Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].[I:22]I>CO>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[C:13]([I:22])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(N)c(I)c1
Yield: 46.5 %

Procedure:
To a mixture of (4-amino-benzyl)-carbamic acid tert-butyl ester (4.8 g, 21.6 mmol) and calcium carbonate (2.7 g, 27 mmol) in methanol (60 mL) was added iodine (5.5 g, 21.6 mmol) in portions. The mixture was heated at reflux overnight and then concentrated in vacuo to give a dark brown residue, which was partitioned between ethyl acetate and saturated sodium bisulfite solution. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by chromatography (5%-20% ethyl acetate in hexanes) to give 3.5 g (47%) of the desired product as a brown semi-solid. MS(APCI+): m/z 349.1 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[F:16][C:17]1[CH:18]=[CH:19][C:20]([S:26][CH3:27])=[C:21](B(O)O)[CH:22]=1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:18]=[C:17]([F:16])[CH:22]=[CH:21][C:20]=2[S:26][CH3:27])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CSc1ccc(F)cc1B(O)O
Product: CSc1ccc(F)cc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
Essentially prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (270 mg, 1.10 mmol) and 5-fluoro-2-(methylthio)phenylboronic acid to give 4-chloro-5,7-difluoro-2-(5-fluoro-2-(methylthio)phenyl)-3-methylquinoline. Mass Spectrum (ESI) m/e=354.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C:14]1([C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[SH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N+:11]([C:8]1[N:6]2[N:7]=[C:2]([S:21][C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
8.0 g (40.3 mmol) of 6-chloro-3-nitroimidazo[1,2-b]pyridazine, 16.7 g (60.4 mmol) of triphenyl-methanethiol and 16.7 g (120 mmol) of potassium carbonate in 150 ml of dioxane are heated to 90° C. for 5 h under an argon atmosphere. After cooling to room temperature, the mixture is filtered and the filtrate is concentrated. The residue is dissolved in a little ethyl acetate and treated with 100 ml of diisopropyl ether. After 18 h, the crystalline precipitate is filtered off and dried. 12.69 g (72%) of the title compound are isolated. M.p.: 168-170° C.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:7]1([CH3:18])[CH3:17])=[O:5])C.CCO.[OH-].[Na+]>O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C@H:8]2[C@H:6]([C:4]([OH:5])=[O:3])[C:7]2([CH3:18])[CH3:17])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)[C@H]1[C@H](c2cccc(OC)c2)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc([C@H]2[C@H](C(=O)O)C2(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.6 %

Procedure:
Trans-3-(3-Methoxy-phenyl)-2,2-dimethyl-cyclopropanecarboxylic acid ethyl ester (15.22 g, 61 mmol) was added to a mixture of EtOH (200 mL) and 2M aqueous NaOH (100 mL). Solid NaOH (5.0 g, 125 mmol) was added, and the reaction mixture was stirred under N2 atmosphere for 15 hours at room temperature. The reaction mixture was diluted with water and extracted twice with a mixture of 1/1 hexanes/diethyl ether and once with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give 11.5 g of trans-3-(3-methoxy-phenyl)-2,2-dimethyl-cyclopropanecarboxylic acid, MS=221 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([S:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=2)=[CH:11][N:12]=1.[NH2:23][CH2:24][C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[OH:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[OH:26][C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][NH:23][C:20](=[O:22])[C:16]1[CH:15]=[C:14]([S:13][C:10]2[S:9][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:12][CH:11]=2)[CH:19]=[CH:18][N:17]=1
Reactant: NCC(O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc(Sc2cnc(Nc3ccccn3)s2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(NCC(O)(c1ccccc1)c1ccccc1)c1cc(Sc2cnc(Nc3ccccn3)s2)ccn1
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 0 %

