Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[C:34]([O:33][C:32](=[O:38])[NH:31][CH2:30][CH2:29][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cncc(Br)c1
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a solution of 5-bromopyridin-3-ol (0.5 g, 2.87 mmol) in THF (30 mL) cooled to 0° C. were added triphenylphosphine (0.829 g, 3.16 mmol) and tert-butyl 2-hydroxyethylcarbamate (0.51 g, 3.16 mmol) in THF (5 mL) followed by di-(4-chlorobenzyl)azodicarboxylate (1.16 g, 3.16 mmol), added portionwise, and the reaction mixture was then stirred at room temperature over night. The mixture was diluted with EtOAc, poured into aq. NaHCO3 (50 mL) and the aqueous layer was extracted with EtOAc (2×100 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was taken up in diethyl ether (50 mL) and left to stand in the fridge for 2 h. After this time, the solid precipitate was filtered off and the resulting filtrate evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtOAc-heptane gradient to give the title compound (0.57 g, 63%) as a white solid. MS: 317.0 and 319.0 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[O:11][C:10]([CH3:17])([CH3:16])[CH2:9]1)C1C=CC=CC=1>CCO.[Pd]>[CH3:16][C:10]1([CH3:17])[O:11][C:12]([CH3:15])([CH3:14])[CH2:13][NH:8][CH2:9]1
Reactant: CC1(C)CN(Cc2ccccc2)CC(C)(C)O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CNCC(C)(C)O1
Reaction time: 24 h
Yield: 100.7 %

Procedure:
Dissolve 4-benzyl-2,2,6,6-tetramethylmorpholine (Bennett, G. B.; Houlihan, W. J.; Mason, R. B.; Engstrom, R. G. J. Med. Chem. 1976, 19, 709-714) (11.0 g, 47.1 mmol) in EtOH (650 mL) and add 3% Pd/C (8.61 g). Shake the mixture under hydrogen (60 psi) at 40° C. for 24 h. Filter the mixture to remove Pd catalyst, and treat the filtrate with 2M HCl in ether, then concentrate. Dry the residue at 80° C. under vacuum to give the title compound (6.79 g) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.8 (2H, br s), 2.88 (4H, s), 1.25 (12H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([CH:10]=1)[C:7](O)=[O:8].P(Br)(Br)Br>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]2[N:11]=[C:12]([O:14][CH2:15][CH3:16])[O:13][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: CCOC(=O)Nc1c(C)cc(Cl)cc1C(=O)O
Agent: BrP(Br)Br
Solvent: Cc1ccccc1
Product: CCOc1nc2c(C)cc(Cl)cc2c(=O)o1
Temperature: 65 °C

Procedure:
A 1-L, three-necked flask equipped with an addition funnel, thermometer, condenser, nitrogen bubbler, and caustic scrubber was charged with 5-chloro-2-[(ethoxy-carbonyl)amino]-3-methylbenzoic acid (i.e. the product of Reference Example 1) (74.0 g, 0.288 mol) and toluene (300 mL). The mixture was heated at 60-65° C. while phosphorus tribromide (39 g, 0.144 mol) was added over about 60 minutes. The mixture was heated at 65° C. for about 30 minutes, which resulted in no more than 0.2% of the intermediate 6-chloro-2-ethoxy-8-methyl-4H-3,1-benzoxazin-4-one remaining according to HPLC analysis. The mixture was sparged with nitrogen to remove hydrogen bromide and ethyl bromide, and then cooled to 20° C. The product was collected under filtration, and the filter cake was successively washed with toluene (30 mL) and water (2×100 mL), and then suction dried. Drying the collected solid in a vacuum oven to constant weight provided the title compound (59 g, about 97% purity by HPLC analysis). A portion of the dried product was recrystallized by dissolving in N,N-dimethylformamide (4 volumes) at 60° C. and cooling to 20° C. to provide a sample of 99% purity melting at >250° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:21]([O:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[C:21]([O:25][C:26](=[O:35])[C:27]1[CH:28]=[CH:29][C:30]([CH2:33][O:10][CH2:9][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:31][CH:32]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COCc1ccc(C(=O)OC(C)(C)C)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
168.5 mg (0.67 mmol) of tert.-butyl-[(2S)-1-hydroxy-3-phenylpropane-2-yl]carbamate were added to 4.9 ml of DMF under argon and mixed with 53.6 mg (1.3 mmol) of sodium hydride (as 60% dispersion in liquid paraffin) at a temperature of 0° C. After 30 minutes 200 mg (0.74 mmol) of tert.-butyl-4-(brommethyl)benzoate was added at a temperature of 0° C. Following completion of measuring, the batch was stirred for 2 hours at RT. Afterwards, the batch was evaporated in the rotation steam boiler, the residue absorbed in ice water and the compound extracted with 50 ml of dichlormethane each. The organic phases were washed in saturated sodium hydride solution, dried over magnesium sulphate and evaporated in a vacuum. The raw product thus obtained is being purified by means of preparative HPLC. 50.2 mg (17% o. th.) of the intermediate of tert.-butyl-4-[({(2S)-2-[(tert.-butoxycarbonyl)amino]-3-phenylpropyl}oxy)methyl]benzoate were obtained.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21]>CS(C)=O.C1COCC1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[C:12]([CH3:4])[C:11]=1[N+:20]([O-:22])=[O:21]
Reactant: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(C(F)(F)F)c(C)c1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 5 h

