Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].C[O:16][CH2:17][CH2:18]OC.C(N(CC)CC)C.[CH2:28]([N:46]=[C:47]=[O:48])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CCCCCCC>[CH2:28]([NH:46][C:47]([O:13][CH2:12][CH3:11])=[O:48])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].[CH2:28]([NH:46][C:47]([O:16][CH2:17][CH3:18])=[O:48])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].[CH2:12]([OH:13])[CH2:11][CH2:10][CH2:9][C:8]#[C:7][C:6]#[C:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:14]
Reactant: COCCOC
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Agent: OCCCCC#CC#CCCCCO
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC
Reaction time: 0.83 h
Yield: 99 %

Procedure:
A mixture of 40 parts 5,7-dodecadiyne-1,12-diol, 215 parts 1,2-dimethoxyethane, 1 part dibutyltin-di-2-ethylhexanoate and 15 parts triethylamine was prepared and the resulting mixture was stirred vigorously. A solution of 133 parts n-octadecylisocyanate in 44 parts of 1,2-dimethoxyethane was added dropwise over a period of 60 min. The reaction temperature rose to 42° C. from 18° C. within 50 min. and then subsided. After the addition, 80 parts of 1,2-dimethoxyethane was then added to the reaction mixture and the mixture was stirred for an additional 2 hrs. To this mixture was added 1390 parts of heptane. The precipitate was collected by filtration, washed with petroleum ether (bp 30°-60° C.) and dried, giving 154.6 parts (99% yield) of desired product, mp 118°-119° C. Anal: calculated C50H92N2O4, C, 76.47%; H, 11.81%; N, 3.57%; found: C, 75.57%; H, 11.65%; N, 3.43%. IR (KBr pellet): 3330 cm-1 (N--H stretching), 2920+2850 cm-1 (C--H stretching), 1680 cm-1 (C=O), 1530 cm-1 (N--H bending), 1470 cm-1 (C--H), 1260 cm-1 (C--O--C stretching). Upon exposure to light, the crystals changed to blue, indicating the compound was solid state polymerizable.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([C:24](=[O:26])[CH3:25])[CH:18]=[CH:17]2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24](=[O:26])[CH3:25])[CH:18]=[CH:17]3)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)c1ccc2cc(Br)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(-c2ccc3nc(C(C)=O)ccc3c2)cc1
Temperature: 110 °C
Yield: 96.4 %

Procedure:
Pd(OAc)2 (62.9 mg, 0.280 mmol) was added to a solution of 4-acetylphenylboronic acid (689 mg, 4.20 mmol), 1-(6-bromoquinolin-2-yl)ethanone (700 mg, 2.8 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (230 mg, 0.560 mmol) and K2CO3 (1.16 g, 8.40 mmol) in dioxane (10 mL) and water (2.500 mL) and the reaction mixture was refluxed at 110° C. for 5 h. The reaction mixture was cooled to rt and partitioned between sat.aq NH4Cl and EtOAc. The organic layer was washed with NaHCO3 and brine and then dried (MgSO4), filtered, concentrated and purified by flash silica gel chromatography (loading solvent: DCM, eluted with 0˜20% EtOAc/hexanes) to yield 1-(6-(4-acetylphenyl)quinolin-2-yl)ethanone (781 mg) as white solid. LC-MS retention time 3.776 min; m/z 290.29 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 8.35 (d, J=8.3 Hz, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.08-8.16 (m, 3H), 7.85 (d, J=8.3 Hz, 1H), 7.82-7.89 (m, 1H), 2.91 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:36]I>C1(C)C=CC=CC=1.C(#N)C.O>[I:36][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1
Reactant: II
Reactant: OCC1Cc2ccccc2N1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: ICC1Cc2ccccc2N1
Reaction time: 0.17 h

