Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>COCCOC>[Cl:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: OB(O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1cccc(Cl)c1
Yield: 71.3 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-chloro-phenylboronic acid (30 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (39 mg, 72%). LC-MS m/e 421.26 (M+H+)
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:25]=[C:18]2[N:19]=[C:20]([CH3:24])[CH:21]=[C:22](Cl)[N:17]2[N:16]=1)(=[O:14])=[O:13].Cl.[CH2:27]([OH:29])[CH3:28]>>[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:25]=[C:18]2[N:19]=[C:20]([CH3:24])[CH:21]=[C:22]([O:29][CH2:27][CH3:28])[N:17]2[N:16]=1)(=[O:13])=[O:14]
Reactant: CCO
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Agent: Cl
Agent: [Na]
Product: CCOc1cc(C)nc2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nn12
Reaction time: 0.25 h

Procedure:
Sodium (0.69 g, 30 mmol) was added to about 50 ml of ethanol and allowed to react. The mixture was allowed to cool and then 4.0 g (9.8 mmol) of N-(2,6-dichloro-3-methylphenyl)-7-chloro-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide was added with stirring. After 15 minutes to starting material remained by thin layer chromatographic analysis although complete solution was never attained. The mixture was acidified with 6N hydrochloric acid and concentrated under reduced pressure. The residue was triturated with water and the solid removed by filtration and washed with water. It was then dissolved in aqueous sodium hydroxide using a minimum amount of the base and the aqueous solution was twice extracted with ether and acidified with 6N hydrochloric acid. The solid that formed was collected by filtration, washed with water, and dried. This was extracted with about 500 ml of boiling chloroform. The chloroform solution was concentrated to about 150 ml and allowed to cool to form a precipitate which was collected by filtration and dried to obtain 1.7 g (42 percent of theory) of the title compound as a white solid, m.p. 228°-9° C.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([Cl:6])=O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[C:11]=1[Cl:18].O.[O:20]1CCC[CH2:21]1>>[Cl:18][C:11]1[C:12]([Cl:17])=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=1[NH:9][C:21]([CH2:2][C:3]([CH3:8])([CH3:7])[CH2:4][Cl:6])=[O:20]
Reactant: Nc1ccc(O)c(Cl)c1Cl
Reactant: C1CCOC1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: O
Product: CC(C)(CCl)CC(=O)Nc1ccc(O)c(Cl)c1Cl

Procedure:
1.55 g (0.01 mol) of chloropivaloyl chloride were added dropwise at 0° C. to a solution of 1.93 g (0.011 mol) of 4-amino-2,3-dichlorophenol in 30 ml of tetrahydrofuran, and stirring of the mixture was continued at 25° C. until starting compound was no longer detectable by thin-layer chromatography. The reaction mixture was subsequently poured into water and extracted three times using 20 ml of methylene chloride. The combined organic phases were washed twice using water, dried and concentrated. The residue was chroamtographed on silica gel (eluent: cyclohexane: ethyl acetate=2:1; yield: 0.75 g, m.p. 115° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])[CH2:26][CH2:25][N:24]1[C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Br:11])[CH:10]=[C:2]([Br:1])[CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1cc(Br)cc(Br)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 52.1 %

Procedure:
197 mg (0.70 mmol) of 3,5-dibromobenzoic acid (prepared according to J. Organometallic Chem. 215, 281 (1981)) are reacted in analogy to Example 2a first with 2 ml (27 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine and 130 μl (0.936 mmol) of triethylamine to give the title compound (168 mg, 52%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.60, FD-MS: M+ =687, 689, 691.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O1CCCC1.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.O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:18])[CH:24]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Reactant: Nc1cccc(B(O)O)c1
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: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2ccc(C(=O)N[C@H]3CN4CCC3CC4)o2)c1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-aminophenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol and water. The compound was purified by flash chromatography using 5-20% 3.5M methanolic ammonia/chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions and extraction into chloroform followed by evaporation to gave the title compound; MS (ES+) 312 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13].O>CS(C)=O>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:13]
Reactant: CCOC(CBr)OCC
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(Cn1ccc2ccccc21)OCC
Reaction time: 1 h

