Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[C:13]([CH:19]=1)[O:14][CH2:15][CH:16]1[CH2:18][O:17]1)([O-:8])=[O:7]>CCOC(C)=O>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([C:20]([F:26])([F:25])[C:21]([F:22])([F:23])[F:24])=[C:13]([CH:19]=1)[O:14][CH2:15][C@@H:16]1[CH2:18][O:17]1)([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCC2CO2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OC[C@@H]2CO2)c1
Reaction time: 4 h

Procedure:
Combined 5-nitro-2-pentafluoromethylphenol (2.69 g), DMF (25 ml) K2CO3 (3.03 g) and (S) toluene-4-sulfonic acid oxiranyl-methyl ester (2.27 g) and stirred the mixture at 90° C. After about 4 hours, the mix was cooled, diluted with EtOAc, washed with H2O, 1N NaOH (2×), 1N HCl and then with brine. Dried over Na2SO4, filtered and concentrated in vacuo. Purified the crude on silica gel column with 5% EtOAc/hexane and drying under high vacuum provided the (S)-2-(5-nitro-2-pentafluoroethyl-phenoxymethyl)-oxirane.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:17][CH3:18])[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:17][CH3:18])[C:9]1=[O:19]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2c(OC)cccc2C1=O
Solvent: CO
Solvent: ClCCl
Product: COc1cccc2c1CC(CC=O)C2=O
Reaction time: 0.58 h
Yield: 84 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted while stirring for 35 minutes through a solution, cooled to -70°, of 6.42 g of (RS)-2-(2-buten-1-yl)-4-methoxy-1-indanone in 180 ml of anhydrous dichloromethane and 60 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 3.3 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 200 ml of dichloromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate, concentrated in a vacuum and the crude product obtained was crystallized from ethyl acetate/hexane. 5.1 g (84%) of (RS)-2-(2-oxoethyl)-4-methoxy-1-indanone were obtained as a white solid with m.p. 71°.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[C:13]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:14][CH:15]=[CH:16][C:3]1=2.[OH-:22].[K+].[OH-].[Na+]>C(O)C.O>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[C:13]([CH:17]([CH3:21])[C:18]([OH:22])=[O:19])=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: [OH-]
Reactant: CC(C(N)=O)c1cccc2c1Oc1ccccc1CC2=O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1cccc2c1Oc1ccccc1CC2=O
Reaction time: 6.5 h
Yield: 84.7 %

Procedure:
To 100 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-4-yl)-propionamide in 2 ml of ethanol was added 400 mg of potassium hydroxide in 2 ml of water and the mixture was refluxed with stirring for 6.5 hours. After the completion of the reaction, the solvent was distilled off to obtain the residue, to which was added 2N-sodium hydroxide solution, and the resulting mixture was extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain brown oil, which was chromatographed over silica gel, eluted with chloroform and crystallized from acetone-n-hexane to give 85 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-4-yl)-propionic acid as pale yellow crystals having a melting point of 159°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Nc1ccc(Cl)cc1
Product: Clc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 27.7 %

Procedure:
Using the procedure of example 1, 4-chloro-aniline (103 mg) was reacted with compound 1f (100 mg) to provide compound 11 (24 mg, 28%). 1H NMR (400 MHz, CD3OD) δ 8.82 (d, J=8.0 Hz, 1H), 8.32 (d, J=5.6 Hz, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.14 (s, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 7.24 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.16 (d, J=4.8 Hz, 1H). MS (ESI) m/z: 322 (M+H)+.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]([CH3:27])[CH3:26])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[OH:28][C:29]1([CH2:35][CH2:36][CH2:37][C:38]2[CH:39]=[N:40][C:41]3[C:46]([CH:47]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[OH:28][C:29]1([CH2:35][CH2:36][CH2:37][C:38]2[CH:39]=[N:40][C:41]3[C:46]([CH:47]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:34][CH2:33][N:32]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:5]([C@H:14]([CH:25]([CH3:27])[CH3:26])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:4]2)[CH2:31][CH2:30]1
Reactant: OC1(CCCc2cnc3ccccc3c2)CCNCC1
Reactant: CC(C)[C@H](C(=O)OCc1ccccc1)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Product: CC(C)[C@H](C(=O)OCc1ccccc1)N1C[C@H](CN2CCC(O)(CCCc3cnc4ccccc4c3)CC2)[C@@H](c2ccccc2)C1
Yield: 78.3 %

