Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1C=CC=[CH:3][CH:2]=1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)([O-:9])=[O:8].BrCC#N>C(COC)OC>[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=1[CH2:3][C:2]#[N:1])([O-:9])=[O:8]
Reactant: c1ccncc1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: N#CCBr
Solvent: COCCOC
Product: N#CCc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
Cuprous chloride (2.97 g, 30 mmol) is added to a goose neck additional funnel fitted to a 500 mL four neck round bottom flask with a rubber septum, thermometer, and magnetic stir bar. The flask is attached to a vacuum line and flame dried under vacuum. It is then allowed to cool to ambient temperature under argon. Potassium t-butoxide (42 mmol, 1M THF solution) is then added via syringe. The THF is carefully removed under vacuum to afford potassium t-butoxide as a white solid, and argon is reintroduced. Anhydrous dimethoxyethane (180 mL) is added via syringe, followed by the cuprous chloride (with stirring) in one portion, giving a dark mixture. Stirring is continued at ambient temperature for 45 min. Anhydrous pyridine (12 mL) is then added to the dark stirred mixture followed by 1,3-dinitrobenzene (2.02 g, 12 mmol) in 30 mL of anhydrous dimethoxyethane. After cooling the reaction to an internal temperature of −20° C., bromoacetonitrile (1.44 g, 12 mmol) in 30 mL of anhydrous dimethoxyethane is added via cannula with stirring over the course of 15 min. During the addition, the internal temperature is maintained at −20° C. and the reaction is stirred at this temperature for another 2 h and warms to ambient temperature for 30 min and then quenched with the addition of 60 mL of 3M HCl solution. The reaction mixture is then added to 600 mL of water and extracted with eight 50 mL portions of diethyl ether. The combined ether extracts are dried over sodium sulfate, filtered and evaporated to afford a dark oil of 2,6-dinitrophenyl acetonitrile whose 1H NMR (CDCl3) is in concert with the literature spectrum.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)[Cl:21].[CH3:25][O:26][CH2:27][O:28][C:29]1[C:30]([CH3:44])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C:34]([CH3:43])([CH:41]=O)[CH2:33][CH2:32]2>C(Cl)Cl.[Zn]>[Cl:21][C:20]([Cl:24])=[CH:41][C:34]1([CH3:43])[CH2:33][CH2:32][C:31]2[C:36](=[C:37]([CH3:40])[C:38]([CH3:39])=[C:29]([O:28][CH2:27][O:26][CH3:25])[C:30]=2[CH3:44])[O:35]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COCOc1c(C)c(C)c2c(c1C)CCC(C)(C=O)O2
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCOc1c(C)c(C)c2c(c1C)CCC(C)(C=C(Cl)Cl)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A mixture of of triphenylphosphine (524 mg, 2.0 mmol), carbon tetrachloride (193 ul, 2.0 mmol), Zinc dust (130 mg, 2.0 mmol) and 6-methoxymethoxy-2,5,7,8-tetramethyl-chroman-2-carbaldehyde (0.25 gram, 0.95 mmol) in 4 ml of DCM was stirred overnight at room temperature. The mixture was rinsed with hexane times and the combined solutions were dried over MgSO4. The solution was concentrated and the residue was purified via flash column chromatography on silica gel (10% ethyl acetate in hexane) to afford 320 mg of 2-(2,2-dichloro-vinyl)-6-methoxymethoxy-2,5,7,8-tetramethyl-chroman.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[CH2:11]2)=[CH:6][CH:5]=1.[C:15](=O)([O:18]C)[O:16][CH3:17]>>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10]([OH:14])=[C:11]2[C:15]([O:16][CH3:17])=[O:18])=[CH:6][CH:5]=1
Reactant: COC(=O)OC
Reactant: O=C1CCc2ccc(Br)cc2C1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1=C(O)CCc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a refluxing stirred suspension of sodium hydride (5.6 g of 80% in oil, 187 mmoles) in dry dimethyl carbonate (120 ml) under a nitrogen atmosphere was added a solution of 7-bromo-2-tetralone (14 g, 61 mmoles) in dry dimethyl carbonate (60 ml) dropwise over 40 minutes. Refluxing was continued for an additional 45 minutes and then cooled to room temperature. The reaction was carefully quenched with glacial acetic acid, diluted with one volume of water and extracted with ethyl acetate (150 ml). The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure to leave a residue which was purified using silica gel column chromatography eluting with ethyl acetate:hexane (39:7) to give methyl 7-bromo-3,4-dihydro-2-hydroxy-1-naphthoate as a white solid. (15.2 g, 86%).
Reaction SMILES: [Cl:1][C:2](C)=[CH:3][C:4]1[CH:13]=[C:12]2C(C(C)=CC(=O)[O:11]2)=CC=1.[C:17]([O:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])(=O)[CH2:18][CH2:19][CH3:20]>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH:3]=[CH:4][C:13]1[C:12]([OH:11])=[CH:20][CH:19]=[C:18]2[C:17]=1[O:22][C:23](=[O:27])[CH:24]=[C:25]2[CH3:26]
Reactant: CC(Cl)=Cc1ccc2c(C)cc(=O)oc2c1
Reactant: CCCC(=O)OC(=O)CCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)oc2c(C=CCCl)c(O)ccc12
Temperature: 180 °C

