Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C(NC1C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([C:8](=[O:15])[C:9](=[N+:37]=[N-:38])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1F
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-(3-chloro-2-fluorophenyl)-3-oxopropanoate (1.30 g, 5.31 mmol), triethylamine (0.618 g, 6.11 mmol, 1.15 equiv), and 4-acetamidobenzenesulfonyl azide (1.40 g, 5.85 mmol, 1.1 equiv) were combined in acetonitrile (15 mL). After stirred at ambient temperature for 30 minutes, the mixture was concentrated in vacuo and the residue was treated with sodium hydroxide (25 mL, 2 M aqueous) and extracted with twice chloroform. The combined organic extracts were washed once with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 40:60; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][O:9][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)CCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CCCCCBr)COC1CCCCO1
Yield: 46.5 %

Procedure:
According to the method described for the synthesis of 207d, 206g (36.0 g, 161 mmol) was treated with 3,4-dihydro-2H-pyran (18.5 g, 220 mmol) and p-toluenesulfonic acid hydrate (0.28 g, 1.5 mmol) in CH2Cl2 (60 mL). After filtration through neutral aluminum oxide (200 g) and concentration, the crude product was purified by column chromatography (silica gel; hexanes/ethyl acetate=50/1), affording 207g (23.0 g, 46%) as an oil. 1H NMR (CDCl3): δ 4.54 (t, 1H, J=3.0), 3.84 (m, 1H), 3.51-3.39 (m, 4H), 2.98 (d, 1H, J=9.3), 1.89-1.80 (m, 3H), 1.70-1.40 (m, 7H), 1.29-1.22 (m, 4H), 0.89 (s, 6H). 13C NMR (CDCl3): δ 99.3, 76.6, 62.1, 39.3, 34.3, 34.2, 33.0, 30.8, 29.2, 25.7, 24.7, 23.2, 19.6. HRMS (LSIMS, gly): Calcd for C14H28BrO2 (MH+): 307.1272, found: 307.1245.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]([CH3:12])[CH3:11])[C:6]([O:13][CH3:14])=[CH:5][N:4]=1.[Mn]([O-])(=O)(=O)=[O:16].[K+].[OH-].[K+]>O.C(O)(C)C>[CH:10]([O:9][C:7]1[C:6]([O:13][CH3:14])=[CH:5][N:4]=[C:3]([C:2]([OH:16])=[O:1])[CH:8]=1)([CH3:11])[CH3:12]
Reactant: COc1cnc(CO)cc1OC(C)C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: COc1cnc(C(=O)O)cc1OC(C)C
Temperature: 70 °C
Yield: 94.2 %

Procedure:
To a stirred and heated (50° C.) solution of the product of step 1 (0.410 g, 2.08 mmol) in water (12 mL) was added, portionwise over 30 minutes, solid potassium permanganate (0.680 g, 4.30 mmol). Following the addition, reaction temperature was increased to 70° C. After 45 minutes the reaction was cooled to room temperature and treated with a solution of potassium hydroxide (0.230 g, 4.10 mmol) in water (6 mL) followed by a few drops of isopropanol. The mixture was stirred for about 5 minutes before filtering through Celite. The filtrate was concentrated to dryness under a nitrogen current. The resulting brown residue was dissolved in water (10 mL), adjusted to pH 2 with concentrated hydrochloric acid and extracted repeatedly with chloroform. The combined extracts were dried (sodium sulfate) and concentrated to afford 0.414 g (94%) of product as a pink-gray foam: 1H NMR (DMSO-d6) δ 8.23 (s, 1H), 7.5 8 (s, 1H), 4.81 (sept, J=6.0 Hz, 1H), 3.90 (s, 3H), 1.29 (d, J=6.0 Hz, 6H) ppm.