Procedure:
The title compound was prepared from 24 mg (0.067 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-3-methylbutanoic acid, benzyl ester (from EXAMPLE 5, Step D) and 22.5 mg (0.073 mmol) of 4-hydroxy-4-(3-(quinolin-3-yl)propyl)piperidine.HCl from EXAMPLE 6, Step A using a procedure analogous to that described in EXAMPLE 1, Step J to provide 32.5 mg (75%) of the title compound: RF: 0.21 (19:1 v/v CH2Cl2/MeOH); 1H NMR (300 MHz) δ 0.88 (d, J=6.7,33H), 1.01 (d, J=6.7, 3H), 1.42-3.22 (m, 24H), 5.16 (ABq, 2H), 7.15-7.41 (m, 10H), 7.49-7.54 (m, 1H), 7.62-7.68 (m, 1H), 7.75 (d, J=8.0, 1H), 7.91 (s, 1H), 8.06 (d, J=8.2, 1H), 8.75 (d, J=2.1, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[S:10][C:9]2[C:11]([CH2:15]O)=[CH:12][CH:13]=[CH:14][C:8]=2[CH:7]=1>ClCCl>[Cl:3][CH2:15][C:11]1[C:9]2[S:10][C:6]([CH3:5])=[CH:7][C:8]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc2cccc(CO)c2s1
Solvent: ClCCl
Product: Cc1cc2cccc(CCl)c2s1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
Thionyl chloride (0.415 mL, 5.69 mmol) was added slowly to an ice cold solution of the alcohol (510) (0.203 g, 1.14 mmol) in dichloromethane (6.0 mL). The reaction mixture was stirred and warmed to room temperature for 1 h. The resulting solution was quenched slowly with saturated sodium bicarbonate (10 mL) and extracted with dichloromethane, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide the intermediate 7-(chloromethyl)-2-methylbenzo[b]thiophene (511) (0.150 g, 67.0%) as a yellow oil.
Reaction SMILES: C1C=C([O:7]O)C(C(O)=O)=C(C(O)=O)C=1.[C:15]([O:23][CH2:24][CH:25]1[S:29][CH2:28][CH2:27][O:26]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:15]([O:23][CH2:24][CH:25]1[S:29](=[O:7])[CH2:28][CH2:27][O:26]1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: O=C(OCC1OCCS1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: O=C(OCC1OCCS1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Monoperoxyphthalic acid, magnesium salt (MMPP, 28 g) was added portionwise under vigorous stirring to a mixture of 2-benzoyloxymethyl-1,3-oxathiolane (example 2) (20 g), tetrabutyl ammonium bromide (0.4 g) in methylene chloride (200 ml), and water (200 ml). The mixture was stirred at room temperature for 30 minutes and the organic layer was collected. The aqueous phase was extracted with methylene chloride (3×75 ml) and the combined organic layer was washed first with water (2×100 ml), then with brine solution (100 ml), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica gel using ethyl acetate as eluant to give 18.5 g (86%) of pure product as a mixture of cis- and trans-isomers in a ratio of 1:2 respectively.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:5]=1.[CH:15]1([C:19]2[N:20]=[C:21](/[CH:24]=[CH:25]/[C:26]3[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=3)[S:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26](/[CH:25]=[CH:24]/[C:21]3[S:22][CH:23]=[C:19]([CH:15]4[CH2:18][CH2:17][CH2:16]4)[N:20]=3)[CH:27]=2)=[O:13])[CH:5]=1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reactant: COC(=O)c1cccc(CC(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)c1
Reaction time: 16 h
Yield: 77.5 %

Procedure:
A solution composed of 1.0 g of 3-carboxymethyl benzoic acid methyl ester, 1.3 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 1.0 g of N-ethyl-N-(dimethylaminopropyl) carbodiimide, 2.4 g of 4-dimethylaminopyridine and 75 ml of methylene chloride was stored at 0° C. After 16 hr., the reaction mixture was washed with 75 ml of water, dried (MgSO4) and the solvents removed by rotary, evaporation. The residual materials were triturated with ethyl acetate/hexane to yield 1.7 g of (E)-3-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid methyl ester; m.p. 119°-120° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]#[N:9])=[CH:3][CH:2]=1
Reactant: CCCCCCCCBr
Reactant: N#CCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCCCCCCC(C#N)c1ccncc1
Yield: 68.6 %

Procedure:
4-Pyridylacetonitrile (1.18 g, 0.01 mole) dissolved in acetonitrile (20 ml) was heated under reflux with n-octyl bromide (1.73 ml, 0.01 mole) and caesium carbonate (4 g) for 1 hour, filtered and concentrated. Elution from a column of silica gel as described in Example 1 gave 2-(4-pyridyl)decanonitrile (1.58 g, 69% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)N2CCCCC2)[C:6]=1[OH:29])([CH3:4])([CH3:3])[CH3:2].[CH:30](O)=[O:31]>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:6]2[O:29][C:30](=[O:31])[CH:15]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:7]=2[CH:8]=1)([CH3:12])([CH3:14])[CH3:13]
Reactant: O=CO
Reactant: CC(C)(C)c1cc(C(c2ccc(F)cc2)N2CCCCC2)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(F)cc1
Temperature: 140 °C
Yield: 89.5 %