Procedure:
A solution of 7-(2-chloro propenyl)-4-methyl coumarin (120 g, 0.48 mol) in a mixture of p-disopropyl-benzene (1L) and n-butyric anhydride 160 mL was heated to 180° C. for 24 hours. The organic layer was evaporated under reduced pressure and residue recrystallizated from ethanol to afford 75 g of the desired compound.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:8](OCC)=[O:9])[S:6][CH:7]=1)#[N:2].[BH4-].[Na+].[NH4+].[Cl-]>CO>[OH:9][CH2:8][C:5]1[S:6][CH:7]=[C:3]([C:1]#[N:2])[N:4]=1
Reactant: CCOC(=O)c1nc(C#N)cs1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: N#Cc1csc(CO)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
To a solution of ethyl 4-cyano-1,3-thiazole-2-carboxylate (336 mg) in MeOH (10 ml) was added NaBH4 (140 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into saturated NH4Cl solution, concentrated in vacuo, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (253 mg) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reactant: NCCN1CCCCC1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NCCN4CCCCC4)c3)C(C)(C)C2=O)cc1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 36 μl of 1-(2-aminoethyl)piperidine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by HPLC (gradient: water/acetonitrile containing 0.1% formic acid) to give 75 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyridin-2-yl)-3-(2-piperidin-1-ylethyl)urea, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][C@@H:25]([NH:28][CH3:29])[CH2:24]3)=[C:19]([F:30])[CH:18]=1)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH3:4].[CH3:31][S:32]([CH:35]=[CH2:36])(=[O:34])=[O:33]>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][C@@H:25]([N:28]([CH2:36][CH2:35][S:32]([CH3:31])(=[O:34])=[O:33])[CH3:29])[CH2:24]3)=[C:19]([F:30])[CH:18]=1)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: C=CS(C)(=O)=O
Reactant: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](NC)C3)c(F)c1)C2=O
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N(C)CCS(C)(=O)=O)C3)c(F)c1)C2=O

