Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O.[Cu]I>[C:24]1([C:30]#[C:31][C:2]2[N:7]=[N:6][C:5]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#Cc1ccccc1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Cl)nn1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)c1ccc(C#Cc2ccccc2)nn1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-chloro-3-phenylsulfonylpyridazine (8.4 g) bis(triphenylphosphine)palladium(II) chloride (98%; 0.24 g), copper(I) iodide (95%; 63 mg), and triethylamine (9.2 ml) in N,N-dimethylformamide (84 ml) was added phenylacetylene (4.7 ml), and the mixture was stirred for 0.5 hour at 80° C. After being cooled to room temperature, water (168 ml) was added to the reaction mixture. The precipitate formed was collected, washed with water, and dried. Recrystallization of the crude product from a mixture of diisopropyl ether and acetone (2:1) gave 6-(2-phenylethynyl)-3-phenylsulfonylpyridazine (5.5 g). After the mother liquor was concentrated in vacuo, the residue was triturated with acetone. The precipitate was collected and dried to give a second crop of the pure material (2.0 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:13][CH3:14].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:14][O:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH:2]=[O:1]
Reactant: COc1c(CO)ccc2ccccc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1c(C=O)ccc2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from Step B (4 g, 27.28 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0° C. To this solution was added pyridinium chlorochromate (5.5 g, 25.53 mmol) and the reaction was stirred at this temperature for 1 h. The reaction mixture was washed with 1 M aqueous solution of hydrogen chloride. The organic layer was separated, dried (MgSO4), and concentrated to give an oil, which was purified by flash chromatography (silica gel, ethyl acetate/hexane: 1/9): 1H NMR (CDCl3) δ 4.15 (s, 3H, CH3), 7.61 (m, 3H, Ar—H), 7.87 (m, 2H, Ar—H), 8.28 (m, 1H, Ar—H), 10.61 (s, 1H, CHO); MS 191 (M+NH4+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.S(Cl)([Cl:20])=O.CN(C)C=O.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]([Cl:20])=[O:17])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)c(-c2ccccc2)n1
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Cl)c(Cl)c(-c2ccccc2)n1
Temperature: 80 °C

Procedure:
To a mixture of 4,5-dichloro-6-phenylpicolinic acid (3.00 g, 11.2 mmol) in toluene (40 mL) was added thionyl chloride (1.22 mL, 16.8 mmol) and dimethylformamide (0.04 mL, 0.6 mmol). Reaction mixture was heated at 80° C. for 3 h. HPLC analysis of an aliquot treated with methanol and dimethylaminopyridine indicated complete conversion of the starting material. Reaction was allowed to cool to room temperature and then concentrated under reduced pressure to provide a white solid. Toluene (40 mL) was added to dissolve the solid and concentrated under reduced pressure and then this process was performed a second time. 4,5-Dichloro-6-phenylpicolinoyl chloride was isolated as a white solid (2.84 g, 89% yield). 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.83-7.75 (m, 2H), 7.55-7.47 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 168.80, 158.88, 146.42, 145.21, 136.79, 134.40, 129.98, 129.61, 128.31, 124.74, LRMS Calcd. C12H6Cl3NO: 284.95. Found: m/z=285 (M+), 250 (M+-Cl), 222, 187, 152, MP. 106-111° C.
Reaction SMILES: [CH2:1]([O:7][C:8](=O)[CH2:9][NH:10][C:11](=O)[C:12]([O:14][CH3:15])=[O:13])[CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH3:6].N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:6][C:5]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:9]=[C:8]2[O:7][CH2:1][CH2:2][CH2:3][C:4]=12
Reactant: C/C=C/CCCOC(=O)CNC(=O)C(=O)OC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ncc2c(c1C)CCCO2

