Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15](SC)[N:14]([CH2:20][CH2:21][CH2:22][OH:23])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]3[O:23][CH2:22][CH2:21][CH2:20][N:14]3[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nc2c(OCc3ccccc3)cccc2n1CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc3c2nc2n3CCCO2)cc1
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a solution of 4-benzyloxy-1-(3-hydroxypropyl)-2-methylthio-1H-benzimidazole (59 mg) in dimethylformamide (1 ml) was added sodium hydride at ambient temperature, and the mixture was stirred overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, v/v) and pulverized with diisopropyl ether to give 9-benzyloxy-3,4-dihydro-2H-[1,3]oxazino-[3,2-a]benzimidazole (43 mg).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:21][C:22]([F:38])([F:37])[CH2:23][NH:24][C:25](=O)[O:26]C1C=CC([N+]([O-])=O)=CC=1>CC#N>[F:21][C:22]([F:38])([F:37])[CH2:23][NH:24][C:25]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:26]
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(NCC(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=C(NCC(F)(F)F)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (150 mg, 541 μmol, Example 87, Step 3) in MeCN (2 mL) was added 4-nitrophenyl 2,2,2-trifluoroethylcarbamate (286 mg, 1082 μmol). The resulting mixture was then subjected to a microwave irradiation at 100° C. for 15 min. Then, the solvent was removed and the residue was dissolved in a solution of DMSO and MeOH (1:1, 2 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was then dissolved in MeOH (2.0 mL). The solution was then washed through PL-HCO3 MP-resin and the resin was then washed with MeOH (2×2 mL). The combined washings were concentrated and dried under vacuum to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 403 (M+H).
Reaction SMILES: [N:1]1[C:2](=[O:9])[NH:3]C(=O)C(=O)C=1.C(O[C:13]([C:15]1([C:39]([O:41]CC)=O)[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21]1[CH:22]=[N:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[O:35][CH:36]=[N:37][N:38]=3)=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)=[O:14])C.NC(N)=O>[O-]CC.[Na+].C(O)C>[O:35]1[CH:36]=[N:37][N:38]=[C:34]1[C:31]1[CH:30]=[CH:29][C:28]([O:27][C:24]2[N:23]=[CH:22][C:21]([N:16]3[C:15]4([C:39](=[O:41])[NH:3][C:2](=[O:9])[NH:1][C:13]4=[O:14])[CH2:19][CH2:18][C:17]3=[O:20])=[CH:26][CH:25]=2)=[CH:33][CH:32]=1
Reactant: O=C1N=CC(=O)C(=O)N1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1c1ccc(Oc2ccc(-c3nnco3)cc2)nc1
Agent: CC[O-]
Agent: NC(N)=O
Agent: [Na+]
Solvent: CCO
Product: O=C1NC(=O)C2(CCC(=O)N2c2ccc(Oc3ccc(-c4nnco4)cc3)nc2)C(=O)N1

Procedure:
Following the procedure for pyrimidinetrione formation outlined in Example 1, reaction of 1-[6-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-5-oxo-pyrrolidine-2,2-dicarboxylic acid diethyl ester (200 mg, 0.44 mmol) with urea (0.080 g, 1.3 mmol) in 1.3 mL of 1M sodium ethoxide in ethanol afforded 25 mg of 1-[6-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4,5]decane-2,6,8,10-tetraone as a colorless solid. 1H NMR (CD3OD, 500 MHz): 9.02 (s, 1H), 8.14 (d, 2H, J=8.0 Hz), 8.06 (d, 1H, J=2.0 Hz), 7.78 (dd, 1H, J=2.5, 9.0 Hz), 7.35 (d, 2H, J=9.0 Hz), 7.12 (d, 1H, J=9.0 Hz), 2.74 (m, 2H), 2.66 (m, 2H) ppm. MS (APCl, m/z): 435 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:5]=1[C:6]1[C:7]([CH2:18][CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=[CH:10][C:11]=1[NH:12]2.[CH3:27]I>CN(C)C=O>[CH3:3][C:4]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:5]=1[C:6]1[C:7]([CH2:18][CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=[CH:10][C:11]=1[N:12]2[CH3:27]
Reactant: CI
Reactant: CCCN(CCC)CCc1cccc2[nH]c3c(C)ccc(C)c3c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)CCc1cccc2c1c1c(C)ccc(C)c1n2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a Suspension of 0.25 ml of 60% sodium hydride (in an oil) in 5 ml of dry N,N-dimethylformamide was added dropwise a solution of 2 g of 5,8-dimethyl-4-(2-di-n-propylaminoethyl)carbazole in 10 ml of dry N,N-dimethyl-formamide, and the mixture was stirred for 30 minutes. To the mixture was added dropwise 1.0 g of methyl iodide, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and extracted with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was chromato-graphed on silica gel column with hexane - acetone (1 : 3) to give 5,8,9-trimethyl-4-(2-di-n-propylaminoethyl)-carbazole, to which a 4N hydrochloric acid - ethyl acetate solution was added. The formed crystals were collected by filtration to give 1.7 g of 5,8,9-trimethyl-4-(2-di-n-propylaminoethyl)carbazole hydrochloride.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:10][C:11]1[N:12]=[CH:13][N:14]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:15]=1
Reactant: N#Cc1ccccc1F
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccccc2C#N)cn1

