Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(N2CCOCC2)ccc1N
Reaction time: 12 h
Yield: 99.5 %

Procedure:
To a suspension of 4-(3-methoxy-4-nitrophenyl)morpholine (100 g, 0.42 mol) in tetrahydrofuran (2 L) was added palladium on carbon (10%, 10 g). The mixture was stirred under an atmosphere of hydrogen for 12 hours. The catalyst was removed by filtration and the filtrate was evaporated to afford the product 2-methoxy-4-morpholinoaniline (87 g, yield 100%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:40][CH2:41][C:42]1[NH:43][C:44](=[O:52])[C:45]2[CH:51]=[CH:50][CH:49]=[N:48][C:46]=2[N:47]=1>CN(C=O)C>[O:52]=[C:44]1[NH:43][C:42]([CH2:41][NH:40][C:9](=[O:11])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:47][C:46]2[N:48]=[CH:49][CH:50]=[CH:51][C:45]1=2
Reactant: O=C(O)CCc1ccccc1
Reactant: NCc1nc2ncccc2c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(CCc1ccccc1)NCc1nc2ncccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To 3-phenylpropionic acid [501-52-0] (66.6 mg, 0.444 mmol) in DMF (4 ml) was added EDCI [25952-53-8] (102 mg, 0.532 mmol), HOBt [2592-95-2] (8 mg, 0.059 mmol) and NMM [109-02-4] (0.15 ml, 1.18 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h, and then was added to a solution of the salt of 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one (CH3CO2H, HBr) (100 mg) in DMF (2 ml). Stirring was continued for 18 h, the solvents were evaporated and the residue as redissolved in EtOAc/THF and a saturated solution of ammonium chloride. The inorganic layer was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtrated and evaporated. Column chromatography with CH2Cl2/MeOH 9:1, followed by trituration with TBME gave N-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-3-phenyl-propionamide (43.1 mg, 47%) as a off-white solid, MS (m/e): 309 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH3:14])[CH:5]=1>CO.C1COCC1.[C].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(N)c(OC)c1
Temperature: 25 °C
Yield: 104.1 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzoic acid methyl ester (150 g) in methanol (600 mL) and THF (300 mL), 10% palladium-carbon (15 g) was added and the reaction mixture was agitated at 50° C. to 64° C. under hydrogen pressure of 0.9 MPa(s) for 6.5 hours. After allowing cool the reaction solution to room temperature, 134 g of the title compound was obtained by filtering the reaction solution on celite and condensing the obtained filtrate under reduced pressure. The physical properties was in agreement with the reported values (CAS#41608-64-4).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8]([OH:10])=O)(=[O:3])[CH3:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C(C)=CC=CC=1C>ClCCl>[CH2:21]([NH:28][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]([O:14][C:15](=[O:17])[CH3:16])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)Oc1cc(C(=O)O)cc([N+](=O)[O-])c1OC(C)=O
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(=O)Oc1cc(C(=O)NCc2ccccc2)cc([N+](=O)[O-])c1OC(C)=O

Procedure:
0.75 g of 3,4-diacetoxy-5-nitrobenzoic acid was converted to the corresponding acid chloride as described in Example 43. It was dissolved in 5 ml of dichloromethane and added to a solution containing 0.27 ml of benzylamine and 0.5 ml of 2,6-lutidine in 7 ml of dichloromethane. Yield 0.95 g (96%), a viscous oil.
Reaction SMILES: [Li].[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[CH:3]1.[CH3:20][C:21]([NH:24][Si:25](Cl)([CH3:27])[CH3:26])([CH3:23])[CH3:22]>C1COCC1>[CH2:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][N:11]1[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([Si:25]([CH3:27])([CH3:26])[NH:24][C:21]([CH3:23])([CH3:22])[CH3:20])[CH:3]=1
Reactant: C1=C(N2Cc3ccccc3C2)c2ccccc2C1
Reactant: CC(C)(C)N[Si](C)(C)Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)C1C=C(N2Cc3ccccc3C2)c2ccccc21
Yield: 99 %

