Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6](=[NH:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].Br[C:10](=[CH:14]OC)[C:11](=[O:13])[CH3:12].C(N(CC)CC)C>S(=O)(=O)(O)O>[C:11]([C:10]1[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([CH3:7])=[N:8][CH:14]=1)(=[O:13])[CH3:12]
Reactant: CC(=N)NC(C)(C)C
Reactant: COC=C(Br)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: CC(=O)c1cnc(C)n1C(C)(C)C
Temperature: 120 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, 18.5 g (0.162 mol) of N-tert-butylacetamidine (which was prepared in the above-mentioned Reference Example 3), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 120° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: ethyl acetate) to give 4.86 g (yield: 25%) of 5-acetyl-1-tert-butyl-2-methyl-imidazole.
Reaction SMILES: C([O:4][CH:5]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:6]1=[O:24])(=O)C.[OH-].[K+].O>CC(C)=O.CO>[OH:4][CH:5]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:6]1=[O:24]
Reactant: COc1ccc(N2C(=O)C(OC(C)=O)C2c2ccccc2Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc(N2C(=O)C(O)C2c2ccccc2Cl)cc1
Yield: 96.9 %

Procedure:
To a solution of β-lactam 23 (8.00 g, 23.1 mmol) in 50 ml of acetone was added KOH (1.30 g, 23.1 mmol) in 20 ml of methanol at 0° C. The resultant mixture was stirred for 5 minutes, and 50 ml of water was added. The product was precipitated and isolated by filtration to yield 6.8 g (96%) of 24 as a white solid, mp 178-180° C. 1H NMR (250 MHz) δ 7.48 (d, J=7.3 Hz, 1H), 7.34-7.24 (m, 5H), 6.85 (d, J=9.0 Hz, 2H), 5.63 (d, J=5.1 Hz, 1H), 5.34 (d, J=5.1 Hz, 1H), 3.78 (s, 3H), 1.74 (bs, 1H). 13C NMR (63 MHz, DMSO-d6), δ 166.6, 156.1, 133.1, 132.9, 131.0, 129.8, 129.6, 128.9, 127.4, 118.6, 115.0, 77.2, 60.0, 55.7.
Reaction SMILES: [C:1](Cl)(=[O:9])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:17]=[N:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][N:13]=1.O.C(OCC)C>N1C=CC=CC=1>[C:18]1([C:15]2[N:16]=[CH:17][C:12]([NH:11][C:1](=[O:9])[O:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:13][CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cnc(-c2ccccc2)cn1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phenyl chlorocarbonate (15.05 mL) was added at 0° C. to a solution of 2-amino-5-phenylpyrazine (17.12 g) in pyridine (200 mL). The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water (200 mL) and ethyl ether (200 mL). The whole was stirred to provide a suspension containing the subject compound as a crystal. The crystal was collected by filtration and further washed with ethyl ether (50 mL) and then dried under reduced pressure to provide the subject compound (24.57 g) as colorless crystals (melting point 192-198° C., decomposed).
Reaction SMILES: [Br:1][C:2]1[C:6](=[O:7])[C:5]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15](SC)=[CH:14][CH:13]=1.O[O:21][S:22]([O-:24])=O.[K+].[CH2:26]1COCC1.O>C(O)C>[Br:1][C:2]1[C:6](=[O:7])[C:5]2([CH2:8][CH2:9][CH2:10][CH2:11]2)[O:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([S:22]([CH3:26])(=[O:24])=[O:21])=[CH:14][CH:13]=1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CSc1ccc(C2=C(Br)C(=O)C3(CCCC3)O2)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)C3(CCCC3)O2)cc1

Procedure:
50 mg of 3-bromo-2-{4-(methylthio)phenyl}-1-oxa-spiro[4,4]non-2-en-4-one was stirred with 292 mg of OXONE at room temperature overnight in 5 ml ethanol, 5 ml THF, and 5 ml water. Then the insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The resulting aqueous layer was extracted with dichloromethane and the organic layer was concentrated in vacuo. The resulting residue was purified to column chromatography (hexane/ethylacetate) to afford 68 mg of 3-bromo-2-{4-(methylsulfonyl)phenyl}-1-oxa-spiro[4,4]non-2-en-4-one as a solid. mp: 127-128° C. NMR: δ1.98 (m, 6H), 2.12 (m, 2H), 3.11 (s, 3H), 8.09 (d, J=8.7 Hz, 2H), 8.37 (d, J=8.7 Hz, 2H).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.Cl>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.O.C(#N)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3]#[C:2][CH2:1][OH:4])[CH:7]=1
