Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([O:15][CH3:16])=[CH:4][N:3]=1.[F-:17].C[N+](C)(C)C>CS(C)=O.C(OC(=O)C)C>[F:17][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([O:15][CH3:16])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cnc(Cl)c2ccc(N(C)C)cc12
Agent: C[N+](C)(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cnc(F)c2ccc(N(C)C)cc12
Temperature: 110 °C
Yield: 55.9 %

Procedure:
To a solution of 1-chloro-4-methoxy-N,N-dimethylisoquinolin-6-amine (250 mg, 1.056 mmol) in DMSO (5 mL) was added tetramethylammonium fluoride (295 mg, 3.17 mmol) and the solution was heated to 110° C. for 1 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 80% DCM/hexanes. The product fractions were collected and the solvent removed under vacuum to give 1-fluoro-4-methoxy-N,N-dimethylisoquinolin-6-amine (130 mg, 56% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (d, J=9.3 Hz, 1H), 7.37 (d, J=1.3 Hz, 1H), 7.28-7.24 (m, 1H), 7.17 (s, 1H), 4.04 (s, 3H), 3.20 (s, 6H); MS m/z 221.0 (M++1).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:25]([C:27]1[NH:28][CH:29]=[CH:30][N:31]=1)[CH3:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:28]3[CH:29]=[CH:30][N:31]=[C:27]3[CH2:25][CH3:26])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: CCc1ncc[nH]1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2C)o1
Temperature: 125 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (1.00 g), 2-ethylimidazole (960 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml), and the solid precipitate was filtered, air-dried and recrystallized from acetone-isopropyl ether to give 4-(4-chlorophenyl)-2-(2-ethyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole as pale yellow prisms (438 mg, 38%). Melting point 91-92° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11](O)C)=C[CH:2]=1.CN1C2C=CC=[C:19]([CH:24]=[O:25])C=2C=C1.C[Mg]I.C(OCC)C>O1CCCC1>[CH3:2][N:1]1[C:10]2[C:5](=[C:6]([CH:24]([OH:25])[CH3:19])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:11]1
Reactant: Cn1ccc2c(C=O)cccc21
Reactant: CC(O)c1ccnc2ccccc12
Agent: C[Mg]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cccc2c1ccn2C

Procedure:
The title compound was prepared by the same procedure for 1-quinolin-4-yl-ethanol from 1-methyl-1H-indole-4-carbaldehyde (2.8 g, 17.6 mmol), 3 M methyl magnesium iodide solution in diethyl ether (10 mL, 30 mmol, Aldrich) and anhydrous tetrahydrofuran (20 mL). The crude title compound obtained in form as yellow oil in 97% yield (3.0 g, 17.1 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:26]([Cl:25])[CH:27]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N)c1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2NCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzyl]carbamate (3.49 g, 10 mmols), 3,4-dichlorobenzyl chloride (2.1 ml, 15 mmols), potassium carbonate (1.38 g. 10 mmols) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 12 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with brine, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to give an oil of tert-butyl[3-[5-chloro-2-(3,4-dichlorobenzylamino)phenoxy]benzyl]carbamate (3.03 g, 59.8%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([N:22]3[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[C:17]([F:29])[CH:16]=2)[CH2:10]1)(C)(C)C.C1(C(C2C=CC=CC=2)CCO[C:41](=[S:45])[CH:42]([F:44])[F:43])C=CC=CC=1>>[F:21][C:19]1[CH:20]=[C:15]([N:11]2[CH2:10][CH:9]([CH2:8][NH:7][C:41](=[S:45])[CH:42]([F:44])[F:43])[O:13][C:12]2=[O:14])[CH:16]=[C:17]([F:29])[C:18]=1[N:22]1[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Reactant: FC(F)C(=S)OCCC(c1ccccc1)c1ccccc1
Product: O=C1C=CN(c2c(F)cc(N3CC(CNC(=S)C(F)F)OC3=O)cc2F)CC1

Procedure:
The title compound compound is prepared from {3-[3,5-difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (250 mg, 0.59 mmol) and difluorothioacetic acid-O-(3,3-diphenyl-propyl) ester (420 mg, 1.25 mmol) following the method described for Example 10. The crude product is purified by silica gel column chromatography (gradient 50 to 100% EtOAc in hexanes). MS (m/z): 418 [M+1]+. 1H NMR (300 MHz, CDCl3) δ11.13 (br. s, 1H), 7.46–7.38 (m, 3H), 6.49 (t, J=55.2 Hz, 1H), 5.07–4.98 (m, 2H), 4.19 (t, J=9.1 Hz), 1H), 4.02–3.76 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C@@H:28]([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[CH3:30][N:29]1[C:22]2[N:23]([C:24](=[O:26])[N:25]=[C:20]([O:18][CH2:17][C:15]3[CH:14]=[CH:13][C:3]([O:4][C:5]4[CH:6]=[N:7][CH:8]=[C:9]([CH:12]=4)[C:10]#[N:11])=[C:2]([F:1])[CH:16]=3)[CH:21]=2)[CH2:27][C@@H:28]1[CH3:31]
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: N#Cc1cncc(Oc2ccc(CO)cc2F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cncc(C#N)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 5-(2-fluoro-4-(hydroxymethyl)phenoxy)nicotinonitrile and (S)-7-chloro-1,2-dimet-hyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:40])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[C:21]=3[NH:26][C:27]([O:29][CH:30]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])[CH3:31])=[O:28])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)C.Cl>CO.O>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:30]([O:29][C:27]([NH:26][C:21]2[C:22]([CH3:25])=[N:23][O:24][C:20]=2[C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:40])=[O:5])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)=[O:28])[CH3:31])=[C:33]([F:39])[CH:34]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccc(Cl)cc3F)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)OC(C)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Excess lithium hydroxide was added to a solution of (4′-{-4-[1-(4-chloro-2-fluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester (0.100 g, 0.19 mmol) in methanol and water, and the reaction was stirred at room temperature overnight. The mixture was acidified with 1N aqueous HCl and extracted with EtOAc, and the combined organic layers were dried, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([O:9][CH3:10])=[O:8])[C@@H:4]([CH3:6])[OH:5].C(N(CC)CC)C.[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:24]([NH:2][C@H:3]([C:7]([O:9][CH3:10])=[O:8])[C@@H:4]([CH3:6])[OH:5])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Temperature: 0 °C
Yield: 86.3 %

