Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6]1)=[O:4].C[O-].[Na+].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(OC)(C)(C)C>[CH3:1][O:2][C:3]([C@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 116 h
Yield: 86.4 %

Procedure:
To a solution of (3R,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (72.74 g, 220.5 mmol) in methanol (730 mL) was added sodium methylate solution (5.4 M methanol, 81.7 mL, 441.1 mmol). The reaction mixture was stirred for 116 h at ambient temperature (after 17.5 h further sodium methylate solution (5.4 M in methanol, 20.4 mL, 110.3 mmol) was added). It was set to pH=1 by addition of sulfuric acid (26.13 mL, 463.1 mmol) and stirred at 60° C. for 19 h. The resulting suspension was cooled to 0° C., tert-butylmethylether (1.6 L) was added and the solution was set to pH=9 with aqueous sodium carbonate (1 M, 440 mL). The aqueous layer was separated and extracted with further tert-butylmethylether (410 mL). The organic layers were washed with brine (310 mL), combined and dried over sodium sulfate. Concentration and filtration over silicagel (heptane: ethyl acetate=80:20) afforded the title compound (62.82 g, 86%) as a light yellow oil. MS m/e: 330.3/332.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][C@H:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[CH3:20]>>[CH3:28][O:27][C:25]([C:24]1[CH:29]=[CH:30][C:21]([C@@H:19]([NH:18][C:14]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH3:20])=[CH:22][CH:23]=1)=[O:26]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2CCCCN2C(=O)OC(C)(C)C)cc1
Yield: 97.9 %

Procedure:
The title compound (D4) (1.95 g) was prepared according to the general procedure for amides preparation starting from 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (1.17 g, available from Sigma Aldrich #495875), and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (1.1 g, for preparation see published International Patent application WO 2005/105733). Reaction time: 18 hrs.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C@@H:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[CH2:9][CH2:10][C:11]([NH:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[N:22][CH:21]=[CH:20]2)=O)=[O:12])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.CCN(C(C)C)C(C)C>C1COCC1>[CH:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[O:12][C:11]([CH2:10][CH2:9][C@@H:8]([NH:7][C:6](=[O:38])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=4)=[N:13][N:14]=3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][N:22]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)NNC(=O)c1ccc2cnccc2c1)Cc1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc3cnccc3c2)o1)Cc1ccc(C(F)(F)F)cc1
Yield: 78 %

Procedure:
tert-Butyl((1R)-4-(2-(6-isoquinolinylcarbonyl)hydrazino)-4-oxo-1-(4-(trifluoromethyl)benzyl)butyl)carbamate (0.080 g, 0.15 mmol) and triphenylphosphine (0.070 mL, 0.30 mmol), and 0.5 mL CCl4 were heated under nitrogen in 10 mL THF at 50° C. for 20 hours. 0.2 mL DIEA was added, and the reaction mixture was heated at reflux 4 hours. The reaction mixture was filtered and the solid was washed with THF. The filtrate was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate (3×). The solvent was evaporated, and the residue was purified by chromatography on silica gel (60% EtOAc in hexane) to provide the product as a white solid (0.06 g, 78%). LCMS (API-ES) m/z: 513 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:25])[CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1C1C=CC=CN=1.[BH4-].[Na+].[BH4-]>C1COCC1.[Co](Cl)Cl.CC(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:25])[CH2:9][O:10][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCC(O)c3cccc(Cl)c3)cc2)S1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(OCC(O)c3cccc(Cl)c3)cc2)S1
Temperature: 0 °C
Yield: 58.2 %

Procedure:
5-{4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione (0.74 g, 2.00 mmol) was dissolved in THF (20 ml). Water (20 ml) was added and then more THF was added until all solids dissolved. A small crystal of cobalt chloride was added, followed by 2,2′-bipyridine (69 mg, 0.44 mmol). The reaction mixture was cooled to 0° C. NaBH4 was added in portions until the blue color persisted. The color gradually faded and was regenerated repeatedly by small additions of borohydride and HOAc. When HPLC indicated that the reaction was complete, the reaction mixture was partitioned between EtOAc and H2O. HOAc was added until the pH of the aqueous phase was ca. 6, and then the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 0-10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.44 g (59%) of a sticky yellow solid. MS (ESI−) for C18H16ClNO4S m/z 376.1 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][O:31]C5CCCCO5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:10]=1.C(Cl)(=O)C>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:10]=1
Reactant: CS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(CCOC5CCCCO5)c4)ccc32)c1
Solvent: CC(=O)Cl
Solvent: CO
Product: CS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(CCO)c4)ccc32)c1
Yield: 49.1 %

Procedure:
To a solution of N-(2′,4′-difluoro-5-(5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)-ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamide (0.15 g, 0.252 mmol) in methanol (5 ml) was added acetyl chloride (1 ml) at 0° C. as in Example 1(d). The solvent was distilled off to afford the product (0.063 g). 1H NMR (300 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.22 (s, 1H), 8.00-7.97 (d, 2H), 7.80-7.69 (m, 2H), 7.67-7.61 (m, 1H), 7.59-7.60 (d, 1H), 7.53 (s, 2H), 7.47-7.41 (m, 2H), 7.29-7.25 (t, 1H), 4.97-4.95 (t, 1H), 4.18-4.15 (m, 2H), 3.80-3.78 (m, 2H), 3.14 (s, 3H) Calculated mass: 509.1; Observed mass: 510.3 [M+H]+ (rt: 1.18 min).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13](=[O:29])[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.I[CH3:31].Cl>C1COCC1>[CH3:11][O:12][C:13](=[O:29])[CH:14]([CH3:31])[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]1
Reactant: COC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.42 h

Procedure:
To a precooled (−78° C.) solution of 1.0M sodium bis(trimethylsilyl)amide in THF (13.1 mL, 13.1 mmol) was added dropwise under a nitrogen atmosphere a solution of tert-butyl 4-(3-methoxy-3-oxopropyl)piperidine-1-carboxylate (1.78 g, 6.56 mmol) in 11 mL of THF. After stirring for an additional 25 min, neat iodomethane (1.23 mL, 19.7 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for two more h. The reaction mixture was then poured into 1N HCl solution and the resulting mixture was extracted twice with ether. The combined ethereal layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 40% ethyl acetate/hexanes) gave tert-butyl 4-(3-methoxy-2-methyl-3-oxopropyl)piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@@H:10](N)[CH2:11]C1C=CC(C2C=CC=C(Cl)C=2)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[C@H](C)C(OCC)=O)(=O)=O>ClCCl>[CH2:1]([O:8][C:9](=[O:26])[CH2:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Agent: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-amino-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (10.0 g, 24.9 mmol) in dichloromethane (100 mL) was added triethylamine (10.4 mL, 74.6 mmol) at 0° C. After stirred for 10 min, ethyl (R)-2-(trifluoromethylsulfonyloxy)propionate (9.3 mL, 49.5 mmol) was added at room temperature and stirred for 1 hour. Additional triethylamine (10.4 mL, 74.6 mmol) and ethyl (R)-2-(trifluoromethylsulfonyloxy)propionate (9.3 mL, 49.5 mmol) were added at room temperature and stirred for additional 2 hours. The reaction mixture was washed with H2O and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/heptane) to give (S)-3-(3′-chloro-biphenyl-4-yl)-2-(S)-1-ethoxycarbonyl-ethylamino)-propionic acid benzyl ester. 1H NMR (400 MHz, CDCl3) δ 1.21 (t, 3H, J=7.3 Hz), 1.27 (d, 3H, J=6.8 Hz), 1.89 (bs, 1H), 2.95-3.07 (m, 2H), 3.38 (dd, 1H, J=6.8, 14.8 Hz), 3.69 (dd, 1H, J=7.1, 7.1 Hz), 4.06-4.17 (m, 2H), 5.06 (d, 1H, J=12.1 Hz), 5.12 (d, 1H, J=12.1 Hz), 7.20-7.25 (m, 4H), 7.28-7.34 (m, 4H), 7.35 (dd, 1H, J=7.6, 7.6 Hz), 7.41-7.46 (m, 3H), 7.53 (dd, 1H, J=1.5, 1.5 Hz); MS: m/z (MH+) 466.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.N1C=CC=CC=1>C(#N)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(S)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc(SC(=O)c2ccc(OC(C)=O)cc2)cc1
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (7.06 g) in dry acetonitrile (15 ml) was added to a solution of 4-methoxythiophenol (5.00 g) in dry acetonitrile (60 ml), and the mixture cooled (ice-bath) and stirred whilst pyridine (2.83 ml) was added dropwise over 10 minutes. The solution was allowed to reach room temperature, stirred for a further 2 hours and the volatile solvents evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the separated organic layer was washed successively with water and brine, dried over magnesium sulphate, and evaporated. Column chromatography of the crude material (silica; ethyl acetate/hexane mixtures as eluant) gave the pure thioester as a pale yellow foam (8.84 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.Cl>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:29]2[C:14](=[O:15])[C:10]3[CH:11]=[C:12]4[CH2:13][CH:5]([N:4]([CH2:20][CH2:21][CH3:22])[CH2:1][CH2:2][CH3:3])[CH2:6][C:7]4=[CH:8][C:9]=3[C:17]2=[O:19])=[CH:26][CH:25]=1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NCc1ccc(Cl)cc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(Cl)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 4-chlorobenzylamine (0.17 mL, 1.4 mmol). Purification using silica gel, eluting with 5:1 hexane/acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 102 as a white solid (m.p. 260-261° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11](=[O:22])[NH:12][C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:23][C:24]([F:29])([F:28])[CH2:25][CH2:26]O.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11](=[O:22])[N:12]([CH2:26][CH2:25][C:24]([F:29])([F:28])[F:23])[C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: OCCC(F)(F)F
Reactant: COc1ccc(NC2=C(c3ccccc3)C(=O)NC2=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(CCC(F)(F)F)C2=O)cc1
Temperature: 130 °C
Yield: 76.9 %

Procedure:
To a solution of 3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione (0.17 mmol, 50 mg), 3,3,3-trifluoropropan-1-ol (0.19 mmol, 21 mg), diethyl azodicarboxylate (0.19 mmol, 33 mg) in dry THF (1 mL) was added triphenylphosphine (0.19 mmol, 49 mg) in dry THF (1 mL). The mixture was heated in a microwave reactor at 130° C. for six min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 51 mg (77%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.27 (bs, 1H), 7.17-7.06 (m, 3H), 7.00-6.95 (m, 2H), 6.64-6.55 (m, 4H), 3.89 (t, J=7.3 Hz, 2H), 3.70 (s, 3H), 2.61-2.48 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH2:28][CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:28][CH2:27]2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: Fc1ccc2c(c1)CCN2
Product: O=C(O)c1ccnc(-c2cn(CCN3CCc4cc(F)ccc43)cn2)c1
Yield: 11 %

Procedure:
The title compound was prepared in 11% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 5-fluoro-2,3-dihydro-(1H)-indole according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.88 (2H, t, J=8.4 Hz), 3.42 (2H, t, J=6.2 Hz), 4.25 (2H, t, J=6.1 Hz), 6.49 (1H, m), 6.76 (1H, td, J=2.2 and 8.8 Hz), 6.89 (1H, dd, J=6.4 Hz), 7.57 (1H, d, J=5.0 Hz), 7.83 (1H, s), 7.94 (1H, s), 8.27 (1H, s), 8.62 (1H, d, J=4.8 Hz). [M+H] Calc'd for C19H17FN4O2, 353. Found, 353.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:2][C:3]#[CH:4].I[C:19]1[C:27]2[O:26][CH2:25][C:24](=[O:28])[C:23]=2[CH:22]=[CH:21][C:20]=1[O:29][CH3:30]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:30][O:29][C:20]1[CH:21]=[CH:22][C:23]2[C:24](=[O:28])[CH2:25][O:26][C:27]=2[C:19]=1[C:4]#[C:3][CH2:2][CH2:1][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: COc1ccc2c(c1I)OCC2=O
Reactant: C#CCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C#CCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 54.2 %

Procedure:
A solution of tert-butyl 4-(but-3-ynyl)piperidine-1-carboxylate (0.370 g, 1.56 mmol) in triethylamine (10 mL) was added with 7-iodo-6-methoxybenzofuran-3(2H)-one (0.452 g, 1.56 mmol) synthesized in Example B46, Step 2, dichlorobis(triphenylphosphine)palladium(II) (0.110 g, 0.156 mmol) and copper(I) iodide (0.0297 g, 0.156 mmol), and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)but-3-ynyl]piperidine-1-carboxylate (0.338 g, 54%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH2:4][C:3]1=[O:15].O1CCCC1>CO>[OH:14][C@H:11]1[CH2:10][CH2:9][C@@H:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:15])[CH2:4]2)[CH2:13][CH2:12]1
Reactant: CN1CCN(C2CCC(=O)CC2)CC1=O
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN([C@H]2CC[C@@H](O)CC2)CC1=O

Procedure:
17 ml of a 1M L-Selctride solution (in tetrahydrofuran) are added dropwise at −78° C. to 3.3 g 4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexan-1-one in 100 ml abs. tetrahydrofuran. After 5.5 hours 20 ml of methanol are added and the solution is evaporated down. The residue is purified by column chromatography. The mixture of cis- and trans-compound is separated by preparative HPLC.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29](O)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.CCCP(=O)=O.[NH2:45][CH2:46][CH2:47][CH2:48][OH:49]>CN(C1C=CN=CC=1)C.ClCCCl>[OH:49][CH2:48][CH2:47][CH2:46][NH:45][C:29]([C:23]1[C:22]2[CH2:21][CH2:20][N:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=4)=[O:12])[CH:14]=3)[CH2:28][C:27]=2[CH:26]=[N:25][CH:24]=1)=[O:30]
Reactant: NCCCO
Reactant: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)NCCCO)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.5 %

Procedure:
To a mixture of 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid (47 mg, 0.113 mmol), triethylamine (0.047 mL, 0.34 mmol), and catalytic DMAP in 3.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.081 mL, 0.136 mmol). After 5 min at rt, 3-amino-1-propanol (0.011 mL, 0.147 mmol) was added and the reaction stirred at rt for 2 hours. The reaction was quenched with aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/EtOAc plus 10% MeOH to give the title compound as a light yellow solid (20 mg, 37%). 1H NMR (CDCl3) δ: 8.46 (s, 1H), 8.41 (s, 1H), 8.02 (s, 1H), 7.54 (s, 1H), 7.44-7.51 (m, 2H), 7.19-7.39 (m, 4H), 7.10 (d, J=8.2 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.81 (t, J=5.6 Hz, 1H), 4.45 (s, 2H), 3.78 (t, J=5.4 Hz, 2H), 3.53-3.65 (m, 4H), 3.17 (t, J=5.6 Hz, 2H), 2.86-2.97 (m, 1H), 1.77-1.86 (m, 2H), 1.27 (d, J=6.7 Hz, 6H)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH:25]([O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1)([CH3:27])[CH3:26].O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([O:28][CH:25]([CH3:27])[CH3:26])=[CH:34][CH:33]=3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc(OC(C)C)nc3)n2n1
Temperature: 110 °C
Yield: 37.2 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 100 mg, 0.290 mmol), 2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (78 mg, 0.296 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 29 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.966 mL of 1,4-dioxane and 0.483 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (50-85% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (48.1 mg, 37.2%). 1H NMR (DMSO-d6) δ: 11.13 (s, 1H), 8.85 (dd, J=2.5, 0.5 Hz, 1H), 8.30-8.35 (m, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.92 (s, 1H), 7.55 (d, J=8.6 Hz, 2H), 6.92 (dd, J=8.7, 0.6 Hz, 1H), 6.32 (d, J=0.5 Hz, 1H), 5.32 (spt, J=6.2 Hz, 1H), 5.13 (br. s., 1H), 3.50 (s, 1H), 2.34 (s, 3H), 1.39 (s, 6H), 1.29 (d, J=6.1 Hz, 6H); ESI-MS: m/z 446.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH:14]([CH3:16])[CH3:15])[N:5]=[C:4]([NH2:17])[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])#[N:19].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[NH2:17][C:4]1[N:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([F:29])[CH:22]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH:14]([CH3:16])[CH3:15])[N:5]=1
Reactant: CC(C)[C@@H]1COCCN1c1cc(Cl)nc(N)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@@H]1COCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
4-Chloro-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine (350 mg, 1.36 mmol), (4-cyano-3-fluorophenyl)boronic acid (337 mg, 2.05 mmol, 1.5 equiv), tricyclohexylphosphine (57.3 mg, 0.20 mmol, 0.15 equiv), Pd2(dba)3 (94 mg, 0.10 mmol, 0.075 equiv) and K3PO4 (492 mg, 2.32 mmol, 1.7 equiv) were charged into a 30 mL microwave vial, followed by addition of 5 mL of 1,4-dioxane and 1.6 mL of water. The mixture was bubbled with argon for 10 minutes, followed by capping and heating in a oil bath at 100° C. for 20 hours. LCMS showed conversion complete. The mixture was filtered through celite and rinsed with EtOAc (40 mL). The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine (10 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 80% EtOAc in CHCl3 to afford the title compound (359 mg) as an off-white foam with a light yellow tint. LC-MS (ES) m/z=342 [M+H]+.