Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].[N:30]1([C:34]([C:36]2[S:40][C:39](Cl)=[N:38][CH:37]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1>C(#N)C>[N:30]1([C:34]([C:36]2[S:40][C:39]([O:7][C:8]3[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:11]([NH:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)=[O:12])=[N:38][CH:37]=2)=[O:35])[CH2:31][CH2:32][CH2:33]1
Reactant: O=C(c1cnc(Cl)s1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)s2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 120 °C
Yield: 74.9 %

Procedure:
Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of 3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (159 mg, 0.5 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazole (152 mg, 0.75 mmol) in acetonitrile (5 mL) and the stirred mixture heated at 120° C. in a microwave reactor for 1 hour. The mixture was cooled to RT and ambient pressure, the acetonitrile evaporated in vacuo, the residue partitioned between water (25 mL) and ethyl acetate (50 mL), the organic layer washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with ethyl acetate, to give the desired product (181 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH2:11](N(CC)CC)[CH3:12].ClC(OCC)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH2:11][CH3:12])=[O:6]
Reactant: O=C(O)c1ccnc(F)c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccnc(F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 81.7 %

Procedure:
To a stirred solution of 2-fluoroisonicotinic acid (27) (1.00 g, 7.09 mmol) in anhydrous dichloromethane (30 mL) was added at 0° C., under argon, triethylamine (991 μL, 7.09 mmol). After 5 min, ethyl chloroformate (681 μL, 7.09 mmol) was added and the mixture was stirred at 0° C. for 5 min before addition of N-dimethyl-4-aminopyridine (DMAP, 86 mg, 0.71 mmol). The mixture was stirred at 0° C. for 4 h. After return back to room temperature, the solvent was evaporated under vacuum and the residue was chromatographed (Al2O3, CH2Cl2) to give ester 28 (0.98 g, 5.79 mmol) as a yellow liquid. Yield 82%; Rf (Al2O3, CH2Cl2) 0.90; IR (CCl4) ν 1096, 1210, 1299, 1409, 1572, 1735 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.39 (t, 3H, J=7.1 Hz), 4.40 (q, 2H, J=7.1 Hz), 7.47 (ddd, 1H, 3JH-F=2.4 Hz, J=0.8, 1.3 Hz), 7.72 (ddd, 1H, 5JH-F=1.8 Hz, J=1.3, 5.1 Hz), 8.33 (td, 1H, 4JH-F=0.8 Hz, J=0.8, 5.1 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Mg]Br>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: Br[Mg]c1ccccn1
Reactant: O=Cc1cccc(Br)c1F
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC(c1ccccn1)c1cccc(Br)c1F
Temperature: -78 °C
Yield: 22.4 %

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (0.250 g, 1.231 mmol) in THF (5.35 mL) cooled to −78° C. was added pyridin-2-ylmagnesium bromide (5.91 mL, 1.478 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr, then allowed to warm to room temperature slowly over 2 hr. The reaction quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2. Layers were separated. The aqueous phase was extracted with CH2Cl2 (2×). The organics were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount CH2Cl2 and chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 1-40% EtOAc in hexanes over 25 min, tr=16 min) gave the title compound (78 mg, 0.276 mmol, 22.45% yield) as a yellow residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[CH:25]1([CH2:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1COCC1>[CH:25]1([CH2:31][C:32]([NH:34][C:35](=[S:36])[NH:24][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[CH:15]=[C:16]([C:18]5[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=5)[S:17][C:10]=34)=[C:2]([F:1])[CH:3]=2)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(CC1CCCCC1)N=C=S
Solvent: C1CCOC1
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=S)NC(=O)CC4CCCCC4)cc3F)c2s1
Reaction time: 3 h
Yield: 36.2 %

Procedure:
To a suspension of 219 (50 mg, 0.145 mmol) in THF (1.5 mL) was added 2-cyclohexylacetyl isothiocyanate (40 mg, 0.22 mmol) [P. A. S. Smith and R. O. Kan. J. Org. Chem., 1964, 2261] and the reaction mixture was stirred for 3 hours transferred onto a flash chromatography column and eluted with EtOAc-MeOH mixture (19:1), to afford title compound 220a (27.5 mg, 31% yield) as a light yellow solid. Characterization of 220a is provided in the table 21.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Br:10])=[CH:8][C:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([Cl:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([C:4]1[C:9]([Br:10])=[CH:8][C:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([Cl:20])[C:5]=1[O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:2]=[CH2:3]
Reactant: C=CCc1c(Br)cc(Cc2ccc(OC)cc2)c(Cl)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCc1c(Br)cc(Cc2ccc(OC)cc2)c(Cl)c1O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 15 h
Yield: 85.6 %