Procedure:
(E)-Methyl 2-((2-(hex-4-en-1-yloxy)-2-oxoethyl)amino)-2-oxoacetate (0.24 g, 1 eq) and DCM (2.4 mL) were added to a vessel with stirring followed by the addition of pyridine (95 mg, 1.2 eq). Tf2O (0.42 g, 1.5 eq) was then added over 45 min at ambient temperature and the mixture was stirred at ambient temperature for 48 h. The mixture was washed with 20 wt % aqueous NaOAc (2×1.5 mL), 10 wt % aqueous citric acid (3×1.5 mL), and water (1×1.5 mL). The organic layer was then concentrated under reduced pressure to provide the title compound as a solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.10 (s, 1H), 4.15-4.25 (m, 2H), 3.94 (s, 3H), 2.71 (t, J=6.56 Hz, 2H), 2.47 (s, 3H), 2.00-2.18 (m, 2H); 13C NMR (75 MHz, CDCl3) δ ppm 166.71, 153.50, 138.69, 136.72, 135.67, 130.36, 65.93, 52.35, 22.18, 21.49, 14.57; HRMS (M+H) m/z, calcd for C11H14NO3, 208.0974; found 208.0981.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Reactant: NN1CCOCC1
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 78 %

Procedure:
As described for example 26b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (75 mg, 0.24 mmol) was converted, using N-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (74 mg, 78%) which was obtained as a white solid. MS: m/e=396.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([OH:17])=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:18][CH:19]([C:21]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][CH:29]([CH2:32]O)[CH2:28][CH2:27]2)[O:23][N:22]=1)[CH3:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:20][CH:19]([C:21]1[N:25]=[C:24]([N:26]2[CH2:27][CH2:28][CH:29]([CH2:32][O:17][C:14]3[CH:15]=[N:16][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[N:12][CH:13]=3)[CH2:30][CH2:31]2)[O:23][N:22]=1)[CH3:18]
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2ncc(O)cn2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3cnc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Yield: 75.5 %

Procedure:
The title compound (0.145 g, 75%) was prepared as a white solid from 2-[4-(methylsulfonyl)phenyl]-5-pyrimidinol (0.106 g, 0.42 mmol), 1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Step 3, 0.10 g, 0.42 mmol) and Ph3P (0.12 g, 0.42 mmol) in THF (3 mL) followed by diisopropyl azodicarboxylate (92 mg, 94%, 0.42 mmol) in THF (1 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CD3OD): δ 8.61 (s, 2H), 8.58 (d, 2H, J=8.6 Hz), 8.04 (d, 2H, J=8.3 Hz), 4.25-4.10 (m, 2H), 4.12 (d, 2H, J=6.2 Hz), 3.25-3.10 (m, 5H), 2.85 (septet, 1H, J=7.0 Hz), 2.25-2.10 (m, 1H), 2.05-1.90 (m, 2H), 1.55-1.40 (m, 2H), 1.26 (d, 6H, J=7.1 Hz); LRMS (ESI), m/z 458 (M+H).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([CH2:12][C:13]1([N:32]2[CH:36]=[C:35]([C:37]3[C:38]4[CH:45]=[CH:44][N:43](COCC[Si](C)(C)C)[C:39]=4[N:40]=[CH:41][N:42]=3)[CH:34]=[N:33]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:25][C@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])=[O:24])=[N:21][CH:22]=2)[CH2:14]1)#[N:11].[OH-].[NH4+].C([O-])(O)=O.[Na+]>C(#N)C.O>[C:10]([CH2:12][C:13]1([N:32]2[CH:36]=[C:35]([C:37]3[C:38]4[CH:45]=[CH:44][NH:43][C:39]=4[N:40]=[CH:41][N:42]=3)[CH:34]=[N:33]2)[CH2:16][N:15]([C:17]2[N:18]=[CH:19][C:20]([C:23]([NH:25][C@H:26]([CH3:31])[C:27]([F:28])([F:29])[F:30])=[O:24])=[N:21][CH:22]=2)[CH2:14]1)#[N:11]
Reactant: C[C@@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C(F)(F)F
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: C[C@@H](NC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
Boron trifluoride etherate (0.078 mL, 0.62 mmol) was added to a solution of 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-2,2,2-trifluoro-1-methylethyl]pyrazine-2-carboxamide in acetonitrile (4.0 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature for 3 h. [LCMS (M+H)+: m/z=527.2]. The mixture was cooled to 0° C., water (1.6 mL) was added. After 30 min., 5.0 M ammonium hydroxide in water (0.38 mL, 1.9 mmol) was added slowly at 0° C. over 5 min. Then the reaction mixture was stirred at room temperature overnight. The mixture was worked up with saturated aqueous NaHCO3, extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-5%) to afford the desired product (60 mg, 58%). LCMS (M+H)+: m/z=497.1. 1H NMR (400 MHz, DMSO-d6): δ 12.73 (br, 1H), 9.13 (s, 1H), 8.87 (s, 1H), 8.83 (d, J=9.2 Hz, 1H), 8.68 (d, J=1.4 Hz, 1H), 8.58 (s, 1H), 8.02 (d, J=1.4 Hz, 1H), 7.82 (dd, J=3.1, 2.2 Hz, 1H), 7.27 (dd, J=3.3, 1.3 Hz, 1H), 4.83 (d, J=9.8 Hz, 2H), 4.81 (m, 1H), 4.58 (d, J=9.9 Hz, 2H), 3.80 (s, 2H), 1.36 (d, J=7.1 Hz, 3H).
Reaction SMILES: B.[Cl:2][N:3]1[CH2:9][C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=2[N:6]2[C:14]3[CH:24]=[CH:23][N:22]=[CH:21][C:15]=3[C:16]3[C:17](=O)[CH2:18][CH:19]=[C:4]1[C:5]=32>C1COCC1>[Cl:2][N:3]1[CH2:9][C:8]2[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=2[N:6]2[C:14]3[CH:24]=[CH:23][N:22]=[CH:21][C:15]=3[C:16]3[CH2:17][CH2:18][CH:19]=[C:4]1[C:5]=32
Reactant: O=C1CC=C2c3c1c1cnccc1n3C1=C(CCCC1)CN2Cl
Agent: B
Solvent: C1CCOC1
Product: ClN1CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C31

