Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1[C:16]2[O:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]=2C=CC=1.Cl>O>[C:6]([C:5]1[C:16]2[O:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]=2[CH:2]=[CH:3][CH:4]=1)#[N:1]
Reactant: Clc1cccc2c(-c3ccccc3)coc12
Reactant: c1ccncc1
Agent: Cl
Solvent: O
Product: N#Cc1cccc2c(-c3ccccc3)coc12
Temperature: 220 °C
Reaction time: 16 h

Procedure:
Pyridine (6.5 ml.), 10.3 g. (0.115 mole) of cuprous cyanide and 22.8 g. (0.1 mole) of 7-chloro-3-phenylbenzofuran (shown at column 14, line 30, of U.S. Pat. No. 3,862,134) are heated at 220° C. for about three hours, then at 150° to 190° C. for about 16 hours. The solution is added to 40 g. of ferrous chloride hexahydrate in 65 ml. of water and 15 ml. of concentrated hydrochloric acid. The resulting mixture is heated with stirring at 90° C. for about one hour, then filtered hot. The filtrate is cooled, and the product separated by filtration. The product is heated in a boiling benzene-toluene mixture (200 ml/250 ml), then the mixture is decanted. The decantate is evaporated to half of its volume and separated from the dark, solid residue. The residues are again extracted with a boiling mixture of benzene-toluene (400 ml/200 ml), and the combined organic extracts are washed with 125 ml. 6 N hydrochloric acid, water, 10 percent sodium hydroxide and water. The extracts are dried, treated with decolorizing charcoal, then evaporated to provide crude 7-cyano-3-phenylbenzofuran which is recrystallized from a mixture of benzene and petroleum ether. The white product has a m.p. 143°-145° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH2:22][CH2:21][CH2:20][C:19]=3[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2N=C(C3C(CC4C=C[CH:58]=[C:57]([O:61][CH3:62])C=4)CCC=3)OC=2C2C=CC=CC=2)C=CC=CC=1.B(Br)(Br)Br.C1(C2N=C(C3CCCC=3CC3C=CC=C(O)C=3)[O:76]C=2C2C=CC=CC=2)C=CC=CC=1.C1(C2N=C(C3C(CC4C=CC=C(O)C=4)CCC=3)OC=2C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH2:22][CH2:21][CH2:20][C:19]=3[CH2:23][C:24]3[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=3)[O:30][CH2:31][C:62]([O:61][CH2:57][CH3:58])=[O:76])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: COc1cccc(CC2=C(c3nc(-c4ccccc4)c(-c4ccccc4)o3)CCC2)c1
Reactant: Oc1cccc(CC2=C(c3nc(-c4ccccc4)c(-c4ccccc4)o3)CCC2)c1
Agent: BrB(Br)Br
Agent: Oc1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(CC2=C(c3nc(-c4ccccc4)c(-c4ccccc4)o3)CCC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of a mixture of 1-(4,5-diphenyloxazol-2-yl)-2-(3-methoxybenzyl)cyclopentene and 1-(4,5-diphenyloxazol-2-yl)-5-(3-methoxybenzyl)cyclopentene (2 g) in methylene chloride (30 ml) was added boron tribromide in methylene chloride (1M, 9.8 ml) at 0C. After being stirred for 2 hours at 0° C., the solvent was evaporated in vacuo to give a residue containing a mixture of 1-(4,5-diphenyloxazol-2-yl)-2-(3-hydroxybenzyl)cyclopentene and 1-(4,5-diphenyloxazol-2-yl)-5-(3-hydroxybenzyl)-cyclopentene. The residue was diluted with ethyl acetate and the solution was washed with water and brine. The dried solvent was evaporated in vacuo. The oily residue was dissolved in N,N-dimethylformamide (20 ml). To the solution were added potassium carbonate (2.0 g) and ethyl bromoacetate (2.2 ml), and the resulting mixture was stirred for 3 hours at room temperature. The reaction solution was partitioned between ethyl acetate and water and the organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed on silica gel using n-hexane--ethyl acetate as an eluent. The first fraction gave ethyl [3-[[2-(4,5-diphenyloxazol-2-yl)-1-cyclopenten-1-yl]methyl]phenoxy]acetate (0.38 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([CH3:17])([CH3:16])[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:8]=2[CH:25]=1)(=O)[CH3:2].Cl.[NH2:27][OH:28]>N1C=CC=CC=1>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[C:8]2[CH:25]=[C:4]([C:1](=[N:27][OH:28])[CH3:2])[CH:5]=[CH:6][C:7]=2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([CH3:17])([CH3:16])[N:10]=1
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccc2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2C

Procedure:
A solution of 13.66 g (40.37 mmol) of 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one and 13.6 g (0.196 mol) of hydroxylamine hydrochloride in 50 ml of pyridine is stirred at room temperature for 18 hours, then poured on to ice and extracted with methylene chloride/ethanol (9:1). The organic phase is washed successively with 3 N hydrochloric acid and water, dried and evaporated. The residue is chromatographed on 150 g of silica gel using methylene chloride as the elution agent and there is obtained, from ether, 5-(o-fluorophenyl)-1,3-dihydro-7-[1-(hydroxyimino)-ethyl]-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 199°.
