Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH2:12])([O-])=O.Cl>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH2:12]
Reactant: NN(Cc1ccccc1[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccccc1CN(N)c1ccc(Cl)cc1
Yield: 77.6 %

Procedure:
To a solution of 6.5 g (0.023 m) of 1-[(2-nitrophenyl)methyl]-1-(4-chlorophenyl)hydrazine of Example 12a in 150 ml of 95% ethanol and 25 ml of water, 12.8 g (0.23 g-atom) of iron and 1 ml of concentrated HCl was added. The mixture was refluxed for 0.5 hours, cooled, Celite added and filtered. The filtrate was evaporated and the residual material was partitioned between 10% NaOH and ether. The ether extract was dried (Na2SO4), filtered and evaporated to afford a solid which was triturated with hexane and filtered giving 4.5 g (80%) of 1-[(2-aminophenyl)methyl]-1-(4-chlorophenyl)hydrazine, m.p. 83°-87° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[C:41]([C:40]1[CH:43]=[C:36]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)[CH:37]=[N:38][CH:39]=1)#[N:42]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1
Temperature: 25 °C

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 200 mg, 0.448 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (206 mg, 0.896 mmol), Pd(PPh3)2Cl2 (31.5 mg, 0.045 mmol) and Na2CO3 (143 mg, 1.345 mmol) were added to a MW vial and treated with a mixture of DME (1.902 mL), water (543 μL) and EtOH (272 μL). The vial was sealed, evacuated/purged with argon and then the RM was subjected to MW irradiation at 120° C. for 10 min, then cooled to RT and finally treated with Si-Thiol (1.27 mmol/g, 176 mg, 0.224 mmol) overnight. The RM was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, 25% for 0.2 min then 25% to 55% in 14 min.) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.30 min, m/z=470.0-471.0 [M+H]+, m/z=468.0-469.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.79 (m, 1H) 1.80-1.92 (m, 1H) 2.86 (d, J=11.25 Hz, 1H) 3.16-3.27 (m, 2H) 3.34-3.44 (m, 1H) 4.17-4.24 (m, 1H) 4.70-5.04 (m, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.82-7.88 (m, 2H) 8.09 (d, J=2.45 Hz, 1H) 8.40 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.90 (d, J=1.96 Hz, 1H) 9.02 (d, J=1.96 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][CH2:34][OH:35])[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:43](Cl)([CH3:46])(=[O:45])=[O:44]>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:14]([CH2:33][CH2:34][O:35][S:43]([CH3:46])(=[O:45])=[O:44])[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:43]([OH:8])(=[O:45])(=[O:44])[CH3:46]
Reactant: CO[C@H]1O[C@H](CCO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@H]1O[C@H](CCOS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Product: CS(=O)(=O)O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of methyl 2,3,4-tri-O-benzyl-6-deoxy-α-D-glucoheptopyranoside (0.35 g, 0.92 mmol) in dry methylene chloride (10 mL) was added triethylamine (0.2 mL, 1.43 mmol). Then the solution was cooled to -10° C. and mesylchloride (0.08 mL), 1 mmol) was added. The mixture was stirred an additional 15 min at -10° C., then the reaction was allowed to warm up to room temperature. The mixture was washed three times with water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Flash chromatography on silica gel and elution with a 40:60 mixture of ethylacetate and hexane afforded the expected mesylate methyl 2,3,4-tri-O-benzyl-6-deoxy-7-O-methylsulfonyl-α-D-glucoheptopyranoside as an oil (0.38 g, 91%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36]O.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Reactant: CN(C)CCCO
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCCN(C)C)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
To a solution of 4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoic acid (for a preparation see Intermediate 18) (250 mg, 0.575 mmol) in DMF (10 mL) were successively added 3-(dimethylamino)-1-propanol (71.2 mg, 0.690 mmol), EDC (220 mg, 1.150 mmol) and DMAP (7.0 mg, 0.057 mmol). The resulting mixture was stirred at room temperature overnight, then concentrated in vacuo, dissolved in a 1:1 MeOH/DMSO mixture and purified by MDAP (HpH). The appropriate fractions were combined and concentrated under reduced pressure to give 3-(dimethylamino)propyl 4-((2S,4R)-1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (41 mg, 17%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.94 min, MH+=520.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10]C1C(OCC2C=CC=CC=2)=C(N)C=CN=1.[ClH:26].C(O[CH2:31][CH3:32])(=O)C.[CH3:33][OH:34]>>[ClH:26].[ClH:26].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:6][C:5]1[C:33]([OH:34])=[CH:32][CH:31]=[CH:3][N:4]=1
Reactant: CO
Reactant: CCOC(C)=O
Reactant: Cc1[nH]cnc1CSCCc1nccc(N)c1OCc1ccccc1
Agent: Cl
Product: Cc1[nH]cnc1CSCCNc1ncccc1O
Reaction time: 48 h