Procedure:
To a solution of 12 g of indole in 100 ml of dimethyl sulfoxide was added 6.5 g of sodium hydride at room temperature. The mixture was stirred at the same temperature for 1 hour, and 20 ml of bromoacetaldehyde diethyl acetal was added thereto, followed by further stirring at 50° C. for 1 hour. After cooling, the reaction mixture was poured into water, and the product was extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 23 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CCN(CC)CC.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:27](Cl)=[O:28]>C1COCC1>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:27]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][N:21]=2)=[O:28])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=C(Cl)c1cnccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1C(=O)O)c1cnccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of pyrazine-2-carboxylic acid (1.36 g, 10.9 mmol, 1 eq.) in SOCl2 (20 mL) was added DMF (2 drops). The mixture was stirred at 60° C. for 2.0 min. The volatiles were removed in vacuo to give crude pyrazine-2-carbonyl chloride, which was used in the next step directly. TO a suspension of 2-amino-5-nitrobenzoic acid (2.00 g, 10.9 mmol, 1.0 eq.) in THF (50 mL) was added Et3N (1.09 g) and pyrazine-2-carbonyl chloride in anhydrous THF (50 mL) dropwise. The resulting mixture was stirred at room temperature for 18 h. After the reaction was completed, the volatiles were removed. The residue was suspended in H2O (10 mL) and the pH was adjusted to 5 by slow addition of 2N HCl in water. The resulting solid was collected and dried in vacuo to give 3.12 g of 5-nitro-2-(pyrazine-2-carboxamido)benzoic acid as a brown solid (99%). LCMS m/z=289.0 (M+1) (Method B) (retention time=1.24 min),
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([O:23][CH3:24])[C:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[C:16]3[Cl:36])([C:7]2[N:11]([CH3:12])[N:10]=[N:9][CH:8]=2)[OH:6])[CH2:2]1.[C:37](OC(=O)C)(=[O:39])[CH3:38].C(Cl)(=O)C>CCN(CC)CC.ClCCl>[Cl:36][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:5]([OH:6])([C:7]3[N:11]([CH3:12])[N:10]=[N:9][CH:8]=3)[CH:3]3[CH2:4][N:1]([C:37](=[O:39])[CH3:38])[CH2:2]3)[CH:14]=2)[N:19]=[C:18]([O:23][CH3:24])[C:17]=1[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:30][CH:31]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1nc2ccc(C(O)(c3cnnn3C)C3CNC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: COc1nc2ccc(C(O)(c3cnnn3C)C3CN(C(C)=O)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.2 %

Procedure:
To a flask containing azetidin-3-yl(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (140 mg, 0.27 mmol, Intermediate 66: step d) was added dichloromethane (8 mL) which gave a suspension at room temperature. Et3N (0.13 mL, 0.9 mmol) was added, followed by acetic anhydride (0.3 mL, 0.32 mmol). After stirring at room temperature for 4 h, more Et3N (200 μL) was added along with more acetyl chloride (25 μL) and the suspension was heated to 35° C. for 18 h. The reaction was quenched with the addition of 1N NaOH (2 mL) and water (5 mL). The aqueous portion was extracted with dichloromethane (3×25 mL). The combined organics were dried over MgSO4, filtered and concentrated. The crude material was chromatographed on silica gel (5% MeOH-dichloromethane) to give the title compound (88 mg) as an off white solid. 1H NMR (500 MHz, CD3CN, racemate) δ 8.25 (dd, J=14.0, 1.9 Hz, 1H), 7.74 (dd, J=8.7, 2.6 Hz, 1H), 7.66 (d, J=4.4 Hz, 1H), 7.58-7.49 (m, 2H), 7.48-7.33 (m, 3H), 5.17 (s, 0.5H), 5.06 (s, 0.5H), 4.43-4.28 (m, 3H), 4.22-4.10 (m, 1H), 4.07-3.98 (m, 4H), 3.93 (dd, J=9.9, 6.0 Hz, 1H), 3.82 (dd, J=9.1, 5.6 Hz, 1H), 3.72 (t, J=8.6 Hz, 1H), 3.65-3.48 (m, 5H). MS (ESI) 560.1 [M+H]+.
Reaction SMILES: CCC[C@H](N[C@H](C([N:15]1[C@H:23](C(O)=O)C[C@H:21]2[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2)=O)C)C(OCC)=O.CC(N)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([C@@H]1C[C@H:53]2[C@H:48]([CH2:49][CH2:50][CH2:51][CH2:52]2)[NH:47]1)(O)=O.C([C@@H](N[C@H](C(O)=O)C)CCC)(OCC)=O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>>[CH:48]1([N:47]=[C:23]=[N:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: O=C(O)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Reactant: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Agent: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CC(C)(C)N
Solvent: CCN(CC)CC
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
WO 01/58868 discloses a method for preparation of perindopril erbumine comprising reacting benzyl ester of (2S,3aS,7aS)-2-carboxyperhydroindole, p-toluenesulfonate salt with (S,S) diastereoisomer of N-[(S)-1-carbethoxybutyl]-(S)-alanine in the presence of 0.4 to 0.6 moles of 1-hydroxybenzotriazole; 1 to 1.2 moles of dicyclohexylcarbodiimide and 1 mole of triethylamine at 77° C. to give the dipeptide compound, which on debenzylation gives perindopril.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:11][NH:12][CH3:13].O>CN(C=O)C>[CH3:11][N:12]([CH3:13])[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1nc2ccccc2[nH]1
Temperature: 200 °C
Yield: 88.5 %

