Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])=[CH:36][CH:35]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 4-fluorobenzylamine (34 mg, 0.27 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration to afford 96 mg of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].C(OCC)C.[Br:11][C:12]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[Cl-].[NH4+]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[Br:11][C:12]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]([OH:15])[CH2:1][CH2:2][CH3:3]
Reactant: CCC[Mg]Cl
Reactant: O=Cc1cccc(Cl)c1Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(O)c1cccc(Cl)c1Br
Temperature: 25 °C
Yield: 62 %

Procedure:
Under an argon atmosphere, zinc chloride (0.68 g, 4.97 mmol) was added to a 2.0 M solution of n-propyl magnesium chloride in diethyl ether (12.42 mL, 24.93 mmol), and the mixture was stirred at room temperature. After stirring for 0.5 hours, a solution of 2-bromo-3-chlorobenzaldehyde (4.36 g, 19.87 mmol), which had been obtained in Reference example 5(5b), in tetrahydrofuran (10 mL) was added dropwise thereto. After stirring for 2 hours under ice cooling, a saturated aqueous ammonium chloride solution (20 mL) was added thereto. The mixture obtained was extracted with ethyl acetate (20 mL×2). After that, the organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=5/1) to give the title compound as a white solid (3.23 g, yield 62%).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[Br:5][C:6]1[CH:7]=[C:8]([OH:17])[CH:9]=[C:10]2[C:15]=1[O:14][C:13](=[O:16])[CH:12]=[CH:11]2.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[Br:5][C:6]1[CH:7]=[C:8]([O:17][CH2:1][O:2][CH3:3])[CH:9]=[C:10]2[C:15]=1[O:14][C:13](=[O:16])[CH:12]=[CH:11]2
Reactant: O=c1ccc2cc(O)cc(Br)c2o1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1cc(Br)c2oc(=O)ccc2c1
Reaction time: 8 h

Procedure:
Add BBr3 (0.75 mL, 8 mmol) to preparation 3(662 mg, 2.0 mmol) in 20 mL of dichloromethane at 0° C. Let stir for 15 min. Add 8 mL of methanol and then concentrate. Adsorb to 6 g of silica gel and purify by flash chromatography (40 g, 10-50% A/B, A=10% MeOH in EtOAc, B=hexanes) to give 476 mg of 8-Bromo-6-hydroxy-chromen-2-one (3). Add chloromethyl methyl ether (0.18 mL) to a solution of 8-bromo-6-hydroxy-chromen-2-one (476 mg, 1.97 mmol) and K2CO3 (660 mg, 4.77 mmol) in 10 of DMF. Let the solution stir overnight, add 0.09 mL more chloromethyl methyl ether, let stir 2 hrs, dilute with EtOAc, wash with water, 1:1 water:brine, brine, dry (Na2SO4), filter and concentrate to yield 524 mg (1.84 mmol, 93%) of preparation 5. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, 1H, J=9.2 Hz), 7.50 (d, 1H, J=2.6 Hz), 7.12 (d, 1H, J=2.6 Hz), 6.46 (d, 1H, J=9.7 Hz), 5.20 (s, 2H), 3.50 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O.C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: NC/C=C\CCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CCC/C=C\CNS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 24 h
Yield: 29.5 %

Procedure:
A rapidly stirred solution of (Z)-7-aminohept-5-enoic acid (0.61 g), sodium hydroxide (0.51 g) in water (5 ml) was treated with 4-chlorobenzenesulphonyl chloride (0.9 g) in chloroform (2.5 ml). The solution was stirred for 24 hours then evaporated with chloroform (4×15 ml). The aqueous layer was treated with hydrochloric acid to pH=1 and extracted with chloroform (4×40 ml). These chloroform extracts were combined, dried over magnesium sulphate and evaporated to dryness. The residue was recrystallised from isopropanol to give the title compound (0.4 g). N.M.R; 250 MHz; δ(CDCl3) (ppm): 1.7 (m, 2H) 2.05 (m, 2H), 2.35 (m, 2H), 3.6 (t, 2H), 4.9 (t, 1H) 5.3 (m, 1H), 5.45 (m, 1H) 7.45 (m, 2H), 7.8 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:2]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:3][CH2:4][CH2:5][C:6]#[CH:7]
Reactant: C1CCNCC1
Reactant: C#CCCCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCCCN1CCCCC1
Yield: 54.8 %

