Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH:10]([C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[NH2:11]>CO.C(O)(=O)C>[NH:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[NH:10][N:11]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: NNc1nc2ccccc2[nH]1
Reactant: CC(=O)c1ccccn1
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NNc1nc2ccccc2[nH]1)c1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-acetyl pyridine (1.00 g, 8.25 mmol) and 2-hydrazinobenzimidazole (1.22 g, 8.25 mmol) in 20 ml of methanol is stirred for 3 days at room temperature after addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored in the refrigerator at approximately 5° C. for 24 hours. The precipitate is filtered, washed several times with 50% methanol, and dried. The product is recrystallized from a mixture of ethyl acetate and diisopropyl ether. Yield: 1.45 g (70% of theory).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[NH2:39][CH2:40][CH2:41][C:42]([CH3:45])([OH:44])[CH3:43].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:39][CH2:40][CH2:41][C:42]([OH:44])([CH3:45])[CH3:43])=[O:5]
Reactant: CC(C)(O)CCN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 27.1 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.046 mL, 0.417 mmol), 4-amino-2-methylbutan-2-ol (12.92 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention time=34.1 min) to give (R/S)-2-hydroxy-N-(3-hydroxy-3-methylbutyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (10.5 mg, 0.019 mmol, 26.9% yield): LCMS=517 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.23 (2 H, m), 7.65-7.77 (4 H, m), 7.54-7.66 (3 H, m), 5.10 (1 H, s), 3.32-3.42 (2 H, m), 1.62-1.78 (2 H, m), 1.22 (6 H, s). HPLC Peak RT=9.2 min (Analytical Method A).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:12]([CH3:13])[CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:13][CH:12]1[CH2:11][CH:10]([C:14]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:16])[CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: NCc1ccccc1
Reactant: CC1CC(C(=O)O)CN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CC(C(=O)NCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 135.9 %

Procedure:
To a solution of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-5-methyl-3-pyrrolidinecarboxylic acid (0.9 g, 3.93 mmol) in CH2Cl2 (15 mL) at room temperature was added Hunig's base (0.89 mL, 5.10 mmol, 1.3 equiv) and benzylamine (0.56 mL, 5.10 mmol, 1.3 equiv) in one portion. The resulting mixture was chilled in an ice bath, followed by addition of HATU (1.64 g, 4.32 mmol, 1.1 equiv) in one portion, and the reaction mixture was stirred in the ice bath for 30 minutes. The mixture was filtered through celite, and rinsed with CH2Cl2. The filtrate was washed with water and dried over Na2SO4, followed by filtration and concentration in vacuo. The resulting residue was purified by silica gel column chromatography resulting in 1.70 g of the title compound as an oil. The ratio of cis/trans isomers could not be determined. LC-MS (ES) m/z=319 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH:4](O)[C:5]([CH3:8])([CH3:7])[CH3:6])[CH3:3].[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1.C([O:18]CC)C>C1C=CC=CC=1>[C:13]([O:14][CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][N:2]([CH3:3])[CH3:1])(=[O:18])[CH2:12][C:11]([CH3:10])=[O:15]
Reactant: C=C1CC(=O)O1
Reactant: CCOCC
Reactant: CN(C)C(O)C(C)(C)C
Solvent: c1ccccc1
Product: CC(=O)CC(=O)OCC(C)(C)CN(C)C
Temperature: 70 °C

Procedure:
To a solution of 1.71 g of 3-(N,N-dimethylamino-2,2-dimethylpropanol (Reference: M. S. Newman et al; Journal of Medicinal chemistry, vol 15, p1003 (1972)) in 2 ml of benzene was added dropwise 1.16 g of diketene with stirring at 70° C. The mixture was stirred at 70° C. for additional 1.5 hr. Solvent was distilled off in cacuo to leave a yellowish oil. The residue was dissolved in diethyl ether and then extracted with an aqueous 2N-hydrochloric acid solution. The extracts were made alkaline with an aqueous 2N sodium hydroxide solution. The mixture was extracted with diethyl ether and then the ethereal extract was washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give 2.8 g of 3-(N,N-dimethylamino)-2,2-dimethylpropyl acetoacetate can oily substance. The physical properties of this compound are as follows.
