Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:24]2[C:28]3[CH:29]=[CH:30][C:31](B4OC(C)(C)C(C)(C)O4)=[CH:32][C:27]=3[S:26][N:25]=2)[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:10][CH:9]=1.[N+:42]([C:45]1[CH:64]=[CH:63][C:48]([C:49]([O:51][C@H:52]2[C:56]3[N:57]=[CH:58][N:59]=[C:60](Cl)[C:55]=3[C@H:54]([CH3:62])[CH2:53]2)=[O:50])=[CH:47][CH:46]=1)([O-:44])=[O:43]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].CN(C=O)C>[N+:42]([C:45]1[CH:46]=[CH:47][C:48]([C:49]([O:51][C@H:52]2[C:56]3[N:57]=[CH:58][N:59]=[C:60]([C:31]4[CH:30]=[CH:29][C:28]5[C:24]([CH:14]([C:11]6[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=6)[CH2:15][NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:23])=[N:25][S:26][C:27]=5[CH:32]=4)[C:55]=3[C@H:54]([CH3:62])[CH2:53]2)=[O:50])=[CH:63][CH:64]=1)([O-:44])=[O:43]
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)NCC(c1ccc(Cl)cc1)c1nsc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(-c3ccc4c(C(CNC(=O)OC(C)(C)C)c5ccc(Cl)cc5)nsc4c3)c21
Temperature: 80 °C
Yield: 51.1 %

Procedure:
DMF (3 mL) and 2M aqueous Na2CO3 (0.38 mL, 0.76 mmol) were added to a nitrogen flushed flask containing tert-butyl 2-(4-chlorophenyl)-2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isothiazol-3-yl)ethylcarbamate (150 mg, 0.291 mmol), (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (117 mg, 0.350 mmol) and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct (12 mg, 0.015 mmol). The mixture was heated at 80° C. for 1 hour. The mixture was cooled to room temperature and partitioned between EtOAc and water. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexanes:EtOAc (4:1 to 1:1) to give (5R,7R)-4-(3-(2-(tert-butoxycarbonylamino)-1-(4-chlorophenyl)ethyl)benzo[d]isothiazol-6-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (102 mg, 51%) as an oil. LCMS (APCI+) m/z 630, 632 [M+H]+; Rt=4.68 min.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([C@H:28]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:36])[O:34][CH3:35])[CH2:23]2)=[O:21])[CH2:9][N:10](C)[C:11](OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]([NH:19][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([C@H:28]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:36])[O:34][CH3:35])[CH2:23]2)=[O:21])[CH2:9][NH:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)NCCO[C@@H](c1cccc(F)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(F)c2)C1
Yield: 49.3 %

Procedure:
A mixture of methyl 2-((R)—((R)-1-((S)-1-cyclohexyl-3-(N-methyl-N-(t-butoxycarbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)(3-fluorophenyl)methoxy)ethylcarbamate (20 mg, 0.03 mmol) and a 20% solution of TFA in CH2Cl2 (2 mL) were stirred for about 1 h at rt until the reaction was complete. The solvent was removed by evaporation and the crude product was purified by preparative HPLC to afford methyl 2-((R)—((R)-1-((S)-1-cyclohexyl-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)(3-fluorophenyl)methoxy)ethylcarbamate (7.5 mg, 44% yield). 1H-NMR (400 MHz, CD3OD): 0.90 (m, 1H), 1.04 (m, 1H), 1.11-1.45 (m, 8H), 1.51 (m, 1H), 1.71 (m, 7H), 2.71 (s, 3H), 2.91 (m, 2H), 3.06 (m, 1H), 3.23 (m, 3H), 3.61 (s, 3H), 3.81 (m, 1H), 4.07 (m, 2H), 7.03 (m, 2H), 7.09 (m, 1H), 7.36 (m, 1H). MS (E/Z): 507 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]([C:19](=[O:24])N(OC)C)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[C:26]([NH:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1[CH3:39])([CH3:29])([CH3:28])[CH3:27]>>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[F:18])[C:19](=[O:24])[CH2:39][C:33]1[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=1[C:31](=[O:40])[NH:30][C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)NC(C)(C)C)c(C)c1
Product: Cc1ccc(C(=O)NC(C)(C)C)c(CC(=O)[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)c1

