Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])[CH3:2].C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:73]([NH2:77])([CH3:76])([CH3:75])[CH3:74]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28](=[O:29])[NH:77][C:73]([CH3:76])([CH3:75])[CH3:74])=[CH:26][CH:27]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:31])([CH3:32])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)O)cc3)c1)N2
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)NC(C)(C)C)cc3)c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of 2-(4′-carboxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (860 mg, 2 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU) (1.2 g, 3 mmol) and triethyl amine (0.86 mL, 6 mmol) in dichloromethane was added tert-butylamine (0.86 mL, 8 mmol) at room temperature and stirred at room temperature for overnight. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(4′-tert-butylcarbamoyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (968 mg, quant.) as a light yellow solid which was used for next step without further purification: LC/MS m/e calcd for C31H36N2O3 (M+H)+: 485.62, observed: 485.2.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[CH:18][CH:17]=1)=[N:4]OS(C1C=CC(C)=CC=1)(=O)=O.[NH3:34]>C(Cl)Cl.CO.O>[F:33][C:2]([F:32])([F:1])[C:3]1([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH3:23])=[CH:18][CH:17]=2)[N:4]=[N:34]1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)ON=C(c2ccc(C(C)NC(=O)OC(C)(C)C)cc2)C(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C2(C(F)(F)F)N=N2)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 46 %

Procedure:
tert-Butyl 1-(4-(2,2,2-trifluoro-1-(tosyloxyimino)ethyl)phenyl)ethylcarbamate (400 mg, 0.82 mmol) was dissolved in CH2Cl2 (5 ml). Ammonia in MeOH (7 ml, 7M) was added and the resulting mixture was stirred at room temperature for 7 days. The reaction was then diluted with water (50 ml) and extracted with CH2Cl2 (2*25 ml). Combined organics were dried over MgSO4, filtered and evaporated. The product was purified by flash chromatography using Pet. Ether/EtOAc (3:1) as eluent to give 125 mg (46%) of the title compound as white solids.
Reaction SMILES: [I:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21].CC1NC=CN=1>>[I:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NCc1ccc(I)cc1)C(=O)O
Reactant: CCCCC(=O)Cl
Agent: Cc1ncc[nH]1
Product: CCCCC(=O)N(Cc1ccc(I)cc1)[C@H](C(=O)O)C(C)C
Yield: 63.4 %

Procedure:
In a manner similar to Example 5 and starting from 800 mg (2.40 mmol) of N-(4-iodobenzyl)-L-Valine, 0.47 mL (3.84 mmol) of valeryl chloride and 296 mg (3.60 mmol) of 2-methylimidazole, 635 mg (64%) of N-(4-iodobenzyl)-N-valeryl-L-Valine is obtained. The solid is recrystallised from a mixture of EtOH:H2O 1:1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15](SC)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.O[O:23][S:24]([O-:26])=O.[K+].[CH3:28]O>O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:24]([CH3:28])(=[O:26])=[O:23])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)Cc2ccc(SC)cc2)cc1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(C(=O)Cc2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
To 7.10 g of 4-(2-(4-methylthiophenyl)-1-oxo-ethyl)benzoic acid methyl ester in MeOH (100 mL) was added oxone (21.0 g) in H2O (20.0 mL) at 0° C. After a few hours at r.t., the reaction mixture was extracted with EtOAc and H2O to afford after flash chromatography (50 to 100% EtOAc in hexane), the title product as a white solid (3.20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:16]/[C:15]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:13]([Cl:12])[CH:14]=2)/[C:9]#[N:10])=[C:4]([F:11])[CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1F
Yield: 76.6 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenyl acetonitrile (4.5 g, 26 mmol) was reacted with 3,4-dichlorobenzaldehyde (Aldrich) (5.5 g, 32 mmol), methanolic solution (25 wt %) of sodium methoxide (6.6 mL, 29 mmol) in methanol (150 mL) at 50° C. for 3 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3,4-dichloro-phenyl)-acrylonitrile as a white powder (6.5 g, 76%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23]C)=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Cl.[NH:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[NH2:25][C:16]1[N:15]=[C:14]([O:13][C@@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])[N:22]=[C:21]2[C:17]=1[NH:18][C:19](=[O:23])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:33]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: ClCCCCCBr
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: C1CCCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Example 19 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate, 1-bromo-5-chloropentane and hexahydro-1H-azepine.