Procedure:
A solution of borane in THF (1 M, 90 ml) was added carefully to a stirred solution-suspension of 6-chloro-1,2,3,4-tetrahydropyrido[4',3':2,3]indolo[1,7-ab][1,4]benzodiazepin-9(8H)-one (Example I-3; 14.4 g) in tetrahydrofuran (200 ml) and the resulting mixture refluxed for 2 hours, cooled and the excess of borane destroyed by dropwise addition of 3 N hydrochloric acid. The mixture was then evaporated to dryness under reduced pressure and the residue refluxed with 3 N hydrochloric acid (200 ml) for 2 hours. Evaporation of the mixture to dryness under reduced pressure provided the salt of the title product which was taken up in a small quantity of water, basified with 10% aqueous sodium hydroxide and extracted thrice with methylene chloride. The combined methylene chloride extracts were washed with water, dried over anhydrous magnesium sulfate and stripped of the solvent under reduced pressure to yield the title product which was recrystallized from a mixture of 2-propanol and methanol, m.p. 210°-212°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[N:11]=[C:12]=[O:13].[CH3:14][NH:15][C:16]1[CH:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:19]=[CH:18][N:17]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12](=[O:13])[N:15]([CH3:14])[C:16]1[CH:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:19]=[CH:18][N:17]=1
Reactant: CNc1cc(Nc2ccc(N3CCN(C)CC3)cc2)ncn1
Reactant: COc1ccc(Cl)c(N=C=O)c1Cl
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(N4CCN(C)CC4)cc3)ncn2)c1Cl
Temperature: 110 °C
Reaction time: 17 h

