Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH3:30])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>C1COCC1>[CH2:29]([O:28][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([O:14][C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[NH2:7])=[N:17][CH:18]=[N:19]2)=[CH:24][C:23]=1[O:26][CH3:27])[CH3:30]
Reactant: Nc1cccc(O)c1
Reactant: CCOc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
To a stirred slurry of cesium carbonate (2.99 g, 9.20 mmol) in anhydrous THF (50 mL) at rt, was added 3-aminophenol (1.00 g, 9.17 mmol). After stirring for 30 mins, 4-chloro-7-ethoxy-6-methoxyquinazoline (prepared as described in Example 6A Steps 1 through 5) (2.19 g, 9.20 mmol) was added and the reaction mixture was heated at 50° C. for 18 h. The mixture was cooled to rt and concentrated under reduced pressure and the resulting solid was washed with water (three times) then ethyl acetate (three times) to afford 3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)aniline (1.75 g, 61%) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.51 (s, 1H), 7.35 (s, 1H), 7.09 (m, 1H), 6.37-6.50 (m, 3H), 5.31 (brs, 2H), 4.25 (q, J=7 Hz, 2H), 3.97 (s, 3H), 1.44 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 312 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[N:28]1([C:34]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[F-].[Cs+]>C(COC)OC.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1[C:39]1[CH:38]=[CH:37][C:36]([C:34]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:35])=[CH:41][CH:40]=1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)CCc1ccc(-c2ccc(C(=O)N3CCOCC3)cc2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (0.8 g, 1.9 mmol) was dissolved in dimethoxyethane (12 mL) and ethanol (1.2 mL). 4-Morpholine-4-carbonylphenylboronic acid (0.50 g, 2.1 mmol) was added and argon: was bubbled in the mixture for 15 minutes. Cesium fluoride (0.6 g, 4.2 mmol) and tetrakistriphenylphosphine palladium (0.11 g, 0.1 mmol) were added and the mixture was brought to reflux under an argon atmosphere for 4 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate/water (15 mL/15 mL). The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 7/3) to yield 0.57 g (65%) of the desired product as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].C([Li])CCC.[O:15]=[C:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:20]=2[N:19]=[C:18]([C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:31][CH3:32])[O:17]1>CCCCCC.O1CCCC1>[O:15]=[C:16]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:20]=1[NH:19][C:18](=[O:17])[C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH3:32])[CH2:8][C:7](=[O:9])[NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CC(=O)Nc1nccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F

Procedure:
Using the procedure of Step B of Example 3, 7.78 g of N-(2-thiazolyl)-acetamide, 240 ml of tetrahydrofuran and 78.3 ml of a solution of n-butyllithium in hexane and 10.2 g of the product of Step A in 75 ml of tetrahydrofuran were reacted to obtain 8.3 g of 1,1-dimethylethyl N-[(S) 2-[[2-[1,3-dioxo-3-(1,1-dimethylethyl N-[(S) 2-[[2-[1,3-dioxo-3-(2-thiazolylamino)-propyl]-6-(trifluoromethyl)-phenyl]-amino]-1-ethyl-2-oxoethyl]-carbamate melting at 190° C. and having a specific rotation of [α]D =-36.5°±2° (c=0.5% in CH3COOH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][CH2:32][Cl:33].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:30][CH2:31][CH2:32][Cl:33])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCCl
Temperature: 40 °C
Reaction time: 8 h
Yield: 82.89 %

