Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[C:16]1([C@H:26]([NH2:28])[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Mg+2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl.C(O)(=O)C>[C:16]1([C@H:26]([NH:28][CH:2]2[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH2:3]2)[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: C[C@@H](NC1CN(C(=O)OCc2ccccc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
To a solution of 5.0 g of 1-benzohydrylazetidin-3-one dissolved in 75 ml of toluene was added 2.98 ml of benzyloxycarbonyl chloride, and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was evaporated, and then, to the residue were added water and ethyl acetate, the mixture was stirred and the liquids were separated. The organic layer was washed with water and a saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1), and then, hexane was added thereto, and after collecting the precipitate by filtration, it was washed with hexane to obtain 2.73 g of benzyl 3-oxoazetidine-1-carboxylate. (3) To a solution of 8.51 g of benzyl 3-oxoazetidine-1-carboxylate and 7.10 g (R)-(+)-1-(1-naphthyl)ethylamine dissolved in 170 ml of methylene chloride, 7.49 g of magnesium sulfate was added to the solution. The mixture was stirred at room temperature for 3 hours, and then, 9.5 ml of acetic acid and 13.18 g of sodium triacetoxy borohydride were added thereto, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution to make the mixture basic, chloroform was added to the same and the mixture was stirred, and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to obtain 7.90 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine-1-carboxylate. (4) To a solution of 9.45 g of benzyl 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine-1-carboxylate dissolved in 190 ml of methanol, 1 g of palladium carbon (10% wet) was added thereto, and the reaction was carried out under hydrogen atmosphere at room temperature for 4 hours. Palladium carbon was removed, the solvent was evaporated, and the residue was purified by NH silica gel column chromatography (chloroform:methano1=1:0→19:1) to obtain 4.60 g of 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine. To a solution of 4.60 g of 3-[(R)-1-(naphthalen-1-yl)ethylamino]azetidine dissolved in 30 ml of ethyl acetate, under ice-cooling, 13 ml of a solution of 4M hydrochloric acid in ethyl acetate was added dropwise, and the mixture was stirred for a while.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][CH2:10][CH:11]([CH2:17][CH:18]=[CH2:19])[C:12](OCC)=[O:13].O.[OH-].[Na+]>CCOCC>[CH3:7][O:8][CH2:9][CH2:10][CH:11]([CH2:17][CH:18]=[CH2:19])[CH2:12][OH:13]
Reactant: C=CCC(CCOC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C=CCC(CO)CCOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A 1M solution of lithium aluminum hydride (135 mL), 134 mmol) was added via cannula to a stirred solution of the ester 3 (25 g, 134 mmol), prepared according to Example 2, in dry ether (200 mL). The mixture was stirred for 2 h at room temperature under nitrogen and cooled to 0° C., and water (10 mL) was added dropwise, with stirring, followed by dropwise addition of 15% NaOH (10 mL) and water (30 mL) at 0° C. to produce a white precipitate. The precipitate was filtered, and washed with ether (2×50 mL). The filtrate was dried over MgSO4, filtered, and concentrated to give the alcohol 4 (16.5 g, 85.4%). IR (KBr) υmax 34,10, 3071, 2930, 2860, 1641, 1442, 1384, 1185, 1109, 1043, 993, 911 cm−1; 1HNMR (CDCl3) δ1.61-1.75 (m, 3 H), 2.02-2.30 (m, 2 H), 3.35 (s, 3 H), 3.36-3.60 (m, 4 H), 5.01-5.06 (m, 2 H), 5.77-5.79 (m, 1 H); 13CNMR (CDCl3): δ31.33, 35.95, 38.56, 58.20, 65.17, 70.98, 116.07, 136.59; mass spectrum (EI), m/z (rel intensity) 145 (7), 144 (M+, 3), 143 (23), 126 (15), 113 (20), 111 (42), 102 (17), 95 (27), 94 (57), 93 (31), 83 (49), 82 (41), 81 (61), 79 (100), 71 (70), 70 (42), 69 (38), 67 (65), 58 (46), 57 (34), 55 (75), 54 (48), 53 (34).