Procedure:
[step 1] Commercially available 2-chloro-1H-benzo[d]imidazole (250 mg, 1.64 mmol) was dissolved in DMF (4.7 mL), dimethylamine (50% aqueous solution, 0.50 mL, 4.92 mmol) was added, and the mixture was stirred with heating at 200° C. for 30 min in an Emrys Optimizer microwave synthesizer. Water was added to the mixture, and the precipitated crystals were collected by suction filtration to give N,N-dimethyl-1H-benzo[d]imidazole-2-amine (234 mg, 89%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH2:31][CH2:32][OH:33]>COCCOC>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:30]([CH3:29])[CH2:31][CH2:32][OH:33])=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Reactant: CNCCO
Solvent: COCCOC
Product: CN(CCO)Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a suspension of 52 (1.2 g, 2.89 mmol) in DME (30 ml) was added 2-(methylamino)ethanol (2.17 g, 10 eq, 28.9 mmol) and the reaction mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated then partitioned between EtOAc/H2O and the EtOAc was collected, dried over Na2SO4, filtered and concentrated. The crude mixture was purified by column chromatography (8:2 EtOAc:MeOH) to afford title compound 85 (813 mg, 45% yield). 1H NMR (DMSO-d6) δ (ppm): 8.57 (d, J=5.48 Hz, 1H), 8.48 (m, 1H), 8.21 (m, 1H), 8.08 (s, 1H), 7.83 (d, J=8.02 Hz, 1H), 7.71 (t, J=8.61 Hz, 2H), 7.43 (d, J=8.22 Hz, 2H), 6.91 (d, J=5.48 Hz, 1H), 4.41 (t, J=5.48 Hz, 1H), 3.53 (m, 4H), 2.42 (t, J=6.46 Hz, 2H), 2.15 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH:6]=[N:7][OH:8].[Cl:14]N1C(=O)CCC1=O>C(Cl)Cl.O>[OH:8][N:7]=[C:6]([Cl:14])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Product: ON=C(Cl)c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Yield: 85.2 %

Procedure:
To a dried flask containing 3-(trifluoromethyl)benzaldehyde oxime (1.89 g, 10 mol) in methylene chloride (100 mL) was added N-chlorosuccinimide (1.40 g, 10.5 mmol) slowly at 0° C. The reaction mixture was warmed to 45° C. for 2 h, poured over ice, diluted with H2O (20 mL), and extracted with EtOAc (100 mL). The organic phase was washed with H2O (2×25 mL) and saline solution (25 mL), dried over sodium sulfate, concentrated in vacuo to give N-hydroxy -3-(trifluoromethyl)benzenecarboximidoyl chloride (2 g, 90% o). LCMS: 224.4 (M+H)+.
Reaction SMILES: [N+]([C:4]1[C:13]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-])=O.C1C2C(=CC=CC=2)C=CC=1.[N+:27]([O-])([OH:29])=[O:28].[N+](C1C2C(=CC=CC=2)C=CC=1)([O-])=O>>[N+:14]([C:9]1[C:8]2[C:13](=[CH:4][CH:5]=[CH:6][C:7]=2[N+:27]([O-:29])=[O:28])[CH:12]=[CH:11][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc2c([N+](=O)[O-])cccc12
Reactant: O=[N+]([O-])O
Agent: O=[N+]([O-])c1cccc2ccccc12
Solvent: c1ccc2ccccc2c1
Product: O=[N+]([O-])c1cccc2cccc([N+](=O)[O-])c12

