Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:14]=23)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c3) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:23]=[CH:24][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1cccc(OCc2ccccc2)c1
Product: O=C(O)c1ccccc1Nc1cccc(OCc2ccccc2)c1

Procedure:
2-(3-Benzyloxyphenylamino)benzoic acid [VII; R and R"=H, OR°=3-OCH2C6H5 ] was prepared from 2-chlorobenzoic acid and 3-benzyloxyaniline according to the procedure of Example 1(a). The green solid obtained was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C:9](=O)[CH2:8][C:7]=2[CH:14]=1.B.[ClH:16]>O1CCCC1>[ClH:16].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)CC(=O)NCC2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCNCC2

Procedure:
A suspension of 8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine (20.4 g, 0.105 m) in tetrahydrofuran (500 ml) was added to 1 M borane in tetrahydrofuran (300 ml) stirred at 5°. The mixture was heated to reflux for 2 hours, cooled, treated with 3N hydrochloric acid (300 ml), concentrated in vacuo to remove tetrahydrofuran and heated to reflux for 1 hour. The mixture was concentrated in vacuo, filtered and the filter cake was dissolved in methanol, heated to reflux, dried with magnesium sulfate and concentrated in vacuo to afford 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 229°-231°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:10]([CH2:21][OH:22])=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:10]([CH:21]=[O:22])=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc2c(c1)c(CO)c(C(C)C)n2Cc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COCOc1ccc2c(c1)c(C=O)c(C(C)C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
General Procedure B. To a solution of (1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indol-3-yl)methanol (Compound 3, 120 mg, 0.35 mmol) in CH2Cl2 was added 4-methylmorpholine N-oxide (NMO, 129 mg, 1.1 mmol) and tetrapropylammonium perruthenate (TPAP, 14 mg, 0.040 mmol). The reaction was stirred at room temperature for 2.5 h, and the product was purified by flash chromatography on silica gel eluting with 20% EtOAc-hexanes to yield 1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indole-3-carboxaldehyde (Compound 4) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:10](S(C)(=O)=O)[C:4]=2[CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3n2S(C)(=O)=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.1 %

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (21) (11.07 g 31.2 mmole) was stirred in methanol (105 mL) at 25° C. and 1M sodium hydroxide (35.3 mL) added. The reaction was stirred at 25° C. for 6 hours. Solvent (85 mL) was removed and water (40 mL) added. The mix was left to cool in ice-water for about 1 hour. The product was filtered off, washed with water (×3) and dried in a vacuum desiccator over potassium hydroxide, overnight. The resulting solid was azeotroped with toluene (100 mL) to give the title compound (8.22 g 95%). 1H-NMR (d6-DMSO, 500 MHz): δ 3.90 (s, 3H), 6.69 (d, J=0.95 Hz, 1H), 7.47 (t, J=0.95 Hz, 1H), 7.94 (d, J=0.63 Hz, 1H), 8.18 (s, 1H), 8.50 (d, J=0.95 Hz, 1H), 11.92 (br s, 1H, NH).
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C:23]([O-])([O-])=O.[Cs+].[Cs+].CI.[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:16]([CH3:23])[S:17]([CH3:20])(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1Cc2ccccc2[C@H]1NS(C)(=O)=O
Agent: [Cs+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CI
Solvent: CN(C)C=O
Product: CN([C@@H]1c2ccccc2C[C@H]1O[Si](C)(C)C(C)(C)C)S(C)(=O)=O
Reaction time: 2 h

