Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O:3][C:4]([CH3:7])(C)C)=O.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[CH2:26])[C:22]([O:24][CH3:25])=[O:23].CC(C)([O-])C.[K+].BrCC#[N:36]>C(O)(C)(C)C>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[CH:26][O:3][CH2:4][C:7]#[N:36])[C:22]([O:24][CH3:25])=[O:23]
Reactant: N#CCBr
Reactant: CC(C)(C)ON=O
Reactant: C=C(C(=O)OC)c1ccccc1OC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=COCC#N)c1ccccc1OC1CCCCO1
Reaction time: 2 h
Yield: 47 %

Procedure:
A solution of 34.3 g (300 mmol) of t-butyl nitrite and 25 g (100 mmol) of methyl 2-[2-(tetrahydropyran-2-yloxy)-phenyl]-acrylate in 30 ml of t-butanol is added dropwise to a solution of 12.3 g (110 mmol) of potassium t-butoxide in 120 ml of t-butanol, and the reaction solution warms to 45° C. After 2 hours, 13.2 g (110 mmol) of bromoacetonitrile are added to this mixture and stirring is continued at 20° C. for a further 18 hours. The reaction mixture is concentrated under reduced pressure, taken up in methyl t-butyl ether, washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue is chromatographed over silica gel using hexane/acetone (8:2). 14.9 g (46.9% of theory) of methyl 2-[2-(tetrahydropyran-2-yloxy)-phenyl]-3-cyanomethoxy-acrylate are obtained.
Reaction SMILES: [CH3:1][C@H:2]1[C@:9]2([O:14][C:13]3[C:15]([Cl:23])=[C:16]([O:21][CH3:22])[CH:17]=[C:18]([O:19][CH3:20])[C:12]=3[C:10]2=[O:11])[C:7](=[O:8])[CH2:6][C:4](=O)[CH2:3]1.C([O-])(=O)C.[NH4+:28].[CH:29]([C:31]([CH2:33]C)=O)=[CH2:30]>C(O)C>[Cl:23][C:15]1[C:13]2[O:14][C@:9]3([C@H:2]([CH3:1])[CH2:3][C:4]4[N:28]=[C:31]([CH3:33])[CH:29]=[CH:30][C:6]=4[C:7]3=[O:8])[C:10](=[O:11])[C:12]=2[C:18]([O:19][CH3:20])=[CH:17][C:16]=1[O:21][CH3:22]
Reactant: [NH4+]
Reactant: COc1cc(OC)c2c(c1Cl)O[C@@]1(C(=O)CC(=O)C[C@H]1C)C2=O
Reactant: C=CC(=O)CC
Agent: CC(=O)[O-]
Solvent: CCO
Product: COc1cc(OC)c2c(c1Cl)O[C@@]1(C(=O)c3ccc(C)nc3C[C@H]1C)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.2 %

Procedure:
A 100 mL round-bottomed flask was charged with 1 g (2.9 mmol, 1 eq.) of griseofulvic acid, 0.34 g (4.4 mmol, 1.5 eq.) ammonium acetate and 347 μL (3.5 mmol, 1.2 eq.) of ethyl vinyl ketone in 10 mL ethanol. The mixture was left under agitation for 4 h at 80° C., cooled to ambient temperature then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2Cl2/AcOEt 98:2 to 80:20). A yellow solid (0.25 g) was obtained with a yield of 21%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[S:16].C1N2CCN(CC2)C1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][C:15](=[S:16])[N:14]([CH3:18])[CH3:13]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)ccc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of 5-Bromo-2-hydroxy-benzoic acid methyl ester (29.8 g, 129 mmol) and dimethylthiocarbamoyl chloride (17.54 g, 142 mmol) in DMF at room temperature was added DABCO (21.7 g, 193.5 mmol). The resulting mixture, after being stirred at room temperature overnight, was diluted with water (1.25 L) and acidified to a pH˜4 using 1 N HCl. The precipitate was collected, rinsed with water and dried in vacuo to provide crude 5-bromo-2-dimethylthiocarbamoyloxy-benzoic acid methyl ester as an off-white solid in 91% yield. The product was used directly in the subsequent reaction without purification.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(N)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 114 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (150 mg, 0.250 mmol) was dissolved in dimethoxyethane (10.5 mL), and the solution was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline (110 mg, 0.500 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (25 mg, 0.030 mmol), potassium carbonate (173 mg, 1.25 mmol) and water (0.090 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=5/1) to obtain 4-(4-aminophenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (76.5 mg, yield 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([O:16]C)=[O:15])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:20][CH:19]=1.[OH-].[Na+].CO>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][C:10]=1[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(-c2ccc(OCCCOC3CCCCO3)cc2)c(-c2ccc(F)cc2Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2ccc(OCCCOC3CCCCO3)cc2)c(-c2ccc(F)cc2Cl)s1