Reaction SMILES: C(O)(=O)CC1C(=CC=CC=1)C(O)=O.O.[O:15]=[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](C(O)=O)=[C:18]([C:29]([F:32])([F:31])[F:30])O1.[OH-].[NH4+:34]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[F:30][C:29]([F:32])([F:31])[C:18]1[NH:34][C:16](=[O:15])[C:25]2[C:20]([CH:19]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: [NH4+]
Reactant: O=C(O)c1c(C(F)(F)F)oc(=O)c2ccccc12
Agent: O=C(O)Cc1ccccc1C(=O)O
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)cc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
Homophthalic acid (1.00 g, 5.55 mmol) dissolved in trifluoroacetic anhydride (7.8 ml) was heated in a sealed tube for 24 h at 110° followed by a further 24 h at 140°. The reaction was poured into water (100 ml), left for 1 h and the resulting precipitate extracted into EtOAc (3×50 ml). The EtOAc solution was dried (MgSO4) and the solvent removed under reduced pressure to give a pale brown solid. LCMS showed these to be a 9:1 mixture of −1-oxo-3-(trifluoromethyl)-1H-isochromene-4-carboxylic acid. m/z (ES+, 70V) 259 (MH+) and 3-Trifluoromethyl)-1H-isochrom-1-one m/z (ES+, 70V) 215 (MH+). The solids were dissolved in concentrated ammonium hydroxide (70 ml) and heated for 4 days at 100°, an additional 10 ml of concentrated ammonium hydroxide added after 24 h. The solution was allowed to cool to room temperature, the precipitate removed by filtration and the filtrate extracted with EtOAc (1×50 ml). The EtOAc was dried (MgSO4). the solvent removed under reduced pressure, and the resulting yellow solids combined with the precipitated material, to give the title compound 825 mg, 70%. δH (CDCl3) 8.48 (1H, d, J 7.5 Hz), 7.77 (1H, t), 7.68 (2H, m), 6.95 (1H, s); m/z (ES+, 70V), 215 (MH+).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][C:3]1([CH3:7])[CH:5]=[CH2:6].C([O:11]CC)C>>[F:1][C:2]1([F:8])[CH2:4][C:3]1([CH2:5][CH2:6][OH:11])[CH3:7]
Reactant: CCOCC
Reactant: C=CC1(C)CC1(F)F
Product: CC1(CCO)CC1(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
0.23 mol of diborane is produced from 6.7 g (0.18 mol) of sodium borohydride and 33 g (0.23 mol) of boron trifluoride etherate in 130 ml of diglyme, and, with the aid of a stream of nitrogen, is passed into a stirred solution of 30 g (0.25 mol) of 2,2-difluoro-1-methyl-1-vinyl-cyclopropane in 300 ml of dry diethyl ether, at room temperature. The reaction mixture is stirred for one hour more at room temperature and concentrated by stripping off the solvent and the excess alkene under reduced pressure. The residue which remains is taken up in 50 ml of diethyl ether, and 130 ml of 10% strength aqueous sodium hydroxide solution are added. 134 ml of a 30% strength aqueous hydrogen peroxide solution are added dropwise to this mixture at room temperature and with stirring. Stirring is continued for an hour at room temperature, the mixture is extracted several times using diethyl ether, and the combined organic phases are dried and distilled under reduced pressure. In this manner, 13 g (55% of theory) of 2-(2,2-difluoro-1-methyl-cyclopropyl)-ethanol are obtained in form of a liquid of boiling point 65°-67° C./20 torr.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:11][O:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:7][N:6]=1)=[O:9]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NCC(F)(F)F)cn1
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