Procedure:
N-[(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-yl]-methanesulphonamide (0.50 g) is dissolved in 2 mL DMF and mixed with Cs2CO3 (0.96 g, 2.93 mmol) and MeI (0.10 mL). The reaction mixture is stirred for 2 h and, once the reaction has ended, combined with DCM and NaOH (1 N). The organic phase is dried on MgSO4 and freed from the solvent using the rotary evaporator. After dissolving in acetonitrile water is added. The precipitate formed is filtered off, washed with water and taken up in DCM. After drying on MgSO4 the solvent is eliminated using the rotary evaporator.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:15]([C:24](=[O:30])[NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:14]([CH3:31])[NH:13][C:12]=1[CH2:32][O:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[CH3:45])=[O:10])C1C=CC=CC=1>[Pd].C(O)C>[C:26]([NH:25][C:24]([C:15]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH2:32][O:33][CH2:34][CH2:35][N:36]2[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=[C:37]2[CH3:45])[NH:13][C:14]=1[CH3:31])=[O:30])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC1=C(C(=O)NC(C)(C)C)C(c2ccccc2Cl)C(C(=O)OCc2ccccc2)=C(COCCn2c(C)nc3ccccc32)N1
Agent: [Pd]
Solvent: CCO
Product: CC1=C(C(=O)NC(C)(C)C)C(c2ccccc2Cl)C(C(=O)O)=C(COCCn2c(C)nc3ccccc32)N1
Temperature: 28 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
Palladium on carbon (0.10 g; 5%) was added to a solution of 3-benzyloxycarbonyl-5-(N-t-butylcarbamoyl)-4-(2-chlorophenyl)-6-methyl-2-[2-(2-methylbenzimidazol-1-yl)ethoxymethyl]-1,4-dihydropyridine (0.143 g, 0.23 mmol) in ethanol (8 ml) and the mixture stirred under hydrogen (1 bar) at 28° C. for 5 hours. The catalyst was removed by filtration, the solvent evaporated and the residue triturated with hot diethyl ether to yield the title product as a white solid (0.097 g, 79%), m.p. 187°-188° C. Found: C,62.77; H, 6.35; N, 10.09. C29H33ClN4.H2O requires C, 63.17; H, 5.96; N, 10.09%.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[N:35]1([CH2:40][C:41](O)=[O:42])[CH:39]=[N:38][CH:37]=[N:36]1>>[N:35]1([CH2:40][C:41]([NH:1][C@H:2]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[CH:24][CH:25]=2)=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:42])[CH:39]=[N:38][CH:37]=[N:36]1
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 20 %

Procedure:
Proceeding as in Example 1, but substituting (S)-benzyl 4-amino-5-(4-(4-fluorophenoxy)phenylamino)-5-oxopentylcarbamate and 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride, gave Compound 165, (S)-benzyl 4-(2-(1H-1,2,4-triazol-1-yl)acetamido)-5-(4-(4-fluorophenoxy)phenylamino)-5-oxopentylcarbamate (90.1 mg, 20%). 1H-NMR (400 MHz, DMSO-D6): σ 10.19 (s, 1H), 8.69 (d, 1H), 8.48 (s, 1H), 7.96 (s, 1H), 7.60 (d, 2H), 7.39-7.29 (m, 5H), 7.21 (m, 2H), 7.04-6.96 (m, 4H), 5.00-4.97 (m, 4H), 4.46-4.39 (m, 1H), 3.04-2.99 (m, 2H), 1.75-1.39 (m, 4H). MS (EI) for C29H29FN6O5. found 560.9 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[CH2:12]([O:14]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:13].Cl>C1(C)C=CC=CC=1.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>[O:11]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:12](=[O:14])[CH3:13])[CH:3]=2)[O:8][CH2:9][CH2:10]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc2c(c1)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
Under an argon atmosphere, 7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (65 mg, 0.30 mmol) was dissolved in toluene (1.5 mL), added tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) and 1-ethoxyethenyl tri n-butyl tin (112 ΞL, 0.33 mmol), and the mixture was stirred at 100° C. overnight. The reaction solution was reverted to room temperature, and added 1N hydrochloric acid. The reaction solution was filtered through a pad of celite. The reaction solution was added ethyl acetate for extraction. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by preparative thin-layer chromatography (n-hexane/ethyl acetate=1/1). The title compound (37 mg (yield 69%)) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:22])[S:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:22])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:34][C:31]2[S:32][CH:33]=[C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:30]=2)=[O:18])=[CH:20][CH:21]=1)(=[O:11])=[O:12]
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: COc1ccccc1N(C)S(=O)(=O)c1ccc(C(=O)O)cc1
Product: COc1ccccc1N(C)S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(N-(2-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (13) (109 mg, 0.34 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 50-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 4-(N-(2-methoxyphenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an off white solid. Yield: 46 mg (34%). 1H-NMR: 8.65-8.62 (m, 1H), 8.27 (d, J=8.5 Hz, 2H), 8.03 (d, J=7.5 Hz, 1H), 7.95-7.89 (m, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.38-7.32 (m, 2H), 7.22 (dd, J=7.5, 1.5 Hz, 1H), 7.01-6.94 (m, 2H), 3.34 (s, 3H), 3.18 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]([CH:18]=[O:19])=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:26])[CH:14]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][Mg]Br.O>C1COCC1>[CH2:1]([N:8]1[C:17]([CH:18]([OH:19])[CH3:28])=[C:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:26])[CH:14]=2)[C:9]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde (500 mg) in THF (5 ml) was added dropwise a solution of methyl magnesium bromide in THF (3M, 0.5 ml) at room temperature, and the mixture was stirred for 10 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate-hexane to give the title compound (470 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])=[O:10]
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1cc(Cl)ccc1O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
To a solution of the product of Example 44A (2.16 g, 9.51 mmol) in CHCl3 (8 mL) was added, with ice cooling, pyrrolidine (4.05 g, 57.04 mmol). The mixture was stirred at 25° C. for 2 hrs, then concentrated in vacuo. The residue was dissolved in toluene, washed with HCl and water, dried (Na2SO4) and concentrated. The resulting oil was crystallized from hexane and chromatographed (CH2Cl2) to yield the title compound (1.92 g), m.p. 101-102° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:32])([CH2:12][CH2:13][C:14]1[N:15]([CH3:31])[C:16]([C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][CH:18]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:32])([CH2:12][CH2:13][C:14]1[N:15]([CH3:31])[C:16]([C:19](=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:18]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(CC[C@](C)(CO)NC(=O)OC(C)(C)C)ccc1C(=O)CCCCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c(CC[C@](C)(C=O)NC(=O)OC(C)(C)C)ccc1C(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.3 %

