Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH:32]3[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]3)=[CH:31][C:26]=2[O:25][CH2:24]1>>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH:32]3[CH2:37][CH2:36][CH:35]([N:1]4[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]5[C:17]6[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=6)[NH:11][N:10]=5)[CH2:4]4)[CH2:34][CH2:33]3)=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3ccc4c(c3)OCO4)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-benzo[1,3]dioxol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([CH:21]1[O:23][CH2:22]1)Br.O>CN(C=O)C.C(OCC)(=O)C>[F:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH:3]=[C:2]([F:1])[CH:7]=1)[O:12][CH2:19][CH:21]1[CH2:22][O:23]1
Reactant: O=[N+]([O-])c1c(O)cc(F)cc1F
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(F)cc(F)cc1OCC1CO1
Temperature: 70 °C
Reaction time: 3 h
Yield: 121.9 %

Procedure:
To a mixture of 3,5-difluoro-6-nitrophenol (100 mg, 0.571 mmol) and potassium carbonate (394 mg) in DMF (5 ml) was added epibromohydrin (80 mg, 0.582 mmol) and was stirred at 70° C. for 3 hr. Water and ethyl acetate were added, the organic phase separated, dried and concentrated. The resulting residue was purified by chromatography (ethyl acetate: heptan 1:3) to give the desired product as a solid 161 mg (0.696 mmol).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21](O)=[O:22].C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[NH2:53][CH2:54][CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60]>CN(C)C=O>[O:20]=[C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][CH:3]2[C:21]([NH:53][CH2:54][CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:22])=[CH:11]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 0.49 g of 4-androsten-3-one-17β-carboxylic acid was added N,N-dimethylformamide (3 ml), N,N-diisopropylethylamine (0.55 ml) and O—(N-Succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.48 g). On stirring at room temperature (under an atmosphere of nitrogen) for 1.5 hours tert Butyl N-(2-aminoethyl)carbamate (0.25 g) was added. The mixture was stirred at room temperature for 3 days after which time the volatile components were removed on a rotary evaporator. Flash column chromatography was performed and the relevant fractions combined and stripped of solvent using a rotary evaporator. This gave 0.50 g of the desired material (Formula XIII).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:21])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)CCC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]2[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=2[CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(Br)c2OC1C(F)(F)F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccccc3)c2OC1C(F)(F)F
Temperature: 110 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
A mixture of ethyl 6-chloro-8-bromo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 74, Step 1)(2.0 g, 5.2 mmol), tetrakis(triphenylphosphine) palladium(0) (2.15 g, 1.7 mmol), triphenylphosphine (0.013 g, 0.05 mmol), and tributylphenyltin (1.9 mL, 5.7 mmol) in toluene (60 mL) was heated to 110° C. for 3 days. The reaction mixture was allowed to cool to room temperature and filtered through a plug of silica gel eluting with 25% ethyl acetate in hexanes. The filtrate was concentrated in vacua and then purified by flash chromatography (silica gel, ethyl acetate-hexanes, 1:9). The fractions containing desired product were combined and concentrated in vacua. To remove the remaining tin impurities the mixture was taken up in THF (10 mL) and aqueous ammonium fluoride solution (10 wt %, 20 mL) and stirred at room temperature for 2 hours. The solution was extracted with ethyl acetate. The extracts were combined, dried over MgSO4, filtered, and concentrated in vacua to afford the ester as an oil (1.30 g, 65%). 1H NMR(CDCl3/300 MHz) 7.67 (s, 1H),7.47–7.36 (m, 5H), 7.31 (d, 1H, J=2.6 Hz), 7.18 (d, 1H, J=2.4 Hz), 5.69 (q, 1H, J=6.8 Hz), 4.30 (m, 2H), 1.33 (t, 3H, J=7.1 Hz). 19FNMR (CDCl3/282 MHz) d −78.27 (d, J=7.2 Hz). FABLRMS m/z 383 (M+H). ESHRMS m/z 400.0937 (M+NH4, Calc'd 400.0927)
