Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([NH:27][N:28]2[NH:32][CH:31]=[CH:30][S:29]2)=[O:26])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([C:22]2[CH:23]=[C:24]([C:25](=[O:26])[NH:27][N:28]3[NH:32][CH:31]=[CH:30][S:29]3)[CH:33]=[CH:34][C:21]=2[CH3:20])=[N:3][CH:4]=1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(C(=O)NN4NC=CS4)ccc3C)nc2)c1

Procedure:
N-(3-Methoxybenzyl)-6-[2-methyl-5-(thiadiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (Intermediate 12) using General Method B. LCMS: retention time 3.02 min, M− 460. NMR: δH [2H6]-DMSO 13.14,(1H, b), 9.32,(1H, t), 9.24,(1H, s), 9.18,(1H, d), 8.40,(1H, dd), 8.26,(1H, s), 8.10,(1H, d), 7.84,(1H, d), 7.55,(1H, d), 7.27,(1H, t), 6.94,(2H, m), 6.84,(1H, d), 4.53,(2H, d), 3.75,(3H, s), 2.46,(3H, s).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:28]O>>[CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)([CH2:7][CH3:8])[CH2:3][C:4]([O:6][CH3:28])=[O:5]
Reactant: CCC(C)(CC(=O)O)c1cccc(OCc2ccccc2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCC(C)(CC(=O)OC)c1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Yield: 91.9 %

Procedure:
Into a solution of 3-(3-(benzyloxy)phenyl)-3-methylpentanoic acid 103.D (184 mg, 617 μmol) in MeOH (3 mL) was injected H2SO4 (3.29 μL, 61.7 μmol), and the mixture was heated at 60° C. overnight. The reaction was quenched with saturated NaHCO3 solution, extracted with DCM, dried over Na2SO4, filtered, stripped, and purified by silica gel chromatography to afford methyl 3-(3-(benzyloxy)phenyl)-3-methylpentanoate 103.E (177 mg, 91.9% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33](=[O:43])[N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:9]=2[C:10]([OH:12])=O)[C:6]=1[CH3:7].[F:44][C:45]([F:57])([F:56])[C:46]1[CH:55]=[C:54]2[C:49]([CH2:50][CH2:51][NH:52][CH2:53]2)=[CH:48][CH:47]=1>>[CH2:35]([N:34]([CH2:39][CH2:40][CH2:41][CH3:42])[C:33]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:20])=[O:21])=[CH:13][C:9]=2[C:10]([N:52]2[CH2:51][CH2:50][C:49]3[C:54](=[CH:55][C:46]([C:45]([F:44])([F:57])[F:56])=[CH:47][CH:48]=3)[CH2:53]2)=[O:12])[N:4]=1)=[O:43])[CH2:36][CH2:37][CH3:38]
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)c(C)c1Cl
Yield: 72.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 93B, 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 21 mg, 0.034 mmol) and 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline (7 mg, 0.037 mmol) were converted to the title compound (20 mg, 71%) following purification by preparative HPLC. 1H NMR (1:1 CD3OD:CDCl3, 1.5:1 mixture of amide rotamers) δ 8.69-8.58 (m, 1H), 8.19-8.13 (m, 1H), 8.08-8.02 (m, 2H), 8.01-7.97 (m, 1H), 7.95-7.91 (m, 1H), 7.90-7.86 (m, 1H), 7.60-7.54 (m, 2H), 7.45-7.34 (m, 2.5H), 7.28-7.23 (m, 1H), 7.17-7.14 (m, 0.5H), 4.89-4.64 (m, 1.5H), 4.52 (s, 1H), 4.16-4.02 (m, 0.5H), 3.70-3.34 (m, 2.5H), 3.24-2.75 (m, 4.5H), 2.28 (s, 2H), 2.23 (s, 1H), 1.51-0.93 (m, 8H), 0.87 (dt, J=17.8, 7.4 Hz, 3H), 0.75 (t, J=7.4 Hz, 2H), 0.64 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 808.3 (M+H)+.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:14]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C(=O)C(C)(C)C)cc1
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)c1ccc(CBr)cc1

