Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/OCC)[CH:7]=1.O.Cl.[CH3:19][NH:20][CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:20]([CH3:21])[CH3:19])[CH:5]=[N:4][C:3]=1[C:13]([F:16])([F:15])[F:14]
Reactant: CCO/C=C/c1cnc(C(F)(F)F)c(Br)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)CCc1cnc(C(F)(F)F)c(Br)c1
Temperature: 105 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
To a solution of 3-bromo-5-[(E)-2-ethoxyvinyl]-2-(trifluoromethyl)-pyridine (0.35 g, 1.18 mmol) in AcOH (9 mL) was added water (3 mL). The resulting mixture was allowed to stir overnight at 105° C. The mixture was allowed to cool to rt. Dimethylamine hydrochloride (0.96 g, 11.8 mmol) and DCM (40 mL) were added. The resulting mixture was allowed to stir for 2 h. Sodium triacetoxyborohydride (0.50 g, 2.36 mmol) was added in portions over 50 min. The resulting mixture was allowed to stir for 3 h and was then concentrated. To the residue was added saturated NaHCO3 (40 mL), and the mixture was extracted with EtOAc (2×30 mL). The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-[5-bromo-6-(trifluoromethyl)pyridin-3-yl]-N,N-dimethylethanamine (0.052 g, 15%) as a solid. LCMS (AA): Rt=1.24 min, m/z=297.0 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17](O)=[O:18].O=S(Cl)Cl.Cl.[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH2:29]>CCN(CC)CC>[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH:29][C:2]([C:3]1[C:17](=[O:18])[C:16]2[C:11]([C:4]=1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:1]
Reactant: O=C(O)C1=C(c2ccccc2)c2ccccc2C1=O
Reactant: COC(=O)CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 101.4 %

Procedure:
A mixture of 1-oxo-3-phenyl-1H-indene-2-carboxylic acid (2.13 g, 8.5 mmol; can be obtained according to M. R. Barvian et al. in Bioorg. Med. Chem. Lett. 1997, 7, 2903-2908) and SOCl2 (17 ml) was refluxed with stirring for 15 min. Excess SOCl2 was then evaporated in vacuo. The residue was dissolved in anhydrous CH2Cl2 (20 ml), and subsequently the solution was concentrated in vacuo again to remove last traces of SOCl2. The residue was dissolved in anhydrous CH2Cl2 (20 ml). The solution was cooled with an ice bath before glycine methyl ester hydrochloride (1.27 g, 10 mmol) and subsequently NEt3 (3.52 ml, 25 mmol, dropwise addition) were added with stirring. The ice bath was then removed and stirring was continued at ambient temperature for 45 min before the mixture was concentrated in vacuo. To the residue was added water (10 ml) and aqueous 2N HCl (15 ml) and the mixture was extracted with ethyl acetate (1×70 ml). The organic phase was dried over MgSO4 and evaporated in vacuo to give an orange solid (2.77 g). Purification by flash column chromatography on silica gel using hexanes:EtOAc=2:1 as the eluent gave the title compound as an orange solid (2.11 g); MS-(+)-ion: M+1=322.0.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:38])[C:14]1[CH:19]=[C:18]([CH:20]=[N:21][O:22][CH2:23][CH:24]([OH:26])[CH3:25])[C:17]([F:27])=[C:16]([F:28])[C:15]=1[NH:29][C:30]1[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=1[F:37])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:28][C:16]1[C:15]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:14]([CH:19]=[C:18](/[CH:20]=[N:21]/[O:22][CH2:23][CH:24]([OH:26])[CH3:25])[C:17]=1[F:27])[C:13]([NH:12][O:11][CH2:10][CH2:9][OH:8])=[O:38]
Reactant: CC(O)CON=Cc1cc(C(=O)NOCCO[Si](C)(C)C(C)(C)C)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)CO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reaction time: 1.5 h

Procedure:
N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-hydroxy-propoxyimino)-methyl]-benzamide (20 mg, 0.029 mmol) prepared in Process B was dissolved in anhydrous tetrahydrofuran (2 mL). Tetra-n-butylammonium fluoride (1 mol/L solution in tetrahydrofuran) (30 μL, 0.03 mmol) was added dropwise at room temperature, and the mixture was stirred for 1.5 hours.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:30][O:31][C:32](=[O:38])[CH2:33][CH2:34][S:35]([O-:37])=[O:36].[Na+]>CS(C)=O.[Cu]I>[CH3:30][O:31][C:32](=[O:38])[CH2:33][CH2:34][S:35]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:6][N:7]=1)(=[O:37])=[O:36]
Reactant: O=C(NC1(c2ccc(Br)nc2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: COC(=O)CCS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CCS(=O)(=O)c1ccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)cn1
Temperature: 110 °C

