Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:21].[BH4-].[Na+]>CO.C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[OH:21]
Reactant: Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(O)c1cccc(Cl)c1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A mixture of [2-amino-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]phenyl](3-chlorophenyl)methanone (prepared as described in WO 98/49157) (0.088 mol) in methanol (300 ml) and THF (100 ml) was cooled on an ice bath. sodium tetrahydroborate (0.088 mol) was added portionwise. The mixture was stirred at a low temperature for 30 min, then hydrolized and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The product was used without further purification, yielding 36.6 g (100%) of 2-amino-α-(3-chlorophenyl)-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-benzenemethanol (intermediate 9).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[N:8]=[C:7]([S:16][CH3:17])[N:6]=[C:5]2SC.[NH3:20]>O1CCCC1>[CH3:17][S:16][C:7]1[N:6]=[C:5]([NH2:20])[C:4]2[C:9](=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: COc1c(Cl)cc2c(SC)nc(SC)nc2c1OC
Reactant: N
Solvent: C1CCOC1
Product: COc1c(Cl)cc2c(N)nc(SC)nc2c1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 0.1 mole of 6-chloro-2,4-dimethylmercapto-7,8-dimethoxyquinazoline in 200 ml. of tetrahydrofuran is added a solution of 0.1 mole of anhydrous ammonia in tetrahydrofuran. The mixture is stirred at room temperature for 18 hours and the precipitate which forms is collected and recrystallized from dimethylformamide/water to yield 2-methylmercapto-4-amino-6-chloro-7,8-dimethoxyquinazoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:6]O.P(Br)(Br)[Br:13]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:6][Br:13]
Reactant: COc1cc(CO)ccc1C
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1cc(CBr)ccc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 187.3 %

Procedure:
A solution of 18.3 g (0.12 mol) of 3-methoxy-4-methylbenzyl alcohol in 150 mL of Et2O was treated with 23.8 g (0.12 mol) of BaCO3 and the mixture cooled in ice. This was treated dropwise with 5.8 mL (0.06 mol) of PBr3. After stirring at 0° C. for 15 minutes, the mixture was allowed to stir at room temperature overnight. The mixture was filtered and the solid washed with Et2O. The Et2O was washed with saturated NaHCO3, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 24.17 g (93.5% yield) of the product as an oil. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].C(=O)(O)[O-].[Na+]>ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])[CH:7]=[CH:6][CH:5]=3)[C:16]=12
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)n1nc(-c2cccc(N)c2)c2c(N)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)Nc1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Reaction time: 1 h
Yield: 23 %

