Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:6])[CH2:2][CH3:3]>[Pd].CO>[NH2:17][C:15]1[CH:14]=[C:9]([CH:8]=[C:7]([C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:20][CH2:21][CH3:22])=[O:6])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Reaction time: 3 h

Procedure:
A suspension of methyl 3-[(dipropylamino)carbonyl]-5-nitrobenzoate (XXX, PREPARATION 9, 6.00 g, 20.0 mmol) and palladium on carbon (5%, 0.600 g) in methanol (40 mL) is shaken in a hydrogenation apparatus under hydrogen (45 psi) for 3 hours. The mixture is then filtered through diatomaceous earth and concentrated to give the title compound, NMR (300 MHz, CDCl3) delta 7.27, 6.77, 4.10, 3.82, 3.38, 3.10, 1.62, 1.46, 0.91 and 0.68.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(OC(F)(F)F)cc2)CC1
Yield: 93.9 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.400 g, 1.34 mmol) in toluene (2.68 mL). Add 4-(trifluoromethoxy)phenylboronic acid (0.303 g, 1.47 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.077 g, 0.067 mmol). Add ethanol (2.68 mL), followed by a 2 N aqueous sodium carbonate solution (2.68 mL). Reflux reaction for 18 hr. Cool reaction to room temperature and concentrate. Add ethyl acetate and wash with water. Extract water layer one time with ethyl acetate. Dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes), to give 3′-(4-trifluoromethoxyphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (534 mg, 94%). MS (ES): m/z=425 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:11][C:10]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: COc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 81A in analogy to the synthesis of the compound of Example 1. 31 mg (84% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:10])[CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[C:1]1([C@@H:7]([CH3:10])[CH2:8][N:15]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H](CO)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccccc1
Yield: 112.4 %

Procedure:
An oven dried 250.0 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel with a continuous nitrogen blanket is charged with (2R)-2-phenylpropan-1-ol (2.0 mL, 14.32 mmol), phthalimide (2.1 g, 14.32 mmol), triphenylphosphine (5.63 g, 21.48 mmol) and THF (70.0 mL). To this solution at room temperature was then added a solution of diethylazodicarboxylate (3.38 mL, 21.48 mmol) dissolved in THF (10.0 mL) over a period of 15-20 minutes (reaction exothermed slightly to 50° C. by the end of addition went from clear to reddish color). Stirred reaction to room temperature overnight). To the red solution was added water (50.0 mL) and the organic extracted with chloroform (140.0 mL). Dried the organic solution with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to an oil. To the oil was added heptane (150.0 mL) with stirring. Filtered of precipitates, then concentrated filtrate to an oil. Plug filtration of the oil over silica gel with 1:1 ethylacetate/hexane and concentrating product fractions afforded the intermediate title compound, 2-((2R)-2-phenylpropyl)isoindoline-1,3-dione, (4.27 g, 96%) as an oil which solidified on equilibrating to room temperature; 1H nmr (CDCl3, 300 MHz) δ 1.3 (d, 3H), 3.3-4.0(m, 1H), 3.7-3.9 (m, 2H), 7.1-7.3 (aromat. m, 2H), 7.63-7.7 (aromat. m, 2H), 7.8-7.85 (aromat. m, 4H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[N:19]1[N:20]=[C:21]([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26](O)=[O:27])[NH:22][CH:23]=1>>[N:19]1[N:20]=[C:21]([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:27])[NH:22][CH:23]=1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Product: O=C(c1ccccc1-c1nnc[nH]1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI) mass calcd. for C23H21N7O, 411.47; m/z found, 412.2 [M+H]+. 1H NMR (CDCl3): 8.28 (s, 1H), 8.11 (d, J=8.1 Hz, 1H), 8.01 (br s, 1H), 7.89 (dd, J=8.2, 1.2 Hz, 1H), 7.69 (dd, J=8.4, 1.0 Hz, 1H), 7.59 (ddd, J=8.4, 7.0, 1.4 Hz, 1H), 7.55-7.43 (m, 2H), 7.42-7.33 (m, 2H), 3.89-4.00 (m, 2H), 3.82-3.72 (m, 2H), 3.71-3.64 (m, 1H), 3.55-3.42 (m, 2H), 3.20-2.98 (m, 3H).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:35])[C:11]2[CH:10]=[C:9]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])[S:8][C:7]=2[C:6]([CH3:34])([CH3:33])[CH2:5][CH2:4]1.[CH2:36]([O:38][C:39]([C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1)=[O:40])[CH3:37]>C1OCCC1>[CH3:35][C:3]1([CH3:2])[C:11]2[CH:10]=[C:9]([C:12]([CH3:13])=[CH:45][C:44]3[CH:47]=[CH:48][C:41]([C:39]([O:38][CH2:36][CH3:37])=[O:40])=[CH:42][CH:43]=3)[S:8][C:7]=2[C:6]([CH3:34])([CH3:33])[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ccc(C=O)cc1
Reactant: CC(c1cc2c(s1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C=C(C)c2cc3c(s2)C(C)(C)CCC3(C)C)cc1
Yield: 55.5 %