Procedure:
To a solution of (2R)-2-t-butoxycarbonylamino-2-methyl-4-[1-methyl-5-(5-phenylpentanoyl)pyrrol-2-yl]butan-1-ol (0.3520 g, 0.80 mmol) obtained in Example (43a) in dichloromethane (8 ml) were added successively molecular sieves 4 A (0.2234 g) and pyridinium dichromate (0.4594 g, 1.22 mmol), and the resulting mixture was stirred at room temperature for 20 hours. After stirring, ether was added to the reaction mixture, and the resulting mixture was filtered. The filtrate was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (3:2) as the eluent to afford the title compound (0.2195 g, yield: 63%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].[C:27]([CH:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([CH:31]1[CH2:32][CH2:33][CH:34]([NH:37][C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=2)=[O:20])[CH2:35][CH2:36]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: CC(C)(C)C1CCC(N)CC1
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(C(C)(C)C)CC4)cc3)c(C#N)cc21
Yield: 97 %

Procedure:
Prepared according to Example 110, Step A where the reacting carboxylic acid replacing 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid with 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid and replacing 2-(benzo[d][1,3]dioxol-5-yl)ethanamine with 4-tert-Butylcyclohexylamine to provide the title compound (73 mg, 97% yield) as a solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[CH:46]=[C:45]3[C:48]([CH2:55][C:56]4[CH:61]=[CH:60][C:59]([CH2:62][CH3:63])=[CH:58][CH:57]=4)=[C:49]([Si](C)(C)C)[S:50][C:44]3=[CH:43][C:42]=1[CH2:41][O:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:67])(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:47]1[CH:46]=[C:45]3[C:48]([CH2:55][C:56]4[CH:61]=[CH:60][C:59]([CH2:62][CH3:63])=[CH:58][CH:57]=4)=[C:49]([Cl:67])[S:50][C:44]3=[CH:43][C:42]=1[CH2:41][O:40]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1ccc(Cc2c([Si](C)(C)C)sc3cc4c(cc23)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1ccc(Cc2c(Cl)sc3cc4c(cc23)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 43.1 %

Procedure:
(3′R,4′S,5S,5′S,6′R)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-3-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-2-trimethylsilyl-spiro[thieno[2,3,f]isobenzofuran-5(7H),2′-[2H]pyran] (0.122 g, 0.139 mmol) was dissolved in acetonitrile (0.93 mL). Sulfuryl chloride (20.6 mg, 0.153 mmol) was added to the resultant solution, and then the solution was stirred for 3.5 hours at room temperature. Saturated aqueous sodium hydrogen carbonate was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (developing solution=ethyl acetate:n-hexane (1:11.5)), to thereby obtain the titled compound (50.2 mg, 43%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][OH:11]>C(Cl)Cl>[N:1]1([CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: OCCCBr
Reactant: C1COCCN1
Solvent: ClCCl
Product: OCCCN1CCOCC1
Temperature: 50 °C
Yield: 100 %