Reactant: C#CCO
Reactant: Ic1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OCC#Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
2-Propynyl alcohol (2.1 g) was added dropwise to a stirred mixture of 3-iodopyridine (2.2 g), bis(triphenylphosphine)palladium chloride (0.1 g), triethylamine (1.4 ml), cuprous iodide (0.1 g) and acetonitrile (10 ml) and the mixture was stirred at ambient temperature for 30 minutes and the heated to 60° C. for 2 hours. The mixture was cooled to ambient temperature, poured into water (100 ml) and neutralised by adding dilute aqueous hydrochloric acid. The mixture was extracted with diethyl ether (2×100 ml) and the combined extracts were washed with water (100 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride to give 3-(3-pyridyl)prop-2-yn-1-yl alcohol (0.8 g), m.p. 99°-100° C.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.[N:27]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[CH2:32][CH2:31][CH:30](OS(C)(=O)=O)[CH2:29][CH2:28]1>>[N:27]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[CH2:32][CH2:31][CH:30]([O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:29][CH2:28]1
Reactant: CS(=O)(=O)OC1CCN(c2ccccn2)CC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OC3CCN(c4ccccn4)CC3)cc12

Procedure:
6-(3,4,5,6-Tetrahydro-2H[1,2′]bipyridinyl-4-yloxy)-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime was prepared in 6% overall yield using the method described in example 169, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and methanesulfonic acid 3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-yl ester (example 170A).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39]([CH3:44])([CH3:43])[CH2:38][CH:37]=[C:36]2[C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=1>>[CH3:43][C:39]1([CH3:44])[CH2:38][CH:37]=[C:36]([C:45]2[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=2)[C:35]2[CH:34]=[C:33](/[C:27](/[Si:28]([CH3:29])([CH3:30])[CH3:31])=[CH:26]/[C:23]3[CH:22]=[CH:21][C:20]([CH2:19][OH:18])=[CH:25][CH:24]=3)[CH:42]=[CH:41][C:40]1=2
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cc1
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)cc1)(c1ccccc1)c1ccccc1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(/C(=C/c4ccc(CO)cc4)[Si](C)(C)C)cc32)cc1

Procedure:
Following General Procedure A, 4-[(trimethylsilyl)ethynyl]benzyl tert-butyldiphenylsilyl ether and 6-bromo-1,1-dimethyl-4-p-tolyl-1,2-dihydronaphthalene (prepared as described in Klein, et al., U.S. Pat. No. 5,952,345) were coupled to give the title compound (Compound 23). PNMR (300 MHz, CDCl3): δ0.13 (s, 9H), 1.47 (s, 6H), 2.48 (d, J=4.4 Hz, 2H), 2.54 (s, 3H), 4.82 (d, J=6.1 Hz, 2H), 6.10 (t, J=4.4 Hz, 1H), 7.00 (d, J=2.2 Hz, 1H), 7.18 (dd, J=2.2, 7.9 Hz, 1H), 7.30-7.45 (m, 10H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([NH2:29])[CH:18]=1)=[O:16]>>[CH3:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:19]([NH:29][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:18]=1)=[O:16]
Reactant: COC(=O)c1ccc(-c2ccccc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: COC(=O)c1ccc(-c2ccccc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (0.0552 g, 0.309 mmol) was reacted with the product from Example 212c (0.070 g, 0.309 mmol) for 92 h following the procedure of Example 1g giving the crude title compound, which was purified by HPLC with AA. The resulting solid was triturated with 4N HCl in dioxane to generate the hydrochloride salt which was collected by vacuum filtration (0.0747 g, 55%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.72 (s, 3 H) 3.91 (s, 3 H) 6.27 (d, J=6.99 Hz, 1 H) 7.30 (m, J=6.99 Hz, 3 H) 7.52 (m, 2 H) 7.74 (d, J=8.82 Hz, 1 H) 7.79 (d, J=8.09 Hz, 1 H) 8.09 (d, J=1.47 Hz, 1 H) 8.16 (dd, J=7.91, 1.65 Hz, 1 H) 8.30 (d, J=6.99 Hz, 1 H) 9.15 (d, J=8.82 Hz, 1 H) 11.54 (s, 1 H); MS (ESI+) m/z 369.9 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]([NH2:15])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([OH:10])[CH:9]=1.[Br-].[Li+].CN1CCCC1=O.[C:25]([O:31][CH:32](Cl)[CH3:33])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(OCC)(=O)C>[OH:10][C:8]1[CH:9]=[C:4]([CH2:3][C@@:2]([CH3:1])([C:12]([O:14][CH:32]([O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:33])=[O:13])[NH2:15])[CH:5]=[CH:6][C:7]=1[OH:11]
