Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:26][CH:27]=2)=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[CH:20]=[N:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[S:26][CH:27]=3)=[CH:17][CH:16]=2)=[N:3]1
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Reactant: COC(=O)Cc1cn(C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (255 mg), 5-chloromethyl-2-(2-phenyl-4-thiazolylmethoxy)pyridine (475 mg), potassium carbonate (415 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [1-methyl-3-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (581 mg, yield 86%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 85–86° C.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[C:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)c1nc(CCl)cs1
Product: CCOP(=O)(Cc1csc(C(C)(C)C)n1)OCC
Temperature: 160 °C
Reaction time: 20 h
Yield: 90.2 %

Procedure:
A mixture of 2-tert-butyl-4-chloromethyl-1,3-thiazole (8.66 g) and triethyl phosphite (15.7 g) was stirred at 160° C. for 20 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2 to 1:0, v/v) to give diethyl [(2-tert-butyl-1,3-thiazol-4-yl)methyl]phosphonate as a colorless oil (12.0 g, yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=O)[NH:8][CH:7]=[N:6]2.C(N(C(C)C)CC)(C)C.O(Cl)[Cl:22].[P+3].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:22][C:9]1[C:10]2=[C:2]([Cl:1])[CH:3]=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: ClOCl
Reactant: O=c1[nH]cnn2ccc(Cl)c12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [P+3]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccn2ncnc(Cl)c12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a solution of 5-chloropyrrolo[2,1-f][1,2,4]triazin-4 (3H)-one (5.00 g, 29.5 mmol) in toluene (100 mL) at rt under nitrogen was added diisopropylethylamine (5.14 mL, 29.5 mmol) followed by phosphorus(III) oxychloride (8.25 mL, 88.5 mmol). The mixture was heated at 100° C. for 20 h and was then cooled to rt. The reaction was slowly added to saturated aqueous sodium bicarbonate solution (500 mL) at 0° C. After the addition was complete, the mixture was stirred at rt for 30 min. The aqueous phase was extracted with ethyl acetate (3×500 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give the crude product (3.73 g, 67%) as a yellow solid which was used without further purification. 1H NMR (CDCl3) δ 8.03 (s, 1H), 7.70 (d, 1H, J=2.8 Hz), 6.84 (d, 1H, J=2.8 Hz); MS(ESI+) m/z 188.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1.[CH3:19][OH:20]>>[CH3:19][O:20][CH2:18][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1
Reactant: CO
Reactant: NS(=O)(=O)c1nc2ccc(OCC3CO3)cc2s1
Product: COCC(O)COc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-(2,3-epoxypropoxy)benzothiazole-2-sulfonamide (2.15 gm, 7.5 mmol) in methanol (60 mL) containing five drops of concentrated sulfonic acid was stirred at room temperature, monitoring reaction progress by TLC until complete (3 hours). The reaction mixture was poured into ice water and the crude product extracted into ethyl acetate which was dried (Na2SO4) and evaporated. The residue was dissolved in a minimum amount of acetonitrile and diluted with chloroform. Upon standing overnight product crystallized (1.8 gm). After several recrystallizations from acetonitrile/chloroform pure product was obtained (1.2 gm), m.p. 153°-155° C.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[O:11]=[C:12]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)CC)C>C(Cl)Cl>[CH3:36][O:35][N:34]([CH3:33])[C:17]([CH:14]1[CH2:15][CH2:16][C:12](=[O:11])[CH2:13]1)=[O:19]
Reactant: O=C1CCC(C(=O)O)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCC(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 1-hydroxybenzotriazole (7.91 g, 58.5 mmol), 3-oxo-1-cyclopentanecarboxylic acid (5.00 g, 39.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.22 g, 58.5 mmol) in 44 mL DCM under nitrogen was added N,O-dimethylhydroxylamine hydrochloride (5.71 g, 58.5 mmol) followed by triethylamine (8.16 mL, 58.5 mmol) in portions. The reaction mixture became warm and was cooled with an ice bath for the remainder of TEA addition, then stirred at ambient temp under nitrogen for 2 d. The reaction mixture was concentrated in vacuo, and taken up in EA (300 mL), washed with water, sat'd aq. Sodium bicarbonate, brine, and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo, to give (rac)-N-methoxy-N-methyl-3-oxocyclopentanecarboxamide as a yellow oil which was used without further purification. 1H NMR (400 MHz, CDCl3-d) δ ppm 3.74 (s, 3 H), 3.41-3.61 (m, 1 H), 3.23 (s, 3 H), 2.52-2.64 (m, 1 H), 2.34-2.50 (m, 2 H), 2.08-2.31 (m, 3 H).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)C.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH2:26].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:16]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1C(F)(F)F)C1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a cold (0° C.) solution of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinecarboxylic acid (3.68 g, 16.1 mmol, 1.00 equiv), {[2-(trifluoromethyl)phenyl]methyl}amine (2.57 mL, 18.3 mmol, 1.14 equiv), and DMAP (392 mg, 3.21 mmol, 0.200 equiv) in CH2Cl2 (100 mL) was added diisopropylethylamine (DIEA, 3.49 ml, 20.1 mmol, 1.25 equiv) and EDCI (3.11 g, 20.1 mmol, 1.25 equiv). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature overnight. The solution was washed with H2O, sat NaHCO3 (aq) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was stirred in CH2Cl2 (60 mL) and TFA (60 mL) for 20 min at room temperature, and then the solvents were removed in vacuo. The residue was diluted with CH2Cl2, and the resulting solution was neutralized carefully with sat NaHCO3 (aq). Solid NaCl was used to saturate the aqueous layer, which was then extracted 3 times with ethyl acetate. The organic layers were combined, dried with Na2SO4, filtered and concentrated to afford 4.43 g (97% yield) of the desired product. MS (ES+): m/e 287.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[N:3]=1.[CH3:18][NH2:19]>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[N:3]=[C:2]([NH:19][CH3:18])[N:7]=1
Reactant: CN
Reactant: Clc1nc(Cl)nc(N2CCc3ccccc32)n1
Solvent: ClCCl
Product: CNc1nc(Cl)nc(N2CCc3ccccc32)n1
Yield: 82 %