Reaction SMILES: OO.[CH:3]([OH:5])=O.[C:6]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C[CH2:9][CH2:8][CH:7]=1>>[C:11]1([CH:6]2[CH2:7][CH2:8][CH2:9][C:3]2=[O:5])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1=C(c2ccccc2)CCC1
Reactant: O=CO
Agent: OO
Product: O=C1CCCC1c1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A mixture of 30% hydrogen peroxide (23 mL, 149 mmol) and 85% formic acid (100 mL, 2619 mmol) was heated at 40° C. for 15 min. The mixture was carefully added to cyclopentenylbenzene (21.49 g, 149 mmol) and the resulting two-phase system was vigorously stirred at room temperature for 4 h. An exothermic reaction was observed in the beginning. By the end of the stirring the solution had become homogeneous. The reaction mixture was carefully quenched with a saturated aqueous solution of sodium bicarbonate. The product was extracted with ether. The combined etherial layers were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the product was purified by column chromatography on silica gel to give 2-phenylcyclopentanone (19.995 g, 125 mmol, 84% yield) as a brown oil. LC-MS (M+H)+=161.0. 1H NMR (500 MHz, chloroform-d) δ ppm 7.38 (1H, t, J=7.3 Hz), 7.30-7.35 (2H, m), 7.19 (2H, d, J=7.3 Hz), 3.28-3.37 (1H, m), 2.71 (1H, td, J=4.6, 2.7 Hz), 2.58-2.63 (1H, m), 2.43-2.55 (1H, m), 2.29 (1H, ddd, J=19.0, 10.5, 9.0 Hz), 2.07-2.21 (1H, m), 1.88-1.99 (1H, m).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12.CN[S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].C([O-])([O-])=O.[K+].[K+].[CH3:36][N:37]1CCCC1=O>C1OCCOCCOCCOCCOCCOC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([CH2:36][NH:37][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=23)(=[O:21])=[O:22])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1Cl
Reactant: CNS(=O)(=O)c1ccc(F)cc1
Reactant: CN1CCCC1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1cnc2c(c(C)nn2C)c1NCS(=O)(=O)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
A mixture of 2.53 g (0.01 mol) of ethyl 4-chloro-1,3-dimethyl-1H pyrazolo[3,4-b]pyridine-5-carboxylate, 1.89 g (0.01 mol) of N-methyl-4-fluorobenzenesulfonamide, 6.91 g (0.05 mol) of anhydrous K2CO3, 0.143 g of 18-crown-6 and 70 ml of anhydrous 1-methyl-2-pyrrolidinone was stirred and heated at 100° C. for 17 hours. The solvent was removed under vacuum and water added to the residue. The mixture was extracted with CH2Cl2, and the extract washed with H2O, brine and dried (Na2SO4). The solution was filtered through a pad of hydrous magnesium silicate and the filtrate concentrated to dryness under vacuum to give 4.98 g of an oil. This oil was chromatographed on a silica gel column with ethyl acetate-hexane(2:3) as solvent to give 3.15 g of solid, mp 107-109° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13](=[O:30])[NH:14][C:15]1[CH:28]=[CH:27][C:26]2[NH:25][C:24](=[O:29])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=1)(C)(C)C.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[ClH:32].[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]([NH:14][C:15]1[CH:28]=[CH:27][C:26]2[NH:25][C:24](=[O:29])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)NCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