Procedure:
A solution of 11.13 g (28.0 mmol) of compound (205), prepared according to Example 2a, in 150 ml of dry toluene is degassed using argon and then 33.6 mg (0.057 mmol) of dichloro-[1,3-bis(diphenylphosphino)propane]palladium(II) and 4.22 ml (112 mmol) of formic acid are added. The autoclave is flushed with carbon monoxide and sealed, and a carbon monoxide pressure of 6 bar is then applied. The reaction mixture is maintained at 140° C. for 14 hours. After cooling to room temperature, the reaction mixture is poured into water and extracted three times using ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Filtration of the residue on silica gel using ethyl acetate and crystallisation of the pure fractions from methanol yields 8.53 g (90%) of compound (105) (Table 1), m.p. 146-147° C. Molecular weight C22H25FO2 (340.44). Analysis, calculated: C 77.62; H 7.40%. Analysis, found: C 77.66; H 7.35%. 1HNMR (300 MHz, CDCl3, ppm): 1.22 (s, 9H); 1.36 (s, 9H); 4.74 (s, 1H); 6.99 (m, 3H); 7.16 (m, 2H); 7.26 (d, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[CH3:16][C:17]([NH2:21])([C:19]#[CH:20])[CH3:18].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:8][C:6](=[CH2:7])[CH2:5][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:3][CH2:2][NH:21][C:17]([CH3:18])([C:19]#[CH:20])[CH3:16]
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Reactant: C#CC(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CC(C)(C)NCCC(O)(CC(=C)C)c1ccccc1
Temperature: 80 °C
Yield: 42.6 %

Procedure:
A stirred mixture of 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (550 mg, 2.45 mmol), 1,1-dimethylpropargylamine (204 mg, 2.45 mmol), KI (447 mg, 2.7 mmol), i-Pr2NEt (05 mL, 2.7 mmol) and dry DMF (3 mL) was heated at 80° C. in an oil bath for 24 h. The mixture was concentrated to leave a brown oil which was purified by chromatography on a 12-g silica cartridge eluted with a 0-10% MeOH in CH2Cl2 gradient to afford 5-methyl-1-(2-methylbut-3-yn-2-ylamino)-3-phenylhex-5-en-3-ol (283 mg, 42%) as a brown solid which was used in the next step without further purification. LC-MS Method 1 tR=1.08 min, m/z=272.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH:20]2[CH:16]1[CH2:17][N:18]([C:21]([C:23]1[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[Cl:32])[CH:24]=1)=[O:22])[CH2:19]2)(C)(C)C>C(Cl)Cl>[NH2:14][CH:15]1[CH:16]2[CH:20]1[CH2:19][N:18]([C:21]([C:23]1[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[Cl:32])[CH:24]=1)=[O:22])[CH2:17]2
Reactant: CC(C)(C)OC(=O)NC1C2CN(C(=O)c3cc4nccc(Cl)c4s3)CC21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1C2CN(C(=O)c3cc4nccc(Cl)c4s3)CC12
Yield: 119.1 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a suspension of {3-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-carbamic acid tert-butyl ester (1.43 g, 3.63 mmol) in CH2Cl2. After 24 h the reaction mixture was concentrated, and the resulting oil was purified on silica gel by flash column chromatography CH2Cl2/MeOH (80/20) to afford the title compound as a white solid (1.27 g, 99%). MS: 294.2/296.2 (MH+); HPLC Rf: 3.085 min.; HPLC purity: 97%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C([Li])CCC.[B:33]([O:38]C)(OC)[O:34]C.Cl>O1CCCC1>[C:5]1([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]([C:22]3[CH:23]=[CH:24][C:25]([B:33]([OH:38])[OH:34])=[CH:26][CH:27]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Temperature: -78 °C
Yield: 84 %