Procedure:
1-methoxy-3-methyl-2-nitro-4-(trifluoromethyl)benzene was prepared by a procedure similar to that described in “Synthesis of 3,6-Disubstituted 2-Nitrotoluenes by Methylation of Aromatic Nitro Compounds with Dimethylsulfonium Methylide”, Kitano, Masafumi, Ohashi Naohito, Synthetic Communications, 30(23), 4247-4254, 2000. To a suspension of NaH (60% by wt. in mineral oil, 362 mg, 9.04 mmol) and trimethylsulfonium iodide (1.84 g, 9.04 mmol) in DMSO (17 ml) and THF (6.7 ml) was added 4-methoxy-3-nitrobenzotrifluoride (1.00 g, 4.52 mmol) as a solution in DMSO (2.7 ml). The reaction mixture was allowed to stir at 10-20° C. for 5 hrs. The reaction mixture was quenched by addition to ice water. The aqueous layer was separated and extracted with toluene 7 times. The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed by distillation at reduced pressure. The residue was purified by automated silica gel chromatography (100% hexanes to 98:2 hexanes:ethylacetate) to provide 1-methoxy-3-methyl-2-nitro-4-(trifluoromethyl)benzene.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][NH:11]C(OC(C)(C)C)=O)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20].C(OCC)C>C(Cl)Cl>[NH2:1][C@H:2]([C:8]([NH:10][NH2:11])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7].[F:22][C:21]([C:19]([OH:25])=[O:20])([F:24])[F:23]
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@@H](N)CCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: NNC(=O)[C@@H](N)CCC(=O)O

Procedure:
A solution of EMC-Glu-NH—NH-BOC (32.4 g) and TFA (165 mL) in DCM (165 mL) was stirred at RT for 80 min after which diethyl ether (4 L) was added. The precipitated product was collected by suction filtration, washed with ether and dried yielding EMC-Glu-NH—NH2 TFA (20 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][O:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][OH:19])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][O:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:17][CH2:18][O:19][S:61]([CH3:60])(=[O:63])=[O:62])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 2 h

Procedure:
To an ice-bath cooled solution of Intermediate 141b (132 mg, 0.19 mmol) in DCM (2.0 mL) was added DIPEA (135 μL, 0.78 mmol) followed by methanesulfonyl chloride (30 μL, 0.39 mmol). The reaction mixture was stirred for 2 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the subsequent step without further purification. LCMS (Method 4): Rt 3.30 min, m/z 759 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([NH:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])[CH2:35][S:34][C:33]1=[O:38])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1CCCCC1.NCCN1C(=O)/C(=C/C2C=CC=CC=2)/SC1=O>>[NH2:29][CH2:30][CH2:31][N:32]1[C:36](=[O:37])/[C:35](=[CH:6]/[C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)/[S:34][C:33]1=[O:38]
Reactant: O=C1CSC(=O)N1CCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: NCCN1C(=O)S/C(=C\c2ccccc2)C1=O
Solvent: C1CCNCC1
Product: Cc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1

Procedure:
The title compound 30d was prepared from 4-methylbenzaldehyde (73 μL, 0.62 mmol), compound 29 (250 mg, 0.62 mmol) and piperidine (7.0 μL, 0.062 mmol) in a manner similar to that described for 30a in 36.0% (83 mg) yield as a cream solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[C@H:7](N)[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12].P([O-])([O-])([O-])=O.N=C=N>O>[CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[CH2:7][C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: N=C=N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Temperature: 4 °C