Methyl 5-aminopyridine-2-carboxylate (Intermediate 168, 200 mg, 1.31 mmol) and cesium carbonate (642 mg, 1.97 mmol) were dissolved in anhydrous DMF (2 mL) and stirred under nitrogen for 10 min. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (246 μL, 1.70 mmol) was added and the mixture was stirred at room temperature for 18 h. Further cesium carbonate (642 mg, 1.97 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (246 μL, 1.70 mmol) were added and the mixture was stirred at 85 C for 6 h. The mixture was diluted with EtOAc (50 mL) and washed with water (3×20 mL), then brine (20 mL) and then dried over sodium sulfate and evaporated under vacuum. The crude residue was purified by flash chromatography (0-10% EtOAc in heptane) to afford the title compound as a white solid (75 mg, 24%). Method B HPLC-MS: MH+ requires m/z=235. Found: m/z=235, Rt=1.76 min (84%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([S:39](Cl)(=[O:41])=[O:40])[CH:33]=[CH:32]2>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][N:15]2[CH2:20][CH2:19][N:18]([S:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([Cl:28])[CH:30]=4)[CH:35]=3)(=[O:40])=[O:41])[CH2:17][C:16]2=[O:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(NN2CCNCC2=O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(NN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the resultant 1-[1-(tert-butoxycarbonyl)-4-piperidinylamino]-2-piperazinone in ethyl acetate (30 ml) and a 10% aqueous solution of sodium carbonate (30 ml) was combined at 0° C. with 6-chloronaphthalene-2-sulfonyl chloride (2.24 g) and stirred at room temperature for 30 minutes, and then the organic phase was separated, washed with brine, dried and concentrated. The residue thus obtained was purified by a column chromatography on a silica gel (hexane:ethyl acetate=1:2) to obtain 1-[1-(tert-Butoxycarbonyl)-4-piperidinylamino]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (3.55 g) as a colorless amorphous material.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[NH:4][C:3]1=[O:10].[H-].[Na+].Cl[C:14]1[N:15]=[N:16][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:19]=1>CN(C=O)C>[CH3:1][N:2]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[N:4]([C:14]2[N:15]=[N:16][C:17]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:19]=2)[C:3]1=[O:10]
Reactant: CN1C(=O)NC2CCCC21
Reactant: Clc1ccc(C#Cc2ccccc2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccc(C#Cc3ccccc3)nn2)C2CCCC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a solution of (3aRS, 6aSR)-1-methyl-hexahydro-cyclopentaimidazol-2-one (Example 106, step 3) (55 mg, 0.39 mmol, 1.5 equiv.) in 3 ml of DMF was added 60% sodium hydride suspension in mineral oil (17 mg, 0.42 mmol, 1.6 equiv.). The white suspension was stirred for 30 min. at room temperature. Then 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (56 mg, 0.261 mmol) was added and the reaction was stirred for 1 hour at room temperature. After workup with ethyl acetate/water, drying over magnesium sulfate and concentration in vaccuo, the residue was purified by flash chromatography over silica gel eluting with a heptane to 50% ethyl acetate/heptane gradient to yield 40 mg (48% yield) of the title compound as an off-white solid, MS: m/e=319.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=O)(OC)OC.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]([CH3:25])[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[C:19]([Cl:24])[CH:18]=3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc2cc(-c3cncc(OCc4ccccc4)c3)[nH]c2c1
Reactant: COC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(-c2cncc(OCc3ccccc3)c2)cc2ccc(Cl)cc21
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A flask is charged with 2-(5-benzyloxy-pyridin-3-yl)-6-chloro-1H-indole (Example 98, 0.435 g, 1.29 mmol), dimethyl carbonate (0.328 mL, 3.89 mmol), potassium carbonate (0.098 g, 0.714 mmol) and DMF (3 mL). The reaction mixture is stirred at 150° C. overnight. It is then cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo, to give a residue which is purified by flash chromatography (heptane-ethyl acetate, 1:1) to afford 2-(5-benzyloxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole as a solid. 1H NMR (400 MHz, MeOD) δ ppm 3.70 (s, 3H), 5.31 (s, 2H), 6.67 (d, J=0.8 Hz, 1H), 7.10 (dd, J=8.3, 1.8 Hz, 1H), 7.35-7.40 (m, 1H), 7.41-7.47 (m, 2H), 7.49-7.55 (m, 3H), 7.57 (d, J=8.3 Hz, 1H), 7.64 (dd, J=2.5, 1.8 Hz, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.39 (d, J=2.8 Hz, 1H); HRMS (ESI) m/z 349.1108 [(M+H)+ Calcd for C21H18ClN2O: 349.1108].
