Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([NH:14][C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[N:26]=2)=[CH:21][CH:20]=1)=[O:16])=[S:13])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].Cl[CH2:47][C:48](=O)[CH3:49].C(#N)C>[Cl-].[Na+].O.ClCCl>[CH:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:48]([CH3:49])=[CH:47][S:13]/[C:12]/1=[N:14]\[C:15]([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:34][CH:35]=3)[N:26]=2)=[CH:23][CH:24]=1)=[O:16])([CH3:3])[CH3:2]
Reactant: CC(=O)CCl
Reactant: Cc1ccc(NC(=S)NC(=O)NCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C(C)C)c1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-n2c(C)cs/c2=N\C(=O)NCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C(C)C)c1
Temperature: 65 °C
Yield: 21.4 %

Procedure:
To a 20 mL vial was added 1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea (PC5) (0.044 g, 0.077 mmol), sodium acetate (0.019 g, 0.23 mmol), 1-chloropropan-2-one (0.0092 mL, 0.12 mmol) and acetonitrile (1.5 mL). The vial was sealed and heated overnight at 65° C. The reaction mixture was diluted with brine solution and dichloromethane and passed through a phase separator. The organic layer was concentrated and the resulting residue was purified by flash column chromatography using 10-80% ethyl acetate/hexanes as eluent providing the title compound as an off-white solid (0.010 g, 21%): 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.14-8.01 (m, 4H), 7.70 (s, 1H), 7.62 (dq, J=7.7, 1.0 Hz, 2H), 7.45-7.35 (m, 2H), 7.34-7.27 (m, 1H), 7.15 (t, J=1.3 Hz, 2H), 6.66 (q, J=0.9 Hz, 1H), 4.47-4.28 (m, 2H), 2.73-2.62 (m, 1H), 2.39 (s, 3H), 2.10 (d, J=1.1 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 607 ([M+H]+).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CN(C)CCN(C)C.CCCCCC.CN(C)[CH:34]=[O:35].[NH4+].[Cl-]>CCOCC>[CH:34]([CH:7]1[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2([CH2:1][CH2:2][CH2:3][CH2:4]2)[CH2:6]1)=[O:35]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
tert-butyl 8-azaspiro[4.5]decane-8-carboxylate (Intermediate 71, 6 g, 25.07 mmol) dissolved in 150 ml of Et2O was cooled to −78° C., then N,N,N′,N′-tetramethyl ethylendiamine (9.08 ml, 60.16 mmol) and secBuLi 1.4M in hexane (42.95 ml, 60.16 mmol) were added. After 10 minutes at −60° C., the temperature was raised to −20° C. for 60 minutes, then the reaction was cooled to −78° C. and dimethylformamide (4.47 ml, 60.16 mmol, dissolved in 5 ml of Et2O) was added. After 30 minutes a saturated aqueous solution of NH4Cl (30 ml) was slowly added, then reaction was allowed to reach room temperature. Reaction was extracted with Et2O (3×100 ml), the organic solvent was dried (Na2SO4) and evaporated to obtain 4 g of the title compound as yellow oil.
Reaction SMILES: C(CC(O)=O)CC([NH2:7])C(O)=O.O=[C:13]([CH2:17][CH2:18][C:19]([O-:21])=[O:20])[C:14]([O-:16])=[O:15].CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:7][C@@H:13]([C:14]([OH:16])=[O:15])[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: NC(CCCC(=O)O)C(=O)O
Reactant: O=C([O-])CCC(=O)C(=O)[O-]
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N[C@H](CCC(=O)O)C(=O)O

Procedure:
To measure the D-aminoacid transaminase activity, D-α-aminoadipic acid (20 mmolar), α-ketoglutarate (10 mmolar) and pyridoxal phosphate (10 μg/ml) are incubated with the enzyme in potassium phosphate buffer (10 mmolar), pH 8, at a temperature of 37° C. This results in the formation of D-glutamic acid which can be determined by thin-layer chromatography after spraying with ninhydrin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.CN(CCN(C)C)C>ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:9]2[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:12]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1c[nH]c(-c2ccccc2Cl)n1
Reactant: OB(O)c1ccc(Br)cc1
Agent: CN(C)CCN(C)C
Solvent: ClCCl
Product: FC(F)(F)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.1 %