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].[CH2:15](Cl)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31].O>CS(C)=O.O1CCCC1>[CH2:31]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCCCCCCCCCCCCCCCl
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C=CCCCCCCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a suspension of sodium theobromine (2.02 g, 10.0 mmol) in dimethylsulfoxide/tetrahydrofuran (2:1, 30 ml) was added 16-heptadecenyl chloride and the reaction stirred for 16 hours at 60° C. The mixture was then poured into water (75 ml) and extracted with ethyl acetate (3×75 ml). The organic portions were combined, dried over magnesium sulfate and the solvent evaporated, leaving a cream-colored solid residue. Recrystallization of the residue from hot hexane resulted in 2.31 g of 1-(16-Heptadecenyl)-3,7-dimethylxanthine as a white solid (85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11](O)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.CNOC.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:11]=[O:12])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CC1(c2ccc(Cl)cc2)CC1
Reaction time: 0.33 h
Yield: 63.8 %

Procedure:
A solution of 1-(4-chlorophenyl)cyclopropane carboxylic acid (784 mg, 3.99 mmol) in dichloromethane (30 mL) was added sequentially at room temperature with N,O-dimethylhydroxylamine hydrochloride (389 mg, 3.99 mmol), benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (2.28 g, 4.39 mmol) and triethylamine (807 mg, 7.97 mmol). The resultant was stirred at the same temperature for 20 min, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was dissolved in toluene (30 mL), added at −78° C. with a solution of diisobutylaluminum hydride in toluene (1.01 M, 4.35 mL), and the resultant was stirred at the same temperature for 1 hour. The reaction solution was added with hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane:ethyl acetate=3:1), and 1-(4-chlorophenyl)cyclopropane carboaldehyde (460 mg, 63.7%) was obtained.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br-].[K+].[Si:8]([O:15][CH2:16][C:17]([O:23][CH3:24])([CH3:22])[CH2:18][CH2:19][CH2:20][OH:21])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].CC1(C)N([O])C(C)(C)CCC1.[O-]Cl.[Na+]>O.C(Cl)Cl>[Si:8]([O:15][CH2:16][C:17]([O:23][CH3:24])([CH3:22])[CH2:18][CH2:19][CH:20]=[O:21])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10]
Reactant: COC(C)(CCCO)CO[Si](C)(C)C(C)(C)C
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: COC(C)(CCC=O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of sodium bicarbonate (627 g, 74.6 mol) and potassium bromide (672 g, 56.5 mol) in water (20 L) was added 5-{[tert-butyl(dimethyl)silyl]oxy}-4-methoxy-4-methylpentan-1-ol (3.5 kg, 11.2 mol), DCM (10 L), TEMPO (17.6 g, 113 mol). The resulting mixture was cooled to <5° C. and NaOCl (13% solution, total 6.7 L, 14.6 mol) was added in portions via a funnel while maintaining the reaction temperature <5° C. The mixture was stirred 6 hours warming to ambient temperature. The organic layer was collected. The aqueous layer was extracted with 4 L DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude material, 4.2 kg, was used in the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 9.75 (t, J=1.8 Hz, 1 H); 3.43 (q, J=10.4 Hz, 2H); 3.17 (s, 3H); 2.43 (t, J=1.8 Hz, 2H); 2.02-1.65 (m, 2 H); 0.99-0.71 (s, 9H); 0.14 (s, 6H).
Reaction SMILES: [F:1][C:2](=[C:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1>CS(C)=O.C(N(CC)CC)C.O>[F:1][C:2]([C:3]1[CH:19]=[CH:18][CH:17]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][N:8]=2)[CH:4]=1)=[C:20]1[CH2:25][CH2:24][N:23]([C:33]([NH:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:22][CH2:21]1
Reactant: FC(=C1CCNCC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cccnc1)N1CCC(=C(F)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Reaction time: 12 h
Yield: 74.6 %

Procedure:
To a solution of 2-(3-(fluoro(piperidin-4-ylidene)methyl)phenoxy)-5-(trifluoromethyl)pyridine (110 mg, 0.312 mmol) and phenyl pyridin-3-ylcarbamate (66.8 mg, 0.312 mmol) in DMSO (2 mL) under N2 was added 3 drops of triethyl amine and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed several times with water to remove the excess DMSO. The title compound was crystallized from CH2Cl2 and hexane to give the pure title compound (110 mg). 1H NMR (500 MHz, CDCl3): δ 2.5 (brs, 2H), 2.6 (brs, 2H), 3.7 (brs, 2H), 3.8 (brs, 2H), 7.0 (d, 1H, J=8.5 Hz), 7.1-7.3 (m, 3H), 7.4 (t, 1H, J=8.5), 7.7 (d, 1H, J=5.5 Hz), 7.9 (d, 1H, J=8 Hz), 8.0 (s, 1H), 8.4 (s, 1H), 9.2 (d, 1H, J=8.5 Hz), 9.6 (brs, 1H), 9.8 (brs, 1H); 13CNMR (125 MHz, CDCl3): 11.4, 14.3, 22.6, 25.5, 27.7, 31.5, 40.8, 44.1, 44.4, 53.4, 111.6, 114.0, 115.5, 119.8, 121.3, 121.4, 121.7, 122.5, 123.8, 125.3, 128.2, 129.6, 133.5, 133.8, 136.8, 140.5, 142.8, 145.3, 151.8, 153.0, 154.7, 156.7, 165.4; m/z (473.3 M+ H+); HPLC: 94.2%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]=[CH2:13].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:13][O:22]1
