Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([CH2:12][CH3:13])([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].[CH2:14]([N:17]1[C:22]([CH3:24])([CH3:23])[CH2:21]C(O)[CH2:19][C:18]1([CH3:27])[CH3:26])[CH:15]=[CH2:16]>C1(C)C(C)=CC=CC=1>[CH2:12]([C:3]([CH2:1][CH3:2])([C:8]([O:10][CH:11]1[CH2:27][C:18]([CH3:19])([CH3:26])[N:17]([CH2:14][CH:15]=[CH2:16])[C:22]([CH3:21])([CH3:23])[CH2:24]1)=[O:9])[C:4]([O:6][CH:7]1[CH2:24][C:22]([CH3:23])([CH3:21])[N:17]([CH2:14][CH:15]=[CH2:16])[C:18]([CH3:27])([CH3:26])[CH2:19]1)=[O:5])[CH3:13]
Reactant: CCC(CC)(C(=O)OC)C(=O)OC
Reactant: C=CCN1C(C)(C)CC(O)CC1(C)C
Solvent: Cc1ccccc1C
Product: C=CCN1C(C)(C)CC(OC(=O)C(CC)(CC)C(=O)OC2CC(C)(C)N(CC=C)C(C)(C)C2)CC1(C)C
Reaction time: 6 h

Procedure:
After the addition of 1 g of tetrabutyl-orthotitanate, 47 g of dimethyl diethylmalonate and 98.6 g of 1-allyl-2,2,6,6-tetramethyl-4-hydroxypiperidine in 100 ml of xylene are heated under a gentle stream of nitrogen to about 140°. The methanol forming during the reaction is continuously distilled off, and after about 6 hours the reaction is virtually completed. The reaction mixture is diluted with 200 ml of toluene, extracted three times with 100 ml of water each time, dried over sodium sulphate and concentrated by evaporation. Crystallisation of the residue from hexane yields bis-(1-allyl-2,2,6,6-tetramethyl-4-piperidinyl) diethylmalonate (compound 18), m.p. 135°-136°.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.CI.[C:15]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:15])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nc(Br)ccc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
A mixture of methyl 6-bromo-3-hydroxypicolinate (10.0 g, 43.10 mmol), MeI (12.3 g, 86.66 mmol) and K2CO3 (12.0 g, 86.83 mmol) in DMF (100 mL) was stirred at RT overnight. Then the reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give methyl 6-bromo-3-methoxypicolinate (4.5 g, yield 42%). 1H-NMR (CDCl3, 400 MHz) δ 7.55 (d, J=8.8 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H). MS (M+H)+: 246/248.
Reaction SMILES: [NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[O:6][C:7]([F:15])([F:14])[C:8](=[O:13])[N:9]([CH2:10][C:11]#[CH:12])[C:4]=2[CH:3]=1.[O:19]=[C:20](Cl)OC(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:15][C:7]1([F:14])[O:6][C:5]2[CH:16]=[C:17]([F:18])[C:2]([N:1]=[C:20]=[O:19])=[CH:3][C:4]=2[N:9]([CH2:10][C:11]#[CH:12])[C:8]1=[O:13]
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N)cc21
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N=C=O)cc21
Reaction time: 8 h

Procedure:
To 6-amino-2,2,7-trifluoro-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (5.1 g, 19.91 mmol) in dry toluene was dropwise added diphosgene (2.64 ml, 21.90 mmol) in dry toluene. The resulting mixture was stirred overnight at reflux. Concentrated and chased with toluene and used as such in the next step.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:26][C:27]1([CH3:48])[O:32][CH2:31][CH:30]([C:33]2[CH:34]=[N:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)[CH2:29][O:28]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:26][C:27]1([CH3:48])[O:32][CH2:31][CH:30]([C:33]2[CH:38]=[C:37]([C:2]3[N:11]=[C:10]([NH:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:3]=3)[CH:36]=[N:35][CH:34]=2)[CH2:29][O:28]1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: CC1(C)OCC(c2cncc(B3OC(C)(C)C(C)(C)O3)c2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OCC(c2cncc(-c3nc(NCc4ccccn4)c4c(-c5ccccc5)cccc4n3)c2)CO1
Temperature: 90 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (80 mg, 0.23 mmol) in 1,4-dioxane (6 mL) and H2O (0.5 mL) under nitrogen was added 3-(2,2-dimethyl-1,3-dioxan-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (110 mg, 0.35 mmol), and potassium carbonate (96 mg, 7.0 mmol). The mixture was degassed with nitrogen for 15 min. (1,1′-Bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (12 mg, 0.015 mmol) was added and the reaction mixture was again degassed for 10 min with nitrogen. The reaction mixture was stirred at 90° C. for 16 h, then allowed to cool to room temperature and quenched by the addition of water. The reaction mixture was extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography using 20% EtOAc in hexanes to provide 2-(5-(2,2-dimethyl-1,3-dioxan-5-yl)pyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (45 mg, 39%). LCMS Method T: retention time 1.75 min; [M+1]=504.2.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][O:3][CH2:2]2.[CH3:7][CH:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1>[OH:6][C@@H:5]1[CH2:4][O:3][CH2:2][C@H:1]1[NH:13][S:10]([CH:8]([CH3:9])[CH3:7])(=[O:12])=[O:11]
Reactant: CC(C)S(N)(=O)=O
Reactant: C1OCC2OC12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)N[C@@H]1COC[C@H]1O
Temperature: 25 °C

Procedure:
3,6-Dioxabicyclo[3.1.0]hexane (1.90 g, 22.1 mmol), propane-2-sulfonamide (prepared according to the method of D. C. Johnson, I I and T. S. Widlanski, Tetrahedron Letters 2004, 45, 8483-8487) (3.13 g, 25.4 mmol), potassium carbonate (584 mg, 4.23 mmol) and benzyltriethylammonium chloride (963 mg, 4.23 mmol) were suspended in dioxane (10 mL) and heated at reflux for 120 hours. The reaction was cooled to room temperature, filtered, concentrated in vacuo and purified by silica gel chromatography (Gradient: 40% to 80% ethyl acetate in heptane), to afford trans-N-(4-hydroxytetrahydrofuran-3-yl)propane-2-sulfonamide as a solid. Yield: 3.76 g, 18.0 mmol, 81%. 1H NMR (400 MHz, CDCl3) δ 1.38 (d, J=6.7 Hz, 3H), 1.40 (d, J=6.7 Hz, 3H) 2.91 (d, J=3.6 Hz, 1H), 3.22 (septet, J=6.8 Hz, 1H), 3.67-3.71 (m, 2H), 3.82 (m, 1H), 4.08-4.12 (m, 2H), 4.40 (m, 1H), 4.77 (d, J=8.4 Hz, 1H), 13C NMR (100 MHz, CDCl3) δ 16.44, 16.69, 54.18, 62.06, 71.47, 73.50, 77.64.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][C:11]#[N:12].CS(O[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C>[C:11]([CH2:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[O:1][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]1)#[N:12]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: COc1cccc(CC#N)c1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(CC#N)c1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 80.3 %

Procedure:
To a solution of 2-hydroxy-3-methoxyphenylacetonitrile (1 g, 6.1 mmol) in DMF (12 mL) was added 1,1-dimethylethyl 4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (1.8 g, 6.1 mmol) and cesium carbonate (4.0 g, 12.2 mmol). The mixture was heated to 70° C. for 3 h and then cooled to rt. Water and ethyl acetate were added followed by brine to reduce emulsification. The layers were partitioned, and the aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (70% hexanes, 30% ethyl acetate) to provide 1.77 g of 1,1-dimethylethyl 4-({[2-(cyanomethyl)-6-(methyloxy)phenyl]oxy}methyl)piperidine-1-carboxylate (4.9 mmol, 81% yield) as a yellow syrup. 1H NMR (400 MHz, CDCl3): δ7.03 (t, 1H), 6.93 (dd, 1H), 6.88 (dd, 1H), 4.14 (br m, 2H), 3.88 (br d, 2H), 3.84 (s, 3H), 3.70 (s, 2H), 2.00 (m, 1H), 1.86 (br d, 2H), 1.47 (s, 9H), 1.35-1.25 (m, 2H).
Reaction SMILES: C(OC([NH:7][C@@:8]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[O:18])[CH2:13][CH2:12][C@@H:11]2[C@H:9]1[C@H:10]2[C:14]([OH:16])=[O:15])=O)C=C.CC1(C)C(=O)NC(=O)NC1=O>>[NH2:7][C@@:8]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[O:18])[CH2:13][CH2:12][C@@H:11]2[C@H:9]1[C@H:10]2[C:14]([OH:16])=[O:15]
Reactant: C=CCOC(=O)N[C@@]1(C(=O)OCc2cccc(Cl)c2)CC[C@H]2[C@H](C(=O)O)[C@H]21
Agent: CC1(C)C(=O)NC(=O)NC1=O
Product: N[C@@]1(C(=O)OCc2cccc(Cl)c2)CC[C@H]2[C@H](C(=O)O)[C@H]21

Procedure:
(1S,2S,5R,6S)-2-Allyloxycarbonylamino-2-(3′-chloro-benzyloxycarbonyl)-bicyclo[3.1.0]hexane-6-carboxylic acid (708 mg, 1.8 mmol) was reacted with dimethylbarbituric acid (421 mg, 2.7 mmol) and tetrakis triphenylphosphine palladium (0) (42 mg; 0.02 mmol) under general procedure 4. The title compound was obtained as a white solid (385 mg, 62% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=[NH:9])=[O:8])[CH3:2].C=O.[CH:23](O)=O.[OH-].[Na+]>O>[CH3:23][N:9]=[S:7]([CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: CCN(CC)CCCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCCS(=O)(=NC)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of S-(3-diethylaminopropyl)-S-(4-nitrophenyl)sulfoximine (0.03 mole), 17 ml of 37% formaldehyde, and 22.6 ml of 98% formic acid is heated at reflux temperature for 48 hr. Water is added to the reaction mixture which is then made slightly basic by addition of 50% sodium hydroxide solution. The mixture is extracted with chloroform and the extract is dried and concentrated to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:27]([F:38])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:35][C:34]([CH3:37])([CH3:36])[CH2:33][O:32][C:28]1[C:29]([F:31])=[CH:30][C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)=[CH:26][C:27]=1[F:38]
Reactant: CC(C)(C)COc1c(F)cc(-c2csc(NC(=O)CBr)n2)cc1F
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCC(C)(C)C)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (25 mg, 0.139 mmol) with 2-bromo-N-{4-[4-(2,2-dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}acetamide (70 mg, 0.167 mmol) in the presence of NaH (8 mg, 0.333 mmol) in dry DMF (5.0 mL) to give 29 mg of the product as an off-white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 1.01 (s, 9H), 3.17 (s, 3H), 3.39 (s, 3H), 3.81 (s, 2H), 5.32 (s, 2H), 6.23 (s, 1H), 7.35 (s, 1H), 7.63 (s, 1H), 7.67 (s, 1H), 7.77 (s, 1H), 12.68 (br s, 1H); APCI-MS (m/z) 518.10 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([CH3:29])[NH:21][C:20]1=[O:30]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([CH3:29])[NH:21][C:20]2=[O:30])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC1NC(=O)C(N)c2ccccc21
Product: CC1NC(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-methyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 205-206° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:23]([N:31]=[C:32]=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[C:23]([NH:31][C:32](=[S:33])[N:12]1[CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:4]=2)[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]12)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Solvent: CC(C)=O
Product: NC(=O)c1cnn2c1N(C(=S)NC(=O)c1ccccc1)CC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3.08 g of 4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 4) in 30 ml of dry acetone, under nitrogen was added 1.5 ml of benzoyl isothiocyanate in 5 ml of dry acetone. The mixture was heated at reflux for 3 hours, then an additional 4.5 ml of benzoyl isothiocyanate was added and the mixture was heated at reflux for 16 hours. The mixture was cooled to room temperature and the solid precipitate that had formed was collected by filtration and washed with ether to give 600 mg of 4-[(benzoylamino)thioxomethyl]-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, m.p. 210°-212° C. To a stirred mixture of 1.5 g of the preceding product (prepared as described above), 30 ml of N,N-dimethylformamide and 2.0 ml of 1N sodium hydroxide was added 4.0 ml of methyl iodide. This mixture was stirred at room temperature for 3 hours then an additional 1.0 ml of 1N sodium hydroxide and 2.0 ml of methyl iodide were added and stirring was continued. After one hour the addition of 1.0 ml of sodium hydroxide and 2.0 ml of methyl iodide was repeated and stirring was concluded within one hour of this addition. The mixture was mixed with water and the solid precipitate was collected by filtration, washed with water and dried in vacuo to give 1.4 g of 3-(aminocarbonyl)-N-benzoyl-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-4(5H)-carboximidothioic acid, methyl ester, m.p. 172°-175° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[CH3:12][N:11]([CH3:13])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)c1ccc(O)cc1
Reactant: C#CC(C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C#CC(C)(C)Oc1ccc(S(=O)(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.1 %

Procedure:
A two-phase mixture of 4-hydroxy-N,N-dimethyl-benzenesulfonamide (13 g), 3-chloro-3-methyl-1-butyne (33 g), tetra-n-butylammonium hydrogen sulfate (22 g), and sodium hydroxide (21 g) in a mixture of dichloromethane (195 ml) and water (97.5 ml) was vigorously stirred at room temperature for 48 hours. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was added to n-hexane and pulverized to give N,N-dimethyl-4-(1,1-dimethyl-2-propynyloxy)benzenesulfonamide (6.4 g).
Reaction SMILES: [F-].[K+].C[Si](C)(C)[C:5]([F:8])([F:7])[F:6].[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19](I)[CH:20]=2)[CH:15]=[CH:14][N:13]=1>CN1C(=O)CCC1.C(OCC)(=O)C.[Cu]I>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:5]([F:8])([F:7])[F:6])[CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Clc1nccc2ccc(I)cc12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc2ccnc(Cl)c2c1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
Into a 8 mL sealed tube, was placed potassium fluoride (300 mg, 5.17 mmol, 6.00 equiv, 100%), copper(I) iodide (900 mg, 4.66 mmol, 5.50 equiv, 100%), trimethyl(trifluoromethyl)silane (720 mg, 5.07 mmol, 5.00 equiv, 100%), NMP (3 mL, 100%) and a solution of 1-chloro-7-iodoisoquinoline (as prepared in the previous step, 250 mg, 0.86 mmol, 1.00 equiv, 100%) in NMP (1 mL). The reaction mixture was stirred for 12 h at 120° C. in an oil bath. The resulting mixture was diluted with 20 mL of ethyl acetate, washed with 3×10 mL of saturated solution of KI, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with ethyl acetate:petroleum ether (1:50). The title compound was obtained as a yellow solid.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1C1NC(C(=O)CCCCCCC(=O)C)=NC=1.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]1[N:38]=[CH:39][N:40]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:41]=1.[Li]CCCC.[CH2:55]([C:57]1([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67](N(OC)C)=[O:68])[O:61][CH2:60][CH2:59][O:58]1)[CH3:56]>C1COCC1.CCCCCC.O>[CH2:55]([C:57]1([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67]([C:39]2[N:40]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:41]=[C:37]([C:28]3[CH:29]=[CH:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:27]=3)[N:38]=2)=[O:68])[O:58][CH2:59][CH2:60][O:61]1)[CH3:56]
Reactant: CCC1(CCCCCC(=O)N(C)OC)OCCO1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc3ccccc3c2)c1
Agent: CC(=O)CCCCCCC(=O)c1ncc(-c2ccc3ccccc3c2)[nH]1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC1(CCCCCC(=O)c2nc(-c3ccc4ccccc4c3)cn2COCC[Si](C)(C)C)OCCO1
Reaction time: 0.5 h

Procedure:
To a solution of Example 5, E2 (1.0 eq.) in THF (0.1 M solution) at −78° C. was added a solution of n-BuLi (1.3 eq.) in hexane. The solution was stirred for 30 min and then a solution of 6-(2-ethyl-1,3-dioxolan-2-yl)-N-methoxy-N-methylhexanamide (1.5 eq.) in THF was slowly added. The reaction mixture was stirred for 1 hr at −78° C. and then 1 hr at RT. Then water was added and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was used without purification in the next step. MS (ES) C30H42N2O4Si requires: 523, found: 524 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[C:35]([NH:37][CH3:38])[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.O1CCOCC1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[C:35]([NH:37][CH3:38])[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CNc1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution mixture of tert-butyl 2-(2-(benzyloxy)-4-(methylamino)benzamido)-4-phenylbenzoate (0.053 g) in methanol (1.5 mL), ethyl acetate (3 mL), and dioxane (4.5 mL), 10% palladium-carbon (27 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and then the solid substance was collected by filtration to obtain 0.027 g of tert-butyl 2-(2-hydroxy-4-(methylamino)benzamido)-4-phenylbenzoate as a white solid.
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.[CH2:42]([OH:45])[C:43]#[CH:44]>C(NCC)C.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)I>[OH:45][CH2:42][C:43]#[C:44][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(C#CCO)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 37.3 %

Procedure:
In a similar manner to Step 2 of Example 161, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (60.0 mg, 0.101 mmol) was dissolved in diethylamine (3.0 mL), and the solution was treated with bis(triphenylphosphine)dichloropalladium (8.6 mg, 0.012 mmol), copper iodide (6.9 mg, 0.036 mmol), propargyl alcohol (0.029 mL, 0.51 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=5/1) to obtain 4-(3-hydroxy-1-propinyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (18.8 mg, yield 37%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C@:7]([CH3:20])([C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])[CH2:6][CH2:5]2.[O:22]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:22][C@@:7]([CH3:20])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:21])[C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(C(=O)NCCO)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CC[C@](C)(O)C(=O)NCCO)=C(C)C1=O
Yield: 90.5 %

Procedure:
Oxidation as described in protocol B, using 3.50 g (11.93 mmol) of (S)-6-hydroxy-N-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 13.73 g CAN (25.06 mmol) yielded 3.341 g of (S)-2-hydroxy-N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a stirred solution of tert-butyloxycarbonyl-L-prolinol (3.50 g, 17.41 mmol) in DCM (25 mL) at 0° C. was added triethylamine (9.7 mL, 60.93 mmol), followed by sulfur trioxide-pyridine complex (8.30 g, 6.96 mmol) in DMSO (10 mL). The reaction mixture was stirred at 0° C. for 1 h. Hexanes (20 mL), Et2O (10 mL) and aqueous sat. NaHCO3 (30 mL) were added and the layers separated. The aqueous layer was extracted with a mixture of hexanes (20 mL) and Et2O (10 mL) twice. The combined organic layers were washed with 1M aqueous NaH2PO4 (30 mL), then brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 20% EtOAc/hexanes) gave the title compound (2.70 g, 77%) as a colourless oil. δH (DMSO-d6), mixture of rotamers: 9.49-9.36 (1H, m), 4.14-4.02 (1H, m), 3.45-3.26 (2H, m), 2.14-2.00 (1H, m), 1.96-1.69 (3H, m), 1.42 and 1.34 (9H, s, rotameric).