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].C(O)(=O)C.C([O-])(=O)C.[Na+].[NH:37]1[CH2:40][CH:39]([C:41]([O:43][CH3:44])=[O:42])[CH2:38]1>C(O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:37]4[CH2:40][CH:39]([C:41]([O:43][CH3:44])=[O:42])[CH2:38]4)[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-[(1-methylethyl)oxy]benzonitrile (D73) (120 mg), acetic acid (0.023 mL) and sodium acetate (32.7 mg) in ethanol (20.00 mL) stirred under nitrogen at room temperature was added methyl 3-azetidinecarboxylate (92 mg) in one charge. The reaction mixture was stirred at room temperature for 30 min, then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) (20 mL), sodium triacetoxyborohydride (169 mg) was added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (30 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the crude product methyl 1-{[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylate (D87) (126 mg). The crude product was used for next step without further purification. MS (ES): C27H29N3O3S requires 475. found 476.2 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2C(OC(C)(C)C)=O)=[O:8])=[CH:3][CH:2]=1.Cl.CCN(C(C)C)C(C)C.[CH3:32][N:33]1[CH:37]=[C:36]([S:38](Cl)(=[O:40])=[O:39])[N:35]=[CH:34]1>O1CCOCC1>[CH3:32][N:33]1[CH:37]=[C:36]([S:38]([N:12]2[CH2:13][CH2:14][CH:9]([C:7]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][N:5]=3)=[O:8])[CH2:10][CH2:11]2)(=[O:40])=[O:39])[N:35]=[CH:34]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(S(=O)(=O)N2CCC(C(=O)c3ccccn3)CC2)c1
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 6 (950 mg, 3.27 mmol) in 1,4-dioxane (5 mL) was added 4 N HCl in dioxane (10 mL) and stirred for 1 h. The solvent was removed under vacuum. The residue was dissolved in CH2Cl2 (10 mL), added DIPEA (1.94 mL, 10.8 mmol) and 1-methylimidazole-4-sulfonyl chloride (589 mg, 3.27 mmol). The reaction was stirred for 18 h at room temperature. The reaction mixture was washed with 2 N NaOH (10 mL), dried over MgSO4 and concentrated under vacuum to afford 7 as a light orange oil (920 mg, 84%); 1H-nmr (400 MHz, CDCl3) δ 8.63 (d, J=5.0 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.85 (td, J=8.0, 1.5 Hz, 1H), 7.50 (s, 1H), 7.48 (dd, J=8.0, 1.5 Hz, 1H), 7.44 (s, 1H), 4.00-3.82 (m, 3H), 3.77 (s, 3H), 2.86 (t, J=11.0 Hz, 2H), 2.04-1.96 (m, 2H), 1.91-1.78 (m, 2H); m/z 335.1 [M+H].
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C@H:5]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:6][CH:7]=[CH2:8])[CH3:2].CCN(C(C)C)C(C)C.[C:25]([C:27]1[CH:28]=[C:29]([C:37](Cl)=[O:38])[C:30]2[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=2[CH:36]=1)#[N:26]>C(Cl)Cl>[C:25]([C:27]1[CH:28]=[C:29]([C:37]([N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH2:6][CH:7]=[CH2:8])=[O:38])[C:30]2[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=2[CH:36]=1)#[N:26]
Reactant: N#Cc1cc2c(c(C(=O)Cl)c1)CCCC2
Reactant: C=CC[C@H](CNCC)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC[C@H](CN(CC)C(=O)c1cc(C#N)cc2c1CCCC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
(2S)-N-Ethyl-2-(4-fluorophenyl)pent-4-en-1-amine (0.13 g, 0.63 mmol) was dissolved in CH2Cl2 and to the solution were added DIPEA (0.18 g, 1.4 mmol) and then 3-cyano-5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride (see WO 00/34243; 0.15 g, 0.66 mmol) dissolved in CH2Cl2 (2 mL). The mixture was stirred for 2 h at room temperature and then diluted with CH2Cl2. The solution was washed with water, aqueous KHSO4 (10 mL, 1M) and brine. The solvent was removed by evaporation after the solution had been dried. The product was purified by chromatagraphy on silica gel using a gradient of methanol-CH2Cl2 (0% methanol-5% methanol). There was obtained 0.13 g (53%) of 3-cyano-N-ethyl-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide as an oil.
