Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@:18]3([CH3:29])[O:22][C:21]4=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:20]4[CH2:19]3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40].O>C(Cl)Cl>[CH3:29][C@@:18]1([CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:30])[F:31])=[CH:5][CH:6]=3)[C:39](=[O:41])[CH3:40])[CH2:12][CH2:13]2)[O:22][C:21]2=[N:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][N:20]2[CH2:19]1
Reactant: C[C@]1(CN2CCC(Nc3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(c1ccc(OC(F)(F)F)cc1)C1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
(S)-2-[4-(4-Trifluoromethoxyphenyl)aminopiperidin-1-yl]methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 282 (153 mg, 0.35 mmol) was dissolved in methylene chloride (5 ml). To the solution, triethylamine (30 μl) and acetyl chloride (30 μl) were added followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and crystallized from methylene chloride-diisopropyl ether to afford (S)-N-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]-N-(4-trifluoromethoxyphenyl)acetamide (82 mg, yield 49%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10]([Cl:12])=[N:11][C:7]=2[CH:6]=1)=[O:4].CCN(C(C)C)C(C)C.Cl[CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[C:10]([Cl:12])=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(Cl)nc2c1
Reactant: COCCOCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCn1c(Cl)nc2cc(C(=O)OC)ccc21
Reaction time: 18 h

Procedure:
To a mixture of 2-chloro-1H-benzoimidazole-5-carboxylic acid methyl ester (2.00 g, 9.50 mmol) and THF (17 mL) was added DIPEA (2.46 mL, 14.3 mmol) followed by 1-chloromethoxy-2-methoxy-ethane (1.30 mL, 11.4 mmol) at 23° C. After stirring for 18 h the reaction mixture was concentrated under reduced pressure. The residue was purified (FCC) (5-50% EtOAc/hexanes) to yield the titled compound as a mixture of regioisomers (1.71 g, 60%). MS (ESI/CI): mass calcd. for C13H15ClN2O4, 298.1; m/z found, 299.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.34-8.31 (m, 1H), 8.21-8.20 (m, 1H), 7.98 (dd, J=8.6, 1.6 Hz, 1H), 7.91 (dd, J=8.5, 1.6 Hz, 1H), 7.83 (dd, J=8.6, 0.5 Hz, 1H), 7.74 (dd, J=8.5, 0.5 Hz, 1H), 5.78 (s, 1H), 5.73 (s, 1H), 3.89 (d, J=6.3 Hz, 6H), 3.64-3.60 (m, 5H), 3.43-3.39 (m, 5H), 3.17 (d, J=2.6 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[CH3:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:29][OH:30].N1C=CC=CC=1.ClC(C(F)(F)F)=C[C@@H]1[C@H](C(OC)=O)C1(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:30][CH2:29][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:17]=2[CH3:16])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: Cc1c(CO)cccc1-c1ccccn1
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Agent: COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1c(COC(=O)[C@H]2[C@@H](C=C(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccn1

Procedure:
This reaction was conducted in the manner of Example 3, Step 2 using 0.58 g (0.002 mol) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride, 0.44 g (0.002 mol) of 2-methyl-3-(2-pyridyl)phenylmethanol, and 0.18 mL (0.002 mol) of pyridine in 30 mL of toluene. The yield of [2-methyl-3-pyridin-2-yl)phenyl]methyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate was 0.8 g, b.p. 170° C./0.05 mm.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[O:11]C.B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[OH:11]
Reactant: COc1cccc2cc(C)[nH]c12
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc2cccc(O)c2[nH]1
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 2-methyl-7-methoxy indole (814 mg, 5.0 mmol) in CH2Cl2 (20 mL) at 0° C. was added BBr3 (15 mL, 15 mmol, 1M in CH2Cl2), and then the ice bath was removed and stirring was continued for 3 h. Ice was added and the reaction mixture diluted with water (30 mL). The aqueous layer was extracted with EtOAc (3×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via passage through a short silica gel column (20% then 50% EtOAc/hex) to afford 2-methyl-7-hydroxy indole as an unstable solid (99% yield).
Reaction SMILES: C[N:2]([CH:4]=O)[CH3:3].O=P(Cl)(Cl)[Cl:8].[CH3:11][N:12]1[C:16]([OH:17])=[CH:15][C:14]([CH3:18])=[N:13]1.[OH-].[Na+]>ClCCCl.ClC(Cl)C.O>[Cl:8][C:4]1[N:2]([CH3:3])[N:13]=[C:14]([CH3:18])[C:15]=1[CH:16]=[O:17].[CH3:11][NH:12][NH2:13]
Reactant: Cc1cc(O)n(C)n1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Solvent: CC(Cl)Cl
Product: CNN
Product: Cc1nn(C)c(Cl)c1C=O
Temperature: 0 °C