Procedure:
2,3-Dihydro-2-(1H-inden-3-yl)-1H-isoindole lithium salt (1.64 g, 6.86 mmol) was dissolved in 10 mL of THF and this solution was added dropwise to N-(tert-butyl)-N-(1-chloro-1,1-dimethylsilyl)amine reagent (1.47 g, 8.91 mmol, 1.3 eq) in 40 mL of THF. The reaction was allowed to stir for several hours, and THF and excess electrophile were removed under reduced pressure. The crude oil was extracted into hexane and filtered through a medium porosity frit. Solvent was removed under reduced pressure to give the desired product as an emerald green oil (2.40 g, 6.79 mmol, 96.5 percent).
Reaction SMILES: [CH:1]([O-:3])=O.[Na+].Br[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[CH:11][CH:10]=[CH:9]2>C(#N)C.CS(C)=O.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>[F:16][C:15]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[CH:1]=[O:3]
Reactant: O=C[O-]
Reactant: Fc1cc2ncccc2cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: O=Cc1cc2cccnc2cc1F
Temperature: 120 °C
Yield: 10.4 %

Procedure:
To a suspension of Pd(PPh3)4 (1.27 g, 1.1 mmol) and sodium formate (13.8 g, 132 mmol, 6 e.q.) in acetonitrile (30 mL) was added a solution of 6-bromo-7-fluoro quinoline (5 g, 22 mmol) in DMSO (30 mL). The reaction mixture was heated at 120° C. under a CO atmosphere (1 MPa) for 4 h, cooled to rt and concentrated under reduced pressure. The residue was partitioned between water (100 mL) and ethyl acetate (150 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The reside was purified by column choromatography, eluting with petroleum:ethyl acetate=10:1˜3:1 to give the title compound as a white solid (400 mg, 10.4%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.95 (s, 1H), 8.46 (m, 1H), 8.20 (m, 1H), 7.75 (d, 1H), 7.53 (m, 1H).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:26])[CH:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:26])[CH:19]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:13][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:16]
Reactant: CCCCCC(Br)C(=O)OCC
Reactant: Oc1ccc(C2=CCCCCC2)cc1
Product: CCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)OCC

Procedure:
Analogously to the process described in Example 1, 13.2 g of p-(1-cycloheptenyl)-phenol and 28 g of 2-bromoheptanoic acid ethyl ester give α-[p-(1-cycloheptenyl)-phenoxy]-heptanoic acid ethyl ester, of boiling point 160°-164° C, as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:6][CH:7]=[C:8]([CH2:11][C:12]#[N:13])[C:9]#[N:10])([CH3:5])[CH3:4].[OH-].[K+]>CCO.O>[NH2:13][C:12]1[N:6]([C:3]([CH3:5])([CH3:4])[C:2]([F:14])([F:15])[F:1])[CH:7]=[C:8]([C:9]#[N:10])[CH:11]=1
Reactant: CC(C)(NC=C(C#N)CC#N)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(n1cc(C#N)cc1N)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-(((1,1,1-trifluoro-2-methylpropan-2-yl)amino)methylene)-succinonitrile (187.2 mg, 0.862 mmol) in EtOH (539 μl) was added to a solution of KOH (87 mg, 1.551 mmol) in water (539 μl) at RT. After being stirred at RT for 4 h, the reaction mixture was concentrated under reduced pressure. The residual brown solid was taken up in water and sonicated. The resulting precipitate was collected by filtration, dissolved in EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a brown solid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:30][CH2:31][CH3:32]>C(OCC)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:30][CH2:31][CH3:32])=[O:11]
Reactant: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CN
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CNC(=O)Cc1c(Cl)cccc1Cl
Reaction time: 0.17 h

