Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:26]1([CH2:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:37]([C:36]3[CH:35]=[CH:34][C:33]([CH2:32][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:40][CH:39]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(c1ccccc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccccc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-[4-(1-phenyl-ethyl)-piperazin-1-yl]-pyridin-2-ylamine (0.060 g, 0.15 mmol) and EtOH (6.0 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.039 g, 0.19 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.60 ml, 0.60 mmol). The reaction mixture was stirred at 70° C. for 5 h, then allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel, the free-running powder was placed on a 10 g isolute silica column and elution with a gradient of methanol (0 to 9%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid which was triturated with diethyl ether. The precipitate was collected by filtration, successively washed with diethyl ether, water, diethyl ether, and dried (0.002 g, 3%). 1H-NMR (500 MHz, DMSO-d6) 1.37 (d, J=6.6 Hz, 3H, CHCH3), 2.38 (br s, 4H) and 3.59 (t, J=4.6 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.54 (br s, 2H), 2.63 (br s, 2H) and 3.65 (br s, 4H) piperazine N(CH2)2), 3.50 (q, 1H, CHCH3), 3.57 (s, 2H, C6H4CH2), 7.26 (m, 1H) and 7.37 (m, 4H) (PhH), 7.47 (d, J=8.9 Hz, 2H) and 8.13 (d, J=8.2 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 8.22 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.45 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:34]/[O:35]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:21]([O:23][CH:24]([O:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:25])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[OH-].[Na+]>C(O)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:34]/[OH:35])/[C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:21]([O:23][CH:24]([O:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:25])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C/C=C\C1=C(C(=O)OC(C)OC(=O)OCC)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: C/C=C\C1=C(C(=O)OC(C)OC(=O)OCC)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
A mixture of the product of Procedure 15 (1.55 g, 2.02 mmol) and 90% formic acid (3 ml) was stirred for 1 hr at room temperature and diluted with EtOAc-ice-water. The mixture was adjusted to pH 3.5 with 30% NaOH below 10° C. The organic layer was separated, washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel. The column was eluted with n-hexane-EtOAc and the fraction containing the desired product was evaporated to give 712 mg (67%) of the desired product.
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[C:19]([O:21][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:18]=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)CCBr
Reactant: CCCCCCCCOc1c(O)c2ccc(O)cc2oc1=O
Product: CCCCCCCCOc1c(O)c2ccc(OCCC(=O)OCC)cc2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-octyloxy-4,7-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-octyloxy-4-hydroxy-7-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([N+:14]([O-])=O)([CH2:12][OH:13])[CH2:10][OH:11])[C:5]([Cl:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[Cl:23][CH2:24][C:25](Cl)=[O:26].Cl.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:14][C:25](=[O:26])[CH2:24][Cl:23])([CH2:12][OH:13])[CH2:10][OH:11])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])C(CO)(CO)c1cc(Br)cnc1Cl
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: O=C(CCl)NC(CO)(CO)c1cc(Br)cnc1Cl
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 2-(5-bromo-2-chloro-pyridin-3-yl)-2-nitropropane-1,3-diol (904 mg, 3.21 mmol) in DCM (64 ml) was added pyridine (2.6 ml, 32.1 mmol), after cooling to −30° C. a solution of chloro-acetylchloride (1.022 ml, 12.84 mmol) in DCM (32 ml) was added within 10 min., the reaction mixture was stirred at −30° C. for 1.5 h. At −30° C. 1M HCl and DCM was added, the layers were separated, the aq. phase extracted with DCM and the combined organic layers washed with halfsaturated aq. NaHCO3 and halfsaturated aq. NaCl, dried with Na2SO4 and evaporated. The obtained per-acetylated product was dissolved in methanol (19.3 ml) and K2CO3 powder (222 mg, 1.6 mmol) added, the mixture was stirred at room temperature for 30 min. After addition of 1M HCl and TBME the layers were separated, the aq. layer was extracted with TBME, the combined organic layers were washed with halfsaturated aq. NaCl, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc 1:0 to cyclohexane/EtOAc 0:1) to provide the title compound as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](Br)[CH:20]=[CH2:21].[I-].[Li+].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH3:11][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:21][CH:20]=[CH2:19])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: CC(C(=O)OCc1ccccc1)c1ccccc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A solution of 2-phenyl-propionic acid benzyl ester (2.0 g, 8.32 mmol), allyl bromide (0.865 mL, 9.99 mmol), and lithium iodide (1 g) in tetrahydrofuran (15 mL) at 0° C. was treated dropwise with the lithium hexamethyldisilazide (9.99 mL, 1M in tetrahydrofuran, 9.99 mmol). The reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.31 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 1.56 (m, 3 H) 2.68 (m, 1 H) 2.85 (m, 1 H) 5.05 (m, 4 H) 5.59 (m, 1 H) 7.26 (m, 10 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[C:3]=1[CH:12]([CH3:14])[CH3:13].[CH2:15]([Mg]Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>[Ni].O1CCCC1>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[C:3]([CH:12]([CH3:14])[CH3:13])=[C:2]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Ni]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc(Cc2ccccc2)c(C(C)C)c(OC)n1