Procedure:
To a suspension of 4-((4-bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (2.17 g), K2CO3 (0.99 g) in DMF (20 mL) was added 1-bromo-3-chloropropane (0.71 mL) at rt, the mixture was stirred at 40° C. overnight. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as a white solid (2.18 g, 82.89%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])=[O:4].Br[CH2:18][C:19]1[CH:23]=[C:22]([C:24]2[S:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[O:21][N:20]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:23]=[C:22]([C:24]3[S:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[O:21][N:20]=2)[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])=[O:4]
Reactant: COC(=O)c1[nH]c(-c2ccccc2)nc1C
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)nc(-c2ccccc2)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 60 mg 5-Methyl-2-phenyl-3H-imidazole-4-carboxylic acid methyl ester in 1 ml DMF 95 mg caesium carbonate and 82 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added and the mixture was stirred for 2 h at 60° C. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 78 mg.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1B1OC(C)(C)C(C)(C)O1)[C:18]([NH:20][CH3:21])=[O:19])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:46])[CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43](Br)[CH:44]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:46])[CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[C:43]([C:24]2[CH:23]=[CH:22][C:17]([C:18](=[O:19])[NH:20][CH3:21])=[CH:16][C:15]=2[CH2:14][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:44]=1)[CH3:35]
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Reactant: CCOC(=O)Cc1cncc(Br)c1
Product: CCOC(=O)Cc1cncc(-c2ccc(C(=O)NC)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1

Procedure:
3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-N-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide and (5-bromo-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 3, Step 6 to provide (5-{2-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-methylcarbamoyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:31])([CH:28]([F:30])[F:29])[CH2:17][O:18][C:19]1[N:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:27]([CH:25]([C:22]3[CH:23]=[N:24][C:19]([O:18][CH2:17][C:16]([F:31])([F:15])[CH:28]([F:30])[F:29])=[CH:20][CH:21]=3)[CH3:26])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: CC(N)c1ccc(OCC(F)(F)C(F)F)nc1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(c1ccc(OCC(F)(F)C(F)F)nc1)N1Cc2c(ccnc2Cl)C1=O
Yield: 60 %

Procedure:
The title compound is prepared in 60% yield (137 mg, pale yellow oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (175 mg, 0.53 mmol) and 1-(6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (164 mg, 0.57 mmol, Amine-6, single enantiomer), and sodium bicarbonate (240 mg, 2.3 mmol) as a base in a similar manner to Step-2 of Intermediate-1.
Reaction SMILES: C([O:8][C:9]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:10]=1[O:11][CH2:12][C@H:13]1[CH2:15][O:14]1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[Pd].C(O)C>[N+:20]([C:18]1[CH:17]=[CH:16][C:10]2[O:11][CH2:12][C@H:13]([CH2:15][OH:14])[O:8][C:9]=2[CH:19]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CO)CO2
Temperature: 50 °C
Yield: 70.3 %

Procedure:
A 5 L four necked flask equipped with a heating mantle, mechanical stirrer, thermocouple, gas inlet adapter and gas outlet adapter is charged with (2R)-2-{[2-(benzyloxy)-4-nitrophenoxy]methyl}oxirane (100.00 g, 0.33 mol), sodium bicarbonate (27.88 g, 0.33 mol), palladium (5% on carbon, 50% water, 15 g) and ethanol (2 L). The mixture is heated to 50° C. The stirring is stopped and the flask is flushed with hydrogen gas (3 L). Stirring is resumed and hydrogen gas is titrated into the solution [7.4 L (0.33 mol) over 130 min]. Heating is discontinued and nitrogen is bubbled through the solution for 20 min. Once the solution is cooled to 25° C., the mixture is filtered through a pad of celite and the filter cake is washed with ethanol (1 L). The resulting solution is concentrated by rotary evaporation removing 2.5 L of ethanol. The solution is transferred to a 5 L four necked flask equipped with a mechanical stirrer, thermocouple and an addition funnel. Water (750 mL) is slowly added to the stirred solution over 30 min, and the solution is stirred for 15 min at which point a precipitate forms. Additional water (1.5 L) is added over 60 min and the suspension is stirred for 48 h. The precipitate is collected by vacuum filtration, and then the filter cake is washed with water and suction dried. The title compound (49.01 g, 70%) is obtained as a tan powder. LCMS (Standard Method): 2.23 min, 212 (M+H)+. 1NMR (300 MHz, CDCl3) δ 7.81-7.76 (m, 2H), 6.96 (d, J=8.5 Hz, 1H), 4.42 (dd, J=2.1, 11.2 Hz, 1H), 4.32-4.18 (m, 2H), 3.98-3.85 (m, 2H), 2.03 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[O-:7][S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9].[F:15][C:16]([F:26])([F:25])[CH2:17][I+]C1C=CC=CC=1>C(Cl)Cl>[O-:10][S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:7].[CH3:1][N+:2]1[CH:6]=[CH:5][N:4]([CH2:17][C:16]([F:26])([F:25])[F:15])[CH:3]=1
Reactant: Cn1ccnc1
Reactant: FC(F)(F)C[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: C[n+]1ccn(CC(F)(F)F)c1

