Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:40]=[CH:39][C:21]2[CH2:22][CH2:23][C:24]3[C:25]([C:36]([NH2:38])=[O:37])=[N:26][N:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C:28]=3[C:20]=2[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:1][C:2]1[C:3]([C:14]([NH:17][C:18]2[CH:40]=[CH:39][C:21]3[CH2:22][CH2:23][C:24]4[C:25]([C:36]([NH2:38])=[O:37])=[N:26][N:27]([C:29]5[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=5)[C:28]=4[C:20]=3[CH:19]=2)=[O:16])=[N:4][C:5]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Reactant: O=C(O)c1nc(N2CCOCC2)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3nc(N4CCOCC4)ccc3Cl)cc1-2

Procedure:
The title compound was synthesized from 0.294 g of 3-chloro-6-morpholinyl-2-pyridine carboxylic acid (from step 1) and (0.258 g) of the title compound of example 244 by the same procedure used for Example 211 except that HATU was replaced by HBTU (BF4). The title compound is a brown solid (0.37 g, 84%), m.p. 252-254° C. Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (CDCl3): δ 2.95 (m, 2H), 3.12 (m, 2H), 3.48 (m, 4H), 3.88 (m, 4H), 5.39 (s, 1H), 6.65-6.82 (m, 3H), 7.16 7.18-7.23 (m, 3H), 7.43-756 (m, 3H), 7.62 (m, 1H), 9.18 (s, 1H). ESI mass spectrum for C28H25ClFN6O3+: 547 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:22][O:23][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14][C:13]3=[O:21].CC1C=CC(S(O[CH2:36][C@H:37]2[CH2:41][CH2:40][CH2:39][O:38]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[C:12]3([CH2:22][O:23][C:8]=2[CH:7]=1)[C:20]1[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[N:14]([CH2:36][C@H:37]1[CH2:41][CH2:40][CH2:39][O:38]1)[C:13]3=[O:21]
Reactant: CN(C)CCOc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CN(C)CCOc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
To a stirred solution of 6-[2-(dimethylamino)ethoxy]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.21 g, 0.64 mmol) in 2-butanone (10 mL) was added (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (0.20 g, 0.76 mmol) followed by cesium carbonate (0.63 g, 1.90 mmol) at 0° C. The mixture was stirred at ambient temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/methanol/ammonium hydroxide, 10/1/0.2) to give 6-[2-(dimethylamino)ethoxy]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.20 g, 76%): 1H NMR (300 MHz, CDCl3) δ 7.31-7.24 (m, 1H), 7.14-6.96 (m, 3H), 6.57 (d, J=8.3 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 6.36 (dd, J=8.3, 2.2 Hz, 1H), 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.31-4.19 (m, 1H), 4.00 (t, J=5.8 Hz, 2H), 3.94-3.63 (m, 4H), 2.68 (t, J=5.8 Hz, 2H), 2.97 (s, 6H), 2.09-1.63 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.1, 177.9, 162.0, 160.7, 142.9, 142.8, 132.5, 132.4, 128.7, 128.6, 123.7, 123.6, 123.5, 123.4, 123.2, 121.1, 121.0, 109.6, 109.4, 108.1, 97.2, 80.6, 80.5, 68.24, 68.2, 66.3, 58.2, 57.5, 45.9, 44.6, 44.5, 29.2, 28.9, 25.7, 25.5; MS (ES+) m/z 409.3 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[N-:11]=[N+:12]=[N-:13].[Na+]>>[N:11]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCCCCCCCBr
Agent: [Na+]
Product: [N-]=[N+]=NCCCCCCCCO
Temperature: 90 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
8-Bromo-octan-1-ol (2.61 g, 12.5 mmol) was dissolved in Dmf (30 mL) and sodium azide (0.89 g, 13.75 mmol) was added. The reaction was heated to 90° C. and stirred overnight. The solution was then cooled to room temperature and poured onto ice. The aqueous was extracted with DCM (3×200 mL) and the combined extracts were washed with brine (2×200 mL), then dried over MgSO4. The solution was filtered and the solvent was removed in vacuo to give a yellow oil, 1.99 g (93% yield);
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18](O)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:31][C:32]1[C:33](=[O:41])[N:34]([CH2:39][CH3:40])[CH:35]=[CH:36][C:37]=1[NH2:38].CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]2[NH:31][C:32]3[C:33](=[O:41])[N:34]([CH2:39][CH3:40])[CH:35]=[CH:36][C:37]=3[N:38]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCCC(C(=O)O)C1)OCc1ccccc1
Reactant: CCn1ccc(N)c(N)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccc2nc(C3CCCC(NC(=O)OCc4ccccc4)C3)[nH]c2c1=O
Temperature: 0 °C
Yield: 88 %