Procedure:
3.1 g of the compound obtained in stage 16F) and then 800 mg of sodium hydroxide pellets are added to 30 ml of methanol and 1 ml of water. The reaction mixture is brought to reflux for 2 hours. It is concentrated to dryness, the residue is taken up in 500 ml of buffer solution at pH 2, extraction is carried out with ether and the extract is dried and concentrated to dryness. 3 g of the expected compound, crystallized from pentane, are obtained.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]([CH3:15])=[O:14])[C:10]([O-:12])=[O:11].O.[C:17](O)(=O)[CH3:18]>>[CH3:6][O:7][N:8]=[C:9]([C:13]([CH2:15][Cl:4])=[O:14])[C:10]([O:12][CH2:17][CH3:18])=[O:11]
Reactant: CC(=O)O
Reactant: O=S(=O)(Cl)Cl
Reactant: CON=C(C(C)=O)C(=O)[O-]
Solvent: O
Product: CCOC(=O)C(=NOC)C(=O)CCl

Procedure:
Sulfuryl chloride (235 ml.) was dropwise added over 20 minutes with stirring and ice-cooling to a solution of ethyl, 2-methoxyiminoacetoacetate (syn isomer) (500 g.) in acetic acid (500 ml.), and the mixture was stirred overnight under cooling with water. Nitrogen gas was introduced to the reaction mixture for 2 hours, and the resulting mixture was poured into water (2.5 l). After extracting with methylene chloride (500 ml.) and twice with methylene chloride (200 ml.), the extracts were combined. The combined extracts were washed with a saturated aqueous solution of sodium chloride, and adjusted to pH 6.5 by adding water (800 ml.) and sodium bicarbonate. Methylene chloride layer was separated, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (559 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].C[Mg+].[Br-].[CH2:20](OCC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]([C:9]([CH3:20])=[CH:8][CH2:7][C:6]2([CH3:16])[CH3:15])=[CH:11][C:12]=1[CH3:13]
Reactant: CCOCC
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1C)C(C)=CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
General Procedure F CeCl3.7H2O (2.6 g, 6.9 mmol) was heated in an oil bath at 140-150° C. under high vacuum without stirring for 1 h, and then with stirring for 2 h. Argon was then introduced, and the flask was cooled to room temperature. Tetrahydrofuran (15 mL) was added, and the resulting slurry solution was stirred at room temperature under the argon atmosphere for 16 h. A solution of 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 30, 1.0 g, 4.6 mmol) and 5 mL of tetrahydrofuran was added, and the reaction mixture was stirred for 1 h, then cooled to 0° C. A solution of 3 M MeMgBr in diethyl ether (2.3 mL, 6.9 mmol) was added, and the ice bath was removed. After 1 h, the reaction was poured into concentrated sulfuric acid in ice, extracted with ethyl acetate, washed with NaHCO3 1 N, brine, dried over MgSO4, and filtered. The solvent was removed to give 1.0 g (100%) of the title compound as an orange oil. PNMR (300 MHz, CDCl3) δ 1.52 (s, 6 H), 2.28 (s, 3 H), 2.42 (d, 2 H, J=3.4 Hz), 2.49 (s, 1 H), 4.07 (s, 3 H), 5.86 (t, 1 H, J=2.5 Hz), 7.08 (s, 1 H), 7.30 (s, 1 H). 4-Ethyl-7-methoxy-1,1,6-trimethyl-1,2-dihydro-naphthalene (Compound 32)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(OC(=O)C1C=CC(CN2C3C=CC=CC=3C3C2=CC=CC=3)=CC=1)C>>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([Br:1])[CH:3]=2)[CH3:25]
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3
Reactant: CCOC(=O)CCCCCBr
Agent: CCOC(=O)c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Product: CCOC(=O)CCCCCn1c2c(c3cc(Br)ccc31)CCCC2

