Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([CH2:14][CH3:15])[CH:3]=1.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[N:45]1([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:48]2[CH2:47][CH2:46][N:45]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49]2)=[O:13])=[C:4]([CH2:14][CH3:15])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1cc(Cl)c(Cl)cc1NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(Cl)c(Cl)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a stirred mixture of 2-(4,5-dichloro-2-ethylphenylamino)acetic acid (100 mg, 0.403 mmol), Et3N (122 mg, 1.21 mmol) in DCM (3 mL) at 0° C., EDCI.HCl (123 mg, 0.604 mmol) and HOBt (8 2 mg, 0.604 mmol) were added. The resulting mixture was stirred at 0° C. for 30 min, and then tert-butyl piperazine-1-carboxylate (90 mg, 0.483 mmol) was added. The mixture was stirred at room temperature for 16 h and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=5:1) to afford the desired product (120 mg, 71.5% yield) as an off-white solid. ESI-MS m/z: 414.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Br:9]Br.[OH-].[Na+]>O>[Br:9][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[Cl:8]
Reactant: Clc1cccc(Cl)c1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(Br)c(Cl)c1
Reaction time: 3 h
Yield: 98.5 %

Procedure:
In a 1,000 ml four necked flask equipped with a reflux condenser, a dropping funnel, a thermometer and a stirrer, 588 g (4 mole) of metadichlorobenzene and 8 g of ferric chloride were charged, and 640 g (4 mole) of bromine was added dropwise to the mixture at room temperature with stirring. The reaction was carried out for about 3 hours. After the reaction, the reaction mixture was poured into water and it was neutralized with sodium hydroxide. The reaction product was extracted with chloroform. The extract was washed with water and dried and was distilled under a reduced pressure to obtain 890 g of 1-bromo-2,4-dichlorobenzene (yield: 98.5%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](B(O)O)=[CH:17][N:16]=1>>[C:9]1([C:6]2[N:5]=[CH:4][C:3]([CH2:2][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=[N:16][CH:17]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cncc2ccccc12
Reactant: BrCc1cnc(-c2ccccc2)nc1
Product: c1ccc(-c2ncc(Cc3cncc4ccccc34)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 64a (85 mg, 0.34 mmol) and isoquinolin-4-ylboronic acid (104 mg, 0.60 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Orange solid. Yield: 68 mg, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=4.40 (s, 2H), 7.44-7.51 (m, 3H), 7.61-7.67 (m, 1H), 7.67-7.74 (m, 1H), 7.87 (dd, J=8.4, 0.8 Hz, 1H), 8.02-8.06 (m, 1H), 8.37-8.42 (m, 2H), 8.49 (s, 1H), 8.66 (s, 2H), 9.24 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=30.9, 122.8, 127.4, 127.5, 127.9, 128.6, 128.6, 128.6, 130.4, 130.6, 131.0, 134.3, 137.2, 143.6, 152.7, 157.0, 163.1; (ESI): m/z=297.91 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1.C(OC)(OC)OC.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[BH4-].[Na+]>CO>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][N:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1)[CH2:11][C:9]1[NH:8][CH:7]=[CH:6][N:10]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CN)cc2n1CCC
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2n1CCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
The compound (130 mg) obtained in Example 3-6 was dissolved in methanol (3.0 ml) and added with trimethyl orthoformate (0.130 ml) and 2-imidazole carboxaldehyde (37.3 mg) and the whole was stirred for 1 hour. After having been cooled to 0° C., the solution was added with sodium borohydride (21.5 mg) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. The solution was washed with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (16.4 mg) of the subject compound as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[C:25]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]([O:28][CH2:29]C)=[O:27])=[CH:20][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Mg]>CO>[CH:11]1[C:12]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(=Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)Oc1ccccc1
Agent: [Mg]
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)Oc1ccccc1
Yield: 84.9 %

