Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](O)=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[NH:3]1.B.C(OCC)(=O)C>O1CCCC1.O>[OH:14][CH2:13][C:11]1[CH:10]=[CH:9][C:8]2[C:2](=[O:1])[NH:3][C:4]3[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=3[S:6][C:7]=2[CH:12]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1NC2=O
Agent: B
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2Sc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve 5.1 gm. of 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-3-carboxylic acid in 100 cc. of tetrahydrofuran and add 35 cc. of 1 M borane in tetrahydrofuran at room temperature under a nitrogen atmosphere. Stir the mixture at room temperature for 3 hours. Slowly dilute the reaction mixture with water and then with ethyl acetate. Wash with aqueous sodium chloride, dry and evaporate to an oil.
Reaction SMILES: [N:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:13][N:14]=[C:15]=[O:16]>C1C=CC=CC=1>[N:10]1[CH:11]=[CH:12][C:7]([N:6]([N:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[C:15]([NH:14][CH3:13])=[O:16])=[CH:8][CH:9]=1
Reactant: CN=C=O
Reactant: c1ccn(Nc2ccncc2)c1
Solvent: c1ccccc1
Product: CNC(=O)N(c1ccncc1)n1cccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution containing 4 g of N-(1H-pyrrol-1-yl)-4-pyridinamine and 1.6 g of methyl isocyanate in 125 ml of benzene was stirred at 50° C. for two hours, and thereafter cooled and evaporated to 6 g of a solid. This material was purified by HPLC (silica gel, 50% ethyl acetate in dichloromethane) to give 5 g of a solid, mp 156°-160° C. This material was recrystallized twice from benzene to give 2.6 g of crystals, mp 162°-163° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=C[CH:2]=1.[N:21]1C=CC=C(B(O)O)C=1>>[N:21]1[CH:4]=[CH:5][CH:6]=[C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3cccnc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 3-pyridylboronic acid (153 mg, 1.24 mmol) were coupled to yield 2-pyridin-3-yl-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 75 mg (25%) as a light brown solid: m.p. 260.5-262.0° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.07 (m, 2H), 3.40 (m, 2H), 7.25 (app t, J=7.8 Hz, 1H), 7.57 (m, 2H), 7.71 (dd, J=7.5, 0.9 Hz, 1H), 8.05 (m, 1H), 8.12 (br t, 1H), 8.59 (m, 1H), 8.88 (m, 1H), 11.75 (br s, 1H). MS (FAB, MH+) 264. Anal. (C16H13N3O.0.2 H2O) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[F:12].[CH3:13]CN(CC)CC.CN(C=O)C>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:11]=[CH:13][NH:8]2)=[CH:4][C:3]=1[F:12]
Reactant: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc2cc[nH]c2cc1Br
Temperature: 130 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A 2 L dry round bottom flask was charged with 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (24.5 g, 0.1 mol, 97%), DMF-DIPA (39 g, 0.22 mol), Et3N (16 mL, 0.11 mol) and dry DMF (100 mL). The mixture was stirred at 130° C. for 2 h. After removal of the volatiles the residue was dissolved in a mixture of toluene (650 mL) and acetic acid (390 mL) followed by addition of iron powder (55 g) and silica gel (50 g). The dark red mixture was heated to 100° C. with vigorous stirring. The dark color disappeared after refluxing for 20 min indicating completion of reaction. The mixture was then cooled to 25° C., diluted with EtOAc and filtered. The cake was washed thoroughly with EtOAc. The combined filtrates were washed with sat. aq. Na2S2O5, sat. aq. NaHCO3, and brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluting with 5/1 hexanes/CH2Cl2 to provide 6-bromo-5-fluoro-1H-indole as a white crystalline solid (16.2 g, 76%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCC)=[O:23])[C:4]1=[O:27])[CH3:2].[NH2:28][C@H:29]([CH3:32])[CH2:30][OH:31]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:28][C@H:29]([CH3:32])[CH2:30][OH:31])=[O:23])[C:4]1=[O:27])[CH3:2]