Procedure:
In a 500 mL three-neck flask were added 20 g (49 mmol) of 9-(4-bromophenyl)-10-phenylanthracene obtained by the above Steps 1(1) to 1(4) of Synthesis Example 3 and 300 mL of tetrahydrofuran (abbr.: THF), and the mixture was stirred under a nitrogen stream at −78° C. Then, 34 mL (54 mmol) of n-butyllithium (1.6 mol/L hexane solution) was dropped, and this mixture was stirred for 2 hours at the same temperature. After the stirring, 13 mL (110 mmol) of trimethyl borate was added to this solution, and the mixture was stirred for 24 hours at room temperature. After the stirring, this mixture was brought back to room temperature, 200 mL of (1.0 molL) hydrochloric acid was added therein, and this mixture was stirred for 1 hour. After that, the organic layer thereof was washed with water and separated into the organic layer and the aqueous layer, and the obtained aqueous layer was extracted with ethyl acetate. After this extracted solution was washed together with the organic layer with saturated saline, magnesium sulfate was added therein for drying. The mixture was subjected to suction filtration, and the obtained filtrate was concentrated to obtain a solid. The obtained solid was recrystallized from a mixed solvent of chloroform and hexane, whereby 15 g of a white powdered solid of 4-(10-phenyl-9-anthryl)phenylboronic acid, which was the object of the synthesis, was obtained in a yield of 84% (synthesis scheme (X-5)).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:31]=[C:32]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]=[N:34][CH:35]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:31]=[C:32]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]=[N:34][CH:35]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cncc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cncc(NS(C)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 66 %

Procedure:
(S)—N-(5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-3-yl)methanesulfonamide (53 mg, 0.06 mmol) was treated with trifluoroacetic acid (1.05 ml, 13.63 mmol) and a solution of ammonia (7N in methanol, 1.05 ml, 7.35 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 10% dichloromethane-2-propanol) to obtain 22 mg (68% yield) of the title compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][N:7](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:6][C:5]=2[N:4]=1.[ClH:34]>CO.O1CCOCC1>[ClH:34].[F:33][C:2]([F:1])([F:32])[C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[N:4]=1
Reactant: FC(F)(F)c1ccc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc2c(n1)CNCC2

Procedure:
A solution of the product (94 mg, 0.20 mmol) from Step A above in 0.5 mL of methanol and 2.0 mL of 4.0M hydrogen chloride in 1,4-dioxane was kept at room temperature for 18 h. The reaction mixture was concentrated under a stream of nitrogen, and the residue was triturated with ether. The resultant precipitate was collected and dried in vacuo to afford the title compound as a pale yellow powder. LC/MS 203.1 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[C:22]([NH:34][CH2:35][CH3:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[C:26]([F:33])[CH:25]=2.[Li+].[OH-]>C1COCC1>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:34][CH2:35][CH3:36])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[C:26]([F:33])[CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCNc1nc2cc(F)c(OC)cc2cc1CCl
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNc1nc2cc(F)c(OC)cc2cc1Cc1c(O)nc(CC)c2cc(OC)c(OC)cc12
Temperature: 155 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (114 mg, 0.49 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-N-ethyl-7-fluoro-6-methoxyquinolin-2-amine hydrochloride SMA 44096 (149 mg, 0.49 mmol) at RT followed by a 2 N aq. LiOH solution (0.49 mL, 0.98 mmol) and the mixture was stirred at 155° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL). The organic solution was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) gave 16 mg of 1-ethyl-4-((2-(ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.5 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-4-((2-(ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 82 as a yellow solid (19 mg, 7% yield).
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:31])(=[O:30])[C:13]=2[CH:32]=1)=[O:8].O>C(O)=O>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:26]([CH:1]=[O:2])[CH2:27][CH2:28]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:31])[C:13]=2[CH:32]=1)=[O:8]
Reactant: O=C[O-]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C=O)CC3)cc(Cl)c1O2
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Sodium formate (0.1 g, 1.37 mmol) was added to a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g, 0.68 mmol) in formic acid (85%, 5 mL), and stirred at 90° C. for 15 h. The reaction mixture was diluted using water (10 mL), extracted using ethyl acetate, washed with water and brine. Solvent was removed and the crude product was purified by column chromatography (silica gel, 1.5% methanol in chloroform) to obtain the title compound. Yield: 0.11 g, (35%); 1H NMR (DMSO-d6, 300 MHz): δ 2.62 (s, 3H, CH3), 3.17-3.24 (m, 4H, 2CH2), 3.47 (s, 4H, 2CH2), 3.85 (s, 3H, OCH3), 5.15 (s, 2H, CH2), 7.13 (s, 1H, Ar), 7.17 (s, 1H, Ar), 8.06 (s, 1H, CHO), 8.08 (t, 1H, Ar), 8.14 (d, 1H, Ar); MS: m/e (ES+) 465 (M+1); analysis: C21H21ClN2O6S.0.5H2O requires C, 53.23; H, 4.64; N, 5.91; Cl, 7.49; S, 6.75. found: C, 53.82; H, 4.48; N, 5.42; Cl, 8.07; S, 7.17%.