Procedure:
The process for the production of 1,5-dinitronaphthalene according to the invention is based on the direct nitration of naphthalene by nitric acid having a concentration of 72–87 wt.-% without mononitronaphthalene isolation. The washing of the reaction products with water and acetone leads to 1,5-dinitronaphthalene of high purity [≧98 wt.-%]. The acetone and nitric acid used in the process may be recovered and returned into the process. 1,8-dinitronaphthalene is produced in the process as a by-product.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-].[Na+].[C:12]1([CH3:21])[C:13]([C:18](Cl)=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.Cl>O>[CH3:4][C:3]([CH3:6])([CH3:5])[CH:2]([NH:1][C:18](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH3:21])[C:7]([OH:9])=[O:8]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(C)(C)[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccccc1C(=O)NC(C(=O)O)C(C)(C)C
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
Racemic tert-butylglycine (502 mg, 3.83 mmol) was dissolved in water (10 mL) containing NaOH (153 mg, 3.83 mmol). This solution was cooled to 5° C. and treated with o-toluoyl chloride (0.501 mL, 3.83 mmol) followed by additional NaOH (153 mg, 3.83 mmol). The mixture was warmed to ambient temperature, stirred for 1.5 hours, recooled to 5° C., and treated with 1M HCl (pH 3). The thick precipitate that formed was collected by filtration and washed with cold water to provide 550 mg of the desired product as a white solid.
Reaction SMILES: [CH3:1]N(C)C=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CI>O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:1])=[C:9]([O:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH:8]=1
Reactant: CN(C)C=O
Reactant: Oc1ccc(Br)cc1OC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1ccc(Br)cc1OC1CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
To 60 ml of N,N-dimethylformamide solution containing 6.22 g (25.6 mmol) of 4-bromo-2-cyclobutoxyphenol obtained in Reference Example 5-(d) were successively added 3.54 g of potassium carbonate and 3.2 ml of methyl iodide, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene), and the obtained crude solid was recrystallized from hexane to obtain 3.90 g of the title compound as a colorless solid. (Yield: 59%)
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.CN(C)C=O.[CH:12]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CCCCCC.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]([C:19]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[S:20])[N:4]=[CH:5][N:6]=1
Reactant: Nc1nc[nH]n1
Reactant: S=C=NC1CCCCC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ncnn1C(=S)NC1CCCCC1
Yield: 14 %

Procedure:
The synthesis method of Example 1-(3) was applied. 3-Amino-1H-1,2,4-triazole (6.07 g), dimethylformamide (30 ml) and cyclohexyl isothiocyanate (20.5 ml) were used as reagents. After the reaction, the mixture was subjected to silica gel column chromatography (hexane-ethyl acetate), whereby 2.26 g of a white solid was obtained (yield 14%). The, solid was subjected to recrystallization from ethyl acetate to give colorless transparent crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:28][CH:29]1[C:33]([CH3:35])([CH3:34])[CH2:32][S:31][C:30]1([CH3:37])[CH3:36]>C(OCC)(=O)C.O1CCCC1>[CH3:36][C:30]1([CH3:37])[CH:29]([NH:28][C:12](=[O:14])[C@@H:9]([CH2:10][OH:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:33]([CH3:35])([CH3:34])[CH2:32][S:31]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: CC1(C)CSC(C)(C)C1N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)C(=O)NC1C(C)(C)CSC1(C)C
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.26 g. (11 mmole) of N-t-butoxycarbonyl-D-serine in 75 ml. of tetrahydrofuran is added 1.47 ml. (10 mmole) of triethylamine and the mixture cooled to -10° C. At this temperature is added 0.96 ml. (10 mmole) of ethyl chloroformate and stirring continued for 15 minutes. After cooling to -20° C., 1.6 g. (10 mmole) of dl-3-amino-2,2,4,4-tetramethyltetrahydrothiophene is added and the resulting mixture is allowed to warm to room temperature. Ethyl acetate is added and the mixture is washed twice with 50 ml. portions of 5% (by weight) aqueous citric acid, aqueous sodium bicarbonate (1×50 ml.) and saturated brine (1×50 ml.). The organic layer is dried (Na2SO4) and evaporated to dryness at reduced pressure to afford N(2,2,4,4-tetramethyltetrahydrothiophene-3-yl)-t-butoxycarbonyl-D-serine amide. This product is used without further purification in the next step. ##STR120##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.O=[C:11]1[CH2:16][CH2:15][N:14]([C@H:17]([CH3:21])[CH2:18][C:19]#[N:20])[CH2:13][CH2:12]1>>[NH2:20][CH2:19][CH2:18][C@H:17]([N:14]1[CH2:15][CH2:16][CH:11]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:12][CH2:13]1)[CH3:21]
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC2CCN([C@H](C)CCN)CC2)cc1

Procedure:
Using general procedure A with p-anisidine (738 mg, 6.00 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (1.11 g, 6.67 mmol) followed by general procedure J gave [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-amine as an orange oil (1.43 g, 86% over 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:27]=[CH:26][C:20]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][CH:4]=1)[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][C:23](=[O:24])[CH2:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([F:28])([F:29])[F:15])=[CH:27][CH:26]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]cc(CCNC(=O)CCc3ccc(C(F)(F)F)cc3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.3 g (1.57 mmol) 5-methoxytryptamine, 0.34 g (1.57 mmol) 4-(trifluoromethyl)hydrocinnamic acid (commercially available), 0.6 g (1.8 mmol) TBTU and 0.6 g (4.6 mmol) DIPEA in 6 mL DMF was shaken for 3 h at room temperature. 50 mL water was added and the mixture was extracted with DCM. The combined organic phases were washed with water, dried with MgSO4 and evaporated to dryness to yield the title compound which was used without further purification in the consecutive step.