Procedure:
To a solution of 4-(2-(pyridine-2-ylamino)thiazol-5-ylthio)picolinic acid (0.063 g, 0.19 mmol) and 2-amino-1,1-diphenylethanol (0.060 g, 0.28 mmol, 1.5 eq, described in Example D) in NMP (3 mL), was added EDAC (0.055 g, 0.28 mmol, 1.5 eq), HOBt (0.026 g, 0.19 mmol, 1 eq) and diisopropylethylamine (0.100 mL, 0.57 mmol, 3 eq). The resulting mixture was stirred at 23° C. for 3.5 h. The mixture was purified on preparative HPLC (ammonium acetate/water/acetonitrile) and freeze dried to give the title compound as a solid (0.024 mg, 24%). The product was converted to the HCl salt by dissolving it in ethyl acetate (2 mL) and tetrahydrofuran (2 mL) and treating the mixture with a solution of HCl (4.0 M in dioxane, 0.011 mL, 0.045 mmol, 1 eq). The mixture was concentrated, then diluted with water and lyophilized to give the HCl salt of the title material (0.029 g) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.10 (2H, d, J=5.56 Hz), 6.30 (1H, s), 7.01 (1H, dd, J=6.69 and 5.43 Hz), 7.11-7.20 (3H, m), 7.28 (4H, t, J=7.71 Hz), 7.37 (1H, dd, J=5.31, 2.02 Hz), 7.42-7.48 (4H, m), 7.66 (1H, d, J=1.52 Hz), 7.79 (1H, ddd, J=9.22, 6.32 and 1.89 Hz), 8.31 (1H, dd, J=5.43 and 1.39 Hz), 8.40 (1H, t, J=4.80 Hz), 8.41 (1H, d, J=4.8 Hz), 11.86 (1H, s). LC/MS (M+H)+: 526. Ret. time: 2.00 (Condition D). HRMS: calcd: 526.1371; found: 526.1387.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:29]=[CH:28][N:27]([CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[N:26]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=[N:12]2)[C:8]([NH:24][C:25]2[CH:29]=[CH:28][N:27]([CH2:30][C:31]([OH:33])([CH3:32])[CH3:34])[N:26]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(OC2CCCC2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(OC3CCCC3)cc2=O)n1
Yield: 23 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-(4-cyclopentyloxy-6-oxo-6H-pyridazin-1-yl)-propionic acid (Intermediate 61) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-(4-cyclopentyloxy-6-oxo-6H-pyridazin-1-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (49.8 mg, 23%) as a white solid; ES+-HRMS m/e calcd for C24H35N5O4 [M+Na+] 480.2581, found 480.2582. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.05 (m, 1H), 1.25-1.80 (m, 14H), 1.83-2.00 (m, 3H), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 4.86 (m, 1H), 5.45 (dd, J=4.3, J=11.1 Hz, 1H), 6.24 (d, J=2.8 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.76 (d, J=2.8 Hz, 1H), 10.74 (s, 1H).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:2][O:16]2)=[CH:13][CH:14]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(C2(c3ccccc3)CO2)cc1
Temperature: 55 °C
Reaction time: 6 h