Procedure:
To a suspension of 28.5 g. (1.17 g. atoms) magnesium turnings in 150 ml. tetrahydrofuran under a nitrogen atmosphere there is added 10 ml. of 4-bromotoluene (1.17 mole) in 650 ml. dry tetrahydrofuran, the reaction is started and the remainder of the bromotoluene solution is added dropwise at a rate that maintains a moderate reflux. After the addition is complete, the mixture is refluxed for an additional 1 1/2 hours. The resulting Grignard solution is added dropwise to a cold solution of 128.0 g. pivaloyl chloride (1.06 mole) in 500 ml. dry tetrahydrofuran at a rate that maintains the temperature at 0° to -5°C. The solution is stirred for an additional 1 1/2 hours at 0° and then at room temperature for 18 hours. The mixture is then cooled to 0° and hydrolyzed by the addition of 100 ml. 2N hydrochloric acid. The layers are separated and 200 ml. of ether is added to the organic phases which is then washed respectively with 100 ml. 2N hydrochloric acid, 100 ml. 10% sodium bicarbonate solution and 100 ml. saturated sodium chloride. The resulting layer is dried over anhydrous sodium sulfate, filtered, and the solvent is removed in vacuo to give p-pivaloyl toluene (b.p. 80°-84°C./0.7 mm,nD21 1.5108). A mixture of 156.3 g. (0.886 mole) of the resulting p-pivaloyl toluene is then added to 157.8 g. (0.886 mole) N-bromosuccinamide, 4.0 g. (0.016 mole) benzoyl peroxide and 150 ml. carbon tetrachloride and heated at reflux for 18 hours. The mixture is cooled and filtered and the resulting precipitate is washed with carbon tetrachloride. The solvents are removed in vacuo and the resulting oil is distilled in vacuo to give α-bromo-p-pivaloyl toluene (b.p. 124°-132°C./0.7 mm, nD22 1.5546-V.P.C. 96% monobromo 4%-dibromo).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26]>O1CCOCC1.[Ag-]=O>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=[Ag-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 43.8 %

Procedure:
Silver (I) oxide (7.15 g.) was added to a solution of 5-nitroindole (5 g.) and methyl 4-bromomethyl-3-methoxybenzoate (B) (7.99 g.) in dioxane (30 ml.), under a nitrogen atomosphere. The mixture was stirred at 60° C. for 20 hours, dioxane removed by evaporation and ethyl acetate (50 ml.) added to the residue. The resulting suspension was separated by filtration through diatomaceous earth. The filtrate was evaporated to give a dark viscous oil, which was purified by flash chromatography on silica gel (600 ml.), eluting with 3:7 v/v ethyl acetate:hexane. The viscous yellow oil obtained was crystallized from a mixture of dichloromethane and hexane to give methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (C) (4.6 g., 45%) as yellow needles, m.p. 153°-155° C. NMR: 3.83(s,3H, COOCH3), 3.93(s,3H, OCH3), 4.12(s,2H, CH2.Ar), 7.25(d,1H), 7.43(d,1H), 7.49(m,3H), 7.95(dd, 1H, H6 -indole), 8.47(d,1H, H4 -indole), 11.65 (broad s,1H, H1 -indole).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)=[C:9]([F:21])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:22]=[O:23])=[CH:5][NH:6]2.Cl([O-])=[O:25].[Na+].P([O-])(O)(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.CC(=CC)C.O>[F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:15][CH:16]=2)=[C:9]([F:21])[CH:8]=[C:7]2[C:3]=1[C:4]([C:22]([OH:25])=[O:23])=[CH:5][NH:6]2
Reactant: O=Cc1c[nH]c2cc(F)c(-c3ccc(OCCO)cc3)c(F)c12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(F)c(-c3ccc(OCCO)cc3)c(F)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.6 %

