Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C.C(OCC)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:6]1[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[C:2]1[CH3:1])[CH3:32]
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCOC(=O)CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
(Scheme 1, (B)) To a solution of 2-methyl-4,5-diphenyl-1H-imidazole (0.20 g, 0.85 mmol) in DMF (6 mL) was added NaH (60% in mineral oil, 0.038 g, 0.94 mmol). The resulting mixture was stirred at rt for 10 min. The stirring continued for 2 hours after addition of ethyl 7-bromoheptanoate (0.21 g, 0.90 mmol). The reaction mixture was diluted with diethyl ether (30 mL), washed by water, and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a colorless oil (0.24 g, 0.61 mmol, 72% yield): 1H NMR (DMSO-d6) δ1.08 (m, 4H), 1.15 (t, J=7.2 Hz, 3H), 1.33 (m, 4H), 2.16 (t, J=6.6 Hz, 2H), 2.40 (s, 3H), 3.68 (t, J=7.8 Hz, 2H), 4.03 (q, J=4.5 Hz, 2H), 7.05)m, 1H), 7.13 (m, 2H), 7.34 (m, 4H), 7.48 (m, 3H); 13C NMR (DMSO-d6) δ13.4, 14.4, 24.3, 25.7, 27.8, 29.6, 33.5, 43.3, 59.9, 125.8, 126.0, 128.1, 128.3, 128.8, 129.3, 131.1, 131.8, 135.2, 135.3, and 144.0. Anal. Calcd for C25H30N2O2: C, 76.89; H, 7.74; N, 7.17. Found: C, 76.33; H, 7.67, N, 6.85.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH:8](=[C:2]1[CH2:3][CH2:4][CH2:5][C:6](=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:1]1=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCCC1
Product: O=C1C(=Cc2ccccc2)CCCC1=Cc1ccccc1
Reaction time: 2 h

Procedure:
(75) Cyclohexanone (10 mmol) and benzaldehyde (20 mmol) were used. The reaction stirred for 2 hours. A solid formed and was filtered. Recrystallization from ethanol yielded 2.01 g (73.4%) of bright-yellow flakes: mp 118.1-119.0° C. (lit. mp 116-117° C., Smith, et al., Can. J. Chem., 1973, 51, 1458-1470). 1H NMR (250 MHz) δ 7.83 (s, 2H), 7.50-7.32 (m, 10H), 2.95 (t, 4H), 1.80 (p, 2H); 13C NMR (62.7 MHz) 190.5, 137.1, 136.4, 136.1, 130.5, 128.8, 128.5, 28.6, 23.2 ppm.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[C:9]2=[O:15])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].I[CH:21]([CH3:23])[CH3:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:21]([CH3:23])[CH3:22])([C:13]#[N:14])[C:9]2=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: N#CC1CCN(C(=O)c2ccc(F)cc2)C1=O
Reactant: CC(C)I
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C1(C#N)CCN(C(=O)c2ccc(F)cc2)C1=O
Reaction time: 0.08 h

Procedure:
To a solution of 1-(4-fluorobenzoyl)-2-oxopyrrolidine-3-carbonitrile (500 mg) obtained in Step F of Example 1 in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in mineral oil, 130 mg) in an ice bath, and the mixture was stirred at the same temperature for 5 min. To the reaction mixture was added 2-iodopropane (1.1 mL) in an ice bath, and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added 10% aqueous citric acid solution in an ice bath, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (310 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:22])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:26][C:27]#[N:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:26][C:27]#[N:28])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (32.5 g, 0.1 mol), NaH (12 g, 0.3 mol) was added at 0° C. The mixture was stirred for 1 h at room temperature. The mixture was cooled to 40° C., then bromoacetonitrile (35.7 g, 0.3 mol) was added drop wise. The mixture was stirred an additional 0.5 h at −20° C. HPLC indicated the reaction was ˜30% complete. The addition of NaH and bromoacetonitrile was repeated two more times. HPLC indicated the reaction was ˜60% completed. The reaction was quenched with sat. NH4Cl. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated to give the crude product as brown oil (36.8 g), which was used for the next step without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(C(C)C)CC)(C)C.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.O>ClCCl>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:24])=[CH:21][CH:20]=1
Reactant: NCCCCCCO
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(NCCCCCCO)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 81.6 %