Procedure:
To a mixture of 2,4-dichloro-6-indolin-1-yl-1,3,5-triazine (30 g, 112 mM) and methylene chloride (300 ml) at 0° C. was added a 33% solution of methylamine (30 ml) in IMS. The mixture was allowed to attain ambient temperature. After two days the mixture was washed with water. The methylene chloride layer was separated, dried (MgSO4), and the solvent evaporated. The resultant solid was recrystallised from toluene: ethanol (70:30). There was thus obtained 2-chloro-4-indolin-1-yl-6-methylamino-1,3,5-triazine (24 g, 82% yield). m.p 239°-240° C.; NMR: DMSOd6 : 2.75-2.95 (3H, complex, rotamers, NHMe), 3.05-3.2 (2H,t,CH2 --CH2N--), 4.0-4.2(2H,q,CH2CH2N) (rotamers), 6.9-7.3(3H, complex, aromatic), 7.9-8.1 (1H, broad, aromatic), 8.1-8.4(1H, broad, NH).
Reaction SMILES: [CH:1]1([N:7]2[C:20](=[O:21])[C:18]3=[C:19]4[C:14](=[CH:15][CH:16]=[CH:17]3)[C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=[C:10]4[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[N+:39]([O-:41])=[O:40].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(O)C>[CH:1]1([N:7]2[C:20](=[O:21])[C:18]3=[C:19]4[C:14](=[CH:15][CH:16]=[CH:17]3)[C:13]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[N+:39]([O-:41])=[O:40])=[CH:12][CH:11]=[C:10]4[C:8]2=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)OB(c2ccc3c4c(cccc24)C(=O)N(C2CCCCC2)C3=O)OC1(C)C
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1c2cccc3c(-c4ccc(Cl)cc4[N+](=O)[O-])ccc(c23)C(=O)N1C1CCCCC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
In a Schlenk tube, 2 g of N-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-naphthalene-1,8-dicarboximide (4.93 mmol), 1.75 g of 1-bromo-4-chloro-2-nitrobenzene (7.40 mmol) were dissolved in 80 mL of toluene, 1.6 g of potassium carbonate (11.6 mmol) in 8 mL of water and 0.8 mL of ethanol are added, and the mixture was thoroughly degassed. After addition of 800 mg of tetrakis(triphenyl-phosphine)palladium(0) (0.717 mmol), the mixture was degassed again and stirred at 80° C. under argon for 2 days.
Reaction SMILES: Cl.[C:2]([NH:5][CH2:6][S:7][CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])(=[O:4])[CH3:3].O1CCOCC1.[O-2].[Mg+2].[C:22]([O:26][C:27](N=[N+]=[N-])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(OCC)(=O)C.C1C=CC=CC=1.O>[C:22]([O:26][C:27]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7][CH2:6][NH:5][C:2](=[O:4])[CH3:3])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)NCSC[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)NCSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
22.8 grams (0.1 mole) of S-acetamidomethylcysteine hydrochloride are dissolved in 250 ml. of 50% dioxane (peroxide-free) in a 500 ml. 3-neck flask equipped with a mechanical stirrer and condenser. 12 grams of magnesium oxide (0.3 mole) are added, and the mixture is stirred at room temperature for 30 minutes. 15.7 grams (0.11 mole) of redistilled t-butoxycarbonylazide are added, and the mixture is stirred for 20 hours in an oil bath at 45° C. The reaction mixture is then cooled to room temperature, and 1 liter of water is added. The aqueous mixture is washed with 2 × 250 ml. of ethyl acetate, cooled in an ice bath, and acidified to pH 3 with 50% citric acid. The acidic solution is then saturated with sodium chloride and extracted with ethyl acetate. The extracts are washed twice with 200 ml. of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to yield an amorphous solid. The solid is dissolved in warm ethyl acetate, and 2 volumes of benzene are added. Upon standing at room temperature, the product crystallizes and, after filtration, is washed with benzene and dried in vacuo. A second and third crop are obtained by adding benzene to the filtrates and seeding. After drying in vacuo, 11 grams of N-t-butoxycarbonyl-S-acetamido-methylcysteine, m.p. 110° - 112° C., are obtained.
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13](=O)[CH3:14])[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]1([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[CH:13]([NH:19][CH:16]2[CH2:18][CH2:17]2)[CH3:14])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: NC1CC1
Reactant: CC(=O)c1cc(F)ccc1C1=CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(NC1CC1)c1cc(F)ccc1C1=CCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 132.6 %

