Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]([CH3:19])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C@@H:23]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])[CH3:21].[F-].[Cs+]>COC(O)C(O)OC>[CH2:20]([O:22][C@@H:23]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N:8]([CH3:19])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[N:7]=2)=[CH:31][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])[CH3:21]
Reactant: CCO[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC
Reactant: CCCCCCCNC(=O)N(C)c1cccc(Br)n1
Agent: COC(O)C(O)OC
Agent: [Cs+]
Agent: [F-]
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 45.3 %

Procedure:
3.2 g (9.7 mmol) of 1-(6-bromopyrid-2-yl)-3-heptyl-1-methylurea, 4.2 g (12.6 mmol) of methyl 2(S)-ethoxy-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate (prepared as in Example 7e) and 4.4 g (29.1 mmol) of caesium fluoride are placed in 200 ml of dimethoxyethylene glycol. The reaction medium is degassed, 0.23 g (0.3 mmol) of dichlorodiphenylphosphinoferrocenepalladium is then added and the reaction medium is stirred at 80° C. for 18 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is washed with water, with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with an 80/20 heptane/ethyl acetate mixture. 2 g (45%) of methyl 2(S)-ethoxy-3-{4-[6-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}propanoate are obtained.
Reaction SMILES: [C:1](=[NH:23])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:24]([CH:26]([CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=1)[C:27](OC)=O)=[O:25].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:37][N:35]1[CH:36]=[C:32]([CH2:31][C:26]2[C:24](=[O:25])[N:23]=[C:1]([O:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)=[CH:10][CH:11]=3)[NH:2][CH:27]=2)[CH:33]=[N:34]1
Reactant: COC(=O)C(C=O)Cc1cnn(C)c1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cn1cc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)nc2=O)cn1
Temperature: 110 °C
Yield: 12.7 %

Procedure:
To the solution of 2-(4-{[4-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate (50 mg, 0.114 mmol) and methyl 2-formyl-3-(1-methyl-1H-pyrazol-4-yl)propanoate (27 mg, 0.138 mmol) in NMP (1 mL), was added K2CO3 (60 mg, 0.434 mmol). The mixture was was heated with a microwave reactor at 110° C. for 1 h. Purification via MDAP then afforded the title compound (6.8 mg, 10.19% yield). LCMS: rt=3.30 min, [M+H+]=471
Reaction SMILES: C([O+](CC)CC)C.[C:8]1([C:14]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]3[C@H:18]([CH2:19][N:20]([C:23](=O)[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])[CH2:21]3)[C:17](=[O:34])[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH3:41].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH:41]=[C:23]([N:20]1[CH2:19][C@H:18]2[C@H:22]([C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:15][CH2:16][C:17]2=[O:34])[CH2:21]1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]
Reactant: COc1ccccc1CC(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reactant: N
Agent: CC[O+](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccccc1CC(=N)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Temperature: -15 °C
Reaction time: 20 h

Procedure:
Triethyloxonium tetrafluoborate (4 g) is added to a solution of (3aR,7aR)-7,7-diphenyl-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone (7.7 g) in anhydrous dichloromethane (13 cc). Stirring of the reaction mixture is continued for 20 hours at ambient temperature; the mixture is then cooled to -15° C. and a 5.4N ethanolic ammonia solution (2.6 cc) is then added. The temperature of the reaction mixture is allowed to rise to ambient temperature and stirring is continued for 5 hours and a half. The reaction mixture is treated with a 10% aqueous solution (20 cc) of potassium carbonate; the precipitate formed is drained and washed with dichloromethane (10 cc). The organic phases are combined, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (10 cc); the crystals obtained are drained, washed with acetonitrile (5 cc) and with isopropyl ether (10 cc) and dried. They are then chromatographed on a Pechiney CBT1 neutral alumina gel column (diameter 4.5 cm, height 28 cm), eluting with a mixture (200 cc) of 1,2-dichloroethane and methanol (98/2 by volume) and then with a mixture of 1,2-dichloroethane and methanol (90/10 by volume), collecting 25 cc fractions. Fractions 8 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (10 cc); the crystals obtained are drained and dried. (3aR,7aR)-2-[1-imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenyl-4-perhydroisoindolone (1.6 g) melting at 190° C. is obtained; [α]20D =-254° (c=1, methanol).
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:9]2=[C:10]3[N:15]([C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[C:8]2[C:7](=[O:27])[N:6]([CH3:28])[C:5]1=[O:29])[C@H:14]([C:23]([OH:25])=[O:24])[CH2:13][CH2:12][C:11]3=[O:26].[CH3:30]O>>[OH:26][CH:11]1[C:10]2[N:15]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:8]3[C:7](=[O:27])[N:6]([CH3:28])[C:5](=[O:29])[N:4]([CH3:3])[C:9]3=2)[C@H:14]([C:23]([O:25][CH3:30])=[O:24])[CH2:13][CH2:12]1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(=O)CC[C@H]3C(=O)O
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)[C@@H]1CCC(O)c2c3c(c(-c4ccccc4)n21)c(=O)n(C)c(=O)n3C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (0.179 g, 4.72 mmol) was added slowly to a suspension of (S)-1,3-dimethyl-2,4,10-trioxo-5-phenyl-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizine-7-carboxylic acid (1.8 g, 4.72 mmol) in methanol (40 mL). The mixture was stirred at room temperature for 30 mins. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated under vacuum to afford the title compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:20]=[C:13]2[C:14]([O:16]C(=O)[NH:18][C:12]2=[CH:11][CH:10]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[NH2:18][C:12]1[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])=[CH:20][C:13]=1[C:14]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)=[O:16]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2N)cc1
Temperature: 80 °C
Yield: 58.7 %