Procedure:
0.15 g of nickel catalyst of expanded formula Ni(Acac)2 is added, in a 0.25 liter three-necked Erlenmeyer flask rendered inert with nitrogen, at a temperature below 5° C. and in one step, to the mixture in solution of 15 g (0.07 mol) of the compound of Example 8, 150 ml of tetrahydrofuran and 34.6 ml (0.07 mol) of a 2M solution of benzylmagnesium chloride in tetrahydrofuran. The medium is brought back to ambient temperature and, at the end of the progression of the coupling, treated by addition of 50 ml of a 10% ammonium chloride solution. The upper organic phase is separated, washed with an additional 50 ml of a 10% ammonium chloride solution and then washed with water. The organic phase is evaporated to dryness in order to obtain an oily residue (boiling temperature under 5 mbar=140-150° C.) which is purified again by chromatography on silica gel, elution being carried out with toluene, in order to result in 3.2 g of 2,4-dimethoxy-5-(1-methylethyl)-6-(phenylmethyl)pyrimidine.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[CH:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[CH:17](=O)[CH2:18][CH3:19].C([BH3-])#N.[Na+]>>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:6]([NH:7][CH2:17][CH2:18][CH3:19])[C:5]([O:4][CH2:2][CH3:3])=[O:16])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(N)Cc1ccc(O)cc1
Reactant: CCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCNC(Cc1ccc(O)cc1)C(=O)OCC