Reaction SMILES: [CH3:1][C@@H:2]([C:27]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:3]([NH:5][C@@H:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([N:9]([CH3:22])[C@@H:10]([CH:19]([CH3:21])[CH3:20])/[CH:11]=[C:12](\[CH3:18])/[C:13]([O:15]CC)=[O:14])=[O:8])=[O:4].O1CCCC1.O.[OH-].[Li+].Cl>CO.O>[CH3:1][C@@H:2]([C:27]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:3]([NH:5][C@@H:6]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:7]([N:9]([CH3:22])[C@@H:10]([CH:19]([CH3:20])[CH3:21])/[CH:11]=[C:12](\[CH3:18])/[C:13]([OH:15])=[O:14])=[O:8])=[O:4]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](C)C(C)(C)c1ccccc1)C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C/C(=C\[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](C)C(C)(C)c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
Ethyl (E,4S)-4-[((2S)-2-{[(2S)-2,3-dimethyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate (0.17 g, 0.35 mmol, from Example 91) is dissolved in methanol (1.2 mL) and tetrahydrofuran (1.2 mL) and cooled to 0° C. (ice water bath). To this solution is added water (0.6 mL) and aqueous lithium hydroxide monohydrate (30 mg, 0.70 mmol). The cooling bath is removed, and the resulting mixture is stirred at 50° C. for 15 hours. Solvents are removed in vacuo to provide a beige foam, which is then dissolved in water. The solution is acidified to pH 1 with 10% aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a white solid (0.16 g, 100%). MS (ES+): (M+H)=459.0
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>COCCOC>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)=[N:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 120 °C
Yield: 81.2 %

Procedure:
A mixture of ethyl 6-chloronicotinate (2.67 g, 14.4 mmol), tert-butyl piperazine-1-carboxylate (2.5 g, 13.4 mmol) and N,N-diisopropylethylamine (3.5 mL, 20 mmol) in DME (15 mL) was heated at 120° C. for 12 hours. The mixture was then cooled to room temperature and partitioned with ethyl acetate and 10% aqueous citric acid. The organic layer was washed twice with 10% aqueous citric acid then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using 3:1 hexanes:ethyl acetate to 100% ethyl acetate afforded tert-butyl 4-(5-(ethoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate (3.65 g). 1H NMR (400 MHz, CDCl3): 8.81 (s, 1H), 8.04 (d, 1H), 6.58 (d, 1H), 4.33 (q, 2H), 3.70-3.67 (m, 4H), 3.56-3.53 (m, 4H), 1.49 (s, 9H), 1.37 (tr, 3H).
Reaction SMILES: [NH2:1][CH:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[OH:19][C:20]1[C:25]([C:26](O)=[O:27])=[CH:24][N:23]=[C:22]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[N:21]=1.OC1C(C(NC(C2C=CC=CC=2)C2C=CC(P(=O)(OCC)OCC)=CC=2)=O)=CN=C(N2C=CC=N2)N=1>>[OH:19][C:20]1[C:25]([C:26]([NH:1][CH:2]([P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)=[O:27])=[CH:24][N:23]=[C:22]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[N:21]=1
Reactant: CCOP(=O)(OCC)C(N)c1ccc(OC)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CCOP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Product: CCOP(=O)(OCC)C(NC(=O)c1cnc(-n2cccn2)nc1O)c1ccc(OC)cc1

Procedure:
Compound 10-1 was prepared from compound 10-b and compound 8-b in a similar manner as the synthesis of compound 8-1. 1H NMR (300 MHz, DMSO-d6) δ1.09-1.20 (m, 6H), 3.73 (s, 3H), 3.84-4.04 (m, 4H), 5.44-5.54 (m, 1H), 6.71-6.73 (m, 1H), 6.92-6.94 (m, 2H), 7.30-7.33 (m, 2H), 8.06 (s, 1H), 8.41 (brs, 1H), 8.60-8.61 (m, 1H). LC-MS: (M+H)+ 462.