Procedure:
To a solution of phenol 185 (2.29 g, 6.23 mmol) in DMF (30 mL) were added tert-butyldimethylsilyl chloride (1M in THF, 9.35 mL, 9.35 mmol), imidazole (1.3 g, 18.7 mmol) and catalytic DMAP. The mixture was stirred at 50° C. for 15 hours. The mixture was extracted with EtOAc/aq. 50% NaCl solution (100 mL/500 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 186 (2.57 g, 86%).
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[OH:7][C@H:8]([CH3:31])[C@H:9]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1)=[O:16])[C:10](OC)=[O:11].Cl>CO>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:15]([NH:14][C@H:9]([C:10]([NH:2][OH:3])=[O:11])[C@H:8]([OH:7])[CH3:31])=[O:16])=[CH:18][CH:19]=1)(=[O:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NO
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(C(=O)c2ccccc2)cc1)[C@@H](C)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)[C@H](NC(=O)c1ccc(C(=O)c2ccccc2)cc1)C(=O)NO
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
To a solution of hydroxylamine hydrochloride (121 mg, 1.74 mmol) in anhydrous MeOH (2.0 mL) at 0° C. under N2 atmosphere was added sodium methoxide (25 wt % in MeOH, 680 mg, 3.14 mmol). A precipitate was immediately observed and the cloudy white solution was stirred for 10 minutes at 0° C. A solution of methyl (2S,3R)-3-hydroxy-2-{[4-(phenylcarbonyl)phenyl]carbonylamino}butanoate (1) (534 mg, 1.56 mmol) in MeOH (3.0 mL) was added and the reaction stirred 3 h at 0° C., then warmed gradually to ambient temperature overnight (18 h total). Aqueous 0.5 M HCl (20 mL) was added and the solution extracted with 5:1 chloroform/isopropyl alcohol (4×40 mL). The organic layers were combined, dried over Na2SO4 and concentrated to give an orange foam. Purification by silica gel chromatography (increasing eluant polarity from 30:1 CH2Cl2/MeOH to 15:1 CH2Cl2/MeOH) afforded 228 mg (43%) of 4-benzoyl-N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}benzamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)OCC(C)C)[CH:5]=[CH:6][C:7]=1[I:8].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:27]([O:32][CH2:33][C@@H:34]1[O:36]C1)(=[O:31])CCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][C@H:33]([CH2:34][OH:36])[O:32][C:27]2=[O:31])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: CC(C)COC(=O)Nc1ccc(I)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of isobutyl 3-fluoro-4-iodophenylcarbamate (Org. Process Res. Dev. 2001, 5(1), 80-83, 5.00 g, 14.83 mmol) in dry tetrahydrofuran (59 mL) at −78° C. under nitrogen was treated with lithium hexamethyldisilazide (1.0M in tetrahydrofuran, 15.6 mL, 15.57 mmol) dropwise and stirred at −78° C. for 45 minutes. Then, (R)-glycidyl butyrate (2.21 mL, 15.57 mmol) was added dropwise, and the resulting mixture was stirred at −78° C. for 1 hour and at ambient temperature for 2.75 days. The reaction mixture was then quenched with saturated aqueous ammonium chloride (20 mL), diluted with water (20 mL) and the layers are separated. The aqueous phase was extracted with ethyl acetate (25 mL), and the combined organic phase was washed with water (25 mL) and saline (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product mixture was then chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient of methanol/methylene chloride (1/99-2/98), and those fractions with an Rf=0.25 by TLC (methanol/chloroform, 5/95) are pooled and concentrated to give the title compound, mp 116-117° C.; MS (ESI+) for C10H9FINO3 m/z 338 (M+H)+; [α]25D=−41 (c 0.98, DMSO)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH:5]=[CH:6][CH:7]=1.[OH:25]O>>[CH3:1][C:2]1[CH:3]=[C:4]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)c1
Reactant: OO
Product: Cc1cccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)c1

