Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C@@:8]12[C@H:14]([O:15][CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[C@H:11]([O:12][CH2:13]1)[C@H:10]([N:27]1[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]1=[O:29])[O:9]2.[Si:35](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.CCOC(C)=O>[Si:35]([O:6][CH2:7][C@:8]12[C@H:14]([O:15][CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[C@H:11]([O:12][CH2:13]1)[C@H:10]([N:27]1[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]1=[O:29])[O:9]2)([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn([C@@H]2O[C@@]3(CO)CO[C@H]2[C@H]3OCc2cccc3ccccc23)c(=O)[nH]1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC[C@]12CO[C@H]([C@H](n3ccc(=O)[nH]c3=O)O1)[C@H]2OCc1cccc2ccccc12)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
Imidazole (5.5 g) was added to Compound 108 (8.83 g) dissolved in anhydrous DMF (100 mL) followed by addition of t-butyldiphenylsilylchloride (8.5 mL). The reaction mixture was stirred for 15 h at room temperature when it was complete. The reaction mixture was diluted with EtOAc (400 mL) and washed with saturated sodium bicarbonate solution (3×500 mL) followed by water (2×200 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Finally the residue was purified on a silica gel column using 30% EtOAc in CH2Cl2 as the eluant. Appropriate fractions were collected and concentrated to give Compound 109 in 78% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:22][CH2:21][C:5]2([C:13]3[C:8](=[CH:9][C:10]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[CH:11][CH:12]=3)[NH:7][C:6]2=O)[CH2:4][O:3]1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:23])[O:3][CH2:4][C:5]2([C:13]3[C:8](=[CH:9][C:10]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)=[CH:11][CH:12]=3)[NH:7][CH2:6]2)[CH2:21][O:22]1
Reactant: CC1(C)OCC2(CO1)C(=O)Nc1cc(N3CCOCC3)ccc12
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)OCC2(CNc3cc(N4CCOCC4)ccc32)CO1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2,2-dimethyl-6′-morpholinospiro[[1,3]dioxane-5,3′-indolin]-2′-one (0.11 g, 0.35 mmol) in toluene (14 mL) was added sodium bis(2-methoxyethoxy)aluminium hydride (60% in toluene, 0.53 mL, 1.74 mmol). After stirring at 80° C. for 40 min, the solution was poured into a mixture of ice and 2N NaOH. The product was extracted with DCM and the combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. Purification by column chromatography (eluting with a gradient of 5-60% EtOAc in hexanes) gave 2,2-dimethyl-6′-morpholinospiro[[1,3]dioxane-5,3′-indoline] as a white solid. Mass Spectrum (ESI) m/e=305.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](B2OC(C)(C)C(C)(C)O2)=[N:22]1>O>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[N:3]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Reactant: COc1cccc(Oc2nc(Cl)nc3c2cnn3C)c1
Solvent: O
Product: COc1cccc(Oc2nc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1

Procedure:
6-Chloro-4-(3-methoxy-phenoxy)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine was reacted with indazole boronic acid pinacol ester in General Procedure A. Addition of water gave a solid which was purified by preparative HPLC to give 114. NMR: (CDCl3): 3.81 (s, 3H, CH3), 4.18 (s, 3H, CH3), 7.02-7.04 (m, 2H, 2×ArH), 7.09 (m, H, ArH), 7.44-7.52 (m, 2H, 2×ArH), 7.70 (d, H, ArH, J=9 Hz), 8.16 (s, H, ArH), 8.22 (d, H, ArH, J=6.9 Hz), 8.34 (s, H, ArH), 13.17 (sbr, H, NH). MS: (ESI+) MH+=373.24
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14])(=[O:4])=[O:3].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>ClCCl>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:20]([N+:17]([O-:19])=[O:18])[CH3:21])=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14])(=[O:4])=[O:3]
Reactant: CC[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(=Cc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1)[N+](=O)[O-]

