Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4](Br)([CH3:6])[CH3:5].[CH3:9][N:10]1[C:18]([CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:32]1[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N:34]=[C:33]1[CH3:41])=[N:14][C:15]=2[N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:5][C:4]([N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][C:18]2[N:10]([CH3:9])[C:11]3[C:16]([N:17]=2)=[C:15]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:14]=[C:13]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH3:41])[N:12]=3)[CH2:25][CH2:24]1)([CH3:6])[C:3]([O:2][CH3:1])=[O:8]
Reactant: COC(=O)C(C)(C)Br
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Product: COC(=O)C(C)(C)N1CCC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
Following General Procedure C, 2-bromo-2-methyl-propionoic acid methyl ester and 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine were reacted to give 507. LCMS m/z: 274.2 (2M+H)
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH2:28]([O:35][C:36](=[O:42])[C@H:37]1[CH2:41][CH2:40][CH2:39][NH:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[N:20]1([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([N:38]1[CH2:39][CH2:40][CH2:41][C@@H:37]1[C:36]([O:35][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:42])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
5.75 g (30.0 mmol) of EDCl was added to 60 ml of tetrahydrofuran (THF) solution of 3.23 g (15.0 mmol) of N-Boc-L-Proline (manufactured by Tokyo Chemical Industry Co., Ltd) and 3.08 g (15.0 mmol) of D-Proline benzylester, followed by stirring for 18 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), it was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1 (volume ratio)), thereby obtaining 4.55 g of the product with a yield of 75.4%.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7](=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:10]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[N:10]=[C:1]=[O:2])=[O:15]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1N=C=O
Yield: 100 %

Procedure:
Phosgene was bubbled through a solution of 10 g (66 mmol) of methylanthranilate in 15 ml of anhydrous toluene for 2 hours at reflux. Then the solvent was distilled off under reduced pressure to give 11.7 g (100%) of 2-methoxycarbonylphenylisocyanate; NMR (CDCl3) 3.89 (s, 3H, CH3); 7.0-7.63 (m, 3H, phenyl H-3,-4,-5); 8.0 (dd, 1H, phenyl H-6). This was converted to the title compound, in 34% overall yield, by condensation with an equimolar amount of 2-pyridylcarbinol followed by saponification of the resulting ester with 1 N sodium hydroxide and acidification of the reaction mixture to pH 4. The crude product was purified by crystallization from ethyl acetate; melting point=172-175° C.; NMR (DMSO-d6) 5.2 (s, 2H, methoxy CH2); 6.8-8.8 (m, 9H, aromatic, NH); 10.8 (broad s, 1H, OH).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.ClC(OCC)=O>C1COCC1.[Cl-].[Na+].O>[C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of BOC-(L)-proline in 60 ml of anhydrous THF, cooled at -10° C. with brine, is added with 6.1 ml of triethylamine and 1 g of 4 A molecular sieves, then, keeping the temperature below -5° C., a solution of 4.16 ml of ethyl chloroformate in 5 ml of anhydrous THF is dropped therein. After 30 minutes under stirring, the reaction mixture is filtered to remove the triethylammonium chloride precipitate and the filtrate is concentrated under reduced pressure to a volume of 30 ml. The resulting solution is dropped into a suspension of 7.5 g of sodium borohydride in 50 ml of anhydrous THF, cooled at -10° C. with brine. After 2 hours the reaction mixture is added with 200 ml of an aqueous saturated solution of sodium dihydrogen phosphate, keeping the temperature at 0° C. with water/ice, then it is extracted with ethyl acetate (3×50 ml). The combined organic extracts are washed repeatedly with an aqueous saturated solution of sodium bicarbonate (3×30 ml), dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue, by crystallization from hexane, yields 6.1 g of BOC-(L)-prolinol, m.p. 59°-60° C., [α]D =-54.9° (c=0.2 in EtOH).