Reaction SMILES: [N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:7])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:48]1[C:60]2[CH:59]([CH2:61][O:62][C:63](=[O:93])[NH:64][C@H:65]3[CH2:69][C@@H:68]([C:70](=[O:82])[NH:71][C@H:72]4[C:81]5[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=5)[CH2:75][CH2:74][CH2:73]4)[N:67]([C:83](=[O:92])[C@@H:84]([NH2:91])[CH:85]4[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]4)[CH2:66]3)[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:52]=2[CH:51]=[CH:50][CH:49]=1>CN(C=O)C.C(OCC)(=O)C>[CH:48]1[C:60]2[CH:59]([CH2:61][O:62][C:63](=[O:93])[NH:64][C@H:65]3[CH2:69][C@@H:68]([C:70](=[O:82])[NH:71][C@H:72]4[C:81]5[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=5)[CH2:75][CH2:74][CH2:73]4)[N:67]([C:83](=[O:92])[C@@H:84]([NH:91][C:4](=[O:6])[C@@H:2]([N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:7])[CH3:3])[CH:85]4[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]4)[CH2:66]3)[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:52]=2[CH:51]=[CH:50][CH:49]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Boc-N-Me-Ala-OH (2.55 g, 12.57 mmol) in DMF (30 mL) were added HATU (4.78 g, 12.57 mmol) and DIPEA (9.9 mL, 57.16 mmol). After 30 min, the mixture was cooled to 0° C. and {(3S,5S)-1-((S)-2-amino-2-cyclohexyl-acetyl)-5-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-pyrrolidin-3-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester (Intermediate 24) (7.5 g, 11.43 mmol) in DMF (50 mL) and the cooling bath removed. After 4 h the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography to afford the title compound as an off white solid (5.32 g) LC-MS: 806 (M+H).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[C@H:2]([C:7](O)=O)CC(=O)O.CO[C:29]1C=CC(CC[NH-])=C[CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1.N[C@H:54]([C:59](O)=O)[CH2:55][C:56](=[O:58])[OH:57]>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:10]([NH:1][CH2:2][CH2:7][CH2:29][CH2:30][CH2:59][CH2:54][CH2:55][C:56]([OH:57])=[O:58])([O:12][CH2:13][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:11]
Reactant: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: COc1ccc(CC[NH-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
Fmoc-Asp-2-(4-methoxyphenyl)ethyl amide from B (8 mmoles) was coupled with Sasrin resin (7 g; 0.7 mmole OH/g resin) in N,N-dimethylformamide (DMF) (50 ml) with dicyclohexylcarbodiimide (8 mmoles) and 4-dimethylamino-pyridine (0.5 g). The reaction was carried out overnight after which the resin was washed with DMF (5 x 40 ml) and CH2Cl2 (2 x 20 ml). The substitution was found to be 0.326 mmole Asp/g resin by amino acid analysis.
Reaction SMILES: [H-].[Na+].[NH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]#[N:5].Cl[CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>C1C=CC=CC=1.CN(C)C=O>[C:28]([O:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19][CH2:18][N:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]#[N:5])(=[O:30])[CH3:29]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: CCOC(=O)CCCCCCNC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC(CCCN(C#N)CCCCCCC(=O)OCC)OC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (57%, in mineral oil) (0.48 g., 0.01 mole) is washed twice with benzene then suspended in benzene (50 ml.) and dimethylformamide (50 ml.). Ethyl 7-cyanamidoheptanoate (1.98 g. 0.01 mole) (Example N, Step 2) is added and the suspension heated on the steam bath for 15 minutes. The reaction mixture is cooled to room temperature, 1-chloro-4-acetoxynonane (2.6 g., 0.01 mole) (Example A, Step 3) is added and then the reaction is heated on the steam bath for 2 hours then stirred 18 hours at room temperature. The reaction is poured into water (300 ml.) and extracted with benzene (3 × 100 ml.). The benzene is washed with brine then dried over sodium sulfate. Removal of the solvent yields an oil which is purified by silica gel chromatography, elution solvent 3% methanol in chloroform, evaporation of the appropriate fraction affords ethyl 7-[N-(4-acetoxynonyl) cyanamido]-heptanoate. The yield is 3.2 g. (83 %).