Procedure:
To a solution of 6-amino-1-hexanol (12.9 g) and diisopropylethylamine (11.9 g) in dry dichloromethane (100 ml) at 5° C. was added 4-chlorobenzoyl chloride (16.1 g) in dry dichloromethane at such a rate to maintain the temperature below 10° C. After stirring for 16 h, the mixture was poured into water and filtered. The solid was washed with water, 2M hydrochloric acid (150 ml), water, dichloromethane and was dried under reduced pressure to give 6-(4-chlorobenzoylamino)hexan-1-ol (19.2 g). 1H-NMR (d6-DMSO) δ 1.25-1.65 (8H, m), 3.24 (2H, q), 3.38 (2H, t), 7.52 (2H, m), 7.84 (2H, m) and 8.54 (1H, bt)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:43]=[C:42]([O:44][CH3:45])[C:41]([C:46](Cl)=[O:47])=[N:40]2)=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:46]([C:41]2[C:42]([O:44][CH3:45])=[CH:43][N:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[N:40]=2)=[O:47])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Reactant: COc1cn(-c2ccc(F)cc2)nc1C(=O)Cl
Product: COc1cc2c(Oc3ccc(NC(=O)c4nn(-c5ccc(F)cc5)cc4OC)cc3F)ccnc2cc1OCCCN1CCOCC1

Procedure:
Q7 was prepared from 3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]aniline and E3 following the general procedure reported in Preparative Example 1 Step 3. 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.01 (m, 2H), 2.51 (m, 6H), 3.61 (m, 4H), 3.86 (s, 3H), 3.94 (s, 3H), 4.20 (t, J=6.2 Hz, 2H), 6.46 (d, J=5.3 Hz, 1H), 7.43 (m, 4H), 7.53 (s, 1H), 7.72 (t, J=9.1 Hz, 1H), 8.01 (m, 3H), 8.47 (d, J=5.3 Hz, 1H), 8.49 (s, 1H), 10.19 (s, 1H). MS (ES) C34H33F2N6O6 requires: 645. Found: 646 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5](=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7].Br[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1.CCOC(C)=O>CN(C=O)C.O>[CH3:7][C:6]([CH3:9])([CH3:8])[C:5](=[O:10])[CH2:4][O:3][C:12]1[N:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(Br)nc1
Reactant: CC(C)(C)C(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)COc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Dissolve sodium hydride (380 mg, 9.5 mmol) in anhydrous DMF (7 mL). Cool at 0° C., add dropwise 1-hydroxy-3,3-dimethylbutan-2-one (1.1 g, 9.5 mmol) and stir at this temperature for 30 min. Add a solution of 6-bromo-nicotinonitrile in DMF (7 mL) and heat at 70° C. overnight. Cool the reaction mixture with ice/water and work-up sequentially with EtOAc and water. Dry the organic fraction over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate (424 mg, 50%). MS (ES+) if/A: 219 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=O)=[C:8](F)[CH:7]=1.O.[OH-].[Li+].[SH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]2[C:10]([OH:12])=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[S:26][C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1ccc(OCc2ccc(Cl)cc2Cl)cc1F
Reactant: CCOC(=O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of ethyl 4-((2,4-dichlorobenzyl)oxy)-2-fluorobenzoate (2.0 g) in DMF (dry) (40 mL) were added lithium hydroxide monohydrate (0.978 g) and ethyl 2-mercaptoacetate (1.92 mL) at room temperature. The mixture was stirred at room temperature for 2 d. The mixture was diluted with water and the precipitate was collected by filtration, and washed with IPE to give the title compound (2.30 g).
Reaction SMILES: [S:1]([C:5]1[S:9][C:8]([C:10]#[N:11])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[OH:14][NH:13][C:10]([C:8]1[S:9][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=1)=[NH:11]
Reactant: N#Cc1ccc(S(N)(=O)=O)s1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc(S(N)(=O)=O)s1
Yield: 57.5 %

Procedure:
A stirred mixture of 5-sulfamoyl-thiophene-2-carbonitrile [CAS-No. 519055-65-3] (0.31 g, 1.65 mmol), hydroxylamine hydrochloride (0.23 g, 3.31 mmol) and sodium carbonate (0.175 g, 1.65 mmol) in water (4.6 ml) and ethanol (1 ml) was heated under reflux conditions for 1.5 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (100 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/MeOH/hexane) to yield the title compound (0.21 g, 58%) as a white solid. MS (ISN) 220.1 [(M−H)−]; mp 189° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:27](=[O:28])[C@@H:19]([NH:18][C:11](=[O:12])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)NCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(Br)cc21
Reaction time: 60 h
Yield: 42.8 %

Procedure:
The 6-bromoindoline (1050 mg, 5.30 mmol), N—BOC-phenylalanine (1.41 g, 5.30 mmol), N-ethyl-N-isopropylpropan-2-amine (2.02 ml, 12.2 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.41 g, 6.36 mmol) (HBTU) were dissolved in DMF. The reaction mixture was stirred for 2.5 days. The reaction was diluted with water and then extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with 1M lithium chloride solution (2×70 mL) and brine (1×70 mL) and dried over magnesium sulfate. The crude product was then recrystallyzed using ethyl acetate:hexanes to give (S)-tert-butyl 1-(6-bromoindolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate (1.01 g, 42.8% yield). MS ESI (pos.) m/e: 445.1 (M+H).
Reaction SMILES: [CH3:1][C:2]([C@@H:4]([C@H:6]([CH2:8]O)O)O)=O.[CH2:10]([O:17][CH2:18][CH:19]=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.OCC(=O)C>C(#N)C>[CH2:10]([O:17][CH2:18][C:19]1[CH:8]=[CH:6][CH:4]=[CH:2][CH:1]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)[C@H](O)[C@@H](O)CO
Reactant: O=CCOCc1ccccc1
Agent: CC(=O)CO
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: c1ccc(COCc2ccccc2)cc1
Reaction time: 48 h
Yield: 32 %

Procedure:
FIG. 41 illustrates Ketone 2111a was easily transformed to 1-deoxy-L-xylulose (1111) by hydrogenation. Benzyloxyacetaldehyde (80 mg, 0.53 mmol) in ) in ) 0.5 mL of acetonitrile, was added to 9 mL of a solution of antibody 38C2 (35 mg, 0.23 mmol) in PBS (phosphate buffer saline, 100 mM), followed by the addition of of hydroxyacetone. (0.5 mL, 6.3 mmol). After 48 hr at room temperature the reaction reached 56% conversion and the mixture was freeze dried. The remaining residue was extracted with methylene chloride. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel, ethyl acetate/hexane, 1/1) to give pure 2111a (39 mg, 0.17 mmol, 32%) in 97% ee. Benzyl ether 2111a (39 mg, 0.17 mmol) was dissolved in 1 mL of methanol and hydrogenated with a catalytic amount of palladium hydroxide on carbon. After two hr, the mixture was filtered through celite and the solvent was removed under reduced pressure to give pure 1-deoxy-L-xylulose (19 mg, 0.14 mmol, 81%).
Reaction SMILES: [F-].C([N+:6](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][N:26]2COCC[Si](C)(C)C)=[CH:22][C:21]=1[C:43]1[CH:48]=[CH:47]C([N+]([O-])=O)=[CH:45][CH:44]=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][NH:26]2)=[CH:22][C:21]=1[C:43]1[CH:44]=[CH:45][N:6]=[CH:47][CH:48]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc([N+](=O)[O-])cc3)cc12
Agent: O=C([O-])O
Agent: [F-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccncc3)cc12

Procedure:
36.8 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 3 g of N-[6-chloro-5-(4-nitrophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 135 cm3 of tetrahydrofuran. The medium is then refluxed for 18 hours and is then allowed to return to room temperature to add 100 cm3 of ethyl acetate and 75 cm3 of saturated aqueous sodium hydrogen carbonate solution. The organic phase is separated out after settling of the phases has taken place, washed with 100 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 100 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa; 50° C.); the residue is taken up in 35 cm3 of diisopropyl ether, filtered off on a sinter funnel and then washed with 2×20 cm3 of diisopropyl ether. After drying (90 Pa; 50° C.), 88 mg of N-[6-chloro-5-(4-nitrophenyl)-1H-indazol-3-yl]butanamide are obtained in the form of yellow crystals melting at 260° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.[CH:27]([N:30](C(C)C)CC)(C)C.CN>S(Cl)(Cl)=O.C1COCC1.CCOC(C)=O>[CH3:27][NH:30][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:16][N:15]=[CH:14]3)[CH:4]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C)c(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
4-Methyl-3-(1-morpholinophthalazin-6-yl)benzoic acid (100 mg, 286 μmol) was dissolved in thionyl chloride (5.7 mL) and heated to 65° C. for 1 h. The reaction was then concentrated in vacuo, dissolved in tetrahydrofuran 99.9% (5.7 mL) and diisopropylethylamine (150 μL, 859 μmol) and methylamine, 2.0 m solution in THF (0.7 mL) were added. The reaction mixture was stirred for 3 h at ambient temperature. The reaction mixture was diluted with 50 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layers were washed 3 times with 50 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, and concentrated via rotovap to give a crude product. After purification by chromatography, the title compound was obtained. Found MS (ES+): 363(M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].C[N:33]1[CH2:38][CH2:37][O:36][CH2:35]C1.F[P-](F)(F)(F)(F)F.[N:46]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:50]2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:46][CH2:50][C:37]1[O:36][CH:35]=[N:33][CH:38]=1)=[O:4]
Reactant: CN1CCOCC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1cnco1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 39.5 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 35 mg, 0.081 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.054 mL, 0.487 mmol), oxazol-5-ylmethanamine, HCl (19.65 mg, 0.146 mmol), and BOP (64.6 mg, 0.146 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.6 min) to give single enantiomer 2-hydroxy-N-(oxazol-5-ylmethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (17.2 mg, 0.032 mmol, 38.8% yield): LCMS=512.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.25 (2 H, m), 7.66-7.78 (4 H, m), 7.54-7.66 (4 H, m), 6.04 (1 H, s), 5.19 (1 H, s), 4.51 (2 H, s). HPLC Peak RT=10.1 min (Analytical Method D).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:32][OH:33])[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1.FC(F)(F)C(O)=O.C(N)CN>CO>[OH:1][CH2:2][C:3]1([CH2:32][OH:33])[CH2:4][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)(CO)C4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: CO
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(CO)(CO)C1

Procedure:
3,3-Bis(hydroxymethyl)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.022 g, 0.000046 mol) was treated with trifluoroacetic acid (0.5 mL, 0.006 mol) at rt for 30 min and evaporated to dryness. The residue was then mixed with ethylenediamine (0.2 mL, 0.003 mol) in MeOH (1 mL) for 2 h. The reaction was concentrated and purified on prep. LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH40H) to give the desired product as free base. LCMS calculated for C17H19N6O2(M+H)+: 339.2; Found: 339.3. 1H NMR (300 MHz, CD3OD): δ 8.72 (1H, s), 8.67 (1H, s), 8.39 (1H, s), 7.51 (1H, d, J=3.3 Hz), 6.97 (1H, d, J=3.3 Hz), 3.62 (2H, s), 3.46 (2H, s), 3.36 (2H, s), 2.80 (2H, d, J=13.8 Hz), 2.54 (2H, d, J=13.8 Hz) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[N:24]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])=[CH:4][CH2:3]1.Cl.Cl[CH2:41][CH2:42][N:43]([CH3:45])[CH3:44].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:44][N:43]([CH3:45])[CH2:42][CH2:41][N:17]1[N:18]=[N:19][C:15]([CH2:14][C:12]2[CH:11]=[CH:10][C:9]([NH:20][C:21]([C:23]3[N:24]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])[CH:25]=[C:26]([C:28]#[N:29])[N:27]=3)=[O:22])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:38])([CH3:1])[CH2:3][CH:4]=3)[CH:13]=2)=[N:16]1
Reactant: CN(C)CCCl
Reactant: CC1(C)CC=C(c2cc(Cc3nnn[nH]3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCn1nnc(Cc2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCC(C)(C)CC3)c2)n1
Temperature: 100 °C
Yield: 24.8 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1H-tetrazol-5-ylmethyl)-phenyl]-amide (as prepared in Example 42, step (b), 78 mg, 0.14 mmol) and (2-chloro-ethyl)-dimethyl-amine hydrochloride (63 mg, 0.43 mmol) in DMF (1 mL) was treated with DIEA (128 μL, 0.73 mmol) and then heated at 100° C. for 1 h. The reaction was allowed to cool to room temperature, diluted with EtOAc (25 mL) and then washed with water (2×10 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo. Purification by preparative tlc (10% MeOH—CHCl3) afforded 21 mg (24%) of the title compound. Mass spectrum (ESI, m/z): Calcd. for C31H45N9O2Si, 604.3 (M+H), found 604.1.