Procedure:
A solution of 6-chlorohex-1-yne (5 mL, 41.3 mmol), piperidine (4.08 mL, 41.3 mmol) and sodium hydrogen carbonate (4.16 g, 49.5 mmol) in DMF (50 mL) was refluxed for 16 hours. The reaction was concentrated in-vacuo and the residue partitioned between ether (150 mL) and water (150 mL). The organic was separated and the aqueous back extracted with diethyl ether (50 mL). The combined organics were washed with brine (150 mL), dried (MgSO4), filtered and concentrated in vacuo to give a crude sample of the title compound (3.74 g). Oxalic acid (2.161 g, 24 mmol) was added to the crude product. The resultant solid was recrystallised from ethanol, collected by filtration and dried in-vacuo to give 1-(hex-5-yn-1-yl)piperidine oxalic acid salt (4.66 g). The solid was partitioned between diethyl ether (150 mL) and saturated aqueous sodium bicarbonate (150 mL). The organic was separated and dried (MgSO4) filtered and concentrated in vacuo to give the title compound as a yellow oil (1.93 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)=[C:6]([NH:8][C:9](=O)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.N>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)CC(=O)Nc1cc(Br)ccc1NCC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)Cc1nc2cc(Br)ccc2n1CC1CC1
Yield: 90.5 %

Procedure:
A mixture of N-{5-bromo-2-[(cyclopropylmethyl)amino]phenyl}-3,3-dimethylbutanamide (Step C, 761 mg, 2.24 mmol) and p-toluenesulfonic acid monohydrate (426 mg, 2.24 mmol) in toluene (40 mL) was stirred under reflux for 23 h with Dean-Stark apparatus. Water (10 mL) and aqueous ammonia (5 mL) were added and the mixture was extracted with ethyl acetate (20 mL×2). The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1 as eluent) to give the title compound (651 mg, 90%) as a brown oil.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:38])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:38])([OH:33])=[O:32]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cccc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cccc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of 750 mg (1.41 mmol) (R)-1-[[3-[2-[(R)-2-tert-Butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 6 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 15 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 581 mg (98%) of the title compound as a white powder. MS m/e (%): 443 (M+Na+, 32), 438 (M+NH4+, 20), 421 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[C:26]([F:29])([F:28])[F:27])[N:19]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:18]1=[O:37])[CH3:16].[H-].[Na+]>O>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[C:26]([F:27])([F:29])[F:28])[N:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:32][CH:31]=2)[C:18]1=[O:37])[CH3:16]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C(F)(F)F)c21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(C(F)(F)F)c21
Temperature: 100 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (81 mg) and 1-ethyl-3-(4-hydroxyphenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (103 mg) in DMF(dry) (1.5 ml) was added NaH (19.12 mg), and the mixture was stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound as white crystals (62.2 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:22]([NH:23][CH:24]=[O:25])[C:21](=[O:26])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:10].[I-:27].[Na+]>CC(C)=O>[CH:24]([NH:23][CH:22]1[C:21](=[O:26])[N:7]2[C:8]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:10])=[C:3]([CH2:2][I:27])[CH2:4][S:5][C@H:6]12)=[O:25]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC=O)C(=O)N23)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3C(NC=O)C(=O)N23)cc1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
14.5 g (36.6 mM) of p-methoxybenzyl 3-chloromethyl-7-formamido-3-cephem-4-carboxylate was dissolved in 360 ml of acetone. Under cooling with ice, 13.7 g (91.4 mM) of sodium iodide was added to this solution, and the mixture was stirred for 30 minutes, and further at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the oily residue was dissolved by an addition of ethyl acetate. The organic layer was washed sequentially with water, a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The oily residue was subjected to silica gel column chromatography (Wakogel C-300, eluted with 20% ethyl acetate-chloroform), and the fraction containing the desired product was concentrated to obtain 15.7 g (yield: 87.9%) of p-methoxybenzyl 7-formamido-3-iodomethyl-3-cephem-4-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:15][NH:10][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:9]
Reactant: C[C@@H](N)c1cccc(F)c1
Reactant: COc1ccc(C=O)cc1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CN[C@H](C)c2cccc(F)c2)cc1Br
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
(R)-1-(3-Fluorophenyl)ethanamine 115 (1.24 g, 8.92 mmol) and 3-bromo-4-methoxybenzaldehyde 114 (1.92 g, 8.92 mmol) were mixed in 100 mL anhydrous methanol in a round bottom flask. After the mixture was stirred at 20° C. for 10 min, the flask was cooled in an ice-water bath. To this flask was added sodium cyanoborohydride (0.56 g, 8.92 mmol) followed by acetic acid (0.54 g, 8.92 mmol). The resulting mixture was stirred for 12 h and allowed to warm to 20° C. After removing most of the methanol, the remaining residue was dissolved in 200 mL ethyl ether and washed with saturated sodium bicarbonate, 3 times. The organic phase was dried over sodium sulfate. After removing the solvent under reduced pressure, the remaining residue was subjected to a silica gel column using 50% ethylacetate in hexane as the eluant to yield a colorless oil as the pure product (R)—N-(3-bromo-4-methoxybenzyl)-1-(3-fluorophenyl)ethanamine 116 (2.3 g, yield=93%). LCMS (M+1) 338, calc. for C16H17BrFNO 338; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (d, J=6.26 Hz, 3H) 3.46-3.60 (m, 2H) 3.78 (q, J=6.39 Hz, 1H) 6.84 (d, J=8.22 Hz, 1H) 6.90-6.98 (m, 1H) 7.09 (t, J=9.00 Hz, 2H) 7.16 (dd, J=8.41, 2.15 Hz, 1H) 7.27-7.34 (m, 1H) 7.48 (d, J=1.96 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.[F:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>N1C=CC=CC=1.ClCCl>[F:24][C:25]1[CH:26]=[C:27]([S:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1cccc(F)c1)N2
Temperature: 25 °C
Reaction time: 6 h
Yield: 131.7 %