Procedure:
To a stirring solution of trimethylsulfonium iodide (5.27 g, 19.15 mmol) in THF (20 mL) was added sodium hydride (0.957 g, 23.94 mmol) and the reaction mixture was stirred at 55° C. for 6 h. A solution of (4-bromophenyl)(phenyl)methanone 50 (5.0 g, 19.15 mmol) in THF (10 mL) was added and the mixture was stirred an additional 16 h at 55° C. The reaction mixture was quenched with water, diluted with ether and layer separated. The organic layer was dried over Na2SO4, filtered and concentrated to afford 2-(4-bromophenyl)-2-phenyloxirane 51 (quantitative yield) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14](O)=O)=[CH:11][NH:12][CH:13]=1.[NH3:17]>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14]#[N:17])=[CH:11][NH:12][CH:13]=1
Reactant: N
Reactant: O=C(O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Solvent: CCO
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2.1 g of the free 4-(2,3-dichlorophenyl)pyrrole-3-carboxylic acid obtained in (b) are dissolved in 30 ml of ethanol. The solution is made alkaline with concentrated ammonia and then evaporated to dryness. The residue is dissolved in 50 ml of ethanol. NH3 gas is added (20 atm) to this solution at room temperature in an autoclave and the reaction mixture is kept for 15 hours at 220° C. The reaction mixture, which has cooled to room temperature, is poured into ice/HCl, the precipitate is isolated by filtration and dried at 60° C. The resultant powder is heated with 17 g of polyphosphoric acid in an open vessel at 180° C., the hot mixture is dropped onto ice, made alkaline with NaOH and extracted with ethyl acetate. The combined extracts are concentrated by evaporation and the residue is purified by column chromatography (silica gel; elution with a 4:1 mixture of toluene/ethyl acetate), affording 4-(2,3-dichlorophenyl)-3-cyanopyrrole of m.p. 148°-150° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH:25][C:27]5[N:32]=[CH:31][CH:30]=[CH:29][N:28]=5)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: NCC1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Product: c1cnc(NCC2(c3ccc(OC4CCN(C5CCC5)CC4)cc3)CCOCC2)nc1
Yield: 25 %

Procedure:
The title compound (31 mg, 25%) was prepared from 1-(4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine and 2-chloropyrimidine similarly to the procedure used for example 145. 1H NMR (400 MHz, CDCl3) δ 1.66-1.73 (m, 2H), 1.83-1.95 (m, 6H), 1.98-2.15 (m, 8H), 2.60-2.66 (m, 2H), 2.75 (m, 1H), 3.57-3.62 (m, 2H), 3.66 (d, 2H), 3.81-3.85 (m, 2H), 4.31 (m, 1H), 4.68 (t, 1H), 6.47 (t, 1H), 6.90 (d, 2H), 7.23 (d, 2H), 8.20 (d, 2H). LRMS APCI+ m/z 423 [MH]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[C:12]2[CH:13]=[N:14][C:15]([NH:17][C:18]([NH:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[O:19])=[CH:16][C:11]=2[N:10]([C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:9]=1.N1C=CC=CC=1.C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]([NH:7][C:8]1[C:12]2[CH:13]=[N:14][C:15]([NH:17][C:18]([NH:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[O:19])=[CH:16][C:11]=2[N:10]([C:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:9]=1)=[O:5]
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: COCC(=O)Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an 8 mL vial charged with 2-methoxyacetyl chloride (6.6 mg, 0.061 mmol) was added (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (30 mg, 0.056 mmol) in DCM (1 ml) and pyridine (0.045 ml, 0.557 mmol). The vial was capped and the contents stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (1 mL), MP-Trisamine (137 mg, 0.278 mmol) added, and the contents of the vial shaken at room temperature for 3 h. The resin was filtered, and washed through with DCM (1 mL). The volatiles were removed in vacuo to afford crude (R)-2-methoxy-N-(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide, which was taken forward without purification. MS ESI calc'd. For C37H35N6O3 [M+H]+ 611. found 611.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:23]([CH3:25])[CH3:24]>>[CH3:24][N:23]([CH3:25])[C:14]([C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: CNC
Product: CN(C)C(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepare by the method of example 20.8 using 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (4.0 mmol) and (CH3)2NH. Purify to give the title compound.
Reaction SMILES: BrCC[CH2:4][CH2:5][O:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Br:25][CH2:26][CH2:27][CH2:28]CCBr>>[Br:25][CH2:26][CH2:27][CH2:28][CH2:4][CH2:5][O:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(-c2ccccc2)oc2c(OCCCCBr)cccc2c1=O
Reactant: BrCCCCCBr
Product: Cc1c(-c2ccccc2)oc2c(OCCCCCBr)cccc2c1=O

