Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:34])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.[OH-].[Li+]>O1CCCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH:18]([F:19])[F:20])[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:24][CH:23]=1)=[C:8]2[CH3:34]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(C(=O)C(C)(C)C)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A solution of {8-chloro-2-difluoromethoxy-3-[4-(2,2-dimethylpropionyl)benzyl]-4-methylquinolin-5-yloxy}acetic acid methyl ester (0.18 g) in tetrahydrofuran (10 mL) and water (1.5 mL) was treated with 1.0M aqueous lithium hydroxide solution (0.71 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, diluted with water and dichloromethane and then acidified by the addition of 0.1M aqueous hydrochloric acid solution. The aqueous phase was extracted with dichloromethane and the combined organic phases dried over magnesium sulfate. The solvent was removed under reduced pressure to give title compound as a white solid (0.16 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH3:18][C:17]1[N:1]([C:2]2[C:7]3[N:8]([CH3:12])[C:9](=[O:11])[NH:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: Cn1c(=O)[nH]c2cccc(N)c21
Reactant: CC(=O)CCC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1cccc2[nH]c(=O)n(C)c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a suspension of 257 mg (1.57 mmol) of 7-amino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one in 2 mL of acetic acid was added 0.18 mL (1.57 mmol) of 2,5-hexanedione, the mixture was stirred at 90° C. for 1 hour. After cooling, the reaction mixture was neutralized by saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 25-50% ethylacetate/n-hexane gradient mixture to give 258 mg (68%) of the title compound.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:9]=1[CH2:10]Br>C(Cl)(Cl)Cl>[F:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:9]=1[CH2:10][N:3]1[CH2:4][CH:5]=[CH:6][N:2]1[OH:1]
Reactant: Fc1cccc(F)c1CBr
Reactant: On1cccn1
Solvent: ClC(Cl)Cl
Product: ON1C=CCN1Cc1c(F)cccc1F
Temperature: 80 °C
Yield: 68.9 %

Procedure:
1-Hydroxypyrazole (49.3 mg, 0.59 mmol, 1.0 eq) was mixed with 165.8 mg (0.80 mmol, 1.36 eq) of 2,6-difluorobenzyl bromide in ˜1-2 mL of anhydrous CHCl3 under argon. The mixture was heated at 80° C. for 18 h under inert atmosphere in a sealed flask without condenser. The residue was partitioned between 37 weight percent aqueous HCl and toluene. The aqueous layer was collected and the toluene fraction extracted again with 37 weight percent aqueous HCl. The combined aqueous HCL fractions were neutralized with 5N aqueous NaOH to pH˜11-12 and then back-extracted with 3×30 mL of CHCl3. The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to yield 86.3 mg (70.1% yield) of 2-(2,6-difluorobenzyl)-1-hydroxy-1H-pyrazole as a tan brown solid. 1H NMR (CDCl3 300 MHz) δ 7.37 (m, 1H), 7.18 (d, 1H), 6.95 (t, 2H), 6.85 (d, 1H), 6.11 (t, 1H), 5.43 (s, 2.00 H). LC/MS (ES) M+1=211.2
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1)[C:9]([CH3:23])([CH3:22])[CH2:8]2)(=[O:4])=[O:3].[CH3:24][O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:25][C:26](=[O:31])[C:27]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:10]2[C:9]([CH3:23])([CH3:22])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)[NH:11]2)[CH:16]=1)([CH3:29])[CH3:28]
Reactant: CC1(C)Cc2cc(S(C)(=O)=O)ccc2NC1c1cccc(N)c1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(S(C)(=O)=O)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 240 h
Yield: 7.7 %

Procedure:
A mixture of 3-(6-methanesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (1 g, 3 mmol), 2-bromo-2-methyl-propionic acid methyl ester (1.65 g, 9 mmol) and potassium carbonate (2.07 g, 15 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 10 d. Then the reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(30% ethyl acetate/hexanes) to afford 2-[3-(6-methanesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (100 mg, 7%) as a brown oil: LC/MS m/e calcd for C23H30N2O4S (M+H)+: 431.57, observed: 431.1.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12]C)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:14]1[CH:18]=[CH:17][CH:16]=[N:15]1.B(Br)(Br)Br>>[N:14]1([C:2]2[N:11]=[CH:10][C:9]3[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: c1cn[nH]c1
Reactant: COc1cccc2cnc(Cl)nc12
Agent: BrB(Br)Br
Product: Oc1cccc2cnc(-n3cccn3)nc12

