Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[Br-:24].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.ClCCl>CO>[Br:24][CH:20]1[CH2:19][CH2:18][C:15]2=[CH:16][C:17]3[C:8]4[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH2:2][Br:1])=[CH:23][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:14]2[C:21]1=[O:22]
Reactant: [Br-]
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
A mixture of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.58 g, 6.95 mmol), pyridinium tribromide (2.56 g, 8.0 mmol), dichloromethane (22 mL) and methanol (2.5 mL) was stirred at about 20° C. for 3 hours to obtain a slurry. The precipitated product was filtered, washed with dichloromethane (10 mL) and dried in a vacuum oven at 40° C. to give 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.62 g, 84% yield). 400 MHz 1H NMR (CDCl3) δ 8.03-8.01 (m, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H), 4.74 (dd, J=4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99-2.92 (m, 1H), 2.59-2.46 (m, 2H).
Reaction SMILES: [Al].[Cl:2][C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[I:12]N1C(=O)CCC1=O>CN(C=O)C>[Cl:2][C:3]1[N:8]=[CH:7][NH:6][C:5]2=[N:9][CH:10]=[C:11]([I:12])[C:4]=12
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Agent: [Al]
Solvent: CN(C)C=O
Product: Clc1nc[nH]c2ncc(I)c1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 250 ml round-bottomed flask, protected from light with aluminum foil, are added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 1 (2.15 g, 14.0 mmol) and N-iodosuccinimide (3.37 g, 14.98 mmol) dissolved in anhydrous DMF. The reaction mixture is stirred at room temperature under nitrogen for 16 hrs. The solvent is removed in vacuo, and the residue is dissolved in methylene chloride (250 ml). The reaction mixture is washed with brine (50 ml), and the organic layer is separated, dried over Na2SO4, and concentrated in vacuo. The crude residue is purified by flash-chromatography on silica gel and eluted with 60% EtOAc in cyclohexane. Fractions containing the desired product (TLC) are pooled and evaporated to afford 4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine as a pale-yellow solid.
Reaction SMILES: [OH:1][C@H:2]([CH3:47])[C@H:3]([NH:16][C:17]([C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH:27]=[C:26]([O:41][C@@H:42]([CH3:46])[CH2:43][O:44][CH3:45])[CH:25]=2)=[CH:22][CH:23]=1)=O)[CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].CS(O)(=O)=O.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:45][O:44][CH2:43][C@@H:42]([O:41][C:26]1[CH:25]=[C:24]([C:21]2[NH:20][C:19]([C:17]3[O:1][C@@H:2]([CH3:47])[C@@H:3]([CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:7]([CH3:9])[CH3:8])[CH:10]([CH3:11])[CH3:12])[N:16]=3)=[CH:23][CH:22]=2)[CH:29]=[C:28]([O:30][Si:31]([CH:32]([CH3:34])[CH3:33])([CH:35]([CH3:36])[CH3:37])[CH:38]([CH3:40])[CH3:39])[CH:27]=1)[CH3:46]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@H](C)O3)[nH]2)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
N-{(2R,3R)-3-Hydroxy-1-[(tripropan-2-ylsilyl)oxy]butan-2-yl)-5-(3-[(2S)-1-methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrole-2-carboxamide (2.52 g, 3.65 mmol) synthesized in Example (110b) was dissolved in tetrahydrofuran (20 mL), and anhydrous methanesulfonic acid (1.05 g, 6.03 mmol) and triethylamine (2.00 mL, 14.35 mmol) were added, followed by stirring at 50° C. for 1 day under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-30%) to afford the desired compound (2.30 g, yield 94%) as a pale yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([Cl:16])[N:3]=1.[CH3:17][Mg]Br>C1COCC1.CN1C(=O)CCC1>[Cl:16][C:4]1[CH:5]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[C:2]([CH3:17])[N:3]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)OC(C)(C)C)cc(Cl)n1
Reaction time: 0.25 h