Reactant: C=Cc1ccc2c(c1Cl)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-chloro-5-ethenyl-2-benzofuran-1(3H)-one (1.1 g, 5.7 mmol) in DCM (40 mL) was added m-CPBA (1.9 g, 8.5 mmol). The solution was allowed to stir at RT for 16 hours. Analysis by TLC and LC showed formation of the desired product, along with some untouched starting material. The reaction was diluted with DCM (200 mL), washed with aqueous Na2S2O3 and Na2CO3, dried over sodium sulfate, concentrated, and purified by silica gel flash chromatography to afford 4-chloro-5-oxiran-2-yl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:14])[CH:8]=[C:9]([N+:11]([O-])=O)[N:10]=1)=[O:5])[CH3:2].N1C=CN=C1.[F:20][C:21]([F:45])([F:44])[C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:29][CH2:30][O:31][C:32](=O)[O:33]C2C=CC([N+]([O-])=O)=CC=2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CC(=O)OCC.C(Cl)Cl.CN(C1C=CN=CC=1)C.[Pd].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:14])[CH:8]=[C:9]([NH:11][C:32]([O:31][CH2:30][CH2:29][S:28][C:25]2[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:45])[F:44])=[CH:23][CH:24]=2)=[O:33])[N:10]=1)=[O:5])[CH3:2]
Reactant: O=C(OCCSc1ccc(C(F)(F)F)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1nc([N+](=O)[O-])cn1C
Agent: [Pd]
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1nc(NC(=O)OCCSc2ccc(C(F)(F)F)cc2)cn1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.4 %

Procedure:
After 1-methyl-4-nitroimidazole-2-carboxylic acid ethyl ester (2.56 g, 12.85 mmol) was dissolved in EA (20 ml), 10% Pd/C (100 mg, catalytic weight) was added thereto. The mixture was stirred for 10 hours at room temperature under hydrogen atmosphere to reduce a nitro group (NO2) into an amino group (NH2), whereby an imidazole-type amino acid was obtained. 10% Pd/C was filtered out by celite 545 filter, and the filtrate was washed with EA and MeOH, and concentrated. To the residue were added carbonic acid 4-nitro-phenyl ester 2-(4-trifluoromethyl-phenylsulfanyl)-ethyl ester (4.52 g, 11.67 mmol) dissolved in anhydrous DCM (40 ml), DIEA (4.06 ml, 23.32 mmol), DMAP (2.85 g, 23.32 mmol), and HOBt (3.57 g, 23.32 mmol), and the mixture was stirred at room temperature. After 12 hours have passed, the reaction was stopped by adding water and the reaction mixture was extracted with DCM. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was purified by silica gel column chromatography (EA/n-hexane=1/2, v/v) to give 1-methyl-4-[2-(4-trifluoromethyl-phenylsulfanyl)-ethoxycarbonylamino]-1H-imidazole-2-carboxylic acid ethyl ester (3.77 g, 77.40%) of a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Nc1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(Nc2ccccc2)n1
Temperature: 100 °C
Yield: 11.8 %

Procedure:
A sealed tube was charged with 2-chloro-4-methoxypyrimidine (1.00 g, 6.92 mmol) in 2-propanol (5 mL). Aniline (0.757 ml, 8.30 mmol) and DIEA (1.45 ml, 8.30 mmol) were added and the reaction mixture was heated at 100° C. until the reaction was complete by HPLC. The reaction mixture was cooled to room temperature. The resulting thick suspension was filtered, washed with ethanol, collected and dried under vacuum to yield the desired product (0.164 g) as a white solid. The filtrate was concentrated and then partitioned between EtOAc and saturated aqueous NaCl. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a yellow solid. The crude product was purified by flash column chromatography, eluting with 25:1 dichloromethane/EtOAc. The desired product (0.548 g) was obtained as a white solid which was combined with the filtered product to yield 0.712 g (51%) total desired product. 1H-NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.20 (d, 1H), 7.77 (d, 2H), 7.27 (t, 2H), 6.94 (t, 1H), 6.28 (d, 1H), 3.91 (s, 3H). LRMS (ESI pos) m/e 202 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.Cl>COCCOC.O.C1COCC1.CCOCC>[N:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[N:12]=[N:11][C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1ccc(-n2nnc(-c3ccccn3)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2nnn(-c3ccc(-c4ccncc4)cc3)n2)nc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