Procedure:
A solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 103 mg of the acid) in 2 ml of diethyl ether was added to a solution of 140 mg of 5'-amino-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine in 2.5 ml of 0.2M sodium hydroxide solution, the mixture was shaken vigorously for 10 minutes and then filtered. The solid was washed with 5 ml of water and 50 ml of diethyl ether, and then recrystallized from acetone to give 60 mg of 5'-[2-(2,6-dichlorophenyl)-acetamido]-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine in the form of a white solid of melting point 249°-250° C.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1)[C:3]([O:5][CH3:6])=[O:4].Cl(O)(=O)(=O)=O.C(=O)([O-])O.[Na+].C(O[C:30]([CH3:33])([CH3:32])[CH3:31])(=O)C>>[C:30]([O:1][CH:2]([C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1cn2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1cn2ccccc2n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 55 %

Procedure:
To a solution of methyl 2-hydroxy-2-{imidazo[1,2-a]pyridin-2-yl}acetate (25b) (153 mg, 0.74 mmol) in tert-butyl acetate (12 mL) at 0° C. was added perchloric acid (1.5 mL). The mixture was stirred at 0° C. for 15 minutes and at room temperature for 45 minutes before being poured into a saturated aqueous solution of sodium hydrogencarbonate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 50/50) to provide the desired product (25c) (108 mg, 0.41 mmol, 55%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:24]=[C:23]([CH2:25][N:26]([CH3:38])[S:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=3)(=[O:29])=[O:28])[CH:22]=[CH:21][C:11]=2[O:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:24]=[C:23]([CH2:25][N:26]([CH3:38])[S:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=3)(=[O:29])=[O:28])[CH:22]=[CH:21][C:11]=2[O:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(F)cc(-c2cc(CN(C)S(=O)(=O)c3ccc(F)c(Cl)c3)ccc2OCC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)cc(-c2cc(CN(C)S(=O)(=O)c3ccc(F)c(Cl)c3)ccc2OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a solution of TFA/DCM (1:3, 80 mL) was added tert-butyl 2-(3-fluoro-5-methoxyphenyl)-4-((3-chloro-4-fluoro-N-methylphenylsulfonamido)methyl)phenoxyacetate (11) (15 g, 26 mol) and the mixture was stirred at room temperature for 2 h. The solvent was evaporated and the resulting solid was rinsed by petroleum ether/EtOAc (10:1 mixture) to yield 2-(3-fluoro-5-methoxyphenyl)-4-((3-chloro-4-fluoro-N-methylphenylsulfonamido)methyl)phenoxyacetic acid (Example 37) (9 g, 67%). 1HNMR (CD3CN, 300 MHz): δ 7.93 (d, 1H), 7.78 (m, 1H), 7.45 (t, 1H), 7.20 (m, 2H), 6.95 (m, 3H), 6.67 (d, 1H), 4.65 (s, 2H), 4.15 (s, 2H), 3.81 (s, 3H), 2.61 (s, 3H). MS (ES-API): MH−=510.0. HPLC (Method A) tR=2.28 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.Br[C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]#[N:33])=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1Br
Reactant: Oc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of 51.4 g of 4-chlorophenol in 500 ml of dry N,N-dimethylformamide (DMF) was added to a suspension of 20 g of 60% sodium hydride in 800 ml of dry DMF under nitrogen. After 30 min at 25° C., 1 g of 18-crown-6 was added. After the addition of 73 g of 2-bromobenzonitrile in 500 ml of dry DMF, the mixture was heated at 100° C. for 16 h. After concentration in vacuo, 2N sodium hydroxide and ethyl acetate were added. The organic layer was separated, washed with 2N sodium hydroxide and water, dried over magnesium sulfate, and evaporated to dryness. The residue was recrystallized from methanol to give in 60% yield 2-(4-chlorophenoxy)benzonitrile. To a suspension of 6 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran (THF) were added under nitrogen 20 g of 2-(4-chlorophenoxy)benzonitrile. The mixture was heated at reflux for 3 h, cooled, and 25 ml of 1N sodium hydroxide were added dropwise. The precipitate formed was filtered off and washed with diethyl ether. The filtrate was evaporated to dryness, dissolved in ethyl acetate and acidified with a saturated solution of hydrochloric acid in ethanol. The precipitate was collected and recrystallized from ethanol to give in 95% yield 2-(4-chlorophenoxy)benzenemethanamine hydrochloride. mp 253° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]#[C:14]C(C)(O)C)[CH:7]=[CH:6]2.[OH-].[Na+].O>C1(C)C=CC=CC=1>[C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)#[CH:14]