Procedure:
30 g of [1-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)ethyl]triphenylphosphonium bromide and 9.5 g of 4-ethoxycarbonylbenzaldehyde are suspended in 300 ml of butylene oxide and the mixture is heated at reflux for 4 hours. The thus-obtained solution is concentrated to one third of the original volume in a water-jet vacuum, poured into 500 ml of a methanol/water mixture (6:4) and extracted several times with hexane. The organic phase is washed three times with water, dried over sodium sulphate and evaporated. There is obtained a light brownish oil which is purified by filtration over silica gel (eluting agent hexane/ether 19:1). After recrystallization from hexane, there are obtained 11.3 g of ethyl p-[2-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)propenyl]-benzoate in the form of colorless crystals, m.p. 118°-120° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[N:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:25]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:26])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CNCC(C(=O)OC)C2)cc1
Reactant: O=C(Cl)N1CCOCC1
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
6.2 g (22.6 mmol) of methyl 5-(4-ethylphenyl)piperidine-3-carboxylate and 4.4 g (29.4 mmol, 1.3 eq.) of morpholine-4-carbonyl chloride were reacted according to the General Method 3A. Yield: 7.9 g (97% of theory)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>>[C:15]([O:12][C:9]1[CH:8]=[CH:7][C:6]([S:3]([C:2]([F:13])([F:1])[F:14])(=[O:4])=[O:5])=[CH:11][CH:10]=1)(=[O:17])[CH3:16]
Reactant: O=S(=O)(c1ccc(O)cc1)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(S(=O)(=O)C(F)(F)F)cc1

Procedure:
Preparation according to Preparation 16 using 4-[(trifluoromethyl)sulfonyl]phenol (4.5 g, 23.2 mmol), acetic anhydride (13.4 g, 130 mmol) and pyridine (10.6 ml, 130 mmol). Crude yield: 6.8 g. MS m/z (rel. intensity, 70 eV) 268 (M+, 6), 157 (bp), 93 (84), 65 (52), 64 (43).
Reaction SMILES: C1(S([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=O)=O)C=CC=CC=1.[OH-].[K+].CS(C)=O>C1(C)C=CC=CC=1>[C:13]12[CH2:12][CH2:11][CH:10]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 86.8 %

Procedure:
10.92 g (0.03 mole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 11.0 g (0.197 mole) of freshly powdered KOH in 40 ml of toluene were heated to reflux for 30 min. as indicated sub letter (b). After addition of 6 ml (0.085 mole) of DMSO, the reaction mixture was heated to reflux for 12 further hours, then cooled, extracted and finally distilled as indicated hereinabove to afford 5.32 g (87% yield) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:13](Cl)(=[O:15])[CH3:14]>C(=S)=S>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([C:13](=[O:15])[CH3:14])=[CH:7][C:2]=1[Cl:1]
Reactant: CC(=O)Cl
Reactant: Oc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
To a stirred solution of 2-chlorophenol (10.0 g, 77.8 mmol) in carbon disulfide (20 ml) was added aluminum chloride (21.8 g, 163.4 mmol) at 0° C. under nitrogen. Acetyl chloride (6.72 g, 85.6 mmol) was added, and the mixture was heated at reflux temperature for 6 hours. The mixture was cooled down to room temperature, and poured into ice-water. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized with diethylether-hexane to give the title compound (6.39 g, 48% yield).
Reaction SMILES: [CH3:1][C:2]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[C:24]1([CH2:30][C:31]([N:10]([C:2]([CH3:1])([CH3:9])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)CCNC(C)(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCN(C(=O)Cc1ccccc1)C(C)(C)c1ccccc1
Reaction time: 24 h
Yield: 89.1 %