Procedure:
Compound 31 was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazole (30) (1.50 g, 6.00 mmol) and ethyl 6-bromohexanoate (1.34 g, 6.00 mmol) using the procedure described above for compound 28 as a solid (1.453 g).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)[C:10]([OH:12])=[O:11].O1CCOCC1.C([O-])([O-])=O.[K+].[K+].[C:34](Cl)(=[O:50])[O:35][CH2:36][CH:37]1[C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2>O>[CH:48]1[C:49]2[CH:37]([CH2:36][O:35][C:34]([NH:8][C@@H:9]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[C:10]([OH:12])=[O:11])=[O:50])[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:44]=2[CH:45]=[CH:46][CH:47]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1cccc(OC[C@H](N)C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(OC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a round-bottom flask equipped with a stir bar and charged with the entirety of (S)-2-amino-3-(m-tolyloxy)propanoic acid TFA salt afforded in Step 3 (assumed 3.36 mmol) was added 1,4-Dioxane (4 mL) and water (16 mL), then K2CO3 (1.17 g, 8.49 mmol). The mixture was cooled to 0° C., then to the mixture was added (9H-fluoren-9-yl)methyl carbonochloridate (549 mg, 2.12 mmol). The mixture was allowed to warm to room temperature with stirring for 18 h. The mixture was diluted with water (10 mL) and then washed with diethyl ether (2×15 mL). The aqueous phase was acidified with aq. HCl (1M) to pH 2-3, and then was extracted with CH2Cl2 (3×20 ml). The combined CH2Cl2 solutions were dried over MgSO4; filtered; then concentrated in vacuo to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(m-tolyloxy)propanoic acid as a white solid, 430 mg (31% over two steps).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]4[CH:30]=[N:29][C:28](=[O:31])[NH:27][C:26]=4[N:32]=3)[CH2:13][CH2:12]2)[CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl.CCOCC>C1COCC1.CO>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]4[CH2:30][NH:29][C:28](=[O:31])[NH:27][C:26]=4[N:32]=3)[CH2:15][CH2:16]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=c1ncc2ccc(OCCCCN3CCN(c4cccc5c4OCCC5)CC3)nc2[nH]1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1NCc2ccc(OCCCCN3CCN(c4cccc5c4OCCC5)CC3)nc2N1
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of 7-[4-(4-chroman-8-yl-piperazin-1-yl)-butoxy]-1H-pyrido[2,3-d]pyrimidin-2-one (320 mg) in THF (6 mL) and MeOH (2 mL) was added NaBH4 (54 mg) in portions. After the addition was over, the mixture was kept stirring overnight. The reaction was quenched with H2O. The mixture was extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel to give a semi-solid which was converted to its HCl salt by treating with 1 equivalent of 1 N HCl in a mixed solvent of THF and Et2O to give the title compound (147 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.40 (d, 1H), 6.98 (s, 1H), 7.70 (m, 3H), 6.25 (d, 1H), 4.30–4.06 (m, 6H), 3.60–3.30 (m, 4H), 3.15 (m, 4H), 3.00–2.70 (, 4H), 2.00–1.60 (m, 6H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[C:28]([CH3:35])[CH:27]=1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C@@H:38]1[C:43]([NH2:45])=[O:44]>>[NH2:45][C:43]([C@H:38]1[CH2:39][CH2:40][CH2:41][CH2:42][C@H:37]1[NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:30]=[CH:31][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:27][C:28]=1[CH3:35])=[O:7])=[O:18])=[O:44]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC(=O)[C@H]1CCCC[C@H]1N
Reactant: Cc1cc(-c2ccccc2C)ccc1C(=O)O
Product: CON=C1C[C@@H](C(=O)N[C@@H]2CCCC[C@@H]2C(N)=O)N(C(=O)c2ccc(-c3ccccc3C)cc2C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,3-dimethyl[1,1′-biphenyl]4-carboxylic acid, and (1S,2R)-2-aminocyclohexanecarboxamide, the title compound was obtained in 91% purity by HPLC. MS(ESI+): m/z=491.
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:2].O=[CH:20][C:21]([Cl:24])([Cl:23])[Cl:22]>>[Cl:22][C:21]([Cl:24])([Cl:23])[CH:20]1[O:12][C:3]([C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:1][O:2]1
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Reactant: O=CC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)C1(c2ccccc2)COC(C(Cl)(Cl)Cl)O1
Yield: 63 %