Procedure:
To a mixture of 2-hydroxymethylindoline (7.77 g, 52.08 mmol), imidazole (8.86g, 130.2 mmol), triphenylphosphine (34.15 g, 130.2 mmol)in toluene (500 mL) was added iodine (26.44 g, 104.16 mmol) in acetonitrile (100 mL) at 0° C. The mixture was stirred for 10 min and water was added. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. The residue was triturated with diethyl ether and insoluble solids were removed by filtration. The filtrate was concentrated to give crude 2-iodomethylindoline. The crude 2-iodomethylindoline was dissolved in DMF (130 mL) and KCN (4.07 g, 62.5 mmol) was added. The mixture was heated at 80° C. for 12 h and after addition of KCN (4.07 g), the heating was further continued for 5 h. The mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 3:1 to 2:1 hexane/ethyl acetate to give 3.04 g of 2-cyanomethylindoline (37%): 1H NMR (270 MHz, CDCl3) δ7.03 (m, 2 H), 6.77 (t, 1H, J=7 Hz), 6.54 (t, 1H, J=7 Hz), 4.42 (m, 1H), 4.13 (bs, 1H), 3.07 (m, 1H), 2.81 (dt, 1H, J=16, 4 Hz), 2.22 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9](C=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)CC.C[Si]([Br:23])(C)C.[OH-].[Na+]>>[Br:23][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=Cc1cc(-c2ccccc2)ccn1
Reactant: C[Si](C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCC#N
Product: Brc1cc(-c2ccccc2)ccn1
Temperature: 25 °C

Procedure:
4-Phenyl-pyridine-2-carbaldehyde: To a clear, colorless solution of 1A (0.850 g, 4.5 mmol) in propionitrile (4.5 mmol) was added trimethylsilyl bromide (2.95 mL, 22.4 mmol). The resulting orange suspension was microwaved in a sealed tube at 150° C. for 10 min. The reaction was cooled to rt and poured into 1.0 N NaOH containing ice. The aqueous layer was extracted with diethyl ether (2×). The combined organic layers were washed with sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give 1.07 g of 2-bromo-4-phenyl pyridine as an off-white solid. MS 233.9 (M+H)+ and 235.9 (M+2+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:43]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:46]1[CH2:45][CH2:44][N:43]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[OH:55])[CH2:48][CH2:47]1)=[O:20]
Reactant: Oc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 71.2 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (588 mg, 1.31 mmol, 71%) was obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[CH:11]1([B-](F)(F)F)[CH2:13][CH2:12]1.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.[NH4+].[Cl-].CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH:11]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=2)[CH2:13][CH2:12]1
Reactant: F[B-](F)(F)C1CC1
Reactant: N#Cc1ccc(Br)cc1O
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2CC2)cc1O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromo-2-hydroxybenzonitrile (1 g, 5.05 mmol), potassium cyclopropyltrifluoroborate (1.495 g, 10.10 mmol), K3PO4 (5.05 ml, 15.15 mmol) and PdCl2(Amphos)2 (0.358 g, 0.505 mmol) in toluene (25 mL) was allowed to stir at 100° C. under nitrogen overnight. The mixture was then cooled to room temperature, diluted with EtOAc/NH4Cl(aq), and filtered through a pad of Celite. The organic layer was seperated, dried over Na2SO4, filtered and concentrated. The residue was purified by FCC (0-50% EtOAc/heptane) to provide 4-cyclopropyl-2-hydroxybenzonitrile, 1H NMR (400 MHz, CH2Cl2) δ 12.17 (br. s., 1H), 7.23 (d, J=8.34 Hz, 1H), 6.51-6.58 (m, 2H), 1.82 (tt, J=5.02, 8.37 Hz, 1H), 0.94-1.00 (m, 2H), 0.68-0.73 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2[CH2:12][CH2:13][N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:15]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CN(C)C=O>[CH2:45]([O:44][C:42]([CH2:41][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2[CH2:12][CH2:13][N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:15]1)=[O:43])[CH3:46]
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)nn1CCC1CCCc2c(O)cccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC2CCn1nc(C(c2ccccc2)c2ccccc2)ccc1=O

Procedure:
A N,N-dimethylformamide solution (15 ml) of crude 2-[2-(5-hydroxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.34 g), potassium carbonate (0.16 g) and ethyl bromoacetate (0.2 ml) was stirred at room temperature for 24 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (n-hexane-ethyl acetate=3:2) over silica gel to afford 2-[2-(5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.17 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of 3-chloro-2-methylaniline (27 g, 0.19 mol) in 270 mL of ETOH at rt was added acetic anhydride (22 mL, 0.23 mol), and the solution was stirred at rt for 2 h. The mixture was concentrated under reduced pressure to give 35 g (100%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:13]=[C:12]([C:21]([OH:23])=O)[CH:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:13]=[C:12]([C:21]([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=[O:23])[CH:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: COc1cc(Br)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: COc1cc(Br)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccnc2)c1