Procedure:
47.0 g (0.2 mol) of ethyl 3-(α,α-dimethylbenzylamino)propionate prepared by the method of Reference Example 16, was dissolved in 200 ml of acetone, and 30 g (0.22 mol) of potassium carbonate was added thereto. 31.0 g (0.2 mol) phenyl acetic acid chloride was dropwise added thereto at room temperature. After completion of the dropwise addition, the reaction solution was stirred for one day and night, and the reaction solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate, washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 63.0 g (yield: 89.1%) of the desired compound.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=2[CH3:18])=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccc(Cl)cc3Cl)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
Lithium hydroxide monohydrate (0.009 g, 0.22 mmol) was added to a stirred solution of {4-[4-(2,4-dichlorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.028 g, 0.054 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(2,4-dichlorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.018 g, 66%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s., 1 H) 8.37 (d, J=7.82 Hz, 1 H) 8.09 (d, J=7.82 Hz, 2 H) 8.01 (dd, J=9.00, 6.70 Hz, 1H) 7.96 (s, 1 H) 7.91 (s, 1 H) 7.83 (d, J=8.80 Hz, 1 H) 7.54 (d, J=7.82 Hz, 2 H) 7.39 (t, J=8.00 Hz, 1 H) 6.63 (d, J=10.76 Hz, 1 H) 3.84 (s, 2 H) 2.05 (s, 3 H) MS calcd. for C25H16Cl2FO4S [(M−H)−] 501, obsd. 501.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[Cu](C#N)[C:26]#[N:27]>ClC(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:26]#[N:27]
Reactant: N#C[Cu]C#N
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#CC(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 180 °C
Yield: 11.2 %

Procedure:
A mixture of 12 parts of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione and 5.4 parts of copper cyanide was stirred and heated first for 3 hours at 130° C. and for 3 hours at 180° C. After cooling, the precipitated product was dissolved in a mixture of trichloromethane and methanol (90:10 by volume). The inorganic precipitate was filtered off and the filtrate was evaporated in vacuo. The residue was purified four times by column chromatography over silica gel using first a mixture of trichloromethane and acetonitrile (90:10 by volume), second a mixture of tetrachloromethane and methanol (93:7 by volume) and then twice a mixture of tetrachloromethane and acetonitrile (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography (HPLC) over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was dried, yielding 1.3 parts (11.2%) of 2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile; mp. 196.8° C. (compound 22).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.O.Cl.C(O[CH:18](OCC)[CH2:19][CH:20](OCC)OCC)C>C(O)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([N:9]2[CH:20]=[CH:19][CH:18]=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: CCOC(CC(OCC)OCC)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cccc(-n2cccn2)c1
Yield: 80 %

Procedure:
Into a 500 ml., 2-neck flask, fitted with a condenser and a magnetic stirrer, is successively added 35.2 g. (0.2 M.) of m-trifluoromethylphenyl hydrazine, 15 ml. of water, 20 ml. of 100% ethanol, 16.5 ml. of concentrated hydrochloric acid (slowly) and 44.0 g. (0.2 M.) of 1,1,3,3-tetraethoxypropane. The reaction mixture is then heated slowly to between 80° C. and 90° C., and after maintaining the mixture at this temperature range for a period of between 2 and 3 hours, the reaction mixture is cooled, quenched on ice water, extracted with ethylacetate and washed several times with water. After drying the organic solution over sodium sulfate, the solvent is evaporated on a rotary evaporator to obtain a very dark liquid which is then distilled at 70° to 80° C. and a pressure of about 100 microns to yield a light yellow oil (Yield: 80%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[C:18]2=[O:31])[CH2:13][CH2:14][NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:32](OC(=O)C)=[O:33]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[C:18]2=[O:31])[CH2:13][CH2:14][N:15]([CH:32]=[O:33])[OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc([C@@H](CCNO)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Reactant: CC(=O)OC=O
Solvent: ClCCl
Product: CCOc1cc([C@@H](CCN(O)C=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Reaction time: 1 h
Yield: 24.1 %