Procedure:
To a solution of 510 mg (2.49 mmol) of 1-[2-(cyclopent-1-en-1-yl)-5-fluorophenyl]ethanone in 5 mL of methanol is added 0.5 g of 3 Å molecular sieves followed by addition of 285 mg (5 mmol) of cyclopropylamine and 375 mg (6.24 mmol) of acetic acid. The reaction mixture is stirred for 90 min at reflux. The reaction mixture is then cooled to 0° C. and 235 mg (3.74 mmol) of sodium cyanoborohydride are slowly added. The reaction mixture is further stirred for 2 hours at reflux. The cooled reaction mixture is filtered over a cake of diatomaceous earth and the cake is washed by ethyl acetate. The aqueous phase is extracted by ethyl acetate and the combined organic extracts are washed by a 1N aqueous solution of sodium hydroxide followed by a saturated aqueous solution of NaCl and dried over a ChemElut™ cartridge. Vacuum concentration yields 810 mg of crude N-{1-[2-(cyclopent-1-en-1-yl)-5-fluorophenyl]ethyl}cyclopropanamine as a brown oil used as such in the next step: (M+H)=246.
Reaction SMILES: [F:1][C:2]1[C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[C:14]([F:20])[C:13]([F:21])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:22]([O-])([O-])[O:23][CH2:24][CH3:25].C(OC(=O)C)(=O)C>>[CH2:24]([O:23][CH:22]=[C:6]([C:4](=[O:5])[C:3]1[CH:12]=[C:13]([F:21])[C:14]([F:20])=[C:15]([O:16][CH:17]([CH3:18])[CH3:19])[C:2]=1[F:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:25]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC(C)C)c1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(OC(C)C)c1F