Procedure:
To DMF (33.29 mL, 0.456 mol) was carefully added POCl3 (134.16 g, 81.5 mL 0.874 mol,) at 0° C. The reaction mixture was diluted with 1,2-dichloroethane (100 mL), then treated with a solution of crude 1,3-dimethyl-1H-pyrazol-5-ol (50 g, from Step 1) in dichloroethane (100 mL) under continued stirring at 0° C. The mixture was refluxed for 3 h, then left to stir overnight at room temperature. In order to decompose the formylating reagent, to the reaction mixture was added a solution of sodium hydroxide (91.2 g, 2.28 mol) in water (200 mL) dropwise at 0° C. The reaction mixture was diluted with water and extracted with dichloromethane (3×250 mL). The organic extracts were washed with water to neutral pH, washed with water, then dried with sodium sulfate. The solvent was removed under vacuum to afford the title product (31.1 g, 51% overall from methylhydrazine) as a yellow crystalline substance.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH3:37][O:38][CH2:39][CH:40]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH2:40][CH2:39][O:38][CH3:37])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCC=O
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCNCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC)[C@@H](O)[C@H]3O)c2n1
Yield: 36.2 %

Procedure:
The title compound was prepared by a similar method to example 5 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (320 mg, 0.63 mmol) (example 1), 2-methoxyacetaldehyde (53 mg, 0.63 mmol) and sodium triacetoxyborohydride (210 mg, 0.95 mmol) in tetrahydrofuran (22 ml). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (92:8:0.4) to give the title compound (125 mg) as a foam. MS: 548 (MH+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl.O>O1CCCC1.C(OCC)(=O)C>[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: c1nc[nH]n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1cncn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a suspension of sodium hydride (4.63 g, 0.12 mol) in tetrahydrofuran (150 ml) was added 1,2,4-triazole (8.0 g, 0.12 mol) at room temperature under nitrogen. The mixture was cooled to 0° C. and 2-(trimethylsilyl)ethoxymethylchloride (20.5 ml, 0.12 mol) added dropwise. The mixture was stirred at room temperature overnight, water (100 ml) was added and the mixture diluted with ethyl acetate. The organic layer was dried ((MgSO4) and evaporated in vacuo and the residue distilled to give the title-compound (14.6 g, 63%), bp 110° C. at 6 mm Hg; 1H NMR (250 MHz, CDCl3) δ 0.01-0.03 (9H, s, 3 of CH3), 0.93 (2H, m, CH2), 3.63 (2H, m, CH2), 5.52 (2H, s, CH2), 7.99 (1H, s, Ar—H), 8.26 (1H, s Ar—H).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH3:2].O.NN>C(O)C.[Ni]>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[CH3:18]
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN(CC)CCCOc1ccc(N)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of diethyl-[3-(4-nitro-phenoxy)-propyl]-amine (15.2 g, 60.4 mmol) is dissolved in absolute ethanol (350 mL) and to this solution is added hydrazine monohydrate (18 mL, 6 equiv.) followed by the addition of e small portion of Raney nickel. The reaction mixture is heated to 50° C. with stirring for 3 h until all gas evolution has ceased. The reaction mixture is filtered through celite to remove the Raney nickel. The filtrate is concentrated under reduced pressure to give the named compound as a greenish brown oil (quantitative). This material is carried on in subsequent steps without purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:18])[CH:10]([O:17][N:20]1[C:24](=[O:25])[C:23]2[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]1=[O:30])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(OCc1ccccc1)C(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C(ON1C(=O)c2ccccc2C1=O)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of benzyl-2-hydroxy-2-phenylacetate (2.42 g, 10 mmol), N-hydroxyphthalimide (1.96 g, 12 mmol) and PPh3 (3.4 g, 13 mmol) in CH2Cl2 (30 mL) was added DIAD (2.63 g, 13 mmol) at −20° C. The resulting mixture was stirred at −20° C. for 1 hour. The reaction mixture was concentrated and purified by flash chromatography (silica gel, Hexanes/CH2Cl2=1/3) giving 3.8 g (98%) of the title compound.