Procedure:
In a similar manner to that described in Reference example 59(a), a reaction is carried out using DL-tyrosine ethyl ester hydrochloride, propionaldehyde and sodium cyanoborohydride and the reaction mixture is treated to afford the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20].C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])=[CH:4][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:30]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC(F)(F)F)c2)CCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1(c2cc(Br)c(N)c(OCC(F)(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.4 g, 8.3 mmol) in dry CHCl3 (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents were dried over Na2SO4, filtered and concentrated under educed pressure. The crude reaction mixture was purified by column chromatography to give ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (1.5 g) as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[C:3]12([C:13](=[O:39])[CH2:14][O:15][C:16]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([C@H:27]5[CH2:32][CH2:31][C@H:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[NH:18][N:17]=3)[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2>O1CCCC1.C(O)C>[C:3]12([CH:13]([OH:39])[CH2:14][O:15][C:16]3[CH:20]=[C:19]([C:21]4[CH:22]=[CH:23][C:24]([C@H:27]5[CH2:28][CH2:29][C@H:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[NH:18][N:17]=3)[CH2:12][CH:7]3[CH2:6][CH:5]([CH2:11][CH:9]([CH2:8]3)[CH2:10]1)[CH2:4]2
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(OCC(=O)C45CC6CC(CC(C6)C4)C5)n[nH]3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(OCC(O)C45CC6CC(CC(C6)C4)C5)n[nH]3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (38 mg, 0.1 mmol) was added to a solution of the product from Example 1F (25 mg, 0.05 mmol) in tetrahydrofuran (3 mL) and ethanol (3 mL) maintained at 0° C. The reaction was allowed to warm to room temperature over 30 min and then stirred at room temperature for 1 hour. After this time the reaction was quenched by addition of water (5 mL) and extracted with ethyl acetate. The organic extracts were combined and washed with water, brine, dried (MgSO4), filtered and concentrated to a brown oil which was purified via flash column (eluting with 15% ethyl acetate in hexanes) to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (m, 2H), 1.19 (t, J=7.32 Hz, 3H), 1.42-1.99 (m, 22H), 2.22 (d, J=6.71 Hz, 2H), 2.47 (m, 1H), 3.89 (dd, J1=10.38 Hz, J2=7.94 Hz, 1H), 4.02 (m, 1H), 4.06 (q, J=7.32 Hz, 2H), 4.24 (dd, J1=10.37 Hz, J2=2.74 Hz, 1H), 4.71 (s, 1H), 6.07 (s, 1H), 7.28 (d, J=8.24 Hz, 2H), 7.59 (d, J=8.24 Hz, 2H), 12.21 (br s, 1H); MS (ESI) m/z 507.4 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1>C(O)(=O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:4]2[C:5](=[C:9]([O:15][CH3:16])[CH:10]=1)[C:6]([OH:7])=[N:2][C:1]([NH:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1)=[CH:3]2
Reactant: COc1cc(CC#N)c(C(=O)O)c(OC)c1
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: COc1cc(OC)c2c(O)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 255.5 %

Procedure:
A mixture of 2-Cyanomethyl-4,6-dimethoxy-benzoic acid (1.75 g×3), 3-amino-5-methylpyrazole (1.5 g×3) in acetic acid (10 ml×3) were sealed in microwave process vial (20 ml×3). The mixture was heated at 140° C. for 30 minutes under microwave irradiation. The mixture was evaporated to oil, and the oil was dissolved in 1.5 ml MeOH. This solution was added dropwise to 50 ml water. After stirred for 1 hour, solid was collected and was purified by flash column chromatography to give product (6.07 g, 85%). LC-MS: m/e 301 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[CH3:14][CH2:15][Mg+].[Br-]>C1COCC1>[OH:1][C:2]1[N:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:14][CH3:15])=[CH:12][CH:13]=1
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)c1ccc(O)nc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 6-hydroxy-N-methoxy-N-methylnicotinamide (800 mg, 1.0 eq) in 20 mL anhydrous THF was added 3 M EtMgBr (6 mL, 4.0 eq) dropwise at 0° C. The reaction mixture was stirred at rt for 2 h., quenched with sat NH4Cl, and extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (320 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 12.13 (brs, 1H), 8.11 (d, J=2.4 Hz, 1H), 8.05 (dd, J=10.0 Hz, 2.8 Hz, 1H), 6.60 (d, J=9.6 Hz, 1H), 2.79 (q, J=7.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: CC(C)=[O:3].[Cl:5][C:6]1[C:7]2[O:25][CH:24]([CH2:26][OH:27])[CH2:23][C:8]=2[C:9]2[O:13][N:12]=[C:11]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[C:10]=2[CH:22]=1.S(=O)(=O)(O)O>[O-2].[Cr+6].[O-2].[O-2].O>[Cl:5][C:6]1[C:7]2[O:25][CH:24]([C:26]([OH:3])=[O:27])[CH2:23][C:8]=2[C:9]2[O:13][N:12]=[C:11]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[C:10]=2[CH:22]=1
Reactant: CC(C)=O
Reactant: OCC1Cc2c(c(Cl)cc3c(-c4c(F)cccc4F)noc23)O1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)C1Cc2c(c(Cl)cc3c(-c4c(F)cccc4F)noc23)O1
Reaction time: 9 h

Procedure:
To the stirred acetone (50 ml) solution of 2.8 g of the 5-chloro-3-(2,6-difluorophenyl)-7,8-dihydrofuro[2,3-g]1,2-benzisoxazole-7-methanol prepared in Example 20, a mixture of chromium (VI) oxide (3.0 g), water (7 ml) and concentrated sulfuric acid (4.2 g) was added dropwise over time, and the agitation was continued for 9 hours at room temperature. The insolubles were filtered off by suction and the acetone was distilled off. Water was added to the residue, and the solution was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 1.0 g of 5-chloro-3-(2,6-difluorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 239.5°-241° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 351.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)=[O:24])=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.21 min; [M+H]+=427.09.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.CCN(CC)CC.[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.Cl>C(Cl)Cl>[C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17]
Reactant: C#Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#Cc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Aminophenyl-acetylene (1.17 g, 10 mmol) was added to DCM (30 mL), and Et3N (2.8 mL, 20 mmol) was added thereto. (BOC)2O (2.3 g, 10 mmol) was added, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, 1N HCl was added, which was then extracted with EtOAc and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 20 %

Procedure:
Using cyclohexyl{1-ethyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}methanol (0.6 g) synthesized in Example 56(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.48 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.19 g, 19%) was obtained as a white solid.
Reaction SMILES: C[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[C:10]3[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:8]1[C:9]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[C:10]2[CH2:15][CH2:14][CH:13]([CH2:16][O:17][S:29]([CH3:28])(=[O:31])=[O:30])[N:11]2[N:12]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccnc4ccccc24)CCC3CO)n1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCC1CCc2c(-c3ccnc4ccccc34)c(-c3ccccn3)nn21
Reaction time: 0.5 h

Procedure:
A solution of [2-(6-methyl-pyridin-2-yl)-3-quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-methanol (30 mg, 0.07 mmol) and 4-dimethylaminopyridine (catalytic) in pyridine (0.2 mL) is cooled to 0° C. and treated with methanesulfonyl chloride (8 mL, 0.105 mmol) and stirred for 30 min. The mixture is stirred at room temperature for 30 min, diluted with ethyl acetate (20 mL), washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to yield the title compound, 30 mg (86%,) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@@H:38]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:39][N:40]2[CH:44]=[C:43]([CH2:45][OH:46])[N:42]=[N:41]2)[C:34]([F:51])=[CH:33][N:32]=1.OCC1N=NNC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:51][C:34]1[C:35]([NH:37][C@@H:38]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:39][N:40]2[CH:44]=[C:43]([CH2:45][OH:46])[N:42]=[N:41]2)=[N:36][C:31]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH:9]=2)=[N:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CC(C)(C)[C@@H](Cn1cc(CO)nn1)Nc1nc(Cl)ncc1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](Cn4cc(CO)nn4)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 115 °C

Procedure:
A solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.158 g, 0.380 mmol), (S)-(1-(2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutyl)-1H-1,2,3-triazol-4-yl)methanol, 217a, (0.100 g, 0.304 mmol) and K3PO4 (0.520 g, 2.440 mmol) in 2-methyl THF (8 mL) and water (2 mL) was degassed under a stream of nitrogen for 30 minutes. X-Phos (0.008 g, 0.018 mmol) and Pd2(dba)3 (0.006 g, 0.006 mmol) were added and the reaction mixture was heated at 115° C. in a pressure vial for 4 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO4), filtered concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-70% EtOAc/Hexanes gradient) to afford 120 mg of the desired product as a white foamy solid: 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.90 (d, J=3.0 Hz, 1H), 5.37 (m, 1H), 4.92 ? 4.83 (m, 1H), 4.78-4.69 (m, 2H), 4.44 (dd, J=13.9, 11.3 Hz, 1H), 2.32 (s, 3H), 1.11 (s, 9H); LCMS Gradient 60-98%, 0.1% formic acid, 7 minutes, C18/ACN, Retention Time=1.29 minutes (M+H) 583.33