Procedure:
A stirred mixture of 4-methanesulfonyl-3-trifluoromethyl-benzaldehyde (Example 5001a) (12 g, 47 mmol), nitroethane (27.5 ml, 380 mol) and ammonium acetate (1.22 g, 16 mmol) is heated at reflux under argon for 18 hours. The mixture is concentrated to give an oil which is dissolved in dichloromethane (200 ml) and washed with water (3×200 ml), followed by brine (200 ml). The organic extract is dried (MgSO4), filtered and the solvent removed to give the product as red oil. This is used immediately in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:12]([Cl:18])=[N:13][CH:14]=[CH:15][C:16]=2[N:17]=1.[Cu][C:20]#[N:21].O>CN1C(=O)CCC1>[Cl:8][C:4]1[C:3]([C:9]2[S:10][C:11]3[C:12]([Cl:18])=[N:13][CH:14]=[CH:15][C:16]=3[N:17]=2)=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:20]#[N:21]
Reactant: N#C[Cu]
Reactant: Clc1cccc(Br)c1-c1nc2ccnc(Cl)c2s1
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Temperature: 150 °C
Yield: 28.9 %

Procedure:
A stirred mixture of 2-(2-bromo-6-chlorophenyl)-4-chlorothiazolo[5,4-c]pyridine (1.48 g, 4.11 mmol) and copper(I) cyanide (0.45 g, 5.0 mmol) in NMP (20 mL) was heated at 150° C. for 20 minutes. After cooling to room temperature, the mixture was poured into water (250 mL) and the insoluble material was collected by filtration. The solid was then suspended in EtOAc (300 mL) and, after vigorous stirring, was collected by filtration. The filtrate was concentrated under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 25-33% diethyl ether in pentane followed by 0-10% MeOH in DCM to afford the title compound as a pale yellow solid (0.364 g, 29% yield). LCMS (Method E): RT=3.59 min, m/z: 306 [M+H+].
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:23]=[O:24].O>C1COCC1.CCOCC.CCCCCC>[C:1]([N:5]1[CH:23]([OH:24])[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[S:6]1(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)N1C(O)c2cccc(Cl)c2S1(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 49.5 g of N-t-butyl-2-chlorobenzenesulfonamide in 875 mls of dry THF was added 262 ml of a 1.6M hexane solution of n-butyl lithium at -20° to -5° C. under an inert atmosphere. The mixture was stirred at 0° C. for 1 hour, room temperature for 2 hours, recooled to -78° C. and contacted with 38 mls of dry dimethylformamide. The mixture was allowed to warm to room temperature overnight, poured into water, acidified to a ph of ~3 and ether extracted. The extract was washed with water and brine, dried over MgSO4 and concentrated to give a yellow oil. The oil was dissolved in 50% ether in hexane solution and allowed to stand, giving, after filtration, 38 g of the title compound as colorless crystals, m.p. 139°-141° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CO[CH:17]([O:32]C)[CH2:18][NH:19][C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([F:30])[CH:22]=1>CS(O)(=O)=O>[F:30][C:23]1[CH:22]=[C:21]([C:20]2[O:32][CH:17]=[CH:18][N:19]=2)[CH:26]=[CH:25][C:24]=1[N+:27]([O-:29])=[O:28]
Reactant: COC(CNC(=O)c1ccc([N+](=O)[O-])c(F)c1)OC
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=[N+]([O-])c1ccc(-c2ncco2)cc1F
Temperature: 145 °C
Yield: 32.7 %

Procedure:
Phosphorous pentoxide (4.14 g, 29.41 mmol) was added portion-wise to a solution of N-(2,2-dimethoxyethyl)-3-fluoro-4-nitro-benzamide (2.0 g, 7.35 mmol) in methane sulphonic acid (3 mL) at 0° C. over a period of 30 min. The mixture was heated to 145° C. for 5 h. The reaction mixture was allowed to cool to ambient temperature and quenched with crushed ice and then extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated to afford the crude residue. Purification by flash chromatography with silica (60-120 mesh) using 15% ethyl acetate-petroleum ether as eluent to afforded 2-(3-fluoro-4-nitrophenyl)oxazole (500 mg, 33%) as a white solid.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[H-].[Na+].[O:11]=[C:12]1[CH2:29][CH2:28][C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1.[I-].[Na+].C([O-])(O)=O.[Na+]>CS(C)=O.CO>[N:6]1[CH:7]=[CH:8][C:3]([O:11][CH:12]2[CH2:13][CH2:14][C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]3)[CH2:28][CH2:29]2)=[CH:4][CH:5]=1
Reactant: Clc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Oc3ccncc3)CC2)CC1
Reaction time: 8 h