Procedure:
A mixture of 5-(tert-butyldimethylsilyloxy)isatoic anhydride (734 mg, 2.50 mmol) and p-anisidine (339 mg, 2.75 mmol) in toluene (6 mL) was heated at 80° C. for 3 h. The reaction mixture was cooled and silica gel (3.5 g) was added. The mixture was concentrated in vacuo and the resulting material was chromatographed (silica gel, 1% ethyl acetate/99% methylene chloride to 4% ethyl acetate/96% methylene chloride) to give 547 mg (59%) of the title compound as a light tan solid; mp 82.5-83.5° C. (dec).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[CH3:12][C:9]1([CH3:13])[O:8][C:6]2[N:7]=[C:2]([C:28]3[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[O:11][CH2:10]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)COc2c(nc(-c3ccc(N)nc3)nc2N2CCOCC2)O1
Temperature: 120 °C
Yield: 51.8 %

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (58 mg, 0.26 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then evacuated and back filled with nitrogen before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 111 as a white solid (32 mg, 53%). LCMS: RT=2.73 min, [M+H]+=344. 1H NMR (400 MHz, CDCl3): δ 9.01 (1H, d, J=2.1 Hz), 8.33 (1H, dd, J=2.1, 8.5 Hz), 6.50 (1H, d, J=8.5 Hz), 4.61 (2H, broad s), 3.89 (2H, s), 3.86-3.77 (8H, m), 1.43 (6H, s)
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([F:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:28][C:9]1[C:8]2[CH2:23][CH2:24][CH2:25][CH2:26][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6](=[O:27])[C:7]=2[N:11]2[CH2:12][CH2:13][C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([F:20])=[CH:18][C:19]=3[C:10]=12
Reactant: COc1cc2c(cc1F)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1F)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of 250 mg 27a in 7 mL dimethylformamide was added 120 mg N-bromosuccinimide. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with 2×ethyl acetate. The combined organic phases were washed with water and brine, dried and concentrated. The crude product was triturated with heptane/diisopropyl ethyl ether (1:1) to afford 230 mg of 27b as a white solid.
Reaction SMILES: Cl.Cl.ClC1C=CC(C2C3C4CCNCCC4NC=3C=CC=2)=CC=1.[O:24]([CH2:31][CH2:32][CH2:33][C:34]1[C:35]2[C:36]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43][C:37]=3[NH:38][C:39]=2[CH:40]=[CH:41][CH:42]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[O:24]([CH2:31][CH2:32][CH2:33][C:34]1[C:35]2[C@@H:36]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43][C@@H:37]3[NH:38][C:39]=2[CH:40]=[CH:41][CH:42]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(OCCCc2cccc3[nH]c4c(c23)CCNCC4)cc1
Agent: Cl
Agent: Clc1ccc(-c2cccc3c2C2CCNCCC2N3)cc1
Product: c1ccc(OCCCc2cccc3c2[C@@H]2CCNCC[C@@H]2N3)cc1