Procedure:
A solution of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [1-(6-bromo-pyridin-3-yl)-cyclopropyl]-amide (0.250 g, 0.553 mmol), sodium 3-methoxy-3-oxopropane-1-sulfinate (289 mg, 1.66 mmol) and copper (I) iodide (316 mg, 1.66 mmol) in DMSO (2 mL) is placed in a microwave tube and evacuated and purged with argon three times. The reaction mixture is heated in a microwave at 110° C. for 2 hours, diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride (4×100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated. The resulting residue is purified by silica gel chromatography eluting with a gradient of 50-100% ethyl acetate in heptane to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].B([O-])=O.[Na+].C(O)(=O)C>COCCOCCOC.O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[CH2:10][OH:11]
Reactant: O=C(Cl)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: O=B[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.1 %

Procedure:
A solution of 41.5 g of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-benzoic acid chloride in 100 ml of diglyme was added to a mixture of 4.2 g of sodium boranate and 60 ml of diglyme at -5° to -10° C. The reaction mixture was stirred for about 15 hours at room temperature, diluted with 1.2 liters of water and acidified with acetic acid, and the product was filtered off. 36 g (94% of theory) of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-benzyl alcohol, of melting point 143° C., were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:34]=[CH:33][N:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccnc(C(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 90 °C
Reaction time: 18 h
Yield: 46.5 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.14 mmol) were added 2-(trifluoromethyl)pyridin-4-ylboronic acid (39 mg, 0.20 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11 mg, 0.01 mmol) and 204 μl of a 2M aqueous solution of cesium carbonate in dioxane (2.5 ml). The mixture was stirred under argon atmosphere at 90° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography using SP1® Purification System (0% to 70% hexane/AcOEt in 25 CV, 70% AcOEt in 10 CV) to give 33 mg (48% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]3[CH:29]=[N:30][C:31]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:32][CH:33]=3)[CH:23]=2)=[CH:17][CH:16]=1>ClCCCl.C(Cl)Cl.[Cl-].[Na+].O>[CH3:42][N:34]([C:31]1[N:30]=[CH:29][C:28]([C:24]2[CH:23]=[C:22]([O:21][C:18]3[CH:19]=[N:20][C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[CH:16][CH:17]=3)[CH:27]=[CH:26][N:25]=2)=[CH:33][CH:32]=1)[C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.062 g, 0.610 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.080 mL, 0.915 mmol), stirred at RT for 1 h, then heated at 75° C. for 3 h. The mixture was cooled to RT, treated with a solution of tert-butyl (4-((6-aminopyridin-3-yl)oxy)-[2,3′-bipyridin]-6′-yl)(methyl)carbamate (0.12 g, 0.305 mmol) and TEA (0.170 mL, 1.220 mmol) in DCM (3 mL) and stirred at RT for 2 h. The mixture was treated with brine, extracted with DCM (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford tert-butyl methyl(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)-[2,3′-bipyridin]-6′-yl)carbamate (100 mg, 63%) as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 10.44 (s, 1H), 9.02 (d, J=2.5 Hz, 1H), 8.55 (d, J=5.7 Hz, 1H), 8.37 (dd, J=8.8, 2.5 Hz, 1H), 8.30 (d, J=2.9 Hz, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.77-7.76 (m, 2H), 7.65 (d, J=2.4 Hz, 1H), 6.89 (dd, J=5.7, 2.4 Hz, 1H), 3.33 (s, 3H), 1.47 (s, 9H), 1.21 (s, 9H); MS (ESI) m/z: 521.3 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1)C>>[CH:11]1([CH2:10][S:9][C:4]2[C:3]([CH2:2][O:26][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])=[CH:21][C:22]=3[F:27])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12]1
Reactant: ClCc1cccnc1SCC1CC1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1
Product: O=C(O)CCc1ccc(OCc2cccnc2SCC2CC2)c(F)c1
Yield: 87 %

Procedure:
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 18 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.031 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.044 g, 86%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:31]4[C:27](=[O:37])[C:28]5[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:30]4=[O:32])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
In a 250 mL flask, 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-ol (3.00 g, 8.24 mmol), phthalimide (2.50 g, 17.3 mmol) and triphenylphosphine (5.20 g, 19.8 mmol) were diluted with tetrahydrofuran (30 mL). The reaction mixture was cooled to 0° C. and diisopropylazodicarboxylate (4.00 g, 19.8 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and loaded onto silica gel. The resulting slurry was purified by flash column chromatography using 10% ethyl acetate/petroleum ether as eluent to afford the title compound as white solid (2.50 g, 75%); mp 114-118° C.; 1H NMR (300 MHz, CDCl3) δ 8.53 (s, 1H), 8.07 (d, J=8.1 Hz, 2H), 7.86-7.76 (m, 4H), 7.72-7.66 (m, 2H), 7.37 (d, J=8.7 Hz, 2H), 7.31 (d, J=7.5 Hz, 2H), 3.77 (t, J=6.9 Hz, 2H), 2.75 (t, J=7.8 Hz, 2H), 2.08 (t, J=6.9 Hz, 2H); ES+API m/z 493 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[C:12]([Si:16]([CH3:31])([CH3:30])[O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:22]=1[CH:23]=O)([CH3:15])([CH3:14])[CH3:13].C[O-].[Na+]>CO>[C:12]([Si:16]([CH3:31])([CH3:30])[O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:22]=1/[CH:23]=[C:8](/[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:11])\[C:9]#[N:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1/C=C(\C#N)c1ccc(Cl)cc1F
Yield: 96.5 %

