Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl-].[Mg+2].[Cl-].[C:6]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH3:7].[Cl:14][CH2:15][C@@H:16]([OH:23])[CH2:17][C:18](OCC)=[O:19].C([N-]C(C)C)(C)C.[Li+]>CCCCCC.O1CCCC1>[Cl:14][CH2:15][C@@H:16]([OH:23])[CH2:17][C:18](=[O:19])[CH2:7][C:6]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CCOC(=O)C[C@H](O)CCl
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CCl
Reaction time: 0.5 h

Procedure:
Separately, 240 mg (6 mmol equivalent) of sodium hydride (60% in mineral oil) was washed with hexane and, then, 6 ml of tetrahydrofuran was added. Then, at 5° C., 1.71 g (18.0 mmol) of magnesium chloride, 1.74 g (15.0 mmol) of tert-butyl acetate and 1.0 g (6 mmol) of ethyl(3S)-4-chloro-3-hydroxybutyrate were added and the mixture was stirred for 30 minutes. To this mixture, the lithium diisopropylamide solution prepared above was added dropwise over 10 minutes at the same temperature and the reaction mixture was further stirred at an elevated temperature of 25° C. for 3 hours.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4](OC)=[O:5].[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>>[CH2:10]([NH:14][C:4](=[O:5])[C:3]([CH3:9])([CH3:8])[CH2:2][OH:1])[CH2:11][CH2:12][CH3:13]
Reactant: COC(=O)C(C)(C)CO
Reactant: CCCCN
Product: CCCCNC(=O)C(C)(C)CO
Yield: 100 %

Procedure:
Prepared as in Example 215d (Method A) from methyl 3-hydroxy-2,2-dimethylpropanoate and n-butyl amine in 100% yield. MS 174 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]3)=[O:25])[CH:19]=2)=[CH:16][CH:17]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH2:12][C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]3)=[O:25])[CH:19]=2)=[CH:16][CH:17]=1
Reactant: CN1CCCN(C(=O)c2cccc(-c3ccc(C=C4C(=O)Nc5ccc(Cl)cc54)o3)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCCN(C(=O)c2cccc(-c3ccc(CC4C(=O)Nc5ccc(Cl)cc54)o3)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5-chloro-3-((5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one (24 mg) in methanol (4 ml) was added sodium borohydride (8 mg). The reaction was stirred at room temperature for 5 min. Water was added and the product was extracted with dichloromethane, dried with sodium sulfate and concentrated under vacuum to give 5-chloro-3-((5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methyl)indolin-2-one as orange powder. LCMS (ES): >95% pure, m/z 464 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.[Cl-].[NH4+]>CO.ClCCl.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cnc(OCC2CC2)c(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Nc1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.2 %

Procedure:
To a solution of 3-bromo-2-cyclopropylmethoxy-5-nitro-pyridine (600 mg, 2.19 mmol) in methanol (30 ml) were added water (15 ml), zinc dust (1 g, 15.37 mmol) and ammonium chloride (1.28 g, 24.09 mmol) at 25° C., and the reaction mixture was stirred for 45 min at 25° C. After total consumption of starting material (monitored by TLC), the reaction mixture was filtered through a bed of celite, and the filtrate was evaporated under reduced pressure to get the crude residue. The residue was dissolved in dichloromethane and washed with water and brine. The organic part was dried over Na2SO4 and evaporated to get the compound (507 mg, 95%). This compound was used in next step without further purification. MS (LC/MS): 244.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=1)[CH3:5].C([O-])([O-])=O.[K+].[K+].[I-].[Na+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>CC(C)=O>[CH3:35][O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:16][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH:4]([C:3]([O:2][CH3:1])=[O:17])[CH3:5])[CH:7]=2)[CH:12]=1
Reactant: COC(=O)CCCCCBr
Reactant: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCCCOc1ccc2cc(C(C)C(=O)OC)ccc2c1
Yield: 55.6 %

