Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Sn](C)(C)C.Br[C:7]1([O:39][C:40]([F:43])([F:42])[F:41])[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]1[CH2:19][CH2:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:7]1([O:39][C:40]([F:43])([F:42])[F:41])[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]1[CH2:19][CH2:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])=[CH:23][CH:22]=1
Reactant: C[Sn](C)(C)C
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(CCC2C=C(c3ccccc3)C=CC2(Br)OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(CCC2C=C(c3ccccc3)C=CC2(C)OC(F)(F)F)cc1
Temperature: 120 °C

Procedure:
Tetramethylstannane (41 μl, 0.295 mmol) was added to the intermediate from Example 1 Step H (35 mg, 0.059 mmol), Pd(PPh3)4 (5 mg, 0.04 mmol) in 3 mL DMF. The solution was then heated at 120° C. overnight under an argon atmosphere. The solution was cooled and partitioned between ethyl acetate and water. The organic phase was washed with water (3×) and brine. The solution was then dried over Na2SO4, filtered and concentrated. The residue was purified by PTLC using 6/4 hexanes/ethyl acetate mobile phase to give tert-butyl N-(4-{2-[4-methyl-4-(trifluoromethoxy)biphenyl-3-yl]ethyl}benzoyl)-β-alaninate. The tert butyl group was removed with TFA as described in EXAMPLE 1 Step I to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.73 (d, J=7.9 Hz, 2H); 7.54 (d, J=8.5 Hz, 2H); 7.36-7.33 (m, 1H); 7.31-7.23 (m, 6H); 6.81-6.76 (m, 1H); 3.80-3.75 (m, 2H); 2.99 (s, 4H); 2.77 (t, J=5.7 Hz, 2H); 2.35 (s, 3H). LCMS1 3.94 min (M+H)=472
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[S:22][CH2:23][C:24]([OH:26])=O.FC(F)(F)C([O-])=O.[NH2:34][C@@H:35]1[C:42](=[O:43])[N:41]2[C@@H:36]1[S:37][CH2:38][C:39](/[CH:47]=[C:48]1/[C:49](=[O:72])[N:50]([CH2:53][C:54]3[CH:59]=[CH:58][N+:57]([CH2:60][C:61](=[O:71])[NH:62][C:63]4[CH:68]=[CH:67][C:66]([OH:69])=[C:65]([F:70])[CH:64]=4)=[CH:56][CH:55]=3)[CH2:51][CH2:52]/1)=[C:40]2[C:44]([OH:46])=[O:45]>CN(C)C(=O)C>[F:70][C:65]1[CH:64]=[C:63]([NH:62][C:61]([CH2:60][N+:57]2[CH:58]=[CH:59][C:54]([CH2:53][N:50]3[CH2:51][CH2:52]/[C:48](=[CH:47]\[C:39]4[CH2:38][S:37][C@H:36]5[N:41]([C:42](=[O:43])[C@H:35]5[NH:34][C:24](=[O:26])[CH2:23][S:22][C:15]5[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=5[Cl:13])[C:40]=4[C:44]([O-:46])=[O:45])/[C:49]3=[O:72])=[CH:55][CH:56]=2)=[O:71])[CH:68]=[CH:67][C:66]=1[OH:69]
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Reactant: O=C(O)CSc1cc(Cl)c(Cl)cc1Cl
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5cc(Cl)c(Cl)cc5Cl)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1

Procedure:
With 60.0 mg (0.36 mmol) 1,1,-carbonyldiimidazole, 99.0 mg (0.36 mmol) (2,4,5-trichloro-phenylsulfanyl)-acetic acid and 200.0 mg (0.30 mmol) (E)-(6R,7R)-7-amino-3 -[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml N,N-dimethylacetamide. The resulting solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water: acetonitril (2:1, 1:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)N1CCC(CO)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)OCC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
600 mg (2.79 mmol) of the compound from Example 22A are dissolved in 6 ml of dry dichloromethane, and 1.5 g of powdered molecular sieve (4 Å) and 490 mg (4.18 mmol) of N-methylmorpholine N-oxide are added. 49 mg (0.14 mmol) of tetrapropylammonium perruthenate are then added, and the mixture is stirred at RT for 1 h. The reaction mixture is then directly purified chromatographically on silica gel 60 (mobile phase: gradient dichloromethane/ethanol 100:1→20:1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:34]=[CH:33][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][P:25](=[O:32])([O:29]CC)[O:26]CC)=[CH:16][C:15]=3[CH3:35])=[CH:7][C:6]=2[C:5]2[CH:36]=[CH:37][C:38]([CH3:40])=[CH:39][C:4]=2[N:3]=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:34]=[CH:33][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][P:25](=[O:26])([OH:29])[OH:32])=[CH:16][C:15]=3[CH3:35])=[CH:7][C:6]=2[C:5]2[CH:36]=[CH:37][C:38]([CH3:40])=[CH:39][C:4]=2[N:3]=1
Reactant: CCOP(=O)(CCCCCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)OCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCCCCCP(=O)(O)O)cc3C)cc12