Procedure:
A conjugate of penicillanic acid and peroxidase was prepared as follows. An alkaline solution (pH=9.0) containing 28.1 mg 6 amino penicillanic acid is mixed with a phosphate buffered peroxidase solution containing 8.8 mg peroxidase and 8.2 mg carbodiimide in water. The reaction mixture is maintained at 4° C. for 24 hours while stirring. As a result, the peroxidase and 6 amino penicillanic acid became covalently linked. The conjugate solution is next dialyzed against 0.05 M phosphate buffered saline (PBS); penicillin activity disappears from the PBS after the first change of solution. After four solution changes, the penicillin-peroxidase conjugate is ready for use.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:27][C:28]2[CH:36]=[CH:35][C:31]3[NH:32][CH:33]=[N:34][C:30]=3[CH:29]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17]2)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:37].[OH-].[Na+]>>[NH2:1][C:2]1[C:3]([Cl:37])=[CH:4][C:5]([S:9]([NH:12][CH:13]([CH2:27][C:28]2[CH:36]=[CH:35][C:31]3[NH:32][CH:33]=[N:34][C:30]=3[CH:29]=2)[C:14]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]2)=[O:15])(=[O:10])=[O:11])=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(Cl)cc(S(=O)(=O)NC(Cc2ccc3[nH]cnc3c2)C(=O)N2CCC(C(=O)O)CC2)cc1Cl

Procedure:
Prepared from 4-amino-N-[1-(1H-benzimidazol-5-yl-methyl)-2-(4-carbethoxy-piperidin-1-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide and 1N sodium hydroxide solution analogously to Example 24.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:20]([CH3:32])[N:21]=[CH:22][C:23]=4[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:34][CH2:35][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:20]([CH3:32])[N:21]=[CH:22][C:23]=4[C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:25])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(O)c3)nc2c1
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(OCF)c3)nc2c1

Procedure:
This compound was prepared in the same manner as described in example 81 starting from 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (Example 80) (250 mg, 0.559 mmol) and toluene-4-sulfonic acid fluoromethyl ester (171 mg, 0.838 mmol). White solid (10 mg, 4%). LC-MS: m/z=480.4 [M+H]+.
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(CCC2C=CC(O)=CC=2)C=1.Cl.ClCCN1CCCCCC1.C[O:42][C:43]1[CH:44]=[CH:45][C:46]([CH:67]2[CH2:76][CH2:75][C:74]3[C:69](=[CH:70][CH:71]=[C:72]([O:77]C)[CH:73]=3)[CH2:68]2)=[C:47]([CH2:49][CH2:50][C:51]2[CH:66]=[CH:65][C:54]([O:55][CH2:56][CH2:57][N:58]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]3)=[CH:53][CH:52]=2)[CH:48]=1>>[N:58]1([CH2:57][CH2:56][O:55][C:54]2[CH:65]=[CH:66][C:51]([CH2:50][CH2:49][C:47]3[CH:48]=[C:43]([OH:42])[CH:44]=[CH:45][C:46]=3[CH:67]3[CH2:76][CH2:75][C:74]4[CH:73]=[C:72]([OH:77])[CH:71]=[CH:70][C:69]=4[CH2:68]3)=[CH:52][CH:53]=2)[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(OCCN3CCCCCC3)cc1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(O)cc1)C2
Agent: Cl
Agent: ClCCN1CCCCCC1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1CCc1ccc(OCCN3CCCCCC3)cc1)C2
Yield: 68.1 %

Procedure:
Synthesized from 4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenoxy}ethyl}azepane (174 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (112 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@H:12]2[C:20]([OH:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.Cl>COCCOC.O>[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@H:12]2[C:20]([OH:22])=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(O)[C@@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 2.15 g (4.66 mmol) of the 2,3-dihydro-1-[(4-iodophenyl)sulfonyl]-(2S)-1H-indole-2-carboxylic acid obtained according to Preparation IV(a) in 40 ml of DME is prepared and 13 ml of water are added, followed by 1.24 g (11.6 mmol) of sodium carbonate, 380 mg (0.46 mmol) of PdCl2dppf and 1.77 g (9.3 mmol) of 2-(trifluoromethyl)phenylboronic acid. The reaction medium is stirred at room temperature for 30 min and then at 90° C. for 30 min. After cooling, water is added and the medium is acidified with N hydrochloric acid. The mixture is then extracted with ethyl acetate. The organic phase obtained is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by reversed phase chromatography on RP18-grafted silica gel using an acetonitrile/water/trifluoroacetic acid mixture (8/2/0.02; v/v/v) as the eluent to give the product in the form of an orange oil (yield=80%).
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=4)=[C:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C[S-].[Na+]>CN(C)C=O>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:26][C@H:25]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[C@H:24]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@@H:23]4[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: COc1ccc(C2=C3[C@H]4CCCCC4=CC[C@H]3[C@@H]3CC45OCCOC4(OCCO5)[C@@]3(C)C2)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12C[C@H](c3ccc(O)cc3)[C@H]3[C@@H](CC=C4CCCC[C@@H]43)[C@@H]1CC13OCCOC12OCCO3