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][C:7]2[N:8]=[C:9]([NH:11][C@H:12]([C:20](O)=[O:21])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:10][C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[Li]C.[CH3:27]COCC.Cl[Si](C)(C)C>C1COCC1>[CH:1]([C:4]1[CH:24]=[CH:23][C:7]2[N:8]=[C:9]([NH:11][CH:12]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20](=[O:21])[CH3:27])[S:10][C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2nc(N[C@@H](Cc3ccccc3)C(=O)O)sc2c1
Reactant: CCOCC
Agent: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C(Cc1ccccc1)Nc1nc2ccc(C(C)C)cc2s1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A solution of 2 g N-(6-isopropylbenzothiazol-2-yl)phenylalanine (5.9 mmol) in 60 mL THF was cooled on an ice-salt bath to -5° C., under nitrogen. A solution of 1.4N MeLi in ether (26 mL, 36.4mmol) was added via syringe over about one minute. After two hours 10 mL chlorotrimethylsilane (78 mmol) was added rapidly and the reaction warmed up to room temperature. The reaction was quenched with 1N HCl and the product extracted into ether, dried (Na2SO4) and concentrated. The product was purified by flash chromatography thru silica gel, eluting with CH2Cl2. Recrystallization from EtOH gave 0.75g product (2.2 mmol, 38%), mp 107°-110° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:5][CH:4]=1)#[N:2].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][NH2:27]>>[C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([NH:27][CH2:26][C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)=[O:18])=[CH:13][CH:14]=2)[CH:6]=[N:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)n2)cc1
Reactant: NCc1ccco1
Product: CC(C)(C(=O)NCc1ccco1)c1ccc(-c2cncc(C#N)n2)cc1
Yield: 30 %

Procedure:
Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid (example 20a) and furan-2-ylmethanamine. Yield 30%. 1H NMR (400 MHz, dMSO): δ 1.51 (s, 6H), 4.23-4.25 (d, 2H), 6.06-6.07 (d, 1H), 6.34-6.35 (t, 1H), 7.48-7.50 (d, 2H), 7.53 (t, 1H), 7.97-8.00 (t, 1H), 9.16 (s, 1H), 9.56 (s, 1H); MS+H (347).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:4].[CH3:18][CH2:19][OH:20]>>[Cl:16][C:12]1[CH:11]=[C:10]([C:9]2[S:8][C:7]([O:20][CH2:19][CH3:18])=[N:6][C:5]=2[C:3]([OH:2])=[O:4])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1nc(Br)sc1-c1cccc(Cl)c1
Reactant: CCO
Product: CCOc1nc(C(=O)O)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of 2-bromo-5-(3-chloro-phenyl)-thiazole-4-carboxylic acid methyl ester with EtOH. LC-MS: tR=0.98 min; [M+H]+=284.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].[OH-].[Na+]>C(Cl)(Cl)Cl>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Product: Cl
Temperature: 25 °C
Yield: 12 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.00 g) and 2-hydroxy-5-methylbenzophenone (1.14 g) were stirred at 170° C. for one hr. The reaction solution was cooled to room temperature. Chloroform was then added to the reaction solution, and separation was carried out with a 10% aqueous sodium hydroxide solution. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using hexane-acetone. Thereafter, 10% hydrochloric acid-methanol (10 ml) was added to the product, followed by concentration. The concentrate was suspended in ether, and the suspension was filtered to give the title compound (234 mg, yield 12%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:4][CH:3]=1.[CH3:16]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:16])=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: Oc1ccccc1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccccc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A mixture of 2-(4-fluorobenzyl)phenol (4.51 gm, 22.41 mmol), DMF (60 mL), potassium carbonate (7.78 gm, 56.02 mmol) and methyl iodine (1.67 mL, 26.81 mmol) was stirred at rt for 16 h. The reaction was poured into 150 mL ethyl acetate, filtered, washed 3× with 50 mL H20, 1× with 100 m]L brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(4-fluorobenzyl)anisole (4.27 gm, 88%); 1H NMR (200 MHz, DMSO-d6): δ 7.11(m, 7H), 3.88(s, 2H), 3.76(s, 3H); TLC conditions: Uniplate silica gel, 250 microns; methylene chloride-hexanes (1:1); Rf=0.64.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[NH:22][CH3:23].[Cl:24]N1C(=O)CCC1=O.[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].C([O:43][C:44](=O)[NH:45][S:46]([C:49]1[S:50][C:51]([Cl:54])=[CH:52][CH:53]=1)(=[O:48])=[O:47])C>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:54][C:51]1[S:50][C:49]([S:46]([NH:45][C:44]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([N:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([F:1])=[C:3]([NH:22][CH3:23])[C:4]=4[Cl:24])[C:9]3=[O:12])=[CH:14][CH:15]=2)=[O:43])(=[O:48])=[O:47])=[CH:53][CH:52]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNc1cc2ccn(-c3ccc([N+](=O)[O-])cc3)c(=O)c2cc1F