Procedure:
This compound was prepared by the method described for the preparation of Intermediate XVI, but using 1,5-dibromopentane in place of 1,4-dibromobutane and purifying the crude product by column chromatography on silica gel (elution with dichloromethane:ethyl acetate 99:1) m.p. 75°-76° C., after rinsing with petroleum ether:diethyl ether 30:4.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15])#[N:2].[OH:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[C:26]([O:25][C:23]([C:22]1[CH:21]=[CH:20][C:19]([O:18][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:31][CH:30]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(C#N)cc21
Temperature: 115 °C
Yield: 75.3 %

Procedure:
A 500 ml flask equipped with a Claisen head and a condenser was charged with oven dried MS 4A powder (14.5 g), methyl 6-cyano-7-fluorochroman-4-carboxylate (14.11 g, 60.00 mmol), tert-butyl 4-hydroxybenzoate (14.57 g, 75.00 mmol), K2CO3 (20.73 g, 150.0 mmol), and 1-methyl-2-pyrrolidinone (120 mL). The mixture was degassed with Argon for 1 hour, then heated to 115° C. for 18 hours. The mixture was cooled to ambient temperature. The mixture was filtered through a CELITE pad and rinsed with EtOAc. The combined filtrates were washed with water. The EtOAc layer was dried over MgSO4, filtered through GF paper, and concentrated to a crude oil. The crude oil was purified on silica gel (EtOAc in hexanes gradient) to provide 18.5 g of the desired compound as semisolid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH:17]([CH2:22][CH3:23])[C:18]([O:20]C)=[O:19])[CH:12]([CH2:15][CH3:16])[C:13]#[CH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[OH-].[Li+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH:17]([CH2:22][CH3:23])[C:18]([OH:20])=[O:19])[CH:12]([CH2:15][CH3:16])[C:13]#[CH:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C#CC(CC)N(C(CC)C(=O)OC)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(CC)N(C(CC)C(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 59 (584 mg, 163 mmol) was dissolved in THF (10 mL). Lithium hydroxide monohydrate (134 mg, 2.0 eq) was added followed by 10 mL of water. The mixture was stirred at room temperature overnight. The solvent was removed and the solution was adjusted to pH 3-4 using 3N HCl, The mixture was then extracted with EtOAc (4×20 mL). The combined organic layers were washed with brine and dried (MgSO4). After removal of the solvent a white solid was obtained as the product 60. LCMS 366.0 (M+23).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1)([O-:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[N:3]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=2)[CH:4]=[N:5][CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cncn1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 2.8 %

Procedure:
A mixture of 4-methyl-1H-imidazole (25.5 g), 4-nitrobenzyl bromide (56 g), potassium carbonate (86 g) and N,N-dimethylformamide (500 ml) was stirred at room temperature for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give 5-methyl-1-(4-nitrobenzyl)-1H-imidazole (1.6 g, 3%) as crystals from a fraction eluted with methanol-ethyl acetate (1:20, v/v). Recrystallization thereof from ethyl acetate-isopropyl ether gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C(O)CCC>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([NH:20][C:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[N:3]=2)[CH:21]=[CH:22][CH:23]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cccc(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Clc1nccc(Nc2cccc(OCc3ccccc3)c2)n1
Temperature: 50 °C
Reaction time: 17 h
Yield: 40.7 %