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[O:22][CH3:21])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1C(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 77.7 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (660 mg, 2.4 mmol) and 2-methoxybenzoyl chloride (0.7 mL, 4.7 mmol) in THF (20 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methoxy-benzamide as a white solid (760 mg, 78% yield): mp, 286-287° C.; 1H NMR (DMSO-d6) (at 340 K) δ 2.09-2.14 (m, 1H, CHH), 2.55-2.66 (m, 2H, CH2), 2.85-2.98 (m, 1H, CHH), 4.14 (s, 3H, OCH3), 5.19 (dd, J=5.5, 12.9 Hz, 1H, NCH), 7.17 (t, J=7.2 Hz, 1H, Ar), 7.30 (d, J=8.3 Hz, 1H, Ar), 7.61-7.68 (m, 2H, Ar), 7.89 (t, J=7.7 Hz, 1H, Ar), 8.12 (dd, J=1.8, 7.9 Hz, 1H Ar), 9.03 (d, J=8.5 Hz, 1H, Ar), 11.17 (s, 1H, NH), 11.64 (s, 1H, NH); 13C NMR (DMSO-d6) (at 340 K) δ 22.09, 31.02, 49.29, 56.19, 112.65, 116.31, 117.93, 120.66, 121.14, 125.52, 131.59, 131.75, 134.34, 136.22, 137.00, 157.64, 163.82, 166.69, 168.15, 169.43, 172.32; Anal Calcd for C21H17N3O6: C, 61.92; H, 4.21; N, 10.31. Found: C, 62.05; H, 4.10; N, 10.38.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:5]([C:4]1[C:3]([F:10])=[C:2]([NH:1][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#Cc1cccc(N)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)OCc2ccccc2)c1F
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a light brown solution of 3-amino-2-fluorobenzonitrile (2.7141 g, 19.94 mmol) and potassium carbonate (4.13 g, 29.9 mmol) in THF (166 mL) was syringed benzyl carbonochloridate (4.49 mL, 29.9 mmol) under nitrogen, and the reaction was stirred overnight. The insoluble material was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with 1 N aqueous HCl (50 mL), water (50 mL) and brine (50 mL), successively. The organic solution was dried over MgSO4 and concentrated in vacuo to give crude product which was stirred in hexanes (75 mL) for 1 hr. The insoluble material was filtered and washed with hexanes to give the desired product (4.4541 g, 16.48 mmol, 83% yield) as a light tan solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[Cl:16][C:17]1[C:18]([NH2:24])=[N:19][C:20]([NH2:23])=[CH:21][N:22]=1>ClCCl.CN(C)C=O.N1C=CC=CC=1>[NH2:24][C:18]1[N:19]=[C:20]([NH:23][C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[CH3:7])=[O:15])[CH:21]=[N:22][C:17]=1[Cl:16]
Reactant: Cc1oncc1C(=O)O
Reactant: Nc1cnc(Cl)c(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1oncc1C(=O)Nc1cnc(Cl)c(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.9 %

Procedure:
Oxalyl chloride (0.8 ml, 10.3 mmol) was added to a solution of 5-Methyl-isoxazole-4-carboxylic acid (1 g, 6.9 mmol) in dichloromethane (30 ml) followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 5 hours before concentrating in vacuo and azeotroping with dichloromethane. The residue was taken up in pyridine (3 ml) and added to a solution of 3-chloro-pyrazine-2,6-diamine (Preparation 1) (0.65 g, 4.6 mmol) in anhydrous pyridine (30 ml) and the mixture heated at 50° C. for 3 hours before cooling to room temperature and concentrating in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate:heptane 1:1, to afford the product as a white solid (360 mg).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:17][C:18]1[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=1[CH:20]=[N+:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:20]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[CH3:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: Cc1ccccc1C=[N+]1CCCC1
Agent: [Cl-]
Product: Cc1ccccc1C(c1c(-c2ccccc2)[nH]c2ccccc12)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-phenyl-1H-indole and 1-(2-methyl-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:22](CC3CC3)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1.F[C:31](F)(F)C(O)=O.ClC1C=CC(N[C:45](=O)[C:46]2[CH:51]=CC=CC=2NC(C2CCNCC2)=O)=NC=1.C1(C=O)CC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH:51]3[CH2:46][CH2:45]3)[CH:21]([CH3:31])[CH2:20]2)=[O:18])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)C1CCNCC1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)C1CCN(CC2CC2)CC1
Agent: O=CC1CC1
Product: CC1CC(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CCN1C1CC1

Procedure:
Using procedures substantially equivalent to those described in example 9-C, N-(5-chloropyridin-2-yl)-2-[(1-cyclopropylmethylpiperidin-4-ylcarbonyl)amino]benzamide (16 mg, 72%, 97% pure by HPLC analysis) was prepared from N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]-benzamide trifluoroacetate and cyclopropanecarboxaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH2:39])[CH2:37][CH3:38].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:39][CH2:36][CH2:37][CH3:38])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: CCCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1F