Procedure:
Prepared analogous to Example 2 from 6-[4-(3-methylphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [C:1]([C:3]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].C(N(CC)CC)C.[CH3:17][N:18]=[C:19]=[O:20]>C(#N)C>[C:1]([C:3]1([NH:9][C:19]([NH:18][CH3:17])=[O:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2]
Reactant: CN=C=O
Reactant: C#CC1(N)CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CC1(NC(=O)NC)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 g (8 mmol) 1-ethynylcyclohexylamine and 2 mL (15 mmol) triethylamine in 10 mL acetonitrile is combined at ambient temperature with 0.5 g (9 mmol) methylisocyanate. The colourless suspension is stirred overnight at ambient temperature and then evaporated down. The residue is taken up in dichloromethane and washed with aqueous potassium carbonate solution. The organic phase is dried and evaporated down. Yield: 1.4 g (colourless solid)
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].OCN([CH2:29][OH:30])C>C(Cl)Cl.N1C=CC=CC=1>[OH:4][CH2:5][CH:10]([CH2:29][OH:30])[NH:11][S:16]([C:7]1[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH:6]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1Oc1ccc(Cl)cc1Cl
Reactant: CN(CO)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(S(=O)(=O)NC(CO)CO)cc1Oc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(2,4-Dichlorophenoxy)-4-methylsulphonylaminobenzene-sulphonic acid chloride (1.8 g, 2.51 mmol) was dissolved in CH2Cl2 (5 ml) and at 0° C. added dropwise to a solution of bis(hydroxymethyl)methylamine (0.44 g, 4.8 mmol) in pyridine (20 ml). The mixture was stirred for 2 hours at 0° C. and then evaporated down. The residue was dried in vacuo and purified by chromatography (silica gel, chloroform/MeOH 19/1) Yield: 0.35 g=29% 13C (100 MHz, DMSO-d6) δ 150.17, 147.50, 138.39, 132.09, 130.34, 129.29, 129.10, 126.02, 123.25, 122.75, 122.51, 115.22, 60.36, 57.07, 40.94
Reaction SMILES: ClC(Cl)C.[NH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([C@@H]1COC(=O)N1[C:25](=[O:47])[C@H:26]([CH2:30][C:31]1[C:36]([Cl:37])=[CH:35][C:34]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:33][C:32]=1[Cl:46])[CH2:27][CH:28]=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:39]([O:38][C:34]1[CH:33]=[C:32]([Cl:46])[C:31]([CH2:30][C@@H:26]2[CH2:27][CH2:28][N:5]([N:6]3[CH2:11][CH2:10][O:9][CH2:8][CH2:7]3)[C:25]2=[O:47])=[C:36]([Cl:37])[CH:35]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: NN1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1N1CCOCC1
Yield: 8 %

Procedure:
Stir a mixture of dichloroethane (25 mL), N-aminomorpholine (0.204 g, 2 mmol), (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (1.064 g, 2 mmol) and sodium triacetoxyborohydride (1.266 g, 6 mmol) at room temperature for 12 hours. Bring the reaction to 60° C. and stir for 3 hours. Cool the reaction, dilute with dichloromethane, and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica with a 50 to 75% ethyl acetate in hexanes gradient to afford 0.07 g (80%) of the titled product. MS (m/z): 435 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([N:20]([CH3:19])[C:21]3[CH:22]=[CH:23][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:25][CH:26]=3)=[O:18])=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CNc1ccc(CN2CCCCC2)cc1
Product: CN(C(=O)/C=C/c1ccc(-c2ccc(Cl)cc2)cn1)c1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 143 starting from (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-acrylic acid (Z34b) and methyl-(4-piperidin-1-ylmethyl-phenyl)-amine. The crude product was purified by column chromatography (silica gel, dichloromethane/EtOH/conc. aqueous ammonia 50:10:0.1).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](Br)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27]([C:30]1[CH:38]=[C:37]2[C:33]([C:34]([Sn](CCCC)(CCCC)CCCC)=[N:35][N:36]2[CH3:39])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>CN(C=O)C.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.[Cu]I>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:34]3[C:33]4[C:37](=[CH:38][C:30]([S:27]([CH3:26])(=[O:28])=[O:29])=[CH:31][CH:32]=4)[N:36]([CH3:39])[N:35]=3)[N:15]=2)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(S(C)(=O)=O)ccc12
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ccc(S(C)(=O)=O)cc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (110 mg, 0.26 mmol) and 6-methanesulfonyl-1-methyl-3-tributylstannanyl-1H-indazole (crude from Step 3, 330 mg, 0.33 mmol) were dissolved in DMF (1.7 ml). The flask was evacuated and backfilled with argon and tetrakis(triphenylphosphine)palladium (0) (15 mg, 0.013 mmol) and copper (I) iodide (10 mg, 0.053 mmol) were added. The reaction mixture was stirred at 90° C. for 3 h then allowed to cool to room temperature overnight. The reaction was quenched with water and extracted with diethyl ether (2×) and EtOAc. The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 25 g silica gel with EtOAc/hexanes (gradient: 0-40% EtOAc) to afford 79 mg (55%) of 2-(6-methanesulfonyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light brown solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=2)[O:20][CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[C:15]2[C:10]([C:11]([C:33]([F:36])([F:35])[F:34])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:41]=[N+:42]=[N-:43])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:16]([C:17]2[CH:32]=[CH:31][CH:30]=[C:19]([O:20][CH2:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]4[NH:43][N:42]=[N:41][N:27]=4)=[CH:24][CH:23]=3)[CH:18]=2)=[C:15]2[C:10]([C:11]([C:33]([F:36])([F:34])[F:35])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(COc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)c2)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc2c(-c3cccc(OCc4ccc(-c5nnn[nH]5)cc4)c3)n(Cc3ccccc3)nc12