Procedure:
6-Butoxy-2-[3-fluoro-4-((R)-3-methylaminopyrrolidin-1-yl)phenyl]-3,4-dihydro-2H-isoquinolin-1-one was reacted with methanesulfonylethene by method G. The product with the molecular weight of 517.67 (C27H36FN3O4S) was obtained in this way; MS (ESI): 518 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1)[NH2:21]>>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[CH3:13])=[O:15])[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH2:27][CH2:26]1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(Br)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(Br)c2)cnn1-c1ccc(Cl)cc1
Yield: 54.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (4.8 g) and 3-bromo-4-(4-morpholinopiperidin-1-yl)aniline (5 g), the title compound (4.5 g) was obtained, melting point: 205–210° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[S:39]1[CH:43]=[CH:42][N:41]=[C:40]1[C:44](Cl)=[O:45]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:44]([C:40]1[S:39][CH:43]=[CH:42][N:41]=1)=[O:45])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: O=C(Cl)c1nccs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2)c1nccs1
Yield: 37 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 1,3-thiazole-2-carbonyl chloride as the starting materials in 37% yield. LCMS for C22H18ClN6OS (M+H)+: m/z=449.2. 1H NMR (400 MHz, DMSO-d6): δ 10.67 (s, 1H), 9.57 (m, 2H), 8.13 (s, 1H), 8.07 (m, 2H), 7.84 (m, 1H), 7.60 (m, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 7.07 (dd, 1H), 6.85 (m, 2H), 2.84 (m, 4H).
Reaction SMILES: C([O:5][C:6](=[O:44])[CH:7]([NH:36]C(OC(C)(C)C)=O)[CH2:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:26]=[C:25]([NH2:27])[N:24]=[C:23]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[N:22]=2)=[CH:16][CH:15]=1)=[O:11])(C)(C)C.C(O)(=O)C.ClCCl.Cl>O1CCOCC1.C(OCC)(=O)C>[NH2:27][C:25]1[N:24]=[C:23]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[CH3:35])[N:22]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C@H:7]([NH2:36])[C:6]([OH:44])=[O:5])=[CH:19][CH:18]=2)[N:26]=1
Reactant: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(COC(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(COC(=O)CC[C@H](N)C(=O)O)cc2)n1
Yield: 90.5 %

Procedure:
A mixture of 2-tert-butoxycarbonylamino-pentanedioic acid 5-{4-[4-amino-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazin-2-ylamino]-benzyl}ester 1-tert-butyl ester (1.45 g, 2.3 mmol), acetic acid (10 ml), dichloromethane (5 ml), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 10 ml) was stirred for 12 hours. The mixture was poured into ethyl acetate (50 ml). The solid was filtered and dried under reduced pressure to provide the hydrochloride salt of the title compound (0.98 g, 75% yield). 1H NMR (CD3OD) δ 7.78 (s, 1H), 7.7-7.9 (br s, 2H), 7.58 (d, 2H), 7.46 (d, 4H), 5.18 (s, 2H) 4.09 (t, 1H) 2.58-2.82 (m, 2H) 2.58 (br s, 3H), 2.1-2.3 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.Cl.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]=2[C:41]([F:44])([F:43])[F:42])[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:26][CH2:27][N:28]([CH2:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[CH:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[N:20][CH:21]=5)[CH:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:37])=[CH:34][C:33]=2[C:41]([F:44])([F:42])[F:43])[CH2:29][CH2:30]1
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(N)cc1Nc1cc(-c2cncnc2)ccn1
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1cc(-c2cncnc2)ccn1

Procedure:
This compound was prepared in the same manner as in Example 1, except that 4-methyl-3-[4-(5-pyrimidinyl)pyridin-2-ylamino]aniline (Reference Example 22) and 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 2) were used, and that the resulting crude crystals were washed with ethyl acetate.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([O:13]C)=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].[BrH:15].C(O)(=O)C>>[BrH:15].[CH3:8][N:6]([CH2:5][C:4]1[C:3]([CH2:1][CH3:2])=[C:12]([OH:13])[CH:11]=[CH:10][CH:9]=1)[CH3:7]
Reactant: CCc1c(CN(C)C)cccc1OC
Agent: Br
Solvent: CC(=O)O
Product: CCc1c(O)cccc1CN(C)C
Reaction time: 21 h
Yield: 78 %