Procedure:
Using general procedure 2 with [(R)-1-(methoxy-methyl-carbamoyl)-2-(2,4,5-trifluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.4 g, 4.1 mmol) and N-tert-Butyl-2,4-dimethyl-benzamide (2.5 g, 12 mmol) followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [OH:1][CH:2]([C:14]([F:17])([F:16])[F:15])[CH2:3][CH:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[O:5]1.[N+:18]([O-])([O-:20])=[O:19].[Na+]>FC(F)(F)C(O)=O>[OH:1][CH:2]([C:14]([F:17])([F:15])[F:16])[CH2:3][CH:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=[CH:13][C:6]=2[O:5]1
Reactant: O=[N+]([O-])[O-]
Reactant: OC(CC1CCc2ccccc2O1)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)CCC(CC(O)C(F)(F)F)O2
Temperature: 0 °C

Procedure:
A solution of 8.5 g (35 mmol) of 2-(2-hydroxy-3,3,3-trifluoropropyl)-3,4-dihydro-2H-1-benzopyran in 106 ml of trifluoroacetic acid is treated with 7.4 g (88 mmol) of sodium nitrate at -10° C. The mixture is allowed to react for 45 min, then poured into ice water and the product is extracted with dichloromethane. The organic phase is then dried over sodium sulfate and concentrated under reduced pressure. By chromatography of the residue on a silica column using dichloromethane, 5.0 g of product are obtained.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[ClH:36].[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:16][CH2:17]1)=[O:11]
Reactant: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1

Procedure:
(2-{4-[(2R)-2-Amino-3-(4-chlorophenyl)propanoyl]-piperazinyl}phenyl)-N,N-dimethylcarboxamide HCl salt was prepared according to the procedure described in Preparation XVI by using [2-(4-{(2R)-2-[(tert-butoxy)carbonylamino]-3-(4-chlorophenyl)propanoyl}-piperazinyl)phenyl]-N,N-dimethylcarboxamide (Step 4) (240 mg, 0.46 mmol) and a satd soln of HCl in EtOAc (10 mL). The white solid that formed was isolated by filtration (200 mg). MS (ESI, pos. ion) m/z: 415 (M+H). Calc'd for C22H28Cl2N4O2: 451.39.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:8]=[N+:9]=[N-:10].[Na+]>C(O)C.O>[N:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CN=[N+]=[N-]
Yield: 80.1 %

Procedure:
To a solution of ethyl bromoacetate (42 g) in ethanol (120 mL) was added a solution of NaN3 (25 g) in water (60 ml). The mixture was stirred at reflux for 4 hours. The mixture was concentrated under vacuum and the residue was partitioned between ether (300 mL) and water (200 mL). The aqueous layer was further extracted with ether. The combined extracts were washed with water (×3), brine and dried over Na2SO4. After filtration, careful concentration of solvent gave ethyl azidoacetate (26 g) which was dissolved in ethanol (100 ml) and 2-bromobenzaldehyde (12.5 g) was added to the solution which was then added dropwise to a cooled (−15° C.) solution of sodium ethoxide (prepared from Na (5.2 g) and ethanol (60 ml)). The mixture was stirred at 0° C. for 4 hours before poured into a mixture of ice and saturated aqueous NH4Cl solution. The mixture was filtered and the precipitate was washed with water and dissolved in ethyl acetate and dried over Na2SO4. Concentration of solvent gave crude intermediate, which was dissolved in xylene (100 ml) and added dropwise to refluxing xylene under nitrogen. After the addition, the mixture was stirred at reflux overnight. Concentration of the mixture under vacuum gave the crude product, which was purified by silica gel chromatography (2% ethyl acetate in hexane).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][C:26](Cl)=[N:27][CH:28]=2)=[CH:19][CH:18]=1)=O)(C)(C)C.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C)C(=O)C>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:30])[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[N:27][C:26]([NH:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[N:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2cnc(Cl)nc2)cc1
Reactant: NCCCN1CCCCC1
Solvent: CC(=O)N(C)C
Product: Nc1ccccc1NC(=O)c1ccc(-c2cnc(NCCCN3CCCCC3)nc2)cc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a solution of N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-5-yl)benzamide (Method 53, 80 mg, 0.19 mmol) in N,N-dimethylacetamide (3.5 ml) was added 3-aminopropylpiperidine (108 mg 0.76 mmol). The reaction mixture was stirred at 50° C. for 20 hours, before being allowed to cool. The reaction mixture was partitioned between water and ethyl acetate, before being filtered under gravity, through a Varian Chem Elut (CE1010) diatomaceous earth column. The resulting solution was then concentrated under reduced pressure and purified by flash column chromatography, eluting with methanol/dichloromethane (0-20%), to give the title compound, which was used without further purification; Mass Spectrum: M+H+ 531.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:20]([C@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:21])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:44]([N:46]=[C:47]=[O:48])[CH3:45].O1CCCC1>O>[C:29]([NH:28][C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@@H:22]1[C:20]([N:19]1[C@@H:15]2[C@@H:16]([C@H:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:47]([NH:46][CH2:44][CH3:45])=[O:48])[CH2:2][CH2:3]3)[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[CH2:17][CH2:18]1)=[O:21])(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](C3CCNCC3)Nc3ccccc3[C@@H]21)c1ccccc1
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCC([C@@H]2Nc3ccccc3[C@H]3[C@@H]2CCN3C(=O)[C@H]2CCCC[C@H]2NC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 87.5 %