Procedure:
80 mg (0.21 mmol) of the compound of Example 50A is reacted analogously to the synthesis of the compound of Example 1 with 29 mg (0.24 mmol) of 4-imidazolinone-hydrochloride. 76 mg (79% of theory) of the title compound is obtained.
Reaction SMILES: [CH3:1][N:2]([CH:27]([CH3:29])[CH3:28])[C:3]1[C:4]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][CH:23]=[C:22]([CH3:25])[C:21]=3[CH:26]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+].O>CO.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH:27]([CH3:29])[CH3:28])[C:3]1[C:4]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][CH:23]=[C:22]([CH3:25])[C:21]=3[CH:26]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc4occ(C)c4c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1coc2ccc(-c3nc4ccc(C(=O)O)cc4nc3N(C)C(C)C)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(3-methyl-1-benzofuran-5-yl)quinoxaline-6-carboxylate (110 mg, 0.28 mmol) in methanol (25 mL) and chloroform (5 mL) was added sodium hydroxide (468 mg, 1.17 mmol) and water (2 mL) with stirring for 3 h at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (15 mL), and adjusted pH to 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(3-methyl-1-benzofuran-5-yl)quinoxaline-6-carboxylic acid (62 mg, 59%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=[O:16])[O:6][C:7]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=2[C:9]=1[OH:10])[CH3:2].[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)(=[O:19])[CH3:18]>>[CH2:1]([O:3][C:4]1[C:5](=[O:16])[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:17](=[O:19])[CH3:18])=[CH:11][C:8]=2[C:9]=1[OH:10])[CH3:2]
Reactant: CC(=O)OCCCCBr
Reactant: CCOc1c(O)c2cc(O)ccc2oc1=O
Product: CCOc1c(O)c2cc(OCCCCOC(C)=O)ccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-ethoxy-4,6-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 4-bromobutyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-ethoxy-4-hydroxy-6-(4-acetoxybutoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:16]([F:36])=[CH:17][C:18]3[C:29](=[O:30])[C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][N:20]4[CH:21]([CH2:25]O)[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.Cl.N12CCCN=C1CCCCC2>C(Cl)Cl.O.C(OCC)(=O)C.C1C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:16]([F:36])=[CH:17][C:18]3[C:29](=[O:30])[C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][N:20]4[C:21](=[CH2:25])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)OCC2CO
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C=C1COc2c(C3(NC(=O)OCc4ccccc4)CC3)c(F)cc3c(=O)c(C(=O)OCC)cn1c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
In 4 ml of methylene chloride was suspended 380 mg of ethyl 10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3de][1,4]benzoxazine-6-carboxylate. To the resulting suspension were added, with ice-cooling, 230 mg of triethylamine and 260 mg of methanesulfonyl chloride in this order. The resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added 10 ml of methylene chloride and 10 ml of water in this order. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue obtained were added 4.4 ml of benzene and 175 mg of 1,8-diazabicyclo-[5,4,0]undec-7-ene in this order. The resulting mixture was refluxed for 1 hour. The reaction mixture was added to a mixture of 20 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=3/2) to obtain 260 mg (yield: 71.0%) of ethyl 10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-methylene-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[OH-].[K+].Br[CH2:10][CH:11]1[CH2:13][CH2:12]1>CS(C)=O.[Cl-].[Na+].O>[CH:11]1([CH2:10][N:4]2[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]2)[CH2:13][CH2:12]1
Reactant: Nc1cc[nH]n1
Reactant: BrCC1CC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccn(CC2CC2)n1
Reaction time: 8 h

Procedure:
3-Aminopyrazole (2.43 g, 29 mmol) were dissolved in 30 ml DMSO. Potassium hydroxide (4.8 g, 86 mmol) was added and the mixture was stirred at room temperature for 30 min. (Bromomethyl)cyclopropane (4.4 g, 32 mmol) was added and stirring was continued at room temperature overnight. The reaction mixture was poured into 100 ml brine and extracted three time with 100 ml ethyl acetate. The organic phases were pooled, dried with sodium sulfate and evaporated. The two regiosomers were separated by flash chromatography and the title compound was obtained as a brown oil (1.739 g, 31%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([O-:16])(=[O:15])=[O:14])[CH:8]=2)[N:3]=1.[Na+:17].[CH2:18]1[CH2:24][S:21](=[O:23])(=[O:22])[O:20][CH2:19]1>>[CH3:1][C:2]1[C:10]([CH3:11])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([O-:16])(=[O:15])=[O:14])[CH:8]=2)[N+:3]=1[CH2:19][CH2:18][CH2:24][S:21]([O-:23])(=[O:22])=[O:20].[Na+:17]
Reactant: CC1=Nc2ccc(S(=O)(=O)[O-])cc2C1(C)C
Reactant: O=S1(=O)CCCO1
Agent: [Na+]
Product: CC1=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C
Temperature: 110 °C
Yield: 97.3 %