Yield: 70 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (100 mg) was dissolved in toluene (10 ml). and triethylamine (2 ml), and a solution of triphosgene (104 mg) in dichloromethane was then added to the solution. The mixture was heated under reflux for 5 min. Next, propylamine (29 mg) was added, and the mixture was heated under reflux for 40 min. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with chloroform/methanol (10/1) to give 89 mg (yield 71%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:26]([O:28][C:29](=[O:50])[CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:27]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:26]([O:28][C:29](=[O:50])[CH:30]=[C:20]1[CH2:19][CH2:18][CH:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:25])([F:1])[F:24])[CH:4]=3)[CH2:14][CH2:13]2)[CH2:22][CH2:21]1)[CH3:27]
Reactant: O=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Yield: 44.7 %

Procedure:
A mixture of 2.77 g (7.8 mmol) of 4-{2-[4-(3-trifluoromethyl-phenyl)piperazin-1-yl]ethyl}cyclohexanone (example 1, path 11, step b) and 3.13 g (9.0 mmol) of (triphenyl-λ5-phosphanylidene)acetic acid ethyl ester in 40 mL of toluene is refluxed overnight. After concentration of toluene, the residue is taken off in diethyl ether and the solid is filtered. The filtrate is concentrated and purified over 150 g of silica gel (eluant dichloromethane/heptane 98/2) to give 1.48 g (45%) of (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[C:4]([C:17]2[C:18]3[CH:27]=[CH:26][NH:25][C:19]=3[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[CH:3]=1.C(N(CC)CC)C.[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36].[OH-:41].[Na+].[Cl-].[NH4+]>ClCCl.O1CCOCC1>[CH2:35]([S:37]([NH:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH2:12])=[O:41])=[CH:13][CH:14]=2)=[C:4]([C:17]2[C:18]3[CH:27]=[CH:26][NH:25][C:19]=3[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[CH:3]=1)(=[O:39])=[O:38])[CH3:36]
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccc(C#N)cc2)c2cc[nH]c2c1=O
Reactant: CCS(=O)(=O)Cl
Reactant: [OH-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(C(N)=O)cc2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a mixture of Example 33b (50 mg, 0.14 mmol) and triethylamine (0.043 g, 0.42 mmol) in dichloromethane (4 mL) was added dropwise ethanesulfonyl chloride (0.072 g, 0.56 mmol), and the reaction mixture stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dioxane (4 mL) and sodium hydroxide (10% w/v, 3 mL, 0.14 mmol) were added, and the reaction mixture was heated at 70° C. for 1 hour. The mixture was cooled to ambient temperature and then neutralized with saturated aqueous ammonium chloride (50 mL) to a pH of 7. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered, and concentrated. The residue was purified by preparative HPLC (C18, 10-100% acetonitrile/water, 0.1% TFA) to afford the title compound (22 mg, 35%). 1H NMR (300 MHz, DMSO-d6) ppm 12.01 (s, 1H) 9.86 (s, 1H) 7.77 (s, 1H) 7.74 (d, J=8.82 Hz, 2H) 7.42 (d, J=2.37 Hz, 1H) 7.22-7.30 (m, 3H) 7.18 (s, 1H) 7.11-7.16 (m, 1H) 6.83 (d, J=8.82 Hz, 2H) 6.23-6.28 (m, 1H) 3.47 (s, 3H) 3.15 (q, J=7.35 Hz, 2H) 1.21-1.29 (m, 3H). MS (ESI+) m/z 467.2 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].Cl>O.C(OCC)(=O)C.CN(C)C=O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 74.5 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 200 ml were charged 6.51 g (47.2 mmol) of potassium carbonate, 20 ml of N,N-dimethylformamide, 6.24 g (46.7 mmol) of dimethyl malonate with a purity of 99% and 5.00 g (30.8 mmol) of 2,4-difluoronitrobenzene with a purity of 98% under argon atmosphere, and under stirring, the mixture was reacted at room temperature for one hour and further by raising to 70° C. for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, 100 ml of ethyl acetate was added to the mixture, and 10.5 ml (62.8 mmol) of 6 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, after adding 50 ml of water to the reaction mixture, the organic layer was separated, and washed successively with 20 ml of water and 20 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: hexane:ethyl acetate=9:1(volume ratio)) to obtain 6.22 g (isolation yield: 73%) of dimethyl 2-(5-fluoro-2-nitro-phenyl)malonate as white crystals with a purity of 98% (areal percentage by high performance liquid chromatography).