Procedure:
tert-butyl (2,6-dichloropyridin-4-yl)carbamate (460 mg, 1.75 mmol) from Step 1 of this example, ferric acetylacetonate (309 mg, 0.87 mmol) was added in THF:NMP (1:1, 17.4 mL), methyl magnesium bromide (3 mL [3M], 8.9 mmol) was added drop-wise and stirred for 15 min. The reaction was quenched with ice-cold ammonia chloride saturated solution (100 mL), extracted with ethyl acetate (100 mL), second wash with brine (50 mL). The organic phase was dried by magnesium sulfate and filtered through silica gel (1 inch deep), concentrated and purified by column chromatography through a 50 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 10% ethyl acetate/hexanes to give the title compounds as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:10]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=1)[C:11]([C@H:13]1[N:17](C(OC(C)(C)C)=O)[CH2:16][Si:15]([CH3:26])([CH3:25])[CH2:14]1)=[O:12])[CH3:9].[ClH:38]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:10]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=1)[C:11]([C@H:13]1[NH:17][CH2:16][Si:15]([CH3:25])([CH3:26])[CH2:14]1)=[O:12])[CH3:9].[ClH:38]
Reactant: COC(=O)c1ccc(CN(C(=O)[C@@H]2C[Si](C)(C)CN2C(=O)OC(C)(C)C)[C@H](C)c2ccccc2F)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(C(=O)[C@@H]2C[Si](C)(C)CN2)[C@H](C)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 5-(((R)-1-(2-fluorophenyl)ethyl)(4-(methoxycarbonyl)benzyl)carbamoyl)-3,3-dimethyl-1,3-azasilolidine-1-carboxylate (85 mg, 0.16 mmol) in DCM (4 mL) was added HCl (4.0 M solution in dioxane, 1.5 mL, 6.0 mmol). The resulting reaction mixture was stirred at rt for 1 h and concentrated in vacuo to give the title compound as a HCl salt (74 mg, 99%, white solid). 1H NMR (DMSO-d6) δ 7.92-7.74 (m, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.60-7.41 (m, 1H), 7.35-7.06 (m, 3H), 7.03 (d, J=8.4 Hz, 1H), 6.96-6.75 (m, 1H), 5.71-5.43 (m, 1H), 4.85-4.41 (m, 2H), 4.37-4.12 (m, 1H), 3.88-3.77 (m, 3H), 3.73-3.48 (m, 1H), 2.70-2.54 (m, 1H), 2.34-2.13 (m, 1H), 1.73-1.56 (m, 2.5H), 1.47 (d, J=7.0 Hz, 0.5H), 1.39-1.17 (m, 1H), 1.00-0.63 (m, 1H), 0.45-0.17 (m, 6H); MS(ESI+) m/z 429.8 (M+H)+.
Reaction SMILES: C([Li])CCC.[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>CCCCCC.O1CCCC1>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22]([N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])(=[O:23])=[O:24]
Reactant: O=C1CCCN1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCCN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: -10 °C
Reaction time: 0.42 h
Yield: 58 %

Procedure:
15.6 cm3 of a 1.6M solution of butyllithium in hexane is added to 2.13 g of 2-pyrrolidinone in solution in 80 cm3 of tetrahydrofuran, cooled to -10° C., maintaining the temperature between -5° C. and +5° C. After agitation at -5° C. for 25 minutes, 6.12 g of beta-naphthalene-sulphonyl chloride is added, without exceeding 0° C. The whole is then left to return to ambient temperature. The solvent is evaporated off under reduced pressure, the residue is taken up in ethyl acetate, and the lithium chloride is filtered off and after evaporating under reduced pressure, the residue is taken up in water and filtered. Finally after crystallization from isopropanol, 4 g of expected product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:2].CC(C)([O-])C.[K+].[Cl:27][CH2:28][C:29]1[C:33]([CH2:34]Cl)=[CH:32][S:31][CH:30]=1.Cl>CN(C=O)C>[ClH:27].[CH2:1]([O:3][C:4]([C:5]1([NH2:6])[CH2:34][C:33]2=[CH:32][S:31][CH:30]=[C:29]2[CH2:28]1)=[O:20])[CH3:2]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: ClCc1cscc1CCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(N)Cc2cscc2C1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
(Benzhydrylidene-amino)-acetic acid ethyl ester (0.113 g, 0.414 mmol) was dissolved in DMF (3 ml) and cooled in an ice bath. Potassium tert-butoxide (94.8 mg, 0.828 mmol) was added, and the mixture was stirred for 10 min. The mixture was cooled to −30° C., and 3,4-bis-chloromethyl-thiophene (50 mg, 0.276 mmol) was added in one portion. The mixture was then placed into an ice bath again, and the reaction allowed to proceed for 20 min. The mixture was acidified with 2 N hydrochloric acid, stirred for 10 min and partitioned between water and diethyl ether. The aqueous phase was neutralized with a saturated sodium hydrogencarbonate solution and extracted with EA. The combined EA extracts were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in diethyl ether, filtered, evaporated to dryness, acidified with hydrogen chloride in methanol and evaporated to dryness. The residue was stirred with an diethyl ether/HEP mixture, and the solid was filtered and dried in vacuo to give crude 5-amino-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl ester hydrochloride. A part of the crude compound (27 mg, 0.109 mmol) was reacted without further purification with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 1 of example 15. After purification by preparative RP HPLC (water/ACN gradient), 23 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:16]=3[NH:15][C:14]2=[O:24])=[CH:3]1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O.[C:37]([O:44][CH2:45][CH3:46])(=[O:43])/[CH:38]=[CH:39]/[CH2:40][CH2:41][CH3:42]>C(OCC)(=O)C>[CH2:45]([O:44][C:37](=[O:43])[CH2:38][CH:39]([N:15]1[C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=2[N:13]([CH2:12][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][C:6]=3[CH3:11])[N:2]([CH3:1])[CH:3]=2)[C:14]1=[O:24])[CH2:40][CH2:41][CH3:42])[CH3:46]
Reactant: CCC/C=C/C(=O)OCC
Reactant: Cc1cc2[nH]c(=O)n(Cc3cn(C)c4cccc(C)c34)c2cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cc(C)c(C)cc21
Temperature: 130 °C