Reactant: COc1ccc2cc(C#CC(C)(C)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C#Cc1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A mixture of 4-(6-methoxy-2-naphthyl)-2-methyl-3-butyn-2-ol (16.9 g, 69.7 mmol), powdered sodium hydroxide (3.7 g, 93 mmol) in toluene (350 mL) was refluxed for 16 hours in a flask equipped with a Dean Stark water trap. The mixture was allowed to cool to room temperature and the solvent was evaporated. The residue was purified by flash chromatography using 2.5-3% ethyl acetate in hexane as an eluant. Drying at 68° C. for 20 minutes afforded 2-ethynyl-6-methoxynaphthalene as a light yellow solid (10.1 g, 80%), mp: 111-112° C. Mass spectrum (+EI, M+) m/z 182. 1HNMR (400 MHz, DMSO-d6): δ8.00 (s, 1H), 7.8-7.85 (m, 2H), 7.45 (dd, 1H, J=8.4 Hz and 1.6 Hz), 7.35 (d, 1H, J=2.4 Hz), 7.2 (dd, 1H, J=8.9 Hz and 2.6 Hz), 4.2 (s, 1H), and 3.9 ppm (s, 3H). Elemental Analysis for C13H10O: Calculated: C, 85.69; H, 5.53; N, 0.00. Found: C, 85.50; H, 5.22; N, 0.07.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:8])(=O)C.N1CCCC1.Cl>C(#N)C>[SH:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:8]
Reactant: CCOC(=O)c1cccc(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1
Agent: Cl
Solvent: C1CCNC1
Solvent: CC#N
Product: CCOC(=O)c1cccc(NC(=O)C(CS)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
Ethyl 3-[(2-acetylthiomethyl-3-phenylpropionyl)-amino]benzoate (compound of Example 68-(a)-[1]) (2.0 g) is dissolved in a 80% aqueous acetonitrile, and thereto is added pyrrolidine (0.5 g), and the mixture is stirred at room temperature for 30 minutes. The mixture is adjusted to pH 5.0 with 10% hydrochloric acid, and acetonitrile is distilled off under reduced pressure, and the residue is extracted with ethyl acetate (50 ml). The extract is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure. The aqueous solution is extracted with ethyl acetate (50 ml), and the extract is dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure to give the title compound (0.5 g) as an oily substance. IR (film; cm-1): 1710, 1660 Elementary analysis for C19H21NO3S: Calcd. (%): C,66.45; H,6.16; N,4.08; S,9.34 Found (%): C,66.37; H,6.25; N,4.04; S,9.05
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>O1CCCC1.[Zn]>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[O:16]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: N#Cc1ccc(F)cc1Br
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
A 0.1 g/mL suspension of highly activated zinc powder in tetrahydrofuran (33 mL, 50 mmol) was transferred via cannula to a solution of 2-bromo-4-fluorobenzonitrile (5.0 g, 25 mmol) in anhydrous tetrahydrofuran (100 mL) at room temperature under an atmosphere of argon. The mixture was stirred at room temperature for 5 h and then sonicated with ultrasound for 30 min. The excess zinc was allowed to settle over night at −20° C. The solution on top was transferred via cannula to another flask under argon atmosphere and cooled to −20° C. To this was added 1 M CuCNx2LiBr complex solution in tetrahydrofuran (26.3 mL). The resulting solution was stirred at −20° C. for 10 min and at 0° C. for 25 min, then it was cooled to −25° C. and 3-bromobenzoyl chloride was added. The mixture was stirred for 1 h while the temperature was kept between −25° C. and −15° C., and then it was stored in a refrigerator at 0° C. for two and a half days. The reaction was quenched by the addition of saturated ammonium chloride solution. The mixture was diluted with ethyl acetate, the phases were separated and the organic phase was washed with 1 M hydrochloric acid and 1 M sodium carbonate solution, dried over magnesium sulfate and evaporated. Purification by column chromatography using a gradient of gradually increasing concentration of ethyl acetate in heptane (0-40%) gave 5.58 g of the title product (73% yield): 1H NMR (CDCl3) δ 7.96 (t, J=1.64 Hz, 1 H), 7.88 (dd, J=8.46, 4.93 Hz, 1 H), 7.80 (m, 1 H), 7.72 (m, 1 H), 7.44-7.37 (m, 2 H), 7.35 (dd, J=8.08, 2.53 Hz, 1 H); MS (EI) m/z 304, 306 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([OH:18])=O)[CH3:15])=[N:9]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([NH:34][CH:31]3[CH2:33][CH2:32]3)=[O:18])[CH3:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(Oc1ncn(-c2ccc(Br)cc2)n1)C(=O)O
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(Oc1ncn(-c2ccc(Br)cc2)n1)C(=O)NC1CC1
Yield: 77 %