Procedure:
To a solution of 4,6-difluoro-5-[4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde (70 mg, 0.221 mmol) in acetonitrile (4.6 mL), t-butanol (4.6 mL) and 2-methyl-2-butene (3.0 mL) was added a solution of sodium chlorite (298 mg, 4.42 mmol) and sodium dihydrogen phosphate (610 mg, 4.42 mmol) in water (4.6 mL) in an ice-bath. The reaction mixture was stirred at room temperature for 18 h. TLC (petroleum ether/EtOAc=1:1) showed the reaction was complete. The reaction was quenched with a solution of sodium sulfite (612 mg, 4.86 mmol) in water (5.0 mL), and extracted with ethyl acetate (20 mL×3). The organic layers were washed with brine (10 mL) and dried over sodium sulfate, filtered and concentrated to give a crude residue, which was purified by reverse phase HPLC to give the title compound (21.1 mg, 29%) as a white solid. MS (AP+) 333.9 (M+1)+. 1H NMR (400 MHz, CD3OD) δ 8.00 (s, 1H), 7.49 (d, 2H), 7.12 (d, 1H), 7.05 (d, 2H), 4.13 (t, 2H), 3.92 (t, 2H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([NH:12]C(=O)OCC1C=CC=CC=1)([CH3:11])[CH3:10])(=[O:6])=[O:5].[H][H]>CO.[Pd]>[NH2:12][C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][S:4]([CH2:3][CH2:2][OH:1])(=[O:6])=[O:5]
Reactant: [H][H]
Reactant: CC(C)(CCS(=O)(=O)CCO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)CCS(=O)(=O)CCO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of benzyl 4-(2-hydroxyethylsulfonyl)-2-methylbutan-2-ylcarbamate (790 mg, 2.40 mmol) in methanol (30 ml) was purged with nitrogen and palladium on carbon (10%, 120 mg) was added. The solution was put under a blanket of hydrogen (1.3 atmospheres) and stirred for 1.5 hours at room temperature. The suspension was filtered through 0.45 um PTFE and concentrated in vacuo to afford the title compound which was used without further purification. LRMS (ESI/APCI) m/z 196 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:5]1[CH2:7][CH2:6]1.Cl.[NH2:18]O.C[O-].[Na+]>>[CH:5]1([C:4]2[C:3]([OH:2])=[N:18][O:15][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6]1
Reactant: NO
Reactant: COC(=O)C(C(=O)c1ccccc1)C1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1noc(-c2ccccc2)c1C1CC1
Yield: 38.6 %

Procedure:
2-Benzoyl-2-cyclopropylacetic acid methyl ester (0.9 g), hydroxylamine hydrochloride (0.6 g) and sodium methoxide (28% methanol solution, 4.0 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(b) to obtain the title compound (0.32 g, 39%) as colorless crystals.
Reaction SMILES: [C:1]([CH2:5][CH2:6][N:7]([CH3:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O:3][CH3:4])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:23])[C:20](Cl)=[O:21]>O>[C:1]([CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][C:11]([C:20]([C:19]([C:11]2[CH:10]=[CH:9][C:8]([N:7]([CH3:14])[CH2:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])=[CH:13][CH:12]=2)=[O:23])=[O:21])=[CH:10][CH:9]=1)[CH3:14])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCN(C)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COC(=O)CCN(C)c1ccc(C(=O)C(=O)c2ccc(N(C)CCC(=O)OC)cc2)cc1