Procedure:
A mixture of 1-(1,4-Dimethyl-1H-indol-3-ylmethyl)-5,6-dimethyl-1,3-dihydro-benzimidazol-2-one (0.1 g, 0.31 mmol), K2CO3 (87 mg, 0.63 mmol) and ethyl trans-2-hexenoate (0.45 g, 3.1 mmol) was heated to 130° C. for 20 min in a microwave. Since the starting material was not soluble in ethyl trans-2-hexenoate even after heating, DMA (2 mL) was added to the reaction mixture and heated again at 150° C. for 30 min. Although the un-reacted starting material was present, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting heterogeneous residue was purified by silica gel prep TLC using 4:1 hexanes:ethyl acetate as an eluent to afford 25 mg of the desired product as an oil. LCMS (ESMS): m/z 462.88 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:15])[C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5](Cl)=[O:6].O1CCCC1.[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH2:28]>C(N(CC)CC)C>[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH:28][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([F:1])[C:10]([O:11][CH2:12][C:13]#[CH:14])=[C:9]([F:15])[CH:8]=1
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Reactant: CC1CCCCC1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCOc1c(F)cc(C(=O)NC2CCCCC2C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 346 mg of 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride and 1 ml of tetrahydrofuran was added dropwise under ice cooling to a mixture of 5 ml of tetrahydrofuran, 170 mg of 2-methylcyclohexylamine and 182 mg of triethylamine. The mixture obtained was stirred at room temperature for 0.5 hour. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 295 mg of N-(2-methylcyclohexyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 42 of the present invention) represented by the formula:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH2:9].CCO[C:13]([S-])=[S:14].[K+]>C(O)C.O>[F:8][C:4]1[C:3]2[N:9]=[C:13]([SH:14])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cccc(F)c1N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Fc1cccc2[nH]c(S)nc12

Procedure:
1,2-diamino-3-fluorobenzene (1.6 g, 12.7 mmol) and potassium ethyl xanthogenate (2.64 g, 16.5 mmol) were dissolved in ethanol (25 ml) and water (6 ml). The mixture was refluxed for 14 hours and then concentrated on a rotavapor. Water (20 ml) was added and the solution was acidified with 2M hydrochloric acid. The precipitate was filtered off and dried. In this way the title compound was obtained (1.23 g, 58%). NMR is given below.
Reaction SMILES: I.CS[C:4]1[NH:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[NH2:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>C(#N)C.C(O)(C(F)(F)F)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][NH:13][C:4]=1[NH:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CSC1=Nc2ccccc2CN1
Reactant: N[C@@H]1CCc2ccccc21
Agent: I
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)CNC(N[C@@H]1CCc3ccccc31)=N2
Temperature: 85 °C
Yield: 24.4 %