A solution of 2-[2-(4-bromophenyl)-2H-tetrazol-5-yl]pyridine (300 mg, 1 mmol), potassium carbonate (0.276 g, 2.0 mmol), and pyridin-4-ylboronic acid (123 mg, 1 mmol) in ethylene glycol dimethyl ether (20 mL) and water (4 mL) was degassed with argon for 15 min. Then tetrakis (triphenylphosphine)palladium(0) (80 mg, 0.068 mmol) was added, the mixture degassed for another 15 min, and the solution was stirred at 65° C. for 12 h. The reaction mixture was then quenched with water (30 mL), extracted with EtOAc (3×30 mL) and washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was chromatographed on silica gel, eluting with EtOAc to afford a yellow solid. This was dissolved in anhydrous THF (10 mL) and HCl (1.5equiv) in ether was added. The
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].C([O:13][C:14](=O)[CH:15]=[C:16]([NH2:20])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:20][C:16]1[NH:6][N:5]([CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[C:14](=[O:13])[CH:15]=1
Reactant: Cc1ccccc1CNN
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccccc1Cn1[nH]c(N)cc1=O
Reaction time: 8 h

Procedure:
27.5 g of o-methylbenzylhydrazine, dissolved in 100 ml of ethanol, were added dropwise at room temperature to a solution of 32 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 300 ml of ethanol. After standing overnight, the reaction solution was concentrated in vacuo and the compound identified above, which separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 138°, 15 g (37%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([F:16])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Product: O=C1NCCn2c1cc1cc(F)cc(-c3ccc(Cl)cc3)c12

Procedure:
The title compound, light grey solid (75 mg, 95%), MS (ISP) m/z=315.1 [(M+H)+], mp 322° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:20]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:21]([C:39](O)=[O:40])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:38])[NH:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].C(O)(C(F)(F)F)=O.[NH2:56][C@H:57]([C:62]([OH:64])=[O:63])[C@H:58]([CH2:60][CH3:61])[CH3:59].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[NH:20]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:21]([C:39]([NH:56][C@H:57]([C:62]([OH:64])=[O:63])[C@H:58]([CH2:60][CH3:61])[CH3:59])=[O:40])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:38])[NH:27][S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Dipeptide Boc-Arg(Tos)-Ile-OH: DIEA (19 mL, 106.5 mmol) and HOBt (5.08 g, 37.63 mmol) were added at room temperature to a solution of Boc-Arg(Tos)-OH (16.13 g, 37.64 mmol) and TFA.H-Ile-OFm (15 g, 35.5 mmol) in anhydrous DMF (100 mL). The resulting mixture was diluted with CH2Cl2 (300 mL) and cooled to 0° C. A solution of DCC (7.76 g) in 30 mL of CH2Cl2 was added to the cooled mixture. The mixture was stirred for 18 h while the temperature of the mixture gradually came to room temperature. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residual oil was dissolved in EtOAc. The solution was washed with H2O, 1N HCl, 5% aqueous NaHCO3 and H2O, dried (Na2SO4 /MgSO4), and concentrated to yield Boc-Arg(Tos)-Ile-OFm as a white solid (22.42 g). The latter compound (22.0 g) was dissolved in DMF (200 mL). Piperidine (40 mL) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 2 h and thereafter concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc. The solution was washed with aqueous citric acid solution (pH 4). The aqueous phase was extracted with fresh EtOAc. The combined EtOAc solutions were washed with 1N HCl and H2O, dried (Na2SO4 /MgSO4), and concentrated to dryness. The residue was rinsed with hexane and then dissolved in warm EtOAc. After filtration to remove insoluble material, the EtOAc solution was diluted with hexane. The resulting precipitate was collected to give the dipeptide (17.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[CH3:43][O:44][CH2:45][CH2:46][NH2:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:47][CH2:46][CH2:45][O:44][CH3:43])=[O:24]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COCCNC(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and methoxyethylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH:23]([N:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:29])=[CH:16][CH:17]=1)[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:25]
Reactant: CC(C)N(Cc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(Cc1ccc(C(=O)N2CCNCC2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(4-diisopropylaminomethylbenzoyl)piperazine (4.6 g) in ethyl acetate (10 ml) was added trifluoroacetic acid (20 ml), and the solution was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in water. The solution was made alkaline with sodium hydroxide solution, extracted with dichloromethane. The extract was dried and concentrated to give amorphous powders which were filtered, washed with hexane and dried to afford the title compound (3.12 g).