Procedure:
4-Chloropyridine hydrochloride (1.3 g) was added to sodium hydride (0.89 g) in DMSO (20 ml) and the mixture was stirred for 10 min. tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (2.0 g) in DMSO (20 ml) was subsequently added slowly and the mixture was stirred overnight (TLC control: conversion approx. 30-35%). A catalytic amount of sodium iodide was added and the reaction mixture was stirred at 80° C. for 8 h (TLC control). Methanol and NaHCO3 solution was added to the reaction mixture and the mixture was stirred for 20 min. It was then extracted with ethyl acetate and the extract was washed again with NaHCO3 solution and cold water. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel, 70% ethyl acetate/hexane). Yield: 1.0 g (40%)
Reaction SMILES: CCCCC.[C:6]([Li])([CH3:9])([CH3:8])[CH3:7].[Cl:11][C:12]1[C:20]2[N:19]=[C:18]([NH:21][C:22]3[C:27]([CH3:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=3[O:30][CH3:31])[N:17]([CH3:32])[C:16]=2[C:15]([C:33](OC)=[O:34])=[CH:14][CH:13]=1>C(OCC)C.O>[Cl:11][C:12]1[C:20]2[N:19]=[C:18]([NH:21][C:22]3[C:27]([CH3:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=3[O:30][CH3:31])[N:17]([CH3:32])[C:16]=2[C:15]([C:33](=[O:34])[C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: CCOCC
Product: COc1cc(Cl)cc(C)c1Nc1nc2c(Cl)ccc(C(=O)C(C)(C)C)c2n1C
Reaction time: 1 h

Procedure:
A n-pentane solution of tert-butyl lithium (1.46 M, 0.5 ml) was added to a solution of methyl 4-chloro-2-[(4-chloro-2-methoxy-6-methylphenyl)amino]-1-methyl-1H-benzimidazole-7-carboxylate (100 mg, 0.23 mmol) in diethyl ether (5 mL) at −78° C. and stirred for 1 h. The reaction mixture was diluted with water (5 mL), stirred at room temperature for 0.5 h and extracted with ethyl acetate. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC. The resultant was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 31 mg (0.073, mmol, 32%) of the title compound.
Reaction SMILES: N[C:2]1[C:3]([O:24]C)=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])[C:8]([Cl:19])=[C:7]([C:20]([F:23])([F:22])[F:21])[CH:6]=2.Cl.[O:27]1CCOCC1>>[Cl:19][C:8]1[C:9]([N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])=[C:10]2[C:5](=[CH:6][C:7]=1[C:20]([F:21])([F:22])[F:23])[NH:4][C:3](=[O:24])[C:2](=[O:27])[NH:11]2
Reactant: CCN(c1c(Cl)c(C(F)(F)F)cc2nc(OC)c(N)nc12)S(C)(=O)=O
Reactant: C1COCCO1
Agent: Cl
Product: CCN(c1c(Cl)c(C(F)(F)F)cc2[nH]c(=O)c(=O)[nH]c12)S(C)(=O)=O
Yield: 48 %

Procedure:
A mixture of N-(3-amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)-N-ethyl-methanesulphonamide (step (a) above, 70 mg, 0.18 mmol), 2M hydrochloric acid (3 ml) and dioxane (6 ml) was heated at reflux for 2 h, cooled and concentrated under reduced pressure. The residue was suspended in water, filtered and the solid was washed with water. After being dried, the title compound (33 mg, 48%) was obtained as a white solid, m.p. >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32](Cl)=[C:27]3[CH:26]=[N:25]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:10][C:3]4[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=4[Cl:1])=[C:27]3[CH:26]=[N:25]2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Temperature: 160 °C
Yield: 34.2 %

