Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([CH:11]1[CH2:20][CH2:19][CH:18]2[CH:13]([CH2:14][CH2:15][CH:16]([CH:21]3[CH2:30][CH2:29][C:24]4(OCC[O:25]4)[CH2:23][CH2:22]3)[CH2:17]2)[CH2:12]1)[CH2:9][CH3:10]>C(O)=O>[CH2:8]([CH:11]1[CH2:20][CH2:19][CH:18]2[CH:13]([CH2:14][CH2:15][CH:16]([CH:21]3[CH2:22][CH2:23][C:24](=[O:25])[CH2:29][CH2:30]3)[CH2:17]2)[CH2:12]1)[CH2:9][CH3:10]
Reactant: CCCC1CCC2CC(C3CCC4(CC3)OCCO4)CCC2C1
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCCC1CCC2CC(C3CCC(=O)CC3)CCC2C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 100.1 %

Procedure:
Sixth step: Toluene (300 ml) and formic acid (98%; 15 g) were added to 8-(6-propyldecahydronaphthalene-2-yl)-1,4-dioxaspiro[4.5]decane (27.9 g) obtained in the fifth step, and the mixture was stirred for 7 hours. After the reaction mixture had been cooled to room temperature, it was washed with aqueous sodium hydroxide solution (1M) and water, and dried over anhydrous magnesium sulfate. The toluene was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-heptane=1/9 by volume) to give 4-(6-propyldecahydronaphthalene-2-yl)cyclohexanone (24.1 g).
Reaction SMILES: [NH2:1][CH:2]([CH3:31])[CH:3]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:4]12[O:11][CH2:10][C:7]([CH3:12])([CH2:8][O:9]1)[CH2:6][O:5]2.C(N(CC)CC)C.Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>O1CCOCC1.O.C(OCC)(=O)C>[CH2:43]([O:42][C:40](=[O:41])[NH:1][CH:2]([CH3:31])[CH:3]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:4]12[O:5][CH2:6][C:7]([CH3:12])([CH2:10][O:11]1)[CH2:8][O:9]2)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)C(NS(=O)(=O)c1ccc(OCc2ccccc2)cc1)C12OCC(C)(CO1)CO2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(NC(=O)OCc1ccccc1)C(NS(=O)(=O)c1ccc(OCc2ccccc2)cc1)C12OCC(C)(CO1)CO2
Temperature: 0 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
A solution of N-[2-amino-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-propyl]-4-benzyloxy-benzenesulfonamide (compound of formula LI, 2.5 g, 5.6 mmol), triethyl amine (1.01 ml, 0.73 g, 7.22 mmol) in 31 ml of 2:1 (v/v) 1,4-dioxane-water was treated with benzyl chloroformate (1.20 ml, 1.43 g, 8.40 mmol) at about 0° C. After stirring for about 3 hours at about 0° C., the mixture was diluted with ethyl acetate, washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 2:1 hexane-ethyl acetate, affording 2.0 g of [2-(4-benzyloxy-benzenesulfonylamino)-1-methyl-2-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-ethyl]-carbamic acid benzyl ester (compound of formula LII) as a colorless syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[S:29]([N:8]1[C:9]2[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)(=[O:31])=[O:30]
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cc(F)ccc2F)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.3 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2,5-difluorobenzenesulfonyl chloride (23 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (3 mg, 10%) as a white solid. MS (ESI+) for C18H18F2N2O3S m/z 381 (M+H)+.
Reaction SMILES: ON1C2N=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.[Br:23][C:24]1[CH:25]=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH:35]([S:39][CH3:40])[C:36]([OH:38])=O)=[CH:29][CH:28]=2.[NH2:41][C:42]([CH3:47])([CH2:45][OH:46])[C:43]#[N:44]>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C.C(N(CC)CC)C>[Br:23][C:24]1[CH:25]=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH:35]([S:39][CH3:40])[C:36]([NH:41][C:42]([C:43]#[N:44])([CH3:47])[CH2:45][OH:46])=[O:38])=[CH:29][CH:28]=2
Reactant: CSC(Oc1ccc2ncc(Br)cc2c1)C(=O)O
Reactant: CC(N)(C#N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CSC(Oc1ccc2ncc(Br)cc2c1)C(=O)NC(C)(C#N)CO
Reaction time: 16 h
Yield: 65.4 %