Procedure:
2-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]-amino3-benzyloxypyridine (1.3 g; 0.0036 moles) was treated with conc. hydrochloric acid (10 ml) and heated to 60° for 4 hours. The reaction mixture was stripped in vacuo to a green oil, dissolved in methanol, treated with ethyl acetate and left to stand for 2 days. The red crystals obtained were filtered off and recrystallised from methanol/ethyl acetate to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-hydroxypyridine dihydrochloride as dark red crystals (0.17 g, mp 210°-212°).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][C:24]=1[Cl:35]>CC1C=CC(C)=CC=1>[Br-:20].[Cl:35][C:24]1[CH:25]=[N:26][C:27]2[C:32]([C:23]=1[CH2:22][CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2
Reactant: COc1ccc2ncc(Cl)c(CCBr)c2c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccc(C)cc1
Product: COc1ccc2ncc(Cl)c(CC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Product: [Br-]
Yield: 91.6 %

Procedure:
Triphenylphosphine (27.7 g, 106.0 mmol, 3.0 eq) is added at room temperature to a stirred solution of 4-(2-bromo-ethyl)-3-chloro-6-methoxy-quinoline (10.6 g, 35.3 mmol, 1.0 eq) in p-xylene (200 mL) and the reaction mixture is heated under reflux for 20 hours. The resulting precipitate is collected by filtration and washed with ethyl acetate (50 mL) to afford [2-(3-chloro-6-methoxy-quinolin-4-yl)-ethyl]-triphenyl-phosphonium bromide as a light yellow solid (18.2 g, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21].O.CC1C=CC(S(O)(=O)=O)=CC=1>CC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[O:21][CH2:20][CH2:19][O:9]2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Yield: 97.8 %

Procedure:
A mixture of (4-chlorophenyl)(4-nitrophenyl)methanone (0.0382 mol), 1,2-ethanediol (0.0764 mol) and 4-methylbenzenesulfonic acid monohydrate 96% (0.19 mol) in methylbenzene (150 ml) was stirred and refluxed in a Dean Stark apparatus for 24 hours. The mixture was washed with K2CO3 (10%) and then with water. The organic layer was dried, filtered off and evaporated. The product was used without further purification, yielding 11.42 g (98%) of 2-(4-chlorophenyl)-2-(4nitro-phenyl)-1,3-dioxolane (interm. 1).
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:41]=[CH:42][CH:43]=1)[CH2:11][N:12]([CH2:20][CH2:21][N:22]1[CH:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:40])[CH:28]=2)[CH2:23]1)C(=O)OC(C)(C)C)(=[O:6])=[O:5])[CH3:3].[H-].[Na+].IC.[C:48](=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:48][N:7]([S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[C:8]1[CH:9]=[C:10]([CH:41]=[CH:42][CH:43]=1)[CH2:11][NH:12][CH2:20][CH2:21][N:22]1[CH:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:40])[CH:28]=2)[CH2:23]1
Reactant: CC(C)S(=O)(=O)Nc1cccc(CN(CCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)C(=O)OC(C)(C)C)c1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N(C)c1cccc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
8.7 mg of tert-butyl 3-(2-propyl sulfonylamino)benzyl-[2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl]carbamate obtained in Example 131-a) was dissolved in 1 mL of THF, and 0.7 mg of sodium hydride was added thereto under ice-cooling, followed by stirring for 15 minutes. 2.6 mg of iodomethane was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction liquid was under ice-cooling, and a saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto. The organic layer was separated, the aqueous layer was further extracted by addition of ethyl acetate, and the organic layer was combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the solvent was removed by evaporation to obtain 10.0 mg of a crude composition. The crude composition was purified by PLC to obtain 6.3 mg (yield 71%) of a desired product.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH3:37])[C:26](O)=[O:27]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([N:32]3[CH:36]=[CH:35][N:34]=[C:33]3[CH3:37])=[C:23]([F:22])[CH:24]=2)[CH2:2][CH2:3]1
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1F
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Product: Cc1nccn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cc1F

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 3-fluoro-4-(2-methyl-imidazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=4.71 min; Mass spectrum (ESI+): m/z=506 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[Cl:27].[H-].C([Al+]CC(C)C)C(C)C.CO>C(Cl)Cl>[Cl:27][C:5]1[CH:6]=[C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:8]=[CH:9][C:4]=1[CH:3]=[O:2].[Cl:27][C:5]1[CH:6]=[C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:17])([F:16])[F:18])[O:12][N:11]=2)[CH:8]=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Product: OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %
Yield: 66 %

Procedure:
To a solution of 2-chloro-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoic acid methyl ester (i.e. the product of Step 1, 2.20 g) in CH2Cl2 was added a solution of diisobutyl aluminium hydride (1 M in CH2Cl2, 10.7 mL) at −78° C. and kept at this temperature for 30 min. MeOH (25 mL) was added carefully and the mixture was allowed to warm to room temp, when aqueous K—Na-tartrate solution was added. The layers were separated and the aqueous phase was extracted with CH2Cl2, combined organic layers were washed with water, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography on silica gel to obtain the title compound (1.35 g, 66%) and 2-chloro-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzyl alcohol (0.49 g, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[N:15][CH:14]=1)(=[O:10])=[O:9].I[CH2:29][CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:12][C:13]1[S:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:19]=2)=[N:15][CH:14]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1cccc(-c2ncc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1cnc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 10, step 3, 2-chloro-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide (example 10, step 2) was reacted with 1-iodo-2-methylpropane and cesium carbonate in N,N-dimethylacetamide to give 2-chloro-N-isobutyl-N-[2-(3-methanesulfonyl-phenyl)-thiazol-5-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 499.0 ([M+H]+)
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:10]([CH2:11][OH:12])[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH2:21][CH2:22][CH3:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:7]2)[C@H:3]1[OH:24].C(N(CC)CC)C.[C:32]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])([CH3:34])[CH3:33]>CN(C1C=CN=CC=1)C.ClCCl>[Si:36]([O:12][CH2:11][C@H:10]1[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH2:21][CH2:22][CH3:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[S:7]2)[C@@H:3]([OH:24])[C@@H:2]1[OH:1])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a stirred solution of tert-butyl (3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(propyl)carbamate (45 g, 124 mmol), DMAP (760 mg, 6 mmol) and triethylamine (25.1 g, 248 mmol) in dichloromethane (300 mL) was added tert-butylchlorodimethylsilane (22.4 g, 149 mmol). After stirred for 6 h at room temperature, the mixture was condensed to provide a residue, which was purified by silica gel column, eluted with 10-30% ethyl acetate in petroleum ether to give compound 17 as a yellow oil (43 g. 65%). (ES, m/z): [M+H]+ 477.1; 1H NMR (300 MHz, CDCl3) δ 6.12-6.14 (d, J=6.3 Hz, 1H), 4.40-4.45 (m, 1H), 3.84-3.96 (m, 4H), 3.64-3.71 (m, 1H), 3.13-3.30 (m, 3H), 1.67-1.74 (m, 2H), 1.53 (s, 9H), 0.93-0.98 (m, 3H), 0.92 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH3:15])[NH:8][CH2:7][CH2:6]2.N1C=CC=CC=1.C(OC(=O)C)(=O)C>>[CH3:15][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:7][N:8]=1
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1OC)C(C)=NCC2
Reaction time: 0.17 h

Procedure:
6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline, conversion>99%, ee 82% (GC, sample derivatised by treatment with acetic anhydride pyridine, Chirasil DEX CB, 25 m×0.25 mm, injector/detector 200° C., helium 20 psi, 170° C. for 20 minutes then ramp at 5° C./min to 200° C., hold for 10 minutes, retention times 30.18 minutes and 30.45 minutes).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].Cl.[O:14]([NH2:16])[CH3:15]>>[CH3:15][O:14][N:16]=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: CON
Reactant: CC(C)Oc1ccccc1C=O
Agent: Cl
Product: CON=Cc1ccccc1OC(C)C

Procedure:
Reaction of 2-isopropoxybenzaldehyde (Hach, Collect. Czech. Commun., 23, 1958, 1902-1907) with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (96% yield). 1HNMR indicated a 95:5 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 1.33 (6H, d, J=6.1 Hz, CH3), 3.97 (3H, s, OCH3), 4.56 (1H, m, CH), 6.90 (2H, m, aromatics), 7.30 (1H, m, aromatic), 7.79 (1H, dd, J=2.0 Hz and J=7.6 Hz, aromatic), 8.47 (1H, s, CH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.N1CCCC1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7](=[CH:20][C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1)[C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCO2
Reactant: O=Cc1cccnc1
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C(=Cc1cccnc1)CO2
Temperature: 25 °C
Reaction time: 60 h
Yield: 57 %

Procedure:
To a 25° C. mixture of 20.0 g (0.112 mol) of 6-methoxy-4-chromanone and 18.09 g (0.169 mol) of 3-pyridinecarbaldehyde in 100 ml of methanol was added 14.1 ml (0.169 mol) of pyrrolidine. The resultant solution was allowed to stir 60 hours at 25° C., cooled to 0° C. and filtered to yield 17.07 g (57%) of the title compound, m.p. 127°-131° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:3].[CH2:14]([Br:19])[CH2:15][CH2:16][CH2:17][CH3:18]>C(OCC)C>[Br-:19].[CH3:1][N+:2]([CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)([CH3:3])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCBr
Reactant: CN(C)CCCc1ccc(Cl)cc1
Solvent: CCOCC
Product: CCCCC[N+](C)(C)CCCc1ccc(Cl)cc1
Product: [Br-]
Temperature: 25 °C

Procedure:
of N,N-dimethyl-3-(4-chlorophenyl)propionamide with diborane provided 16.88 g. of N,N-dimethyl-3-(4-chlorophenyl)propylamine. B.P. 147-148 at 30 torr. A solution of 5.71 g. of the free amine in 150 ml. of diethyl ether was stirred at room temperature while 3.0 g. of n-pentyl bromide was added in one portion. The reaction mixture then was stirred at room temperature for twelve hours, during which time a white precipitate formed. The precipitate was collected by filtration and recrystallized from 125 ml. of methyl ethyl ketone and 10 ml. of methanol to provide N,N-dimethyl-N-n-pentyl-3-(4-chlorophenyl)propylammonium bromide.
Reaction SMILES: [F:1][C:2]([F:19])([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([F:18])=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].C1COCC1.[OH-].[Na+]>CO.O>[F:19][C:2]([F:1])([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([F:18])=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)(F)c1ccc(F)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(F)(F)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of ethyl 2,2-difluoro-2-(4-fluoronaphthyl)acetate (9.6 g, 35.8 mmol), as prepared in the preceding step, in methanol (20 mL) and THF (20 mL) was added a solution of NaOH (2.0 g, 50 mmol) in water (40 mL). The reaction mixture was stirred at room temperature for 2 hours. After evaporating the methanol and THF in vacuo, the aqueous phase was acidified to pH 2 using 10% HCl, and extracted with DCM (3×50 mL). The extracts were combined, washed with brine, dried over Na2SO4, and concentrated to give the title compound (8.1 g, 94% yield) as an off white solid. 1H-NMR (400 MHz, CDCl3) δ 9.68 (br s, 1H), 8.18 (m, 2H), 7.83 (dd, J=8.1, 5.3 Hz, 1H), 7.62 (m, 2H), 7.19 (t, J=8.3 Hz, 1H).
Reaction SMILES: C[Si]([CH:5]([S:8][CH3:9])[S:6][CH3:7])(C)C.CCCCCC.C([Li])CCC.[CH:21]1[CH:26]=[CH:25][C:24]([C:27]([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=O)=[CH:23][CH:22]=1.[Cl-].[Na+]>O1CCCC1>[CH3:7][S:6][C:5]([S:8][CH3:9])=[C:25]([C:24]1[CH:23]=[CH:22][C:30]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:29][CH:27]=1)[CH2:26][CH3:21]
Reactant: O=C(CCOc1ccccc1)c1ccccc1
Reactant: CSC(SC)[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=C(SC)SC)c1ccc(Oc2ccccc2)cc1
Temperature: -73 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Trimethylsilyl-bis(methylthio)methane, 2.65 g, was dissolved in 15 ml of tetrahydrofuran and 7 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow under ice cooling. The mixture was stirred at the same temperature for 30 minutes. After cooling to -73° C., a solution of 2.26 g of 4-phenoxypropiophenone in 5 ml of tetrahydrofuran was dropwise added to the mixture. Then, the temperature was gradually elevated to room temperature followed by stirring for 16 hours. After saturated sodium chloride aqueous solution was added to the mixture, it was extracted with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform : hexane =1 : 1) to give 3.04 g of the oily product.