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CNc1c(F)cc2c(=O)n(-c3ccc(NC(=O)NS(=O)(=O)c4ccc(Cl)s4)cc3)ccc2c1Cl
Temperature: 80 °C
Yield: 6.4 %

Procedure:
To a mixture of 7-Fluoro-6-methylamino-2-(4-nitro-phenyl)-2H-isoquinolin-1-one (100 mg, 0.27 mmol) (Example 104) in DMF (3 mL) was added N-chlorosuccinimide (76 mg, 0.57 mmol). After 18 hours all starting material was consumed. Tin dichloride dehydrate 244 mg (0.11 mmol) was added to the reaction mixture, and the reaction was heated to 80° C. for 2 hr. Upon cooling the reaction mixture was treated with 1 mL of 10% sodium carbonate and extracted 3 times with EtOAc. The combined organic layers were dried over Na2SO4 anhydrous and concentrated in vacuo to give a mixture of the 5-Cl and 4,5-dichloro anilines. This mixture was coupled directly with 76 mg (0.28 mmol) of (5-Chloro-thiophene-2-sulfonyl)-carbamic acid ethyl ester (Example 12) in toluene (0.54 mL) and refluxed for 4 h. The resulting mixture of monochloro and dichloro sulfonylureas were separated by preparative RP-HPLC to give 9.4 mg (6% yield overall) of 5-chloro-N-[({4-[5-chloro-7-fluoro-6-(methylamino)-1-oxoisoquinolin-2(1H)-yl]phenyl}amino)carbonyl]thiophene-2-sulfonamide. ES-MS (M+H)+=541.3 (2Cl).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)C>[O:12]=[C:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])=[CH:23][CH:22]=3)=[CH:3][CH:4]=2)[NH:9]1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1ccc(COc2ccc3c(c2)NC(=O)CC3)cc1
Temperature: 60 °C
Yield: 55.4 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (2.015 g, 12.35 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added potassium carbonate (1.880 g, 13.60 mmol) with stirring, and tert-butyl 4-(bromomethyl)benzoate (2.960 g, 10.83 mmol) in N,N-dimethylformamide (10 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, then heated to 60° C. for 72 hours. The mixture was cooled, the solvent volume reduced to half under reduced pressure, and the residue poured slowly into water (100 mL) with stirring. Diethyl ether (5 mL) was added, the mixture sonicated, filtered, and the white solid thus obtained was washed with saturated sodium carbonate (60 mL), water (200 mL), diethyl ether (15 mL), and dried to afford tert-butyl 4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoate (2.122 g, 6.00 mmol, 55%). LCMS mz 376.0 (M+Na), anal HPLC >92% in purity, 1H NMR (400 MHz; CDCl3) 8.00 (d, J=8.6 Hz, 1H); 7.55 (s, 2H); 7.45 (d, J=8.6 Hz, 2H); 7.05 (d, J=8.2 Hz, 1H); 6.57 (dd, J=8.4 and 2.5 Hz, 1H); 6.35 (d, J=2.3 Hz, 1H); 2.90 (m, 2H); 2.61 (m, 2H); 1.60 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:41])([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:32]O.[K+].[Br-].Cl>>[CH3:30][C:31]([CH3:41])([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:32][O:24][C:23]([C:18]1([C:20]([O:22][CH2:30][C:31]([CH3:41])([CH3:32])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(C)(CO)Cc1ccccc1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC(C)(C)Cc1ccccc1)(C(=O)OCC(C)(C)Cc1ccccc1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2 -[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2,2-dimethyl-3-phenylpropanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 0.82 (s, 12H, 4×CH3), 1.08 (d, J=6.37 Hz, 3H, CH3), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 3.96 (s, 4H, OCH2, OCH2), 5.04 (m, 1H, CH), 6.35 (d, J=4.17 Hz, 1H, OH), 6.89 (dd, J=8.13, 1.53 Hz, 1H, Ar--H), 7.05 (m, 4H, Ar--H), 7.14 (m, 8H, Ar--H), 7.38-7.42 (m, 3H, Ar--H), 7.5 (s, 1H, Ar--H), 8.81 (brs, 1H, NH), 9.38 (brs, 1H, NH); IR (KBr, cm-) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 714 (M+H)+ ; Analysis for: C42H48ClNO7 ×HCl: Calc'd: C, 67.19; H, 6.58; N, 1.87; Found: C, 66.69; H, 6.53; N, 1.83.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[CH:10]=[C:11]([CH:17]2[C:21]3[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=3[O:19][C:18]2=[O:34])[CH:12]=[C:13]([CH3:16])[C:14]=1[OH:15]>C1(C)C(C)=CC=CC=1.CS(O)(=O)=O>[C:1]([O:15][C:14]1[C:13]([CH3:16])=[CH:12][C:11]([CH:17]2[C:21]3[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:20]=3[O:19][C:18]2=[O:34])=[CH:10][C:9]=1[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc(C)c1O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: CC(=O)Oc1c(C)cc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1C
Temperature: 105 °C
Yield: 96.7 %

Procedure:
53.6 g (0.53 mol) of acetic anhydride are added dropwise over a period of about 10 minutes to a suspension of 183.3 g (0.50 mol) of 3-(3,5-dimethyl-4-hydroxyphenyl)-5,7-di-tert-butylbenzofuran-2-one (compound (107), Table 1, Example 2) in 250 ml of xylene and 0.5 ml (7.7 mmol) of methanesulfonic acid which is stirred at 105° C. under a nitrogen atmosphere. The clear, colourless reaction mixture is concentrated at about 170° C. under a slight vacuum. 500 ml of 1-butanol are carefully added to the residue and the mixture is cooled with ice/water. The precipitated product is filtered and washed with 100 ml of 1-butanol. Drying gives 197.6 g (97%) of 3-(4-acetoxy-3,5-dimethylphenyl)-5,7-di-tert-butylbenzofuran-2-one, melting point 165°-166° C. (compound (109), Table 1).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18]1)=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[CH2:11]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([CH:22]=[O:23])[CH2:18]1)=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N1CCC(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1CCC(C=O)C1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of dimethyl sulfoxide (13.03 ml) in dichloromethane (25 ml) was dropwise added to a solution of oxalyl chloride (9.1 ml) in dichloromethane (100 ml) below -65° C. with stirring. The mixture was stirred at the same temperature for 30 minutes. A solution of 1-allyloxycarbonyl-3-hydroxymethylpyrrolidine (17.0 g) in dichloromethane was added to the mixture at the same temperature. The mixture was stirred below -65° C. for 30 minutes, followed by dropwise addition of triethylamine (38.5 ml) below -65° C. The cooling bath was then removed and the reaction mixture was allowed to warm up to ambient temperature, washed with water (250 ml×2), 1N hydrochloric acid (150 ml), saturated sodium hydrogen carbonate (150 ml) and brine (150 ml) in turn, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (200 g) and eluted with a mixture of methanol and dichloromethane (1:99 V/V) to give 1-allyloxycarbonyl-3-formylpyrrolidine (13.50 g).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr.O.C([O-])=[O:19].[K+]>ClCCl>[CH2:1]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH2:12][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[O-]
Reactant: CC(=O)CC(=O)NCc1ccccc1
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CO)CC(=O)NCc1ccccc1
Temperature: 7.5 °C
Reaction time: 1.5 h
Yield: 38.7 %

Procedure:
To a solution of N-benzyl-3-oxobutanamide (compound A 50 g, 261 mmol) in dichloromethane (350 ml) was added bromine (14.82 ml, 288 mmol) at 0-5° C., then stirred at 20-25° C. for 3 hours (bromine colour disappeared). Water (300 ml) was added to the mixture with stirring, stirred for 10 min. Organic phase was separated, washed with sodium bicarbonate solution, dried, evaporated to dryness (compound B). The solid residue (compound B) dissolved in methanol (900 ml), added potassium formate (44.0 g, 523 mmol) and the mixture was heated under reflux for 2 hours. Methanol was removed on a rotavap, the residue was taken up into ethyl acetate (EA) (500 ml) under reflux, filtered hot, the filter cake washed with warm EA (100 ml). The combined filtrate was cooled to 5-10° C., aged for 1.5 hours. The precipitate was collected, washed with cold EA (50 ml), dried to give 25 g (46.1%) of crude product, light beige. Re-crystallised from water (300 ml), with active carbon (1 g). Filtered hot on celite, cooled in ice, aged for 1 hour, crystals collected, washed with cold water (20 ml), dried on air overnight to give N-benzyl-4-hydroxy-3-oxobutanamide (21 g, 101 mmol, 38.8% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1.[C:11]1([P:17]([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>C1(C)C=CC=CC=1.CCOCC>[Cl-:8].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A solution of 4-methoxybenzyl chloride (1.153 g, 0.0074 moles) in anhydrous toluene (10 mL) was treated with triphenylphosphine (1.93 g, 1 equivalent). The resulting solution was refluxed under nitrogen. After 8-10 hours, the reaction was cooled to room temperature and diluted with ether. The phosphonium salt was collected by filtration. Yield=1.5 g (53%). MALDI-TOF MS 383.9 obs. (383.45 calc.).