Procedure:
A mixture of the compound (0.20 g, 0.41 mmol) synthesized in Example 69, triethylamine (0.17 g, 1.64 mmol), ethylisocyanate (0.058 g, 0.82 mmol) and tetrahydrofuran (20 ml) was stirred at room temperature for 60 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous Na2SO4), and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (0.20 g, 87%) as white crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:19])[NH:12][C@H:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20](Br)[C:21]#[CH:22]>C1COCC1.CN(C=O)C>[CH2:3]([O:10][C:11](=[O:19])[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:22][C:21]#[CH:20])[C:14]1=[O:18])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@H]1CCNC1=O)OCc1ccccc1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#CCN1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 0.08 h
Yield: 100 %

Procedure:
Sodium hydride (1.11 g, 27.7 mmol, 60% mineral oil dispersion) is added to a solution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid benzyl ester (6.20 g, 26.4 mmol) in THF/DMF (88 mL, 3/1 v/v) at 0° C. The mixture is stirred for 5 min. then propargyl bromide (4.4 mL, 49.4 mmol) is added dropwise. The resulting solution is stirred for 1 h then brought to room temperature and stirred for 2 h. The reaction is quenched with saturated ammonium chloride solution then diluted with ethyl acetate and washed with water (×4) and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The residue is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the product (7.20 g, 26.4 mmol) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[N:3]=[C:4]1[CH2:9][CH2:8][N:7]([N:10]([CH3:12])[CH3:11])[CH2:6][CH2:5]1.C[Si]([C:18]#[N:19])(C)C>O>[CH3:11][N:10]([CH3:12])[N:7]1[CH2:8][CH2:9][C:4]([NH:3][N:2]([CH3:13])[CH3:1])([C:18]#[N:19])[CH2:5][CH2:6]1
Reactant: CN(C)N=C1CCN(N(C)C)CC1
Reactant: C[Si](C)(C)C#N
Solvent: O
Product: CN(C)NC1(C#N)CCN(N(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
2.25 g [4-(Dimethyl-hydrazono)-piperidin-1-yl]-dimethyl-amine (from Step 1) is dissolved in 25 ml water, cooled in an ice bath, and 3.64 g trimethylsilyl cyanide is added at such a rate, that the internal temperature does not exceed 10° C. Then the mixture is stirred at ambient temperature for 18 hours, extracted with ethyl acetate, the organic layer washed with brine, dried over sodium sulfate, and the solvent evaporated, to give 2.1 g 1-Dimethylamino-4-(N′,N′-dimethyl-hydrazino)-piperidine-4-carbonitrile. 1H-NMR (CDCl3): 2.74 ppm (m, 2H), 2.50 ppm (m, 2H), 2.40 ppm (s, 6H), 2.35 ppm (s, broad, 1H), 2.24 ppm (s, 6H), 1.95 ppm (m, 2H), 1.60 ppm (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:11]1[C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][O:13][C:12]1=[O:22])=[O:10].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:34][C:35]#[N:36].[Na+].[Cl-].Cl>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([C:9](=[O:10])[N:11]1[C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][O:13][C:12]1=[O:22])[CH2:34][C:35]#[N:36]
Reactant: N#CCBr
Reactant: O=C(Cc1ccccc1F)N1C(=O)OC[C@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: N#CC[C@@H](C(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccccc1F
Temperature: -2.5 °C
Reaction time: 1 h

Procedure:
A solution of 546 g of 3-[2-(2-fluorophenyl)-1-oxoethyl]-4(R)-phenyl-2-oxazolidinone in 2,180 mL of peroxide-free tetrahydrofuran is cooled to an internal temperature of -5 to -8° C. A solution of 1,773 mL of lithium hexamethyldisilazide in tetrahydrofuran (1M) is added over a period of 55 minutes, while maintaining an internal temperature of 0 to -5° C. The solution is stirred at an internal temperature of 0 to -5° C. for 1 hour and then cooled to an internal temperature of -20° C. 150 mL of Bromoacetonitrile is added over a period of 40 minutes, while maintaining an internal temperature of -15 to -20° C. The reaction mixture is stirred at an internal temperature of -15 to -20° C. for 4.5 hours and added to a solution of 478 g of NaCl in 2,164 mL of water and 214 g of concentrated HCl cooled to an internal temperature of 0 to 5° C., over a period of 20 minutes, while maintaining the internal temperature below 9° C. After addition of 500 mL of tetrahydrofuran, the slurry is stirred for 15 minutes at an internal temperature of 5 to 8° C., and then warmed to room temperature (17 to 19° C.) over a period of 30 minutes. The organic layer is separated and washed with a solution of 632 g of NaCl in 2,180 mL of water. The slurry is stirred for 15 minutes, the organic layer is separated and concentrated under reduced pressure (20 mm Hg; bath temperature 45° C.) to a final volume of 1.4-1.6L. 2,500 mL of t-Butyl methyl ether is added and the slurry is vigorously stirred for 1 hour at room temperature (18 to 20° C.). The solid is collected and washed with 2×150 mL of t-butyl methyl ether and dried at 45 to 50° C. (20 mm Hg) for 20 hours to obtain β-(R)-(2-fluorophenyl)-γ,2-dioxo-4(R)-phenyl-3-oxazolidinebutyronitrile as an off-white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([NH2:26])=[N:21][N:22]2[CH3:25])=[CH:18][CH:17]=1.[C:27](Cl)(=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([NH:26][C:27](=[O:36])[C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[N:21][N:22]2[CH3:25])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc4c(N)nn(C)c4c3)c2cc1OC
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2nn(C)c3cc(Oc4ccnc5cc(OC)c(OC)cc45)ccc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-((6,7-bis(methyloxy)-4-quinolinyl)oxy)-1-methyl-1H-indazol-3-amine (Example 120, 119 mg, 0.34 mmol) in pyridine (1 mL), p-anisoyl chloride (116 mg, 0.68 mmol) was added. The reaction was stirred at RT for 16 h. The mixture was concentrated in vacuo. Trituration with MeOH and filtration afforded the title compound. MS (ESI, pos. ion) m/z: 485.1 (M+1). Mass Calc'd for C25H22N3: 484.51.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[CH2:5]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:14](=[O:15])[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CO>[OH:2][CH2:1][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:14]([O:13][CH3:12])=[O:15]
Reactant: C[O-]
Reactant: O=C1CCCCCCCCCCCCCCO1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CCCCCCCCCCCCCCO
Temperature: 25 °C
Yield: 85 %

Procedure:
Sodium methoxide was generated by the addition of sodium metal (2.4 g, 104.3 mmol, 5.0 eq) to methanol (130 mL) at 0° C. with stirring. The mixture was warmed to room temperature and stirred until all of the sodium was consumed. ω-Pentadecalactone (5.0 g, 20.8 mmol, 1.0 eq) was added in a single portion, and the solution was stirred at 80° C. for 3 hours. The reaction was quenched with hydrochloric acid (1 M, 175 mL) and diluted with water (175 mL). The aqueous layer was extracted with ether (3×100 mL), and the combined organic layers were washed with water (150 mL), brine (150 mL), and dried over magnesium sulphate. The product was purified by silica gel chromatography (2:1 hexane:ethyl acetate), yielding methyl 15-hydroxypentadecanoate (4.24 g, 85%) as a colourless solid.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:21]2[C:16]([CH:17]=[N:18][C:19](S(C)=O)=[N:20]2)=[CH:15][CH:14]=1)=O)(C)(C)C.[NH2:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[NH:29][C:30](=[O:32])[CH3:31].C(O)(C(F)(F)F)=O>>[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:21]2[C:16]([CH:17]=[N:18][C:19]([NH:25][C:26]3[CH:27]=[C:28]([NH:29][C:30](=[O:32])[CH3:31])[CH:33]=[CH:34][CH:35]=3)=[N:20]2)=[CH:15][CH:14]=1
Reactant: CS(=O)c1ncc2ccc(-c3cccn3C(=O)OC(C)(C)C)n2n1
Reactant: CC(=O)Nc1cccc(N)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cccc(Nc2ncc3ccc(-c4ccc[nH]4)n3n2)c1

Procedure:
Following the synthetic and purification procedures described in Example 1291c, 2-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-pyrrole-1-carboxylic acid tert-butyl ester (80 mg, 0.2 mmol) was coupled with 3′-aminoacetanilide (77.0 mg, 0.513 mmol). Yield of TFA salt: 6 mg (7%); LC/MS: 333 (M+H); HPLC: 97% pure, RT=2.32 min; 1H NMR (DMSO, δ): 11.35 (s, 1H), 9.90 (s, 1H), 9.34 (s, 1H), 8.85 (s, 1H), 7.89 (s, 1H), 7.51 (d, J=8.5, 1H), 7.25 (t, J=8.2, 1H), 7.17 (s, 1H), 7.14 (d, J=4.7, 1H), 7.07 (s, 1H), 6.96 (m, 1H), 6.92 (d, J=4.7, 1H), 6.22 (m, 1H), 2.05 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)[CH2:4][CH2:3]1>CCOC(C)=O.CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[CH:13][N:14]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(Nc2ncc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCC(Nc2ncc(N)cn2)CC1
Reaction time: 8 h

Procedure:
The crude N-(1-methylpiperidin-4-yl)-5-nitropyrimidin-2-amine was combined with 10% Pd/C (500 mg) in EtOAc (8 mL) and MeOH (20 mL) was added. The mixture was purged with H2 and allowed to stir under 1 atm H2 overnight. Filtration through a pad of celite and concentration afforded N2-(1-methylpiperidin-4-yl)pyrimidine-2,5-diamine 17 as a tan solid, which may be used without further purification. MS: m/z found 285 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([I:11])[CH:3]=1.[CH2:12](O)[CH3:13]>S(Cl)(Cl)=O>[CH2:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[I:11])[CH3:13]
Reactant: O=C(O)c1ccc(Br)cc1I
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Br)cc1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-iodo-benzoic acid (4.0 g; 12.24 mmol) is stirred in thionyl chloride (8.0 ml) under reflux for 1 hour. The reaction mixture is evaporated under reduced pressure and taken up immediately in 20 ml methylene dichloride and cooled down to 0° C. Ethanol (20.0 ml; 342.96 mmol) is added and stirred for 1 hour at ambient temperature. The ethanol is evaporated and the residue taken up in methylene dichloride and extracted with saturated NaHCO3 solution. The organic layer is separated, dried over MgSO4 and evaporated to dryness.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]([OH:14])[C@@H:8]([N:15]([CH2:22][C:23](OCC)=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:28]=1)#[N:2].[CH2:29]([NH2:31])[CH3:30]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]([OH:14])[C@@H:8]([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][C:23]([NH:31][CH2:29][CH3:30])=[O:24])[C:7]=2[CH:28]=1)#[N:2]
Reactant: CCOC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O
Reactant: CCN
Product: CCNC(=O)CN(c1ccccc1)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O

Procedure:
The title compound was prepared from (3R-trans)-[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)phenylamino]acetic acid, ethyl ester (the title compound of Example 3) and ethyl amine by the same procedure as described for the title compound of Example 7. The product was triturated with hexanes to give the title compound as a colorless solid, mp 213°-215° C. Analysis calculated for C22H25N3O3 : C, 69.64; H, 6.64; N, 11.07. Found: C, 69.31; H, 6.33; N, 10.96. [α]D =+76.6° (c=0.47, CDCl3).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br>CN(C=O)C.C(OCC)(=O)C>[N:1]1([CH:2]2[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: BrCCOCCBr
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCC(N2CCOCC2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of tert-butyl N-(4-aminocyclohexyl)carbamate (1.07 g, 4.99 mmol, 1.00 equiv) in DMF (10 mL) was added triethylamine (1.26 g, 12.48 mmol, 2.50 equiv) and 1-bromo-2-(2-bromoethoxy)ethane (1.4 g, 6.04 mmol, 1.20 equiv). The resulting solution was stirred overnight at 70° C. The resulting solution was diluted with ethyl acetate (100 mL), washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give 1.2 g (crude) of tert-butyl N-[4-(morpholin-4-yl)cyclohexyl]carbamate as a light yellow solid. MS (ES): m/z 285 (M+H)+.