Procedure:
To a mixture of 2-(6-Hydroxy-naphthalen-2-yl)-propionic acid methyl ester 6 (150 g, 652 mmol), anhydrous K2CO3 (480 gr, 3.473 mol) and sodium iodide (22.5 grams, 150 mmol) in anhydrous acetone (2000 ml) was added methyl 6-bromohexanoate (216 g, 1.033 mol) and refluxed for 60 hours. Acetone was distilled off and water (1500 ml) was added. Crude 9 was extracted into ethyl acetate, dried over Na2SO4, distilled and purified by column chromatography on silica gel using hexane as eluant to give pure 9 (130 g, 55.6%) as a light yellow syrup. The structure was confirmed with NMR.
Reaction SMILES: C(OC(N[C:9]1[CH2:10][C:11](C(O)=O)=[CH:12][C:13]2[CH:19]=CC(C3C=CC(C(N4CCCC4)=O)=CC=3)=C[C:14]=2[N:15]=1)=O)(C)(C)C.N[OH:37]>>[CH3:12][C:13]([OH:37])([CH3:19])[CH2:14][NH:15][CH2:9][CH2:10][CH3:11]
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Reactant: NO
Product: CCCNCC(C)(C)O

Procedure:
The following examples 115 and 117 were prepared by the procedures as described in Example 101 (Steps H and I) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and the appropriate amines (2-methyl-1-(propylamino)propan-2-ol was prepared by the procedure reported in J. Am. Chem. Soc. 1939, 61, 3562) or the hydroxylamine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#[N:2].[CH3:16][Sn:17]([N:20]=[N+:21]=[N-:22])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:16][Sn:17]([CH3:19])([CH3:18])[N:20]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[N:2][N:22]=[N:21]1
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2-c2nnnn2[Sn](C)(C)C)cc1
Temperature: 70 °C

Procedure:
A solution of 2-cyano-4'-methylbiphenyl (1.93 g) in toluene (25 mL) was treated with trimethyltin azide (2.65 g) and heated at reflux for 24 hours. The resulting suspension was cooled to 70° C. and filtered. The collected solid was dried at reduced pressure to give the title compound. 1H-NMR (CDCl3) δ7.5 (m, 4H), 7.0 (q, 4H), 2.3 (s, 3H), 0.4 (s, 9H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@@H:26]4[CH2:30][C:29](=[O:31])[NH:28][CH2:27]4)[CH3:25])=[N:10][C:11](C4C=C5C(CC(=O)N5)=CC=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH:50]4[CH2:52][CH:48]([O:49]4)[CH2:47]3)=[CH:42][CH:41]=2)O1>>[CH:50]12[CH2:52][CH:48]([O:49]1)[CH2:47][N:46]([C:43]1[CH:42]=[CH:41][C:40]([C:11]3[N:10]=[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:27][NH:28][C:29](=[O:31])[CH2:30]4)[CH3:25])[C:8]4[N:4]([CH:1]5[CH2:3][CH2:2]5)[CH:5]=[N:6][C:7]=4[CH:12]=3)=[CH:45][CH:44]=1)[CH2:51]2
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)NC(=O)C3)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC1(C)OB(c2ccc(N3CC4CC(C3)O4)cc2)OC1(C)C
Product: C[C@@H](Oc1nc(-c2ccc(N3CC4CC(C3)O4)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 41 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of 6-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)indolin-2-one:, using instead 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-oxa-3-azabicyclo[3.1.1]heptane (123.7 mg, 0.41 mmol) to afford 51.2 mg (41%) of (4R)-4-((1R)-1-((6-(4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)phenyl)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.21 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.61 (s, 1H), 7.55 (s, 1H), 6.79 (d, J=8.7 Hz, 2H), 5.57 (m, 1H), 4.71 (m, 2H), 3.50 (m, 6H), 3.21 (m, 2H), 2.83 (m, 1H), 2.32 (m, 2H), 1.91 (m, 1H), 1.39 (d, J=6.2 Hz, 3H), 1.14 (m, 4H). MS (ESI+) m/z 460.2 (M+H).
Reaction SMILES: [N:1]([C:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH:5]=1)=[N+]=[N-].[H][H]>[Pd]>[NH2:1][C:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH:5]=1
Reactant: [H][H]
Reactant: CCOC1OC(=O)C=C1N=[N+]=[N-]
Agent: [Pd]
Product: CCOC1OC(=O)C=C1N
Yield: 100.9 %

Procedure:
A mixture of 4-azido-5-ethoxy-5H-furan-2-one (0.62 g, 3.67 mmol) and 10% palladium on charcoal (0.31 g) in de-oxygenated ethyl acetate (20 mL) was stirred at 1 atm hydrogen for 24 h. The reaction was filtered (Celite) and evaporated to provide 4-amino-5-ethoxy-5H-furan -2-one (0.53 g, 100% yield) as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ 5.60 (s, 1H), 4.85 (br s, 2H), 4.81 (s, 1H), 3.81 (m, 1H), 3.67 (m, 1H), 1.22 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:29][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: NC1CCCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CNC2CCCC2)cc1
Yield: 31.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-((cyclopentylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), cyclopentanamine (0.091 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 2 to 10% methanol in dichloromethane) furnished 0.025 g (31%) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)[CH:17]=3)=[CH:13][C:8]=2[O:7][CH:6]=1.[OH-].[Li+]>>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C:5]([CH2:4][C:3]([OH:34])=[O:2])=[CH:6][O:7][C:8]=3[CH:13]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)Cc1coc2cc(OCc3cccc(OCc4ccc(C(F)(F)F)cc4)c3)ccc12
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1coc2cc(OCc3cccc(OCc4ccc(C(F)(F)F)cc4)c3)ccc12

Procedure:
The title compound was prepared in the manner analogous to example 24 using {6-[3-(4-trifluoromethyl-benzyloxy)-benzyloxy]-benzofuran-3-yl}-acetic acid methyl ester and lithium hydroxide. mp 155–157° C.; IR (thin film) cm−1: 1722, 1585, 1492, 1319, 1157, 1114; 400 MHz 1H NMR (DMSO-d6) 12.39 (br s, 1H), 7.69–7.71 (m, 3H), 7.62 (d, 2H, J=8.1 Hz), 7.41 (d, 1H, J=8.5 Hz), 7.26 (t, 1H, J=7.9 Hz), 7.18 (d, 1H, J=2.2 Hz), 7.08–7.09 (m, 1H), 7.00 (d, 1H, J=7.8 Hz), 6.88–6.94 (m, 2H), 5.19 (s, 2H), 5.08 (s, 2H), 3.58 (s, 2H); MS m/z 455 (M−1). Anal. Calc'd for C25H19F3O5: C, 65.79; H, 4.20; found: C, 65.60; H, 4.08.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2C([O-])=O)[CH:5]=[CH:6][C:7]=1[C:8](=O)[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18]C)=[O:17])[C:11]=1[OH:20].[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH:5]=[CH:6][C:7]=1[C:8]1[O:20][C:11]2[C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(C3CCCN3C(=O)[O-])cc2F)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc2nc(-c3ccc(C4CCCN4)cc3F)oc12
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
The mixture of polyphosphoric acid (4 g) and 2-(3-fluoro-4-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamyl)phenyl)pyrrolidine-1-carboxylate (1.1 g, 2.23 mmol) was stirred at 180° C. for 0.5 h under nitrogen, and then cooled to 0° C. Water (50 mL) was added to the mixture and adjusted to pH=7 with sodium hydroxide at 0° C., the solution was extracted with ethyl acetate; the liquid layer was adjusted to pH=5, the water was evaporated under vacuum, the methanol was added, filtered, the solvent was dried over anhydrous sodium sulfate, evaporated to obtain 2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)benzo[d]oxazole-7-carboxylic acid (500 mg, yield 69%). LC-MS (ESI) m/z: 327 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][Si](C)(C)C)[N:4]=1.C1C=CC(O[C:23](Cl)=[S:24])=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]=[C:23]=[S:24])[N:4]=1
Reactant: COc1cc(OC)nc(N[Si](C)(C)C)n1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: CC#N
Product: COc1cc(OC)nc(N=C=S)n1
Yield: 43.5 %

Procedure:
A solution of 45.0 g of 4,6-dimethoxy-2-trimethylsilylaminopyrimidine and 35.0 g of phenyl chlorothionocarbonate in 300 ml of acetonitrile is refluxed for 10 hours. The reaction solution is concentrated under reduced pressure to remove acetonitrile. Toluene (300 ml) is added to the residue and filtered to remove insoluble substance. The filtrate is concentrated under reduced pressure and purified by silica gel column-chromatography (eluent: ethyl acetate:hexane =1:1). 4,6-Dimethoxy-2-isothiocyanatopyrimidine (17.0 g) is obtained from the first eluate. mp 85°~86° C.
Reaction SMILES: O[CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=O)=O.C[S-].[Na+]>C(Cl)Cl.CN(C=O)C>[CH3:24][S:25][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1
Reactant: CC(C)(C)OC(=O)NN1C[C@@H](CO)OC1=O
Reactant: CS(=O)(=O)Cl
Agent: C[S-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSC[C@@H]1CN(NC(=O)OC(C)(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a turbid solution of (S)-tert-butyl 5-(hydroxymethyl)-2-oxooxazolidin-3-ylcarbamate (800 mg, 3.44 mmol) in DCM (5 mL), triethylamine (436 mg, 4.31 mmol) and methanesulfonyl chloride (493 mg, 4.31 mmol) were added and the reaction was stirred, at r.t., under nitrogen for 1 h 30 min. Conversion into the corresponding methanesulfonyl intermediate was complete. The solution was washed with cold citric acid (pH=4-5) and cold brine and the organic layer was separated and dried over Na2SO4. Evaporation of the solvent at 32° C. yielded a colourless foam (980 mg; yield=92%) that was dissolved in DMF (5 mL). Sodium methanethiolate (302 mg, 4.31 mmol) was added and the mixture stirred at 60° C. for 1 h. Conversion into the title product was complete. AcOEt was added and the solution was washed with cold citric acid (pH=3-4), then cold water and cold brine. The organic layer was dried over Na2SO4 and the solvent evaporated, leaving the title compound as a yellow sticky solid that was crystallized from diisopropyl ether into a white solid (404 mg, 1.539 mg). Yield=45%.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:20]1([C:23]([NH2:31])([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)[CH3:24])[CH2:22][CH2:21]1>>[CH:20]1([C:23]([NH:31][C:10]([C:7]2[CH:6]=[C:5]([O:13][C@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)[CH3:24])[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Product: Cc1nc(C(C)(NC(=O)c2cc(O[C@H](C)C(F)(F)F)c(C3CC3)cn2)C2CC2)no1

Procedure:
The mixture of epimers was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 73a) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (135 mg, 70%) as light yellow oil. The mixture of epimers was separated by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the first epimer collected and isolated as colorless oil; MS (ESI, m/z): 425.5 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[CH:17]N(C)C)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C(O)(C)C>[CH2:1]([O:8][C:9]([NH:11][C:12](=[CH:17][N:27]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: COC(=O)C(=CN(C)C)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C(=CN(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
36 g (129 mmol) of methyl 2-benzyloxycarbonylamino-3-dimethylaminoacrylate and 24.12 g (142 mmol) of diphenylamine were dissolved in 630 ml of isopropanol at 40° C. Subsequently, the solution was admixed with 17.4 ml of concentrated hydrochloric acid within 5 min and stirred at 40° C. for a further 30 min. The reaction solution was concentrated to 300 ml and admixed slowly with 300 ml of water. The crystallized product was filtered off with suction and dried at 40° C. under reduced pressure. Yield: 30.5 g (59% of theory) 1H NMR: 3.62 (s, 3H), 4.68 (s, 2H), 6.95-7.10 (m, 6H), 7.20-7.50 (m, 9H), 7.61 (s,1 H)
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]2[CH:7]=[C:8]([NH2:18])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH2:5][CH2:4]1.N1C=CC=CC=1.[Cl:25][C:26]([Cl:33])([Cl:32])[CH2:27][O:28][C:29](Cl)=[O:30]>C1COCC1>[Cl:25][C:26]([Cl:33])([Cl:32])[CH2:27][O:28][C:29](=[O:30])[NH:18][C:8]1[N:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:10]=[C:6]([C:3]2([O:2][CH3:1])[CH2:5][CH2:4]2)[CH:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COC1(c2cc(N)n(-c3ccc(C)cc3)n2)CC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC1(c2cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c3ccc(C)cc3)n2)CC1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To an ice-salt cooled solution of 5-(1-methoxy-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (Preparation 11, 2.43 g, 10 mmol) and pyridine (0.9 mL, 11 mmol) in THF (30 mL), add a solution of 2,2,2-trichloroethylchloroformate (2.12 g, 10 mmol) in THF (10 mL) dropwise. Stir at −15° C. for 0.5 hour, then at 22° C. for 1 hour. Partition the reaction mixture between dichloromethane (50 mL) and saturated aq. sodium bicarbonate (50 mL). Isolate the aqueous phase and extract twice with dichloromethane (25 mL each). Dry the combined organic phases over sodium sulfate and concentrate. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to give a white solid (3.73 g, 89% yield, ES+(m/z) 418.1 [M+H]).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]1([C:14]2[C:18]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][NH:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CS(O[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[N:42]=[C:43]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:44][C:45]=2[CH3:46])=[CH:35][CH:34]=1)(=O)=O>O>[CH3:46][C:45]1[O:44][C:43]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[N:42][C:41]=1[CH2:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH2:31][N:16]2[CH:17]=[C:18]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[N:15]2)=[CH:38][CH:37]=1
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCOS(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(CCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Sodium hydride (60%, oily, 170 mg) was added to an N,N-dimethylformamide solution (50 ml) of ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (890 mg) at 0° C., and this mixture was stirred at 0° C. for 30 minutes. 2-[4-(5-Methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl methane sulfonate (2.79 g) was added to the reaction mixture, which was stirred at 90° C. for 1 hour. 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), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-3-phenyl-1H-pyrazol-4-yl]propionate (1.19 g, yield: 62%) was obtained as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 81–82° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:32]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH2:30]O)[CH:27]=[CH:28][CH:29]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS([Cl:44])(=O)=O>ClCCl>[Cl:44][CH2:30][C:26]1[CH:25]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:10][CH:11]=4)[N:32]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: OCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(3-{2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl)-methanol (0.35 g, 0.815 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (508 μL, 3.670 mmol) was added and the mixture cooled to 0° C., then methanesulfonyl chloride (252 μL, 3.260 mmol) was added dropwise and the reaction was allowed to warm to room temperature and stirred overnight. A small sample of the desired product was purified by preparatory HPLC. RT: 2.56 min, MI: 448 and 450.18, Method: 2.
Reaction SMILES: C[Mg]Br.[CH3:4][C:5]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][N:32]=[C:31](C(OCC)=O)[CH:30]=2)=[CH:25][CH:24]=1)([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][N:10]=1)[CH:6]([CH3:8])[CH3:7]>C1(C)C=CC=CC=1.C1COCC1.C1COCC1>[CH3:4][C:5]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[O:33][N:32]=[C:31]([C:12]([OH:15])([CH3:13])[CH3:11])[CH:30]=2)=[CH:27][CH:28]=1)([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:11][N:10]=1)[CH:6]([CH3:7])[CH3:8]
Reactant: CCOC(=O)c1cc(-c2ccc(C(C)(c3ccc(OCc4ccccn4)cn3)C(C)C)cc2)on1
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(C)(c1ccc(-c2cc(C(C)(C)O)no2)cc1)c1ccc(OCc2ccccn2)cn1
Reaction time: 1 h

Procedure:
Methyl magnesium bromide (334 μL of a 1.4M solution in toluene:THF (75:25), 0.468 mmol) was added to a stirred solution of 1c (55.0 mg, 0.117 mmol) in THF (1.00 mL) at 0° C. After approximately 1 h, the reaction was quenched with water, and the resulting mixture was purified directly by flash chromatography on silica gel (gradient elution; 0%-100% EtOAc/hexanes as eluent) to afford the title compound 2a. m/z (ES) 457 (MH)+. 1HNMR (500 MHz, CDCl3): δ 8.61 (d, 1H, J=4.6 Hz), 7.67 (m, 1H), 7.67 (d, 2H, J=8.5 Hz), 7.58 (d, 1H, J=8.0 Hz), 7.36 (d, 2H, J=8.5 Hz), 7.25 (m, 1H), 7.19 (d, 2H, J=8.3 Hz), 6.92 (d, 2H, J=8.9 Hz), 5.22 (s, 2H), 2.72 (m, 1H), 1.68 (s, 6H), 1.63 (s, 3H), 0.89 (d, 3H, J=6.7 Hz), 0.86 (d, 3H, J=6.7 Hz).