Procedure:
2-(2-Chloro-phenyl)-4-trifluoromethyl-1H-imidazole (370 mg, 1.5 mmol), 4-bromo-phenylboronic acid (600 mg, 3 mmol), and [Cu(OH).TMEDA]2Cl2 (140 mg, 0.3 mmol) were mixed with 6 mL dry dichloromethane, and stirred at room temperature under atmosphere of dioxygen for 2 days. The reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was concentrated under vacuum, and the residue was purified by chromatography on silica gel (Hexane/EtOAc 8/2) to give a solid (151 mg, 25% yield). 1H-NMR (400 MHz, CDCl3): δ 7.02 (d, 2H), 7.34 (m, 3H), 7.47 (d, 2H), 7.53 (dd, 1H), 7.56 (dd, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]#[C:15][C:16]2[C:17]([NH:23]C(OC(C)(C)C)=O)=[N:18][CH:19]=[CH:20][C:21]=2[Cl:22])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[NH:23][C:17]3=[N:18][CH:19]=[CH:20][C:21]([Cl:22])=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C#C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](c2cc3c(Cl)ccnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of Example 74B (150 mg, 0.429 mmol) in N,N-dimethylformamide (5 mL) was treated with potassium tert-butoxide (122 mg, 1.085 mmol) and the mixture was stirred at room temperature for 12 hours. The mixture was quenched with ice water and extracted into ethyl acetate (30 mL×2). The organic layer was washed with water and brine solution (25 mL each) and the organic layer was separated, dried over sodium sulfate, filtered, and concentrated to afford the title compound. LCMS: 250.1 (M+H)+.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cccc(F)c3)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a mixture of 7-(1-azido ethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.50 g, 1.6 mmol) and (3-fluorophenyl)boronic acid (0.27 g, 1.9 mmol) in 1,4-dioxane (10 mL) was added 1 N solution of sodium carbonate in water (2.1 mL, 2.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.080 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated and purified on silica gel (0-40% ethyl acetate/hexanes) to give the desired product (0.32 g, 61%). LCMS calculated for C15H13FN5OS (M+H)+: m/z=330.1. Found: 330.0. The product was subjected to chiral HPLC separation (ChiralPak IA Column: 20×250 mm, 5 μm; Mobile Phase: 10% Ethanol 90% Hexanes; Flow Rate: 18 mL/min) to give two enantiomers. On analytic HPLC (ChiralPak IA Column: 4.6×250 mm, 5 μm; Mobile Phase: 10% Ethanol-90% Hexanex; Flow Rate: 1 mL/min), the first enantiomer has retention time of 6.38 minutes and the second peak has retention time of 6.99 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CC1C=CC(S(O[CH2:20][CH2:21][CH2:22][NH:23][C:24]2[C:25](=[O:41])[N:26]([C:37]([CH3:40])([CH3:39])[CH3:38])[S:27](=[O:36])(=[O:35])[C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=O)=O)=CC=1>>[C:37]([N:26]1[C:25](=[O:41])[C:24]([NH:23][CH2:22][CH2:21][CH2:20][O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:27]1(=[O:35])=[O:36])([CH3:38])([CH3:39])[CH3:40]
Reactant: Oc1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccc(Cl)c2)=C(c2ccccc2)S1(=O)=O
Yield: 72 %