Reactant: CC(Cl)OC(=O)C(C)(C)C
Reactant: C[C@](N)(Cc1ccc(O)c(O)c1)C(=O)O
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(OC(=O)C(C)(C)C)OC(=O)[C@@](C)(N)Cc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 grams (0.047 mole) of α-methyldopa, 4.7 grams of powdered 4A molecular sieves, 6.1 grams (0.070 mole) of lithium bromide and 47 milliliters of N-methylpyrrolidinone were stirred for about one hour at 25° C. To this mixture, 8.1 grams (0.049 mole) of α-chloroethyl pivalate was added and the mixture was aged at 55° C. for 8 hours. At the end of this time, the mixture was cooled to 25° C., diluted with 100 milliliters of ethyl acetate and washed successively with one 200 milliliter and two 100 milliliter portions of saturated sodium bicarbonate solution. The combined sodium bicarbonate washes were extracted with two 100 milliliter portions of ethyl acetate and the combined ethyl acetate extracts concentrated under vacuum to 150 milliliters. The assay yield of α-pivaloyloxyethyl (S)-3-(3,4-dihydroxyphenyl)-2-methylalaninate was found to be 14.4 grams or 90 percent of theoretical.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:7][C:6]=1[NH2:18])=[O:4].[Cl:19][C:20]([Cl:27])([Cl:26])[C:21]([N:23]=[C:24]=[O:25])=[O:22]>C1COCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[S:7][C:6]([NH:18][C:24]([NH:23][C:21](=[O:22])[C:20]([Cl:27])([Cl:26])[Cl:19])=[O:25])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)sc1N
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(OC)cc2)sc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 2-Amino-5-(4-methoxy-phenyl)-thiophene-3-carboxylic acid methyl ester (7.15 g, 27.2 mmol) in anhydrous THF (150 mL) was added trichloroacetyl isocyanate (6.4 mL, 54 mmol) slowly over a period of 5 min. After the addition was complete, a precipitate formed and the reaction stirred for an additional 1 h. The desired product was obtained by filtration to give 6.9 g (56%) an off-white solid. The product was used in the next step without purification 1H NMR (d6-DMSO δ 12.3, br s, 1H; δ 12.2, s, 1H; δ 7.46, d, 2H; δ 7.32, s, 1H; δ 6.85, d, 2H; δ 3.75, s, 3H; δ 3.66, s, 3H), LC/MS (APCI, ES, M+H=451).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19](=[O:21])[NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(C)(C)C.Br[CH2:24][C:25](=O)[CH2:26][CH3:27].C(OCC)C>CC#N>[CH2:26]([C:25]1[N:20]=[C:19]([C@@H:8]([NH2:7])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[O:21][CH:24]=1)[CH3:27]
Reactant: CCC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=O
Solvent: CC#N
Solvent: CCOCC
Product: CCc1coc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C

Procedure:
A mixture of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl ester, 1, (10 g, 32.3 mmol) and 1-bromo-2-butanone (90%, 4.1 mL, 36 mmol) in CH3CN (500 mL) is refluxed for 18 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to the solution and the precipitate which forms is removed by filtration and is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:33])[N:10]1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:57][S:58]([NH2:61])(=[O:60])=[O:59].C1CCN2C(=NCCC2)CC1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:26]([C:27](=[O:28])[NH:61][S:58]([CH3:57])(=[O:60])=[O:59])[CH:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:33])[N:10]1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42]
Reactant: CS(N)(=O)=O