Procedure:
(2-Ethyl-3-methoxybenzyl)dimethylamine (1.30 g, 6.73 mmol) was suspended in 30% hydrogen bromide/acetic acid (10 mL) and heated to reflux with stirring for 21 h. The cooled reaction mixture was triturated and decanted with successive portions of diethyl ether (3×), then triturated with diethyl ether overnight. The solid was collected by filtration, washed with ether and dried to give 3-dimethylaminomethyl-2-ethylphenol hydrobromide (1.37 g, 78%) as a tan solid.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([O:9][C:10]1[CH:18]=[C:17]([CH2:19][C:20]2[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[N:24][CH:25]=2)[CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)[CH3:8].[CH3:28][N:29]([CH3:34])[S:30](Cl)(=[O:32])=[O:31]>CN(C)C=O>[CH3:28][N:29]([CH3:34])[S:30]([N:14]1[C:15]2[C:11](=[C:10]([O:9][CH2:7][CH3:8])[CH:18]=[C:17]([CH2:19][C:20]3[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[N:24][CH:25]=3)[CH:16]=2)[CH:12]=[CH:13]1)(=[O:32])=[O:31]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc2[nH]ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc2c1ccn2S(=O)(=O)N(C)C
Yield: 53 %

Procedure:
Potassium tert-butylate (42 mg, 0.37 mmol) was added to a solution of 5-(4-ethoxy-1H-indol-6-ylmethyl)-pyrimidine-2,4-diamine (Example 1; 100 mg, 0.353 mmol) in N,N-dimethylformamide (5 mL). After 15 min dimethylsulfamoyl chloride (53 mg, 0.37 mmol) was added, then after 30 min the solvent was distilled off and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Suspension of the residue in ether and collection of the precipitate afforded the title compound (73 mg, 53%). Off-white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2>CN(C=O)C>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:16])[CH2:27]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: COc1cccc2c1CNC2
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 66.7 %

Procedure:
136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 224 mg of 4-methoxyisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 132 mg of the target compound.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[CH2:8]1[CH:12]2[CH2:13][C:14](=[O:16])[CH2:15][CH:11]2[CH2:10][NH:9]1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>C(#N)C>[C:3]([N:9]1[CH2:10][CH:11]2[CH2:15][C:14](=[O:16])[CH2:13][CH:12]2[CH2:8]1)(=[O:4])[CH3:2]
Reactant: O=C1CC2CNCC2C1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2CC(=O)CC2C1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f (717 mg, 3 mmol) was dissolved in 20 mL of acetonitrile followed by addition of di-tert-butyl dicarbonate (0.42 mL, 4.5 mmol) and triethylamine (0.98 mL, 9 mmol) upon cooling by an ice-water bath. The reaction mixture was stirred overnight at the same temperature. The mixture was concentrated and diluted with 50 mL of water. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-acetyl-hexahydro-cyclopenta[c]pyrrol-5-one 5a (0.36 g, yield 72%) as a colorless oil
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH:30][O:31]C4CCCCO4)=[O:29])=[CH:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]>CO>[OH:31][NH:30][C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]1[CH:24]=[CH:25][N:21]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=3)=[CH:17][CH:16]=2)(=[O:19])=[O:20])[CH:22]=1
Reactant: CS(=O)(=O)Nc1ccc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NOC4CCCCO4)c3)cc2)cc1
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NO)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
A mixture of 0.223 g (E)-3-[1-(4′-methanesulfonylamino-biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide with 6.0 ml methanol and 12.0 ml 1M aqueous HCL is stirred at ambient temperature for 24 h. The suspension is evaporated and the solid is washed with water and diisopropylether. The title compound is dried in vacuo. By this method 0.155 g light pink solid are obtained. Melting point: 160-167° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][O:10][C:11]1[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]C)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][O:10][C:11]1[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1OCNC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCOc1ccccc1C(=O)O
Yield: 81 %