Procedure:
6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)hexylphosphonic acid (23) was prepared according to the procedure described in Example 1—Step 3, but using diethyl 6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)hexylphosphonate. TFA was added to the 1H NMR sample to solubilize the compound for analysis. The 1H NMR (dimethyl sulfoxide-d6) obtained for 6-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)hexylphosphonic acid (23) was: δ 8.95 (s, 1H), 8.81 (s, 1H), 8.50 (d, 1H, J=8.4 Hz), 7.52 (s, 1H), 7.40 (d, 1H, J=8.4 Hz), 7.01 (d, 1H, J=8.4 Hz), 6.71 (s, 1H), 6.64 (d, 1H, J=10.9 Hz), 3.87 (t, 2H, J=6.34 Hz), 3.13 (t, 2H, J=7.1 Hz), 2.96 (t, 2H, J=7.0 Hz), 2.69-2.66 (m, 1H), 2.35-2.32 (m, 1H), 2.25 (s, 2H), 1.72-1.62 (m, 2H), 1.62-1.51 (m, 2H), 1.51-1.40 (m, 2H). LRMS [M+H]=508.2
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11]CC)=[O:10].Cl.N1C=CC=C1CC(O)=O>[OH-].[Na+]>[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)Cc1cc(C)cn1C
Agent: Cl
Agent: O=C(O)Cc1ccc[nH]1
Agent: [Na+]
Product: Cc1cc(CC(=O)O)n(C)c1
Yield: 89 %

Procedure:
A reference sample of 1,4-dimethylpyrrole-2-acetic acid was prepared as follows: A 9.05 g sample of ethyl 1,4-dimethylpyrrole-2-acetate [J. R. Carson and S. Wong, J. Med. Chem., 16, 172 (1973)] was heated under reflux with 30 ml of 10% sodium hydroxide solution for one hour. The solution was acidified with dilute HCl and extracted with ether. The ether was washed with brine and dried (MgSO4). The solvent was evaporated in vacuo and the residue was triturated with hexane and collected by filtration to give 6.8 g (89% yield) of 1,4-dimethylpyrrole-2-acetic acid as a pink crystalline solid, mp 86°-7° C. (d).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([N:15]2[CH2:20][CH2:19][C@:18]([CH2:28][CH:29]=[CH2:30])([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[O:17][C:16]2=[O:31])[CH3:14])=[CH:9][CH:8]=1)(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.C1COCC1>CCOC(C)=O>[CH2:28]([C@@:18]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:17][C:16](=[O:31])[N:15]([C@H:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]3[O:32][C:1]([CH3:2])=[N:4][N:5]=3)=[CH:12][CH:11]=2)[CH3:14])[CH2:20][CH2:19]1)[CH:29]=[CH2:30]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(C(=O)NNC(C)=O)cc2)C(=O)O1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3nnc(C)o3)cc2)C(=O)O1
Temperature: 180 °C
Yield: 29.1 %

Procedure:
Crude N′-acetyl-4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzohydrazide (5 mg, 0.0114 mmol) was mixed with Burgess reagent (˜4 mg, excess), dry THF (1 mL) and put into Microwave Oven, heated to 180° C. for 10 min. at 100 W. LC-MS found reaction completed. The mixture was diluted with EtOAc (8 mL), washed with water (2×3 mL), concentrated and purified by prep HPLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (1.4 mg, 29%). LC-MS Method 1 tR=1.61, min, m/z=422; 1H NMR (CDCl3) 7.77 (d, 2H), 7.26 (m, 3H), 7.01 (m, 3H), 5.70 (m, 2H), 5.07 (dd, 2H), 2.98 (m, 1H), 2.62 (s, 3H), 1.55 (d, 3H).
Reaction SMILES: [Cl-].[NH4+].C([N:6](C(C)C)CC)(C)C.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH:22]3[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[CH:14]=[N:13]1.N.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH:22]3[CH2:27][CH2:26][CH:25]([C:28]([NH2:6])=[O:30])[CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[CH:14]=[N:13]1
Reactant: O=C(O)C1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 16 h
Yield: 94.6 %