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:48]1[CH:53]=[CH:52][C:51]([CH2:54]O)=[CH:50][CH:49]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:54][C:51]3[CH:52]=[CH:53][N:48]=[CH:49][CH:50]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Reactant: OCc1ccncc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(Cc2ccncc2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
1,4-Diethylazodicarboxylate (205 μL) is added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41, triphenylphospine (341 mg), and 4-pyridylmethanol (273 mg) in THF (10 mL). The reaction mixture is stirred at room temperature for 20 h and then poured into 0.5 N aqueous NaOH solution (25 mL). The mixture is extracted with EtOAc (3×25 mL). The organic layer is dried (Na2SO4) and concentrated. The crude product is purified by column chromatography (CH2Cl2/methanol, 50/1; 20/1) followed by recrystallization from ethanol to afford 107 mg (21%) of the title compound as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2Cl)[C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[NH3:32].CO>>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([CH2:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH2:32])[C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1cnc2c(Cl)ncnc21
Solvent: CO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)Cn1cnc2c(N)ncnc21
Reaction time: 20 h
Yield: 67 %

Procedure:
A solution of 49 (4.2 g. 8.65 mmol) in 60 ml of 6M NH3/MeOH was sealed in a 100 ml Parr bomb and heated with stirring for 20 hrs. The reaction was cooled and concentrated to a white solid, which was re-crystallized from 10% ethyl acetate/hexane to afford 2.7 g (67%) of 50 as white crystals. 1H NMR (DMSO-d6): δ 8.10 (s, 1H), 8.02 (s, 1H), 7.16 (s, 2H), 4.18 (m, 1H), 4.06 (m, 1H), 4.00 (m, 1H), 3.53 (m, 2H), 2.29 (m, 1H), 1.16 (d, J=6 Hz, 3H), 0.84 (s, 9H), 0.79 (s, 9H), 0.01 (s, 6H), −0.10 (s, 6H).
Reaction SMILES: P([O-])([O-])([O-])=O.[Na].[F:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[C:12]([F:18])[CH:11]=[CH:10][C:9]=1[C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:41])[CH2:26][C:27]2[N:28]([CH3:40])[N:29]=[C:30]3[C:35]=2[C:34](=[O:36])[N:33]([CH3:37])[C:32](=[O:38])[N:31]3[CH3:39])[S:22][CH:23]=1.[P:42]([O:54][CH2:55]I)([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C=O)C>[P:42]([O:54][CH2:55][N:20]1[C:19]([C:9]2[CH:10]=[CH:11][C:12]([F:18])=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=2[F:7])=[CH:23][S:22][C:21]1=[N:24][C:25](=[O:41])[CH2:26][C:27]1[N:28]([CH3:40])[N:29]=[C:30]2[C:35]=1[C:34](=[O:36])[N:33]([CH3:37])[C:32](=[O:38])[N:31]2[CH3:39])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:43]
Reactant: CC(C)(C)OP(=O)(OCI)OC(C)(C)C
Reactant: Cn1nc2c(c1CC(=O)Nc1nc(-c3ccc(F)c(C(F)(F)F)c3F)cs1)c(=O)n(C)c(=O)n2C
Agent: O=P([O-])([O-])[O-]
Agent: [Na]
Solvent: CN(C)C=O
Product: Cn1nc2c(c1CC(=O)N=c1scc(-c3ccc(F)c(C(F)(F)F)c3F)n1COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared according to the general procedure as described in step 2 of method B for the preparation of phosphate derivatives by the reaction of sodium salt of N-(4-(2,4-difluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)-2-(2,5,7-trimethyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl)acetamide (500 mg, 0.93 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (Intermediate 2) (489 mg, 1.39 mmol) dry DMF (5 ml) to yield 460 mg of product as a white solid. The title compound was also prepared according to the general procedure as