Procedure:
As described for example 84a, 2-fluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup the title compound was obtained as a white solid (yield: 60%). MS: m/e=184.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:25])[C:17]4[CH:26]=[C:27](F)[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:38](C1C=C(OC)C=CC=1C1NC2C(C=1C1CCCCC1)=CC=C(C(OC(C)(C)C)=O)C=2)(=[O:40])C>>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:25])[C:17]4[CH:26]=[C:27]([O:40][CH3:38])[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2[nH]c3cc(C(=O)OC(C)(C)C)ccc3c2C2CCCCC2)c(C(C)=O)c1
Reactant: COC(=O)C1=C(C)c2cc(F)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Product: COC(=O)C1=C(C)c2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1

Procedure:
The title product 10-tert-butyl 6-methyl 13-cyclohexyl-3-methoxy-5-methyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate 16a was synthesized by following a similar procedure to that used for the synthesis of 10-tert-butyl 6-methyl 13-cyclohexyl-3-fluoro-5-methyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate 20a, using tert-butyl 2-(2-acetyl-4-methoxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate 37d instead of tert-butyl 2-(2-acetyl-4-fluorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate 33c.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:6]2[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][CH2:18][CH3:19])[N:10]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:10]=[C:5]([NH:2][NH2:3])[C:6]2[N:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:7]=2[N:8]=1)[CH3:19]
Reactant: NN
Reactant: CCSc1ccccc1-c1nc(Cl)c2ncc(C(F)(F)F)cc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccccc1-c1nc(NN)c2ncc(C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
41 μl of hydrazine monohydrate was added to a mixture of 263 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidine and 4 ml of THF, under ice cooling, and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and then concentrated under reduced pressure to obtain 246 m of [2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidin-4-yl]-hydrazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[C:10]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([Br:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: Cc1ccc(N)cc1Br
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C)c(Br)c1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a solution of 3-bromo-4-methylaniline (1.27 g, 6.82 mmol) in DCM (20 mL) at (0° C. is added acetic anhydride (0.676 mL, 7.16 mmol) dropwise. After 30 minutes, the mixture is partitioned between DCM and saturated sodium carbonate solution. The layer is separated and the aqueous layer is extracted with DCM. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound (1.55 g, 99%). The residue is used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]=[C:14]=[O:15])[C:10]([F:16])=[CH:9][C:8]=1[Cl:17])(=[O:5])=[O:4].[OH:18][C@H:19]1[CH2:24][CH2:23][NH:22][C@@H:21]([C:25](OC)=[O:26])[CH2:20]1>ClCCl>[Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:25](=[O:26])[CH:21]3[CH2:20][CH:19]([OH:18])[CH2:24][CH2:23][N:22]3[C:14]2=[O:15])[C:10]([F:16])=[CH:9][C:8]=1[Cl:17])(=[O:4])=[O:5]
Reactant: COC(=O)[C@H]1C[C@@H](O)CCN1
Reactant: O=C=Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: ClCCl
Product: O=C1C2CC(O)CCN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the title compound of Example 1, Step E (4.54 g, 15.2 mmol) in dichloromethane (20 mL) was added dropwise a solution of methyl cis-4-hydroxy-2-piperidinecarboxylate (2.41 g, 15.2 mmol, prepared as described in J. Org. Chem. (1991), 4084) in dichloromethane (20 mL) at room temperature. The reaction was stirred at room temperature for 20 hours, quenched by the addition of water, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and the title compound of Step A, a compound of this invention, was isolated as a foam by flash chromatography (4.98 g). 1H NMR (Me2SO-d6) δ 10.1 (br s, 1H), 7.75 (m, 1H), 7.4 (dd, 1H), 5.1 (m, 1H), 4.9 (s, 2H), 4.1-3.9 (m, 3H), 3.75 (m, 1H), 2.95 (m, 1H), 2.05 (m, 1H), 1.9 (br d, 1H), 1.2 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>COCCOC>[CH2:18]([O:17][C:15]([C:14]1[N:1]=[C:2]2[CH:7]=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][N:3]2[CH:13]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cnc(C(F)(F)F)cn1
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cn2cc(C(F)(F)F)ncc2n1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-amino-5-(trifluoromethyl)pyrazine (500 mg, 3.07 mmol) in 1,2-dimethoxyethane (10 mL) was added dropwise ethyl bromopyruvate (0.5 mL, 4.0 mmol). The reaction mixture was warmed to 60° C. for 72 hours. The reaction mixture was then cooled to room temperature, and water was added (10 mL) to precipitate a solid. The suspension was stirred for 10 minutes, filtered, and the isolated solid was washed with water to afford the desired ester which was used in the next step without further drying. 1H NMR (CDCl3) δ 9.22 (s, 1H), 8.59 (s, 1H), 8.39 (s, 1H), 4.50 (q, 2H), 1.47 (t, 3H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:24])[C@H:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:12][C:13](=[O:16])[CH2:14][NH2:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1C=C(Cl)C(Cl)=CC=1[O:34][C:35](=O)[CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CN1CCOCC1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:24])[C@H:11]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:12][C:13](=[O:16])[CH2:14][NH:15][C:35](=[O:34])[CH2:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: NCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 6.1 parts glycyl-L-phenylalanine benzyl ester hydrochloride, 7.0 parts N-t-butoxycarbonylglycine 2,4,5-trichlorophenyl ester and 1.8 parts N-methylmorpholine in 150 parts methylene chloride is stirred overnight at room temperature. The solvents are then removed by evaporation under reduced pressure to yield the crude tripeptide. Purification by low pressure column chromatography affords pure N-t-butoxycarbonylglycylglycyl-L-phenylalanine benzyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18]CC)=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.[OH-].[Na+].Cl>C(O)C.O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([OH:18])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2