Procedure:
Ethyl 2,4,5-trifluoro-3-isopropyloxybenzoylacetate (2.9 g) was stirred together with ethyl orthoformate (2.4 g) and acetic anhydride (2.8 g) at 140° C. for 1 hour while removing distillate. The reaction mixture was concentrated under reduced pressure at the same temperature. After the residue was allowed to cool, a process of adding toluene (10 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethyl 3-ethoxy-2-(2,4,5-trifluoro-3-isopropyloxybenzoyl)acrylate obtained as the residue was dissolved in chloroform (20 ml). N-(tert-Butoxycarbonyl)-2,4-difluoro-m-phenylenediamine (900 mg) was added to a half of this solution. The resultant mixture was concentrated under reduced pressure. Anhydrous potassium carbonate (1.3 g) and N,N-dimethylformamide (2.5 ml) were added to the resultant residue, and the mixture was stirred at 90° C. for 10 minutes. The reaction mixture was allowed to cool, and chloroform (50 ml) and distilled water (300 ml) were added to conduct liquid separation. A chloroform layer was washed twice with distilled water (300 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Deposits were dispersed in ethanol, collected by filtration and washed with ethanol to obtain the title compound (1.18 g) as a pale yellow powder.
Reaction SMILES: Br[CH2:2][C:3]1[S:18][C:6]2[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:19]([O:21][CH3:22])=[O:20].[CH3:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][C:25]1=[O:33]>>[CH3:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]([CH2:2][C:3]2[S:18][C:6]3[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=3[C:4]=2[C:19]([O:21][CH3:22])=[O:20])[C:25]1=[O:33]
Reactant: Cn1c(=O)[nH]c2ccccc21
Reactant: COC(=O)c1c(CBr)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Product: COC(=O)c1c(Cn2c(=O)n(C)c3ccccc32)sc2c1c(=O)n(C)c(=O)n2CC(C)C

Procedure:
The subtitle compound was prepared by the method of example 1 step c) using the product of example 1 step b) and N-methylbenzimidazolone.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11]Br)=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>O.C1(C)C=CC=CC=1>[C:22]([O:21][C:20]([NH:19][CH:16]1[CH2:15][CH2:14][N:13]([CH2:11][CH2:10][C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][CH:2]=2)[CH2:18][CH2:17]1)=[O:26])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: BrCCc1coc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CCc2coc3ccccc23)CC1

Procedure:
10 mmol of 2-(benzofuran-3-yl)-1-bromoethane, 9.62 mmol of tert-butyl 4-piperidyl-carbamate, 2.65 g of potassium carbonate and 0.65 g of tetrabutylammonium sulphate are added to 10 ml of toluene. After refluxing for 12 hours, the mixture is taken up in water. The organic phase is then washed with water, dried and then filtered. Evaporation under reduced pressure allows the expected product to be isolated.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8]P(OCC)(OCC)=O)=[O:7].[CH3:17][C:18]1([CH3:29])[C:27](=O)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:19]1>O1CCCC1>[CH2:4]([O:5][C:6]([CH2:8][C:27]1[C:18]([CH3:29])([CH3:17])[O:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:7])[CH3:3]
Reactant: CC1(C)Oc2ccccc2CC1=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1=Cc2ccccc2OC1(C)C
Reaction time: 1 h