Procedure:
A solution of dichloromethane (2 mL), compound 22 (20 mg, 0.075 mmol) and triethylamine (11 μL, 0.079 mmol) was cooled to 0° C. 2-chloro-1-ethane sulfonyl chloride (7 μL, 0.067 mmol) was added and the reaction was allowed to proceed for 1 hour prior to addition of saturated sodium bicarbonate (10 mL) and extraction with dichloromethane (3×10 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The product was purified by preparative RP-HPLC and lyophilized (5.6 mg, 23% yield): 1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.31 (s, 1H), 7.49 (t, J=7.9, 1H), 7.45 (s, 1H), 7.38 (d, J=7.8, 1H), 7.27 (d, J=7.3, 1H), 6.86 (dd, J=16.4, 10.0, 1H), 6.17 (d, J=16.4, 1H), 6.08 (d, J=9.9, 1H), 5.08 (hept, J=6.7, 1H), 1.50 (d, J=6.7, 6H). 13C NMR (100 MHz, DMSO) δ 155.01, 151.96, 151.19, 144.29, 138.50, 136.32, 133.09, 130.22, 127.79, 123.73, 120.09, 119.20, 96.94, 48.85, 21.73; [M+H]+ calculated for C16H18N6O2S 359.1, found 359.4.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].CC1C=CC(S(O[CH2:22][CH2:23][O:24][CH3:25])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:4][C:3]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: Oc1ccc(O)cc1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(O)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
To a solution of 60% sodium hydride (436 mg, 18.2 mmol) in DMF (2.0 mL) was added hydroquinone (1.0 g, 18.2 mmol) in DMF (10.0 mL) dropwisely. The solution was added with 2-methoxyethyl 4-methylbenzenesulfonate (12-2, 2.10 g, 21.8 mmol) dropwisely. The reaction was stirred at 65° C. for 16 h. The solution was cooled to room temperature, poured into icy H2O, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 4-(2-methoxyethoxy)phenol (12-3, 1.0 g), which was used directly for the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[C@:18]3([C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:27])[CH2:17]2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C@H:16]2[C@@:18]3([C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:2][CH:3]4[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]4)[C:19]3=[O:27])[CH2:17]2)=[CH:14][CH:15]=1
Reactant: ClCC1CCNCC1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Product: O=C1N(CC2CCNCC2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 70 starting from 4-(chloromethyl)piperidine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C22H23ClN2O: 366, observed (M+H)+: 367.2 1HNMR (400 MHz, MeOD-d4) δppm 1.51-1.67 (m, 2 H) 1.96 (br. s., 2 H) 2.12-2.21 (m, 2 H) 2.21-2.35 (m, 1 H) 2.93-3.07 (m, 2 H) 3.22 (t, J=8.59 Hz, 1 H) 3.38-3.50 (m, 2 H) 3.84 (d, J=7.33 Hz, 2 H) 6.09 (d, J=7.58 Hz, 1 H) 6.77 (t, J=7.58 Hz, 1 H) 7.11 (d, J=7.83 Hz, 1 H) 7.16-7.26 (m, 3 H) 7.29-7.35 (m, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 7.6 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1H-indazol-5-yl)pyridin-2(1H)-one (0.362 g, 1.14 mmol) in DMSO (1.5 mL) was added 4-(2-chloroethyl)morpholine (0.466 g, 2.50 mmol) and Cs2CO3 (1.85 g, 5.67 mmol). After stirring at ambient temperature for 5.5 h, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×40 mL). The organics were washed with brine (2×25 mL), dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) yielded the title compound (37.3 mg, 7%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J=1.0 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.43-7.38 (m, 6H), 7.29 (d, J=7.5 Hz, 1H), 6.09-6.06 (m, 2H), 5.06 (s, 2H), 4.53 (t, J=7.0 Hz, 2H), 3.68 (t, J=4.5 Hz, 4H), 2.88 (t, J=6.5 Hz, 2H) 2.52 (t, J=4.5 Hz, 4H); ESI MS m/z 431 [M+H]+; HPLC (Method A) 98.9% (AUC), tR=14.0 min.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:27])([C:23]([F:26])([F:25])[F:24])[CH2:14][CH2:15][CH2:16][S:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>C(Cl)Cl>[F:27][C:13]([F:12])([C:23]([F:24])([F:25])[F:26])[CH2:14][CH2:15][CH2:16][S:17]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OCCCCSCCCC(F)(F)C(F)(F)F
Solvent: ClCCl
Product: O=S(CCCCO)CCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
m-CPBA (64 mg, 0.37 mmol) was added to a cooled (0° C.) solution of 4-((4,4,5,5,5-pentafluoropentyl)thio)butan-1-ol (76 mg, 0.28 mmol) in DCM (3 mL) and it was stirred at 0° C. for 30 min. The reaction mixture was warmed to room temperature and was partitioned between a saturated solution of sodium bicarbonate and DCM. The organic layer was dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0 to 10% MeOH/DCM to afford 52 mg of 4-((4,4,5,5,5-pentafluoropentyl)sulfinyl)butan-1-ol as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:16](=[O:17])[N:15]=[C:14]2[N:4]([C@@H:5]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:7]([OH:12])[C@@H:6]3[O:13]2)[CH:3]=1>COCCO>[CH3:5][O:9][CH2:8][CH2:7][O:12][C@@H:6]1[C@H:7]([OH:12])[C@@H:8]([CH2:10][OH:11])[O:9][C@H:5]1[N:4]1[CH:3]=[C:2]([CH3:1])[C:16](=[O:17])[NH:15][C:14]1=[O:13]
Reactant: Cc1cn2c(nc1=O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Solvent: COCCO
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Yield: 124.6 %