Procedure:
Methyl N-tert-butoxycarbonylaminomethylsalicylate (8.7 g, 30.9 mmoles) was dissolved in dry tetrahydrofuran (100 mL), and potassium trimethylsilanolate (4.4 g, 30.9 mmoles, 90% pure) was added. The yellow solution was refluxed for 24 hours, during which time a tan precipitate formed and the solvent turned light brown. The mixture was evaporated to dryness, and the solid was dissolved in cold water (100 mL). The brown solution was chilled in an ice bath, and saturated aqueous potassium hydrogen sulfate solution was used to titrate the stirred solution to pH 2-3. An off-white solid precipitated during the titration. The solid was filtered, washed with cold water, and dried in vacuo over potassium hydroxide to afford 6.7 g, (81% yield) of crude N-tert-butoxycarbonylaminomethylsalicylic acid (m.p. 141°-144° C., decomposes with effervescence on melting, open capillary, uncorrected).
Reaction SMILES: ClC(OCCCC)=O.[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]=1[CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=1.[CH2:28]([N:30](CC)CC)C.Cl.CN>CN(C)C=O.O>[CH3:28][NH:30][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:10]2[NH:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Reactant: CCN(CC)CC
Agent: CCCCOC(=O)Cl
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Reaction time: 18 h
Yield: 37.7 %

Procedure:
2.8 ml of butyl chloroformate are added dropwise at -5° to a solution of 5.0 g (0.020 mol) of p-[(2-benzimidazolyl)methyl]benzoic acid and 2.8 ml (0.020 mol) of triethylamine in 68 ml of dimethylformamide. After stirring at 0°-5° for 30 minutes 1.32 g (0.020 mol) of methylamine hydrochloride and 2.8 ml (0.020 mol) of triethylamine in 28 ml of dimethylformamide and 1.4 ml of water are added. The temperature is then left to rise to room temperature and the mixture is stirred for a further 18 hours. After concentration under reduced pressure the residue is chromatographed on 400 g of silica gel with chloroform/ethanol (4:1) as the elution agent. The uniform fractions give 2.0 g (38%) of N-methyl-p-[(2-benzimidazolyl)methyl]benzamide, m.p. 250°-255° (dec.), as a colourless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[C:2]=1[NH2:8].Cl.C(O[C:13](=N)[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1)C>CO>[NH:7]1[C:3]2[C:2](=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[C:13]1[CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]1
Reactant: CCOC(=N)CC1CCN(C(=O)OCC)CC1
Reactant: Nc1cccnc1N
Agent: Cl
Solvent: CO
Product: CCOC(=O)N1CCC(Cc2nc3ncccc3[nH]2)CC1
Yield: 52.7 %

Procedure:
A mixture of 2,3-pyridinediamine (0.05 mol) and ethyl 4-(2-ethoxy-2-iminoethyl)-1-piperidinecarboxylate monohydrochloride (0.05 mol) in methanol (150 ml) was stirred and refluxed for 3 days. The solvent was evaporated and the residue was taken up in CH2Cl2. The organic solution was washed with K2CO3 10%, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 94/6/0.1). The pure fractions were collected and the solvent was evaporated, yielding 7.6 g of ethyl 4-[(1H-imidazo[4,5-b]pyridin-2-yl)methyl]-1-piperidinecarboxylate (52%) (interm. 9).
Reaction SMILES: [O:1]=[C:2]1[O:6][C:5]([CH2:7][CH2:8][C:9]([OH:11])=O)=[N:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C=O)C>[O:11]=[C:9]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:8][CH2:7][C:5]1[O:6][C:2](=[O:1])[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1
Reactant: C1CCNCC1
Reactant: O=C(O)CCc1nn(-c2ccccc2)c(=O)o1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(CCc1nn(-c2ccccc2)c(=O)o1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50 mg (0.21 mmol) of 3-(5-oxo-4-phenyl-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-propionic acid, 245 mg (2.13 mmol) of NEM and 77 mg (0.23 mmol) of TOTU were dissolved in 2 ml of DMF and stirred at room temperature for 15 min. 20 mg (0.23 mmol) of piperidine were added, and the reaction mixture was stirred at room temperature for 16 h. After evaporation, the product was purified by silica gel chromatography. Yield: 45 mg.