Procedure:
A solution of ethyl diethylphosphino phenoxy acetate in dry THF was added slowly to a stirred ice cooled suspension of sodium hydride in dry THF under nitrgen atmosphere. The mixture was stirred at 0° C. for 30 min. and added a solution of 4-[2-(Phenoxazin-10-yl)ethoxy]benzaldehyde in dry THF dropwise at ice temperate. The mixture was allowed to warm to room temperature and stirred for overnight. The solvent was evaporated under reduced pressure, residue was diluted with water and extracted with ethylacetated. The organic layer was washed with water, brine, dried and concntrated. The residue was chromatographed with 10% ehylacetate in pet. ether as an eluent to afford ethyl 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropenoate (59%) as thick liquid. Ethyl 3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-phenoxypropenoate (3.5 gm) and magnesium turnings in dry methanol was stirred at room temp for 12 h. Methanol was evaporated and the residue was taken into water, acidified with 2 N HCI and extracted with ethylacetate. The organic layer was washed with water, brine, evaporated and chromatographed with 10% ethylacetate in per. ether to yield the title compound (2.9 g, 85%). mp: 106-110° C.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C([O-])(O)=O.[Na+]>CCO>[C:11]1([N:17]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNc1ccccc1
Reactant: N#CCC(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 90 °C
Yield: 90.6 %

Procedure:
A mixture of 4,4,4-trifluoro-3-oxobutanenitrile (2.056 g, 15 mmol) and phenylhydrazine hydrochloride (2.169 g, 15 mmol) in EtOH was heated at 90° C. for 8 hours. The reaction was quchened with water, basified with saturated NaHCO3 solution, and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as yellow solid (3.089 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.54 (m, 5H), 5.85 (s, 1H), 3.95 (br, 2H); LC-MS (ESI) m/z 228 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]2[N:18]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:16]=3[N:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:28][C:27]1[C:16]2[N:15]=[C:14]([C@@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[N:18]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[C:17]=2[CH:24]=[CH:25][CH:26]=1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2c(Cl)cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCn1c([C@@H]2CCCNC2)nc2c(Cl)cccc21

Procedure:
(R)-tert-Butyl3-(4-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (0.245 mmol, 0.100 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir under nitrogen for 4 hr. The reaction was then concentrated and dried in-vacuo affording (R)-4-chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (48A) as a light brown oil that was used without further purification. ESI-MS: m/z 308.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[NH2:22][C:23]1[C:24]([C:30](O)=[O:31])=[N:25][C:26]([Br:29])=[CH:27][CH:28]=1>>[NH2:22][C:23]1[C:24]([C:30]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:31])=[N:25][C:26]([Br:29])=[CH:27][CH:28]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1
Yield: 45 %

Procedure:
Following method 11, (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate was coupled to 3-amino-6-bromopicolinic acid and purified by SiO2 chromatography (EtOAc eluant) yielding (S)-tert-butyl 1-(3-(3-amino-6-bromopicolinamido)pyridin-4-yl)piperidin-3-ylcarbamate (45%). LCMS (m/z): 491.1 (MH+); LC Rt=2.89 min.
Reaction SMILES: [C:1]([C@@H:4]1[N:7]([C:8](=[O:10])[CH3:9])[C:6](=[O:11])[C@H:5]1[CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:28]C(OCC1C=CC=CC=1)=O)=[N:17]C(OCC1C=CC=CC=1)=O)([OH:3])=[O:2].[ClH:39]>[Pd].CO.C(OCC)(=O)C>[ClH:39].[C:1]([C@@H:4]1[N:7]([C:8](=[O:10])[CH3:9])[C:6](=[O:11])[C@H:5]1[CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH2:28])=[NH:17])([OH:3])=[O:2]
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=N)N)[C@@H]1C(=O)O
Yield: 33 %