Reactant: C[C@@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Product: CCn1c(=O)c(C(=O)N[C@H](C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 85 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.162 mmol) and (2R)-2-amino-1-propanol (0.05 mL) was prepared 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-methylethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (50 mg, 85% yield) as a white solid after purification by reverse phase HPLC. Analytical data was identical to that described in example 576.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1>[Pd].C(O)C>[CH3:1][O:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([NH2:10])[CH:5]=1
Reactant: COCc1cc([N+](=O)[O-])nn1C
Agent: [Pd]
Solvent: CCO
Product: COCc1cc(N)nn1C
Reaction time: 15 h
Yield: 101.6 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 336a (4.0 g, 23 mmol), Pd/C (1.0 g), and ethanol (100 mL). The mixture was hydrogenated at room temperature for 15 h. It was then filtered and the filtrate was concentrated under reduced pressure to afford 336b as a yellow oil (3.3 g, 99%), which was used in the next step without further purification. MS-ESI: [M+H]+ 142.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.FC(F)(F)C(O)=O>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[OH:12])=[CH:4][CH:3]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: O=C1CCCc2ccc(Br)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCCc3ccc(Br)cc32)cc1

Procedure:
A solution of 0.55 g (1.65 mmol ) of 7-bromo-1-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol, obtained analogously to Example 1a) from 7-bromo-3,4-dihydro-2H-naphthalen-1-one and 4-methoxyphenyl-magnesium bromide, and 0.2 ml of trifluoroacetic acid in 20 ml of tetra-hydrofuran is warmed at 50° C. for 12 hours and subsequently evaporated to dryness. 10 ml of saturated sodium hydrogencarbonate are added to the residue, and the aqueous mixture is extracted twice with 10 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the crude product is purified by column chromatography on silica gel (petroleum ether ethyl acetate 9:1), giving 0.54 g of 7-bromo-1-(4-methoxyphenyl)-3,4-dihydronaphthalene; LC/MS: 338 (M+Na).
Reaction SMILES: [C:1]([NH:11][NH2:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].O.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17](S(O)(=O)=O)=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([C:24]2[O:3][CH:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1](=[O:10])[NH:11][N:12]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NNC(=O)C(O)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NN=C(c2ccccc2)OC1c1ccccc1
Yield: 482.6 %

Procedure:
Mandelic acid hydrazide (1.66 g) and trimethyl o-benzoate (1.82 g) were heated under stirring in dimethyl formamide (30 ml) at 120° C. for 12 hours in the presence of p-toluene sulfonate monohydrate (0.2 g). The solvent was evaporated, and the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The ethyl acetate layer was washed with water (50 ml×2) and brine (50 ml), and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel chromatography (ethyl acetate/hexane, 1:1), to give the title compound as a white powder (1.28 g, 51%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2[C:41]1[CH:40]=[CH:39][CH:38]=[C:37]([F:36])[CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A mixture of methyl 6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (10.26 