Procedure:
To a solution of (1R)-N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (350 mg, 0.82 mmol) in methylene chloride (3 mL) was added a solution of acetyl formate (84 mg) in methylene chloride (1 mL) at 0° C. After 1 h, the mixture was extracted with ethyl acetate (25 mL) and water (25 mL). The organic layer was washed with brine (20 mL) and dried over MgSO4. The solvent was removed in vacuo. The residue was purified with prep HPLC to give (1R)-N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (90 mg, 24% yield): mp: 96-98° C.; 1H NMR (CDCl3) δ 1.46 (t, J=7 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.81-2.83 (m, 2H, CH2), 3.56 (t, J=6 Hz, 2H, CH2), 3.85 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 5.25 (t, J=8 Hz, 1H, NCH), 6.82 (d, J=8 Hz, 1H, Ar), 7.06-7.09 (m, 2H, Ar), 7.45 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 7.72 (s, 1H, CH), 8.75 (d, J=8 Hz, 1H, Ar), 9.49 (s, 1H, NH); 13C NMR (CDCl3) δ 14.73, 24.95, 28.35, 46.61, 51.92, 55.93, 64.46, 111.37, 112.79, 115.21, 118.05, 120.63, 124.90, 130.33, 131.09, 136.02, 137.47, 148.48, 149.40, 155.73, 167.72, 169.27, 170.07; Anal Calcd for C23H25N3O7+0.3 H2O: C, 59.95; H, 5.60; N, 9.12; H2O, 1.17. Found: C, 59.94; H, 5.59; N, 8.98; H2O, 1.22.
Reaction SMILES: [IH:1].[CH3:2][O:3][CH:4]([O:12][CH3:13])[CH2:5][NH:6][C:7](SC)=[N:8][CH3:9].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=[C:23]2[CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][NH2:40])[CH2:34][CH2:33]2)=[CH:17][CH:16]=1>CC(O)C>[IH:1].[CH3:2][O:3][CH:4]([O:12][CH3:13])[CH2:5][NH:6][C:7]([NH:40][CH2:39][CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([CH2:31][C:23]2[N:22]([CH2:21][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=2)[CH2:33][CH2:34]1)=[N:8][CH3:9]
Reactant: CN=C(NCC(OC)OC)SC
Reactant: NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: I
Solvent: CC(C)O
Product: CN=C(NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)NCC(OC)OC
Yield: 99 %

Procedure:
A mixture of 6.4 parts of methyl N-(2,2-dimethoxyethyl)-N'-methylcarbamimidothioate monohydroiodide, 7.3 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidineethanamine and 80 parts of 2-propanol was stirred and refluxed overnight. The reaction mixture was evaporated, yielding 12.77 parts (99%) of N-(2,2-dimethoxyethyl)-N'-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]N"-methylguanidine monohydroiodide (450).
Reaction SMILES: O[C:2]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20]([NH:22][CH3:23])=[O:21])[CH:14]=[CH:13]3)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1.C([OH:26])C>>[OH:26][C:8]1[N:7]=[CH:6][N:5]2[CH2:4][CH2:3][C@@H:2]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([C:20]([NH:22][CH3:23])=[O:21])[CH:14]=[CH:13]4)[C:9]=12
Reactant: CCO
Reactant: CNC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Product: CNC(=O)c1ccc2cc([C@@H]3CCn4cnc(O)c43)ccc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide (5.20 kg, 16.9 mol), ethanol (130 L) and activated carbon (260 g) were stirred at room temperature, and the insoluble material was filtered off, and washed with ethanol (15.6 L). The above-mentioned operations were repeated three times. The filtrates and washings were combined, and (2S,3S)-tartranilic acid (15.95 kg, 70.8 mol) and ethanol (20.8 L) were added thereto. The mixture was heated to about 50° C., allowed to cool to room temperature, stirred for about 4 hr, cooled to about 0° C., and stirred for about 1 hr. The precipitated crystals were collected by filtration, and washed with ethanol (31.2 L). The obtained wet crystals (about 23 kg) in ethanol (156 L) were stirred at room temperature for about 2 hr, and the mixture was cooled to about 0° C., and stirred for about 1 hr. The precipitated crystals were collected by filtration, and washed with ethanol (31.2 L). The obtained wet crystals (about 20 kg) were added to 1 mol/L aqueous sodium hydroxide solution (104 L), and the mixture was stirred at room temperature for about 1 hr. The precipitated crystals were collected by filtration, washed with water (93.6 L), and dried under reduced pressure to a constant amount to give 6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide 1 hydrate (4.11 kg, 12.6 mol). yield 25%. containing 5.6 wt % water (by Karl-Fisher water measurement).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([C:18]#[N:19])[CH:11]=2)[CH2:6][C:7]([OH:9])=O)[CH2:3][CH2:2]1.[CH2:20]([NH2:22])[CH3:21]>>[CH:1]1([CH2:4][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([C:18]#[N:19])[CH:11]=2)[CH2:6][C:7]([NH:22][CH2:20][CH3:21])=[O:9])[CH2:2][CH2:3]1
Reactant: CCN
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C#N
Product: CCNC(=O)CN(CC1CC1)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(cyclopropylmethyl)-N-(3,4-dicyanophenyl)glycine and ethylamine: MS (ES) m/z 283 (M+1).