Procedure:
4-({3-[2-Benzyl-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}methyl)benzonitrile (37 mg, 1 eq) was treated with trimethylsilyl azide (21 μL, 2 eq) and di-n-butyltin oxide (5 mg, 0.3 eq) in toluene (2.5 mL) at 100° C. until full conversion. After cooling, most of the solvent was removed in vacuo and the residue was taken in methanol. Purification by flash chromatography, eluent 10% methanol in dichloromethane, afforded the title compound in 87% yleld.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([CH:17]=O)=[CH:10][CH:9]=2)=[O:4].[C:19]1([C@@H:25]2[CH2:27][C@H:26]2[NH:28][C:29]2[S:30][CH2:31][C:32](=[O:34])[N:33]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11](/[CH:17]=[C:31]1/[C:32](=[O:34])[N:33]=[C:29]([NH:28][C@@H:26]3[CH2:27][C@H:25]3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:30]/1)=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1
Reactant: COC(=O)c1cnc2ccc(C=O)cc2c1OC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)c1cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc2c1OC
Temperature: 150 °C
Yield: 29.9 %

Procedure:
To the suspension of 6-formyl-4-methoxy-quinoline-3-carboxylic acid methyl ester (example 1e, 100 mg, 0.4 mmol), 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one (example 1f, 93 mg, 0.4 mmol) and benzolic acid (5 mg, 0.04 mmol) in toluene (2 mL) were added and piperidine (5 uL, 0.04 mmol). The mixture was heated to 150° C. by microwave for 20 min. After cooling to room temperature, the solid was collected by filtration, washed with toluene and dried. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-10% methanol in methylene chloride in 30 min) afford 4-methoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carboxylic acid methyl ester (55 mg, 30%) as a light yellow solid. LC-MS m/e 460 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18]([O:20]CC)=[O:19])[C:15]2[N:23]=[CH:24][CH:25]=[CH:26][C:14]=2[C:13](=[O:27])[N:12]=1.[OH-].[Li+]>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:15]2[N:23]=[CH:24][CH:25]=[CH:26][C:14]=2[C:13](=[O:27])[N:12]=1
Reactant: CCOC(=O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2cccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1c(CCc2ccc(F)cc2F)nc(=O)c2cccnc21
Reaction time: 2 h
Yield: 76.6 %

Procedure:
Ethyl [2-[2-(2,4-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetate (Int. C1) (32.76 g, 1 equiv) was dissolved in ethanol (350 ml) and water (70 ml), cooled in ice, then aqueous lithium hydroxide (2M solution, 43.42 ml, 0.99 equiv) was added. Stirring was continued for 2 h at room temperature. The solution was concentrated in vacuo and the residue was redissolved in water (700 ml) and saturated aqueous sodium bicarbonate (50 ml), then washed with ethyl acetate (200 ml). The aqueous layer was acidified to pH 2 with 2M hydrochloric acid, and the precipitate was filtered off, washed with ice water (50 ml) and dried in vacuo (50° C., 16 h) to obtain the desired product (23.2 g).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6].[N:20]1([C:24]([C:26]2[CH:31]=[N:30][C:29](Cl)=[CH:28][N:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[N:20]1([C:24]([C:26]2[N:27]=[CH:28][C:29]([O:18][C:16]3[CH:15]=[C:10]([CH:9]=[C:8]([O:7][C@@H:5]([CH3:6])[CH2:4][O:3][CH:2]([F:19])[F:1])[CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])=[N:30][CH:31]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)COC(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@@H](C)COC(F)F)c1
Temperature: 140 °C
Reaction time: 5 h
Yield: 74.7 %

Procedure:
A mixture of methyl 3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxybenzoate (0.28 g, 1.01 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (201 mg, 1.01 mmol) and potassium carbonate (280 mg, 2.03 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours. The reaction mixture was reduced in vacuo, ethyl acetate (50 mL) added and the organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 20 to 70% ethyl acetate in isohexane, to give the desired compound as a colourless oil (330 mg). 1H NMR δ (CDCl3): 1.38 (d, 3H), 2.37 (quin, 2H), 3.90 (s, 3H), 3.93-4.04 (m, 2H), 4.26 (d, 2H), 4.61-4.70 (m, 3H), 6.25 (t, 1H), 6.95 (t, 1H), 7.43-7.44 (m, 1H), 7.49-7.50 (m, 1H), 8.32 (d, 1H), 8.85 (d, 1H); m/z 438 (M+H)+