g, 20 mmol), 3-fluorophenylboronic acid (3.36 g, 24 mmol) and sodium carbonate (5.30 g, 50 mmol) in toluene (50 mL), ethanol (10 mL) and water (10 mL) was stirred under an argon atmosphere at room temperature for 30 min. To the obtained mixture was added tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol) and the mixture was refluxed under heating under an argon atmosphere for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (6.31 g, 68.7%) as crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]([CH:22]([CH3:45])[CH:23]([C:25]1[C:33]2[C:28](=[C:29]([F:35])[CH:30]=[C:31]([F:34])[CH:32]=2)[N:27](S(C2C=CC=CC=2)(=O)=O)[CH:26]=1)O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCOCC1.O1CCCC1>[CH2:15]([N:14]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C@@H:22]([CH3:45])[CH2:23][C:25]1[C:33]2[C:28](=[C:29]([F:35])[CH:30]=[C:31]([F:34])[CH:32]=2)[NH:27][CH:26]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[C@@H](Cc1c[nH]c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
Lithium aluminum hydride (LAH) (0.7 g, 18 mmol) is added portionwise to a dioxane/tetrahydrofuran (90 ml/10 ml) solution of 2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol (1.9 g, 3.3 mmol) under N2 at 0° C. After the addition is complete, the reaction is allowed to warm to room temperature, then is refluxed for 1 hour. The reaction is quenched with H2O and 15% aqueous NaOH, filtered, and the filtrate is diluted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated, and the residue is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 1.2 g of dibenzyl-[2-(5,7-difluoro-1H-indol-3-yl)-l(S)-methyl-ethyl]-amine (86%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]2[S:23][C:22]([SH:24])=[N:21][N:20]=2)=[C:13]([N+:25]([O-:27])=[O:26])[CH:12]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]2[S:23][C:22]([S:24][CH3:1])=[N:21][N:20]=2)=[C:13]([N+:25]([O-:27])=[O:26])[CH:12]=1
Reactant: COc1cc(-c2nnc(S)s2)c([N+](=O)[O-])cc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(-c2nnc(SC)s2)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.6 %

Procedure:
Potassium carbonate (13.8 mg, 1.0 mmol) and 0.0624 ml (1.0 mmol) of methyl iodide were added to a solution of 150 mg (0.510 mmol) of 5-(4,5-dimethoxy-2-nitrophenyl)-1,3,4-thiadiazole-2-thiol produced in Reference Example 2 in N,N-dimethylformamide (2 ml), and the mixture was stirred at room temperature for 10 min. The mixture was diluted with 30 ml of ethyl acetate, and the diluted solution was washed with 30 ml of a 10% aqueous ammonium chloride solution and 30 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure, and the resultant crystal was washed with diisopropyl ether to give 140 mg (yield 89%) of the title compound.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)=[O:21].[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][N:33]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH:40]12[CH2:32][CH:37]([CH2:38][CH2:39]1)[CH2:36][CH:35]2[CH2:34][NH:33][C:29]([C:26]1[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH2:13]2)=[O:21])=[CH:24][CH:25]=1)=[O:31]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1
Agent: NCCCc1ccccc1
Product: O=C(NCC1CC2CCC1C2)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting bicyclo[2.2.1]hept-2-ylmethamine for 3-phenylpropan-1-amine and 6-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 10.05 (bs, 1H), 8.92 (d, J=42.7 Hz, 1H), 8.61 (s, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.29 (d, J=9.3 Hz, 1H), 8.10 (d, J=9.3 Hz, 1H), 7.47-7.41 (m, 1H), 5.07-4.74 (m, 4H), 3.23-2.84 (m, 2H), 2.30-2.02 (m, 3H), 1.86-1.57 (m, 2H), 1.58-0.99 (m, 6H); MS (ESI(+)) m/e 393 (M+H)+.
