Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CSC.[C:4]1([Mg]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[CH:27]=[CH:28][C:29]([N:31]1[C@H:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][O:33][C:32]1=[O:42])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.[Cu]Cl>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=1[C@H:27]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:28][C:29]([N:31]1[C@H:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:34][O:33][C:32]1=[O:42])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(C=Cc1cc(Br)ccc1OCc1ccccc1)N1C(=O)OC[C@H]1c1ccccc1
Agent: Cl[Cu]
Solvent: C1CCOC1
Solvent: CSC
Product: O=C(C[C@@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
To a precooled (−30° C.) mixture of copper-(I) chloride (21.0 g) and dimethylsulfide (45 ml) in dry tetrahydrofuran (150 ml) was added dropwise an ethereal solution of phenyl-magnesiumbromide (0.3 mol). The mixture was stirred 20 min at the same temperature and then cooled to −40° C. A solution of 3-[3-(2-Benzyloxy-5-bromophenyl)-acryloyl]-(4R)-4-phenyl-oxazolidin-2-one (50.0 mmol) in dry tetrahydrofuran (150 ml) was added during 10 min. The cooling bath was removed and stirring was continued for 18 hrs. The mixture was quenched with half-saturated aqueous ammonium chloride solution and the product was isolated by extraction with ethyl acetate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:23])[C:10](=[O:22])[CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32](O)=[O:33])[CH:27]=1>>[NH2:7][C:8]1[N:9]([CH3:23])[C:10](=[O:22])[CH2:11][C@:12]([C:15]2[CH:16]=[C:17]([NH:21][C:32]([C:28]3[CH:27]=[C:26]([Cl:25])[CH:31]=[CH:30][N:29]=3)=[O:33])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: CN1C(=O)C[C@@](C)(c2cccc(N)c2)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C[C@@](C)(c2cccc(NC(=O)c3cc(Cl)ccn3)c2)N=C1N

Procedure:
The coupling of [(S)-4-(3-amino-phenyl)-1,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester from experiment F1 and 4-chloro-pyridine-2-carboxylic acid followed by deprotection of the intermediate yielded the title compound as a colourless solid. MS (ESI): m/z=372.1 [ M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](B2OC(C)(C)C(C)(C)O2)=[N:22]1>>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[N:3]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Product: COc1cccc(Nc2nc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with indazole boronic acid pinacol ester using General Procedure A. Purification on silica yielded 122. NMR: (CDCl3): 3.88 (s, 3H, CH3), 4.19 (s, 3H, CH3), 6.88-6.91 (m, H, ArH), 7.16-7.18 (m, H, ArH), 7.31 (sbr, H, NH), 7.40 (t. H, ArH, J=8.1 Hz), 7.50 (s, H, ArH), 7.55 (t. H, ArH, J=4 Hz), 7.65 (d, H, ArH, J=8.3 Hz), 8.45 (d, H, ArH, J=7.49 Hz), 9.17 (s, H, ArH) 10.2 (sbr, H, NH). MS: (ESI+) MH+=372.25
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@@H:7]([NH2:24])[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[CH2:13][CH2:14][C:15]([Cl:23])=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])=[CH:5][CH:6]=1.C([O-:28])(C)C.C([O-])(C)C>O>[CH2:13]1[CH:12]2[CH:11]([NH:10][C:8]([C@H:7]([NH2:24])[C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[O:9])[C:18](=[O:19])[N:17]2[C:16]([C:20]([OH:22])=[O:21])=[C:15]([Cl:23])[CH2:14]1.[OH2:28]
Reactant: CC(C)[O-]
Reactant: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CC[C@H]12)c1ccccc1
Solvent: O
Product: N[C@@H](C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CCC12)c1ccccc1
Temperature: 75 °C

Procedure:
A sample of loracarbef isopropanolate is charged to the 300 mm. Allihn condenser. Deionized water (200 g) is charged to a 1 L., 1-neck, round bottom flask. The flask is placed in the Kugelrohr oven and connected to the condenser. The system's pressure is pulled down to approximately 300 mbar. The jacket on the condenser is heated to 75° C. with a constant temperature bath. The Kugelrohr oven is heated to 65° C. The system's pressure is further reduced to 250 mbar and the isopropanolate is subjected to a relative humidity of 100% with agitation for approximately 6 to 8 hours. The oven and condenser are cooled to 20°-25° C. The system is vented to atmospheric pressure. The hydrated product is removed and placed in a vacuum oven at 40°-45° C. The product is dried overnight under full vacuum with a slight nitrogen sweep.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=1>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:23]=[CH:22][N:21]=1
Reactant: COc1cc(Br)ccn1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COc1cc(-c2ccc(C)nc2)ccn1
Yield: 95.3 %

Procedure:
2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.5 g, 16 mmol) and 4-bromo-2-methoxypyridine (2.0 g, 11 mmol) were reacted according to Example 31 (step a) to provide the title compound (2.1 g, 98%) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 8.75 (d, J=2.1 Hz, 1H), 8.23 (d, J=5.4 Hz, 1H), 7.78 (dd, J=8.0, 2.4 Hz, 1H), 7.24 (d, J=8.1, 1H), 7.08 (dd, J=5.4, 1.5 Hz, 1H), 6.84 (d, J=1.0, 1H), 3.98 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=1[O:30][CH3:31].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=3[O:30][CH3:31])[CH2:6][CH2:5]2)=[N:8]1
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 83.4 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H-indazole (3.0 g, 15 mmol), K2 CO3 (1.6 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into water and a white solid separated from solution. The solid was collected, dried and afforded 5.1 g of product. Recrystallization from ethanol yielded 3.6 g of the compound, which upon chromatography (preparative HPLC on silica gel, eluting with methylene chloride/methanol--9:1) gave 3.0 g (49%) of an off-white solid. Recrystallization from ethanol afforded the analytically pure 1-[4-[3-[4-(1H-indazol-1 3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=171°-173° C.
Reaction SMILES: [CH2:1]([C:6]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:13]1CC1>>[CH3:3][C:2]([CH3:5])([CH2:1][C:6](=[CH2:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:4]
Reactant: C1CC1
Reactant: CC(C)(C)CC(=O)CC(C)(C)C
Product: C=C(CC(C)(C)C)CC(C)(C)C

Procedure:
The ratio between dineopentyl ketone and the cyclopropane derivative in this case was 2.5 g/g.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.[H-].[Na+].CC(N(C)C)=O.C([Li])CCC>O1CCCC1>[CH3:38][N:14]1[C:15]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:36])([CH3:37])[CH3:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[C:16]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]2[N:4]=[CH:3][CH:2]=[CH:7][N:6]=2)=[N:13]1
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2c(OCCOc3ncccn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 5.8 %

Procedure:
To N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 3, 100 mg) in anhydrous tetrahydrofuran (2 ml) at 0° C. under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 18 mg), followed by dimethyl acetamide (0.5 ml). The mixture was cooled to −78° C. and n-butyl lithium (1.6 M in hexanes, 0.1 ml) was added dropwise under an atmosphere of nitrogen. The yellow solution was allowed to stir at −78° C. for 20 minutes. 1.25 ml of this solution was withdrawn by syringe and added dropwise to a mixture of ether (10 ml) and water (10 ml). The aqueous layer was extracted with ether (3×10 ml). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ethyl acetate:hexane (2:1) to yield the title compound as a white solid (5 mg).
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][CH2:24][C:10]2([N:13]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH2:11]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([N:13]1[C:10]2([CH2:24][CH2:25][CH2:26][NH:8][CH2:9]2)[CH2:11][CH2:12]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN2C(=O)OCc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCC12CCCNC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
To a solution of an optically-active compound of 1,6-diazaspiro[3,5]-nonane-1,6-dicarboxylic acid 1-benzyl ester 6-tert-butyl ester (5.35 g) in chloroform (134 ml) cooled to 0° C. was added trifluoroacetic acid (27 ml), and the mixture was stirred for 30 minutes, warmed to room temperature and stirred for additional 30 minutes. The reaction mixture was cooled to 0° C., and thereto was added 4M aqueous sodium hydroxide solution (91 ml). The aqueous layer was extracted with chloroform (100 ml, 50 ml) twice, and the combined organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 4/1) to give the titled compound (2.37 g).
Reaction SMILES: [F:1][CH:2]([F:40])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12](=[O:39])[N:13]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([NH:31]C(=O)OC(C)(C)C)=[N:29][CH:30]=3)[S:14](=[O:23])(=[O:22])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1.FC(F)OC1C=CC(N)=CC=1>>[NH2:31][C:28]1[N:29]=[CH:30][C:25]([CH2:24][N:13]2[C:12](=[O:39])[C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:40])[F:1])=[CH:9][CH:8]=3)=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:14]2(=[O:22])=[O:23])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2C(=O)C(Nc3ccc(OC(F)F)cc3)=C(c3ccccc3)S2(=O)=O)cn1
Agent: Nc1ccc(OC(F)F)cc1
Product: Nc1ccc(CN2C(=O)C(Nc3ccc(OC(F)F)cc3)=C(c3ccccc3)S2(=O)=O)cn1

Procedure:
The title compound was prepared from tert-butyl (5-{[4-{[4-(difluoromethoxy)phenyl]amino}-1,1-dioxido-3-oxo-5-phenylisothiazol-2(3H)-yl]methyl}pyridin-2-yl)carbamate and 4-(difluoromethoxy)aniline in a similar manner as described for e.g. Example 5. 1H NMR (400 MHz, DMSO): δ 3.57-3.71 (m, 2H), 5.77 (s, 2H), 6.15 (d, 1H), 6.91 (d, 1H), 7.23-7.28 (m, 2H), 7.38-7.48 (m, 6H), 7.86 (d, 1H); Mass Spectrum: M+H+ 473.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][C@H:33]([CH:38]([CH3:40])[CH3:39])[C:34]([O:36][CH3:37])=[O:35].[C:41]1([C:47]2[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[C:41]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:46]=[CH:45][C:44]([O:32][C@@H:33]([CH:38]([CH3:40])[CH3:39])[C:34]([O:36][CH3:37])=[O:35])=[CH:43][CH:42]=1
Reactant: COC(=O)[C@H](O)C(C)C
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Oc1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethylazodicarboxylate (11.5 ml) in dry tetrahydrofuran (40 ml) was added dropwise over 30 minutes to a stirred solution of triphenylphosphine (22 g), methyl (R)-2-hydroxy-3-methylbutanoate (11.2 g, J.Am.Chem.Soc., (1990), 112, 21, 7659) and 4-phenylphenol (14.5 g) in dry tetrahydrofuran (120 ml). The resulting solution was stirred at room temperature overnight and was then concentrated under reduced pressure. A mixture of isohexane:ether (9:1) (750 ml) was added to the residue and the mixture stirred at room temperature for 30 minutes. The solution was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with isohexane:dichloromethane (1:4) then (1:1) to give the sub-title compound as a solid, which was recrystallised from hexane to give a crystalline solid (7.9 g).
Reaction SMILES: [C:1](OCC)(=O)CC(OCC)=O.[Na].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>C1(C)C=CC=CC=1>[CH3:1][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: Cc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
Into a flask containing diethyl malonate (20 g, 0.125 mol) was added sodium (2.0 g, 0.087 mol). The reaction mixture was stirred for 1 h at room temperature and then allowed to warm to 120° C. (oil bath temperature) for 50 min. To this yellow suspension of the solid mass was added toluene (120 mL) followed by addition of a solution of 2-chloro-3-nitropyridine 1 (12.8 g, 0.08 mol) in 40 mL of toluene. The reaction mixture was refluxed for 8 h, and then stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in 30% H2SO4 (60 mL). This reaction mixture was heated to 125° C. (oil bath) for 7 h, cooled and poured into ice (200 g). The reaction mixture was neutralized with saturated NaHCO3 solution, filtered through Celite, extracted several times with ether. The combined extracts were dried over anhydrous Na2SO4. The solvent was evaporated and the residue was distilled under reduced pressure to provide 6.65 g (60%) of the desired product 3.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1([NH:13][C:14]([C@@H:16]2[CH2:20][C@@H:19]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:18][NH:17]2)=[O:15])[CH2:12][CH2:11]1)#[N:9].[O:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1>>[C:8]([C:10]1([NH:13][C:14]([C@@H:16]2[CH2:20][C@@H:19]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH2:18][N:17]2[C:36]([CH:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)=[O:37])=[O:15])[CH2:12][CH2:11]1)#[N:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3)CN2)CC1
Reactant: O=C(O)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3)CN2C(=O)C2CCOCC2)CC1

Procedure:
(2S,4R)-4-benzenesulfonyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide trifluoro-acetate from experiment K3 was coupled with tetrahydro-pyran-4-carboxylic acid in analogy to experiment A1 to give (2S,4R)-4-benzenesulfonyl-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 432.3 [M+H]+.
Reaction SMILES: [NH2:1][P:2]([NH2:18])([NH:4][C:5](=[O:17])[CH:6]=[CH:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)=[O:3]>CO>[NH2:18][P:2]([NH2:1])([NH:4][C:5](=[O:17])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)=[O:3]
Reactant: NP(N)(=O)NC(=O)C=Cc1nc2ccccc2o1
Solvent: CO
Product: NP(N)(=O)NC(=O)CCc1nc2ccccc2o1
Reaction time: 1 h

Procedure:
N-(Diaminophosphinyl)-3-(2-benzoxazolyl)prop enamide (0.25 g) was dissolved in methanol (30 ml) with heating, and 10% Pd--C (wet) (0.05 g) was added. The mixture was hydrogenated at room temaperature under atmospheric pressure for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Precipitated crystals were collected by filtration to give N-(diaminophosphinyl)-3-(2-benzoxazolyl)propinonamide (0.17 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18](=[O:20])[CH3:19])[CH:14]=[N:15][CH:16]=1>>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:18]([OH:20])[CH3:19])[CH:14]=[N:15][CH:16]=1
Reactant: CC(=O)Cc1cncc(Br)c1
Reactant: ClCc1ccc(Cl)cc1
Product: CC(O)C(Cc1ccc(Cl)cc1)c1cncc(Br)c1

Procedure:
The title compound was prepared following the procedure described in Reference Example 67, Step B-C, substituting 2-bromomethyl-5-chloropyridine with 4-chlorobenzyl chloride and 3-bromophenylaceatone with 5-bromo-3-pyridylacetone (Step A). 1H NMR (500 MHz, CD3OD): δ 8.43 (d, 1H), 8.24 (d, 1H), 7.98 (dd, 1H), 7.17 (d, 2H), 7.07 (d, 2H), 4.04 (m, 1H), 3.16 (dd, 1H), 3.0-2.9 (m, 2H), 1.04 (d, 3H).
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[NH2:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)[C:10](O)=[O:11]>C1COCC1>[NH2:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)[CH2:10][OH:11]
Reactant: NC(C(=O)O)c1cccc(Cl)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(CO)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a stirred solution of lithium borohydride in THF (10.5 ml, 2 M solution) under an argon atmosphere was added dropwise chlorotrimethylsilane (5.34 ml). The resulting suspension was cooled to 0° C. and amino-(3-chlorophenyl)-acetic acid (2.0 g) was added portionwise. The ice bath was removed and stirring at r.t. was then continued for 16 h. The mixture was quenched by dropwise addition of methanol (15 ml) and then concentrated in vacuo. The residue was suspended in ethyl acetate and washed with 2 N aq NaOH. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated in vacuo to afford (RS)-2-amino-2-(3-chloro-phenyl)-ethanol (1.84 g, quant.) as a yellow viscous oil. MS (ISP): 174.2 ([{37Cl}M+H]+), 172.2 ([{35Cl}M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20](F)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.N12CCCN=C1CCCCC2>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Reactant: C1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(Cc2ccc(N3CCCC3)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 160 °C
Yield: 69 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456,100 mg, 0.289 mmol), pyrrolidine (60.3 uL, 0.723 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (204 uL, 1.45 mmol). The mixture was heated to 160° C. for 30 minutes and then cooled to room temperature. The reaction mixture was diluted with dichloromethane (25 mL) and washed with 0.5M HCl (3×10 mL). The combined aqueous portions were extracted with dichloromethane (15 mL), the organic portions were combined, washed with brine (15 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 10% acetone/dichloromethane as the eluent to produce 79 mg of P-582 as a pale orange semisolid in 69% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.89-1.93 (m, 4H), 3.31-3.34 (m, 4H), 3.71 (s, 3H), 3.77 (s, 2H), 6.37 (d, J=9 Hz, 1H), 6.91 (d, J=9 Hz, 1H), 7.23-7.28 (m, 2H), 7.32 (dd, J=9, 2 Hz, 1H), 7.36 (s, 1H), 7.41-7.47 (m, 2H), 7.95 (d, J=2 Hz, 1H) ppm. MS (APCI+): 397.1 (M+1) LC-MS: 98%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=2)=[CH:4][C:3]=1[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[O:33]=[C:34]1[NH:38][C:37](=[O:39])[CH:36]([CH2:40][C:41]2[CH:51]=[CH:50][C:44]([O:45][CH2:46][C:47](O)=[O:48])=[CH:43][CH:42]=2)[S:35]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:33]=[C:34]1[NH:38][C:37](=[O:39])[CH:36]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:45][CH2:46][C:47]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[C:11]([C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]([OH:19])=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:14]=4)=[CH:4][C:3]=3[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:48])=[CH:50][CH:51]=2)[S:35]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 82.1 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3,5-di-t-butyl-4-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.55 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.42 g), diethyl cyanophosphonate (0.24 g), triethylamine (0.15 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (0.72 g).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26]>>[C:1]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CN(C)CCCN
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 180 °C

Procedure:
(a-2) was synthesized by a dehydration amidation reaction between stearic acid and N,N-dimethyl-1,3-propanediamine. Specifically, 161 g of N,N-dimethyl-1,3-propanediamine and 373.3 g of the fatty acid were placed in a four-neck flask equipped with a stirrer, a temperature gage and a dehydrating pipe and the mixture was raised to 180° C. The mixture was stirred under heating at this temperature for about 5 hours while distilling generated water. Then, the reaction mixture was cooled to 120° C. and unreacted amine was distilled under reduced pressure to obtain the target N-stearoylaminopropyl-N,N-dimethylamine (a-2).