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(C(=O)O)c2)C1c1ccc(Cl)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)c1cccc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a solution of 330 mg of 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid in 5 ml of DMF was added 122 mg of CDI, followed by stirring at room temperature for 30 minutes. To the reaction solution were added 71 mg of methane sulfonamide and 0.11 ml of DBU, followed by stirring at room temperature for 3 hours. To the reaction solution was added ethyl acetate, followed by washing with 1 M hydrochloric acid and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain a crude purified product. This was recrystallized with acetonitrile-water to obtain 273 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-N-({3-[(methylsulfonyl)carbamoyl]benzyl}oxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[NH:13][C:14]([CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C(O)=O)=[O:15].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:38]([NH:52][NH2:53])(=[O:51])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C1COCC1>[O:15]=[C:14]([NH:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[CH:16]([CH:39]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:38]([NH:52][NH2:53])=[O:51])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(OC)c(NC(=O)C(C(=O)O)c2ccccc2)c(OC)c1
Reactant: CCCCCCCCCCCCC(=O)NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(C(=O)NN)C(C(=O)Nc1c(OC)cc(OC)cc1OC)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of α-[[(2,4,6-trimethoxyphenyl)amino]carbonyl]-benzene acetic acid (46.73 g, 0.1353 mol), and 1,1'-carbonyldiimidazole (24.7 g, 0.152 mol) in dry THF (1.0 L) was stirred at room temperature under nitrogen for 2 hours. A white solid precipitated. To the suspension was added tridecanoic acid hydrazide (30.90 g, 0.1353 mol), and the mixture was stirred at room temperature for 17 hours, then at 40° C. for 21 hours. The mixture was chilled (+5° C.) and filtered. The filtercake was washed (THF, ether, water) and dried under house vacuum/air stream; yield 54.36 g (72%); mp 175°-180° C.
Reaction SMILES: C1([SiH](C2C=CC=CC=2)Cl)C=CC=CC=1.[Cl-].[In+3].[Cl-].[Cl-].O[C:20]1([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:23][CH:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:21]1.CC(O)C>C(Cl)CCl.O>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([C@H:20]2[CH2:21][C@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:23]2)=[CH:33][CH:32]=1.[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([C@@H:20]2[CH2:21][C@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH2:23]2)=[CH:33][CH:32]=1
Reactant: COC(=O)C1CC(O)(c2ccc(OC)cc2)C1
Agent: Cl[SiH](c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [In+3]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCCl
Product: COc1ccc([C@H]2C[C@@H](C(=O)OC)C2)cc1
Product: COc1ccc([C@H]2C[C@H](C(=O)OC)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diphenylchlorosilane (0.806 mL, 3.71 mmol) was added to a mixture of indium(III) chloride (0.021 g, 0.093 mmol) and methyl 3-hydroxy-3-(4-methoxyphenyl)cyclobutanecarboxylate (0.438 g, 1.85 mmol) in dry ClCH2CH2Cl (3.71 mL) under N2. The reaction mixture was stirred at 25° C. for 15 min. The reaction mixture was diluted with water (20 mL) and extracted with Et2O (3×20 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 20% EtOAc in hexanes over 2394 mL) to afford a mixture of diastereoisomers (0.37 g, 91% yield). The sample was resolved by chiral HPLC (OJ, 20×250 mm, 9 mL/min, 5% i-PrOH in heptanes) to afford in order of elution methyl trans-3-(4-methoxyphenyl)cyclobutanecarboxylate and methyl cis-3-(4-methoxyphenyl)cyclobutanecarboxylate. trans-diastereoisomer: Rf=0.54 (20% EtOAc/hexanes). LCMS calc.=221.12. found=221.15 (M+H)+. 1H NMR (600 MHz, CHCl3): δ 7.66 (d, J=8.4 Hz, 2H); 7.37 (d, J=8.4 Hz, 2H); 4.29 (s, 3H); 4.25 (s, 3H); 4.24-4.15 (m, 1H); 3.67-3.61 (m, 1H); 3.20-3.14 (m, 2H); 2.93-2.87 (m, 2H). cis-diastereoisomer: Rf=0.54 (20% EtOAc/hexanes), 1H NMR (600 MHz, CHCl3): δ 7.68 (d, J=8.4 Hz, 2H); 7.36 (d, J=8.3 Hz, 2H); 4.28 (s, 3H); 4.20 (s, 3H); 3.93-3.84 (m, 1H); 3.63-3.54 (m, 1H); 3.12-3.06 (m, 2H); 2.94-2.86 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@@H:10]([O:12][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](O)COCc1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 179.8 %