Procedure:
Step B In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (1.7 g, 10 mmol) was reacted with 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde (3.8 g, 12.5 mmol), methanolic solution (25 wt %) of sodium methoxide (2.5 mL, 11 mmol) in methanol (60 mL) at 50° C. for 3 h to give (Z)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a yellow oil (4.5 g, 80%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:35][CH:34]=1)[C:9](=[O:32])[NH:10][C@H:11]([C:20](=[O:31])[NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[O:30])[CH2:28][CH3:29])[N:26]=1)[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C@H:8]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:35][CH:34]=1)[C:9]([NH:10][C@@H:11]([C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C:20]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[O:30])[CH2:28][CH3:29])[N:26]=1)=[O:31])=[O:32]
Reactant: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(OCCN3CCOCC3)cc2)[C@@H](C)c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(OCCN3CCOCC3)cc2)[C@@H](C)c2ccccc2)n1
Reaction time: 2 h

Procedure:
{(R)-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-[(1S,2S)-2-phenyl-1-(4-propionyl-thiazol-2-ylcarbamoyl)-propylcarbamoyl]-methyl}-carbamic acid-tert-butyl ester (0.19 mmol) was dissolved in a 30% v/v solution of trifluoroacetic acid in dichloromethane (5 mL) at 0° C. After stirring for 2 hours the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was adjusted to pH=8 by the addition of solid sodium bicarbonate. The aqueous layer was again extracted with ethyl acetate (2×). The combined organic layers was dried over sodium sulfate, filtered and concentrated in vacuo to give crude (2S,3S)-2-{(R)-2-amino-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide which was used immediately and without further purification.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].CC(C)([O-])C.[K+].[Cl:24][C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1.Cl>CN(C=O)C>[ClH:24].[C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:25]3[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[N:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: O=C(O)c1ccc(-c2n[nH]c3ccccc23)o1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2nn(-c3nccc(C(F)(F)F)n3)c3ccccc23)o1

Procedure:
1.3 g (5.7 mmol) of 3-(5-carboxy-2-furyl)indazole together with 1.3 g (11.4 mmol) of potassium tert-butoxide were dissolved in 5 ml of dry DMF and admixed with 2-chloro-4-trifluoromethylpyrimidine dissolved in 5 ml of DMF. The mixture was stirred at 60° C. the hydrochloride was precipitated from the aqueous phase by addition of 1N hydrochloric acid. This gave 420 mg (25%) of the title compound. m.p.: 258-261° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10])=[CH2:2].C(=O)([O-])[O-:14].[K+].[K+]>C(Cl)(Cl)Cl>[O:14]1[CH2:2][CH:1]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: C=Cc1ccccc1S(N)(=O)=O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)c1ccccc1C1CO1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution consisting of 2-ethenylbenzenesulfonamide (1.5 g, 8.1 mmol) m-chloroperbenzoic acid (1.4 g, 8.1 mmol) and potassium carbonate (1.1 g, 8.1 mmol) in 150 ml of chloroform was stirred for 4 days at room temperature. The reaction was filtered and the filtrate was washed with saturated sodium bicarbonate. The organic layer was separated, dried and concentrated. The resulting oil was flash chromatographed (methylene chloride) to yield the subject compound as a white solid, m.p. 136°-139° C.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[C@@:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13]3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[CH2:2].Br[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=1.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:31][C:27]1[CH:26]=[C:25](/[CH:2]=[CH:1]/[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C@H:12]4[C@@:14]5([C:22]6[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=6)[NH:16][C:15]5=[O:23])[CH2:13]4)=[CH:9][CH:10]=3)[NH:5][N:4]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Cc1cc(Br)ccn1
Reactant: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(/C=C/c2n[nH]c3cc([C@@H]4C[C@@]45C(=O)Nc4ccccc45)ccc23)ccn1
Yield: 29.3 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-vinyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (60.2 mg, 0.2 mmol) and 4-bromo-2-methylpyridine (34.4 mg, 0.2 mmol) in DMF (2 mL) was added iPr2NEt (0.07 mL), followed by Pd(OAc)2 (2.2 mg, 0.01 mmol) and P(o-tol)3 (6.7 mg, 0.022 mmol). The resulting mixture was purged with argon, and then microwaved 2 h at 125° C. Purification by prep-HPLC gave the title compound as a yellow solid (23 mg, 23%). NMR indicated 7% of the branched isomer. 1H NMR (400 MHz, CD3OD) δ 8.53 (d, J=6.4 Hz, 1H), 8.13-8.03 (m, 4H), 7.59 (d, J=16.4 Hz, 1H), 7.53 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.56 (t, J=7.6 Hz, 1H), 5.97 (d, J=7.6 Hz, 1H), 3.56 (t, J=8.0 Hz, 1H), 2.77 (s, 3H), 2.25 (dd, J=7.6 Hz, J=4.8 Hz, 1H), 2.18 (dd, J=9.2 Hz, 4.8 Hz, 1H); MS ESI 393.2 [M+H]+, calcd for [C25H20N4O+H]+ 393.2.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[C@H:23]([CH2:34][OH:35])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[ClH:36]>C(Cl)(Cl)Cl.CCOCC>[ClH:36].[ClH:36].[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][NH:24][C@H:23]([CH2:34][OH:35])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1CO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: OC[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1
Temperature: 25 °C
Reaction time: 7 h
Yield: 60.7 %

