Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:22])([O:20][CH3:21])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])=O.[NH4+].C(OCC)(=O)C>CO.[Pd]>[C:1](=[O:22])([O:20][CH3:21])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([F:12])=[CH:5][C:4]=1[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C1(C)CCCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Oc1cc(N)c(F)cc1C1(C)CCCCC1
Yield: 82.1 %

Procedure:
To a solution of 4-fluoro-2-(1-methylcyclohexyl)-5-nitrophenyl methyl carbonate 24.1 g, 77.5 mmol) in 220 mL of CH3OH was added Pd/C 10%, 9.6 g, then ammonium formate (26.7 g, 445 mmol) was portion-wise added to the above reaction mixture at room temperature until starting material is consumed. The mixture was filtrated and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica gel diluted with hexane:ethyl acetate=50:1 to give 5-amino-4-fluoro-2-(1-methylcyclohexyl)phenyl methyl carbonate as a red brown oil (17.9 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J=13.6 Hz, 1H), 6.51 (d, J=8.4 Hz, 1H), 3.89 (s, 3H), 3.43 (brs, 2H), 1.96-1.91 (m, 2H), 1.58-1.38 (m, 8H), 1.18 (s, 3H): MS m/z: 281.9 [M+H]+
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>>[CH:18]1([N:13]2[C:12]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[C:37]([F:38])[CH:36]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Fc1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1F
Yield: 47.9 %

Procedure:
The title compound (70 mg) was prepared according to Example 180 using 209 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 218 mg of 3,4-difluorophenylboronic acid. MS (ESI): exact mass calculated for C18H21F2N3, 317.17; found, m/z 318.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.45 (m, 1H), 7.36-7.32 (m, 1H), 7.18-7.17 (m, 1H), 4.49 (m, 1H), 3.43-3.41 (m, 2H), 3.21-3.19 (m, 2H), 2.80-2.78 (m, 2H), 2.15-1.87 (m, 6H), 1.66-1.61 (m, 2H).
Reaction SMILES: C1(C2N3C=CN=C(N)C3=C(I)[N:6]=2)CCC1.[CH3:16][O:17][C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]2[N:30]3[CH:31]=[CH:32][N:33]=[C:34](Cl)[C:29]3=[C:28]([I:36])[N:27]=2)[CH2:22][CH2:21]1)=[O:19]>>[CH3:16][O:17][C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]2[N:30]3[CH:31]=[CH:32][N:33]=[C:34]([NH2:6])[C:29]3=[C:28]([I:36])[N:27]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(N)nccn32)CC1

Procedure:
Prepared according to the procedure described above for 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine, except using trans-4-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclohexanecarboxylic acid methyl ester. 1H NMR (d6-DMSO): δ 7.65 (d, J=4.8 Hz, 1H), 6.96 (d, J=4.8 Hz, 1H), 6.52 (br s, 2H), 3.65 (s, 3H), 3.16 (m, 1H), 2.71 (m, 1H), 2.15-2.00 (m, 2H), 1.80-1.60 (m, 6H) MS (ES+): m/z 400.98 (100) [M+1].
Reaction SMILES: CC1(C)C(C)(C)OB(/[CH:9]=[CH:10]/[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)O1.I[C:26]1[C:34]2[O:33][CH2:32][C:31](=[O:35])[C:30]=2[CH:29]=[CH:28][C:27]=1[O:36][CH3:37].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[CH3:37][O:36][C:27]1[CH:28]=[CH:29][C:30]2[C:31](=[O:35])[CH2:32][O:33][C:34]=2[C:26]=1/[CH:9]=[CH:10]/[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:15][CH2:16]1
Reactant: COc1ccc2c(c1I)OCC2=O
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 25 °C
Yield: 27.2 %

Procedure:
A solution of tert-butyl (E)-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]piperidine-1-carboxylate (0.253 g, 0.750 mmol) in 1,4-dioxane (5 mL) was added with 7-iodo-6-methoxybenzofuran-3(2H)-one (0.198 g, 0.682 mmol) synthesized in Example B46, Step 2, 2 M aqueous sodium carbonate (0.680 mL, 1.36 mmol) and tetrakis(triphenylphosphine)palladium (0.0788 g, 0.0682 mmol), and the mixture was refluxed for 10 hours by heating. The reaction mixture was cooled to room temperature, and then added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was subjected to silica gel column chromatography (chloroform/methanol), and the resulting crude product was further purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (E)-4-[2-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)vinyl]piperidine-1-carboxylate (0.0692 g, 27%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:29])[CH3:28])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]([CH3:28])[CH3:29])[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:11]1
Reactant: CC(C)c1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc2c(cc1NC1CNC1)N1C(=NNC(=O)[C@H]1C)CO2