Procedure:
2-Methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (50 mg, 0.28 mmol) and (R)-1-aminoindane (37 mg, 0.28 mmol) were suspended in acetonitrile (1 ml) and heated in a screw-capped vial to 85° C. (6 h). The product was isolated from the reaction mixture by preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min) to give the title compound (18 mg, 24%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][CH2:12][C:13](Cl)=[O:14])(=[O:10])[CH3:9].[F:16][C:17]([F:22])([F:21])[CH2:18][NH:19][CH3:20]>C1(C)C=CC=CC=1>[F:16][C:17]([F:22])([F:21])[CH2:18][N:19]([CH3:20])[C:13](=[O:14])[CH2:12][O:11][C:8](=[O:10])[CH3:9]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CNCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OCC(=O)N(C)CC(F)(F)F
Temperature: 20 °C
Reaction time: 15 h
Yield: 79.8 %

Procedure:
10 g (0.1 mol) of triethylamine and 13.6 g (0.1 mol) of acetoxyacetyl chloride were added to a solution of 9.9 g (0.1 mol) of N-(2,2,2-trifluoroethyl)-N-methylamine in 150 ml of toluene and the mixture was stirred at 20° C. for 15 hours. It was then filtered and the filtrate was distilled. 17 g (79.8% of theory) of N-(2,2,2-trifluoroethyl)-N-methyl-acetoxyacetamide of boiling point 110° C./3 mbar were obtained. ##STR11## was obtained analogously; ND20 :1.4333. ##STR12##
Reaction SMILES: [Cl:1][C:2]1[C:26]([O:27][CH2:28][C@@H:29]([NH:34]C(=O)OC(C)(C)C)[CH2:30][CH:31]([CH3:33])[CH3:32])=[C:25]([F:42])[C:5]2[N:6](CC3C=CC(OC)=CC=3)[C:7](=[O:15])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][C:9]=3[CH3:14].CS(O)(=O)=O.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>>[NH2:34][C@@H:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:28][O:27][C:26]1[C:2]([Cl:1])=[CH:3][C:4]2[C:13]3[C:8](=[C:9]([CH3:14])[N:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[NH:6][C:5]=2[C:25]=1[F:42].[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]
Reactant: COc1ccc(Cn2c(=O)c3c(C)nccc3c3cc(Cl)c(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(F)c32)cc1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccc2c1c(=O)[nH]c1c(F)c(OC[C@@H](N)CC(C)C)c(Cl)cc12
Temperature: 70 °C

Procedure:
To a solution of (S)-tert-butyl (1-((9-chloro-7-fluoro-6-(4-methoxybenzyl)-4-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.08 g, 0.037 mmol) in TFA (8 mL) cooled to 0° C. was added methanesulfonic acid (0.243 μl, 3.75 μmol). The reaction mixture was then heated at 70° C. for 2 h. The volatiles were evaporated. The residue was taken up in water and neutralized with 10% aqueous NaHCO3. The solution was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (1×15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: X-Bridge (19×150 mm) 5 μm, Flow rate: 15 ml/min; Solvent A: 0.01% TFA, Solvent B: ACN) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-9-chloro-7-fluoro-4-methylbenzo[c][2,7]naphthyridin-5(6H)-one, 3 TFA (9.5 mg, 0.013 mmol, 34.4% yield) as an off-white solid. LC/MS (ESI) m/e 378.0 [(M+H)+, calcd for C19H22ClFN3O2 378.1]; LC/MS retention time (method C): tR=2.02 min; HPLC retention time (method A): tR=7.47 min; HPLC retention time (method B): tR=8.41 min; 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.70 (d, J=6.0 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.35 (d, J=6.3 Hz, 1H), 4.49 (dd, J=10.7, 2.6 Hz, 1H), 4.35 (dd, J=10.5, 5.8 Hz, 1H), 3.75-3.69 (m, 1H), 3.14 (s, 3H), 1.90-1.74 (m, 2H), 1.70-1.56 (m, 1H), 1.04 (d, J=2.3 Hz, 3H), 1.03 (d, J=2.5 Hz, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1.[CH3:14]O>>[Cl:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=1
Reactant: CO
Reactant: O=C(O)c1csc(Cl)n1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1csc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Thionyl chloride (4.4 mL, 61 mmol) was added dropwise to a solution of 2-chlorothiazole-4-carboxylic acid (2.00 g, 12.2 mmol) in MeOH (40 mL) at 0° C., and the reaction mixture was allowed to warm to rt. After stirring overnight, the reaction mixture was concentrated under reduced pressure. The resulting solid was recrystallized from EtOH/H2O (1:1), yielding 1.40 g (65%) of the title compound as an orange solid. LC-MS: RT=6.17 min, [M+H]+=178.1.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([NH:9][CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3].S(OCC)(O[CH2:19][CH3:20])(=O)=O.[OH-].[Na+]>O>[NH:1]([C:5]1[CH:13]=[CH:12][C:8]([N:9]([CH2:19][CH3:20])[CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3]
Reactant: CCNc1ccc(NC(C)=O)c(C)c1
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)c1ccc(NC(C)=O)c(C)c1
Yield: 64.4 %

