Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)C.[F:6][C:7]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])C=1N.C(=O)([O-])[O-].[K+].[K+].CI>O>[F:6][C:7]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:4]=1[NH:2][CH3:1]
Reactant: CN(C)C=O
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CNc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a DMF solution (50 mL) of 2,3-difluoro-6-nitroaniline (3.0 g) were added potassium carbonate (14.3 g), and methyl iodide (3.23 mL), and the mixture was stirred at 50° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.66 g).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([F:21])[CH:12]=1)=[O:10])C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:21][C:13]1[CH:12]=[C:11]([CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:9]([OH:10])=[O:8]
Reactant: COC(=O)c1ccc(C(=O)OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.7 %

Procedure:
Catalytic amount of 10 wt % palladium carbon was added to a solution of methyl 4-benzyloxycarbonyl-2-fluorobenzoate (35.4 mg, 0.123 mmol) in ethanol (2 mL), and the mixture was stirred overnight at room temperature under hydrogen atmosphere. After completion of the reaction, the mixture was filtered through celite and the filtrate was concentrated to obtain 26.0 mg of the desired product as a colorless solid (yield 100%).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[CH3:17][S:18]SC.O>O1CCCC1>[CH3:6][O:7][C:8]1[C:16]2[O:15][C:14]([S:18][CH3:17])=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc2ccoc12
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2cc(SC)oc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.6M in hexanes, 10.2 ml) was added dropwise to a cooled (-78° C.) solution of 7-methoxybenzofuran (2.0 g) in tetrahydrofuran (40 ml) under an inert atmosphere. Methyl disulfide (1.46 ml) was added and the reaction mixture was stirred at -78° C. for 30 minutes, then at room temperature for 1 h. Water was added and the tetrahydrofuran was removed in vacuo. The aqueous residue was extracted with ether (3×100 ml) and the combined organic phases were washed with water (100 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford the title compound as a yellow oil (2.73 g).
Reaction SMILES: CC(C)([O-])C.[Na+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:48]1[CH:56]=[C:55]2[C:51]([C:52]3([CH2:69][O:68][C:67]([CH3:71])([CH3:70])[O:66][CH2:65]3)[C:53](=[O:64])[N:54]2C(OC(C)(C)C)=O)=[CH:50][CH:49]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:70][C:67]1([CH3:71])[O:66][CH2:65][C:52]2([C:51]3[C:55](=[CH:56][C:48]([N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)=[CH:49][CH:50]=3)[NH:54][C:53]2=[O:64])[CH2:69][O:68]1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(COC(C)(C)OC2)c2ccc(Br)cc21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC1(C)OCC2(CO1)C(=O)Nc1cc(N3CCOCC3)ccc12
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
To a microwave vessel was added sodium tert-butoxide (0.19 g, 1.99 mmol), morpholine (0.13 mL, 1.49 mmol), XPhos (0.095 g, 0.20 mmol), Pd2(dba)3 (0.091 g, 0.099 mmol), and tert-butyl 6′-bromo-2,2-dimethyl-2′-oxospiro[[1,3]dioxane-5,3′-indoline]-1′-carboxylate (0.41 g, 0.99 mmol) in 1,4-dioxane (9.9 mL). The mixture was deoxygenated with argon for 5 min and stirred at 110° C. for 90 min under microwave irradiation. The resulting mixture was purified by column chromatography (eluting with a gradient of 10-70% EtOAc in hexanes) to give 2,2-dimethyl-6′-morpholinospiro[[1,3]dioxane-5,3′-indolin]-2′-one as a white solid. Mass Spectrum (ESI) m/e=319.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]=1)=[O:5])[CH3:2]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NCCc2cc(OC)c(OC)cc21
Agent: [Pd]
Product: CCOC(=O)c1nccc2cc(OC)c(OC)cc12
Yield: 95.7 %

Procedure:
To a refluxing solution of 2.0 g (8.0 mmol) of 6,7-dimethoxy-3,4-dihydro-isoquinoline-1-carboxylic acid ethyl ester was added to 2.0 g of 10% Pd-C. After 12 h at reflux, the reaction mixture was cooled, filtered through celite, and evaporated under reduced pressure to provide 2.0 g (98%) of 6,7-dimethoxy-isoquinoline-1-carboxylic acid ethyl ester. LCMS: 262 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:17])=[N:11][C:12](I)=[CH:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[C:18]([NH2:21])(=[O:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([NH:21][C:18](=[O:20])[CH3:19])=[N:11][C:10]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: CC(N)=O
Reactant: Cc1cc(I)nc(C)c1Oc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(C)c(Oc2ccnc(Cl)c2)c(C)n1
Temperature: 85 °C
Yield: 51 %

Procedure:
A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-iodo-2,4-dimethylpyridine (1.45 g, 4.02 mmol), acetamide (950 mg, 16.09 mmol), Cs2CO3 (1.965 g, 6.03 mmol) and X-phos (96 mg, 0.201 mmol) in dioxane (25 mL) was sparged with Ar, treated with Pd2(dba)3 (184 mg, 0.201 mmol), sparged again with Ar and heated at 85° C. overnight. The mixture was cooled to RT, diluted with EtOAc and the solids removed via filtration through diatomaceous earth. The filtrate was washed with water, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(5-((2-chloropyridin-4-yl)oxy)-4,6-dimethylpyridin-2-yl)acetamide (598 mg, 51%). 1H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1 H), 8.26 (d, J=5.8 Hz, 1 H), 7.94 (s, 1 H), 6.99 (d, J=2.3 Hz, 1 H), 6.85 (dd, J=5.8, 2.3 Hz, 1 H), 2.17 (s, 3 H), 2.06 (d, J=1.7 Hz, 6 H); MS (ESI) m/z: 292.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[C:23]([CH3:24])=[C:22](/[CH:25]=[C:26]3\[C:27](=[O:47])[NH:28][C:29]4[C:34]\3=[CH:33][C:32]([S:35]([CH2:38][C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:46])(=[O:37])=[O:36])=[CH:31][CH:30]=4)[NH:21][C:20]=2[CH3:48])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[C:23]([CH3:24])=[C:22](/[CH:25]=[C:26]3\[C:27](=[O:47])[NH:28][C:29]4[C:34]\3=[CH:33][C:32]([S:35]([CH2:38][C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:46])(=[O:37])=[O:36])=[CH:31][CH:30]=4)[NH:21][C:20]=2[CH3:48])=[O:18])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[2-({5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (370 mg, 0.52 mmol) and TFA (3 mL) in DCM (20 mL) was stirred at rt for overnight. The reaction was concentrated and purified to give 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-piperazin-1-yl-ethyl)-amide.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:4][CH:5]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cn1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The crude 1-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline was dissolved in CH2Cl2 (1.0 mL) and 1-fluoro-4-isocyanatobenzene (32 μL, 273 μmol) was added. The reaction was stirred 17 h under N2 at RT. The reaction was directly purified by HPLC to give N-(4-fluorophenyl)-1-(6-(trifluoromethyl)-pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 416 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][CH2:8][S:7][C:6]=2[CH:23]=1.I.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](SC)=[NH:31].C([O-])(O)=O.[Na+]>C(O)C>[CH3:22][N:14]([CH2:13][CH2:12][CH2:11][N:10]1[CH2:9][CH2:8][S:7][C:6]2[CH:23]=[C:2]([NH:1][C:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)=[NH:31])[CH:3]=[CH:4][C:5]1=2)[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20]
Reactant: CSC(=N)c1cccs1
Reactant: CN(CCCN1CCSc2cc(N)ccc21)C(=O)OC(C)(C)C
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(CCCN1CCSc2cc(NC(=N)c3cccs3)ccc21)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
A solution of tert-butyl 3-(7-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)propyl(methyl)carbamate (0.52 g, 1.541 mmol) in dry ethanol (20 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.879 g, 3.08 mmol) at room temperature and stirred over night (18 hours). The reaction was basified with saturated NaHCO3 solution (50 mL), and the product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (2:98 (2 M NH3 in MeOH):CH2Cl2) on silica gel to obtain the title product (0.60 g, 87%) as a solid. ESI-MS (m/z, %): 447 (MH+, 100).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[CH3:28][C:25]([CH3:29])([CH2:24][CH2:23][CH2:22][CH2:21][O:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1)[C:26]#[N:27]
Reactant: CC(C)(C#N)CCCCBr
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C#N)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
The procedure in Example 4 is followed but using 4,6-diphenyl-2-pyridinone (6.3 g)0 6-bromo-2,2-dimethylhexanonitrile (2.60 g) (prepared according to the method of M. Larcheveque et al., Bull. Soc. Chim. Fr., 1710 (1974)), silver carbonate (3.5 g) and toluene (300 cc). The product is purified by chromatography under pressure on silica gel (30-60 mm); eluent: n-hexane-ethyl acetate 9.5-0.5).yellowish solid. (m.p.=71° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH2:20][CH2:21][C:22]([O:24]CCCCCCCC)=[O:23])[CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=3[OH:15])[N:8]=[C:4]2[CH:3]=1.[OH-].[Na+].Cl>CC(C)=O>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:12]=[C:13]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:14]=3[OH:15])[N:8]=[C:4]2[CH:3]=1
Reactant: CCCCCCCCOC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(Cl)cc3n2)c1O
Reaction time: 24 h

Procedure:
225 g (0.46 mol) of octyl 3-(5-chloro-2H-benzotriazole-2-yl)-5-(1,1-dimethylethyl)-4-hydroxy-benzene propanate manufactured by CIBA GEIGY INC. under the trade name of "TINUVIN 109" were dissolved in 700 ml of acetone. To the resulting solution were added 600 ml of a 2N aqueous solution of sodium hydroxide followed by agitation at room temperature for 24 hours. Then, 650 ml of a 2N aqueous solution of hydrochloric acid was added to give an acidic solution and an insolubilized product was filtered off and rinsed with distilled water until the filtrate turned neutral. After vacuum-drying the product, it was recrystallized from toluene to give 3-(5-chloro-2H-benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxy benzene propanoic acid, referred to hereinafter as a precursor (3).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C:15]1[CH:16]=[C:17]([CH2:25][CH2:26][NH2:27])[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:27][CH2:26][CH2:25][C:17]2[CH:18]=[CH:19][C:20]([C:21]([F:22])([F:23])[F:24])=[C:15]([F:14])[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(C(F)(F)F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
1 ml of 4-tert-butylbenzaldehyde (6.16 mmol), 1 g of 2-(3-fluoro-4-trifluoromethyl-phenyl)-ethylamine hydrochloride (4.1 mmol) and 567 mg of potassium carbonate (4.1 mmol) were suspended in 12 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 3.5 h. After cooling down to rt, 233 mg (6.16 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 0.8 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:6 then 1:4) to give 1.156 g light yellow oil (79%). MS (ISP) 354.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl.O.[OH-].[K+]>C(O)C.Cl>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C=NCC2
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)C=NCC2
Temperature: 60 °C
Yield: 88.5 %

Procedure:
7-Nitro-3,4-dihydroisoquinoline (0.60 g, 3.4 mmol) [prepared according to the procedure of A. P. Venkov et al, Syn. Commun., 1996 26 127] was dissolved in ethanol (100 ml) and heated to 60° C. This hot solution was treated with a solution of tin (II) chloride dihydrate (3.08 g, 13.7 mmol) in conc. HCl (10 ml). The resultant mixture was heated at 60° for 1 h. Upon cooling, the reaction mixture was poured into water (100 ml) and basified (pH 9) with KOH pellets, liberating an oily residue. This residue was extracted into dichloromethane and dried over magnesium sulfate. Purification by chromatography through silica gel, eluting with (0.5% conc. ammonia: 4.5% methanol: 95% dichloromethane) yielded the title compound as a dark yellow oil (0.44 g, 88%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:32])[CH2:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH2:32])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCCCCCN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCCCN)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and pentane-1,5-diamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CDCl3) δ ppm 7.96 (d, J=7.6 Hz, 1 H), 7.54 (d, J=6.8 Hz 1 H), 7.42 (m, 2 H), 7.30 (d, J=6.4 Hz, 1 H), 7.21 (m, 2 H), 5.81 (s, 1 H), 5.03 (s, 2 H), 4.61 (m, 2 H), 3.49 (brs, 2 H), 3.19 (m, 2 H), 2.71 (d, J=6.40 Hz, 2 H), 2.94 (m, 2 H), 2.34 (s, 3 H), 1.61 (s, 2 H), 1.49 (m, 4 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]Cl.[N:13]1([C:19]([S:21][CH3:22])=[S:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][N:16]1[CH2:17][CH2:18][N:13]([C:19]([S:21][CH3:22])=[S:20])[CH2:14][CH2:15]1
Reactant: COc1ccc(CCl)cc1OC
Reactant: CSC(=S)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CN2CCN(C(=S)SC)CC2)cc1OC
Yield: 14.9 %

Procedure:
In a nitrogen atmosphere, 5.615 g (30.08 mmol.) of 3,4-dimethoxybenzyl chloride, 5.57 g (30.08 mmol., purity 95%) of methyl 1-piperazinecarbodithioate, 3.19 g (30.08 mmol.) of anhydrous sodium carbonate and 50 ml of ethanol were mixed and refluxed under heating for 5.5 hours. The solvent was distilled off under reduced pressure. To the residue were added 20 ml of dichloromethane and 20 ml of water. The organic solvent portion was taken out and washed with 30 ml of 1-N hydrochloric acid. To the organic portion was added 1-N aqueous sodium hydroxide solution. The organic solvent portion was again taken out and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. To the residue was added 20 ml of ethanol. Precipitated crystals were collected by filtration and washed with ethanol to give 1.465 g of methyl 4-(3,4-dimethoxybenzyl)-1-piperazinecarbodithioate, yield 14.9%.
Reaction SMILES: [CH:1]([O:3][CH:4]1[CH2:9][CH:8]2[CH2:10][CH:5]1[CH:6]=[CH:7]2)=[O:2].[CH:11]([CH:13]=[CH2:14])=[O:12]>>[CH:1]([O:3][CH:4]1[CH:5]2[CH2:10][CH:8]([CH:7]3[CH:6]2[O:12][CH:11]=[CH:13][CH2:14]3)[CH2:9]1)=[O:2]
Reactant: O=COC1CC2C=CC1C2
Reactant: C=CC=O
Product: O=COC1CC2CC1C1OC=CCC21
Yield: 49 %

Procedure:
248 g of 5-norbomene-2-yl formate and 33.6 g of acrolein were reacted in the same manner asin Examplel1-1to synthesize adesired product. As aresult, 57 g of 3-oxa-tricyclo[6.2.1.02,7]undec-4-ene-10-yl formate was obtained.
Reaction SMILES: [O:1]=[C:2]([C@H:23]([CH3:61])[C@@H:24]([O:52][C:53]([O:55][CH2:56][C:57]([Cl:60])([Cl:59])[Cl:58])=[O:54])[C@@H:25]([CH3:51])[CH2:26]/[CH:27]=[CH:28]/[C:29](/[CH3:50])=[CH:30]\[CH2:31][C@H:32]([O:42][Si](CC)(CC)CC)/[C:33](/[CH3:41])=[CH:34]/[C:35]1[N:36]=[C:37]([CH3:40])[S:38][CH:39]=1)[C:3]([CH3:22])([CH3:21])[C@@H:4]([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O.Cl.P([O-])([O-])([O-])=O>C(Cl)Cl.C(OCC)(=O)C>[O:1]=[C:2]([C@H:23]([CH3:61])[C@@H:24]([O:52][C:53]([O:55][CH2:56][C:57]([Cl:58])([Cl:59])[Cl:60])=[O:54])[C@@H:25]([CH3:51])[CH2:26]/[CH:27]=[CH:28]/[C:29](/[CH3:50])=[CH:30]\[CH2:31][C@H:32]([OH:42])/[C:33](/[CH3:41])=[CH:34]/[C:35]1[N:36]=[C:37]([CH3:40])[S:38][CH:39]=1)[C:3]([CH3:21])([CH3:22])[C@@H:4]([O:13][Si:14]([CH2:19][CH3:20])([CH2:15][CH3:16])[CH2:17][CH3:18])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC[Si](CC)(CC)O[C@@H](C/C=C(C)\C=C\C[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)OC(C)(C)C)O[Si](CC)(CC)CC)/C(C)=C/c1csc(C)n1
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@@H](CC(=O)O)C(C)(C)C(=O)[C@H](C)[C@@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C/C=C/C(C)=C\C[C@H](O)/C(C)=C/c1csc(C)n1
Reaction time: 10 h

Procedure:
A solution of tert-butyl (3S,6R,7S,8S,10E,12Z,15S,16E)-5-oxo-3,15-bis(triethylsilyloxy)-17-(2-methylthiazol-4-yl)-4,4,6,8,12,16-hexamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-heptadeca-10,12,16-trienoate (2.38 g) in 12 mL of CH2Cl2 is treated with 2,6-lutidine (0.86 mL) and triethylsilyl trifluoromethanesulfonate (0.98 g) at 0° C. for 30 minutes, then at ambient temperature for 10 hours. The mixture is diluted with 50 mL of ethyl acetate and poured into 20 mL of 1 N HCl. The organic phase is separated, washed with pH 7 phosphate buffer, dried with Na2SO4, filtered, and concentrated. The residue is dissolved in 5 mL of THF and treated with 0.5 mL of 0.1 N HCl in methanol. The reaction is monitored by thin-layer chromatography, with additional aliquots of methanolic HCl being added to achieve complete reaction. When complete, the reaction is poured into 15 mL of pH 7 phosphate buffer and extracted with ethyl acetate. The extract is washed with brinei dried with Na2SO4, filtered, and evaporated. The product is purified by flash chromatography on SiO2 (1:1 hexanes/ethyl acetate).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([OH:20])[CH2:9]2)=[CH:3][CH:2]=1.[CH3:27][CH2:28][OH:29]>Cl.Cl.CCO>[CH2:28]([O:29][C:11](=[O:19])[C@H:10]([OH:20])[CH2:9][C@H:8]([NH2:12])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:6][CH:5]=1)[CH3:27]
Reactant: CC(C)(C)C(=O)N1C(=O)[C@H](O)C[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
(3R,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-hydroxypyrrolidin-2-one (56 g, 0.156 mol) was dissolved in EtOH (700 mL) and 12N HCl (700 mL). The mixture was heated to 90˜95° C. for 20 hours. The mixture was concentrated on an 80° C. water bath under reduced pressure. EtOH (100 mL) was added to the residue, and the resulting mixture was filtered to yield a yellow solid. This solid was suspended in 3N HCl/EtOH (800 mL). The mixture was refluxed for 3 hours. The solution was concentrated to a reduced volume (˜200 mL volume), and ether (200 mL) was added. The resulting slightly yellow solid was filtered and dried under reduced pressure to yield (2R,4R)-4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (43 g).
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.C(=O)([O-])[O-].[Ca+2].[CH2:24]([OH:27])[CH2:25][CH3:26].O>C1COCC1>[CH2:24]([O:27][CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2)[CH2:25][CH3:26]
Reactant: O=C1c2cccc(Cl)c2C(Br)c2cccc(Cl)c21
Reactant: CCCO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: CCCOC1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21

Procedure:
To a solution of compound (6) (2.0 mmol) and anhydrous calcium carbonate (0.5 g) in dry THF (20 ml) was added dropwise a solution of an appropriate propanol (10 ml) in dry THF (10 ml) under N2. The reaction mixture was refluxed for 3 hours. Water (250 ml) was added and then extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO4), and concentrated. The resulting precipitate was collected by filtration, washed with water and further purified by crystallization (CH3CN).