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.[C:41]1([C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][N:48]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.ClCCl.C([O-])([O-])=O.[K+].[K+]>O.COCCOC>[CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:50]3[CH:49]=[N:48][C:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:52][CH:51]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a pressure tube were charged tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-9g, 1.7 g, 2.4 mmol), 2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (800 mg, 2.8 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (100 mg, 0.12 mmol), K2CO3 (666 mg, 4.8 mmol), DME (10 mL) and water (5 mL). The tube was degassed with Ar briefly, capped and heated at 100° C. with stirring overnight. After cooling, the reaction mixture was diluted with EtOAc and water, the organic layer was isolated, washed with brine and dried (MgSO4). After the solvent was removed under reduced pressure, the residue was purified on silica. Elution with EtOAc in hexanes (0-50%) gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenyl pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxy late (Int-9h) (1 g, 57%). LC/MS: m/z=731 (M+H+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=O)[CH2:14][OH:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:17](#[N:21])[CH2:18][C:19]#[N:20].C(NCC)C.O>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[C:18]([C:19]#[N:20])=[C:17]([NH2:21])[O:15][CH:14]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(C(=O)CO)ccc21
Reactant: N#CCC#N
Solvent: CCNCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2cc(-c3coc(N)c3C#N)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a suspension of 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-hydroxyethanone (0.53 g, 2.41 mmol) and malononitrile (176 mg, 2.66 mmol, 1.1 equiv) in DMF (4 mL) chilled in an ice bath was added diethylamine (380 uL, 3.63 mmol, 1.5 equiv) over a 3 minute period. The resulting mixture was stirred in the ice bath for another 20 minutes, and then the ice bath was removed. The brownish suspension was stirred at ambient temp for 2 hours. LCMS showed product formed in 75%. To the suspension was added 20 mL of water. The warm suspension was filtered. The cake was washed with water, and dried under house vacuum overnight to give 4-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-amino-3-furancarbonitrile (360 mg) as beige solids. LC-MS (ES) m/z=268 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][C:27]=1[O:36][CH3:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:34])=[CH:28][C:27]=1[O:36][CH3:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Product: COc1cc(CC(=O)Nc2ccc3cnn(CCN4CCCC4)c3c2)ccc1OCc1ccccc1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and (4-benzyloxy-3-methoxy-phenyl)-acetic acid were processed to provide the title compound. MS (DCI/NH3) MS m/z 485 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.81 (m, 2 H), 1.97 (m, 2 H), 3.02 (m, 2 H), 3.51 (m, 2 H), 3.62 (s, 2 H), 3.69 (q, J=5.82 Hz, 2 H), 3.78 (s, 3 H), 4.66 (t, J=6.24 Hz, 2 H), 5.06 (s, 2 H), 6.84 (m, 1 H), 6.99 (m, 2 H), 7.12 (m, 1 H), 7.32 (m, 1 H), 7.40 (m, 4 H), 7.71 (m, 1 H), 8.08 (s, 1 H), 8.27 (s, 1 H), 9.59 (br s, N H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14][C:15]1[C:20]([CH3:21])=[C:19]([Cl:22])[N:18]=[C:17](OS(C(F)(F)F)(=O)=O)[C:16]=1[N+:31]([O-:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[CH:52]=[CH:51][C:39]([CH2:40][NH:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)=[CH:38][CH:37]=1.C(N(CC)CC)C.C(OCC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14][C:15]1[C:20]([CH3:21])=[C:19]([Cl:22])[N:18]=[C:17]([N:41]([CH2:40][C:39]2[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:52][CH:51]=2)[CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[C:16]=1[N+:31]([O-:33])=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: Cc1c(Cl)nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1NCCOCCNC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(Cl)c(C)c(NCCOCCNC(=O)OC(C)(C)C)c2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
A solution of trifluoromethanesulfonic acid 4-[(2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl)amino]-6-chloro-5-methyl-3-nitropyridin-2-yl ester (14.3 g, 27.4 mmol), bis(4-methoxybenzyl)amine (7.00 g, 27.4 mmol), and triethylamine (3.82 mL, 27.4 mmol) in toluene (250 mL) was heated at 90° C. for two hours and then allowed to cool to room temperature overnight. Diethyl ether (300 mL) was added, and the solution was washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified twice by column chromatography on silica gel (eluting sequentially with 80:20 hexanes:ethyl acetate and 70:30 hexanes:ethyl acetate) to provide 8.73 g of {2-[2-(2-[bis{4-methoxybenzyl}amino]-6-chloro-5-methyl-3-nitropyridin-4-ylamino)ethoxy]ethyl}carbamic acid tert-butyl ester.