described in method A by coupling of N-(4-(2,4-difluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)-2-(2,5,7-trimethyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl)acetamide (2.50 g, 4.86 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (Intermediate 2) (5.95 g, 17.02 mmol) in the presence of sodium hydride (60% dispersion in mineral oil, 291 mg, 7.29 mmol) in dry DMF (25 ml) to yield 1.35 g of pure product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 1.44 (s, 18H), 3.34 (s, 3H), 3.51 (s, 3H), 3.92 (s, 3H), 4.74 (s, 2H), 6.44 (d, J=9.6 Hz, 2H), 7.09 (t, J=9.3 Hz, 1H), 7.51 (s, 1H), 8.45 (q, J=9.0 Hz, 1H). ESI (m/z): 736.56 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=O)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.B.C1COCC1>CO>[CH:1]1[CH:2]=[C:3]([CH2:10][C:12]2[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: N#Cc1ccc(C(=O)c2ccc3ccccn23)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(Cc2ccc3ccccn23)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To 4-(indolizine-3-carbonyl)-benzonitrile (24 g, 100 mmol) CH3CN (600 ml) solution containing MeOH (9 ml) was added BH3-THF (1M, 480 ml). The resulting mixture was stirred at 50° C. for 1 hr. The reaction was quenched with water (200 ml), and extracted with EtOAc (700 ml), and washed with water (300 ml×3). The organic layer was evaporated under reduced pressure, and the residue was dissolved in ether (or EtOAc) (400 ml), diluted with hexanes (100 ml) and filtered with celite to give 4-indolizin-3-ylmethyl-benzonitrile (15.6 g, 92% purity by HPLC). This product was used directly for the next step. δ (ppm) 8.54 (m, 1H); 7.59 (m, 3H); 7.39 (m, 2H); 7.31 (m, 1H); 7.19 (m, 1H); 3.01 (t, J=6.9 Hz, 2H); 2.75 (t, J=6.9 Hz, 2H). ESMS calcd. (C16H12N2): 232.1. found: 233.1 (M+H)+.
Reaction SMILES: C[O-].[Na+].C([O:7][C:8]1[CH:22]=[CH:21][C:11]2[O:12][C:13]([C:16]([O:18][CH2:19]C)=[O:17])=[CH:14][O:15][C:10]=2[CH:9]=1)(=O)C>CO>[OH:7][C:8]1[CH:22]=[CH:21][C:11]2[O:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][O:15][C:10]=2[CH:9]=1
Reactant: CCOC(=O)C1=COc2cc(OC(C)=O)ccc2O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=COc2cc(O)ccc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
Add 3.8 mmol of a 2M solution of sodium methanolate to a solution of 0.38 mmol of ethyl 6-acetoxy -1,4-benzodioxin-2-carboxylate in 5 cm3 of anhydrous methanol. After stirring for 4 hours at room temperature and neutralising with acid Dowex resin, the reaction mixture is concentrated under reduced pressure and the crude product obtained is purified by chromatography on a silica column (eluant:petroleum ether/diethyl ether, 80:20). Methyl 6-hydroxy -1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 87%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24].O>C(OCC)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]([CH:23]=[O:24])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(OCc2ccccc2)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=Cc1ccc(OCc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 2-benzyloxy-5-bromopyridine described in Manufacturing Example 231-1-1 (53.0 g, 201 mmol) in diethyl ether (500 mL) was added n-butyl lithium (82.8 mL, 2.67 M n-hexane solution, 221 mmol) was added dropwise on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 30 minutes at −78° C. While cooling at the same temperature, N,N-dimethylformamide (17.6 g, 241 mmol) was added to this reaction mixture, which was stirred for 30 minutes. Water and ethyl acetate were added to the reaction mixture, which was stirred for 10 minutes at room temperature, the organic layer was then separated. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5 then 1:4) to obtain the title compound (36.8 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.CN(C)[CH:10]=[CH:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=O>C(O)(=O)C>[CH3:7][C:5]1[N:6]=[C:2]2[N:1]=[CH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)[N:3]2[N:4]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: Cc1nc(N)n[nH]1