Procedure:
To a stirred solution of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (1.0 g, 3.22 mmol, 1.0 eq.) in pyridine (5 mL) and dichloro methane (20 mL) at 0° C. was dropwise a solution of 3-fluorobenzene-1-sulfonyl chloride (940 mg, 4.83 mmol, 1.5 eq.) in dichloromethane (30 mL). The mixture was stirred at room temperature for 6 h. Thin layer chromatography and LC-MS showed reaction completed. The mixture was quenched with 50 mL water and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to afford 1.987 g of methyl 2-(2-(3-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (pyridine included) as light yellow solid, which was used in next step without further purification.
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2]1.[CH2:13](OC1C=CC(O)=CC=1)[C:14]1C=CC=C[CH:15]=1.[OH-].[Na+].O>CS(C)=O>[CH2:6]([O:5][C:4]1[CH:15]=[CH:14][CH:13]=[CH:2][C:3]=1[OH:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Oc1ccccc1OCc1ccccc1

Procedure:
A solution of 8.3 g (36.1 mmol) of (2S):1-chloro-2-hydroxy-3-N-mesylisopropylaminopropane and 8.69 g (43.4 mmol) of p-benzyloxyphenol in 75 ml DMSO was treated with 10.86 ml 4 N NaOH (43.4 mmol) and the mixture was heated at 100° for 5 hours. To the cooled reaction mixture 40 ml 1 N NaOH and 60 ml H2O were added with stirring and the resulting solid was collected by filtration and was washed well with H2O. The dried crude product was recrystallized from EtOAc-hexane to yield the end product as white needles, mp 93°-94°.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[C:7]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([N:19]1[CH2:33][C:22]2=[C:23]3[N:28]([N:29]=[C:21]2[CH2:20]1)[C:27]([CH3:30])=[C:26]([Cl:31])[C:25]([CH3:32])=[N:24]3)=[O:18])([F:9])[F:8])C>O1CCOCC1.CC(=O)OCC>[Cl:31][C:26]1[C:25]([CH3:32])=[N:24][C:23]2[N:28]([N:29]=[C:21]3[CH2:20][N:19]([C:17]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[O:10][C:7]([F:8])([F:9])[CH2:6][OH:5])=[O:18])[CH2:33][C:22]3=2)[C:27]=1[CH3:30]
Reactant: CCOC(=O)C(F)(F)Oc1ccccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC(F)(F)CO)C3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21.8 %

