Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11](=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][C:22]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=3)=[CH:15][C:14]=2[F:38])=[CH:6][C:5]=1[C:40]([F:43])([F:42])[F:41])(=[O:3])[CH3:2].[CH3:44][Mg]Br.O>C1COCC1>[CH2:26]([O:25][C:23]1[CH:24]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][C:11]([NH:10][C:7]3[CH:8]=[N:9][C:4]([C:1]([OH:3])([CH3:44])[CH3:2])=[C:5]([C:40]([F:41])([F:43])[F:42])[CH:6]=3)=[O:39])=[C:14]([F:38])[CH:15]=2)[CH:20]=[N:21][C:22]=1[O:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[CH3:27]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cnc(C(C)=O)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cnc(C(C)(C)O)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a mixture of N-(6-acetyl-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (100 mg, 0.167 mmol) in THF (10 mL) was added methylmagnesium bromide (0.167 mL, 0.502 mmol). The mixture was stirred at 0° C. for 2 h under a N2 atmosphere. Then the mixture was added to H2O and extracted with EA. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (DCM/MeOH=15:1, Rf=0.6) to yield a yellow solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(6-(2-hydroxypropan-2-yl)-5-(trifluoromethyl)pyridin-3-yl)acetamide (70 mg, 0.086 mmol, 51.1% yield): 1H NMR (400 MHz, CD3OD) δ 8.87 (d, J=2.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.44-7.40 (m, 3H), 7.29 (d, J=2.4 Hz, 1H), 6.88 (s, 2H) 6.78 (d, J=2.4 Hz, 1H), 5.35 (s, 2H), 4.17-4.11 (m, 2H), 3.83 (s, 2H), 3.77 (s, 3H), 1.59 (s, 6H), 1.41 (t, J=7.1 Hz, 3H); ES-LCMS m/z 494.2 (M-PMB+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][NH2:7])=[O:4].C(N(CC)CC)C.[C:15](=S)=[S:16].ClC(OCC)=O>C(Cl)Cl.ClC.C(OCC)(=O)C.CCCCCC>[N:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[C:15]=[S:16]
Reactant: S=C=S
Reactant: COC(=O)CCN
Agent: CCOC(=O)Cl
Agent: CCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)CCN=C=S
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To β-alanine methyl esterhydrochloric acid salt suspended in methylene chloride (60 mL) was added triethylamine (10.87 g, 107.4 mmol). The reaction mixture was cooled downed to -15° C. before adding carbon disulfide (4.1 g, 53.8 mmol) dissolved in chloromethane (30 mL) dropwise over 25 minutes. The reaction was warmed to 10° C. and stirred for 10 minutes. before lowering the temperature to 0° C. and adding ethyl chloroformate (5.83 g, 53.7 mmol) dissolved in chloromethane (5 mL) dropwise over 15 minutes. The temperature was increased to room temperature and stirred for 20 minutes before lowering to 0° C. Triethylamine (5.43 g, 53.7 mmol) was then added. The temperature was increased to room temperature and then stirred for 30 minutes. The reaction mixture was washed with water (50 mL), 1N hydrochloric acid (50 mL), 5% sodium bicarbonate and water (50 mL), dried over magnesium sulfate, filtered and concentrated under vacuo to give 7.3 g. of crude product. Flash chromatography (ethyl acetate/hexane, 1:4) afforded the desired product (4.03 g, 52%).
Reaction SMILES: CC1C=CC(S([NH:11][CH:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][P:14](=[O:21])([O:18]CC)[O:15]CC)(=O)=O)=CC=1.C1(O)C=CC=CC=1.Br>O>[NH2:11][CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][P:14](=[O:15])([OH:21])[OH:18]
Reactant: CCOP(=O)(CC(Cc1ccccc1)NS(=O)(=O)c1ccc(C)cc1)OCC
Agent: Br
Solvent: Oc1ccccc1
Solvent: O
Product: NC(Cc1ccccc1)CP(=O)(O)O
Yield: 85.3 %

Procedure:
A mixture of [2-[[(4-methylphenyl)sulfonyl]amino]-3-phenylpropyl]phosphonic acid, diethyl ester (5.9 g., 13.9 mmole), phenol (8.0 g., 85.1 mmole), and 48% aqueous hydrobromic acid (50 ml.) was refluxed for 5.5 hours. The cooled mixture was diluted with water (50 ml.) and washed with ethyl acetate (2×50 ml.). The aqueous phase was evaporated to dryness, taken up in water (30 ml.) and evaporated again. This was repeated twice more. Finally, the residue was taken up in water and applied to an AG50W-X2 (H+ form) column (60 ml. bed volume) and eluted first with water then with 5% pyridine-water. The fractions containing the desired product were combined and evaporated to dryness. The solid residue was triturated with acetonitrile to give 2.55 g of (2-amino-3-phenylpropyl)phosphonic acid as an off-white crystalline solid; m.p. 347° (dec.); Rf (isopropanol/conc. NH4OH/water; 7:2:1)=0.27.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])=[CH2:3]>C1(C)C=CC=CC=1.C1(O)C=CC=CC=1>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:2]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)([CH2:4][C:2]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)([CH3:4])[CH3:3])[CH3:3])=[CH:6][CH:7]=1
Reactant: C=C(C)c1ccc(O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Oc1ccccc1
Product: CC(C)(CC(C)(c1ccc(O)cc1)c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
Hydrogen chloride is introduced for 6 hours at 0° C into a solution of 78.6 g (0.2 mol) of the bischlorocarbonic acid ester of dimeric p-isopropenylphenol prepared according to (a) in 180 ml of toluene and 150 g of phenol. The solvent and excess phenol are removed at reduced pressure and the reaction product is dissolved in 400 ml of methanol, and 200 ml of concentrated sodium hydroxide solution are added dropwise. The reaction mixture is then diluted with an equal quantity of water and heated to reflux. The methanol is distilled off, 400 ml of toluene are added and the tris-phenol is precipitated with dilute hydrochloric acid. The solvent phase is washed with water, dehydrated over sodium sulphate and concentrated by evaporation. After removal of the excess phenol by distillation, a small amount of bisphenol A distils over, which is followed by the tris-phenol fraction which distils over at 270°-280° C/0.05 Torr. Melting point 150°-151° C (from methylene chloride). Yield: 48 g = 66% of theoretical.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]=2[N:3]=1.Cl.Cl.Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[H-].[Na+].CN(C)CCCON=C1CC(C2C=C(F)C=CC=2C2C=CC=CC=2)CC2N=C(N)N=C(C)C1=2>O>[N:33]1([CH2:32][CH2:31][CH2:30][O:14][N:13]=[C:8]2[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]3[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]2=3)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Reactant: ClCCCN1CCNCC1
Agent: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Agent: Cl
Agent: [H-]
Solvent: O
Product: Cc1nc(N)nc2c1C(=NOCCCN1CCNCC1)CC(c1ccccc1-c1ccccc1)C2

Procedure:
The title compound was prepared from 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 66, (100 mg, 0.290 mmol), 1-(3-chloro-propyl)-piperazine dihydrochloride (82 mg, 0.350 mmol) and sodium hydride (60% dispersion in oil) (18 mg, 465 mmol), following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88), except after addition of water the solvent was removed under reduced pressure. The crude material was taken up in methanol (20 ml) and the resulting solution was filtered. The solvent was removed under reduced pressure. The title compound was purified by preparative HPLC (UV directed fraction collection).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1cccc(Cl)c1N=C=O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4c(C)cccc4Cl)cc3)c2cc1OC
Yield: 74 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 2-chloro-6-methylphenyl isocyanate (0.1 ml) was added, and the admixture was refluxed with heat for 17 minutes. The separated crystals were filtered and then washed with toluene to obtain 61 mg of the title compound (yield: 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][CH2:13][C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][CH2:13][C:14]1([N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6]
Reactant: CN1CCN(C2(CN)CCCCC2)CC1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: c1ccccc1
Product: CN1CCN(C2(CNC(=O)c3ccc(Cl)c(Cl)c3)CCCCC2)CC1
Yield: 49.3 %

Procedure:
A solution of 3,4-Dichlorobenzoylchloride (1.05 g.,) in benzene (10 ml) was added dropwise over 40 mins. to a stirred solution of 1-[1-(Aminomethyl)cyclohexyl]-4-methyl piperazine (1.06 g.,) in benzene (15 ml). The mixture was heated under reflux for 1 hr. on a steambath and the solution was evaporated. The solid residue was dissolved in ethanol, acidified with ethereal HCl and evaporated to give a white solid. This solid was suspended in water, made alkaline with 5NNaOH and extracted with chloroform (x2). The combined chloroform extracts were dried (anhyd.Na2SO4) and evaporated. The solid residue was dissolved in hot petroleum ether (80°-100°) decolourised with charcoal and crystallised from petroleum ether (80°-100°) to give 1-[1-(3,4 Dichlorobenzamido methyl) cyclohexyl]-4-methyl piperazine (0.95 g; 49%) m.p. 143° -146°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Br:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cc(F)cc(Br)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(F)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
To a mixture of 4-{[1-(3-bromo-5-fluoro-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.25 g, 6.43 mmol) and ytterbium(III) triflate hydrate (0.40 g, 0.64 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.59 mL, 6.43 mmol) and water (0.12 mL, 6.43 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-5-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.33 g, 86%) as a light yellow oil: LC/MS m/e calcd for C20H21BrFNO3 M+: 422.3, observed: 404.3, 406.3.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:14][CH2:15][CH:16]([CH2:19][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:17][CH2:18]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Reactant: C1COCCN1
Product: c1cc(N2CCC(CN3CCOCC3)CC2)ccc1CN1CCCC1

Procedure:
Prepared from the product of Example 16 and morpholine.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[CH:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[C:18]1[CH2:27][CH2:26][CH2:25][CH2:24][N:19]12.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:17]2[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][CH:15]=3)[N:19]3[CH2:24][CH2:25][CH2:26][CH2:27][C:18]=23)=[O:13])=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)cc1n2CCCC1
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2c3n(c4ccccc24)CCCC3)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-methyl-1-naphthoyl chloride (37 mg, 0.18 mmol) and 6,7,8,9-tetrahydropyrido[1,2-a]indole (30 mg, 0.18 mmol) in 1 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (0.22 mL, 0.40 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature and stirred for 3 d then cooled to −70° C. and 4-methyl-1-naphthoyl chloride (4 mg, 0.020 mmol) and ethyl aluminum dichloride (20 μL, 0.036 mmol) added and allowed to warm to room temperature and stirred 6 h. The reaction mixture was again cooled to −70° C. and 4-methyl-1-naphthoyl chloride (4 mg, 0.020 mmol) and ethyl aluminum dichloride (20 μL, 0.036 mmol) added and allowed to warm to room temperature overnight. It was again cooled to −70° C. and 4-methyl-1-naphthoyl chloride (8 mg, 0.040 mmol), ethyl aluminum dichloride (40 μL, 0.072 mmol), and 1 mL CH2Cl2 added and allowed to warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 25% ethyl acetate in hexanes to give CBX005 (22 mg, 0.065 mmol). 1H NMR (500 MHz, CDCl3, δ): 1.80-1.95 (m, 2H), 2.05-2.33 (m, 2H), 2.82 (s, 3H), 2.97 (t, J=6.3 Hz, 2H), 4.13 (t, J=6.2 Hz, 2H), 7.09 (t, J=7.6 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.30-7.37 (m, 2H), 7.40 (d, J=7.1 Hz, 1H), 7.43-7.52 (m, 2H), 7.58 (t, J=7.6 Hz, 1H), 8.08-8.19 (m, 2H). 13C NMR (500 MHz, CDCl3, δ): 19.87, 20.03, 22.31, 25.20, 42.65, 108.94, 113.75, 121.25, 122.03, 122.44, 124.31, 124.99, 125.93, 126.05, 126.24, 126.41, 126.97, 130.34, 132.89, 136.27, 139.26, 147.09, 193.08. MS m/z 340.4 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:3]=1.[NH4+].[Cl-]>CCO.[Fe]>[I:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:3]=1)[NH2:8]
Reactant: COc1ccccc1Oc1cc(I)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccccc1Oc1cc(N)cc(I)c1
Temperature: 75 °C
Yield: 76.7 %

Procedure:
7 (4.9 g, 13 mmol), Fe (5.9 g, 100 mmol) and a solution of NH4Cl (2.3 g in 23 mL H2O, 42 mmol) were suspended in 67 mL of EtOH and heated at 75° C. for 6 h. The mixture was allowed to cool to room temperature, filtered over celite, and concentrated by rotary evaporation. The residue was partitioned between EtOAc and water; combined organic extracts were dried over anhydrous Na2SO4, concentrated by rotary evaporation, and purified by column chromatography to give 3-iodo-5-(2-methoxyphenoxy)aniline (8) (3.4 g, 77%). 1H NMR (600 MHz, CDCl3) δ 7.18-7.13 (m, 1H), 7.00 (ddd, J=7.7, 5.7, 1.5 Hz, 2H), 6.94 (td, J=7.7, 1.4 Hz, 1H), 6.83-6.79 (m, 1H), 6.71-6.68 (m, 1H), 6.30 (t, J=2.0 Hz, 1H), 3.82 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C@@H:6]([C:26]1[CH:34]=[CH:33][C:29]2[CH2:30][CH2:31][O:32][C:28]=2[CH:27]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[C:8]1=[O:25])[CH3:2].[H][H]>CCO.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C@@H:6]([C:26]1[CH:34]=[CH:33][C:29]2[CH2:30][CH2:31][O:32][C:28]=2[CH:27]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[C:8]1=[O:25])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCc2ccc3cccnc3n2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCc2ccc3c(n2)NCCC3)C1=O

Procedure:
A mixture of 4-3 (460 mg, 1.0 mmol) and 10% Pd/carbon (300 mg) in EtOH (20 mL) was stirred under a balloon of hydrogen for 3 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) to give 4-4 as a yellow oil.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C@@H:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]1=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.Cl.C(OCC)(=O)C>CCOCC>[CH3:6][NH:8][CH2:9][CH2:10][C@@H:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:19]1=[O:32])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(CC[C@H](c1ccccc1)N1C(=O)C2(CCCCC2)c2ccccc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CNCC[C@H](c1ccccc1)N1C(=O)C2(CCCCC2)c2ccccc21
Reaction time: 16 h
Yield: 95.7 %

Procedure:
1′-[(1R)-3-(tert-butoxycarbonyl-methylamino)-1-phenylpropyl] spiro [cyclohexane-1,3′-indol]-2′(1′H)-one (70 mg, 0.15 mmol) was dissolved in ether (5 mL) and 2N HCl in ethyl acetate (0.3 mL, 0.6 mmol) was added. The mixture was stirred 16 hours then concentrated under a stream of nitrogen. The residue was purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 50 mg of 1′-[(1R)-3-(methylamino)-1-phenylpropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one. The freebase was dissolved in ether (2 mL) and treated with 1N hydrochloric acid in ether (0.14 mL, 0.14 mmol, 1 equivalent). The white precipitate was collected and dried under vacuum to give 56 mg of 1′-[(1R)-3-(methylamino)-1-phenylpropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one hydrochloride.
Reaction SMILES: C([O:8][C:9]([CH:11]([CH2:25][CH2:26][C:27]([O:29]CC1C=CC=CC=1)=[O:28])[CH2:12][P:13]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:15])[OH:14])=[O:10])C1C=CC=CC=1.[H-].[Na+].C=C(CCC(OCC1C=CC=CC=1)=O)C(OCC1C=CC=CC=1)=O.Cl>C1COCC1.CCOC(C)=O>[C:19]1([CH2:18][CH2:17][CH2:16][P:13]([CH2:12][CH:11]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:9]([OH:10])=[O:8])([OH:15])=[O:14])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CCC(CP(=O)(O)CCCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CCC(CP(=O)(O)CCCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 125.1 %

Procedure:
To a solution of 4-methylbenzyl-O-benzylphosphinic acid (2, R=4-methylbenzyl)(2.16 g, 8.3 mmol) in THF (15 mL) was added sodium hydride (0.10 g, 60% dispersion in oil) followed by dibenzyl 2-methylenepentanedioate at 0 C., and the mixture was stirred at rt for 4 h. The reaction mixture was then diluted with EtOAc (50 mL) and poured into 1N HCl (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This material was purified by silica gel chromatography (hexanes:EtOAc, 4:1 to 1:1) to give 3.41 g of 2,4-di(benzyloxycarbonyl)butyl(4-methylbenzyl)-o-benzylphosphinic acid (4, R=4-methylbenzyl) as colorless oil (70% yield): Rf 0.61 (EtOAc); 1H NMR (CDCl3) delta 1.6-1.8 (m, 1H), 1.9-2.0 (m, 2H), 2.1-2.4 (m, 6H), 2.7-2.9 (m, 1H), 3.05 (dd, J=9.0, 16.8 Hz, 2H), 4.8-5.1 (m, 6H), 7.0-7.1 (m, 4H), 7.2-7.4 (m, 15H).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=O.Cl.[NH2:7][C:8]1[CH:9]=[C:10]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:11]([NH:13][CH:14]1[CH2:16][CH2:15]1)=[O:12]>C1(C)C=CC=CC=1>[CH:14]1([NH:13][C:11](=[O:12])[C:10]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:8]([NH:7][C:3](=[O:5])[CH2:2][SH:1])[CH:9]=2)[CH2:15][CH2:16]1
Reactant: O=C(O)CS
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)CS
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of mercaptoacetic acid (1.65 mL, 24.2 mmol) and 5.0 g (22 mmol) of 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (prepared as described in WO 04/071440) in toluene (40 mL) was refluxed for 16 h. At this time, an additional 0.8 mL of mercaptoacetic acid was added and the mixture was continued at reflux for an additional 2 days. After cooling to rt, the solid was collected by vacuum filtration and was rinsed with EtOAc (2×50 mL). The resulting solid was then slurried in water (50 mL) and the solid was recollected by vacuum filtration and rinsed with add'n water. The resulting solid was air dried in the funnel then under vacuum overnight to afford 1.86 g (32%) of a white solid as compound a. HPLC Ret time=1.83 min. LCMS [M+H]+ 265.37.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH3:48])=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH3:48])=[CH:45][C:46]=2[CH3:47])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K32) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown foam (388 mg, 83%).
Reaction SMILES: Cl[P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4](Cl)[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[OH:27])([CH3:17])[CH3:16]>C(N(CC)CC)C>[CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]([CH3:17])[CH3:16])[C:19]=1[O:27][P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4]([O:27][C:19]2[C:20]([CH:24]([CH3:25])[CH3:26])=[CH:21][CH:22]=[CH:23][C:18]=2[CH:15]([CH3:17])[CH3:16])[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N1P(Cl)N(C(C)(C)C)P1Cl
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1OP1N(C(C)(C)C)P(Oc2c(C(C)C)cccc2C(C)C)N1C(C)(C)C

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-di-tert-butyl-1,3,2,4-diazadiphosphetidine, 2,6-diisopropylphenol and triethylamine to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[N:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1>>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccncc1
Reactant: Fc1ccc(Br)cn1
Product: Fc1ccc(-c2ccncc2)cn1

Procedure:
Prepared from 5-bromo-2-fluoropyridine (881 mg, 5.00 mmol) and pyridin-4-ylboronic acid (979 mg, 7.96 mmol) according to Method K, except the product was purified by silica gel chromatography (10% ethanol in ethyl acetate, Rf=0.32) instead of preparative HPLC: 1H NMR (300 MHz, chloroform-D) δ ppm 7.08 (dd, J=8.5, 3.0 Hz, 1H), 7.48-7.50 (m, 2H), 8.01-8.07 (m, 1H), 8.51 (d, J=2.7 Hz, 1H), 8.72-8.74 (m, 2H). MS (DCI/NH3) m/z=175 (M+H)+.