Procedure:
A mixture of the 2-chloride 113 (0.5 mmol) and pyrazole (2.5 mmol) was heated at 175° C. in a steel autoclave for 48 h. The crude product was then treated with BBr3 according to the procedure described in Example 6. Subsequent purification by column chromatography gave 2-pyrazol-1-yl-quinazolin-8-ol (A131).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[CH2:12]OS(C)(=O)=O)[O:8][CH2:7][CH2:6][O:5]1.[N+:21]([C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+].[Br-]>CC(C)=O>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[CH2:12][N:26]2[CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:28]=[N:27]2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cccc(COS(C)(=O)=O)c2)OCCO1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: CC1(c2cccc(Cn3cc([N+](=O)[O-])cn3)c2)OCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl ester (220 mg, 0.81 mmol) and 4-nitro-1H-pyrazole (103 mg, 0.81 mmol) in acetone (8.0 mL) was treated with K2CO3 (564 mg, 4.04 mmol) followed by TBA bromide (48 mg, 0.15 mmol). The reaction mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure. Water (10 mL) and EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (80:20 hept-EA) gave the title compound as a pale yellow solid. TLC: rf (50:50 hept-EA)=0.5. LC-MS-conditions 02: tR=0.97 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[CH:9]=2)[C:4](=[O:17])[O:3]1.CC(C)([O-])C.[K+].F[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>CN(C)C=O>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([CH:11]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:17])[O:3][C:2]3([CH3:18])[CH3:1])=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: CC1(C)OC(=O)c2ccc(Cn3cncn3)cc21
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2ccc(C(c3ccc([N+](=O)[O-])cc3)n3cncn3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,3-Dimethyl-5-[1,2,4-triazol-1-ylmethyl]-3H-isobenzofuran-1-one (200 mg, Intermediate 1) was dissolved in N,N-dimethylformamide (8 ml) at 0° under nitrogen and potassium tert-butoxide was added (138 mg). After 30 minutes 4-fluoronitrobenzene (232 mg) in N,N-dimethylformamide (1 ml) was added and stirring continued for one hour. The mixture was warmed to room temperature, stirred for one hour then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate then the combined organic extracts were washed with water, brine, dried then evaporated to a yellow solid. The crude material was purified by column chromatography on Merck 9385 silica eluting with dichloromethane:methanol (50:1) to give a yellow oil, 5-[(4-nitrophenyl)-1,2,4-triazol-1-ylmethyl]-3,3-dimethyl-3H-isobenzofuran-1-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:68][C@H:69]([CH:73]1[CH2:77][CH2:76][CH2:75][CH2:74]1)[C:70]([OH:72])=[O:71].[BH4-].[Na+]>CN(C=O)C.CO.O>[CH:73]1([C@@H:69]([NH:68][C:34](=[O:35])[CH2:33][NH:32][C:30](=[O:31])[CH2:29][O:28][C:27]2[CH:26]=[CH:25][C:24]([C@@H:9]3[C@@H:10]([S:13][CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[OH:16])[C:11](=[O:12])[N:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:38][CH:37]=2)[C:70]([OH:72])=[O:71])[CH2:77][CH2:76][CH2:75][CH2:74]1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: N[C@@H](C(=O)O)C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: O
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@@H](C(=O)O)C1CCCC1
Reaction time: 1 h

Procedure:
N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.035 g, 0.065 mmol) was dissolved in DMF (2 ml) at 30° C. N-Methyl morpholine (0.026 g, 0.259 mmol) and TBTU (0.027 g, 0.084 mmol) were added. After 1 h, (2R)-amino(cyclopentyl)acetic acid (0.014 g, 0.097 mmol) was added. The mixture was stirred for 1 h and water (1 ml) was added. After 10 minutes, MeOH (2 ml) and NaBH4 (0.037 g, 0.971 mmol) were added. Full conversion to the corresponding alcohol was obtained after 5 minutes. The reaction was quenched by the addition of 0.1M NH4OAc buffer (2 ml). The mixture was purified by preparative HPLC (eluent 0-50% CH3CN in 0.1M NH4OAc buffer). Freeze-drying of the pure fractions gave the title compound (0.018 g, 42%) as a colourless solid. M/z: 666.0 (M−1). 1H NMR [(CD3)2SO), 400 M] δ 1.19-1.62 (m, 8H), 2.09-2.19 (m, 1H), 2.83-2.95 (m, 2H), 3.78 (d, 2H), 4.06-4.10 (m, 1H), 4.25-4.30 (m, 1H), 4.51 (s, 2H), 4.68-4.75 (m, 1H), 5.03-5.06 (m, 1H), 6.97-7.37 (m, 12H), 7.95-8.00 (m, 1H), 8.22 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][CH:32]=1)[CH2:15][NH:16][C:17]1[C:26]2[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][N:18]=1.C(N(CC)CC)C.CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[C:14]([CH:30]=[CH:31][CH:32]=2)[CH2:15][NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4ccc(F)cc4)c3)ncnc12
Reaction time: 8 h
Yield: 77 %

Procedure:
4-fluorobenzoyl chloride (240 μL, 0.5 M in anhydrous DCM, 0.11 mmol, 1.1 equiv.) was added to a solution of 4-[(3-aminobenzyl)amino]quinazoline-8-carboxamide (32 mg, 0.1 mmol, 1.0 equiv.) and triethylamine (40 μL, 0.3 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at it overnight. Ether (2 mL) was added. The precipitate was filtered, washed with ether and DCM to yield the title compound in 77% yield. Mass: M+H+: 416.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[F:38]C1C=CC=CC=1B(O)O>>[F:38][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]1[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[N:21]([CH3:36])[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=3)[N:24]=2)[CH2:16][CH2:15]1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: OB(O)c1ccccc1F
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccccc2F)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 2-fluorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=515, obsd.=515).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[C:6]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:7][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:23]=3[CH3:24])=[CH:13][CH:12]=2)[CH:9]=1.[C-:37]#[N:38].[Na+].CS(C)=O>O>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:20][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:8]2[CH:9]=[C:5]([CH2:4][CH2:3][CH2:2][C:37]#[N:38])[C:6]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:7]2)=[CH:12][CH:13]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCCI)c(-c3ccccc3)n2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCCC#N)c(-c3ccccc3)n2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
A mixture of 1-iodo-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propane (1.75 g), sodium cyanide (291 mg), and dimethyl sulfoxide (5 ml) was stirred at 60° C. for 2 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and 4-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]butyronitrile (1.34 g, yield: 92%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:7][C:8]([NH:10][C@H:11]([C@H:19]1[O:23][C:22](=[O:24])[C@H:21]([CH3:25])[CH2:20]1)[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@@H:19]([OH:23])[CH2:20][C@@H:21]([CH3:25])[C:22]([NH:2][CH3:1])=[O:24])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
Gaseous methylamine was introduced into a solution of 0.2 g (0.615 mole) of (3R, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 2) in 6 ml of methanol for 3 minutes, after which the mixture was allowed to stand for 3 hours. The reaction mixture was then concentrated by distillation under reduced pressure, and the resulting residue was triturated with hexane to afford 0.23 g of the title compound as white crystals, melting at 144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([N:18]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19]2)[CH2:14][CH2:13]1)=[O:10].[O-:25][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([N:18]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19]2)[CH2:16][CH2:17]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(n3ccc(C=O)c3)CC2)c(Cl)c1Cl
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(n3ccc(C(=O)O)c3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Solutions of 3,4-dichloro-N-[1-(3-formyl-1H-pyrrol-1-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 259, 90 mg, 0.24 mmol) in 10 ml acetone and KMNO4 (39 mg, 0.24 mmol) in 3 ml water were combined and stirred at ambient temperature overnight. Due to incomplete conversion, solutions of KMnO4 (15 and 20 mg) in 3 ml water were added at 5 hour intervals. The mixture was quenched with aqueous NaHSO3 and partitioned between EtOAc and water. The EtOAc was separated and washed with brine. Drying (MgSO4) and removal of solvent gave product as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][S:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:23])=[O:22])[C:9]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40].Cl>CN(C=O)C>[OH:5][CH2:4][CH2:3][O:6][C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[N:11]=[C:10]([NH:20][S:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:23])=[O:22])[C:9]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40]
Reactant: OCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)CCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)CCc2ccccn2)nc(-c2ccncc2)nc1OCCO
Temperature: 90 °C
Reaction time: 40 h

Procedure:
To a suspension of NaH (701 mg, 60% in mineral oil) in DMF (15 ml) was added ethylene glycol (15 ml). After the evolution of gas had ceased, 2-pyridin-2-yl-ethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide (800 mg) was added and the resulting solution was stirred at 90° C. for 40 h. The solution was neutralised with 2 N aq. HCl (7 ml) before it was evaporated. The brown residue was purified by chromatography on prep. tlc-plates with EA:methanol:sat. aq. ammonia 10:2:1. The product was further purified by crystallisation from methanol:diethyl ether:pentane to give 2-pyridin-2-yl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide (280 mg) as beige crystals. 1H-NMR(300 MHz, CDC3): 3.36–3.43(m, 2H), 3.86–3.90(m, 2H), 3.94(s, 3H), 4.23–4.30(m, 2H), 4.564.62(m, 2H), 6.91(dt, Jd=1.5, Jt=7.7, 1H, 7.00(dd, J=1.7, 8.2, 1H, 7.08–7.20(m, 4H), 7.57(dt, Jd=1.8, Jt=7.9, 1H), 8.15(dd, J=1.7, 4.6, 2H), 8.43(d, J=4.4, 1H), 8.72(dd, J=1.7, 4.6, 2H); LC-MS: tR=3.23 min, [M+1]+=524.48, [M−1]−=522.25.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19]([F:27])([F:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[F:27][C:19]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][CH2:17][CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: O=C(OCc1ccccc1)N1CCC(CCC(F)(F)c2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(CCC1CCNCC1)c1ccccc1
Reaction time: 6 h
Yield: 103.6 %

Procedure:
The partially purified 1-(benzyloxycarbonyl)-4-(3,3-difluoro-3-phenylprop-1-yl)piperidine (247 mg) was hydrogenated at atmospheric pressure in 95% ethanol (4.0 mL) containing 20% Pd(OH)2/C (60 mg). After 6 h, additional 20% Pd(OH)2/C (32 mg) was added and the hydrogenation was continued for another 16 h. The mixture was filtered and the catalyst was washed with 95% ethanol. Evaporation of the filtrate gave 164 mg of crude 4-(3,3-difluoro-3-phenylprop-1-yl)piperidine as a colorless syrup.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@@H:29]([CH3:34])[C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][C@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[C:30](=[O:32])[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: C1CCNC1
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)N1CCCC1
Yield: 51.6 %

Procedure:
Using the same procedure as in Example 26, methyl (2S)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) was reacted with pyrrolidine (0.46 ml, 5.5 mmol) to give the title compound as a beige solid (140 mg, 50%), except that the mixture was heated at 55° C. for 20 hours and purified by chromatography on silica gel (eluant: 4% methanol in DCM); NMR Spectrum 1.60 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.49-3.30 (m, 3H), 3.76 (m, 1H), 5.62 (q, 1H), 5.77 (s, 2H), 6.95 (d, 1H), 7.28 (m, 2H), 7.35 (d, 1H), 7.74-7.68 (m, 3H), 7.82 (dd, 1H), 8.15 (s, 1H), 8.53 (m, 3H), 11.08 (br s, 1H); Mass spectrum MH+ 494.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[N:28]=[C:27]([CH:29](Cl)[C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])[CH:26]=[CH:25][CH:24]=1>C1COCC1>[Br:22][C:23]1[N:28]=[C:27]([CH:29]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: N#Cc1cccc(C(Cl)c2cccc(Br)n2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cccc(C(c2cccc(Br)n2)C(c2cccnc2)c2cccnc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(pyridine-3-ylmethyl)pyridine (0.700 g, 4.11 mmol) in anhydrous THF (20 mL) @ −78° C. under N2 was added LDA (3.43 mL, 1.8 M) dropwise. The mixture was stirred for 1 hr @ −78° C., and 3-[(6-bromopyridin-2-yl)(chloro)methyl]benzonitrile was added. The reaction was warmed to 0° C., and stirred for 2 hr. The resulting mixture was quenched with saturated aqueous NH4Cl, and extracted 3× with EtOAc. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (1-4% MeOH in CH2Cl2) to give racemic 3-[1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]benzonitrile. LRMS m/z (M+H) Calcd.: 441.0, found: 441.0. The racemic mixture was separated by ChiralPak AD (40% iPrOH in Hexanes+1 mL/L DEA to 80% iPrOH in Hexanes+1 mL/L DEA over 45 min). The first peak was enantiomer A of 3-[1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]benzonitrile, and the second peak was enantiomer B of 3-[1-(6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]benzonitrile.