Reaction SMILES: [C:1]([Si:5]([CH3:41])([CH3:40])[O:6][CH:7]([CH:19]([NH:27][C:28]([C:30]1[CH:39]=[N:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][CH:9]([CH2:13][CH2:14][C:15]([F:18])([CH3:17])[CH3:16])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:42]([CH2:44][NH2:45])[OH:43].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:20]([CH:19]([NH:27][C:28]([C:30]1[CH:39]=[N:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1)=[O:29])[CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:41])[CH3:40])[CH2:8][CH:9]([C:10](=[O:11])[NH:45][CH2:44][CH2:42][OH:43])[CH2:13][CH2:14][C:15]([F:18])([CH3:17])[CH3:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)O
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NCCO
Reaction time: 17 h
Yield: 62 %

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxy)-2-(3-fluoro-3-methyl-butyl)-6-phenyl-5-[(quinoxaline-2-carbonyl)-amino]-hexanoic acid (515 mg, 0.885 mmol) in methylene chloride (9 mL) was added ethanolamine (0.080 mL, 1.33 mmol), 1-hydroxybenzotriazole (215 mg, 1.59 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.50 mmol) and triethylamine (0.247 mL, 1.77 mmol). The resulting solution was stirred for 17 hours then diluted with ethyl acetate and washed with water then saturated aqueous sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel gave the title compound (343 mg, 62%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](=[O:17])([O-])[O-].[Na+].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:17][CH2:14][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Product: CCCCCCCCCCCCOCCCCCCCCCCCC
Temperature: 125 °C

Procedure:
After placing 390 parts by weight of n-dodecanol into a reaction vessel and heating to 125° C., one part by weight of p-toluene sulfonic acid as a catalyst was added to the solution, and then the pressure in the vessel was reduced to 5-10 mmHg. Separately, 100 parts by weight of anhydrous crystalline cyclotetrasaccharide, obtained by the method in Example B-3, was suspended in 130 parts by weight of n-dodecanol. The suspension was added into the above vessel drop by drop in a flow rate of 2.3 parts by weight/min with taking a time of 100 min for the reaction. Successively, the reactant was neutralized with aqueous sodium carbonate solution, and cyclotetrasaccharide dodecyl ether was obtained by evaporating residual alcohol.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12]C)=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([O:31][CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:26][C:25]=2[CH3:39])[CH:21]=[CH:22][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH3:39][C:25]1[CH:26]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][O:1][C:2]2[CH:15]=[CH:14][C:5]3[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=3[CH:3]=2)[CH:19]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CCl)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (85.00 g) and 3′-chloromethyl-2,6-dimethyl-4-[3-(methylsulfonyl)propoxy]biphenyl (149.91 g) in N,N-dimethylformamide (255 mL) was added tripotassium phosphate (130.00 g), and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, ethyl acetate (1020 mL) and water (1020 mL) were added, and the mixture was partitioned. The organic layer was washed with water (1020 mL) and 10% brine (1020 mL) and concentrated under reduced pressure. To the concentrated residue were added dimethyl sulfoxide (510 mL) and 2M aqueous sodium hydroxide solution, and the mixture was stirred at 60° C. for 1 hr. The mixture was allowed to cool to room temperature, and washed with ethyl acetate (1020 mL). The organic layer was washed with water (1223 mL). 6M Hydrochloric acid was added, and the mixture was extracted with ethyl acetate (1020 mL). The organic layer was washed with water (1020 mL) and 10% brine (1020 mL) and concentrated to give [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid (212.60 g). 100% ee. (high performance liquid chromatography conditions)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[CH:11]([N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])[CH3:12].C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[CH:11]([N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])[CH3:12]