Procedure:
The procedure of Example 1 was repeated except that the starting materials were α-methylolbenzoin and chloral. The product was a 63% yield of 2-trichloromethyl-4-benzoyl-4-phenyl-1, 3-dioxolane, analyzed as follows:
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.[CH:49]1([C:54]([OH:56])=O)[CH2:53][CH2:52][CH2:51][CH2:50]1>>[CH:49]1([C:54]([N:46]2[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][NH:40][C@:5]34[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]3[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4]4)[C@@:19]4([CH3:20])[C@@H:10]([C@:11]5([CH3:33])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[CH2:44][CH2:45]2)=[O:56])[CH2:50][CH2:51][CH2:52][CH2:53]1
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
Reactant: O=C(O)C1CCCC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C4CCCC4)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 (3.1 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 cyclopentanecarboxylic acid as the acylating agent. LCMS: m/e 738.8 (M+H)+, 3.84 min (method 14). 1H NMR (500 MHz, METHANOL-d4) δ 7.89 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.6 Hz, 1H), 4.79 (s, 1H), 4.69 (s, 1H), 3.78-3.52 (m, 4H), 3.13-3.01 (m, 2H), 2.97-2.89 (m, 1H), 2.86-2.73 (m, 2H), 2.72-2.61 (m, 3H), 2.60-2.41 (m, 2H), 2.20-1.80 (m, 8H), 1.75 (s, 3H), 1.74-1.18 (m, 22H), 1.23 (s., 3H), 1.11 (s, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:10]=[C:9]3O)[CH2:3][CH2:2]1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:39][C:40]1[NH:44][N:43]=[C:42]([NH2:45])[CH:41]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:10]=[C:9]3[NH:45][C:42]2[CH:41]=[C:40]([CH3:39])[NH:44][N:43]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(N)n[nH]1
Reactant: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C3CC3)cccc12
Agent: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(C4CC4)cccc23)n[nH]1
Temperature: 95 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (50 mg, 0.15 mmol) were added phosphoryl tribromide (0.86 g) and toluene (2 mL) followed by DIEA (0.053 mL, 0.3 mmol). The mixture was heated at 95° C. for 0.5 h. The mixture was cooled and partitioned between EtOAc and a saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (100 mg, 1 mmol) in DMF (3 mL) and the mixture was stirred at rt overnight. The mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (30 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79-0.90 (m, 2H) 1.04-1.16 (m, 2H) 2.17 (s, 3H) 2.95-3.10 (m, 1H) 5.97 (s, 1H) 7.32 (d, J=7.35 Hz, 1H) 7.52 (t, J=7.91 Hz, 1H) 7.96-8.06 (m, 2H) 8.43 (d, J=8.10 Hz, 1H) 8.67 (s, 1H) 10.57 (br s, 1H) 12.15 (br s, 1H); LC-MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: [C:1]1([P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8]CC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:22])([F:21])[CH2:19]I>>[F:17][C:18]([F:22])([F:21])[CH2:19][P:7](=[O:8])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: FC(F)(F)CI
Reactant: CCOP(c1ccccc1)c1ccccc1
Product: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 51 %

Procedure:
Ethyl diphenylphosphinite (b1; 20.0 g) and 1,1,1-trifluoro-2-iodoethane (b2; 36.5 g) were put into a reaction vessel under an argon atmosphere, and stirred at room temperature for 4 days. The resulting mixture was purified by means of fraction-collecting column chromatography using ethyl acetate as the eluent and silica gel as the stationary phase powder, and further purified by recrystallization from a mixed solvent of toluene and heptane (volume ratio of toluene:heptane=1:1), and then dried, whereby 12.6 g of 2,2,2-trifluoroethyl diphenylphosphine oxide (b3) was obtained. The yield based on the compound (b1) was 51.2%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[F:22])=[N:12][N:11]3[CH:23]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[C:27]([Si:29]([CH3:32])([CH3:31])[CH3:30])#[CH:28].C(N(CC)CC)C>C1COCC1.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.[Cu]I>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:23]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:28]#[C:27][Si:29]([CH3:32])([CH3:31])[CH3:30])=[C:3]([N+:24]([O-:26])=[O:25])[CH:4]=3)[N:9]=2)[N:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cc(-c2cn3nc(-c4ccccc4F)ccc3n2)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 81.6 %

Procedure:
To a mixture of 2-(4-bromo-3-nitrophenyl)-6-(2-fluorophenyl)imidazo[1,2-b]pyridazine (0.500 g, 1.21 mmol), ethynyltrimethylsilane (2.42 mmol), PdCl2(PPh3)2(0.0242 mmol) in THF (50 mL) containing triethylamine (6.05 mmol) is added CuI (0.0242 mmol). The mixture is degassed with N2 (5 minutes) then heated at 60° C. for 12 hours. The mixture is filtered, followed by washing with EtOAC, filtrate collected, concentrated under reduced pressure and crude product is purified via chromatography using CH2Cl2 to afford the title compound (0.425 g, 81%) as a yellow solid: Rf 0.56 (CH2Cl2); LCMS (m/z)=431.4 [M+H]+, tR=3.86 min.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:4]=[CH:5][N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.C([Li])CCC.[O:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>O1CCCC1>[F:17][C:2]([F:16])([F:1])[C:3]1[N:4]=[C:5]([C:26]2([OH:29])[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cnc(C(F)(F)F)c1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1C1(O)CCOCC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
Into a 100-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (compound 216.2, 5 g, 18.77 mmol) in tetrahydrofuran (50 mL). This was followed by the addition of n-butyllithium (9 mL, 22.5 mmol, 2.5N in hexane) dropwise at −78° C. and stirred for 1 h at -60° C. To this was added dihydro-2H-pyran-4(3H)-one (6 g, 59.93 mmol). The resulting solution was stirred for 4 h at 0° C. in an ice/salt bath, then quenched with 10 mL of water. The resulting solution was diluted with 100 mL of NH4Cl (sat.). The aqueous phase was extracted with 2×100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:4) as eluent to furnish 6 g (87%) of the title compound as a light yellow oil.