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]1[C:9]([N:19]2[CH2:24][C@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]2)=[C:10]([F:18])[C:11]([F:17])=[C:12]([C:14](=[O:16])[CH3:15])[CH:13]=1)(C)(C)C.Cl.O>O1CCOCC1>[CH3:25][C@H:23]1[O:22][C@@H:21]([CH3:26])[CH2:20][N:19]([C:9]2[C:8]([CH2:7][OH:6])=[CH:13][C:12]([C:14](=[O:16])[CH3:15])=[C:11]([F:17])[C:10]=2[F:18])[CH2:24]1
Reactant: CC(=O)c1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1cc(CO)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-4-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-2,3-difluoro-phenyl]-ethanone (Intermediate 9, 7.2 g, 28 mmol) and 4N HCl in dry dioxane (75 mL) was stirred at room temperature for 12 hours. The reaction mixture was treated with cold water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases combined were dried (Na2SO4) and concentrated. The residue was purified over a silica gel flash column using a gradient of ethyl acetate in pet. ether to give the title compound as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=1)[C:9]([OH:11])=O.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH2:35])=[N:32][CH:31]=1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:34][C:33]([NH:35][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=[C:6]([O:5][C:4]3[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[CH:3]=3)[CH:7]=2)=[N:32][CH:31]=1)[CH3:25]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: COC[C@H](C)Oc1cc(Oc2cccc(F)c2)cc(C(=O)O)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3cccc(F)c3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-(3-fluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.ClCCl.[N:22]1([C:28]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=2[NH2:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O>[N:22]1([C:28]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][C:29]=2[NH:30][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)ccc2N2CCCCC2)cc1
Reaction time: 60 h

Procedure:
p-Toluenesulfonyl chloride (233 g, 1.22 mmol, commercially available product) and triethylamine (254 μl, 1.83 mmol) were sequentially added at room temperature to a dichloromethane (5 ml) solution of 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (149 mg, 0.610 mmol), obtained as described in Referential Example 1-2. The resulting mixture was stirred for 60 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=10/1). Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]-p-toluenesulfonamide (GIF-0622) (243 mg, quant) was yielded as a colorless solid.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:7]1[C:53]2[C:48](=[CH:49][C:50]([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([CH2:62][CH3:63])=[CH:58][CH:57]=3)=C(Cl)[CH:52]=2)[C@:9]2([C@H:14]([O:15]CC3C=CC=CC=3)[C@@H:13]([O:23]CC3C=CC=CC=3)[C@H:12]([O:31]CC3C=CC=CC=3)[C@@H:11]([CH2:39][O:40]CC3C=CC=CC=3)[O:10]2)[CH2:8]1)[CH:5]=C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[BH4-].[Na+].[CH2:85]([Cl:87])Cl>>[Cl:87][C:85]1[CH:52]=[C:53]2[C:48](=[CH:49][C:50]=1[CH2:55][C:56]1[CH:57]=[CH:58][C:59]([CH2:62][CH3:63])=[CH:60][CH:61]=1)[C@:9]1([C@H:14]([OH:15])[C@@H:13]([OH:23])[C@H:12]([OH:31])[C@@H:11]([CH2:39][OH:40])[O:10]1)[CH2:8][CH:7]2[CH2:4][CH2:5][OH:1]
Reactant: ClCCl
Reactant: O=[O+][O-]
Reactant: C=CCC1C[C@]2(O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2cc(Cc3ccc(CC)cc3)c(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1ccc(Cc2cc3c(cc2Cl)C(CCO)C[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