Procedure:
4,4'-bis(N-2-carbomethoxyethyl-N-methylamino)benzil was prepared according to the procedure of Tuzun, et al. (Org. Syn., 41, 1 (1961)). Charges were 86.4 g of N-2-carbomethoxyethyl-N-methylaniline (prepared according to the procedure in Example 1), 41.7 g of anhydrous aluminum chloride and 6.7 ml of oxalyl chloride. After the addition of 157 ml of water the reaction mixture was extracted three times with 100 ml portions of chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was removed on a steam bath and the dark brown residue was chromatographed on Activity I basic alumina (the most active and dried form, in terms of absorbing power, of chromatographic grade alumina) using a 1:1 mixture of ethyl acetate and heptane. Fractions containing a new product which appeared to be free of starting material by TLC (thin layer chromatography) were combined and concentrated to a brown gum. The combined chromatography fractions were dissolved in 50 ml of 10 percent methanolic sodium hydroxide and refluxed overnight. A tan solid separated which was isolated by filtration, washed with methanol and dried. This material in water had λmax=382 nm and εmax=14,650. This is only one third the extinction coefficient reported for 4,4'-bis(dimethylamino)benzil. No further purification was attempted.
Reaction SMILES: C([O:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)[CH2:25][CH2:24]2)=[N:12][N:11]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl>[OH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)[CH2:25][CH2:24]2)=[N:12][N:11]=1
Reactant: COc1ccc2c(COCc3ccccc3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(CO)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A solution of 120 mg of 4-benzyloxymethyl-7-methoxy-N-[1-(naphthalen-2-ylmethyl)piperidin-4-yl]phthalazin-1-amine in 4 mL of dichloromethane is stirred under nitrogen at 0° C., followed by dropwise addition of 2.3 mL of a molar solution of boron trichloride in dichloromethane. The reaction medium is stirred for 1 hour at 0° C. and then for 30 minutes at room temperature. It is hydrolysed with aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue is purified on a column of silica (eluent: 100/0 to 85/15 v/v dichloromethane/methanol). 58 mg of product are obtained in the form of a beige-coloured powder.
Reaction SMILES: [Cl:1][C:2]1C=CC(C=NO)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22]3[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:21]=3[O:20][N:19]=2)=[CH:14][CH:13]=1.C([N-]C(C)C)(C)C.[Li+].ClCCCI>C1COCC1.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:22]3[C:23](=[O:27])[CH:24]([CH2:4][CH2:3][CH2:2][Cl:1])[CH2:25][CH2:26][C:21]=3[O:20][N:19]=2)=[CH:16][CH:17]=1
Reactant: O=C1CCCc2onc(-c3ccc(Cl)cc3)c21
Reactant: ON=Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: ClCCCI
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2c(-c3ccc(Cl)cc3)noc2CCC1CCCCl
Temperature: -78 °C

Procedure:
In a similar manner to that of Examples 7a-d starting with 4-chlorobenzaldehyde oxime, the starting ketone is prepared. In 220 ml anhydrous THF was dissolved 8.1 g 3-(4-chlorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one under nitrogen atmosphere with stirring. The solution was cooled to -78° C. and 32.8 ml lithium diisopropylamide (1.5 molar in cyclohexane) was added dropwise. The resulting solution was stilted for fifteen minutes at -78° C. and 4.6 ml 1-chloro-3-iodopropane was added. Upon warming to room temperature, the reaction mixture was poured into water and the layers were separated. The aqueous phase was extracted twice with dichloromethane and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Column chromatography on silica gel (start with 5% dichloromethane in hexane and gradually increase polarity to 100% dichloromethane) gave 5.2 g of 3-(4-chlorophenyl)-5-(3-chloropropyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[CH:14][CH:15]=1)[CH3:20]
Reactant: NC(N)=S
Reactant: CCc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Solvent: CCO
Product: CCc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 87.5 %