Procedure:
The product from Step A (0.017 g, 0.036 mmol) was dissolved in CHCl3 (1.0 mL). HCl (0.27 mL, 1.1 mmol, 4.0M in dioxane) was added. The reaction stirred at ambient temperature for 7 hours. The reaction was diluted with Et2O (10 mL) and the mixture filtered. The solid was washed with Et2O and dried in vacuo to afford 0.0098 g (55%) of the desired product as an off-white solid. MS ESI (+) m/z 376.1 (M+1) detected.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])C(=O)O1>C1(OC2C=CC=CC=2)C=CC=CC=1>[I:21][C:18]1[CH:19]=[C:20]2[C:11](=[C:12]([C:13]([O:15][CH3:16])=[O:14])[CH:17]=1)[NH:10][CH:9]=[CH:5][C:6]2=[O:8]
Reactant: COC(=O)c1cc(I)ccc1NC=C1C(=O)OC(C)(C)OC1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc(I)cc2c(=O)cc[nH]c12
Temperature: 250 °C
Reaction time: 0.75 h
Yield: 87.8 %

Procedure:
Compound 98 (3.00 g, 6.96 mmol) was added under argon to refluxing diphenylether (20 mL). The mixture was stirred at 250° C. for 45 min. After cooling to room temperature, the crude mixture was chromatographed (SiO2). Diphenylether was first eliminated by elution with dichloromethane and the desired product was recovered using elution by gradient (CH2Cl2→CH2C2/EtOH (95/5, v/v)) to give compound 99 (2.01 g, 6.11 mmol) as a green solid. Yield 88%; Rf (SiO2, CH2Cl2/EtOH, 95/5, v/v) 0.31; mp 75-77° C.; IR (KBr) ν 1213, 1271, 1303, 1491, 1560, 1577, 1628, 1701, 3100-3300 cm−1; 1H NMR (200 MHz, CDCl3) δ 4.02 (s, 3H), 6.36 (dd, 1H, J=1.4, 7.6 Hz), 7.72 (dd, 1H, J=6.0, 7.6 Hz), 8.59 (d, 1H, J=2.2 Hz), 8.92 (d, 1H, J=2.2 Hz), 11.61 (se, 1H); ESI-MS m/z 329.7 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:26])[NH:5][C:6](=[O:25])[N:7]([CH:24]=1)[C@@H:8]1[O:23][C@H:12]([CH2:13][N:14](C)[CH2:15]C2C=CC=CC=2)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[C:4](=[O:26])[NH:5][C:6](=[O:25])[N:7]([CH:24]=1)[C@@H:8]1[O:23][C@H:12]([CH2:13][NH:14][CH3:15])[C@@H:10]([OH:11])[CH2:9]1)[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN(C)Cc3ccccc3)O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC)O2)c(=O)[nH]c1=O
Yield: 101.9 %

Procedure:
1.1 g of 2',5'-dideoxy-5-ethyl-5'-(N-methyl-N-benzylamino)uridine were taken up in 75 ml of ethanol and 1 g of palladium-on-carbon catalyst in 25 g ml of ethanol was added under a nitrogen atmosphere. The mixture was hydrogenated at room temperature and under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated to give 0.84 g of 2',5'-dideoxy-5-ethyl-5'methylaminouridine of melting point 145°-147° C.