Procedure:
In a 100 mL round bottom flask, 3-benzyloxycarbonylamino-cyclohexanecarboxylic acid (0.53 g, 1.96 mmol), TEA (0.44 g, 4.31 mmol), and HOBt (0.53 g, 3.92 mmol) were added sequentially to a solution of 3,4-diamino-1-ethyl-1H-pyridin-2-one (0.30 g, 1.96 mmol) in DMF (15 mL) at room temperature. The solution was then cooled to 0° C., EDCI (0.75 g, 3.92 mmol) was added, and the reaction mixture was allowed to stir, with warming to room temperature. After stirring for 17 h, the reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2. The combined extracts were dried with MgSO4, and concentrated. The solid was rinsed with Et2O to give [3-(5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.68 g, 84% yield). The intermediate amide (0.43 g, 1.04 mmol) was dissolved in glacial acetic acid (6.26 g, 104.2 mmol) and heated at 120° C. for 2 days. After cooling to room temperature, the solvent was removed in vacuo and the crude product was purified by flash chromatography eluting with 3% MeOH in CH2Cl2 to give [3-(5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.22 g, 54% yield). 1H-NMR (DMSO): δ 7.35 (m, 6H), 6.53 (m, 1H), 5.01 (s, 2H), 3.99 (m, 2H), 3.43 (m, 1H), 2.86 (m, 1H), 2.07 (m, 1H), 1.83 (m, 3H), 1.42 (m, 3H), 1.20 (m, 3H), 1.17 (m, 1H). MS: calculated for C22H26N4O3+H 395.2; found: 395.4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][C:61]1[CH:66]=[CH:65][C:64]([CH2:67][NH2:68])=[CH:63][CH:62]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH2:67][C:64]3[CH:65]=[CH:66][C:61]([CH3:60])=[CH:62][CH:63]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: Cc1ccc(CN)cc1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 1-(4-methylphenyl)methanamine (63.8 mg, 0.526 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (190 mg) as a yellow solid. LC-MS (ES) m/z=459 [M+H]+.
Reaction SMILES: [C:1]([CH2:8][NH:9][C:10]1[C:11](=[CH:22][C:23]([O:26]CC2C=CC=CC=2)=[CH:24][CH:25]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>C1COCC1.C(OCC)(=O)C>[C:1]([CH2:8][NH:9][C:10]1[C:11](=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[C:12]([OH:14])=[O:13])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CNc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNc1ccc(O)cc1C(=O)O
Yield: 100.4 %