Procedure:
1-Methylimidazole (0.82 g, 10 mmol) was added to methylene chloride (20 ml), and (2,2,2-trifluoroethyl)(phenyl)iodonium triflate (4.54 g, 10 mmol) was added thereto while stirring in an ice bath. Thereafter, the mixture was stirred at room temperature for 3 hours. Methylene chloride was removed by distillation, and the residue was then dried using a vacuum pump while being heated. Thus, 1-methyl-3-(2′,2′,2′-trifluoroethyl)imidazolium triflate of interest was obtained in a substantially quantitative manner.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:31])[O:29][CH3:30]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:28]([O:29][CH3:30])=[O:31]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2cccc(F)c2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Methyl 2-(3-fluorobenzyl)piperidine-4-carboxylate (7.6 g, 30.24 mmol) was dissolved in DCM (200 mL) and DIPEA (6.32 mL, 36.29 mmol), then methyl carbonochloridate (3.3 mL, 41.91 mmol) was added. The solution was stirred at room temperature for 2 h. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(3-fluorobenzyl)piperidine-1,4-dicarboxylate (9.30 g, 99%) as a brown oil. MS m/z 310 (M+H)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:7]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:8]([C:24](O)=[O:25])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1>>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C@@H:8]([C:24]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:25])[NH:7][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as in Example 5, morpholine (1.41 ml) and Boc-L-Tyr(Bzl)-OH (6.00 g, manufactured by Peptide Institute, Inc.) were condensed to give N-(O-benzyl-Boc-L-tyrosyl)morpholine (8.10 g) as a white powder (yield quantitative). After Boc group elimination with TFA, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate (2.76 g) as obtained in Reference Example 8 to yield the title compound (compound 58; 6.14 g) as a white powder (yield 81%).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH2:5][CH3:6])[C:3]#[CH:4].Br[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:7][C:2]([CH3:1])([CH2:5][CH3:6])[C:3]#[C:4][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: C#CC(C)(O)CC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C)(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, 3-methyl-1-pentyn-3-ol (75 mg, 0.75 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1 supra) (200 mg, 0.63 mmol) using (Ph3P)2PdCl2 (25 mg) and Cul (12 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 17 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-3-methyl-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 66 mg, 31%).
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[CH3:49][C:50]1([C:53]([OH:55])=O)[CH2:52][CH2:51]1>>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][N:46]([C:53]([C:50]3([CH3:49])[CH2:52][CH2:51]3)=[O:55])[CH2:47][CH2:48]1)[CH2:4][CH2:3]2
Reactant: CC1(C(=O)O)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C4(C)CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (0.9 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using 1-methylcyclopropane-1-carboxylic acid as the acylating agent. LCMS: m/e 724.8 (M+H)+, 4.49 min (method 15). 1H NMR (500 MHz, METHANOL-d4) δ 7.89 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.6 Hz, 1H), 4.78 (s, 1H), 4.67 (s, 1H), 3.90-3.63 (m, 4H), 3.09-2.98 (m, 1H), 2.96-2.82 (m, 2H), 2.81-2.73 (m, 1H), 2.71-2.61 (m, 3H), 2.54 (br. s., 2H), 2.24-2.12 (m, 1H), 2.11-1.82 (m, 5H), 1.75 (s, 3H), 1.72-1.14 (m, 16H), 1.32 (s., 3H), 1.23 (s., 3H), 1.11 (s, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.97 (s, 3H), 0.93-0.88 (m, 2H), 0.68-0.58 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]3=[C:11]([S:17][CH3:18])[S:12][C:13]([C:14](O)=[O:15])=[C:9]3[CH2:8][CH2:7][C:5]=2[N:6]=1.C(Cl)(=O)C(Cl)=O.C[N:26](C)C=O>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]2[C:10]3=[C:11]([S:17][CH3:18])[S:12][C:13]([C:14]([NH2:26])=[O:15])=[C:9]3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: CSc1sc(C(=O)O)c2c1-c1oc(C)nc1CC2