Procedure:
130 g of the compound prepared in Example 1 c) are dissolved in 1.4 l of absolute dimethylformamide, 7.81 g of sodium methanethiolate are added and the reaction mixture is heated under reflux for 3 hours. The mixture is cooled and then poured onto water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed repeatedly with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel with a mixture of ethyl acetate/hexane and 76.9 g of 3,3;17,17-Bis-(ethylenedioxy)-11β-(4-hydroxyphenyl)-5-oestrene are obtained in the form of a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[C:15]([O:19][C:20](=[O:25])[C@@H:21]([NH2:24])[CH2:22][CH3:23])([CH3:18])([CH3:17])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CN=CC=1)C.C(Cl)CCl>[C:15]([O:19][C:20](=[O:25])[C@@H:21]([NH:24][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[CH2:22][CH3:23])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC[C@H](NC(=O)c1cc(Cl)ccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a stirred solution of 5-chloro-2-nitro-benzoic acid (4.68 g) in anhydrous tetrahydrofuran (100 ml) at 0° C., was added (S)-2-amino-butyric acid-tert-butyl ester hydrochloric acid salt (5 g), HOBt (3.45 g), DMAP (2.98 g), followed by EDC (4.88 g) and diisopropylethylamine (3.30 g). The reaction mixture was stirred for 10 minutes then warmed to room temperature and stirred for 16 hours before concentration at reduced pressure. The resulting residue was partitioned between EtOAc (100 ml) and saturated sodium bicarbonate solution (100 ml), the organic layer separated and further washed with 1M hydrochloric acid and saturated brine solution, dried (MgSO4), filtered and concentrated to give the sub-title compound as a pale yellow oil (6.82 g, 68% yield). 1H NMR (400 MHz, CDCl3) δ 8.05 (1H, d), 7.55 (2H, m), 6.4 (1H, m) 4.7 (1H, m), 2.1 (1H, m), 1.95 (1H, m), 1.5 (9H, s), 1.0 (3H, t) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)([N:22]1C=CN=C1)=O.N>CN(C=O)C>[F:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4]([NH2:22])=[O:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1c(F)cncc1Nc1ccc(I)cc1F
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
5.000 g of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (13.294 mmol, 1. eq.) and 4.980 g of 1,1′-carbonyldiimidazol (30.710 mmol. 2.31 eq) were weighed into a round-bottom flask. 650 mL of dry DMF were added under a nitrogen atmosphere and the resulting mixture was stirred at 60° C. for 1.5 hours. The mixture was cooled to 3° C. in an ice bath, then ammonia (25 weight % in water) was added dropwise and the mixture stirred at room temperature for 18 hours. The resulting slurry was filtered off, the precipitate was rinsed with water and then dried in vacuo to yield 2.54 g (6.36 mmol, 48%) of the analytically pure target compound.
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3.[C:17](Cl)([Cl:19])=[O:18].C(N(CC)CC)C>ClCCl.C1C=CC=CC=1>[N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:8]3[C:17]([Cl:19])=[O:18]
Reactant: O=C(Cl)Cl
Reactant: c1ccc2c(c1)NC1CCCc3onc-2c31
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(Cl)N1c2ccccc2-c2noc3c2C1CCC3

Procedure:
In 50 ml of dichloromethane was dissolved 4.08 g of 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine. Phosgene in benzene (26 ml of 12.5% phogene in benzene) was then added all in one portion. This solution was then chilled with an ice/water bath as a solution of triethylamine (2.92 g) in 20 ml of dichloromethane was added dropwise. After the addition was complete (30 minutes), the reaction mixture was washed with dilute hydrochloric acid and then dried and concentrated. The residue obtained in this manner was recrystallized from dichloromethane/hexane to give 3.66 g of product, m.p. 189° C. (d).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27](Cl)[C:28](OCC)=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][C:8]2=[O:34])(=[O:3])[CH3:2].[NH2:36][C:37]([NH2:39])=[S:38].S1(CCCC1)(=O)=O>>[C:1]([O:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]3[S:38][C:37](=[NH:36])[NH:39][C:28]3=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][C:8]2=[O:34])(=[O:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Solvent: O=S1(=O)CCCC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc(CC3SC(=N)NC3=O)cc1)O2

Procedure:
A mixture of 2.0 g of ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate (prepared as described in Preparation 45), 0.62 g of thiourea, and 3.1 g of sulfolane was heated at 120°-125° C. for 7 hours under a nitrogen stream. The reaction mixture was extracted with benzene and then the benzene was distilled off from the extract. Water was then added to the residue and the oily layer was separated. The oily layer was subjected to silica gel column chromatography [successively with an eluent of (1) a 2:1 by volume mixture of n-hexane and ethyl acetate, (2) ethyl acetate, and (3) a 1:1 by volume mixture of ethyl acetate and ethanol] to yield 5-[4-(6-acetoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2-iminothiazolidin-4-one in a yield of 0.74 g. This was further purified by recrystallization from ethyl acetate, to give the purified title compound melting at was 218°-222° C.