Procedure:
The title compound was prepared as described for Example 12 from 3-chlorophenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. The reaction mixture was evaporated and purified by silica gel column chromatography (Horizons Biotage) using 15% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.079 g, 72%). 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.46-7.40 (m, 3H), 7.20 (t, 1H), 6.95 (d, 1H), 6.84 (s, 1H), 6.75 (dd, 1H), 5.67 (t, 1H), 3.86 (t, 1H), 3.11-3.04 (m, 2H), 1.86-1.80 (m, 2H), 1.75 (s, 9H), 13C NMR (125 MHz CDCl3): δ 159.8, 159.3, 135.3, 135.1, 131.8, 130.5, 129.8, 128.8, 125.3, 121.5, 115.0, 113.2, 107.4, 66.2, 61.7, 42.4, 28.9, 27.8: Mass Spectrum M+H+ 449.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCN2CCOCC2)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and 4-(2-chloroethyl)morpholine (136 mg, 0.73 mmol) in order. The mixture was stirred at room temperature for 8 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (8% methanol/chloroform) to give the subject compound (34 mg, yield 18%).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([Cl:16])=[O:7]
Reactant: O=C(O)COc1cccc(Cl)c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)COc1cccc(Cl)c1Cl
Yield: 93.9 %

Procedure:
After filling in a dry 250 ml flask respectively 59.89 g (0.271 mol) of 2,3-dichlorophenoxyacetic acid synthesized in Example 5 and 79.1 ml (1.084 mol) of thionyl chloride, the reaction mixture was then heated and refluxed for 4-5 hours. When treated as in Example 2 on completion of the reaction, 60.93 g of 2,3-dichlorophenoxyacetyl chloride was obtained as a raw reaction product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[CH2:25][C@@H:12]3[O:13]C(C4C=CC(OC)=CC=4)[O:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:3]=1.N[C@@H]1C2C(=CC=CC=2)CC1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[CH2:25][C@H:12]([OH:13])[C@H:11]([CH2:16][OH:15])[CH2:10]2)[CH:3]=1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](Nc4cc(Cl)ncn4)C[C@@H]3O2)cc1
Agent: N[C@H]1CCc2ccccc21
Product: OC[C@@H]1C[C@@H](Nc2cc(Cl)ncn2)C[C@@H]1O
Temperature: 180 °C
Yield: 40.9 %

Procedure:
A neat mixture of 6-chloro-N-[(4aS,6R,7aS)-2-(4-methoxyphenyl)-hexahydrocyclopenta[d][1,3]dioxin-6-yl]pyrimidin-4-amine (120. mg, 0.332 mmol) and (S)-(+)-1-aminoindan (0.170 mL, 1.33 mmol) was heated to 180° C. for 6 h in a sealed tube using MWI. The reaction was purified via silica gel chromatography eluting with a gradient of 0 to 15% MeOH in DCM to afford the title compound (33.1 mg, 41%). LC/MS: Rt=0.90 min, ES+ 244 (AA standard).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:15][O:14][C:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]=2[NH:11][C:10]1=[O:21].[C:22]([O:26][C:27]([N:29]([CH3:35])[C@@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:22]([O:26][C:27](=[O:28])[N:29]([CH3:35])[C@H:30]([C:31](=[O:32])[NH:8][C@@H:9]1[C:10](=[O:21])[NH:11][C:12]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=2[O:14][CH2:15]1)[CH3:34])([CH3:23])([CH3:25])[CH3:24]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Cc1ccc2c(c1)OC[C@H](N)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)OC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N2
Yield: 103.3 %

Procedure:
A mixture of (S)-3-amino-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate (1.60 g, 5.23 mmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (1.06 g, 5.23 mmol, Eq: 1.00), HOBT (801 mg, 5.23 mmol, Eq: 1.00), HBTU (1.98 g, 5.23 mmol, Eq: 1.00) at 0° C. and DIEA (2.03 g, 2.73 mL, 15.7 mmol, Eq: 3.00) in DMF (50 mL) was stirred at 0° C. for 1 h, diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to afford methyl-[(S)-1-((S)-3-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (2.04 g) which was used without purification.
Reaction SMILES: CC1=C(C)C(OC1=O)=O.[NH2:10][CH2:11][CH2:12][C:13]12[CH2:19][CH:16]([CH2:17][CH2:18]1)[CH:15]=[CH:14]2>C1(C)C=CC=CC=1>[C:11]([CH2:12][C:13]12[CH2:19][CH:16]([CH2:17][CH2:18]1)[CH:15]=[CH:14]2)#[N:10]
Reactant: NCCC12C=CC(CC1)C2
Agent: CC1=C(C)C(=O)OC1=O
Solvent: Cc1ccccc1
Product: N#CCC12C=CC(CC1)C2
Temperature: 25 °C
Yield: 168.7 %