Procedure:
Lithium borohydride (2.81 mg; 0.13 mmol; 1 eq.) was added to a solution of [2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-difluoro-acetic acid ethyl ester (60 mg; 0.13 mmol; 1 eq.) in 1,4-dioxane (1 mL) and the resulting mixture was stirred at room temperature for 1.5 hour. The solution was diluted with EA, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (30% to 75% EA in cyclohexane) followed by crystallization from ACN afforded the title compound (12 mg, 22%). HPLC (max plot) 98.4%, Rt 3.46 min. UPLC/MS: (MS+) 423.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([OH:17])=O.[C:22]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C1C=CC=CN=1)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([NH:31][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])=[O:17]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1cc2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
A solution of N-(3,4-dichlorobenzyl)indole-2-carboxylic acid (0.23 g), benzenesulphonamide (129 mg), dimethylaminopyridine (0.22 g) and 1-ethyl-3-(3-dimethylaniinopropyl)carbodiimide hydrochloride (0.19 g) in dichloromethane was allowed to stir for 24 hours at room temperature. 2N HCl was added and the reaction stirred vigorously for 2 hours, then extracted with dichloromethane. Combined organic extracts were dried (MgSO4) and concentrated to yield the desired end product as a white crystalline solid (122 mg, 32%); NMR δ (CD3SOCD3) 5.65 (s, 2H), 6.73 (dd, 1H), 7.12 (m, 2H), 7.30 (t, 1H), 7.38 (d, 1H), 7.56 (m, 4H), 7.70 (m, 2H), 7.91 (d, 2H); M/z (−) 457 (M−H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]2[C:9](N3CCOCC3)([C:10](=[O:15])[NH:11][CH2:12][CH2:13]2)[N:8]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:15])[C:9]=2[N:8]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NN(c2ccc(OC)cc2)C2(N3CCOCC3)C(=O)NCCC12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCNC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Method B. A solution of 1-(4-methoxy-phenyl)-7a-morpholin-4-yl-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridin-3-carboxylic acid ethyl ester (51, 402 mg, 1.0 mmol) in methylene chloride (CH2Cl2, 4 mL) was treated with trifluoroacetic acid (TFA, 1.0 mL) at 25° C., and the resulting reaction mixture was stirred at 25° C. for an additional 30 min. When HPLC and TLC showed the reaction was complete, the solvents were removed in vacuo. The residue was directly purified by flash column chromatography (SiO2, 5–30% EtOAc/hexane gradient elution) to afford the desired elimination product (50, 299 mg, 315 mg theoretical, 95%) as a pale-yellow oil, which solidified upon standing at room temperature in vacuo. This material was found to be identical with the product obtained from method A in every comparable aspect.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].F[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N+:35]([O-:37])=[O:36]>CN(C)C=O.CCOCC>[C:1]([NH:8][C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N+:35]([O-:37])=[O:36])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccc(Oc2ccccc2[N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-Boc-(L)tyrosine, methyl ester (500 mg) and potassium carbonate (467 mg) in dimethylformamide (5 mL) was added dropwise 1-fluoro-2-nitrobenzene (189 μL). The yellow solution was stirred for 3 days at room temperature. The mixture was diluted with ether which was subsequently washed with 1N hydrochloric acid, water, saturated salt solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed by rotoevaporation to yield the title compound (700 mg) which was used in the subsequent reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=O)(=O)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CCN(CC)CC.[CH2:25]([N:27]([CH2:31][CH3:32])[C:28](Cl)=[S:29])[CH3:26]>CCOC(C)=O>[CH2:25]([N:27]([CH2:31][CH3:32])[C:28](=[S:29])[O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH3:26]
Reactant: O=S1(=O)c2ccccc2Oc2cc(O)ccc21
Reactant: CCN(CC)C(=S)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=S)Oc1ccc2c(c1)Oc1ccccc1S2
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A solution of 3-hydroxyphenoxathiin (310 mg, 1.43 mmol) (Example 7), Et3N (0.30 ml, 2.15 mmol) and N,N-diethylthiocarbamoyl chloride (238 mg, 1.57 mmol) in EtOAc (25 mL) was refluxed for 3 h, cooled to room temperature and the precipitated hydrochloride salt filtered. The filtrate was washed with 10% aqueous HCl (30 mL), saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried (Na2SO4), and concentrated in vacuo to an orange oil (479 mg). The crude product was purified by radial chromatography (EtOAc/hexane 10:90) to give 282 mg (66%) of the title compound as a white solid: mp 121-123° (EtOAc); TLC (EtOAc/hexane, 15:85) Rf =0.43; 1H-NMR (CDCl3) δ 1.32 (=7Hz, 6H), δ 3.68 (q. J=7 Hz, 2 H), δ 3.90 (q, J=7 Hz, 2 H), δ 6.75 (d, J=6 Hz, 1 H, C2 -H), δ 6.78 (s, 1 H, C4 -H), δ 6.95-7.13 (m, 5H): MS m/e (relative intensity) 332 (MH+, 100), 116 (22).