Solvent: CC(=O)O
Product: Cc1nc2nccc(-c3cccc(C(F)(F)F)c3)n2n1

Procedure:
A mixture of 0.49 g. of 3-amino-5-methyl-1,2,4-triazole and 1.26 g. of 3-dimethylamino-3'-trifluoromethylacrylophenone in 25 ml. of glacial acetic acid refluxed for 16 hours. The resulting mixture is worked up as described in Example 54 to give the product of the Example, m.p. 153°-154° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](OCC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CCc1ccccc1
Yield: 97 %

Procedure:
To a solution of 10 g of ethyl phenylacetate in 100 mL of dry toluene cooled to −78° C. under nitrogen was added drop-wise 68 mL of 0.9 M di-isobutyl-aluminum hydride in toluene, keeping the internal temperature below −68° C. When the addition was complete, the reaction was quenched with 200 mL of 10% HCl, and extracted into 2×100 mL portions of ether. The combined ether layers were washed with 2×100 mL portions of 10% HCl, 100 mL of saturated sodium bicarbonate, diluted with 100 mL of toluene, and dried over magnesium sulfate. Concentration under reduced pressure gave 7.1 g of phenyl acetaldehyde as a volatile liquid. 1H NMR (400 MHz, CDCl3) 9.8 (s, 1H), 7.5-7.2 (m, 5H), 3.7 (s 2H). To a stirred mixture of 10 g of trans-2-(4-(tert-butyl-dimethyl-silyloxy-cyclohexyl)-isoindole-1,3-dione (Compound 2), 150 mL of anhydrous acetonitrile, 7 mL of triethylsilane and 0.7 g of bismuth tribromide was added 5 g of the freshly prepared phenyl acetaldehyde slowly keeping the temperature at or below 25° C. by means of a cooling bath. After stirring for 2 h, the reaction was quenched with 50 mL of saturated sodium bicarbonate and extracted with 3×150 mL portions of ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography over silica gel eluting with a gradient of 2%-25% ethyl acetate in hexane gave 9.0 g of product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) 7.8 (m, 2H), 7.7 (m, 2H), 7.3-7.1 (m, 5H), 4.15 (m, 1H), 3.7 (t, 2H), 3.38 (m, 1H), 2.9 (t, 2H), 2.22 (d, 2H), 2.3 (dd, 2H), 2.18 (d, 2H), 1.78 (d, 2H), 1.4 (dd, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([NH:53][C:54]2[C:59]([N+:60]([O-])=O)=[CH:58][N:57]=[C:56]3[N:63]([S:66]([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)(=[O:68])=[O:67])[CH:64]=[CH:65][C:55]=23)[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[C:40]([O:44][C:45]([N:47]1[CH2:48][CH2:49][CH:50]([NH:53][C:54]2[C:59]([NH:60][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:58][N:57]=[C:56]3[N:63]([S:66]([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)(=[O:67])=[O:68])[CH:64]=[CH:65][C:55]=23)[CH2:51][CH2:52]1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(NC(=O)CC#N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Cyanoacetic acid (0.134 g, 1.58 mmol), HATU (0.600 g, 1.58 mmol), and diisopropylethylamine (0.300 ml, 1.72 mmol) were added sequentially to a solution of 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.677 g, 1.44 mmol, prepared as described in Example 115) in a 6:1 mixture of CH2Cl2 and DMF (7 ml) at 25° C. The reaction mixture was stirred for 14 h at 25° C., then saturated NaHCO3 (7 ml) was added and the mixture was vigorously shaken by hand for 1 min. The phases were separated using a phase separation column (Biotage) and the organic layer was concentrated under reduced pressure to give crude 4-[1-benzenesulfonyl-5-(2-cyano-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester as a brown oil. LCMS (Method G, ESI): RT=0.99 min, m+H=539.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C@@H:13]([C:15]1[S:19][C:18]([C:20]([O:22]C(C)(C)C)=O)=[CH:17][CH:16]=1)[CH3:14])=[O:11].FC(F)(F)C(O)=O.CN(C([O:41][N:42]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Si](ON)(C(C)(C)C)(C)C.Cl>CS(C)=O.C(Cl)Cl>[OH:41][NH:42][C:20]([C:18]1[S:19][C:15]([C@H:13]([NH:12][C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[O:11])[CH3:14])=[CH:16][CH:17]=1)=[O:22]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@H](NC(=O)c1cc2ccccc2s1)c1ccc(C(=O)OC(C)(C)C)s1