Procedure:
(S)-1-hydroxy-2-tetrahydropyranyloxypropane (120 g, 0.75 mol) prepared according to the method of C. Malanga et al, Synthetic Communications, 12,(1), 67-70 (1982)) was dropwise added to sodium hydride (44.8 g, 1.87 mol) in tetrahydrofuran (400 ml) (hereinafter abbreviated to THF), followed by adding dimethylformamide (hereinafter abbreviated to DMF) (200 ml), agitating the mixture for 2 hours, dropwise adding benzyl bromide (140.8 g, 0.82 mol) at 30° C. or lower, agitating the mixture at room temperature for 6 hours, adding toluene, sufficiently agitating the mixture, washing the resulting organic layer with 2N-NaOH aqueous solution and then with water, drying it over anhydrous magnesium sulfate, distilling off toluene, adding to the resulting oily residue, (S)-1-benzyloxy-2-tetrahydropyranyloxypropane, pyridium p-toluenesulfonate (18 g) and ethanol (500 ml), heating the mixture to 70° C. for one hour, distilling off ethanol, adding toluene to the residue, sufficiently washing it with water, distilling off toluene, and distilling the residue to obtain (S)-1-benzyloxy-2-hydroxypropane (98 g)(b.p. 94.0° C./2.5 mmHg). A mixture of this (S)-1-benzyloxy-2-hydroxypropane (60 g, 0.36 mol) with anhydrous pyridine (300 g) was cooled with ice, followed by dropwise adding a solution of p-toluenesulfonyl chloride (75.8 g, 0.20 mol) in pyridine (70 ml) at 0° C., agitating the mixture at room temperature for 3 hours, adding toluene (800 ml), agitating the mixture, several times washing the resulting organic layer with water, drying it over anhydrous magnesium sulfate and distilling off toluene to obtain (S)-1-benzyloxy-2-(p-toluenesulfonyloxy)propane (115.2 g). On the other hand, a solution of 4-hydroxy-4'-octyloxybiphenyl (50 g, 0.17 mol) in THF (200 ml) was dropwise added to a mixture of sodium hydride (8.5 g, 0.35 mol) with THF (100 ml), followed by dropwise adding a solution of the above (S)-1-benzyloxy-2-(p-toluenesulfonyloxy)propane (64.5 g)(0.20 mol) in DMF (100 ml), agitating the mixture at 60° C. for 4 hours, allowing the mixture to cool down, adding toluene, agitating the mixture, washing with 6N-HCl, then with 2N-NaOH and further with water, drying over anhydrous magnesium sulfate, distilling off toluene, dissolving the residue in a mixture of ethanol (250 ml) with ethyl acetate (250 ml), adding Pd/C catalyst (10 g), agitating the mixture in hydrogen gas, filtering off the Pd/C, distilling off the solvent, and recrystallizing the residue from heptane (150 ml), to obtain (R)-4-(2'-hydroxy-1'-methyl)ethyloxy-4'-octyloxybiphenyl (m.p. 107.9° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([O:29]CC)=[O:28])[CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[CH:5][CH:4]=1.[OH-].[K+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([OH:29])=[O:28])[CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cccc(-c2csc(-c3ccc(OC)c4oc5ccccc5c34)n2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc(-c3cccc(C(=O)O)n3)cs2)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a slurry of ethyl 6-(2-(4-methoxydibenzo[b,d]furan-1-yl)thiazol-4-yl)picolinate (50 mg, 0.116 mmol) in ethanol (5 mL), potassium hydroxide (30 mg, 0.535 mmol) in water (0.5 mL) was added. The reaction slurry was stirred at room temperature for 2 h. Subsequently the reaction mixture was poured into water acidified with 1N HCl to a pH of 3-4; the precipitated solid was filtered and washed with ether and hexane. Yield—42%; Rf 0.23 (Chloroform:Methanol (8.5:1.5); HPLC (purity): 96%; 1H-NMR (CDCl3) δ: 4.15 (s, 3H), 7.09 (d, 1H), 7.29-7.32 (m, 1H), 7.51-7.55 (m, 2H), 8.08-8.12 (m, 1H), 8.24 (d, 1H), 8.56 (d, 1H), 8.75 (d, 1H); MS m/z: 403.1 (M+1).