Procedure:
19.1g (0.1 mole) of 4-acetamino-3-methyl-N-ethylaniline obtained in Example 1, Part C, and 100g of water were mixed, and, after 12.5g of diethyl sulfate were added dropwise thereto while stirring, the entire reaction system was stirred overnight at room temperature. Next, the reaction mixture was neutralized with sodium hydroxide and the crystals separated were recrystallized from methanol to obtain 11.5g of white crystals of 4-acetamino-3-methyl-(N,N-diethyl)aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.N1CCCC1>CO>[Cl:11][C:12]1[CH:20]=[C:19]2[C:15](/[C:16](=[CH:4]/[C:3]3[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=3[Cl:1])/[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: O=Cc1cc(Cl)ccc1Cl
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)ccc1Cl
Yield: 107.8 %

Procedure:
In a manner similar to the method described in Example 227b, 2,5-dichloro-benzaldehyde (5 g, 28.57 mmol) was reacted with 6-chlorooxindole (4.77 g, 28.57 mmol) and pyrrolidine (2.43 g, 34.3 mmol) in methanol to give title compound as yellow solid (10 g).
Reaction SMILES: [C:1]([O:4][C:5]1[C:21]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[C:20]([OH:27])[CH:19]=[C:18]([OH:28])[C:6]=1[C:7](=[O:17])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:4][C:5]1[C:21]([CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26])=[C:20]([OH:27])[CH:19]=[C:18]([OH:28])[C:6]=1[C:7](=[O:17])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(CC=C(C)C)c(O)cc(O)c1C(=O)C=Cc1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Oc1c(CCC(C)C)c(O)cc(O)c1C(=O)CCc1ccc(O)cc1
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A solution of 1.55 g of the 2'-acetoxy-4,4',6'-trihydroxy-3'-(3-methyl-2-butenyl)chalcone obtained in Specific Example 18 in ethanol (30 ml) was added to a suspension of 1.5 g of 5% palladium/carbon in 30 ml of ethanol, in which hydrogen had been sufficiently absorbed in advance, and the mixture was stirred under atmospheric pressure in a hydrogen gas atmosphere for 1 hour. After the reaction, the reaction mixture was filtered and the solvent was removed from the filtrate by distillation. The obtained residue was subjected to the silica gel column chromatography (25 g of 230-400 mesh silica gel, n-hexane/ethyl acetate=3/1, 0.3 kg/cm2). Fractions of 50 ml were collected and the 5th to 9th fractions were combined The solvent was removed by distillation and the obtained residue was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 1.22 g (yield=77.7%) of 1-(2-acetoxy-4,6-dihydroxy-3-isopentylphenyl)-3-(4-hydroxyphenyl)-1-propanone in the form of a colorless prism.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].C(OC([N:37]1[CH2:42][CH2:41][CH:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49](O)=O)=[CH:45][CH:44]=2)[CH2:39][CH2:38]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:49][C:46]1[CH:45]=[CH:44][C:43]([CH:40]2[CH2:41][CH2:42][NH:37][CH2:38][CH2:39]2)=[CH:48][CH:47]=1)[C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Product: CCN(Cc1ccc(C2CCNCC2)cc1)c1cc2c(cc1C1CCc3cc(O)ccc3C1)OCO2
Yield: 40.8 %

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (60 mg) according to an analogous synthetic method to Example 209, the title compound (20 mg) was obtained.