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CSc1sc(C(N)=O)c2c1-c1oc(C)nc1CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
4,5-Dihydro-2-methyl-8-methylthiothieno[3,4-g]benzoxazole-6-carboxylic acid (0.47 g) was suspended in tetrahydrofuran (15 ml); oxalyl chloride (0.32 g) and then N,N-dimethylformamide (6 μl) were added. After this mixture was stirred at room temperature for 2 hours, it was concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (5 ml) and cooled with ice; concentrated aqueous ammonia (4.0 ml) was added. After the reaction mixture was stirred at room temperature for 1 hour, it was poured over water (150 ml) and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-g]benzoxazole-6-carboxamide (0.27 g, 57%), which was then recrystallized from chloroform-methanol. Light-yellow needles. Melting point over 300° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]([NH:8][CH2:9][C:10]1[CH:31]=[CH:30][C:13]2[NH:14][C:15]3[S:16][C:17]([CH3:29])=[CH:18][C:19]=3[C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[N:21][C:12]=2[CH:11]=1)=[O:7].[Li+].[OH-].Cl>C1COCC1.O>[CH3:29][C:17]1[S:16][C:15]2[NH:14][C:13]3[CH:30]=[CH:31][C:10]([CH2:9][NH:8][C:6](=[O:7])[CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:11][C:12]=3[N:21]=[C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[C:19]=2[CH:18]=1
Reactant: COC(=O)CCC(=O)NCc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cc(C)sc1N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(s1)Nc1ccc(CNC(=O)CCC(=O)O)cc1N=C2N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of N-[2-methyl-10-(4-methyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulen-7-ylmethyl]-succinamic acid methyl ester, prepared as described in the previous step, (80 mg, 0.18 mmol) in THF (1.5 mL) was added LiOH (14 mg) in water (0.5 mL). The solution was stirred at room temperature for 3 h, acidified with dilute HCl, and concentrated to dryness. LC-MS: m/z 442 (M+1 of the parent).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[F:26].[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[C:15]([O:14][C:12]([NH:6][C@H:5]([CH2:10][CH2:9][CH2:8][C:7]([C:23]1[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=1)=[O:11])[C:3]([O:2][CH3:1])=[O:4])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1ccc([Mg]Br)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CCCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 7 h

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS No. 183890-36-0, 5.8 g) in THF (200 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in THF, 50 mL) was added dropwise at −40° C., and the reaction solution was stirred at −40° C. for seven hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the mixture was heated to room temperature. Thereafter, the organic layer was separated, and the resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 3.8 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCC(CCCN)CCc1cccnc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)CCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.127 g (9.045 mmol) of methyl 8-amino-5-[2-(3-pyridyl)ethyl]-octanoate in 5 mL methylene chloride are added a few crystals of 4-dimethylaminopyridine followed by 0.1 mL (0.7 mmol) triethylamine and 0.112 g p-chlorophenylsulfonyl chloride, and the solution is stirred at room temperature for 16 hours. The reaction is diluted with 10 mL methylene chloride and washed with saturated aqueous sodium bicarbonate solution. The organic phase is dried (MgSO4), filtered and evaporated to obtain an oil which is purified by preparative thin layer chromatography to give methyl 8-(p-chlorophenylsulfonamido)-5-[2-(3-pyridyl)ethyl]-octanoate as an oil.