Procedure:
0.86 ml of Triethylamine, 0.672 g of 1-hydroxy-7-azabenzotriazole and 0.946 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide.HCl were added at R.T. to a suspension of 1.35 g of (3-bromo-quinolin-6-yloxy)-methylsulfanyl-acetic acid in 11 ml of dry DMF. To this suspension, 0.494 g of 2-amino-3-hydroxy-2-methyl-propionitrile dissolved in 2 ml of dry DMF were added dropwise. The reaction mixture was stirred 16 hrs at R.T and then poured onto a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted thrice with ethyl acetate. The organic layers were combined, washed once with brine and then dried over sodium sulphate. After filtration and concentration under reduced pressure 1.886 g of a crude mixture were isolated as a dark orange oil. The crude mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate) to give 1.103 g of 2-(3-bromo-quinolin-6-yloxy)-N-(1-cyano-2-hydroxy-1-methyl-ethyl)-2-methylsulfanyl acetamide in mixture with 3-(3-bromo-quinolin-6-yl)-2-methylsulfanyl-propionic acid 2-[2-(3-bromo-quinolin-6-yloxy)-2-methylsulfanyl-acetylamino]-2-cyano-2-methyl-ethyl ester resulting from the homo coupling process.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:48])[CH:39]([C:41]1[CH:46]=[CH:45][C:44](Br)=[CH:43][CH:42]=1)[CH3:40])[CH3:36]>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>[CH2:35]([O:37][C:38](=[O:48])[CH:39]([C:41]1[CH:46]=[CH:45][C:44]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH3:9])=[O:34])=[CH:19][CH:20]=2)=[CH:43][CH:42]=1)[CH3:40])[CH3:36]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1F
Reactant: CCOC(=O)C(C)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3F)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 17, Step 2 using {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-fluoro-phenyl)-ethyl ester, 2-(4-bromo-phenyl)-propionic acid ethyl ester, and bis(triphenylphosphine)palladium(II) dichloride; purification by preparative HPLC, followed by silica gel chromatography, was utilized.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.COB(OC)OC.OO>C(O)(=O)C.O1CCCC1>[CH3:10][O:9][C:3]1[CH:2]=[CH:7][C:6]([Br:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(Br)cc1Br
Agent: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 500 mL round bottom flask was charged 2,4-dibromoanisole (5.0 g, 18.8 mmol) followed by 200 mL of dry tetrahydrofuran under nitrogen. The reaction mixture was then cooled to −78° C., and n-butyllithium (16.11 mL, 22.56 mmol) was added dropwise. The reaction mixture was stirred for 30 min at −78° C. The reaction mixture was then warmed to 0° C. and trimethylborate (2.57 mL, 22.56 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min. 5 mL of glacial acetic acid was added followed by 10 mL of 35% wt. hydrogen peroxide in a drop wise fashion. The reaction was allowed to stir 12 h at room temperature. The reaction was quenched with 1 N HCl, extracted with ethylacetate (100×3) and the combined organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by column chromatography yielded 1 g (26%) of 3-hydroxy, 4-methoxybromobenzene (white crystals). (96:4 Hexanes:ethylacetate).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure M, 1-(6-bromo-4-((trans-4-(dimethylamino)cyclohexyl)amino)quinolin-3-yl)propan-1-one (125 mg, 0.31 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (93 mg, 0.34 mmol) to afford the desired product (81 mg, 56%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.56 (d, J=8.0 Hz, 1H), 8.97 (s, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.04 (dd, J=8.7, 1.9 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.65-7.58 (m, 2H), 4.18-4.12 (m, 1H), 3.13 (q, J=7.2 Hz, 2H), 2.39-2.32 (m, 1H), 2.27-2.19 (m, 8H), 1.93-1.86 (m, 2H), 1.56-1.39 (m, 4H), 1.12 (t, J=7.2 Hz, 3H). ESI MS m/z 470 [C26H29ClFN3O2+H]+; HPLC>99% (AUC), tR=7.97 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2ncccc2c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)CCCN2
Reaction time: 40 h
Yield: 94.6 %

Procedure:
6-Methoxyquinoline (1.00g) was dissolved in absolute ethanol (20 ml) and hydrogenated under pressure in the presence of 10% palladium on charcoal (0.10g) with shaking for about 40 hours. Filtration and evaporation to dryness of the filtrate gave 1,2,3,4-tetrahydro-6-methoxyquinoline as a light-brown gum (0.97g). The structure was supported by nmr spectrum.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[O:10])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CCCCCCC(C=O)c1ccc(Cl)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(CO)c1ccc(Cl)nc1
Temperature: 0 °C
Yield: 83.3 %

Procedure:
2-(6-Chloro-pyridin-3-yl)-octanal (1.02 g, 4.26 mmol) is dissolved into denatured ethanol (20 mL) at room temperature then cooled to 0° C. in an ice bath. Sodium borohydride (0.162 g, 4.26 mmol) is then carefully added in small portions. The reaction is allowed to warm slowly to room temperature and is monitored by HPLC. Upon complete consumption of starting material, the reaction is carefully quenched with water and diluted with ethyl acetate. The ethanol is removed and the residue is extracted with ethyl acetate, washed, dried, and concentrated. The 2-(6-Chloro-pyridin-3-yl)-octan-1-ol (0.856 g, 3.55 mmol), 83%, is obtained in purified form after flash column chromatography.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][CH2:21][O:22]CC2C=CC=CC=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.B(Cl)(Cl)Cl>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CCOCc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: ClB(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@H](CCO)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 74.3 %

Procedure:
A solution of 0.50 g (1.10 mmol) of 4-((S)-3-benzyloxy-1-methoxycarbonyl-propyl)-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester (evaporated twice with toluene) in 9 ml dichloromethane was treated with 1.10 ml (1.10 mmol, 1 M in dichloromethane) of boron trichloride. The solution was stirred 6.5 h at room temperature, cooled (0° C.) and treated with 0.99 ml (0.90 mmol, 1 M in dichloromethane) of boron trichloride, after 15 h at room temperature, additional 0.28 ml (0.28 mmol, 1 M in dichloromethane) of boron trichloride were added to the cooled (0° C.) reaction. After 24 h at room temperature, the mixture was extracted with cold sat. aq. sodium hydrogencarbonate solution and ethyl acetate (3×). The organic phases were washed with sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated to give 0.298 g (75%) of the title compound as light yellow oil. MS: 365.0 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:41])[C:5]2[N:6]=[CH:7][N:8]([C:39]=2[N:40]=1)[C@@H:9]1[O:38][C@H:28]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@@H:19]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@H:10]1[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[CH:42]1([CH2:48][CH2:49][OH:50])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH:42]1([CH2:48][CH2:49][O:50][C:2]2[N:3]=[C:4]([NH2:41])[C:5]3[N:6]=[CH:7][N:8]([C:39]=3[N:40]=2)[C@@H:9]2[O:38][C@H:28]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@@H:19]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@H:10]2[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: OCCC1CCCCC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(OCCC4CCCCC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 50 °C

Procedure:
To a dry 250-mL, 3-neck roundbottom flask was added 2-chloro-2′,3′,5′-tri-O-(TERT-butyldimethylsilyl)adenosine (5 g, 7.8 mmol, Example 1) and 2-(cyclohexyl)ethanol (15 mL). The mixture was flushed with nitrogen for 5–10 minutes, then heated to 50° C. To this mixture was added sodium hydride (1.56 g, 39 mmol, as a 60% dispersion in mineral oil) at such a rate as to avoid excessive gas evolution. The reaction was maintained at 50° C. until the reaction was complete by HPLC. The reaction was then cooled to room temperature, carefully quenched with water (50 mL), and extracted with ethyl acetate (100 mL, 2×60 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to afford a viscous oil. This material was purified by passing through a plug of silica gel, eluting with CH2Cl2, 2% MeOH in CH2Cl2, 5% MeOH in CH2Cl2, and 10% MeOH in CH2Cl2. Those fractions containing products were combined and evaporated to dryness, to afford a mixture of monosilyl-protected and disilyl-protected alkylated products (LC/MS m/z=622 and 508). This mixture was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([CH2:17][C:18]([OH:20])=O)=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=[CH:24]1)=O.CNC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([CH2:17][C:18]([N:23]([CH3:24])[CH3:21])=[O:20])=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1c(-c2ccc(Cl)cc2)nn2cccnc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1c(-c2ccc(Cl)cc2)nn2cccnc12
Reaction time: 4 h
Yield: 83.1 %