Procedure:
DMMIEtNB: A 3 L, 4 neck RBF was equipped with a thermowell, Dean Stark trap connected to condenser with a nitrogen inlet, addition funnel and mechanical stirrer. The RBF was charged with 600 mL toluene followed by dimethylmaleic anhydride (DMMA, 92 g, 0.73 mol) with stirring. The mixture cooled to 14° C. as the dimethylmaleic anhydride dissolved in the toluene. The mixture was warmed to 25° C. to clear the solution. The addition funnel was charged with aminoethylnorbornene (104 g, 0.73 mol, 96.4% pure) in 100 mL toluene and added drop wise over 15 minutes. An additional 130 mL toluene was added to rinse in the aminoethylnorbornene and the addition funnel was replaced by a stopper. The mixture immediately exothermed to 50° C. and a white thick precipitate was observed. The mixture was heated carefully (to avoid excessive foaming) to reflux over 30 minutes and refluxed for 2 hours. A clear solution was observed and 13.1 mL water (99.5% of theoretical) was collected in the Dean Stark trap. GC analysis revealed the reaction was complete (94.9% product with 1.8% DCPD and 1.7% unknown impurity at 7.8 minute). The reaction mixture was cooled to room temperature and transferred to 5 L flask and concentrated on the rotary evaporator. The crude product was further dried under high vacuum (0.94 torr) at 75° C. bath temperature on the rotary evaporator for 5 h and gave 179 g of crude product as dark orange color viscous oil. GC analysis indicated the purity of crude product after drying under high vacuum was 97.4% with 0.3% DCPD and 1.8% unknown impurity. The 179 g of crude product was adsorbed in 179 g of silica gel and chromatographed over 500 g of silica gel eluting with heptane (8 L), 2% EtOAc in heptane (2 L), 2.5% EtOAc in heptane (2 L), 3% EtOAc in heptane (4 L) and 5% EtOAc in heptane (1 L). The concentrated purified fractions yielded 164 g of product as colorless viscous oil (91% yield) with 99.8% purity by GC. 1H NMR and mass spectrum were consistent with the structure. Data: GC analysis done on a DB5 Column, 30 meters, 0.32 mm ID, 0.25 μm film, 75° C. to 300° C. at 15° C./min, 2 min hold at 300° C., Injector temperature: 275° C., Detector temperature: 350° C., Retention time: 11.893 minute.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[Na].Cl[CH2:13][C:14](=[N:16][OH:17])[NH2:15]>C(O)C>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:13][C:14](=[N:16][OH:17])[NH2:15]
Reactant: CN(C)c1ccccc1S
Reactant: NC(CCl)=NO
Agent: [Na]
Solvent: CCO
Product: CN(C)c1ccccc1SCC(N)=NO
Reaction time: 2 h