Procedure:
A mixture of 2-chloro-4-methoxy-phenol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 29 mg, 0.178 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.178 mmol), and potassium carbonate (54 mg, 0.391 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to afford 4-[4-(2-chloro-4-methoxy-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (28 mg, 34%) as a white solid. Mass spectrum MH+=460.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:16]2[CH:15]=[C:14]([O:17]C)[C:13]([O:19]C)=[C:12]([C:21]([NH:23][CH2:24][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])=[O:22])[C:11]=2[CH:10]=[C:9]([CH3:33])[C:8]=1[C:34]1[C:43]([CH3:44])=[CH:42][C:41]2[C:40]([C:45]([NH:47][CH2:48][CH:49]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH3:50])=[O:46])=[C:39]([O:57]C)[C:38]([O:59]C)=[CH:37][C:36]=2[C:35]=1[O:61]C.Cl>C(Cl)Cl>[OH:6][C:7]1[C:16]2[CH:15]=[C:14]([OH:17])[C:13]([OH:19])=[C:12]([C:21]([NH:23][CH2:24][CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])=[O:22])[C:11]=2[CH:10]=[C:9]([CH3:33])[C:8]=1[C:34]1[C:43]([CH3:44])=[CH:42][C:41]2[C:40]([C:45]([NH:47][CH2:48][CH:49]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH3:50])=[O:46])=[C:39]([OH:57])[C:38]([OH:59])=[CH:37][C:36]=2[C:35]=1[OH:61]
Reactant: COc1cc2c(OC)c(-c3c(C)cc4c(C(=O)NCC(C)c5ccccc5)c(OC)c(OC)cc4c3OC)c(C)cc2c(C(=O)NCC(C)c2ccccc2)c1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1cc2c(C(=O)NCC(C)c3ccccc3)c(O)c(O)cc2c(O)c1-c1c(C)cc2c(C(=O)NCC(C)c3ccccc3)c(O)c(O)cc2c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
0.65 mL of BBr3 solution (1.72 g, 6.85 mmol) was added dropwise into a solution of compound 7 (420 mg, 0.55 mmol) in 20 mL of anhydrous CH2Cl2 at −78° C. Stirring was continued at −78° C. for 1 h, 0° C. for 1 h, and ambient temperature for 1 h. 50 grams of ice containing 10 mL of 6M HCl was added to the mixture and stirred for 30 min at room temperature. The aqueous layer was extracted with ethyl acetate (3×60 mL). The combined organic layer was washed with water, brine and dried over MgSO4. The solvent was concentrated in vacuo and the residue was purified using C-18 column chromatography followed by preparative HPLC (H2O/Acetonitrile) to give 150 mg of compound 9 (39%) as white-yellow solid. 1H NMR (600 MHz, CD3OD) δ 7.39 (d, J=4.2 Hz, 2H), 7.19 (m, 4H), 7.15 (t, J1=6.0 Hz, J2=6.0 Hz, 4H), 7.03 (t, J1=6.0 Hz, J2=6.0 Hz, 2H), 6.89 (s, 1H), 6.81 (s, 1H), 3.49 (m, 4H), 3.02 (m, 2H), 1.72 (s, 3H), 1.71 (s, 3H), 1.25 (s, 3H), 1.24 (s, 3H). HRMS calcd for C42H40N2O8 701.2857 (M+H), found 701.2865. 100 mg of compound 9 was further purified using a CHIRALCEL OD-RH 5 μM 250 mm×10 mm reverse phase chiral column to give 25 mg of compound 11 and 28 mg of compound 12, respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: OCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 98.4 %