Procedure:
A methanol/ethyl acetate (3 mL/0.5 mL) solution of compound 29 (200 mg, 0.38 mmol) and 1N HCl (0.5 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere until TLC indicated the disappearance of the starting material (15 min). The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 37 mg (33%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])=[CH:4][C:5]([S:10]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[C:6]([O:8]C)[CH:7]=1.B(Br)(Br)Br.Cl>C(Cl)Cl>[F:1][C:2]1[C:3]([N:24]2[C:25](=[O:34])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]2=[O:33])=[CH:4][C:5]([S:10]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:11])=[O:12])=[C:6]([OH:8])[CH:7]=1
Reactant: COc1cc(F)c(N2C(=O)c3ccccc3C2=O)cc1S(=O)(=O)N1CCCCc2ccccc21
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
To a solution of 5-fluoro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl-sulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)anisole (0.57 g) in methylene chloride (12 mL) was added boron tribromide (1 mol/L methylene chloride solution, 3.53 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (0.46 g).
Reaction SMILES: [ClH:1].C(OC([N:12]([CH2:20][CH:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[CH2:24][CH2:23][NH:22]1)[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=O)C1C=CC=CC=1.Cl>C(O)(=O)C>[ClH:1].[ClH:1].[C:16]1([CH3:19])[CH:15]=[CH:14][C:13]([NH:12][CH2:20][CH:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[CH2:24][CH2:23][NH:22]2)=[CH:18][CH:17]=1
Reactant: COc1cc2c(cc1OC)C(CN(C(=O)OCc1ccccc1)c1ccc(C)cc1)NCC2
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C(CNc1ccc(C)cc1)NCC2
Temperature: 100 °C
Yield: 144 %

Procedure:
A mixture of 1-(N-benzyloxycarbonyl-p-toluidinomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (470 mg), acetic acid (4.7 ml) and conc. hydrochloric acid (4.7 ml) was heated for 1 hour at 100° C. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in methanol. To the solution was added ethyl acetate and the precipitating crystals were collected by filtration to give 1-(p-toluidinomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride (270 mg), mp 180° to 184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[C:30]([Cl:37])[N:29]=1.[N-]=C=O>C(Cl)(Cl)Cl.ClCCl>[Cl:37][C:30]1[N:29]=[C:28]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(Cl)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)amine (7.79 g, 30.3 mmol) and triethylamine (2.89 g, 28.6 mmol) in chloroform (20 mL) was added dropwise over 20 minutes to a cold (ice-bath), stirred solution of 2,6-dichloro-3-nitropyridine (5.0 g, 26.0 mmol) in chloroform (25 mL). The mixture was warmed to room temperature and stirred overnight. The solvent was evaporated and the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated to give an oil. The mixture was taken up in dichloromethane (120 mL) and polymer-supported isocyanate resin (1.6 mmol/g, 8.0 g) was added and the mixture was shaken at room temperature for 2 days. The mixture was filtered and the filtrate was evaporated to give the title compound (10.7 g, 100%) as a bright yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1.C(NC(C)C)(C)C.O>CN(C=O)C>[N+:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2cccc([N+](=O)[O-])c2)C1
Temperature: 75 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (450 mg), 1-(chloromethyl)-3-nitrobenzene (435 mg) in DMF (4.5 mL) was added N,N-diisopropylamine (463 uL), which was stirred at 75° C. for 4 hours. To the resultant was added H2O. The mixture was extracted with ethyl acetate. The organic phase was washed brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl [(3R)-1-(3-nitrobenzyl)-3-pyrrolidinyl]carbamate (, 757 mg) as a orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH:14]=O)=[CH:9][CH:8]=1.[CH3:21][O:22][C:23]([C@@H:25]1[CH2:34][C:33]2[C:28](=[CH:29][C:30](O)=[C:31]([NH2:35])[CH:32]=2)[CH2:27][N:26]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl>ClCCCl.O>[CH3:21][O:22][C:23]([CH:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[C:30]([O:16][C@@H:13]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]5[CH:17]=[CH:18][C:19]([Cl:20])=[C:2]([Cl:1])[CH:3]=5)=[CH:12][CH:11]=4)[CH2:14][NH:35]3)=[CH:29][C:28]=2[CH2:27][N:26]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:24]
Reactant: COC(=O)[C@@H]1Cc2cc(N)c(O)cc2CN1C(=O)OC(C)(C)C
Reactant: O=CC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
[4-(3,4-Dichloro-benzyloxy)-phenyl]-oxo-acetaldehyde (616 mg) was dissolved in DCE (25 mL), and (S)-6-amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (644 mg) and sodium triacetoxyborohydride (520 mg) were added. The mixture was stirred overnight at room temperature. DCM (50 mL) was added to the reaction mixture and poured into water (25 mL). The organic layer was washed with 10% Na2CO3 solution and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (hexanes/ethyl acetate from 90:10 to 70:30) to give (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester (855 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C@@H:11](O)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=O.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2[N:17]1CCC2.COC(C1C=CC2C(=O)CCCC=2C=1)=O.CO>C1(C)C=CC=CC=1.C1COCC1>[NH2:17][C@@H:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([CH2:3][OH:2])[CH:14]=[CH:13][C:12]1=2
Reactant: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Reactant: COC(=O)c1ccc2c(c1)CCC[C@@H]2O
Agent: COC(=O)c1ccc2c(c1)CCCC2=O
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: N[C@@H]1CCCc2cc(CO)ccc21
Temperature: -10 °C