Procedure:
A mixture of 4.0 g (0.013 mole) of 2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid and 2.25 g (0.013 mole) of 1,1'carbonyldiimidazole in 150 ml of anhydrous tetrahydrofuran was stirred for 4 hours while a stream of nitrogen was bubbled through the mixture. A solution of dimethylamine in tetrahydrofuran (14.1 ml; 0.0417 mole; 2.59M) was added, and the reaction was stirred for 17 hours under nitrogen atmosphere. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with water, aqueous 7% sodium bicarbonate, and water, and dried over magnesium sulfate and re-evaporated under reduced pressure. The crystalline residue (4.0 g) was recrystallized from isopropanol to give 3.4 g (79%) of product, mp 174°-175.5° C.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@@H:13]([OH:25])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl:26][C:27]1[CH:32]=[C:31](Cl)[N:30]=[CH:29][N:28]=1>C1COCC1>[Si:3]([O:10][C@@H:11]1[C@H:15]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:14][C@@H:13]([O:25][C:31]2[CH:32]=[C:27]([Cl:26])[N:28]=[CH:29][N:30]=2)[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 112.5 %

Procedure:
To a suspension of sodium hydride (75.6 mg, 0.00189 mol) in THF (2 mL) at 0° C. under an atmosphere of nitrogen was added (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (0.60 g, 0.0017 mol) in 1.5 mL THF dropwise at 0° C. The mixture was stirred at 0° C. for 10 min. To this was next added 4,6-dichloro-pyrimidine (0.225 g, 0.00151 mol) in 2 mL THF at 0° C. The suspension was stirred at 0° C. for 2 hrs. The reaction was quenched with 9 mL saturated aqueous NH4Cl and extracted with t-BuOMe (3×). The organic layers were combined and washed with brine, dried over anhydrous MgSO4 and then concentrated to give 0.804 g of an oil. The residue was purified by flash chromatography (0 to 10% EtOAc/hexanes) to give 0.63 g (80%) of the title compound.
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:42](=[O:45])([O-])[O-].[K+].[K+].O>C(COC)OC>[OH:45][C:42]1[CH:14]=[CH:15][C:7]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[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:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 131.9 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (300 mg, 0.505 mmol) was dissolved in dimethoxyethane (21 mL), and the solution was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (222 mg, 1.01 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (33.0 mg, 0.0404 mmol), potassium carbonate (349 mg, 2.53 mmol) and water (0.182 mL), followed by purification by flash column chromatography (chloroform/methanol=90/10 to 80/20) to obtain 4-(4-hydroxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (179 mg, yield 66%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15]([C:17](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:18])=[O:16])[CH3:13]>O1CCCC1>[CH3:18]/[C:17](=[CH:8]\[C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)/[C:15]([O:14][CH2:12][CH3:13])=[O:16]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 4-nitrobenzaldehyde (2 g, 13.2 mmol) and (1-ethoxy carbonylethylidene)triphenyl phosphorane (4.80 g, 13.2 mmol) in tetrahydrofuran (130 mL) was refluxed for 24 hours. The reaction was concentrated in vacuo and was purified by flash column chromatography on silica gel with hexanes and EtOAc to give (E)-ethyl 2-methyl-3-(4-nitrophenyl)acrylate (645).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12.[CH2:18]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN1CCCC1=O>[CH2:18]([N:25]([S:26]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)(=[O:28])=[O:27])[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1Cl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnc2c(c(C)nn2C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 36901.3 %

Procedure:
The mixture was heated in an oil bath at 50° C. overnight and then was heated in an oil bath at 100° C. for 1.5 days. The mixture was poured into 800 ml of water and extracted with ethyl acetate. The extract was washed with water, 2N citric acid, water, brine and dried (Na2SO4). The solvent was removed and the residue chromatographed on silica gel with hexane-ethyl acetate (2:1) as eluent to give 0.64 g of product as a solid, mp 170-172°. From a larger scale run of 5.07 g (0.02 mmol) of ethyl 4-chloro-1,3-dimethylpyrazolo[3,4-b]pyridine-5-carboxylate and 8.0 g (0.0289 mmol) of benzyl-(4-methoxybenzenesulfonyl) amine (as sodium anion) in 30 ml of 1-methyl-2-pyrrolidinone heated at 90° C. for 3 days there was obtained 3.65 g of product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](O)=[O:37]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][CH:41]=[C:33]([O:32][CH3:31])[CH:34]=2)[CH:25]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cccc(OC)c3)c2)c1

Procedure:
In a manner similar to that described in Example 25, methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate and 3-methoxybenzoic acid were coupled to give the title compound as a white solid (75 mg).