Reaction SMILES: [Si](I)(C)(C)C.[CH3:6][O:7][C:8](=[O:46])[C@@H:9]([NH:38]C(OC(C)(C)C)=O)[CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:30]4[O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:29]=4[CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH3:6][O:7][C:8](=[O:46])[C@@H:9]([NH2:38])[CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:30]4[O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:29]=4[CH:28]=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
TMS-I (870 mg, 0.63 mL, 4.35 mmol) was added dropwise to a stirred solution of (2R)-methyl-2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionate (2.24 g, 3.96 mmol) in anhydrous methylene chloride (50 mL). The reaction mixture was stirred at room temperature for 20-30 mins (TLC control), and then diluted with water (50 mL). Saturated sodium bicarbonate solution was added to adjust the solution to pH 8-9. The reaction mixture was extracted with diethyl ether (2×50 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5% methanol in methylene chloride as eluent, afforded the title compound has a pale yellow solid (1.76 g, 95%); Rf: 0.20 (5% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz): δ 8.00 (3H, d, J=8 Hz, Ar—H), 7.94 (1H, d, J=8 Hz, Ar—H), 7.76 (2H, d, J=9 Hz, Ar—H), 7.64 (4H, m, Ar—H), 7.34-7.51 (5H, m, Ar—H), 3.81 (2H, s, PhCH2S), 3.75 (3H, s, OMe), 3.67 (1H, m CHN), 2.91 (1H, dd, J=15, 5 Hz, CHHCHN), 2.86 (1H, dd, J=15, 8 Hz, CHHCHN), 1.91 (2H, s, NH2); ESI-LCMS e/z calcd for C29H25NO3S 467.586, found 468 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([O:20][Si](CC)(CC)CC)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=2)[NH:3]1.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37]Cl)[CH:32]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C1COCC1>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:12]([F:14])([F:15])[F:13])=[CH:6][CH:5]=3)[CH2:10][CH:2]2[CH3:1])[CH:32]=1
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2)(C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cccc(CCl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3CC2C)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 56.4 %

Procedure:
To a solution of 94 mg (0.23 mmol) of 2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole in 0.5 mL of DMF were added 104 mg (0.45 mmol) of 3-chloromethyl-benzoic acid methyl ester and the mixture was stirred at 80° C. for 10 hrs. After cooling to RT the mixture was treated with 0.5 mL of a 1M solution of TBAF in THF and stirred for an hour at 60° C. Evaporation of the solvent and chromatography on silica gel with EtOAc/n-heptane gave 58 mg (99%) of 3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-benzoic acid methyl ester, light red oil, MS: 448 (MH+).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[N:12]([O-:14])=O.[Na+].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)(=O)C.O>[NH2:19][C:17]1[S:18][CH:2]=[C:3](/[C:4](=[N:12]/[OH:14])/[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[N:16]=1
Reactant: NC(N)=S
Reactant: C=CCOC(=O)CC(=O)CCl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CCOC(=O)/C(=N\O)c1csc(N)n1
Yield: 48.1 %