Agent: CC(C)(C)[Si](C)(C)ON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@@H](NC(=O)c1cc2ccccc2s1)c1ccc(C(=O)NO)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
To the vial containing crude (R)-tert-butyl 5-(1-(benzothiophene-2-carboxamido)ethyl)thiophene-2-carboxylate from Step 2 was added DCM (4 mL) and trifluoroacetic acid (0.43 mL, 5.6 mmol). The mixture was stirred at rt for 16 h and then completely evaporated to give an oil residue. To the residue was added HATU (0.160 g, 0.42 mmol), triethylamine (0.39 mL, 2.80 mmol), and DCM (4 mL). After stirring at rt for 30 min, O-(tert-butyldimethylsilyl)hydroxylamine (0.083 g, 0.56 mmol) was added. The mixture was stirred at rt for 2 h then the solvent was completely removed to give a sticky brown oil. To this oil residue was added hydrochloric acid (6.0 mL, 1% v/v in IPA). After stirring at rt for 30 min, the mixture was evaporated to dryness to give a solid to which was added DMSO (1.1 mL). The solution was filtered and purified by Gilson prep-HPLC [25-50% MeCN—H2O] to give the title compound (0.0098 g, 10.1%) as a white solid. LC-MS: (FA) ES+ 347; 1H NMR (Methanol-d4, 400 MHz) δ 8.00 (s, 1H), 7.89 (m, 2H), 7.42 (m, 3H), 7.06 (d, J=4.0 Hz, 1H), 5.51 (q, J=7.5 Hz, 1H), 1.69 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:4]1[N:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:8]2=[N:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:12]=[C:7]2[CH2:6][CH2:5]1)[CH:2]=[CH2:3].N#N.[C:37]([O:43][CH2:44][CH3:45])(=[O:42])[CH2:38][CH2:39]C=C>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.[Cu]I>[CH2:44]([O:43][C:37](=[O:42])[CH2:38][CH2:39][CH:3]=[CH:2][CH2:1][CH:4]1[N:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:8]2=[N:9][C:10]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:12]=[C:7]2[CH2:6][CH2:5]1)[CH3:45]
Reactant: C=CCC1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N1C(=O)OC(C)(C)C
Reactant: C=CCCC(=O)OCC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: [Cu]I
Agent: N#N
Solvent: ClCCl
Product: CCOC(=O)CCC=CCC1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2N1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Tert-butyl 6-allyl-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 2)(97 mg, 0.213 mmol) in DCM (3 ml) degassed with N2 was treated with ethyl pent-4-enoate (0.036 ml, 0.255 mmol), copper(I) iodide (4.05 mg, 0.021 mmol) and Grubbs (II) catalyst (9.04 mg, 10.65 μmol). After stirring at 40° C. for 4 hours, the mixture was concentrated under reduced pressure and purification by chromatography on silica eluting with 0-10% EtOAc in iso-hexane afforded the titled compound as a brown oil;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1
Reactant: COc1ccc(Br)cc1CC(=O)O
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (5-bromo-2-methoxyphenyl)acetic acid (20.0 g, 81.6 mmol) in THF (400 mL) cooled to 0°, followed by dropwise addition of 1M BH3.THF in THF (122.4 mL, 122.4 mmol). After addition is complete, the solution is warmed to room temperature and stirring is continued for 1 hour. At this time, the reaction is cooled back to 0° and quenched with water (50 mL). The mixture is concentrated to 80 mL in vacuo, and the residue is extracted with EtOAc (3×150 mL). Te combined organic phase is washed with water (1×50 mL) and brine (1×50 mL), dried over MgSO4, and concentrated in vacuo to give 2-(5-bromo-2-methoxyphenyl)-1-ethanol.