Procedure:
The process was carried out according to Example 59, starting with 3 g of the compound of Example 37, 2.4 g of carbonyldiimidazole and 1.1 g of cyclopropylamine. product was recrystallized from ethanol to obtain 2.6 g of the desired product, m.p. 170°-172°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1.C[Si]([N:32]=[C:33]=[O:34])(C)C>ClCCCl.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([C:33]([NH2:32])=[O:34])[CH2:24][CH2:25]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCNCC1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: NC(=O)N1CCC(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)CC1
Reaction time: 60 h

Procedure:
To a solution of 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-piperidin-4-ylmethyl-piperazin-2-one (20 mg, 0.047 mmol) in a mixture of 1,2-dichloroethane (1 mL) and THF (1 mL) is added trimethylsilyl isocyanate (0.006 mL, 0.05 mmol) and stirred 60 hours. The reaction is concentrated and purified by column chromatography (silica, 20% methanol/dichloromethane) to provide 4-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-piperidine-1-carboxylic acid amide. 1H NMR (300 MHz, CD3OD) d 8.09 (s, 1H), 8.02 (d, 2H), 7.53 (dd, 1H), 3.90 (d, 4H), 3.49 (d, 4H), 3.30-3.24 (m, 2H), 2.65 (dt, 2H), 1.49 (d, 2H), 1.12-0.97 (m, 2H); MS (Ion spray) 471 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1)(O)(=O)=O>>[CH3:25][N:24]([C:21]1[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=1)[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Product: CN(c1ccc(O)cc1)c1nc2ccccc2nc1Cl

Procedure:
2,3-Dichloroquinoxaline (prepared according to the method of H M Woodburn, J. Org. Chem., 1958, 23, 262) was reacted with 4-(N-methylamino)phenol sulfate, following essentially the same procedure as that described in Example 1 Part (a), to give 4-[N-methyl-N-(3-chloro-2-quinoxalinyl)amino]phenol. Proton magnetic resonance spectrum (d6 -acetone; δ in ppm): 7.5-8.1 (4H, m, quinoxaline protons); 7.1 (4H, m, phenoxy protons); 3.5 (3H, s, N-CH3).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:31](O)=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8].[CH3:34][O:35][C:36](=[O:41])[C@H:37]([CH2:39][OH:40])[NH2:38].C(N(CC)CC)C>C(#N)C>[CH3:34][O:35][C:36](=[O:41])[C@H:37]([CH2:39][OH:40])[NH:38][C:31](=[O:32])[C@H:20]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[NH:19][C:17](=[O:18])[C@H:10]([CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)[NH:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C1CC[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)N1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
L-Pyroglutamyl-L-histidyl-L-tryptophan (IV) (0.452 g) and L-serine methyl ester (V) hydrochloride (0.155 g) in dry acetonitrile (50 ml) are treated with triethylamine (0.14 ml) and DCI (0.227 g) in dry acetonitrile (5 ml) at 0°C. After stirring at room temperature for 24 hours, the reaction mixture is evaporated to dryness. The residue is dissolved in methanol and the dicyclohexylurea is removed by filtration. The filtrate is concentrated to dryness to L-pyroglutamyl-L-histidyl-L-tryptophyl-L-serine methyl ester (VI).