Procedure:
A mixture of 2-bromo-1-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)ethanone (7.70 g, 22.2 mmol) and thiourea (1.69 g, 22.2 mmol) in 95% EtOH (31.7 mL) was heated at reflux for 180 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (6.30 g) as yellow solids in 88% yield: 1H NMR (500 MHz, CDCl3) δ 7.18 (d, J=7.5 Hz, 2H), 6.95 (d, J=8.5, 2H), 6.71 (s, 2H), 6.29 (s, 1H), 5.45 (bs, 2H), 2.64 (q, J=7.5 Hz, 2H), 2.14 (s, 6H), 1.25 (t, J=8.0 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:21])[NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(C)(C)C.[ClH:23]>C(Cl)Cl.O1CCOCC1>[ClH:23].[ClH:23].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)Nc1cccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCCCCC(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cold mixture of (5-(Pyridin-3-ylcarbamoyl)pentyl)carbamic acid tert-butyl ester (3, 3.07 g, 10 mmole) in methylene chloride (30 mL) was added a solution of HCl in dioxane (4M, 10 mL). The mixture was stirred at room temperature overnight. The separated solid was filtered, washed with methylene chloride, dried in vacuum oven to give the product 4 as the hydrochloride salt (2.7 g, 96%). The 1H NMR spectrum of the pure solid was consistent with structure 4. 1H NMR (D2O) δ 9.20 (s, 2H), 7.91 (m, 1H), 2.90 (t, 2H), 2.42 (t, 2H), 2.62 (m, 4H), 1.36 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([O-])(=[O:25])=[O:24])=[C:7]1[CH3:27])[CH3:2].[Na+].[Cl:30]S(O)(=O)=O>>[Cl:30][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:28])[C:7]=1[CH3:27])(=[O:25])=[O:24]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)[O-])c2cc(F)ccc21
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Sodium 2-((1-(2-ethoxy-2-oxoethyl)-5-fluoro-2-methyl-1H-indol-3-yl)methyl)benzenesulfonate (2.30 g, 5.38 mmol) was added portionwise to chlorosulfonic acid (10 ml) at room temperature (20° C.) over 20 min. The resulting mixture was stirred at room temperature for 2 hours, then poured onto ice/water (300 mL). The solution was next extracted with CH2Cl2, and the separated organics washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford ethyl 2-(3-(2-(chlorosulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetate (2.03 g, 4.79 mmol, 89%), which was used in the next step without further purification.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])C(=C)C.[Al].[CH2:14](C1(O)C=CC=CC1O)[C:15](=[CH2:17])[CH3:16]>>[CH2:16]([C:10]1[CH:11]=[C:6]([OH:5])[C:7](=[CH:8][CH:9]=1)[OH:12])[C:15](=[CH2:14])[CH3:17]
Reactant: C=C(C)CC1(O)C=CC=CC1O
Reactant: C=C(C)COc1ccccc1O
Agent: [Al]
Product: C=C(C)Cc1ccc(O)c(O)c1
Yield: 36.6 %

Procedure:
By carrying out the reaction under the temperature and treatment conditions described in Example 1, starting from ortho-methallyloxyphenol (1.043 g), without using an aluminium derivative, a mixture containing unconverted ortho-methallyloxyphenol (0.189 g), DDHB (0.0126 g), ortho-methallylpyrocatechol (0.520 g) and para-methallylpyrocatechol (0.188 g) is obtained, i.e.:
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:3]1.[N+](C1C=CC([O:30][C:31]([N:33]2[CH:37]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=3)[CH2:36][O:35][C:34]2=[O:46])=O)=CC=1)([O-])=O>C1COCC1>[CH3:1][CH:2]1[CH2:3][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:31]([N:33]1[CH:37]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=2)[CH2:36][O:35][C:34]1=[O:46])=[O:30]
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H]1CN(c2ccccc2[N+](=O)[O-])CCN1CCCN
Solvent: C1CCOC1
Product: CC1CN(c2ccccc2[N+](=O)[O-])CCN1CCCNC(=O)N1C(=O)OCC1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of (S)-(+)-3-methyl-1-(2-nitrophenyl)-4-(3-aminopropyl)-piperazine (35 mg, 0.126 mmol) in 10 mL of THF, 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester (50 mg, 0.137 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by MeOH:EtOAc=1:9 (Rf=0.58, MeOH:EtOAc=1:3 ) to obtain 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {3-[2-methyl-4-(2-nitro-phenyl)-piperazin-1-yl)-propyl)-amide (55 mg, 87%). The compound was dissolved in CH2cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a pale yellow solid. M.P. 115-119° C.; [α]D=+38.3, (c=0.22, CH2Cl2); Anal. Calcd. For C24H28N5O5F2Cl.0.72 C6H12: C, 56.50; H, 6.38; N, 11.63. Found: C, 56.63; H, 6.35; N, 10.08.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CO.ClCCl>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:9][CH2:10]1
Reactant: C1CNCCN1
Reactant: CC1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Solvent: ClCCl
Solvent: CO
Product: CC1CCN(c2cc(N3CCNCC3)ccc2[N+](=O)[O-])CC1
Yield: 94 %

Procedure:
The procedure of Example 4, step (b) was followed using 460 mg (1.81 mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared in the Example 12, step (a)) and 3.12 g (36.2 mmol) of piperazine for 24 h to afford, after chromatography on a 20-g silica SPE column with 0-10% MeOH-dichloromethane, 518 mg (94%) of the title compound as an orange resin: Mass spectrum (ESI, m/z): Calcd. for C16H24N4O2, 305.2 (M+H), found 305.1.