Procedure:
2,4-Dibenzyloxybenzaldehyde [V] (20 g) was dissolved in methanol (700 ml) and then, thereto was added sodium boronhydride (3.6 g) and this was left to stand at room temperature (20° C.) for 1.5 hours. To the reaction mixture was added water (1.5 liter) and the resulting precipitate was collected by filtration and recrystallized from ethanol to obtain 2,4-dibenzyloxybenzyl alcohol [VI] (19.8 g, yield 98%). Melting point: 84°-85° C.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][C@H:6]([CH2:9][C@H:10]3[CH2:14][O:13]C(C)(C)[N:11]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][O:4]2)[CH2:2]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CO>[CH2:2]1[C:3]2([CH2:8][CH2:7][C@H:6]([CH2:9][C@H:10]([NH:11][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:14][OH:13])[CH2:5][O:4]2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCC3(CC3)OC2)COC1(C)C
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)C[C@H]1CCC2(CC2)OC1

Procedure:
The (S)-tert-butyl 4-(((R)-4-oxaspiro[2.5]oct-6-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (3.0 g, 9.17 mmol) and camphor sulphonic acid (2.2 g, 9.17 mmol, 1.0 equiv) were dissolved in 200 mL of MeOH and allowed to react at ambient temperature for 3 hr. The mixture was quenched with saturated NaHCO3 solution, the methanol removed in vacuo, and the mixture diluted with EtOAc. The layers were separated and the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. This yielded 1.70 g (65%) of tert-butyl (S)-1-((R)-4-oxaspiro[2.5]oct-6-yl)-3-hydroxypropan-2-ylcarbamate which was used in the next step with no further purification. MS ESI +ve m/z 310 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[Br:11][CH2:12][C:13](Br)=[O:14].C(N(CC)CC)C.O>C(Cl)Cl>[Br:11][CH2:12][C:13]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:14]
Reactant: COc1ccc(CN)cc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNC(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
7.42 g of 4-methoxybenzylamine was dissolved in 70 mL of methylene chloride, and a solution (10 mL) of 23.2 g of bromoacetyl bromide in methylene chloride was added thereto at −10° C. To the reaction liquid was added dropwise a solution (10 mL) of 8.0 mL of triethylamine in methylene chloride at 0° C., followed by stirring at room temperature for 30 minutes. To the reaction liquid was added water under ice-cooling, followed by extraction with methylene chloride. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10 to 0:100) to obtain a product, which was recrystallized from ethyl acetate to obtain 6.11 g of 2-bromo-N-(4-methoxybenzyl)acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:32]C(=O)C)=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:32])=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccc(C(F)(F)F)c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cccc(C(F)(F)F)c3)c2)=C(C)C1=O
Yield: 95.9 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3-trifluoromethylaniline (0.100 g, 0.193 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.088 g, 0.185 mmol, 96%).
Reaction SMILES: [Na:1].C(C1(C[CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])OCC2(OCCO2)CO1)C.ClC1C=CC=C(C(OO)=O)C=1.[CH3:47][C:48]1([CH2:53]CO)[O:52][CH2:51][CH2:50][O:49]1>>[Na:1].[CH3:35][C:18]1[C:19]([CH2:23][S:24]([C:26]2[NH:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)=[O:25])=[N:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:47][C:48]1([CH3:53])[O:52][CH2:51][CH2:50][O:49]1
Reactant: CC1(CCO)OCCO1
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: Cc1c(OCCC2(C)OCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 14.4 %

Procedure:
The same procedure as in the steps (4f) to (4j) of Example 4 (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using 2-(2-methyl-1,3-dioxolan-2-yl)ethanol obtained in the step (69b) to obtain the title compound (410 mg, total 14.4% yield) as a light yellow solid.
Reaction SMILES: C=CCC.C=CCCCCCC.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCO
Agent: C=CCC
Solvent: C=CCCCCCC
Product: C=CCCCCCCC

Procedure:
Another way to obtain didecyl phthalic mixtures is described in European Patent Application 04 24 767. The esters are prepared by a multi-stage process by dimerization of butene mixtures, hydroformylation, and hydrogenation of the resulting octene mixture to a nonanol mixture, dehydration of the nonanol mixture to form a nonene mixture, followed by hydroformylation and hydrogenation of the nonene mixture to form a decanol mixture.