCCC1)C(=O)c1cc(-c2ccccc2)no1

Procedure:
From 1.5 g (6.6 mmol) of 3-phenyl-5-(3-methyl-butyryl)isoxazole prepared above in the procedure (2), 0.84 g (7.9 mmol) of piperidine hydrochloride, and 0.26 g (8.7 mmol) of paraformaldehyde, the free base of 3-phenyl-5-{2-(1-pyrrolidinylmethyl)-3-methylbutyryl}-isoxazole was obtained as crystals in a manner similar to Example 28. Analytical results of the crystals obtained: Yield: 0.7 g (34.3%). Melting point: 77°-79° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16]Br)[CH:3]=1.C(N(CC)CC)C.Cl.[C:26]([O:30][C:31](=[O:34])[CH2:32][NH2:33])([CH3:29])([CH3:28])[CH3:27]>C(#N)C>[C:26]([O:30][C:31](=[O:34])[CH2:32][NH:33][CH2:16][C:4]1[CH:3]=[C:2]([Br:1])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1nc2cc(Br)cc(CNCC(=O)OC(C)(C)C)c2nc1OC

Procedure:
850 mg (2.35 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxy-quinoxaline, 0.982 ml of triethylamine and 719 mg of glycine tert-butyl ester hydrochloride are dissolved in 15 ml of acetonitrile and the solution is stirred at reflux for 18 hours. The mixture is concentrated by evaporation and the residue is dissolved in diethyl ether and washed with aqueous 5% sodium carbonate solution and brine. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate and petroleum ether (1:2). The title compound is obtained in the form of a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(CCCC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Solvent: C1COCCO1
Product: O=C(CCCC1CCN(Cc2ccccc2)CC1)c1ccc(N2CCCC2)cc1
Temperature: 100 °C

Procedure:
To a solution of the 1-benzyl-4-[3-(4-fluorobenzoyl)propyl]piperidine (0.6 g) synthesized in 4) in dioxane (1 ml) was added 3 ml of pyrrolidine and the mixture was heated at 100° C. for 16 hours. Thereafter, the procedure of Example 37 was repeated to give 0.58 g of 1-benzyl-4-[3-(4-pyrrolidinobenzoyl]propyl]piperidine as colorless crystals melting at 115°-116° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[N:8]=1.[OH-].[Na+].CC(O)=O>O>[F:24][C:2]([F:1])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[N:8]=1
Reactant: CCOC(=O)CCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NC(=NCC(F)(F)F)Nc1ccnc(SCCCC(=O)O)n1
Yield: 78.9 %

Procedure:
A mixture of ethyl 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyrate (1.03 g.) and a solution of sodium hydroxide (0.13 g.) in water (10 ml.) was heated under reflux for 1 hour and then cooled. The solution was acidified with glacial HOAc and the white solid which crystallised was collected to give 4-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylthio]butyric acid (0.75 g.), m.p. 234°-236°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[H][H]>[Ni].CCCCCC>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: [H][H]
Agent: [Ni]
Solvent: CCCCCC
Product: NCc1c(F)cccc1F
Yield: 94.6 %

Procedure:
To an autoclave of 1 l, 150 g of 2,6-difluorobenzonitrile, 150 g of hexane and 7.5 g of Ra—Ni were charged, replacement with hydrogen gas was carried out, and a reaction was carried out at a hydrogen pressure of from 30 to 40 kg/cm2 at a reaction temperature of 130° C. for 2.5 hours. After the completion of the reaction, the reaction mixture was subjected to filtration to separate off the catalyst, and hexane was recovered by distillation, followed by distillation under reduced pressure to obtain 146 g of 2,6-difluorobenzylamine (boiling point: 82° C./25 mmHg).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.CN1CCOCC1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:2][CH:3]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1ccc(N)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC(=O)Nc1ccc(N)cc1
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of 1,4-phenylenediamine (0.5 g, 4.62 mmol) in anhydrous CH2Cl2 (15 mL) was added NMM (0.51 mL, 4.62 mmol). To the resulting mixture was added dropwise butyryl chloride (0.45 mL, 4.62 mmol) in anhydrous CH2Cl2 (5 mL) at 0° C., and stirred for 0.5 h. The reaction mixture was extracted with CH2Cl2 (20 mL) and washed with H2O (20 mL). The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography over silica gel (EtOAc:hexane=1:3) to give N-(4-aminophenyl)butyramide (KYJ3-006-2, 0.31 g, 36%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:33][C:32](=O)[CH2:31][N:30]3[C:26](=[N:27][C:28]([CH2:35][O:36][CH3:37])=[N:29]3)[C:25]=2[CH:38]=1>C(#N)C.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:33]=[C:32]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH2:31][N:30]3[C:26]([C:25]=2[CH:38]=1)=[N:27][C:28]([CH2:35][O:36][CH3:37])=[N:29]3
Reactant: c1nc[nH]n1
Reactant: COCc1nc2n(n1)CC(=O)Nc1ccc(Cl)cc1-2
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COCc1nc2n(n1)CC(n1cncn1)=Nc1ccc(Cl)cc1-2
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
1,2,4-Triazole (74.3 g, 1.08 mol) was dissolved in acetonitrile (850 mL) and N,N-diisopropylethylamine (195 mL, 1.14 mol) was added. After cooling to 0° C. phosphorous oxychloride (29.8 mL, 326 mmol) was added dropwise and the reaction mixture was stirred at 0-5° C. for 2 h. 9-Chloro-2-methoxymethyl-6H-1,3,3a,6-tetraaza-benzo[e]azulen-5-one (45.4 g, 279 mmol) was added at once and the resulting suspension was heated to reflux for 20 h. After cooling to ambient temperature, water (1.30 L) was added and stirring was continued for another 30 min. The solid was filtered off and washed with water (300 mL) and diethylether (200 mL). Drying in vacuo (65° C.) afforded the title compound (33.8 g, 63%) which was obtained as an off-white solid. MS: m/e=330.1 [M+H]+.
Reaction SMILES: IC.[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([CH:18]=[C:19]2[N:23]([CH3:24])[C:22](=[S:25])[NH:21][C:20]2=[O:26])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])[CH3:5].[CH:27](N(C(C)C)CC)(C)C>C(O)C.O>[CH3:6][C:4]([C:7]1[CH:8]=[C:9]([CH:18]=[C:19]2[N:23]([CH3:24])[C:22]([S:25][CH3:27])=[N:21][C:20]2=[O:26])[CH:10]=[C:11]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:12]=1[OH:13])([CH3:3])[CH3:5]
Reactant: CN1C(=S)NC(=O)C1=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CI
Solvent: CCO
Product: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N1C
Temperature: 25 °C
Yield: 69.3 %

Procedure:
Iodomethane (1.2 mL, 19 mmols) is added to a stirred suspension of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1-methyl-2-thioxo-4-imidazolidinone (4.0 g, 12 mmols) and diisopropylethylamine (2.4 mL, 14 mmols) in ethanol (50 ml) and the mixture is stirred under an inert atmosphere at room temperature. After 18 hours the mixture is stirred in water (300 mL) for an hour and the product is filtered off, washed three times with water, and dried. Recrystallization from ethyl acetate gave the pure 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-1,5-dihydro-1-methyl-2-(methylthio)-4H-imidazol-4-one (3.0 g), mp 177°-179° C., retaining 0.25 equivalents of solvent of crystallization.