Procedure:
2-Dimethylaminobenzenethiol (4.6 g; 3×10-2 mol) was added dropwise to a solution of sodium (0.69 g; 3×10-2 mol) in absolute ethanol (50 ml) at 25°. Immediately chloroacetamidoxime was added. Stirring at 25° was continued for 2 hours, sodium chloride was removed by filtration and the filtrate evaporated under reduced pressure. Re-crystallisation of the residue from isopropanol gave 2-(2-dimethylaminophenylthio)acetamidoxime, m.p. 133°.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CS(C)=O.CCOC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][S:15][C:13](=[O:16])[CH3:14])=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)SCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
A solution of 2.00 g (8.69 mmol) of 1-(2-bromo-ethyl)-4-nitro-benzene in DMSO (10 mL) was treated with 1.99 g (17.4 mmol) of potassium thioacetate and stirred at RT for 5 h. The mixture was diluted with EtOAc (100 mL) and washed with water (6×60 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 1.48 g (76%) of the title compound as a brown oil: 1H-NMR (CD3OD; 400 MHz): δ 8.23-8.15 (m, 2H), 7.60-7.53 (m, 2H), 3.27-3.10 (m, 4H), 3.03-2.94 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:30]I>ClCCl.N1C=CN=C1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][I:30])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Brc1ccc(CCI)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A solution of 2-(4-bromophenyl)ethanol (40.0 g, 0.199 mol) in dichloromethane (10 mL) was added dropwise to a solution of imidazole (22.4 mg, 0.329 mmol), triphenylphosphine (66.5 g, 0.254 mol), and iodine (65.0 g, 0.26 mol) in dichloromethane (50 mL) at 0° C. When the addition was complete it was warmed to rt. After 1 hour the reaction was filtered through celite, the filtrate was washed with saturated aqueous sodium thiosufate (2×100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (heptane/ethyl acetate 4:1) afforded the title compound as a yellow-white solid (59.09 g, 60%). 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 3.14 (t, J=7.69 Hz, 2H) 3.33 (t, J=7.69 Hz, 2H) 7.08 (d, J=7.89 Hz, 2H) 7.45 (d, J=8.31 Hz, 2H)
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][C:6]1[N:7]=[C:8]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[CH3:22])(=[O:14])=[O:13])[S:9][CH:10]=1.OC1C=NC=CC=1.Cl>O1CCCC1>[Cl:21][C:17]1[C:16]([CH3:22])=[C:15]([S:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH:5]=[CH2:4])[N:7]=2)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCBr)cs1
Agent: Cl
Agent: Oc1cccnc1
Agent: [H-]
Solvent: C1CCOC1
Product: C=Cc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1

Procedure:
Sodium hydride (95% dry, 32 mg, 1.27 mmol) was added to a stirred solution of the product from Step 3 (240 mg, 0.61 mmol) and 3-hydroxypyridine (63 mg, 0.67 mmol) in tetrahydrofuran (10 mL) at 0° C. After 2 h at reflux temperature the reaction was neutralized by adding 2 M HCl and the product mixture was extracted with dichloromethane. The organic phase was dried (Na2SO4) and the solvent was evaporated. The crude material was purified by flash chromatography on silica gel gradient eluting with 2-5% acetone in dichloromethane giving the title compound as a solid (33 mg, 17%). MS (Ionspray, [M+H]+) m/z 314; Anal. Calcd. (found) for C12H11ClN2O2S2: C 45.8 (45.0) % H 3.5 (3.9) %N 8.9(9.1) %.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:10][N:9]([C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:13][CH:12]=2)[CH2:8]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][CH:7]1[CH2:8][N:9]([C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:15][CH:16]=2)[CH2:10]1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(O[Si](C)(C)C(C)(C)C)C2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(O)C2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
2.6 g (7.46 mmol) (S)—N-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide (IV.1) are added to 20 mL THF and the mixture is cooled to 5° C. 14.9 mL (14.9 mmol) tetrabutylammonium fluoride (1 N in THF) are added and the mixture is allowed to warm to rt. Stirring is continued for 1 h and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel; DCM:MeOH; gradient 9:1→8:2) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:20])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(CC(=O)O)ccc2c1Cc1cc(O)ccc1-2
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2c(c1)Cc1c-2ccc(CC(=O)O)c1C

Procedure:
A mixture of 59mg. of methyl 7-hydroxyfluorene-2-acetic acid, 1.3g. of potassium carbonate, and 0.5ml. methyl iodide in 11ml. of acetone is refluxed for 22 hr., filtered and the solid washed with additional acetone. The filtrate is evaporated and the residue plate chromatographed on silica gel employing chloroform-hexane (2:1) as the developing solvent. Elution of the least polar band with ethyl acetate, evaporation and crystallization of the residue from ethyl acetate-isopropyl ether gives 17mg. of the title compound, mp 114-115°. Recrystallization from ethyl acetate-isopropyl ether gives the analytical sample, mp 114.5°-115.5°; λKBr 5.80μ.