Procedure:
25 g (0.6 mol) of sodium hydride dispersion (57% in mineral oil) are substantially freed of mineral oil by repeated washing with n-hexane and are then covered with a layer of 500 ml of dried tetrahydrofuran. Under a nitrogen atmosphere and while cooling in an ice bath, 134 g (0.6 mol) of phosphonoacetic acid triethyl ester of formula (H5C2O)2P(=O)CH2C(=O)OC2H5 are added dropwise thereto within a period of 1 hour. The mixture is stirred for a further 1 hour at 0°. To the homogeneous solution there is then added dropwise within a period of 30 minutes a solution of 88.57 g (0.5 mol) of 2,2-dimethyl-3-oxo-chroman [F. Camps et al., J. Heterocyclic Chem. 22, 1421 (1985)] in 300 ml of tetrahydrofuran. The mixture is stirred overnight at room temperature. The solution is then concentrated to approximately 350 ml in vacuo and poured onto 3 liters of ice-cold phosphate buffer solution (pH=6). The mixture is extracted with diethyl ether. The combined organic phases are washed with water and dried over sodium sulfate and then concentrated by evaporation in vacuo. The yellow residue is chromatographed on 4 kg of silica gel (0.040-0.063 mm) with toluene as eluant, yielding 60.3 g (49% of the theoretical yield) of 3-ethoxycarbonylmethyl-2,2-dimethyl-2H-chromene in the form of a light-yellow oil.
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:7][CH2:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:1])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C1NC(=O)c2c(CCCCCCCCN3CCCC3)cccc21
Reactant: NN
Solvent: CO
Product: NCCCCCCCCN1CCCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 8-pyrrolidinyloctylphthalimide (263 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH2:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:11][C:10]([NH:19][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1ccccc1)c1ccccc1
Yield: 97.6 %

Procedure:
In a similar manner to Step 1 of Example 16, benzoyl chloride (10.0 g, 71.1 mmol) was dissolved in dichloromethane (200 mL), and the solution was treated with cumylamine (11.3 mL, 78.3 mmol), triethylamine (14.9 mL, 107 mmol) and DMAP (870 mg, 7.11 mmol), followed by purification by slurry using diisopropylether to obtain N-(1-methyl-1-phenylethyl)benzamide (16.6 g, yield 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([CH2:25][NH:26][C:27](=[O:29])[O-:28])[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:30])=[CH:14][CH:15]=2)[N:10]=1.[ClH:31].[CH3:32][CH2:33][O:34][CH2:35]C>C(Cl)Cl>[ClH:31].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([CH2:25][NH:26][C:27](=[O:28])[O:29][CH2:32][CH2:33][O:34][CH3:35])[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:30])=[CH:14][CH:15]=2)[N:10]=1
Reactant: Cc1ccc2c(N3CCC[C@@H](CNC(=O)[O-])C3)nc(-c3c(O)cccc3F)nc2c1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: COCCOC(=O)NC[C@@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Reaction time: 0.04 h

Procedure:
To a solution of ((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (352 mg, 0.75 mmol) in CH2Cl2 (3 mL) was added dropwise a 2.0 M HCl solution in ether (0.375 mL, 0.75 mmol) under an N2 atmosphere. It was followed by the addition of 20 mL ether which lead to the precipitation of 2-methoxyethyl ((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride (350 mg, 92%) which was then filtered and dried. LC/MS: m/z 469.5 (M+H)+ at 2.29 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=7.9 Hz, 1H), 7.63 (s, 1H), 7.45 (m, 3H), 6.89 (d, J=8.3 Hz, 1H), 6.82 (t, J=9.5 Hz, 1H), 4.54 (s, 1H), 4.03 (d, J=2.7 Hz, 2H), 3.47 (t, J=4.6 Hz, 4H), 3.24 (s, 3H), 2.99 (m, 2H), 2.54 (s, 3H), 1.89 (m, 3H), 1.70 (m, 1H), 1.38 (m, 1H) ppm.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([NH:15][CH2:16][C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=O)=[O:18])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[NH2:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=1>>[C:1]([NH:11][CH2:12][C:13]([NH:15][CH2:16][C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([NH:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=1)=[O:23])=[O:18])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: NCCc1ccc(O)c(O)c1
Reactant: O=C(CNC(=O)OCc1ccccc1)NCC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Product: O=C(CNC(=O)OCc1ccccc1)NCC(=O)N1CCC[C@H]1C(=O)NCCc1ccc(O)c(O)c1

Procedure:
In the same manner as described in Example 1, 800 mg of carbobenzoxyglycylglycylproline and 380 mg of dopamine hydrochloride were reacted and treated to obtain N-carbobenzoxyglycylglycylprolyl dopamine. This compound was subjected to the catalytic reduction treatment in the same manner as described in Example 1. At the gel filtration, fractions Nos. 40 to 48 were collected. There was obtained 380 mg of a white powdery product, which was an acetate of the intended product. Elementary Analysis Values as C17H24N4O5.CH3COOH.1/2 H2O: