Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2([CH3:17])[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[C:6]1=[O:18].CCN(CC)CC.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32]>C(Cl)Cl>[N+:31]([C:34]1[CH:35]=[CH:36][C:37]([C:38]([O:16][CH:13]2[CH2:14][CH2:15][C:10]([N:7]3[CH2:8][CH2:9][CH:5]([CH2:4][C:3]4[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=4[Cl:1])[C:6]3=[O:18])([CH3:17])[CH2:11][CH2:12]2)=[O:39])=[CH:41][CH:42]=1)([O-:33])=[O:32]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC1(N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CCC(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CCC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 147.4 %

Procedure:
Dissolve 3-(2,4-dichlorobenzyl)-1-(4-hydroxy-1-methylcyclohexyl)pyrrolidin-2-one (0.50 g, 0.51 mmol) in DCM (100 mL) and cool the solution to 0° C. under N2. Add Et3N (0.71 g, 7.06 mmol) and 4-nitrobenzoyl chloride (0.52 g, 2.82 mmol) and stir the reaction overnight at room temperature. Add water (100 mL) and extract the aqueous with EtOAc (3×100 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 20-60% of EtOAc/Hexane) to give 0.38 g (54%) of the title compound as a white solid. 1H NMR (CDCl3) δ 8.25 (m, 2H), 8.16 (m, 2H), 7.38 (d, 1H), 7.20 (d, 1H), 7.16 (dd, 1H), 5.18 (m, 1H), 3.25 (m, 3H), 2.65 (m, 2H), 2.42 (m, 1H), 2.19 (m, 1H), 1.95 (m, 1H), 1.80 (m, 6H), 1.62 (m, 1H), 1.28 (s, 3H).
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH:7]([CH3:16])[C:6]1=[O:17]>CCOCC>[CH3:2][C:6]1([OH:17])[CH:7]([CH3:16])[CH2:8][CH:9]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][CH:5]1[CH3:4]
Reactant: CC(C)CCC1CC(C)C(=O)C(C)C1
Reactant: CI
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CCC1CC(C)C(C)(O)C(C)C1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a Grignard solution prepared from magnesium (14.5 g, 0.6 g-atom) and methyl iodide (85.2 g. 0.6 mol) in anhydrous ether (500 mL) was added 2,6-dimethyl-4-(3-methylbutyl) cyclohexanone (59 g, 0.3 mol, produced according to Example 8) over 1 h at 15°-20° C. The mixture was stirred for an additional 1 h and then quenched into saturated ammonium chloride solution. The layers were separated and the aqueous solution was extracted with ether. The combined extracts were washed with 5% sodium bicarbonate solution, brine and then dried. Solvent removal and distillation gave 40 g of the alcohol, bp 92° C. (1 mm). NMR (CDCl3) δ0.8-1.1 (12H, m), 1.1-2.2 (16H, complex pattern with a singlet at 1.2). IR (film) 3550, 1025, 920, 890 cm-1. MS (m/e 212 (M+), 85, 43, 57, 86.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[N:20]2[CH3:23])=[C:16]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:15]=1>>[CH:1]([C:4]1[N:5]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[N:15]=2)[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)([CH3:3])[CH3:2]
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)c1nc2ccccc2[nH]1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-isopropylbenzimidazole and 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol were reacted to give 195. LCMS m/z: 533.3 (MH+). 1H-NMR (DMSO-d6): 7.89 (m, 1H), 7.64 (m, 1H), 7.24 (m, 2H), 4.25 (s, br, 4H), 4.00 (s, 1H), 3.92 (m, 1H), 3.81 (s, 3H), 3.77 (t, 4H), 3.73 (s, 2H), 2.91 (d, 2H), 2.00 (t, 2H), 1.67 (t, 2H), 1.35 (d, 6H), 1.22 (m, 3H), 1.02 (s, 6H).
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[NH2:25]>CN(C=O)C>[C:13]1([C:2]2[N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]3=[N:25][C:3]=2[C:5]2[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(C(=O)C(Br)c2ccccc2)cc1
Reactant: Nc1ncccn1
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2nc3ncccn3c2-c2ccccc2)cc1

Procedure:
4.6 g 4-[bromo(phenyl)acetyl]benzaldehyde and 1.64 g pyrimidin-2-amine are stirred in 140 ml DMF at 90° C. for 4 h. The DMF is evaporated and the residue suspended in ethylacetat over night, collected by filtration.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.Br[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([CH2:22][CH2:21][CH2:20][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Product: O=C(N[C@H]1CCN(CCCc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2
Yield: 21.4 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.38 g) and 3-bromopropylbenzene (0.37 g) were reacted under the same conditions as in Example 1 to give (S)-N-(1-(3-phenylpropyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.12 g), melting point 118-120° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[N:48]([CH:51]1[CH2:55][CH2:54][CH2:53][CH2:52]1)=[C:49]=[O:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:49]([NH:48][CH:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)=[O:50])[CH2:42][CH2:41]1
Reactant: O=C=NC1CCCC1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)NC2CCCC2)CC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 68 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isocyanatocyclopentane as starting materials in 68% yield. LCMS for C31H37ClN7O2 (M+H)+: m/z=574.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH3:14])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:16]([O:18][CH:19]1[CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:22][CH:21]([CH3:28])[CH2:20]1)=[O:17].[Na+].[Cl-]>N1C=CC=CC=1>[CH2:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[N:12][C:16]([O:18][C@@H:19]1[CH2:20][C@H:21]([CH3:28])[CH2:22][CH2:23][C@H:24]1[CH:25]([CH3:27])[CH3:26])=[O:17])=[O:11])[CH3:14]
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Reactant: CCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCS(=O)(=NC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.47 mmol) of (RS)-S-(4-nitrophenyl)-S-ethyl sulfoximide in 4.40 ml of pyridine is mixed drop by drop at room temperature with 0.46 ml (2.17 mmol) of (+) menthyl chloroformate. The batch is stirred for 4 hours at room temperature and then added to dilute NaCl solution. It is extracted from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 1:1). 161 mg (0.41 mmol, corresponding to 87% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C:10]([C:18]#[N:19])=[C:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([CH3:24])([O-])=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:8][C:9]([C:10]1([C:18]#[N:19])[CH2:24][C:11]1([CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH3:17])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: CCCC(CCC)=C(C#N)C(=O)OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCC1(CCC)CC1(C#N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
To a solution of 2-cyano-3-propyl-hex-2-enoic acid benzyl ester (0.91 g, 3.35 mmol) in 50 mL acetonitrile was added nitromethane (0.91 mL, 16.77 mmol), followed by DBU (0.50 mL, 3.35 mmol) resulting in an orange solution. The reaction was stirred at room temperature for 16 hours, then partitioned between Et2O and 1N HCl (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (5→10% EtOAc/hexanes) afforded 0.71 g (81%) of 1-cyano-2,2-dipropyl-cyclopropanecarboxylic acid benzyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.21 (dd, J=18.3, 12.4 Hz, 2H), 1.79 (d, J=5.1 Hz, 1H), 1.74 (m, 1H), 1.52 (m, 3H), 1.43 (d, J=5.1 Hz, 1H), 1.36 (m, 3H), 1.04 (m, 1H), 0.95 (t, J=7.1 Hz, 3H), 0.73 (t, J=7.1 Hz, 3H). 13C NMR δ 166.40, 135.22, 128.81, 128.69, 128.48, 118.60, 68.23, 41.26, 36.45, 30.27, 29.76, 24.91, 19.74, 19.65, 14.22, 14.10. IR (neat) 2240, 1734 cm−1. Anal. Calcd for C18H23NO2: C, 75.76; H, 8.12; N, 4.91. Found: C, 75.38; H, 8.02; N, 4.97.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=[O:24])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[P:27]([O-:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30].C1CCN2C(=NCCC2)CC1.[Cl-].[NH4+]>ClCCl>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]([P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[OH:24])=[CH:14][N:15]3[CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOP([O-])OCC
Reactant: CCC(CC)n1cc(C=O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(O)c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 5.0 ml dichloromethane solution of 500 mg of 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde were added 0.23 ml of diethyl phosphite and 0.22 ml of 1,8-diazabicyclo[5.4.0]-7-undecene at −40° C., followed by overnight stirring at room temperature. Aqueous saturated ammonium chloride was added to the reaction mixture, followed by extraction with chloroform and then washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate and subsequent evaporation under a reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 400 mg of diethyl [[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](hydroxy)methyl]phosphonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].[CH:11]([Mg]Br)=[CH2:12].Cl.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH:11]=[CH2:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: C=C[Mg]Br
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dichlorobenzaldehyde (7.5 g, 43 mmol) in THF (75 mL) was cooled to 0° C. and vinylmagnesium bromide (1M in THF, 48 mL, 48 mmol) was added dropwise. The reaction was warmed to room temperature and was stirred overnight. Aqueous HCl (1N) and EtOAc were added. The aqueous solution was extracted with EtOAc and the organic solution was dried (MgSO4), filtered, and concentrated. The residue was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[Cl:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:32][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:21]=2)=[O:19])=[CH:16][C:11]=1[NH:10][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:37]2[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]2)[CH:7]=1)=[O:9]
Reactant: CN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(N2CCOCC2)c1
Product: CN1CCN(c2cc(C(=O)Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3Cl)ccn2)CC1
Yield: 69 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-methylpiperazine to give the title compound in 69% yield; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 2.4 (m, 4H), 3.53 (m, 8H), 3.71 (m, 4H), 7.09 (m, 2H), 7.25 (d, 2H), 7.53 (d, 1H), 7.71 (d, 1H), 8.02 (s, 1H), 8.26 (t, 1H), 10.19 (s, 1H), 10.48 (s, 1H); Mass Spectrum: M+H+ 536.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:3])[CH3:2].[N+:24]([O-])([OH:26])=[O:25].N([O-])=O.[Na+]>O.C(O)(=O)C>[CH:1]([C:4]1[CH:9]=[C:8]([N+:24]([O-:26])=[O:25])[CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cc([N+](=O)[O-])cc2C(C)C)cc1

Procedure:
To 8.7 g of N-(2, 6-diisopropylphenyl)-p-toluenesulfonamide (8.7 g) were added 6.3 ml of 60% nitric acid, 50 ml of water and 50 ml of acetic acid, then 0.18 g of sodium nitrite, and the resultant mixture was stirred under refluxing and heating for 5 hours. After cooling, the reaction mixture was mixed with 200 ml of water, and the precipitated crystals were filtered and recrystallized from 50 ml of ethanol to give 4.7 g of N-(2, 6-diisopropyl-4-nitropheyl)-p-toluenesulfonamide. This compound was hydrolyzed in aqueous sulfuric acid to give 2.7 g of 2, 6-diisopropyl-4-nitroaniline.
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:19]=[O:20]>C(N(CC)CC)C>[OH:20][CH2:19][P:1](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=O
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=P(CO)(OCc1ccccc1)OCc1ccccc1
Temperature: 55 °C

Procedure:
100 ml of dibenzyl phosphite, 12.5 g of paraformaldehyde and 6.2 ml of triethylamine were mixed together with stirring. On slow warming to 55° C., a temperature increase to 120° C. took place. The solution, which was now clear, was allowed to cool to 90° C. and was stirred at this temperature for a further 30 minutes. After cooling to room temperature, it was chromatographed on 1 kg of silica gel at elevated pressure (eluent: n-hexane/ethyl acetate 1:4). After concentrating the fractions and drying the residue in vacuo at 60° C. for 12 hours, 96.1 g of pure, oily dibenzyl hydroxymethylphosphonate were obtained, which was reacted without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)C)(C(C)C)C(C)C)=[C:12]([Cl:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)cc1Cl)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(O)c(Cl)c2)n1
Yield: 34.5 %

Procedure:
A solution of Intermediate 49a (152 mg, 0.19 mmol) and TBAF (1M in THF, 0.225 mL, 0.225 mmol) in THF (4 mL) was stirred at RT for 10 min. The solution was concentrated in vacuo, suspended in water (5 mL) and extracted with EtOAc (2×5 mL). The combined organics were washed with brine (5 mL), dried (Na2SO4), filtered and concentrated in vacuo. FCC, using 5-15% [2M NH3 in MeOH] in DCM, gave a solid. Further purification by HPLC (XBridge C18 column, 25-75% MeCN in H2O, 0.1% NH4OH) gave the title compound (42.9 mg, 35%). LCMS (Method 5): Rt 4.46 min, m/z 655 [MH+]. NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.60-1.66 (2H, m), 1.69-1.76 (4H, m), 1.82-1.96 (2H, m), 1.99-2.07 (1H, m), 2.09-2.16 (1H, m), 3.14 (4H, t, J=5.2 Hz), 4.78-4.84 (1H, m), 5.54 (1H, t, J=4.3 Hz), 6.28 (1H, s), 7.05 (2H, d, J=8.6 Hz), 7.16 (1H, dd, J=2.2, 9.8 Hz), 7.29-7.27 (4H, m), 7.38 (1H, d, J=7.6 Hz), 7.43 (1H, d, J=2.5 Hz), 7.61 (1H, dd, J=0.7, 11.9 Hz), 7.62 (1H, s), 8.00 (1H, s), 10.46 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13](OCC)=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH2:13][OH:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24]
Reactant: CCOC(=O)c1c(-c2ccccc2F)c2cc(Cl)ccc2[nH]c1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2F)c1CO
Reaction time: 0.5 h

Procedure:
A solution of 3.5 g (0.01 mol) of ethyl 6-chloro-4-(2-fluorophenyl)quinolin-2(1H)-one-3-carboxylate,* in 50 ml of tetrahydrofuran was added to a suspension of 1 g (0.022 mol) of lithium aluminum hydride in 50 ml of tetrahydrofuran. After stirring for 30 min at -20° to 0°, the hydride was hydrolized by addition of 5 ml of water. The mixture was then partitioned between methylene chloride and 2N hydrochloric acid. The methylene chloride layer was washed with water dried and evaporated. Crystallization of the residue from ethanol/chloroform yielded 6-chloro-4-(2-fluorophenyl)-3-hydroxymethylquinolin-2(1H)-one, with mp 282°-286°.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[F:20][C:21]([F:35])([F:34])[C@:22]([OH:33])([C:27]1[S:31][C:30]([SH:32])=[N:29][CH:28]=1)[CH2:23][C:24]([OH:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:35][C:21]([F:20])([F:34])[C@@:22]([C:27]1[S:31][C:30]([S:32][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[CH:7][C:8](=[O:12])[O:9]3)=[CH:4][CH:3]=2)=[N:29][CH:28]=1)([OH:33])[CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C(O)C[C@@](O)(c1cnc(S)s1)C(F)(F)F
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccc(Br)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)C[C@@](O)(c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1)C(F)(F)F

Procedure:
Employing the procedure of Example 1, Step 3, using 7-bromo-4-(4-fluorophenyl)-2H-chromen-2-one (0.467 g, 1.5 mmol), (3S)-4,4,4-trifluoro-3-hydroxy-3-(2-mercapto-1,3-thiazol-5-yl)butanoic acid (enantiomer #1, 0.400 g, 1.5 mmol) and potassium carbonate (0.708 g, 5.1 mmol) in NMP at 120° C., the title compound was obtained. Purification was done on silica gel (CH2Cl2/MeOH/HOAc; 90:10:0.5). [α]25D−30° (c=0.5, CHCl3). 1H NMR (400 MHz, acetone-d6): δ 7.99 (s, 1H), 7.68 (m, 2H), 7.58 (m, 2H), 7.48 (dd, 1H), 7.39 (dd, 2H), 6.43 (s, 1H), 3.33 (dd, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B(O)O)[C:6]([O:12][CH3:13])=[CH:5][N:4]=1.Br[C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>>[Cl:23][C:21]1[CH:22]=[CH:15][C:16]([C:17]#[N:18])=[C:19]([C:7]2[C:6]([O:12][CH3:13])=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:20]=1
Reactant: COc1cc(B(O)O)c(OC)cn1
Reactant: N#Cc1ccc(Cl)cc1Br
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(OC)cn1

Procedure:
7.87 g (purity 95%, 40.86 mmol) of 2,5-dimethoxypyridin-4-ylboronic acid and 8.85 g (40.86 mmol) of 2-bromo-4-chlorobenzonitrile in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 6.23 g (purity 92%, 51% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][CH2:14][NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.O.Cl>O>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][CH2:14][NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCc2ccc(OCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
A mixture of 6.0 g. of ethyl p-[(p-benzyloxyphenethyl)amino]benzoate (prepared as described in Example 18) 6.0 g. of potassium hydroxide and 100 ml. of ethanol-water (9:1) is refluxed for 3.5 hours. The mixture is acidified while hot with concentrated hydrochloric acid, diluted with water, filtered and the solid washed with water to give tan crystals, m.p. 180°-185° C. Recrystallization from glacial acetic acid gives tan crystals, m.p. 187°-189° C.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])=[O:6])[CH2:2][CH:3]=[CH2:4].[CH2:22](O)[CH:23]=[CH2:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:1]([S:5]([N:8]([CH2:24][CH:23]=[CH2:22])[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])=[O:6])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCO
Reactant: C=CCCS(=O)(=O)Nc1cc(CCC)cc(C(=O)OC)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCCS(=O)(=O)N(CC=C)c1cc(CCC)cc(C(=O)OC)c1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of methyl 3-[(3-buten-1-ylsulfonyl)amino]-5-propylbenzoate (D134) (1.3 g, 4.2 mmol, 1 equiv), 2-propen-1-ol (280 μl, 4.2 mmol, 1 equiv) and triphenylphosphine (1.28 g, 4.9 mmol, 1.15 equiv) in toluene (20 ml) at room temperature was slowly added diisopropyl azodicarboxylate (964 ml, 4.9 mmol, 1.15 equiv). The resulting solution was stirred at this temperature for 30 min then concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 4:1) gave methyl 3-[(3-buten-1-ylsulfonyl)(2-propen-1-yl)amino]-5-propylbenzoate (D135) (1.1 g, 75%) as a yellow oil. [M+H]+=352.1, RT=3.63 min.