Reactant: CC(c1cc2ccsc2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(c1cc2ccsc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
A mixture of 2-(1-(6-chlorothieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione (300 mg, 0.875 mmol), 2-(tributylstannyl)pyridine (340 μL, 1.05 mmol, 1.2 eq) and tetrakis(triphenylphosphine)palladium(0) (101 mg, 0.0875 mmol, 0.1 eq) was dissolved in 10 mL of dioxane under nitrogen. The reaction was heated to 100° C. for 2 days, cooled to rt and concentrated in vacuo. Purification by column chromatography using ethyl acetate/hexanes afforded 2-(1-(6-(pyridin-2-yl)-thieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione. LC/MS (M+1, found=386.0). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.66 (ddd, J=4.9, 1.6, 0.8 Hz, 1H), 7.76 (td, J=7.8, 1.8 Hz, 1H), 7.73-7.62, series of m, 5H), 7.57 (d, J=5.9 Hz, 1H), 7.36 (d, J=5.9 Hz, 1H), 7.31 (ddd, J=7.2, 4.7, 1.4 Hz, 1H), 6.33 (q, J=7.2 Hz, 1H), 1.99 (d, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][N:2]([C:21]1[CH:29]=[C:28]2[C:24]([C:25]([CH3:30])=[N:26][NH:27]2)=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)[N:4]=1.[C:31]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C.O>[CH3:31][N:26]1[C:25]([CH3:30])=[C:24]2[C:28]([CH:29]=[C:21]([N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)[N:4]=3)[CH:22]=[CH:23]2)=[N:27]1
Reactant: Cc1n[nH]c2cc(N(C)c3ccnc(Nc4cccc(CS(C)(=O)=O)c4)n3)ccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cc1c2ccc(N(C)c3ccnc(Nc4cccc(CS(C)(=O)=O)c4)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of N4-methyl-N4-(3-methyl-1H-indazol-6-yl)-N2-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine (Example 23) (389 mg, 0.92 mmol) in DMF (4 ml) was added Cs2CO3 (600 mg, 1.84 mmol) followed by iodomethane (64 ul, 1.02 mmol). The mixture was stirred at rt overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. Purification of crude product by prep TLC provided 120 mg N4-(2,3-dimethyl-2H-indazol-6-yl)-N4-methyl-N2-{3-[(methylsulfonyl)methyl]-phenyl}-2,4-pyrimidinediamine. 1H NMR (300 MHz, d6DMSO) δ 9.23 (s, 1H), 7.84–7.86 (m, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.42 (s, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.85–6.90 (m, 2H), 5.81 (d, J=5.8 Hz, 1H), 4.23 (s, 2H), 4.04 (s, 3H), 3.45 (s, 3H), 2.83 (s, 3H), 2.61 (s, 3H). MS (ES+, m/z) 437 (M+H).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([B:25]([OH:27])[OH:26])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[Cl:38][C:39]1[C:40]2[C:50]([F:51])=[CH:49][CH:48]=[C:47]([F:52])[C:41]=2[S:42][C:43]=1[C:44](Cl)=[O:45]>C(Cl)Cl>[C:1]([N:8]([CH3:28])[CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH2:16][C:17]2[CH:18]=[C:19]([B:25]([OH:26])[OH:27])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:44]([C:43]2[S:42][C:41]3[C:47]([F:52])=[CH:48][CH:49]=[C:50]([F:51])[C:40]=3[C:39]=2[Cl:38])=[O:45])[CH2:13][CH2:14]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of boronic acid 4 (7.60 g, 19.4 mmol) in DCM (300 mL) at 0° C. is treated with DIPEA (7.40 mL, 42.7 mmol), followed by acid chloride 8 (6.21 g, 23.3 mmol) in one portion. After warming to RT, the solution is stirred 3 h. Analysis by LC/MS at this juncture confirmed the reaction is complete. Thus the solvent is removed in vacuo and the residue purified by chromatography (gradient elution—60% EtOAc in heptane with 0.5% triethylamine increasing to neat EtOAc with 0.5% triethylamine, then 10-20% MeOH in EtOAc with 0.5% triethylamine) to afford the title compound.