Procedure:
A solution of 3-(7-isopropyl-4(R)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 11) Rt=2.948 min.; 0.33 g, 0.77 mmol) in DCM (8 mL) and TFA (2 mL) was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-7-isopropyl-4(R)-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale yellow solid (Example #57-1, Enantiomer 1, SFC (Table 1, Method 11) Rt=3.79 min, 0.31 g, 92%). LC/MS (Table 1, Method 5) Rt=1.676 min.; MS m/z: 330 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[O:13])([O:3][CH3:4])=[O:2].[CH:14]([NH2:18])([CH2:16][CH3:17])[CH3:15]>O1CCCC1>[CH:14]([NH:18][C:12](=[O:13])[NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:1]([O:3][CH3:4])=[O:2])([CH2:16][CH3:17])[CH3:15]
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: CCC(C)N
Solvent: C1CCOC1
Product: CCC(C)NC(=O)Nc1ccccc1C(=O)OC

Procedure:
250 mg of 2-carbomethoxyphenylisocyanate (Compound II), prepared as described in Preparation I above, and 0.145 ml of sec-butylamine in dry tetrahydrofuran were stirred at room temperature for about 8 hours. The solvent was removed under reduced pressure and the resulting solid was recrystallized from ether and petroleum ether to give methyl 2-(3-sec-butylureido)-benzoate, m.p. 124°-124° C.; 'H NMR:(delta CDCl3); 0.95 (s, 3H, CH3CH2), 1,2(d, 3H, CH3CH), 1,5(m, 2H, CH3CH2), 3.8 (m, 1H, CH--N), 3.9 (s, 3H, OCH3), 4.6 (broad s, 1H, CONH--sec--Bu), 6.8, 7.2 (2 m, 2H, Ar--H), 8.0, 8.6 (2 dd, 2H, Ar--H), 10.3 (broad, 1H, ArNHCO).
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[CH2:4][CH2:3][NH:2]1.[CH:15]1([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2I)[CH2:17][CH2:16]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:15]1([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:2]2[CH2:3][CH2:4][C:5]3[S:9][C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[C:6]=3[C:1]2=[O:14])[CH2:17][CH2:16]1
Reactant: Ic1cnccc1C1CC1
Reactant: O=C1NCCc2sc3ccccc3c21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2c(sc3ccccc23)CCN1c1cnccc1C1CC1
Yield: 29.7 %

Procedure:
3,4-Dihydro-2H-benzo[4,5]thieno[3,2-c]pyridin-1-one (I-9d: 100 mg, 0.491 mmol) was reacted with 4-cyclopropyl-3-iodo-pyridine (I-73c: 133 mg, 0.65 mmol), 1,4-dioxane (3 mL), copper iodide (9.31 mg, 0.049 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (6.9 mg, 0.049 mmol) and potassium phosphate (313.3 mg, 1.47 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 46.8 mg of the product (29.8% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5]2[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:14][C:13]([C:4]1[C:5]2[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=[C:2]([Br:1])[CH:3]=1)=[O:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cc(Br)cc2c1NCCCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(Br)cc2c1NCCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To 7-bromo-2,3,4,5-tetrahydro-1H-1-benzazepine-9-carboxylic acid (8.53 g) dissolved in DMF (80 ml), were added potassium carbonate (13.8 g) and benzyl bromide (4.5 ml) and the mixture was stirred for 2 hours at room temperature. After the insoluble matter was filtered off and the filtrate was concentrated, a mixed liquid of ethyl acetate-benzene (1:1, 400 ml) was added to the residue, and the mixture was washed with water, dried over anhydrous sodium sulfate and then subjected to distilling off the solvent to give the intended compound 11.35 g (99.7%) as brown oily matter.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH:22]([C:33]([OH:35])=[O:34])[CH2:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)[C:16]1=[O:36].C([BH3-])#N.[Na+]>>[C:33]([CH:22]([N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C@H:15]([NH:14][CH:2]([C:3]([OH:5])=[O:4])[CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:16]1=[O:36])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)([OH:35])=[O:34]
Reactant: N[C@H]1CCCCN(C(Cc2c[nH]c3ccccc23)C(=O)O)C1=O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@H]1CCCCN(C(Cc2c[nH]c3ccccc23)C(=O)O)C1=O

Procedure:
Methyl 3-[3-indolyl]-2-oxopropionate (1.09 g) and α-t-Boc-L-lysine (0.246) are dissolved in ethanol solvent containing powdered 4 Å molecular sieves (1.87 g). A solution of sodium cyanoborohydride (0.189 g) in ethanol is added at room temperature over six hours. When reaction is complete, the solvent is removed and the residue is partitioned between ether and water. The aqueous layer is isolated and pH adjusted to 3.6. The crude product is extracted into ethyl acetate and purified by LH-20 chromatography. Ring closure to 3-(S)-t-butoxycarbonylamino-1-[1-carbomethoxy-2-(3-indolyl)ethyl]perhydroazepin-2-one is carried out as described in Example 3. Saponificaton of the methyl ester and subsequent formic acid treatment to remove the t-butoxycarbonyl protecting group yields 3-(S)-amino-1-[1-carboxy-2-(3-indolyl)ethyl]perhydroazepin-2-one. 2-Oxo-4-phenylbutyric acid and this caprolactam are condensed in the presence of sodium cyanoborohydride to yield 1-[1-carboxy-2-(3-indolyl)ethyl]-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one. The silylated mass spectrum shows a parent ion at 693 m/e [3TMS+477 MWt], and loss of CH3 =678 m/e is observed.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])C.O.[NH2:14][NH2:15]>C(O)C>[O:11]=[C:7]1[N:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[CH2:10][CH2:9][O:8]1
Reactant: NN
Reactant: CCOC(=O)CN1CCOC1=O
Solvent: O
Solvent: CCO
Product: NNC(=O)CN1CCOC1=O

Procedure:
As described for example 112a, (2-oxo-oxazolidin-3-yl)-acetic acid ethyl ester (Potts, Kevin T.; Bhattacharjee, Debkumar; Kanemasa, Shuji. Journal of Organic Chemistry (1980), 45(24), 4985-8) in ethanol was reacted with hydrazine hydrate (1.0 equivalent) at rt for 72 h. All volatiles were evaporated, the residue was chromatographed (SiO2, dichloromethane:methanol:aq.ammonia (25%)=90:10:1) and the title compound was obtained as a white solid (yield: 77%). MS: m/e=160.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[Cl:16][CH2:17][C:18](O)=[O:19].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:18](=[O:19])[CH2:17][Cl:16])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=C(O)CCl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCl)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)aniline (3.74 g, 16.3 mmol) in DCM (60 mL) was added chloroacetic acid (2.31 g, 24.4 mmol), EDC (5.0 g, 32.6 mmol) and DMAP (cat.). The reaction mixture was stirred at RT overnight. The contents were transferred to a separatory funnel and DCM layer was washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4. The crude product was purified by flash column chromatography using 3:1 Pet. Ether:DCM in. Purified product was isolated as a white solid weighing 3.67 g (yield: 74%).
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[C:11]([Cl:18])[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[OH:20])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:36](=[O:39])([O-])[O-:37].[K+].[K+]>O>[Cl:18][C:11]1[C:10]2[C:9](=[O:19])[C:8]3[CH:7]=[CH:6][C:5]4[O:20][CH:2]([C:36]([OH:37])=[O:39])[CH2:1][C:4]=4[C:17]=3[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)ccc2c(=O)c3c(Cl)cccc3oc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C1Cc2c(ccc3c(=O)c4c(Cl)cccc4oc23)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.3 %

Procedure:
A mixture of 4-allyl-8-chloro-3-hydroxy-9-oxo-9H-xanthene (15 g), m-chloroperbenzoic acid (14 g) and chloroform (1,000 ml) was stirred at room temperature for 5 hours and left to stand overnight. To the mixture, potassium carbonate (20 g) and water (500 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (2,000 ml) and, to the stirred solution, a mixture of chromium trioxide (15 g), water (90 ml) and concentrated sulfuric acid (26 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 8.0 g of 7-chloro-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 283°-286° C. This compound produced a mass spectrum having a molecular ion peak at m/e 316.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[C:14]([Cl:21])=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.C1COCC1>>[Cl:21][C:14]1[C:13]([B:22]([OH:27])[OH:23])=[CH:18][C:17]([O:19][CH3:20])=[CH:16][N:15]=1
Reactant: COc1cnc(Cl)c(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cnc(Cl)c(B(O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
2.5 M n-BuLi in hexane (3.7 mL, 9.3 mmol) was added slowly to a stirred premixed solution of 3-bromo-2-chloro-5-methoxypyridine (1.73 g, 7.8 mmol) and triisopropyl borate (2.1 mL, 9.3 mmol) in THF (10.0 mL, 122 mmol) at −78° C., and the resulting deep colored mixture was stirred at the same temperature for 1 h and then allowed to warm up to room temperature over 1 h. The reaction was quenched with 1 N NaOH(aq) and then some EtOAc. The separated aqueous layer was acidified with 5 N HCl until pH about 5 and then extracted with EtOAc (×2) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 2-chloro-5-methoxypyridin-3-ylboronic acid (1.0276 g, 71%) as a brown solid. LCMS (API-ES) m/z 188 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][OH:25])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C.S(=O)(=O)(O)O>CN(C)C=O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:25][C:27]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:34])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: O=C1CCCC(=O)O1
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CO
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CCCC(=O)O
Yield: 56.2 %

Procedure:
In 10 ml of dimethylformamide is dissolved 0.5 g of 16β-ethyl-17β-glycoloyloxy-4-estren-3-one, and 0.2 g of glutaric anhydride and then 0.3 ml of triethylamine are added to the above solution. The mixture is allowed to stand at room temperature (15°-25° C.) for 3 hours and poured into 20 ml of 10% aqueous sulfuric acid, followed by extraction with 100 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography, elution being carried out with 200 ml of ethyl acetate. The eluate is evaporated under reduced pressure to remove the solvent, giving a colorless oil, which is allowed to stand to give 0.37 g of the above-identified compound as a solid.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=4)[CH:11]=[C:10]([C:23]([NH:25][CH2:26][C:27]4[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=4[CH3:33])=[O:24])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:56].O>C(Cl)Cl>[Br:56][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:11]=[C:10]([C:23]([NH:25][CH2:26][C:27]3[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=3[CH3:33])=[O:24])[C:9]3[CH:8]=[N:7][N:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[C:14]=3[CH:13]=2)=[CH:20][CH:19]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CO)cc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CBr)cc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-(hydroxymethyl)phenyl)-1H-indazole-4-carboxamide (1.5 g, 3.2 mmol) in DCM (20 mL), triphenyl phosphine (1.33 g, 5.10 mmol) was added and stirred at room temperature for 10 min. CBr4 (1.69 g, 5.10 mmol) was then added portion-wise to it and the resulting solution stirred at room temperature overnight. After completion, water was added and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 6-(4-(bromomethyl)phenyl)-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (1.0 g, 58.8%).
Reaction SMILES: [CH3:1][N:2]([CH:28]([CH3:30])[CH3:29])[C:3]1[C:4]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH:28]([CH3:30])[CH3:29])[C:3]1[C:4]([C:17]2[O:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc(-c4ccccc4)o3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(5-phenylfuran-2-yl)quinoxaline-6-carboxylate (150 mg, 0.37 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (59.8 mg, 1.50 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(5-phenylfuran-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid (100 mg, 69%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:1][N:2]2[N:11]=[C:10]([CH:12]3[CH2:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:26])=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(C2CCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(C2CCC2)c2ccccc2c1=O

Procedure:
The product of Example 67A and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.57 (s, 1H), 8.31 (d, J=8.3 Hz, 1H), 7.83-8.03 (m, 3H), 7.42 (s, 4H), 4.05 (p, J=8.5 Hz, 1H), 3.70 (s, 2H), 2.21-2.44 (m, 4H), 2.02-2.14 (m, 1H), 1.78-1.87 (m, 1H); MS (ESI) m/z 368 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH:7]1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])=[O:5])[CH3:2]>Cl.O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH:7]1[CH2:16][N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC2(CC1CN1C(=O)c3ccccc3C1=O)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(=O)CC1CN1C(=O)c2ccccc2C1=O
Temperature: 75 °C
Reaction time: 18 h
Yield: 106 %

Procedure:
A solution of the above 7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid ethyl ester (0.44 g, 1.2 mmol) in a mixture of 1N hydrochloric acid (18 ml) and tetrahydrofuran (18 ml) was heated a 75° C. under nitrogen with stirring for 18 h. The tetrahydrofuran was removed in vacuo and the residue was extracted with dichloromethane (2×75 ml). The combined organic extracts were washed with a saturated sodium bicarbonate solution (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo affording 0.42 g (>100%) of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-oxo-piperidine-1-carboxylic acid ethyl ester as a solid.