Procedure:
2,2′-Anhydro-5-methyluridine (195 g, 0.81 M) tris(2-methoxyethyl)borate (231 g, 0.98 M) and 2-methoxyethanol (1.2 L) were added to a 2 L stainless steel pressure vessel and placed in a pre-heated oil bath at 160° C. After heating for 48 hours at 155-260?C., the vessel was opened and the solution evaporated to dryness and triturated with MeOH (200 mL). The residue was suspended in hot acetone (1 L). The insoluble salts were filtered, washed with acetone (150 mL) and the filtrate evaporated. The residue (280 g) was dissolved in CH3CN (600 mL) and evaporated. A silica gel column (3 kg) was packed in CH2C2/acetone/MeOH (20:5:3) containing 0.5% Et3NH. The residue was dissolved in CH2Cl2 (250 mL) and adsorbed onto silica (150 g) prior to loading onto the column. The product was eluted with the packing solvent to give 160 g (63%) of product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[CH2:7][C:8]([OH:10])=[O:9])=[O:4].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].Cl.[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH2:33]>C(O)(=O)C>[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:33][C:11](=[O:13])[C@H:6]([CH2:7][C:8](=[O:9])[OH:10])[NH:5][C:3](=[O:4])[C:2]([F:1])([F:15])[F:14]
Reactant: O=C(O)C[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)C(F)(F)F
Reaction time: 6 h
Yield: 79 %

Procedure:
In 63.3 g of acetic acid, 22.9 g (0.1 mole) of N-trifluoroacetyl-L-aspartic acid was suspended and 10.2 g (0.1 mole) of acetic anhydride was added. The mixture was warmed to 55°-60° C. and stirred for 6 hours at the same temperature. After finishing the reaction, the resulting mixture was cooled to 15°-20° C. and then 9.2 g (0.11 mole) of sodium acetate and 20.5 g (0.095 mole) of L-phenylalanine methyl ester hydrochloride were successively added at the same temperature. The reaction was carried out for 2 hours with stirring at the same temperature. Precipitated crystals were filtered, washed and dried. Crystals of N-trifluoroacetyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained in the yield of 29.3 g (79.0% yield on L-phenylalanine methyl ester hydrochloride). The crystals thus obtained were analyzed by high performance liquid chromatography to find α-isomer alone.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[CH:4][N:3]=1.[F-:16].[Cs+]>CS(C)=O.C(OC(=O)C)C>[F:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH3:15])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: CCCOc1cnc(Cl)c2ccccc12
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCOc1cnc(F)c2ccccc12
Temperature: 140 °C
Yield: 68.8 %

Procedure:
To a solution of 1-chloro-4-propoxyisoquinoline (1.1 g, 4.96 mmol) in DMSO (6 mL), added CsF (1.508 g, 9.92 mmol) and heated to 140° C. for 6 h. The reaction was diluted with ethylacteate and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give the crude product which was purified by silica gel chromatography using a gradient of 5-25% EtOAc/Hexanes. The product fractions were collected and the solvent removed under vacuum to give 700 mg of the desired product 1-fluoro-4-propoxyisoquinoline as a white solid. MS: MS m/z 206.17 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)[C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(=O)C(Cc1ccc(Cl)cc1)c1cc(Cl)cc(Br)c1