(3-{[(6-oxo-5,6-dihydro-phenanthridin-2-ylcarbamoyl)-methyl]-amino}-propyl)-carbamic acid tert-butyl ester (32 mg, 0.075 mmol) was dissolved in dichloromethane (1 mL) and 4N hydrochloric acid in dioxane (1 mL) was added. The reaction mixture was stirred at room temperature overnight and then evaporated, affording 32 mg (97% yield) of 2-(3-amino-propylamino)-N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-acetamide bis-hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)[O:8][C:4]=2[CH:3]=1.Cl.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C@@H:10]3[CH2:14][CH2:13][N:12]([C:21]([C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[CH3:18])=[O:22])[CH2:11]3)[O:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2nc(NC3CCNC3)oc2c1
Reactant: Cc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)N1CC[C@@H](Nc2nc3ccc(Cl)cc3o2)C1
Yield: 61.4 %

Procedure:
A mixture of 32.9 mg (0.12 mmol) (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-yl-amine; hydrochloride, 19.6 mg (0.144 mmol) 2-methyl-benzoic acid, 53.9 mg (0.168 mmol) TBTU and 77.5 mg (0.6 mmol) DIPEA in 2 mL DMF was stirred at room temperature for 16 h. The mixture was concentrated, taken up in methanol and formic acid and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 26.2 mg (61%) of the title compound. (MH+) 356.1.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]([O:17][C:18](=[O:30])[NH:19][CH2:20][CH2:21][CH:22]([OH:29])[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)([CH3:16])[CH3:15].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:16][C:14]([O:17][C:18](=[O:30])[NH:19][CH2:20][CH2:21][CH:22]([O:29][C:33]1[CH:34]=[C:35]([C:38]([F:40])([F:41])[F:39])[CH:36]=[CH:37][C:32]=1[Cl:31])[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccnc1
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(Oc1cc(C(F)(F)F)ccc1Cl)c1cccnc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
Diethyl azodicarboxylate (0.71 ml, 4.47 mmol) was added to a solution of [3-hydroxy-3-(3-pyridinyl)propyl]carbamic acid 1,1-dimethylethyl ester (Example 58(b)) (291 mg, 1.15 mmol), 2-chloro-5-trifluoromethylphenol (232 mg, 1.18 mmol) and triphenylphosphine (455 mg, 1.73 mmol) in tetrahydrofuran (6 ml) at 0° C. and stirred at 20° C. for 18 h. The reaction was concentrated in vacuo and the residue purified by chromatography on silica, eluting with petrol—diethyl ether to afford the sub-title compound (394 mg, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:40][CH2:39]1>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[CH2:50][CH2:49]3)=[O:22])[CH:17]=2)(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (63 mg, 0.18 mmol), CDI (58 mg, 0.36 mmol) and 1-[(1-methylpiperidin-4-yl)methyl]piperazine (59 mg, 0.30 mmol) in DCE (4.5 mL). The crude product was purified using Ambersep and PL-MIA resins to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C@@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C@H:9]1[C:16]([O-:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:21]1([C@H:20]([NH3+:27])[CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCCC2C1C(=O)O
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)[O-]
Product: C[C@@H]([NH3+])c1ccccc1
Temperature: 23.5 °C
Reaction time: 16 h
Yield: 21.4 %

Procedure:
To a solution of racemic N-t-butyloxycarbonyl-3-azabicyclo[3.3.0]octane-2-carboxylic acid (4.66 g) in ethyl acetate (100 mL) was added (R)-α-methylbenzylamine (56.7 g) and the solution was stirred for 16 hr at 22-25° C. The mixture was filtered and the solids were rinsed with ethyl acetate. The solids were dried at 20-30° C. under vacuum for 4 hours to give 1.47 g of product (43%, 82% ee, 92:8 ratio of exo:endo diastereomers).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:14]1([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[N:14]1[CH2:15][CH2:16][N:17]([C:2]2[C:3](=[O:13])[C:4]3[C:9]([C:10](=[O:12])[C:11]=2[OH:1])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:18][CH2:19]1