Procedure:
A solution of 12.45 g (0.04 mol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 1.6 g (0.04 mol) of sodium hydroxide in 100 ml of ethanol and 25 ml of water is heated to boiling under reflux for 30 minutes. Subsequently, 40 ml of 1 N hydrochloric acid are added thereto and the mixture is evaporated to half of the volume. The crystals which thereby precipitate are filtered off under suction, washed with water and dried. There is obtained (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid of decomposition point 225°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Mg].Br[CH2:12][CH2:13][CH:14]=[CH2:15].[Cl-].[NH4+]>CCOCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:15][CH2:14][CH:13]=[CH2:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C=CCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCCC(O)c1ccc(Cl)cc1
Yield: 50.8 %

Procedure:
A solution of 70 g (0.5 mole) of 4-chlorobenzaldehyde in 100 ml of absolute ether is added dropwise to a Grignard solution of 12.2 g (0.5 mole) of magnesium and 67.5 g (0.5 mole) of 4-bromo-1-butene in 350 ml of absolute ether, with stirring, and, when the addition has ended, the mixture is heated at the reflux temperature for 2 hours. The cooled reaction mixture is poured into a mixture of 1 liter of saturated ammonium chloride solution and ice, the organic phase is separated off, washed twice with water, dried over sodium sulphate and concentrated in vacuo and the residue is then distilled under a high vacuum. 50 g (58% of theory) of 5-(4-chlorophenyl)-pent-1-en-5-ol of boiling point 100° C.-105° C./0.13 mbar are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([CH2:21][OH:22])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1.Cl>C1COCC1.CN(C1C=CN=CC=1)C.CO>[F:27][C:28]([F:38])([F:39])[C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36](=[O:37])[O:22][CH2:21][C:8]2([C:6](=[O:7])[NH:5][CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[Cl:1])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(C(=O)NCc2ccccc2Cl)CC1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(C(F)(F)F)cc1)OCC1(C(=O)NCc2ccccc2Cl)CCNCC1
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 4-(2-chlorobenzylcarbamoyl)-4-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 1.3 mmol), in THF were added DMAP (32 mg, 0.26 mmol, 0.2 equiv.) and 4-trifloromethylphenylisocyanate (0.28 mL, 1.97 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated to dryness. To a solution of the above crude mixture in CH3OH (3 mL) was added HCl (4 M in dioxane, 1 mL, 4 mmol, 3 equiv.). The reaction mixture was stirred overnight. The white solid was filtered and dried to give (4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (615 mg, 93%). LRMS (M-Boc+H+) m/z 470.1.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([C:7]#[N:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH3:10].O=O>>[CH:4]1[CH:3]=[C:2]([C:7]#[N:8])[C:1]([C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: N
Reactant: Cc1ccccc1C#N
Agent: O=O
Product: N#Cc1ccccc1C#N

Procedure:
750 ml of a catalyst having a particle size of from 0.05 to 0.3 mm are introduced into a quartz reactor which has a diameter of 60 mm and a length of 1000 mm and is provided with an external heater and a quartz frit for uniformly distributing the reaction gas. The catalyst is composed of 5.0% by weight of V2O5, 5.9% by weight of Sb2O3 0.24% by weight of K2O, 0.56% by weight of BaO and 88.3% by weight of γ-Al2O3. The reactor is heated to 470° C. and a gas mixture consisting of 3.25% by volume of o-xylene, 13% by volume of oxygen and 83.75% by volume of ammonia is passed through. The hot reaction gases are cooled to 70° C. with ammonia water in two wash towers arranged in series. An aqueous suspension of crystals is formed, from which the o-phthalodinitrile is isolated by filtration. 2,687 parts of o-xylene give 2,581 parts of o-phthalodinitrile and 195 parts of o-tolunitrile. By reacting the 195 parts of o-tolunitrile again with ammonia and oxygen, a further 170 parts of o-phthalodinitrile are obtained. The total yield of o-phthalodinitrile is 84.8 mol %, based on converted o-xylene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.[CH3:30][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH3:30])[C:5]1[N:6]=[CH:7][N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester (1.01 g, 2.63 mmol) in THF (25 ml) was cooled to -78° C. Lithium hexamethyldisilazide (2.76 ml of a 1 M solution in THF, 2.76 mmol) was added dropwise and the reaction stirred 30 min at -78° C. Methyl iodide (0.164 ml, 2.76 mmol) was added and the reaction stirred a furthur 1 hr at -78° C. and then at -20° C. for 4 hrs. The reaction was quenched with water (10 ml) and saturated NaHCO3 solutuon (10 ml) and extracted with EtOAc. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. Chromatography of the residue (SiO2, 2 to 3% MeOH in CH2Cl2, gradient elotion) afforded the product.
Reaction SMILES: [CH3:1][S:2]([N:5]=[CH:6]OCC)(=[O:4])=[O:3].[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1>C(OCC)C>[CH3:1][S:2]([N:5]=[CH:6][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[O:3])=[O:4]
Reactant: CCOC=NS(C)(=O)=O
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCOCC
Product: CS(=O)(=O)N=CNC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 39.3 %

Procedure:
Into a solution of 760 mg of ethyl N-methanesulfonyl-formimidate in diethyl ether (20 ml) was dropped 0.95 g of 4-amino-1-benzylpiperidine at room temperature. After stirring for 2 hours, the crystals thus precipitated were filtered and washed with diethyl ether to thereby give 580 mg of N2-methanesulfonyl-N1-(1-benzylpiperidin-4-yl)formamidine as colorless needles. These crystals were dissolved in 30 ml of methanol and 500 mg of 10% palladium-carbon was added thereto. Then the resulting mixture was stirred in a hydrogen atmosphere under atmospheric pressure for 1 hour followed by filtration through celite. After distilling off the solvent under reduced pressure, the residue was recrystallized from acetone/ethyl acetate to thereby give 310 mg of the title compound as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([C:12]#[N:13])=[C:4]([CH3:14])[N:3]=1.Cl[Sn]Cl.C(OCC)(=O)C>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[C:5]([C:12]#[N:13])=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1C#N
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc(N)c(N)c(C)c1C#N
Temperature: 70 °C
Yield: 41.9 %

Procedure:
A mixture of 1.16 g (6.04 mmol) of 2-amino-4,6-dimethyl-3-nitro-5-pyridinecarbonitrile (17) and 5.72 g (30.1 mmol) of SnCl2 in 15 mL of ethanol was heated at 70° C. for 1 h. The solution was evaporated and the residue was treated with 40% NaOH to pH=12. The mixture was filtered and the solid was dried to leave a yellow solid. The solid was stirred with ethyl acetate (100 mL) and the mixture was filtered. The filtrate was evaporated to leave a pale yellow solid (410 mg, 41%). 1H NMR (CDCl3), 2,334 (s, 3), 2.522 (s, 3), 3.151 (mb, 2), 4.65 (mb, 2).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].Br[CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].Cl.C(O)C>C(O)C>[C:1]([NH:4][C:5]([CH2:21][CH2:22][CH2:23][S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCSCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCSCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC

Procedure:
Diethyl acetamidomalonate (1.6 g) was dissolved in 30 ml of dehydrated ethanol and 505 mg of sodium ethoxide and 2 g of 3-bromopropyldodecyl sulfide were added thereto. The mixture was refluxed under a nitrogen atmosphere overnight. The reaction mixture was neutralized with concentrated hydrochloric acid-ethanol (1:11) and concentrated. The concentrate was purified by silica gel column chromatography using hexane-ethyl acetate (5:1→5:2) as an eluent to give 1.722 g of colorless, powdery diethyl 2-acetamido-2-(3-dodecylthiopropyl)malonate.