Procedure:
To a vigorously stirred solution of (3-bromo-5-chlorophenyl)acetone (4.0 g, 17 mmol) and 4-chlorobenzyl chloride (2.2 g, 14 mmol) in 60 mL of acetonitrile at 0° C. was added cesium carbonate (11 g, 35 mmol), and the reaction was allowed to warm to room temperate overnight. The reaction mixture was partitioned between ethyl acetate (200 mL) and saturated aqueous ammonium chloride (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.21 (s, 1H), 7.19 (d, 2H), 7.04 (d, 2H), 6.97 (d, 1H), 6.87 (d, 1H), 4.16 (dd, 1H), 3.25 (dd, 1H), 2.86 (dd, 1H), 2.03 (s, 3H).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[F:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[C:14]([O:26][CH3:27])[C:15](=[O:25])[N:16]([CH3:24])[C:17]=3C(Cl)=O)[C:12]2=[O:28])=[CH:8][CH:7]=1>O.CC(C)=O>[NH2:1][C:17]1[N:16]([CH3:24])[C:15](=[O:25])[C:14]([O:26][CH3:27])=[C:13]2[C:18]=1[CH2:19][CH2:20][N:11]([CH2:10][C:9]1[CH:29]=[CH:30][C:6]([F:5])=[CH:7][CH:8]=1)[C:12]2=[O:28]
Reactant: COc1c2c(c(C(=O)Cl)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1c2c(c(N)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Reaction time: 0.5 h

Procedure:
To a solution of sodium azide (0.091 g, 1.4 mmol) in 2 mL water cooled to 0° C. was add 6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carbonyl chloride (0.48 g, 1.28 mmol) in acetone (8 mL). The solution was stirred for 30 minutes, then evaporated. The residue was partitioned between CHCl3 and saturated Na bicarbonate, dried with Na2SO4, filtered and evaporated to give the crude product, which was chromatographed on silica eluting with 5% MeOH/CHCl3 saturated with NH3.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[C:16]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)(=[O:25])=[O:24])=[CH:15]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C>ClCCCl>[Cl:32][C:28]1[CH:27]=[C:26]([S:23]([C:16]2[C:17]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:14]([CH2:13][CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[CH:15]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)c1cn(CC2CCCN2Cc2ccccc2)c2ncccc12
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=S(=O)(c1cccc(Cl)c1)c1cn(CC2CCCN2)c2ncccc12
Temperature: 25 °C
Yield: 68 %

Procedure:
A stirred solution of 1-[(1-benzyl-pyrrolidin-2-yl)methyl]-3-(3-chlorophenyl-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.812 g, 1.74 mmol) in 1,2-dichloroethane under a nitrogen atmosphere is treated with 1-chloroethylchloroformate (0.47 mL, 4.35 mmol); heated at reflux temperature until the disappearance of starting material by thin layer chromatography (3 h), cooled and concentrated in vacuo. The resultant residue is dissolved in CH2Cl2 and re-evaporated twice. This residue is dissolved in ethanol, heated at reflux temperature for 1.5 h, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The extracts are combined, washed sequentially with water and brine, and concentrated in vacuo. The final residue is purified by flash column chromatography (10–15% methanol in CH2Cl2 as eluent) to afford the title compound as an oil, 443 mg (68% yield), identified by HNMR and mass spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([O:25][C:26]([NH:28][CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:34][C:33]3[CH:35]=[CH:36][C:30]([CH2:29][NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:27])=[CH:31][CH:32]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 96.2 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and p-tert-butoxycarbonylaminomethylaniline (130 mg, 0.5 mmol) to give 230 mg of the title compound (80%): mp 156°~157° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (s, 1H), 9.98 (s, 1H), 7.48 (d, 2H, J=8.6 Hz), 7.34 (t, 1H, J=5,7 Hz), 7.24 (bs, 1H), 7.17 (bs, 1H), 7.15 (d, 2H, J=8.6 Hz), 5.16~5.26 (m, 1H), 4.06 (d, 2H, J=5.7 Hz), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.56~2.65 (m, 2H), 2.10 (dm, 1H, J=13.5 Hz), 1.81~1.96 (m, 1H), 1.39 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[F:21][C:22]([F:30])([F:29])[CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:28][CH:23]([C:24]([F:27])([F:26])[F:25])[C:22]([F:30])([F:29])[F:21]
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCCBr)c(Cl)c1
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)C(OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.2 %

Procedure:
A reaction vessel was charged with 0.42 g of 3,5-dichloro-4-(4-bromobutyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.25 g of 1,1,1,3,3,3-hexafluoro-2-propanol, 0.17 g of potassium carbonate and 10 ml of N,N-dimethylformamide. After stirring at room temperature for 48 hours, the reaction mixture was poured into water and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then concentrated. The residue was subjected to silica gel chromatography, which afforded 0.077 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(1,1,1,3,3,3-hexafluoro-2-propyloxy)butyloxy)benzene (yield, 15%), nD24.0 1.4805.
Reaction SMILES: FS([O-])(=O)=[O:3].[CH3:6][N+:7]1[S:8][C:9]([Cl:14])=[C:10]([Cl:13])[C:11]=1Cl>C([O-])(=O)C.[Na+]>[Cl:13][C:10]1[C:11](=[O:3])[N:7]([CH3:6])[S:8][C:9]=1[Cl:14]
Reactant: C[n+]1sc(Cl)c(Cl)c1Cl
Reactant: O=S(=O)([O-])F
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cn1sc(Cl)c(Cl)c1=O
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
2-Methyl-3,4,5-trichloroisothiazolium fluorosulfonate (16.9 g, 0.058 mol) was added in portions to 150 ml of a saturated sodium acetate solution. After stirring for 30 min. the solid was collected, washed with water, and recrystallized from ethanol to yield 7.5 g (70%) of 4,5-dichloro-2-methyl-4-isothiazolin-3-one, mp 119°-120°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:30][CH3:31])=[CH:11][C:12]2[CH:13]3[CH:21]([CH2:22][CH2:23][C:24]=2[CH:25]=1)[CH:20]1[C:16]([CH3:29])([C:17](=[CH:26][CH2:27][OH:28])[CH2:18][CH2:19]1)[CH2:15][CH2:14]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I.O>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:30][CH3:31])=[CH:11][C:12]2[CH:13]3[CH:21]([CH2:22][CH2:23][C:24]=2[CH:25]=1)[CH:20]1[C:16]([CH3:29])([C:17](=[CH:26][CH2:27][O:28][CH3:34])[CH2:18][CH2:19]1)[CH2:15][CH2:14]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCc1cc2c(cc1OCc1ccccc1)CCC1C2CCC2(C)C(=CCO)CCC12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc2c(cc1OCc1ccccc1)CCC1C2CCC2(C)C(=CCOC)CCC12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(3-Benzyloxy-2-ethyl-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-cyclopenta[a]phenanthren-17-ylidene)-ethanol (0.62 g, 1.5 mmol) in 10 ml dry THF was cooled to 0° C. under nitrogen. NaH (0.08 g, 2 mmol of NaH 60% dispersion in mineral oil) was added portion wise and the solution stirred for 30 minutes before CH3I (0.19 ml, 3 mmol) was added dropwise. The solution was then allowed to warm to room temperature and stirred for 18 hours. After addition of water (20 ml) the organics were extracted with ethylacetate. The organic layer was washed with water, brine, dried over MgSO4 and the solvents were evaporated under vacuum. The crude oil was purified by chromatography (hexane/ethylacetate 20/1) to give 3-benzyloxy-2-ethyl-17-(2-methoxy-ethylidene)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene, 0.59 g (91%), as a colourless oil; 1H NMR (CDCl3, 270 MHz): 0.84 (s, 3H, CH3), 1.24 (t, J=7.4 Hz, 3H, CH3), 1.26-1.66 (m, 6H), 1.82-2.02 (m, 3H), 2.20-2.51 (m, 3H), 2.70 (q, J=7.4 Hz, 2H, CH2), 2.87 (m, 2H, H6), 3.36 (s, 3H, CH3O), 3.94 (m, 2H, CH2OMe), 5.06 (s, 2H, CH2Ph), 5.27 (m, 1H, CHCH2OH), 6.66 (s, 1H, ArH), 7.15 (s, 1H, ArH), 7.31-7.48 (m, 5H, Ph).