Reaction SMILES: [C:1](=[O:61])([O:3][C@@H:4]([C@@H:55]([CH3:60])/[CH:56]=[CH:57]\[CH:58]=[CH2:59])[C@@H:5]([CH3:54])[C@H:6]([O:44]CC1C=CC(OC)=CC=1)[CH2:7][CH2:8]/[CH:9]=[CH:10]\[C@H:11]([CH3:43])[C@H:12]([O:33]CC1C=CC(OC)=CC=1)[C@@H:13]([CH3:32])/[CH:14]=[CH:15]\[CH2:16][CH2:17][C@H:18]1[C@H:23]([CH3:24])[C@H:22]([O:25][CH2:26][O:27][CH3:28])[C@@H:21]([CH3:29])[C@H:20]([O:30][CH3:31])[O:19]1)[NH2:2].C(=O)(O[C@@H]([C@@H](C)/C=C\C=C)[C@@H](C)[C@H](O)CC/C=C\[C@H](C)[C@H](O)[C@@H](C)/C=C\CC[C@H]1[C@@H](C)[C@H](O)[C@@H](C)C(=O)O1)N>CCOC(C)=O.CCCCCC>[C:1](=[O:61])([O:3][C@@H:4]([C@@H:55]([CH3:60])/[CH:56]=[CH:57]\[CH:58]=[CH2:59])[C@@H:5]([CH3:54])[C@H:6]([OH:44])[CH2:7][CH2:8]/[CH:9]=[CH:10]\[C@H:11]([CH3:43])[C@H:12]([OH:33])[C@@H:13]([CH3:32])/[CH:14]=[CH:15]\[CH2:16][CH2:17][C@H:18]1[C@H:23]([CH3:24])[C@H:22]([O:25][CH2:26][O:27][CH3:28])[C@@H:21]([CH3:29])[C@H:20]([O:30][CH3:31])[O:19]1)[NH2:2]
Reactant: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@@H](CC/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)/C=C\CC[C@@H]1O[C@@H](OC)[C@H](C)[C@@H](OCOC)[C@H]1C)OCc1ccc(OC)cc1
Agent: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)CC/C=C\[C@H](C)[C@H](O)[C@@H](C)/C=C\CC[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@@H]1C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)CC/C=C\[C@H](C)[C@H](O)[C@@H](C)/C=C\CC[C@@H]1O[C@@H](OC)[C@H](C)[C@@H](OCOC)[C@H]1C
Yield: 91.8 %

Procedure:
Carbamate 39 (4.25 mg, 0.005 mmol) was subjected to the deprotection procedure of PMB described in the preparation of 40. Flash chromatography (EtOAc/hexane 3:2) of the crude product provided 42 (2.8 mg, 92%) as a colorless oil: IR(CHCl3) 3115, 2749, 2328, 1676, 1508, 1215 cm−1; 1H NMR (300 MHz, CDCl3) 6.76 (ddd, 1H, J=16.8, 11.0, 10.1 Hz), 6.18 (t, 1H, J=10.8 Hz), 5.70-5.46 (m, 5H), 5.35 (d, 1H, J=16.8 Hz), 4.49 (dd, J=4.5, 6.6 Hz), 4.82 (d, 2H, J=2.4 Hz), 4.73 (br s, 2H), 4.43 (d, 1H, J=5.1 Hz), 4.15, (m, 1H), 3.78 (m, 1H), 3.56 (s, 3H), 3.54 (s, 3H), 3.36 (t, 2H, J=6.9 Hz), 3.14 (m, 1H), 2.76 (m, 2H), 2.35-2.18 (m, 6H), 2.00-1.60 (m, 7H), 1.22 (d, 3H, J=7.2 Hz), 1.16-1.12 (m, 12H), 1.07 (d, 3H, J=7.2 Hz); 13C NMR (125 MHz, CDCl3) 157.3, 133.7, 133.5, 132.2, 132.0, 130.0, 128.7, 118.0, 109.6, 103.0, 96.5, 82.1, 79.7, 79.1, 72.7, 55.8, 39.9, 39.5, 38.3, 35.5, 35.0, 34.8, 34.6, 30.2, 29.8, 24.3, 18.1, 17.7, 15.7, 15.4, 14.2, 13.2, 8.1; LRMS (ESI) 632.4 (M+Na); HRMS (ESI) calcd for C33H55NO8Na 632.4138, found 632.4139; [α]20D+21.6 (c 0.25, CHCl3).