Procedure:
Following the procedure for the preparation of 10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole dihydrochloride, making non-critical variations, starting from 10-(3-phenoxypropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole the title compound was prepared: 1H NMR (CDCl3) δ 2.02-2.14, 2.27, 2.74, 2.90-3.03, 3.45, 3.50, 3.98, 4.14, 4.50, 6.47, 6.63, 6.91, 6.95, 7.03, 7.30. HRMS (FAB) calcd for C21H26N2O (MH+) 323.2123, found 323.2104.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.Cl[Si](C)(C)C.[CH2:39]=[O:40].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)([CH2:39][OH:40])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C=O
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one (7.50 g, 17.9 mmol) in dry dichloromethane (150 mL) was added triethylamine (10.9 g, 108 mmol) and chlorotrimethylsilane (7.80 g, 71.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and diluted with dichloromethane (100 mL). The mixture was washed with water (3×50.0 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was dissolved in THF (150 mL) followed by the additions of formaldehyde solution (4.90 mL, 179 mmol, 37 wt % in water) and ytterbium (III) trifluoromethanesulfonate (1.11 g, 1.79 mmol). The resulting mixture was stirred at ambient temperature for 36 h. After the solvent was removed under reduced pressure, the residue was diluted with dichloromethane (200 mL), washed with saturated sodium bicarbonate (50.0 mL), saturated ammonium chloride (50.0 mL) and water (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to yield the title compound (6.32 g, 79%) as a fluffy solid: 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.10 (t, 1H), 7.00 (dd, 1H), 6.89 (dd, 1H), 6.83 (s, 1H), 6.27 (s, 1H), 6.85 (dd, 2H), 4.52-4.41 (m, 2H), 3.90 (dd, 1H), 3.70-3.65 (m, 2H), 1.68-1.57 (m, 2H), 1.36-1.29 (m, 4H), 0.83 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 178.1, 150.3, 147.2, 147.2, 140.5, 129.6, 129.2, 125.6, 118.4, 114.8, 109.2, 106.9, 101.0, 98.2, 62.6, 57.6, 39.9, 28.9, 26.7, 22.2, 13.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][CH:21]1[CH2:26][C:25](=[O:27])[CH2:24][CH2:23][O:22]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:25]2([OH:27])[CH2:24][CH2:23][O:22][CH:21]([CH3:20])[CH2:26]2)[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(Br)cc(OCc2ccccc2)c1
Reactant: CC1CC(=O)CCO1
Product: CC1CC(O)(c2cc(OCc3ccccc3)cc(C(F)(F)F)c2)CCO1
Yield: 16 %

Procedure:
The procedure described in the second paragraph of Note e. below Table IV in Example 15 was repeated, except that 3-benzyloxy-5-trifluoromethylbromobenzene (8.3 g) was used and 2-methyltetrahydropyran-4-one was used in place of tetrahydropyran-4-one. There were thus obtained a less polar isomer, (2RS,4SR)-4-(3-benzyloxy-5-trifluoromethylphenyl)-4-hydroxy-2-methyltetrahydropyran (1.44 g, 16%), as an oil,
Reaction SMILES: [CH:1]1([CH2:7][P:8](C(OCC)OCC)(=[O:12])[O:9]CC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O>[CH:1]1([CH2:7][P:8]([OH:12])[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(OCC)P(=O)(CC1CCCCC1)OCC
Agent: Cl
Solvent: O
Product: OP(O)CC1CCCCC1
Temperature: 25 °C

Procedure:
A solution of 38.3 g of ethyl P-cyclohexylmethyl-P-diethoxymethylphosphinate in 27 ml of water is treated with 27 ml of 37% aqueous hydrochloric acid and the mixture heated to reflux for 5 hours. The mixture is cooled to room temperature and washed with ether/hexane 1:1. Three phases are obtained. The lower 2 phases are removed and the water is removed under reduced pressure to afford cyclohexylmethylphosphonous acid as a white solid; 1H-NMR (CDCl3): δ (ppm)=7.40 (1H, broad singlet, exchanges D2O, P--OH), 7.12 (1H, d, J=526 Hz, H--P), 2.10-1.75 (7H, m, 3×CH2 +CH), 1.48-1.05 (6H, m, 3×CH3).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:19]([C:21]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][C:24](O)=[O:25])#[N:20].Cl.[O:40]([CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[O:25]=[C:24]([N:50]1[CH2:51][CH2:52][CH:47]([O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:48][CH2:49]1)[CH2:23][CH2:22][C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:19]#[N:20]
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: N#CC(CCC(=O)O)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CC(CCC(=O)N1CCC(Oc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
1-Hydroxybenzotriazole hydrate (5.67 g, 42 mmol) and triethylamine (14.88 mL, 107 mmol) were added to 4-cyano-4,4-diphenylbutanoic acid (WO97/24325) (10.39 g, 39 mmol) and 4-phenoxy-piperidine hydrochloride (6.32 g, 36 mmol) in N,N-dimethylformamide (150 mL). The mixture was stirred for 10 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.20 g, 42 mmol) was then added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with water (100 mL) and brine (30 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether, filtered off, washed through with diethyl ether and purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 75:25 to 50:50, to afford the title compound as a white solid (14.4 g) in a 95% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@@H:5]([NH2:18])[C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[OH:7])[CH3:2].Cl.C(O[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=N)C.C(N(CC)CC)C>O>[CH2:1]([O:3][C:4]([C@@H:5]1[C@@H:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[O:7][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:18]1)=[O:19])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc(S(C)(=O)=O)cc1