Procedure:
N-(Carbo-t-butoxymethyl)-5-benzyloxyanthranilic acid, benzyl ester (45.0 g, 101 mmol) was dissolved in 1:1 THF/ethyl acetate (1200 mL) in a 2 liter round bottom flask. The atmosphere was flushed with argon and 10% Pd/C (4.0 g) was added. The reaction atmosphere was replaced with hydrogen gas (4 purge-fill cycles) and the reaction mixture stirred under a balloon of hydrogen for 23 hours. The atmosphere was replaced with argon and the reaction mixture filtered through a pad of Celite, washing the Celite pad with methanol (250 mL). The solvents were removed in vacuo and the resulting yellow solid placed under high vacuum overnight to yield N-(carbo-t-butoxymethyl)-5-hydroxyanthranilic acid (27.1 g, 100% yield).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[Br:20][CH2:21][C:22](Br)=[O:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=1)[C:22](=[O:23])[CH2:21][Br:20])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Br)CBr
Reactant: CCCCNc1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCN(C(=O)CBr)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 3.42 g (19.2 mmol) of the compound of Example 532A in 20 ml toluene, was added 2.42 ml (30 mmol) pyridine. The mixture was cooled to 0° C.; 4.025 gm (20.0 mmol) of bromoacetyl bromide (diluted with 5 ml toluene) was added in a dropwise fashion. The reaction mixture was allowed to stir for 5 hours at 0° C. and then was allowed to warm to room temperature. Saturated potassium carbonate solution was added, and the mixture was stirred vigorously for 2 hours. The mixture was extracted with EtOAc; the organic layer was washed with 1N H3PO4, water, and brine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:29])[CH2:16][N:17]1[C:21]2=[CH:22][N:23]=[CH:24][CH:25]=[C:20]2[C:19]([C:26]([NH2:28])=[O:27])=[N:18]1)=[O:8].ClC1C=C(C=CC=1)C(OO)=[O:39]>C(O)(=O)C>[C:26]([C:19]1[C:20]2[C:21](=[CH:22][N+:23]([O-:39])=[CH:24][CH:25]=2)[N:17]([CH2:16][C:15]([N:10]2[C@H:9]([C:7](=[O:8])[NH:6][CH2:5][C:4]3[CH:30]=[CH:31][CH:32]=[C:2]([Cl:1])[C:3]=3[F:33])[CH2:14][C@@H:13]3[C@H:11]2[CH2:12]3)=[O:29])[N:18]=1)(=[O:27])[NH2:28]
Reactant: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cnccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Product: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2c[n+]([O-])ccc12
Temperature: 55 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2-((1R,3S,5R)-3-(3-chloro-2-fluorobenzylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 703, 100 mg, 0.21 mmol) in acetic acid (4 mL) was added 3-chlorobenzoperoxoic acid (58 mg, 0.34 mmol) at 55° C. The reaction mixture was stirred at 55° C. for 18 h and then cooled to RT. Volatiles were evaporated and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to afford the title compound as a white solid. MS: 487 [M+H]+; tR (HPLC conditions c): 3.44 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH3:58])[CH2:53][CH2:52]2)=[O:50])=[CH:44][CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[CH:44][C:45]([CH2:48][C:49]([N:51]6[CH2:52][CH2:53][N:54]([CH2:57][CH3:58])[CH2:55][CH2:56]6)=[O:50])=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CCN1CCN(C(=O)Cc2ccc(Br)cc2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CCN1CCN(C(=O)Cc2ccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)cc2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 2-(4-bromo-phenyl)-1-(4-ethyl-piperazin-1-yl)-ethanone (137 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 2-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-ethyl-piperazin-1-yl)-ethanone was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-185) as a yellow powder (92 mg, 47%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18]>CN(C=O)C.O>[CH3:21][O:20][C:16]([C:17]1[S:18][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=1)=[O:19]
Reactant: O=Cc1cnccc1Br
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cnccc2s1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-pyridine-3-carbaldehyde (1.50 g, 8.06 mmol) in DMF (10 mL) and water (1 mL) was added K2CO3 (1.34 g, 9.68 mmol) and methyl thioglycolate (0.87 mL, 9.68 mmol). The mixture was heated at 45° C. for 18 hours. The reaction mixture was removed from the heating bath and diluted with water (50 mL). After 1 hour, the fluffy solid that formed was filtered and washed with water. The material thus obtained was dried in a 60° C. vacuum oven to a constant weight of 0.92 g (59%). MS m/z 194 (M+H)+.
Reaction SMILES: CON(C)[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:15]=3[CH:27]=2)[CH:6]=1.[F:30][C:31]1[CH:32]=[C:33]([Mg]Br)[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[CH:12]=[CH:13][C:14]4[O:18][C:17]([CH2:19][CH2:20][N:21]5[CH2:25][CH2:24][CH2:23][C@H:22]5[CH3:26])=[CH:16][C:15]=4[CH:27]=3)[CH:6]=2)=[O:28])[CH:34]=[CH:35][CH:36]=1
Reactant: CON(C)C(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Reactant: Fc1cccc([Mg]Br)c1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(=O)c4cccc(F)c4)c3)ccc2o1
Yield: 46 %