Procedure:
A mixture of 14 g of sodium 2,3,3-trimethyl-3H-indole-5-sulfonate and 14 g 1,3-propanesultone in 100 mL dicholorobenzene was heated at 110° C. for 2 h. After it cooled down, the solvent is decanted. The resulting solid was then dissolved in 100 mL of acetonitrile, and 300 mL of ethyl acetate was added. The resulting sticky solid was again stirred in 300 mL of ethyl acetate to yield 20 g of the product.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:11]([C:14]3[C:15](=[O:21])[NH:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=[C:33]([N:46]([CH3:48])[CH3:47])[N:32]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[CH:19]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:36]4[C:31]([O:30][CH3:29])=[N:32][C:33]([N:46]([CH3:47])[CH3:48])=[N:34][CH:35]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:15](=[O:21])[NH:16][CH:17]=1
Reactant: COc1nc(N(C)C)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c[nH]c1=O)C2=O
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1nc(N(C)C)ncc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)c[nH]c1=O)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-5-(5-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate M) and 4-methoxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Intermediate W) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively to afford the title compound as a white solid. ESI-MS: tR=1.14 min, [M+H]+ 553/555 (LC-MS 1); 1H-NMR (d6-DMSO, 400 MHz): 12.15 (br s, 1H), 8.02 (s, 1H), 7.44 (s, 1H), 7.35-7.42 (m, 3H), 7.22 (m, 2H), 6.66 (s, 1H), 6.23 (s, 1H), 3.93 (m, 1H), 3.84 (s, 3H), 3.14 (s, 6H), 1.28 (m, 3H), 0.45 (m, 3H).
Reaction SMILES: O[C:2]([CH3:17])([CH2:15][CH3:16])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].C(NCC)C.C([OH:25])C>>[CH2:15]([C:2]1([CH3:17])[C:3](=[O:25])[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[O:6]1)[CH3:16]
Reactant: CCO
Reactant: CCC(C)(O)C#CC(=O)c1ccc(SC)cc1
Solvent: CCNCC
Product: CCC1(C)OC(c2ccc(SC)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5.34 g of 4-hydroxy-4-methyl-1-{4-(methylthio)phenyl}-2-hexyn-1-one was dissolved in 200 ml ethanol, added dropwise 3 ml diethylamine diluted with 50 ml ethanol. The reaction solution was stirred at room temperature for 4 hours, and the solvent was removed in vacuo. The resulting residue was extracted with water and dichloromethane (100 ml×3). Concentration of the organic layer afforded crude 2-ethyl-2-methyl-5-{4-(methylthio)phenyl}-3(2H)-furanone, which was used in the next step without further purification.
Reaction SMILES: [C:1]([SiH:5]([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:15]([O:18][CH2:19][C:20]1[O:25][CH2:24][N:23]([C:26]([CH3:38])([CH3:37])[C:27]([O:29]CC2C=CC=CC=2)=[O:28])[C:22](=[O:39])[C:21]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:17])[CH3:16]>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:15]([O:18][CH2:19][C:20]1[O:25][CH2:24][N:23]([C:26]([CH3:38])([CH3:37])[C:27]([O:29][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[O:28])[C:22](=[O:39])[C:21]=1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)(=[O:17])[CH3:16]
Reactant: C[SiH](C)C(C)(C)C
Reactant: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)OCc2ccccc2)CO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O[Si](C)(C)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of palladium (II) acetate (25 mg), tert butyl-dimethylsilane (1.25 ml) and triethylamine (0.05 ml) in dichloromethane was stirred at room temperature under an inert atmosphere for 0.25 hour. A solution of benzyl 2-(6-acetoxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (1.0 g) was added and stirring continued for 18 hours. The mixture was filtered (hyflo) and evaporated to give tert butyldimethylsilyl 2-(6-acetoxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (0.92 g) as a yellow oil, NMR (CDCl3)δ 0.25(s,9H), 1.5(s,6H), 2.0(s,3H), 4.5(s,2H), 5.2(s,2H), 7.0-7.3(m,5H).