Procedure:
To a solution of 2,6-dichloro-3-methoxyphenylisocyanate (preparation 1, 52.3 mg, 0.24 mmol, 1.2 eq.) in toluene (2.5 ml) is added N-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine (59.7 mg, 0.2 mmol, 1.0 eq.). The obtained suspension is stirred under argon at 110° C. for 17 h. After cooling the crude product is filtered off und purified by flash chromatography (100% DCM to 5% MeOH in DCM within 35 min). Fractions containing the product are pooled and evaporated to dryness. The residue is triturated with ether (2 ml) and treated with ultra sound until a homogeneous suspension is obtained. The precipitate is filtered off and vacuum dried at 60° C. over night to afford the title compound as a colorless powder: m.p. 161.5-163° C., HPLC: tR=5.07 min (purity: >99%, gradient A), ESI-MS: 516.6/518.5/520.4 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=S.[CH2:12]([O:14][C:15](=[O:32])[C:16]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH:28][CH3:29])[C:22]=1[C:30]#[N:31])([CH3:20])[C:17](=[O:19])[CH3:18])[CH3:13]>C1COCC1>[CH2:12]([O:14][C:15](=[O:32])[C:16]([C:21]1[CH:26]=[CH:25][C:24]2[N:27]=[C:10]([NH:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[N:28]([CH3:29])[C:23]=2[C:22]=1[C:30]#[N:31])([CH3:20])[C:17](=[O:19])[CH3:18])[CH3:13]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc(N)c(NC)c1C#N
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C(C)=O)c1ccc2nc(Nc3c(Cl)cccc3Cl)n(C)c2c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
2,6-Dichlorophenyl isothiocyanate (3.46 g, 17.0 mmol), THF (100 mL), and 2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (4.91 g, 17.0 mmol), were added to a 250 mL round bottom flask equipped with a magnetic stir bar and the reaction was stirred at room temperature. After 2 hours, mercuric oxide (4.04 g, 18.7 mmol) was added and the reaction stirred for an additional 14 h. The resultant brown slurry was filtered through celite and washed with THF. The filtrate was concentrated and the residue triturated with diethyl ether to provide 2-[4-cyano-2-(2,6-dichloro-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (4.2 g, 54%) as a gray solid, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@@H:7]1[CH2:15][C@@H:10]2[O:11][C:12](=[O:14])[CH2:13][C@@H:9]2[C@H:8]1[CH2:16][CH2:17][C@@H:18]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:5])[CH3:2].CC(C[AlH]CC(C)C)C.C(OCC)(=O)C.C([O-])(=O)C(C(C([O-])=O)O)O.[Na+].[K+]>C1COCC1>[CH2:1]([O:3][CH:4]([O:6][C@@H:7]1[CH2:15][C@@H:10]2[O:11][CH:12]([OH:14])[CH2:13][C@@H:9]2[C@H:8]1[CH2:16][CH2:17][C@@H:18]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@@H](CCc1ccccc1)CC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(C)OCC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(C)O[C@@H](CCc1ccccc1)CC[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1OC(C)OCC
Reaction time: 0.25 h

Procedure:
(3aR,4R,5R,6aS)-5-(1-Ethoxyethoxy)-4-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-one (X, EXAMPLE 6) is dissolved in THF (14 mL) and the mixture cooled to −40°. Using a syringe pump, DIBAL (1.0 M, 3.78 mL in toluene) is added over 15 minutes, maintaining the internal temperature at less than −30°. The mixture is stirred for 15 minutes after the completion of the addition, then ethyl acetate (0.38 mL) is added. The mixture is poured into a solution of potassium sodium tartarate (10 g in 30 mL of water) and warmed to 20-25°. The two phase mixture is heated to 45° for 1 hr and then cooled. The phases are separated and the organic phase is concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:58]=[CH:57][C:6]([CH2:7][N:8]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C@H:32]([N:34]4[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][C@H:35]4[CH3:47])[CH3:33])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.ClCCl.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:76][S:77](Cl)(=[O:79])=[O:78]>>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=4)[CH2:7][C:6]4[CH:57]=[CH:58][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=3)=[CH:17][C:18]([C@H:32]([N:34]3[CH2:39][CH2:38][N:37]([S:77]([CH3:76])(=[O:79])=[O:78])[CH2:36][C@H:35]3[CH3:47])[CH3:33])=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)C[C@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)C[C@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 1 h
Yield: 77 %

Procedure:
To a 100 mL round-bottomed flask was added (R)-tert-butyl 4-((R)-1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.200 g, 0.252 mmol), dichloromethane (5 mL, 78 mmol), trifluoroacetic acid (5 mL, 67.3 mmol). The solution was stirred for 1 hr. The solution was concentrated down and the residue was dissolved in DCM and slowly washed with NaHCO3, to get rid off the TFA. The DCM solution was dried over sodium sulfate, filtered and concentrated. The residue was dried under a high vacuum overnight. The residue was dissolved in DCM, cooled down in a dry ice/IPA cooling bath and treated with triethylamine (0.349 mL, 2.52 mmol), and methanesulfonyl chloride (0.098 mL, 1.260 mmol).The solution was stirred at −50° C. for 30 minutes. The solvent was removed under a vacuum and the crude product was washed with water (30 mL), stirred, and sonicated. The resulting suspension was collected, washed with water, and dried in a vacuum oven overnight to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((R)-1-((R)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.150 g, 0.194 mmol, 77% yield).
Reaction SMILES: [C:1]([C:3]1[C:9]([C:10]#[N:11])=[C:8]([OH:12])[CH:7]=[CH:6][C:4]=1[OH:5])#[N:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[Cl-].[Cl-].[Ca+2].C(Cl)Cl>C(O)CCC.O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]=[C:10]1[C:9]2[C:3](=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=2[OH:12])[C:1](=[N:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[NH:2]1
Reactant: N#Cc1c(O)ccc(O)c1C#N
Reactant: Nc1ccccn1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCCCO
Product: Oc1ccc(O)c2c1C(=Nc1ccccn1)NC2=Nc1ccccn1
Temperature: -40 °C
Reaction time: 480 h