Procedure:
The product from Example 145 and 3-fluorophenylmagnesium bromide were processed as described in Example 146 to provide the title compound (46% yield). MS (ESI APCI) m/z 428 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.17 (d, 3 H), 1.36-1.53 (m, 1 H), 1.72-1.86 (m, 2 H), 1.94-2.07 (m, 1 H), 2.22-2.33 (m, 1 H), 2.39-2.58 (m, 2 H), 2.93-3.14 (m, 2 H), 3.18-3.3 (m, 2 H), 6.62 (s, 1 H), 7.37-7.45 (m, 1 H), 7.49-7.52 (m, 2 H), 7.52-7.66 (m, 4 H), 7.72 (ddd, 1 H), 7.77 (dd, 1 H), 7.94 (ddd, 1 H), 8.02 (dd, 1 H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26](=[O:28])[CH3:27].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38]>>[C:26]([C:20]1[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=1[O:18][CH:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=1)[C:37]([O:39][CH3:40])=[O:38])(=[O:28])[CH3:27]
Reactant: CC(=O)c1cc(C)ccc1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: COC(=O)C(Oc1ccc(C)cc1C(C)=O)c1ccccc1
Yield: 62.8 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.67 mmol) of 2'-hydroxy-5'-methylacetophenone was alkylated with 1.68 g (7.34 mmol) of methyl 2-bromophenylacetate to afford 1.25 g (63%) of the title compound.
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CC(O)=O)[C:12](=[O:13])[CH:11]=C1.C([O:29]C(Cl)=O)C(C)C>C(N(CC)CC)C>[OH:29][C:17]1[CH:16]=[CH:15][C:14]([C:12](=[O:13])[CH3:11])=[CH:19][CH:18]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(O)cc1

Procedure:
Following the procedure of Example 1 but using 0.508 g. of PGA1, 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.309 g. of p-hydroxyacetophenone, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-hexane (2:3), followed by ethyl acetate-hexane (7:3). The residue obtained by concentration of selected fractions, 0.500 g., an oil, is the title compound, having Rf 0.4 (TLC on silica gel in ethyl acetate-hexane (1:1)).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[N:8]([CH3:15])[N:7]=1.[OH-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[N:8]([CH3:15])[N:7]=1
Reactant: COCCOc1cc(C(=O)OC)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCOc1cc(C(=O)O)n(C)n1
Yield: 96.4 %

Procedure:
Using methyl 3-(2-methoxyethoxy)-1-methyl-1H-pyrazole-5-carboxylate (3.03 g, 14.1 mmol), methanol (15 mL) and 8N aqueous sodium hydroxide solution (3.00 mL), and in the same manner as in Reference Example 58, the title compound (2.72 g, yield 96%) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([OH:11])=[C:7]([CH:10]=1)C#N)=[O:2].[OH:15][C:16]1C=CC(C=O)=C[C:17]=1[O:24]CCO>>[OH:11][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([CH:1]=[O:2])=[CH:10][C:7]=1[O:15][CH2:16][CH2:17][OH:24]
Reactant: O=Cc1ccc(O)c(OCCO)c1
Reactant: N#Cc1cc(C=O)cc([N+](=O)[O-])c1O
Product: O=Cc1cc(OCCO)c(O)c([N+](=O)[O-])c1

Procedure:
Followed procedure described for Intermediate 61, starting from the 4-hydroxy-3-(2-hydroxyethoxyl)benzaldehyde to give desired product, Intermediate 71.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:27][CH3:28])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[N:6]1.[OH:29]O>CO>[CH3:1][O:2][CH:3]([O:27][CH3:28])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:29])=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[N:6]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc2cnn(CC(OC)OC)c12
Reactant: OO
Solvent: CO
Product: COC(=O)c1cc(O)cc2cnn(CC(OC)OC)c12
Reaction time: 3 h

Procedure:
At room temperature, to a solution of methyl 1-(2,2-dimethoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-7-carboxylate (287 mg, 0.7 mmol) from Step E above in methanol (12 ml) was added 30% hydrogen peroxide (20.0 eq). The reaction mixture was stirred for 3 h, and then quenched with aqueous sodium sulfite. The mixture was extracted with ethyl acetate and washed with water. The organic extract was concentrated in vacuo to give methyl 1-(2,2-dimethoxyethyl)-5-hydroxy-1H-indazole-7-carboxylate as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.50 (d, J=2.5 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H), 4.90 (d, J=5.5 Hz, 2H), 4.86 (s, 1H), 4.52 (t, J=5.5 Hz, 1H), 3.97 (s, 3H), 3.27 (s, 6H); MS (ESI+) m/z 249 (M+H).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:15]=[CH:14][N:13]3[C:16]([CH3:29])=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[N:18]=[C:12]3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+].C(OCC)(=O)C.C(O)C.N>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:15]=[CH:14][N:13]3[C:16]([CH3:29])=[C:17]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:42])[NH2:28])=[CH:25][CH:26]=4)[N:18]=[C:12]3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C#N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccn2c(C)c(CCc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Yield: 62 %

Procedure:
Prepared analogously to Example 1 from 3-methyl-2-[2-(4-cyanophenyl)ethyl]imidazo[1,2-a]pyridin-7-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 62% of theory, C29H31N5O3 (497.60); Rf value: 0.23 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5); EKA mass spectrum: (M+H)+=498.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH3:15][O:16][C:17]1[CH:40]=[CH:39][C:20]([CH2:21][O:22][CH2:23][CH:24]([O:37][NH2:38])[CH2:25][CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22][CH2:23][CH:24]([O:37][NH:38][C:2]2[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=[C:6]([Cl:11])[C:7]=2[NH:8][CH:9]=[O:10])[CH2:25][CH2:26][O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[CH:39][CH:40]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: COc1ccc(COCCC(COCc2ccc(OC)cc2)ON)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(COCCC(COCc2ccc(OC)cc2)ONc2nc(NC=O)nc(Cl)c2NC=O)cc1

Procedure:
A solution of 4,6-dichloro-2,5-diformamidopyrimidine (3.27 g, 13.9 mmol), 1,4-bis(4-methoxybenzyloxy)but-2-oxyamine (5.06 g, 14 mmol) and triethylamine (5.88 ml, 42 mmol) in dioxan (100 ml) was heated at 100° C. for 90 minutes. The solution was allowed to cool, filtered and the solvent removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (30:1) to afford 6-[1,4-bis (4-methoxybenzyloxy)but-2-oxyamino]-4-chloro-2,5-diformamidopyrimidine as a pale yellow foam. 1H NMR: δH (CDCl3) 1.88 (2H, m, 3-H), 3.54 (4H, m, 1'-H and 4'-H), 3.73 (3H, s, CH3), 3.74 (3H, s, CH3), 4.07 (1H, m, 2'-H), 4.37 (4H, m, 2×ArCH2), 6.88 (4H, m, ArH), 7.21 (4H, m, ArH), 9.17, 9.27, 9.30, 9.43 (total 2H, 4×s, D2O exchange leaves s at 9.27, 2×HCO), 10.67 (1H, br.s, D2O exchangeable, NH) and 10.85 (1H, br.s, D2O exchangeable, NH).