O3 was bubbled into a cooled solution (−78° C.) of (1S,3′R,4′S,5′R,6′R)-3-allyl-3′,4′,5′-tris(benzyloxy)-6′-(benzyloxymethyl)-5-chloro-6-(4-ethylbenzyl)-2,3,3′,4′,5′,6′-hexahydrospiro[indene-1,2′-pyran] (100 mg, 0.12 mmol) in CH2Cl2 (20 mL). After 5 min, N2 was bubbled into this solution for 20 min while the reaction temperature was gradually raised to room temperature. PPh3 (50 mg, 0.24 mmol) was added and the resulting mixture was stirred for 1 h at room temperature and concentrated. The resulting crude aldehyde was dissolved in THF (20 mL), and NaBH4 (9 mg, 0.24 mmol) was added. After being stirred at room temperature for 2 h, the reaction mixture was quenched by saturated aqueous NH4Cl solution and concentrated. The residue was partitioned between water and AcOEt, the organic layer was separated, washed with brine and dried over Na2SO4. Concentration and purification by preparative HPLC gave 85 mg (95%) of tetra-benzyl-protected alcohol, which was deprotected using the standard hydrogenation procedure to provide the title compound (30 mg). 1H NMR (CD3OD, 300 MHz) δ 7.26 (s, 1H), 7.24 (s, 1H), 7.09 (m, 4H), 4.05 (s, 2H), 3.82-3.21 (m, 9H), 2.77 (dd, J=12.9, 7.8 Hz, 1H), 2.58 (q, J=7.8 Hz, 2H), 2.13 (m, 1H), 1.77 (dd, J=12.9, 7.8 Hz, 1H), 1.68 (m, 1H), 1.19 (t, J=7.8 Hz, 3H); MS ESI (m/z) 463 (M+1)+, calc. 460.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9](=[O:21])[C:10]3[CH:20]=[C:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1([CH3:30])[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1.O1CCCC1>ClCCl>[CH3:30][C:22]1[CH:27]=[CH:26][C:25]([C:9]([C:10]2[C:11]([NH:12][C:7](=[O:8])[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[CH:20]=2)=[O:21])=[CH:24][CH:23]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: O=c1oc(-c2ccccc2)nc2cc3c(cc12)CCCC3
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cc3c(cc2NC(=O)c2ccccc2)CCCC3)cc1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
N-[3-(4-Methyl-benzoyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-benzamide was prepared by a modification of the route described in Okabe, M. and Sun, R. C.; Tetrahedron 1995, 51(7), 1861-1866). To a 100 mL flask containing a solution 2-phenyl-6,7,8,9-tetrahydro-naphtho[2,3-d][1,3]oxazin-4-one (220 mg, 0.793 mmol) in dichloromethane (20 mL) under nitrogen and cooled to −78 C was added dropwise by syringe p-tolylmagnesium bromide solution in tetrahydrofuran (1.0 M, 0.87 mL, 0.87 mmol) and the yellow solution was allowed to warm to room temperature overnight with stirring. Reaction had not proceeded to completion and was re-cooled to −78 C and added more p-tolylmagnesium bromide solution (0.30 mL, 0.38 eq) and transferred the reaction to an acetonitrile-CO2 bath (−42 C) and stirred for 1 hour. Quenched by addition of saturated ammonium chloride solution (2 mL) and allowed to warm to ambient temperature. Diluted further with water (10 mL) and the organic fraction was removed using a hydrophobic frit, evaporated onto silica gel, and chromatographed using ISCO Companion with a Redisep silica gel 40 g cartridge and a gradient of heptane and ethyl acetate (0% to 20%). Evaporation gave N-[3-(4-methyl-benzoyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-benzamide as a pale yellow solid 191.4 mg (65.3% Yield). LCMS (5 min acidic) 3.52 min 100% pure by ELSD and UV ES+ 370. HNMR (CDCl3) >95% pure 11.69 (s, 1H), 8.08-8.06 (m, 2H), 7.65-7.63 (m, 2H), 7.55-7.48 (m, 3H), 7.33-7.29 (m, 3H), 2.92-2.89 (m, 2H), 2.71-2.68 (m, 2H), 2.46 (s, 3H), 1.87-1.79 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:14][C:13](=[O:15])[C:12]1(Cl)Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>C(O)(=O)C.[Zn]>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:12][C:13](=[O:15])[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(CCOCc2ccccc2)C1(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1CC(CCOCc2ccccc2)C1
Temperature: 60 °C

Procedure:
Zinc dust was added to a solution of 3-(benzyloxyethyl)-2,2-dichlorocyclobutanone in glacial acetic acid at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in CH2Cl2, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by silica gel flash chromatography (Hexane:EtOAc=6:1). 1H NMR (CDCl3, 400 MHz): δ 1.85-1.90 (q, J=6.0, 2H), 2.45-2.56 (m, 1H), 2.66-2.74 (m, 2H), 3.07-3.15 (m, 2H), 3.48-3.51 (t, J=6.0, 2H), 4.48 (s, 2H), 7.24-7.35 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 21.29, 36.02, 52.56, 68.85, 72.99, 127.56, 127.62, 128.40, 138.33, 208.25. Rf=0.45 (Hexane:EtOAc=3:1). IR (neat) νmax 3054, 2927, 2856, 1779, 1266, 737, 704.