Procedure:
Preparation 5(S)-Hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester: To an oven-dried 2 L round-bottomed flask equipped with an argon inlet/outlet and magnetic stirring was added (R)-2-methyl-CBS-oxazaborolidine (7.4 mL of a 1M soln in toluene, 7.4 mmol, Aldrich). Toluene 190 mL was added and the reaction was cooled in an ice-salt bath (bath temp. =−10° C.). BH3—SMe2 was added (17 mL, 180 mmol, Aldrich), then 5-oxo-5,6,7,8-tetrahydro-naphth-alene-2-carboxylic acid methyl ester (30 g, 150 mmol, Albany Molecular) in 200 mL of THF was added over 5 h using a syringe pump. After the addition was complete, the mixture was stirred for an additional 1 h. The mixture was poured into an addition funnel, and the mixture was added to 200 mL of MeOH, cooled in a ice-salt bath, over 30 min at such a rate that the internal temp. was kept below 0° C. The mixture was concentrated in vacuo. Et2O (1 L) was added, and the mixture was washed with 1M H3PO4 (3×), satd NaHCO3, and brine (ca. 400 mL each wash). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in Et2O again (500 mL), and the mixture was washed with 1M H3PO4 (3×200 mL), satd NaHCO3, and brine. After drying the organic layer over MgSO4, the mixture was filtered and concentrated in vacuo, which gave the title compound as a white-yellow solid. MS (+ion ESI) m/z=207 (MH+), 189 (MH+—H2O).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH2:11][CH:12](C)[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Br:51][C:52]1[CH:57]=[CH:56][C:55]([SH:58])=[CH:54][CH:53]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]([S:58][C:55]2[CH:56]=[CH:57][C:52]([Br:51])=[CH:53][CH:54]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:8][CH:9]=1
Reactant: CCCCC(C)CC(O)c1ccc(C(=O)OC)cc1
Reactant: Sc1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCC(Sc1ccc(Br)cc1)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-3-methyl-heptyl)-benzoic acid methyl ester (1760 mg, 7.04 mmol) in toluene (70 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 2664 mg, 10.56 mmol) at 0° C., followed by the additions of tributylphosphine (2.63 mL, 8.38 mmol) and 4-bromo-benzenethiol (1597 mg, 8.45 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4-bromo-phenylsulfanyl)-heptyl]-benzoic acid methyl ester. 1700 mg of the ester product is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 2 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (2 mL), and extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-heptyl]-benzoic acid (1700 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Si:10]([O:17][CH2:18]/[CH:19]=[N:20]/[S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][CH2:18][C@@H:19]([NH:20][S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Fc1ccc(Br)cc1F
Reactant: CC(C)(C)[S@@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[S@@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)c(F)c1
Yield: 65 %

Procedure:
(R)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(3,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (4.12 g, 65%) was prepared by the procedure described in Example 99, Step 1, using 4-bromo-1,2-difluorobenzene and (R,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide.