Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].[C:16]([O-])([O-])=O.[K+].[K+].O.CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH3:16]
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: CSC(=NC(C)=O)Nc1c(Cl)cccc1Cl
Reaction time: 5 h

Procedure:
26.3 g (0.1M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 9.9 g (0.06M) of ground 2 K2CO3.3 H2O, 8.3 ml (0.13M) of methyliodide and 200 ml of acetone are put to boil and are energetically shaken for 5 hours. The acetone is distilled off and the residue is washed with water and filtered. The sediment on the filter is washed once or twice more with water. After drying the product is boiled in a reflux with isopropanol 1:6, weight:volume) and is filtered. From the filtrate 22.0 g of N-(2,6-dichloro-phenyl)-N'-acetyl-S-methylisothiourea (79.4% of the theoretical yield), melting point 137° to 140° C. are isolated.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2(CC=O)[CH2:12][N:13](C(OC(C)(C)C)=O)[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.NC1C=CC=CC=1.CCN(S(F)(F)F)CC.[C:40](O)([C:42]([F:45])(F)[F:43])=O>C(Cl)Cl>[F:43][CH:42]([F:45])[CH2:40][C:10]12[CH2:12][NH:13][C:8]3[C:9]1=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3][C:2](=[O:1])[CH2:11]2
Reactant: CC(C)(C)OC(=O)N1CC2(CC=O)CC(=O)Nc3cccc1c32
Reactant: O=C(O)C(F)(F)F
Agent: CCN(CC)S(F)(F)F
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: O=C1CC2(CC(F)F)CNc3cccc(c32)N1
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 4-oxo-2a-(2-oxoethyl)-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-carboxylate, enantiomer A, (150 mg, 0.474 mmol, described in Intermediate 24) in CH2Cl2 (2 mL) at 0° C. was added DAST (0.125 mL, 0.948 mmol) and the mixture was stirred for 1 h. Additional DAST (0.066 mL) was added and the mixture was stirred for 1 h. To the resulting mixture was added TFA (2 mL) and stirring was continued for 1 h. The mixture was concentrated in vacuo and partitioned between saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (10 mL). The layers were separated and the aqueous layer further extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=239 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][C:19](=[O:31])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O>CN(C)C=O.[Ni]>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:33][CH:32]=2)=[O:31])=[CH:27][CH:26]=1
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCOCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1ccc(OCC(=O)OCCOCCOC(=O)COc2ccc(N)cc2)cc1
Reaction time: 3 h
Yield: 81.9 %

Procedure:
(4-nitrophenoxy)-acetic acid 2-{2-[2-(4-nitrophenoxy)-acetoxy]-ethoxy}-ethyl ester (600 g) was dissolved in dimethylformamide (1.8 l) in a pressure vessel. Raney Nickel (800 grams) added and the mixture was stirred under an atmosphere of hydrogen (20 Kg) for 3 hours. The catalyst was removed by filtration and the solution was added to cold water to precipitate the crude product. The product was filtered off, slurried in methanol and re-filtered. The compound was dried to give pure (4-aminophenoxy)-acetic acid 2-{2-[2-(4-aminophenoxy)-acetoxy]-ethoxy}-ethyl ester (428 grams) as off-white powder with a melting point of 95-97° C. The product was characterized by 1H NMR (CDCl3) δ 3.10 (bs, 2H, NH2), 3.70 (t, 2H, CH2), 4.35 (t, 2H, CH2), 4.55 (s, 2H, CH2), 6.60 (d, 2H, Ar), 6.75 (d, 2H, Ar).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])=[CH:6][C:5]=1[F:21])=[N+:2]=[N-:3].[CH2:22]([O:24][CH:25]([O:28][CH2:29][CH3:30])[C:26]#[CH:27])[CH3:23]>C1C=CC=CC=1>[F:21][C:5]1[CH:6]=[C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:8]=[CH:9][C:4]=1[N:1]1[CH:27]=[C:26]([CH:25]([O:28][CH2:29][CH3:30])[O:24][CH2:22][CH3:23])[N:3]=[N:2]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N=[N+]=[N-])c(F)c2)C(=O)O1
Reactant: C#CC(OCC)OCC
Solvent: c1ccccc1
Product: CCOC(OCC)c1cn(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)nn1
Yield: 81.8 %

Procedure:
A solution of 1.70 g (5.8 mmol) of the azide of example 17 in 50 mL benzene was treated with 4.46 g (34.8 mmol) of 1,1-diethoxy-2-propyne followed by warming at reflux for 18 h. The solution was treated with 1.0 g (7.80 mmol) of 1,1-diethoxy-2-propyne followed by warming at reflux for an additional 3 h. The solution was cooled and concentrated in vacuo to afford an oil which was chromatographed over 200 g of 230-400 mesh silica gel, eluting with 2-3% (v/v) methanol in dichloromethane to afford 2.0 g (80%) of (S)-N-[[3-[3-Fluoro-4-(4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)phenyl]-2-oxo-5-oxazoldinyl]methyl]acetamide and (S)-N-[[3-[3-Fluoro-4-(5-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)phenyl]-2-oxo-5-oxazoldinyl]methyl]acetamide as an inseparable mixture of isomers. Of this material, 410 mg (0.973 mmol) was dissolved in 10 mL THF and treated with 1 mL of 1N HCl solution followed by stirring at ambient temperature for 48 h, and then warming at reflux for 1 h. The mixture was dissolved in ethyl acetate and extracted with water. Drying (Na2SO4) and concentration in vacuo afforded an oil which was subjected to radial chromatography on a 2 mm chromatotron plate eluting with 7% (v/v) methanol in dichloromethane. The less polar fraction [110 mg (33%)] from the chromatography proved to be the title compound, isolated as a white solid. 1H NMR (CDCl3) δ 8.60, 7.99, 7.85, 7.36, 6.1, 4.86, 4.12, 3.89, 3.72, 2.04.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>>[NH2:19][CH:20]1[CH2:24][CH2:23][N:22]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:21]1
Reactant: Clc1ccccc1OCCOc1nccnc1Cl
Reactant: NC1CCNC1
Product: NC1CCN(c2nccnc2OCCOc2ccccc2Cl)C1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(2-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0.53 mmol) and 3-aminopyrrolidine (252 mg, 2.92 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 100 mg (56%) of the title product. Anal. (C16H19ClN4O2) C, H; N: calcd, 16.73; found, 16.0.
Reaction SMILES: C[O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[O:16][C:11]1([CH2:14][N:13]([CH3:15])[CH2:12]1)[CH2:10][C:9]2=[O:20].Cl>CC(O)=O>[CH3:15][N:13]1[CH2:12][C:11]2([CH2:10][C:9](=[O:20])[C:8]3[C:17](=[CH:18][CH:19]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:21])=[O:2])[CH:7]=3)[O:16]2)[CH2:14]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: CN1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Yield: 95.7 %

Procedure:
(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester (410 mg, 1.53 mmol) was hydrolyzed with AcOH (10 ml) and aqueous 20% HCl (10 ml) following the procedure described in Example 31, Step B, giving (E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (400 mg, hydrochloride salt) as a pale yellow oil.
Reaction SMILES: CS([O:5][CH2:6][C:7]([CH3:18])([CH3:17])[CH2:8][NH:9]C(OC(C)(C)C)=O)(=O)=O.[N:19]1[N:20]=[C:21]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[C:31](O)[CH:32]=[C:33]([F:38])[CH:34]=3)[N:29]=2)[N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=12>>[N:19]1[N:20]=[C:21]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[C:31]([O:5][CH2:6][C:7]([CH3:17])([CH3:18])[CH2:8][NH2:9])[CH:32]=[C:33]([F:38])[CH:34]=3)[N:29]=2)[N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=12
Reactant: CC(C)(CNC(=O)OC(C)(C)C)COS(C)(=O)=O
Reactant: Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12
Product: CC(C)(CN)COc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12

Procedure:
The desired product was prepared as described in Example 25 using 3-(tert-butoxycarbonylamino)-2,2-dimethylpropyl methanesulfonate in place of (cis)-tert-butyl-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate, and 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol in place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol. MS ESI (+) m/z 366 (M+1) detected.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[Br-].[Li+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN1CCCC1=O>[NH2:1][CH:2]([CH2:3][OH:4])[C:5]([O:7][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: N[C@@H](CO)C(=O)O
Reactant: BrCc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: NC(CO)C(=O)OCc1ccccc1

Procedure:
In a similar manner 1.09 grams (0.0105 mole) of serine, 1.76 grams (0.02 mole) of lithium bromide, 2.02 grams (0.0118 mole) of benzyl bromide and 16 grams of N-methylpyrrolidinone were stirred together at 25° C. for 16 hours and at 50° C. for 3 hours to obtain the desired benzyl α-amino-β-hydroxypropionate product. High pressure liquid chromatographic assay indicated a 86 percent yield of the desired product.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16]C2C=CC=CC=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:54][OH:55])CO)C1C=CC=CC=1.F[C:57](F)(F)[C:58](O)=O.C(=O)(O)[O-].[Na+].O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:58]2[CH:57]=[CH:54][CH:10]=[CH:9][CH:14]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:11][C@@:10]1([CH2:54][OH:55])[CH2:32][O:31]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 102.3 %

Procedure:
To a solution of [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl) methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 23m (3.30 g, 4.26 mmol) in dichloromethane (70 mL) was added trifluoroacetic acid (1.26 mL, 17.03 mmol) at 0° C. The mixture was warmed up to room temperature and stirred for 12 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate to pH 7 and 40 mL of water was added, and then the mixture was partitioned. The aqueous layer was extracted with dichloromethane (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 23n as yellow oil (1.62 g, 50%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.36 (m, 13H), 7.20 (m, 3H), 6.92 (m, 2H), 6.66 (m, 1H), 6.53 (m, 1H), 4.88 (m, 3H), 4.78 (d, 1H), 4.31 (m, 2H), 4.06 (m, 5H), 3.98 (d, 1H), 3.89 (d, 1H), 3.83 (d, 1H), 3.72 (m, 3H), 1.45 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH:21]1[CH2:24][CH2:23][CH2:22]1)([C:16](OCC)=[O:17])[C:11](OCC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>CCOCC>[CH2:1]([O:8][CH2:9][C:10]([CH:21]1[CH2:24][CH2:23][CH2:22]1)([CH2:11][OH:12])[CH2:16][OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(COCc1ccccc1)(C(=O)OCC)C1CCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: OCC(CO)(COCc1ccccc1)C1CCC1
Reaction time: 8 h
Yield: 103 %

Procedure:
A solution of diethyl 2-benzyloxymethyl-2-cyclobutylmalonate (65 g, 0.19 mol) in dry ether (50 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (11.5 g, 0.3 mol) in dry ether (200 ml) at 0° C. under a nitrogen atmosphere. After the addition, the solution was heated to gentle reflux for 1 hour, allowed to cool and an excess of saturated aqueous ammonium chloride was added. Stirring was continued overnight and the resulting mixture was filtered and the solids washed with ether. The filtrate was extracted with ether, the ether extracts were combined, dried over anhydrous magnesium sulphate and evaporated to leave 2-benzyloxymethyl-2-cyclobutylpropane-1,3-diol (49 g) as an oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[C:25](Cl)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1COCC1>[C:25]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(S)-benzyloxazolidin-2-one (56 mmol) (Aldrich, Milwaukee, Wis.) in THF at −78° C. was added 2.5 M n-BuLi in hexane (22.4 mL, 56 mmol) and the reaction stirred at −78° C. for 2 hr. To this was added via cannula a −78° C. solution of hexanoyl chloride (65 mmol) in THF and the mixture stirred at −78° C. for 2 hr, then allowed to warm to room temperature and stirred overnight. The reaction was then quenched with aqueous saturated NH4Cl, extracted with ethyl acetate, dried, and purified by silica gel chromatography (hexanes/ethyl acetate) to afford N-hexanoyl-4-(S)-benzyloxazolidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=1.[Cl:17][C:18]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:19]=1[CH2:20][NH:21][CH2:22][C@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:21]([CH2:20][C:19]2[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:36])([F:37])[F:38])[C:18]=2[Cl:17])[CH2:22][C@H:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:24])[CH:6]=1
Reactant: C[C@H](CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Reactant: COC(=O)Cc1cccc(OCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)C[C@@H](C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
A solution of (3-{3-bromo-propoxy}-phenyl)acetic acid methyl ester (0.55 g, 1.5 mmol) and (S)-(2-Chloro-3-trifluoromethyl-benzyl)-(2-phenyl-propyl)-amine (0.55 g, 1.6 mmol) in acetonitrile (10 ml) was treated with solid potassium carbonate(0.4 g, 2.4 mmol). The reaction was heated to reflux and stirred for 48 h. Upon cooling to RT, the reaction was filtered through a pad of celite, washed with ethyl acetate, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatograph (Ethyl acetate:Hexane/20:80) to give the title compound as an oil (0.6 g, 67%). MS (ESI) 534.6 (M+H)+.
Reaction SMILES: [S:1]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@H:2]1[O:10][C@@H:9]([CH3:11])[C@@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1.[OH-].[Na+].CO>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:4][C@H:3]2[C@H:5]([O:6][CH2:18][C:19]3[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=3)[C@H:7]([O:8][CH2:18][C:19]3[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=3)[C@H:9]([CH3:11])[O:10][C@@H:2]2[S:1][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:21][CH:20]=1
Reactant: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: Cc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(CO[C@@H]2[C@H](OCc3ccc(C)cc3)[C@H](C)O[C@H](Sc3ccccc3)[C@H]2OCc2ccc(C)cc2)cc1
Yield: 29.5 %

Procedure:
3.0 g (11.9 mmol) of compound of example 9 and 1.22 g (3.6 mmol, 0.3 eq.) tetrabutylammonium hydrogen sulphate is suspended in 20 ml of dichloromethane. The suspension is refluxed, under vigorous stirring, until a homogenous solution is obtained. To this solution p-methylbenzyl chloride (7.23 ml, 53.6 mmol, 4.5 eq) followed by 5 ml of 50% (w/w) NaOH solution are added. The thick emulsion is refluxed for 3 hours while vigorously stirred, then 8 ml of MeOH are added and the reaction mixture is additionally refluxed for one night. After cooling DCM and water are added. The phases are separated and the aqueous phase is washed with DCM. The combined organic phases are washed with brine and the solvents are evaporated. The crude product is purified by column chromatography. The purest fractions are collected and the product is recrystallized from MeOH to yield 2.0 g of white solid. M.p.: 84-85° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([CH2:16][CH3:17])([CH3:15])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:16]([C:10]1([CH3:15])[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:17]
Reactant: [H][H]
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCCC1O

Procedure:
A mixture of 1-benzyl-3-ethyl-4-hydroxy-3-methylpiperidine (1.1 g, 4.74 mmole) and 20% palladium hydroxide (0.4 g) in methanol (20 ml) was stirred at ambient temperature in hydrogen atmosphere (1 atm.) for 20 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3-ethyl-4-hydroxy-3-methylpiperidine as oil. Yield 0.6 g (90%), C8H17NO, m/z 144 (M+1), PMR (CDCl3): 0.7-1.06 (6H, m, 2×CH3), 1.24-2.0 (5H, m, CH2, H5, NH & OH, NH & OH D2O exchangeable), 2.3 (1H, m, H5), 2.62-3.18 (2H, m, H2), 3.3-3.8 (3H, m, H4 & H6).
Reaction SMILES: [Cl:1]C1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:36]=[CH:35][C:16]([CH2:17][S:18][CH:19]([S:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[CH:15][CH:14]=1.CCOCC.Cl>C(Cl)(Cl)Cl>[ClH:1].[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][S:18]([CH:19]([S:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[O:9])=[CH:35][CH:36]=1
Reactant: Cc1ccc(CSC(Cn2ccnc2)SCc2ccc(C)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(CSC(Cn2ccnc2)S(=O)Cc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 85% m-chloroperbenzoic acid (1.66 g, 9.63 mmoles) in chloroform (80 ml) was added dropwise during 1 hour to a stirred, cooled (ice/water) solution of 1-[2,2-bis(4-methylbenzylthio)ethyl]-1H-imidazole (3.55 g, 9.63 mmoles) in chloroform (125 ml). The solution was stirred for 18 hours at ambient temperature and then washed successively with aqueous Na2CO3 (2×), H2O and brine. The solution was dried over Na2SO4 and concentrated to leave a mixture of the diastereoisomeric mono-sulfoxides as a cloudy oil. Trituration of the oil with ether afforded the free base of diastereomer A (1.45 g), mp 86°-92° which was converted into the hydrochloride salt, mp 167°-170° with ethereal hydrogen chloride. Hydrogen chloride was bubbled into the ethereal mother liquor from the trituration step to give a mixture of the hydrochloride salts which after recrystallization from acetonitrile provided additional diastereomer A, mp 164°-168° (0.42 g) and 0.57 g of diastereomer B, mp 141°-146°.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1)=O.[O:18]=[C:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:18]=[C:19]1[CH2:24][CH2:23][S:22][CH2:21][C:20]1=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C1CCSCC1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C(=O)OC(C)(C)C)c1ccc(C=C2CSCCC2=O)cc1
Yield: 20.1 %

Procedure:
To a solution of tert-butyl 2-(4-formylphenyl)propionate (2.0 g), 4-oxothiane (1.2 g) and piperidine (1.0 ml) in toluene (10.0 ml) was added acetic acid (2.0 ml) at room temperature, and then the mixture was refluxed by heating for 3 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the title compound (570 mg, 20%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.[H-].[Na+].[C:25]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:36]=[C:35]([C:37]3[CH:38]=[C:39]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:40]=[CH:41][CH:42]=3)[N:34]=[C:33](Cl)[N:32]=2)[CH:26]=1>CN(C)C=O.C1COCC1>[C:39]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:40]=[CH:41][CH:42]=[C:37]([C:35]2[N:36]=[C:31]([C:27]3[CH:26]=[C:25]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[CH:30]=[CH:29][CH:28]=3)[N:32]=[C:33]([N:13]3[C:12]4[CH:11]=[C:10]5[C:2]([CH3:22])([CH3:1])[C:3]6[C:8]([C:9]5=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:7][CH:6]=[CH:5][CH:4]=6)[N:34]=2)[CH:38]=1
Reactant: Clc1nc(-c2cccc(-c3ccccc3)c2)nc(-c2cccc(-c3ccccc3)c2)n1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4nc(-c5cccc(-c6ccccc6)c5)nc(-c5cccc(-c6ccccc6)c5)n4)c3cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
18.6 g (64.6 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene are dissolved in 400 ml of dimethylformamide under a protective-gas atmosphere, and 3.1 g of 60% NaH in mineral oil (77.5 mmol) are added. After 1 h at room temperature, a solution of 2,4-bisbiphenyl-3-yl-6-chloro-1,3,5-triazine (32.6 g, 64.6 mmol) in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum, the purity is 99.9%. Yield: 41.5 g (61 mmol), 80% of theory.