Procedure:
To a mixture of morpholine (33 mL, 371 mmol) and CH2Cl2 (650 mL) was added 3-bromopropanol (25.8 g, 186 mmol), and the mixture was heated at 50° C. for 18 h. The reaction was cooled, diluted with CH2Cl2, and filtered. The filtrate was chromatographed (150 g SiO2, CH2Cl2 to 5% 2 M NH3/MeOH in CH2Cl2) to give the title compound as a liquid (27.0 g, 50%).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1>Cl[Ti](Cl)(Cl)Cl.C1COCC1>[CH:2](/[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)=[CH:2]\[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: COc1cc(C=O)ccc1O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(/C=C/c2ccc(O)c(OC)c2)ccc1O
Temperature: -78 °C
Yield: 46.4 %

Procedure:
A flask was charged with 2.35 g of Mg (96.7 mmol) and anhydrous THF (100 mL). The mixture was chilled to −78° C. and then TiCl4 (10.6 mL, 96.5 mmol) was added dropwise through an addition funnel. The flask was allowed to slowly warm up to room temperature and the mixture transitioned to a green slurry and finally a black solution. After stirring at room temperature for 30 min a THF (50 mL) solution of vanillin (7.01 g, 46.1 mmol) was added dropwise. The reaction was mildly exothermic and resulted in a dark brown mixture. The mixture was heated at reflux for 16 h and was then cooled to room temperature. The solvent was removed under reduced pressure and the residue treated with 100 mL of 2 M HCl to yield a dark solution with pale brown suspended solid. The mixture was filtered on a medium frit and the isolated solid was washed with water (3×50 mL) and chilled ethanol (3×25 mL 0° C.). The solid was dried in a vacuum oven (˜10 Torr, 45° C.) overnight to yield 2.91 g of pale brown solid (46% yield). The purity of the crude product (>98%) was suitable for later synthetic procedures, but the material can be further purified by dissolution in THF followed by precipitation with hexane. X-ray quality crystals were grown by slow evaporation of a concentrated THF solution. 1H NMR (DMSO-d6): δ 9.07 (s, 2H, Ph-OH), 7.13 (d, 2H, J=2 Hz), 6.94 (s, 2H), 6.93 (dd, 2H, J=8, 2 Hz), 6.73 (d, 2H, J=8 Hz), 3.81 (s, 6H, OMe): 13C NMR (DMSO-d6): δ 147.8, 146.2, 129.2, 125.8, 119.5, 115.6, 99.6, 55.6.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10]P(OCC)(=O)OCC)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].COC([O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O)C>>[C:1]([C:5]1[CH:9]=[C:8]([CH:10]=[CH:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[OH:23])[O:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(Cc1cc(C(C)(C)C)no1)OCC
Reactant: COC(C)Oc1ccccc1C=O
Product: CC(C)(C)c1cc(C=Cc2ccccc2O)on1

Procedure:
Using the method described in Example I, 35 g (0.13 mole) of diethyl (3-tert.-butyl-isoxazol-5-yl)methanephosphonate and 23 g (0.13 mole) of o-(1-methoxy-ethoxy)-benzaldehyde are reacted and the product is recrystallized from toluene. 24.8 g (78% of theory) of colorless crystals, of melting point 152°-155° C., are obtained.
Reaction SMILES: C(Cl)Cl.S(Cl)(Cl)=O.Cl.[CH2:9]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH3:35][NH:36][CH3:37]>CN(C)C1C=CN=CC=1.C(COC)OC.C(OCC)C>[CH3:35][N:36]([CH3:37])[C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([NH:25][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:27][CH:28]=1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
In a solution of 100 ml. of methylene dichloride and 25 ml. of glyme was dissolved in 10 ml. of thionyl chloride and 4.0 g. of 4-(n-hexadecylamino)benzoic acid hydrochloride. The reaction mixture was heated to the reflux temperature for 2 hours and then cooled to room temperature. To this solution of acid chloride was added a solution of 200 ml. of diethyl ether, 25 ml. of glyme, and 0.1 g. of 4-dimethylaminopyridine which had been saturated with dimethylamine gas. This reaction mixture was stirred at room temperature for 2 hours whereby there was obtained a 92% yield of product, melting point 70°-72° C.