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound VIc) (10 g, 0.0348 moles) is reacted at about ambient room temperature in a reaction vessel with benzenecarboximidic acid ethyl ester hydrochloride (Compound IV wherein R2 is phenyl and R4 is ethyl) (about 7.37 g, 0.03828 moles) in 1,2-dichloromethane (about 650 mL) containing triethylamine (about 3.9 g, 0.03828 moles). Thereafter, water (about 500 mL) is added. Next, the organic layer is separated. Thereafter, the organic layer is heated to evaporate the 1,2-dichloromethane, and methanol is added (about 50 mL) to yield (4S-trans)-4,5-Dihydro-5-[4-(methylsulfonyl)phenyl]-2-phenyl-4-oxazolecarboxylic acid ethyl ester (Compound IIIk) which is not isolated. The unisolated compound is reacted with potassium borohydride (about 2.8 g, 0.0522 moles) over about 6 hours while maintaining the temperature below about 60° C. The reaction is cooled to ambient room temperature and about 1N HCl (about 10 ml) and water (about 500 ml) are added. The resulting solids are filtered, washed with water, then dried to yield (4R,5R)-4,5-dihydro-5-[4-(methylsulfonyl)phenyl]-2-phenyl-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl, R2 is phenyl and R3 is ethyl).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].CN1CCOCC1.Cl.C(C(NCCCN(C)C)=N)C.[C:38]([C:41]1[N:42]=[C:43]([CH:46]2[CH2:54][C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]2[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[NH:44][CH:45]=1)(O)=[O:39]>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH:17][C:38]([C:41]1[N:42]=[C:43]([CH:46]2[CH2:54][C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]2[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[NH:44][CH:45]=1)=[O:39]
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1c1nc(C(=O)O)c[nH]1
Agent: CCC(=N)NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1c[nH]c(C2Cc3ccccc3N2C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
1-Hydroxybenzotriazole hydrate (0.00036 mole), glycine methylester, hydrochloride (0.00047 mole), 4-methylmorpholine (0.00055 mole), and N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine monohydrochloride (0.00047 mole) were added to compound 117 (0.00036 mole) dissolved in DCM (30 ml) at 0° C. The mixture was allowed to warm to room temperature under nitrogen, and stirred overnight. The mixture was extracted with water, saturated NaHCO3, 2N citric acid, then saturated NaHCO3, dried, filtered, and concentrated, yielding 0.100 g (69%) of 1,1-dimethylethyl 2,3-dihydro-2-[4-[[(2-methoxy-2-oxoethyl)amino]carbonyl]-1H-imidazol-2-yl]-1H-indole-1-carboxylate (compound 118).
Reaction SMILES: [CH2:1]([C:3]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:4]=1[C:5]([CH:7](C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([C:3]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:4]=1[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1CC
Yield: 80.4 %

Procedure:
Employing diethyl 2-ethyl-3,4,5,6-tetrafluorobenzoylmalonate (17.2 g) and p-toluenesulfonic acid (0.25 g), the procedure of Reference Example 19 is repeated to give ethyl 2-ethyl-3,4,5,6-tetrafluorobenzoylacetate (11.09 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[O:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH:14]([C:16]([CH3:18])=O)=[CH2:15]>>[CH2:12]1[O:11][C:5]2[C:4](=[C:3]3[C:2](=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=2)[N:1]=[CH:15][CH:14]=[C:16]3[CH3:18])[O:13]1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: C=CC(C)=O
Product: Cc1ccnc2c([N+](=O)[O-])cc3c(c12)OCO3
Yield: 63 %

Procedure:
4-Amino-1,2-methylenedioxy-5-nitrobenzene was made according to the method of Lott, et al.--J. Amer. Chem. Soc., 70, 3621 (1848). It was subjected to a Skraup reaction with methyl vinyl ketone to provide 5,6-methylenedioxy-4-methyl-8-nitroquinoline. The crude compound was crystallized from acetone to give a 63% yield of pure substance; mp 183°-185°.
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:11]1([C:14]([CH3:16])=[O:15])[CH2:13][CH2:12]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:11]1([C:14](=[O:15])[CH2:16][C:1]([C:2]2[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=2)=[O:9])[CH2:13][CH2:12]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1ccncc1

Procedure:
A mixture of 13.7 g. of methyl isonicotinate, 16.8 g. of cyclopropylmethyl ketone and 6 g. of sodium methoxide in 150 ml. of benzene is heated under reflux for 8 hours. The mixture is filtered and the collected solid is dissolved in water. The aqueous mixture is made weakly acidic with dilute hydrochloric acid and extracted with ether. The ethereal solution is dried over magnesium sulfate and concentrated under reduced pressure to give 1-cyclopropyl-3-(4-pyridyl)-1,3-propanedione as a mobile, yellow liquid, infra-red sectrum 6.15μ (CHCl3, β-diketone).