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Reactant: O=C1c2ccccc2C(=O)C2OC12
Solvent: CCO
Product: O=C1C(O)=C(N2CCN(c3nc4ccccc4o3)CC2)C(=O)c2ccccc21
Reaction time: 18 h
Yield: 14.2 %

Procedure:
A mixture of 3.48 g of 2,3-epoxy-2, 3-dihydro-1,4-naphthoquinone, 2.03 g of 2-(1-piperazinyl)benzoxazole and 200 ml of absolute ethanol was stirred for 18 hours and then filtered. The filtrate was concentrated to dryness and the residue flash chromatographed, eluting with dichloromethane, then 1% methanol in dichloromethane. The desired fraction was evaporated, then recrystallized twice from dichloromethane/ethanol, giving 533 mg of the desired product, mp 190° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:13]2=[O:30])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[C:31]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]3([C:11]4[C:2](=[CH:3][C:4]5[O:8][N:7]=[C:6]([CH3:9])[C:5]=5[CH:10]=4)[O:1][CH2:31]3)[C:13]2=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(CN2C(=O)C(c3cc4c(C)noc4cc3O)c3ccccc32)cc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: COc1ccc(CN2C(=O)C3(COc4cc5onc(C)c5cc43)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(4-methoxybenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 138-139° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J=9.0 Hz, 2H), 7.35 (d, J=9.0 Hz, 2H), 7.21-7.18 (m, 1H), 7.11-7.09 (m, 1 H), 6.96 (d, J=9.0 Hz, 1H), 6.94-6.88 (m, 2H), 6.79 (d, J=9.0 Hz, 1H), 5.16-4.79 (m, 4H), 3.78 (s, 3H), 2.45 (s, 3H); MS (ES+) m/z 412.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[F:10][C:11]1[CH:12]=[C:13](OB(O)O)[CH:14]=[C:15]([F:18])[C:16]=1[F:17].C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.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.C1(C)C=CC=CC=1>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[C:13]1[CH:12]=[C:11]([F:10])[C:16]([F:17])=[C:15]([F:18])[CH:14]=1
Reactant: OB(O)Oc1cc(F)c(F)c(F)c1
Reactant: Oc1ccc(Br)c(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: O
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: Oc1ccc(-c2cc(F)c(F)c(F)c2)c(F)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
At first, 75.0 g of 4-bromo-3-fluorophenol (S3-1), 82.9 g of 3,4,5-trifluorophenyl-boric acid (S3-2), 13.6 g of tetrakis(triphenylphosphine)palladium, 108.5 g of sodium carbonate and 1100 ml of a mixed solvent of dimethoxyethane/water=2/1 (volume ratio) were added into a reactor under nitrogen atmosphere, and the mixture was heated to 80° C. and stirred for 4 hr. Next, the reaction solution was cooled to room temperature, added with toluene and then washed with 1N hydrochloric acid and water. Afterwards, the solution was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. Subsequently, the product was purified by silica-gel column chromatography with a mixed solvent of heptane/ethyl acetate=4/1 as the eluent and then dried under reduced pressure. The obtained residue was recrystallized in heptane to obtain 77.5 g of 3-fluoro-4-(3,4,5-trifluorophenyl)phenol (S3-3). The yield of (S3-3) from (S3-1) was 81.5%.
Reaction SMILES: CC([OH:5])(C)C.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.CS(N)(=O)=O.[CH3:69][O:70][N:71]([CH3:77])[C:72](=[O:76])[C:73]([CH3:75])=[CH2:74].[OH2:78]>>[OH:78][C@:73]([CH3:75])([CH2:74][OH:5])[C:72]([N:71]([O:70][CH3:69])[CH3:77])=[O:76]
Reactant: C=C(C)C(=O)N(C)OC
Reactant: CC(C)(C)O
Reactant: O
Agent: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Product: CON(C)C(=O)[C@](C)(O)CO
Temperature: 25 °C
Yield: 120 %

Procedure:
A round bottom flask was charged with t-BuOH (850 mL), water (850 mL), Ad-Mix-α (230 g, 166 mmol) and methanesulfonamide (15.8 g, 166 mmol). The mixture was stirred at ambient temperature until both phases were clear (about 5 minutes) and then cooled to 0° C., after which orange salts precipitated. N-methoxy-N-methylmethacrylamide (21.5 g, 166 mmol) was added and the heterogeneous slurry was stirred vigorously at 0° C. for 2 hours, warmed to ambient temperature and stirred for 24 hours. The reaction was quenched by the slow, portionwise addition of sodium bisulfite (223 g) and stirred for 1 hour. The reaction mixture was extracted with EtOAc (3×300 mL), dried over sodium sulfate, filtered and concentrated to afford (R)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32.7 g, 200 mmol, 120% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](Cl)(=[O:27])=[O:26])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29]>>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:25](=[O:27])(=[O:26])[NH2:29])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(SCc2ccccc2)c(Oc2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: N
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Oc1ccccc1
Reaction time: 1 h

Procedure:
3-Benzylthio-5-chlorosulfonyl-4-phenoxybenzoic acid (0.6 g) is added to concentrated aqueous ammonia (10 ml). After 1 hour, the reaction mixture is heated on a steam-bath for 15 minutes, and crude 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid precipitated by addition of a 1 N hydrochloric acid until pH 2.5. The crude product is dissolved in aqueous sodium hydrogen carbonate by heating. After cooling, the precipitated sodium salt of 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration. The salt is redissolved in hot water (20 ml) and 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid precipitated by addition of 1 N hydrochloric acid. After cooling and collecting by filtration, and drying in vacuo at 80° C, the compound is obtained with a melting point of 235°-236° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(OCC)(=O)C.O1CCCC1>[CH3:24][S:25]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17])[CH2:4][CH2:3]1)(=[O:27])=[O:26]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
10.1 g (0.1 mol) of 4-hydroxypiperidine and 11 g (0.11 mol) of triethylamine are placed in 200 ml ethyl acetate and 250 ml tetrahydrofuran and a solution of 23.3 g (0.11 mol) of 2,2,2-trichloroethyl chloroformate is added dropwise at 0-4° C. The mixture is stirred for 1 hour at 0° C. and for 1 hour at ambient temperature. The precipitate is suction filtered, the filtrate is combined at −12 to −14° C. with 12 g (0.105 mol) of methanesulphonic acid chloride and at −8 to −12° C. 12 g (0.12 mol) of triethylamine in 50 ml tetrahydrofuran are added dropwise. It is stirred for 40 minutes at −10° C., the cooling bath is removed and the mixture is stirred for 30 minutes. After washing with water and saturated saline solution it is dried with magnesium sulphate, concentrated by evaporation, the residue is triturated with diisopropylether and suction filtered. 32.4 g (91.5% of theory) of 4-methanesulphonyloxy-N-2,2,2-trichlorethoxycarbonylpiperidine are obtained as colourless crystals, melting point 93° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1.[C:11]1([C:17](Cl)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:17]([O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OCCC1CCC(O)CC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: OC1CCC(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-(2-Hydroxyethyl)cyclohexanol (crude from the previous reaction) (1.88 g, 0.0130 mol) was dissolved in pyridine (20.00 mL) and was cooled at 0° C. To the reaction was added triphenylmethyl chloride (4.0 g, 0.014 mol) and this mixture was stirred at 0° C. for 2 hours and at 25° C. for 16 hours. The reaction was concentrated using a rotary evaporator and the concentrate was extracted with ethyl acetate. The organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel (30% EtOAc/hexanes) to give the trans isomer (1.98 g)