Procedure:
Ammonium chloride (173 ml, 3.23 mmol) and diisopropylethylamine (0.75 ml, 4.30 mmol) were added to a solution of the 4-(1H-indazol-5-yloxy)cyclohexanecarboxylic acid (280 mg, 1.08 mmol) obtained in Example 368 in N,N-dimethylformamide (10 ml). After aqueous ammonia (1 ml) was added thereto to effect dissolution, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (309 mg, 1.61 mmol) and hydroxybenzotriazole (160 mg, 1.18 mmol) were added thereto. After 16 hours, it was confirmed that the starting material remained. Therefore, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (309 mg, 1.61 mmol) and hydroxybenzotriazole (160 mg, 1.18 mmol) were further added thereto. After 7 hours, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the resulting mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml×3) and chloroform (20 ml×2). The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was washed with diethyl ether by repulping to obtain 4-(1H-indazol-5-yloxy)cyclohexanecarboxamide (265 mg, 95%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[CH:12]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:11]3[O:10][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1[Cl:22])(=[O:3])[CH3:2]>C1C=CC=CC=1>[C:1]([NH:4][C:5]1[C:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[O:10][C:9]=2[C:8]([C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:6]=1[Cl:22])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OC1CCCCC21
Solvent: c1ccccc1
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c3c(oc12)CCCC3
Temperature: 80 °C

Procedure:
A mixture of 1 g methyl 1-acetylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate and 1 g of dichlorodicyanoquinone in 15 ml of benzene is stirred and heated at 80° C in a sealed tube for 8 hours. The cooled reaction mixture is then diluted with benzene, filtered and evaporated to dryness. Purification by recrystallization from ethyl acetate/hexane gives pure methyl 1-acetylamino-2-chloro-6,7,8,9-tetrahydrodibenzofuran-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([N+:19]([O-])=O)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:4]>CO.[H][H].[Ni]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH2:19])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1OCCN1CCCC1

Procedure:
1.65 g (5.61 mmol) of 3-methoxycarbonyl-4-(2-pyrrolidin-1-ylethoxy)nitrobenzene (V.1.a) is dissolved in 100 mL of methanol and hydrogenated with hydrogen and 200 mg of Raney nickel as catalyst until the reaction is complete. Then the catalyst is filtered off and the solvent is eliminated. Yield: 1.43 g (97% of theory); Rf value: 0.15 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1); C14H20N2O3; EII mass spectrum: m/z=265 [M+H]+.
Reaction SMILES: COC[N:4]1[C:13](=[O:14])[C:12]2[C:11]3[CH:15]=[C:16]([CH2:19][O:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:32].Cl>C1COCC1.O>[CH3:32][C:5]1[NH:4][C:13](=[O:14])[C:12]2[C:11]3[CH:15]=[C:16]([CH2:19][O:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CCOC(=O)c1ccc(OCc2ccc3ccc4nc(C)n(COC)c(=O)c4c3c2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ccc3ccc(COc4ccc(C(=O)O)cc4)cc3c2c(=O)[nH]1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 4-((1,2-dihydro-2-methoxymethyl-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoate in THF:1N HCl: concentrated HCl (15:10:1, 26 ml) was stirred at 60° C. overnight. The resulting suspension was diluted with water, concentrated in vacuo to remove the THF, and chilled in an ice bath. The solid was filtered, washed with water, and dried in vacuo at 100° C. The resulting ester was dissolved in 1N NaOH (10 ml) and ethanol (~3 ml) and stirred at 60° C. for 4 hours. The solution was acidified with concentrated HCl to pH 1.5 and the resulting precipitate filtered and dried in vacuo at 110° C. to give 4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoic acid (0.195 g). 1H NMR (DMSO-d6, 300 MHz) δ: 2.59 (s, 3H, CH3), 5.46 (s, 2H, CH2O), 7.17 (d, J=9 Hz, 2H, Ar), 7.80 (overlapping d, J=9 Hz, 2H, Ar), 7.91 (d, J=9 Hz, 2H, Ar), 8.16 (d, J=8 Hz, 1H, Ar), 9.85 (s, 1H, Ar).
Reaction SMILES: C(C1OC1)Cl.C(C(CCCCC)CO)CC.Cl[CH2:18][CH:19]([OH:32])[CH2:20][O:21][CH2:22][CH:23]([CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CC(C)([O-])C.[K+]>O1CCCC1>[CH2:20]([O:21][CH2:22][CH:23]([CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:19]1[O:32][CH2:18]1
Reactant: CCCCCC(CCC)COCC(O)CCl
Agent: CC(C)(C)[O-]
Agent: CCCCCC(CO)CCC
Agent: [K+]
Solvent: ClCC1CO1
Solvent: C1CCOC1
Product: CCCCCC(CCC)COCC1CO1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a flame dried, 500 mL round bottomed flask equipped with an addition funnel charged with epichlorohydrin (15.62 gm., 0.17 moles), is added 2-propylheptanol (Pfaltz & Bauer, Inc., 172 E. Aurora Street, Waterbury Conn., 06708, USA) (20 gm., 0.127 moles) and stannic chloride (0.20 gm., 0.001 moles). The reaction is kept under an argon atmosphere and warmed to 90° C. using an oil bath. Epichlorohydrin is dripped into the stirring solution over 60 minutes followed by stirring at 90° C. for 18 hours. The reaction is fitted with a vacuum distillation head and 1-chloro-3-(2-propyl-heptyloxy)-propan-2-ol is distilled at a temperature range of 90° C.->95° C. under 0.2 mm Hg. Wt.=22.1 gm. The 1-chloro-3-(2-propyl-heptyloxy)-propan-2-ol (5.0 gm., 0.020 moles) is dissolved in tetrahydrofuran (50 mL) and stirred at RT under an argon atmosphere. To the stirring solution is added potassium tert-butoxide (2.52 gm., 0.022 moles) and the suspension is stirred at RT for 18 hours. The reaction is then evaporated to dryness, residue dissolved in hexanes and washed with water (100 mL). The hexanes phase is separated, dried with Na2SO4, filtered and evaporated to dryness to yield the crude 2-propylheptyl glycidyl ether, which can be further purified by vacuum distillation.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18]([C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)[CH2:19][CH:20]=[CH:21][CH3:22]>C(Cl)Cl>[O:9]1[CH:21]([CH3:22])[CH:20]1[CH2:19][CH2:18][C@H:23]1[CH2:24][CH2:25][C@H:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:27][CH2:28]1
Reactant: CC=CCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1OC1CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.49 g of 90% m-chloroperbenzoic acid in 100 ml of methylene chloride was treated with 11.3 g of powdered potassium carbonate. The mixture was treated dropwise at 0° C. within 5 minutes with a solution of 5.93 g of p-[trans-4-(3-pentenyl)cyclohexyl]benzonitrile in 20 ml of methylene chloride and stirred at room temperature for 2 hours. The mixture was subsequently treated with a further 4.49 g of 90% m-chloroperbenzoic acid and the resulting mixture was stirred further. After a total of 70 hours, the mixture was partitioned three times in methylene chloride/10% sodium thiosulphate solution. The organic extracts were washed with sodium thiosulphate solution and water, dried over magnesium sulphate, filtered and concentrated. Chromatographic separation of the resulting, light yellowish oil (6.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 10:90) gave 6.27 g (99.5%) of p-[trans-4-(3,4-epoxypentyl)cyclohexyl]benzonitrile as a colourless oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:30])[NH:13][C:14]([CH3:29])([CH3:28])[CH2:15][N:16]([C:24](=[O:27])[CH2:25]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])([CH3:10])([CH3:9])[CH3:8].[Cl-].[NH4+]>O1CCCC1.O>[C:7]([O:11][C:12]([N:13]1[CH2:25][C:24](=[O:27])[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:15][C:14]1([CH3:29])[CH3:28])=[O:30])([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1ccccc1N(CC(C)(C)NC(=O)OC(C)(C)C)C(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
A solution of 1.3 g of potassium t-butoxide (12.0 mmol) in tetrahydrofuran (80 ml) was added to a solution of 3.2 g of {2-[(2-bromoacetyl)-(2-methylphenyl)amino]-1,1-dimethylethyl}carbamic acid t-butyl ester obtained in Example (51b) (8.0 mmol) in tetrahydrofuran (80 ml) under a nitrogen atmosphere and under cooling in a dry ice-acetone bath over 30 minutes, and the mixture was stirred at the same temperature for 10 minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture. The mixture was returned to room temperature and diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=3/1) to obtain 1.8 g of the title compound (yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]3[CH2:13][CH2:14][C:15]([CH3:21])([C:17]([O:19]C)=[O:18])[CH2:16][C:11]3(N3CCCC3)[O:10][N:9]=2)=[CH:4][CH:3]=1>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][C:15]([CH3:21])([C:17]([OH:19])=[O:18])[CH2:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1(C)CCC2C(c3ccc(Cl)cc3)=NOC2(N2CCCC2)C1
Agent: Cl
Product: CC1(C(=O)O)CCc2c(-c3ccc(Cl)cc3)noc2C1
Yield: 75.2 %

Procedure:
A solution of 9.1 g of methyl 3-(4-chlorophenyl)-3a,4,5,6,7,7a -hexahydro-6-methyl-7a-pyrrolidino-1,2-benzisoxazole-6-carboxylate in 100 ml of 2N hydrochloric acid was heated under reflux for 6 hours. The product which separated on cooling was extracted with ethyl acetate and the ethyl acetate extract was dried over magnesium sulfate and evaporated. After crystallization from ethyl acetate/hexane there was obtained 5.3 g of 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-6-methyl-1,2-benzisoxazole-6-carboxylic acid of melting point 185°-187° C.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][NH:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)C.N>Cl>[S:9]1[C:8]2[CH2:7][NH:6][CH2:5][CH:4]([OH:3])[C:12]=2[CH:11]=[CH:10]1
Reactant: CCOC(CNCc1cccs1)OCC
Agent: Cl
Agent: N
Product: OC1CNCc2sccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
2,2-Diethoxy-N-(thiophen-2-ylmethyl)ethaneamine (72.5 g) prepared in the step 2 was dissolved in 5N aqueous solution of hydrochloric acid and stirred overnight at room temperature. The reaction solution was neutralized with 10% aqueous ammonia and subjected to extraction with ethyl acetate. The organic layer was separated, washed with water and a saturated solution of sodium chloride successively, dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 14.0 g of the objective compound.
Reaction SMILES: [OH:1][B:2]([OH:11])[C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[CH3:12][O:9][C:8]([C:6]1[O:7][C:3]([B:2]([OH:1])[OH:11])=[CH:4][CH:5]=1)=[O:10]
Reactant: O=C(O)c1ccc(B(O)O)o1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(B(O)O)o1
Reaction time: 0.75 h

Procedure:
5-(Dihydroxyboryl)-2-furoic acid (200 mg, 1.283 mmol) was dissolved in CH2Cl2 (5 mL) and MeOH (0.556 mL). Trimethylsilyldiazomethane (1.283 mL, 2.57 mmol) was added dropwise. After 45 min, the reaction was quenched with AcOH dropwise until the yellow color disappeared. The reaction was concentrated in vacuo to give [5-(methoxycarbonyl)-2-furyl]boronic acid. 1H NMR (500 MHz, CD3OD): δ 7.20 (d, J=3.5 Hz, 1H); 7.05 (d, J=3.6 Hz, 1H); 3.87 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([O:15][P:16]([CH:21]([NH2:23])[CH3:22])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]>>[CH2:18]([O:17][P:16]([CH:21]([NH:23][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:22])(=[O:20])[O:15][CH2:13][CH3:14])[CH3:19]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOP(=O)(OCC)C(C)N
Product: CCOP(=O)(OCC)C(C)Nc1ccc(C#N)cc1[N+](=O)[O-]
Yield: 77.4 %

Procedure:
2.77 g (15.24 mmol) of 4-chloro-3-nitrobenzonitrile is stirred with 10.5 g (38 mmol) of 1-aminoethanephosphonic acid diethyl ester for 16 hours at 30° C. The reaction mixture is then chromatographed on silica gel with methylene chloride:ethanol=95:5 as eluant. 3.86 g (80% of theory) of 1-[N-(2-nitro-4-cyanophenyl)amino]ethanephosphonic acid diethyl ester is obtained.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])SCCCS2)[CH2:3][CH2:2]1.BrN1C(=[O:22])CCC1=O>CC#N.O>[CH:1]1([CH2:4][C:5](=[O:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(CC2CC2)SCCCS1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(=O)CC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate (19.6 g, 79.67 mmol) in CH3CN (20 mL) was slowly added, over 30 minutes, to a well-stirred suspension of NBS (N-bromosuccinimide) in CH3CN (210 mL) and water (55 mL). After the mixture was stirred for 1 h, the resulting red solution was poured into an ice-cold CH2Cl2-Hexane solution (1:1 500 mL). The resulting mixture was washed with saturated aqueous NaHSO3 and water. The colorless organic phase was carefully washed with saturated aqueous K2CO3 and water. The organic phase was dried over MgSO4, then evaporated to give 6.88 g (55%) of ethyl 3-cyclopropyl-2-oxopropanoate as a yellow oil. 1H NMR (CDCl3): δ 4.29 (2H, q, J=8 Hz), 2.71 (2H, d, J=9 Hz), 1.35 (3H, t, J=8 Hz), 1.05-0.98 (1H, m), 0.59-0.54 (2H, m), 0.17-0.14 (2H, m).