Procedure:
A solution of 1.0 g (6.24 mmol) 2,3-dicyanohydroquinone, 1.23 g (13.11 mmol) 2-aminopyridine and 0.14 g (1.3 mmol) CaCl2 in 20 ml 1-butanol was refluxed under N2. Despite the presents of fluorescent blue 2,3-dicyanohydroquinone starting material, as observed by TLC (CH2Cl2), the reaction was discontinued after 20 days. The reaction mixture was poured into 500 mL of H2O. The precipitate was collected by filtration and was washed with water until no blue fluorescents was observed from the filtrate. The precipitate was then dissolved in boiling CH2Cl2 and then cooled to −40° C. overnight. Precipitate was then collected by filtration and washed with MeOH. 0.485 g (24%), yellow needles. MS (Maldi-TOF): m/z=331.85. HRMS-FAB (m/z): [M+H]+ calcd for C18H14N5O2, 332.1142; found, 332.1136. 1H NMR (400 MHz, CDCl3), δ 13.3 (s, 1H), 8.57 (ddd, J=4.8, 2.0, 0.8 Hz, 2H), 7.75 (ddd, J=8.0, 7.6, 2.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.11 (ddd, J=7.6, 4.8, 0.8 Hz, 2H), 7.00 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 159.3, 154.9, 149.0, 147.9, 147.9, 138.1, 122.4, 121.4, 120.4, 116.2.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([NH:15][NH:16][C:17](=O)[C:18]1[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][C:21]([Cl:28])=[N:20][CH:19]=1)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[O:14][C:17]([C:18]2[CH:19]=[N:20][C:21]([Cl:28])=[CH:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])=[N:16][N:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)NCCCO[Si](C)(C)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(NCCCO[Si](C)(C)C(C)(C)C)o1
Temperature: 50 °C

Procedure:
N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinecarboxamide (50) (1 g, 2.2 mmol) in DCM (40 mL) was stirred at room temperature. Added triphenyl phosphine (6 mmol, 3 equiv.), Et3N (18 mol, 8 equiv.) and CCl4 (6 mmol, 3 equiv.). The reaction mixture was heated at 50° C. for 3 h. Reaction mixture was diluted using DCM. The DCM layer was washed with water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography through silica gel and EtOAc: Pet. Ether as eluent to provide the desired compound, N-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-amine. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 1.2 min; LCMS (ES-API), m/z 426.9 (M+H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]=[CH:8][CH2:9]CCCCC.C=C>CCCCCC>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]=[CH:8][CH3:9]
Reactant: C=CCCCCCC
Agent: C=C
Solvent: C=CCCCC
Solvent: CCCCCC
Product: C=CC

Procedure:
The procedure used for the preparation of copolymer S-2 was repeated except that 1-hexene was replaced with 1 -octene. A tacky amorphous polymer was obtained in 56% conversion having an inherent viscosity of 4.2 dL/g in n-hexane and a Tg of -51° C. It contained 89 mole percent of 1-octene and 11 mole percent of ethylene.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)(O)[CH2:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:22]1(/[CH:21]=[C:20](/[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)\[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1ccc(C(O)(CC2CCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCC2)c2cc3cc(F)cnc3[nH]2)cc1
Yield: 62.1 %

Procedure:
A solution of 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclobutyl-1-(4-methylsulfonyl-phenyl)-ethanol (520 mg, 1 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 5.0 mL, 5.0 mmol) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[(E)-2-cyclobutyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (230 mg, 62.1%) as a light yellow solid: LC/MS m/e calcd for C20H19FN2O2S [M+H]+ 371.45, observed 371.0; 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (d, J=8.3 Hz, 3H), 7.50-7.58 (m, 3H), 6.66 (d, J=9.3 Hz, 1H), 5.86 (s, 1H), 3.22 (s, 3H), 2.99 (m, 1H), 2.04-2.16 (m, 4H), 1.85-1.94 (m, 2H).