Procedure:
A mixture of 2,6-dichloropyrimidine (2.00 g, 13.4 mmol), 3-benzyloxyaniline (2.07 g, 13.4 mmol) and triethylamine (2.72 g, 26.8 mmol) in 1-butanol (20 mL) was stirred at 50° C. for 17 h. The reaction mixture was concentrated to remove most of the 1-butanol, the crude product was preabsorbed onto silica gel using chloroform and purified by flash chromatography (95:5 chloroform/methanol) to afford N4-(3-benzyloxyphenyl)-2-chloro-4-pyrimidineamine (1.70 g, 40%) as colorless oil: 1H NMR (300 MHz, DMSO-d6) δ 10.2 (s, 1H), 8.16 (d, J=6.0 Hz, 1H), 7.48-7.24 (m, 7H), 7.12 (d, J=9.0 Hz, 1H), 6.78 (m, 2H), 5.11 (s, 2H); ESI MS m/z 312 [C17H14ClN3O+H]+.
Reaction SMILES: CC([O:5][CH2:6][C:7]1[C:11]([CH2:12][OH:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[O:9][N:8]=1)(C)C.O[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[C:29]([C:34]([O:36][CH3:37])=[O:35])[CH:28]=[CH:27]3)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[OH:5][CH2:6][C:7]1[C:11]([CH2:12][O:13][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36][CH3:37])=[O:35])[CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:10]([CH:14]([CH3:15])[CH3:16])[O:9][N:8]=1
Reactant: CC(C)c1onc(COC(C)(C)C)c1CO
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CO)noc4C(C)C)cc3)ccc2n1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
To a solution of [3-{[(1,1-dimethylethyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methanol (407 mg, 1.79 mmol), methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (500 mg, 1.79 mmol) and triphenylphosphine (517 mg, 1.97 mmol) in dichloromethane (4 mL) was added diisopropyl azodicarboxylate (0.354 mL, 1.97 mmol) dropwise. The solution was heated in a microwave reactor at 100° C. for 10 minutes and then adsorbed onto silica gel and purified by chromatography (silica gel, 0-40% ethyl acetate in hexanes gradient elution) to afford a solid which was dissolved in dichloromethane (114 mL). Trifluoroacetic acid (114 mL, 1.48 mol) was added at a rapid pace. The mixture was stirred for approximately 1.5 hours and then concentrated. The residue was taken up with ethyl acetate and poured into water. Then solid sodium carbonate was added until the pH was between 9 and 10. The layers were separated and the ethyl acetate layer was dried over magnesium sulfate and concentrated. The resulting solid was washed with ether to afford methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (545 mg, 54%). 1H-NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=9 Hz, 1H), 8.33 (s, 1H), 8.18 (s, 2H), 8.12 (d, J=9 Hz, 1H), 7.83 (d, J=9 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 5.46 (br s, 1H), 5.06 (s, 2H), 4.54 (s, 2H), 3.94 (s, 3H), 3.33 (septet, J=7 Hz, 1H), 1.24 (d, J=7 Hz, 6H). LRMS (ESI) m/z 433 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[O:21]=[C:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: CCCC(=O)Cl
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reaction time: 8 h

Procedure:
Butyryl chloride (0.31 mL, 2.94 mmol) was added to a solution of N-[4-(4-oxo-piperidin-1-yl)-phenyl]amine (which was obtained in Example 224) (0.70 g, 2.77 mmol) and triethylamine (1.9 mL, 13.9 mmol) in anhydrous methylene chloride(10 mL). The reaction was stirred overnight. The reaction was quenched with water (50 mL) and washed with methylene chloride (3×20 mL). The organic extracts were combined, dried (sodium sulfate) and concentrated. The desired product was isolated using silica gel flash chromatography to give the title compound as a yellow solid (0.41 g); 1H NMR (300 MHz, CDCl3) δ 1.01 (t, 3H, J=7.38 Hz), 1.72 (m, 2H), 2.29(t, 2H, J=7.62 Hz), 2.55(t, 4H, J=6.03 Hz), 3.55(t, 4H, J=5.97 Hz), 6.95(d, 2H, J=7.91), 7.42(d, 2H, J=8.97 Hz). MS (ES) m/z: 260.9(MH+); HRMS found for C15H20N2O2: 260.1511. Anal. Calcd. for C, 69.20; H, 7.74; N, 10.76. Found: C, 69.03; H, 7.94; N, 10.59.