Procedure:
A solution of 35.2 g of allyl 4-chloro-acetoacetate in 34 ml of acetic acid is treated dropwise within 45 minutes while stirring and cooling with a solution of 14.6 g of sodium nitrite in 21 ml of water. During the addition the temperature falls gradually from 0° C. to -15° C. The mixture is subsequently stirred at -15° C. for 2 hours. A solution of 15.2 g of thiourea in 120 ml of water, pre-warmed to 30° C., is treated with the resulting solution at such a rate that the temperature remains at about 30°-35° C. After stirring for an additional 7 hours, the crystalline precipitate obtained is filtered off, washed successively with water, acetonitrile and ether and crystallized from acetonitrile. There are obtained 21.8 g (48%) of allyl 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate of melting point 184°-185° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[CH2:18](Br)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH2:20][CH:19]=[CH2:18])([O-:3])=[O:2]
Reactant: C=CCBr
Reactant: CCOC(=O)C(C)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(C)C(=O)OCC)cc1[N+](=O)[O-]

Procedure:
A mixture of 2.39g of ethyl 2-(3-nitro-4-hydroxyphenyl)propionate, 1.45g of allylbromide and 1.65g of potassium carbonate in 20ml of acetone was refluxed for 4 hours. After cooling, the solvent was distilled under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. After the solution was dried over magnesium sulfate, the solvent was distilled off. The thus obtained oily substance was purified by means of silica gel chromatography, to give the object compound in a yield of 2.51g (90%).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=1.[C:33]([C:35]1[S:39][C:38](B(O)O)=[CH:37][CH:36]=1)#[N:34].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:33]([C:35]1[S:39][C:38]([C:2]2[C:7]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])[CH2:10][C:6]=3[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=2)=[CH:37][CH:36]=1)#[N:34]
Reactant: N#Cc1ccc(B(O)O)s1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(Cl)c3C2=O)c(OC)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(-c4ccc(C#N)s4)c3C2=O)c(OC)c1
Temperature: 160 °C

Procedure:
A solution of (R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanamide (114 mg, 0.245 mmol), 5-cyanothiophen-2-ylboronic acid (113 mg, 0.736 mmol), tris(dibenzylideneacetone)di-palladium(0) (13.47 mg, 0.015 mmol), and 2-(dicyclohexylphosphino)biphenyl (5.16 mg, 0.015 mmol) in dioxane (2 mL) and DMF (0.5 mL) was heated to 160° C. under microwave irradiation for 45 min. UPLC showed 50% conversion. The reaction mixture was subsequently heated at 160° C. under microwave irradiation for 45 min. Additional 5-cyanothiophen-2-ylboronic acid (113 mg, 0.736 mmol) was added and the reaction mixture was heated at 160° C. under microwave irradiation for 60 min. After removal of the solvent, the resulting crude material was reconstituted in MeOH/DMF (6.0 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (40-80% gradient, 0.035% TFA). The collected fractions were stripped to dryness via rotary evaporation to yield the title compound. [M+H] calc'd for C27H28FN5O4S, 538; found, 538.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([OH:22])=[O:21].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:20]([OH:22])=[O:21])=[CH:26][CH:27]=2)=[N:3][C:4]=1[C:9]1[N:10]([CH2:18][CH3:19])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccc(CCC(=O)O)cc3)cnc2N)nc2cnccc21
Temperature: 200 °C
Yield: 21.6 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 4-(2-carboxyethyl)benzeneboronic acid (0.039 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes. The reaction mixture was concentrated in vacuo and the residue purified by HPLC to give 0.0084 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](Cl)=[O:26].CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][CH:42]=[C:41]3[C:37]=2[CH:38]=[N:39][NH:40]3)O1>>[NH:40]1[C:41]2[C:37](=[C:36]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][C:25](=[O:26])[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=5)=[CH:8][C:6]=4[N:7]=3)[CH:44]=[CH:43][CH:42]=2)[CH:38]=[N:39]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=C(Cl)c1ccccn1
Product: O=C(NCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)c1ccccn1

Procedure:
(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 was acylated with picolinoyl chloride following General Procedure K and then reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (34 mg) following General Procedure A to give 287. MS (Q1) 472 (M)+