Procedure:
Methyl L-threoninate hydrochloride (16.9 g, 100 mmol), prepared by the method of Lall, J. Org. Chem., 67, pp. 1536-1547, was dissolved in 200 mL of anhydrous CH2Cl2 and the solution was cooled to 0° C. under N2. Triethylamine (27.8 mL, 200 mmol) was then added followed by triphenylmethylchloride (27.9 g, 100 mmol) and the reaction was stirred and allowed to warm to ambient temperature overnight. The reaction mixture was then filtered and the resulting solid was rinsed with several portions of CH2Cl2. The combined filtrates were concentrated under reduced pressure and the resulting syrup was dissolved in 150 mL of ethyl acetate and then washed successively with 100 mL of saturated aqueous NaHCO3 solution, 100 mL of 10% aqueous citric acid solution, 50 mL of H2O and 50 mL of brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a syrup. The syrup was treated with 200 mL of hexanes and the mixture was stirred rapidly overnight to give a white solid. The solvent was decanted and the solid was washed with an additional portion of hexanes. The mixture was filtered and the isolated white solid was dried under vacuum for several days to give methyl N-trityl-L-threoninate (32.4 g) as a sticky, white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]3[C:20]([C:21]=2I)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[CH2:30]([OH:34])[CH2:31][C:32]#[CH:33].O>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]3[C:20]([C:21]=2[C:33]#[C:32][CH2:31][CH2:30][OH:34])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: C#CCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)c(I)c2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)c(C#CCCO)c2ccccc21
Temperature: 50 °C
Reaction time: 3.7 h
Yield: 86.6 %

Procedure:
3-Amino-6-[1-(tert-butoxycarbonyl)-3-iodoindol-2-yl]phtalimide (150 mg, 0.298 mmol) was dissolved in diethylamine (7.5 mL), and the solution was added with bis(triphenylphosphine)dichloropalladium (16.7 mg, 0.0234 mmol), copper iodide (11.4 mg, 0.0596 mmol) and 3-butyn-1-ol (0.226 mL, 2.98 mmol), followed by stirring at 50° C. for 3.7 hours under argon atmosphere. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 3-amino-6-[1-(tert-butoxycarbonyl)-3-(4-hydroxy-1-butynyl)indol-2-yl]phtalimide (115 mg, yield 87%).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[C:2]=[S:3].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH2:30])=[CH:18][CH:17]=1>O1CCCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:30][C:2]([NH:1][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]2)=[S:3])=[CH:18][CH:17]=1
Reactant: Nc1cnccc1NCc1ccc(F)cc1
Reactant: CCOC(=O)N1CCC(N=C=S)CC1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(=S)Nc2cnccc2NCc2ccc(F)cc2)CC1
Yield: 52 %

Procedure:
A mixture of 84.7 parts of ethyl 4-isothiocyanato-1-piperidinecarboxylate, 86.8 parts of N4 -[(4-fluorophenyl)-methyl]-3,4-pyridinediamine and 450 parts of tetrahydrofuran was stirred and refluxed for 3 hours. The reaction mixture was evaporated and the residue was crystallized from acetonitrile, yielding 90 parts (52%) of ethyl 4-[[[[4-[[(4-fluorophenyl)methyl]amino]-3-pyridinyl]-amino]thioxomethyl]amino]-1-piperidinecarboxylate; mp. 166° C. (15).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>ClCCl>[CH3:20][O:19][C:17](=[O:18])[CH:13]([NH:12][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:14]([CH3:16])[CH3:15]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COC(=O)[C@H](N)C(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Step 1A [Intermediate 1] To a dry round-bottom flask was added 4-Bromo-benzenesulfonyl chloride (12.2 g, 47.7 mmol, 1 equiv.), anhydrous methylene chloride (170 mL), and H-D-Val-OMe (8.0 g, 47.7 mmol, 1 equiv.). The mixture was cooled to 0° C. in an ice bath followed by the addition of Hunig base (19.11 mL, 109.7 mmol, 2.3 equiv.). The reaction mixture was allowed to warm to room temperature and was stirred overnight. Reaction was complete as determined by TLC. The reaction mixture was then diluted with dichloromethane (100 mL) and washed with brine. The organic layer was dried over anhydrous MgSO4, solvent evaporated to yield 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester in 96% yield (16.0 g). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.87 (d, J=6.82 Hz, 3 H) 0.96 (d, J=6.82 Hz, 3 H) 2.04 (m, 1 H) 3.49 (s, 3 H) 3.74 (d, J=14.40 Hz, 1 H) 5.10 (d, J=9.85 Hz, 1 H) 7.66 (m, 4 H
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:14][CH2:15][O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18]>C(O)C>[OH:1][C:11]1[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[C:2]=1[N:22]1[CH2:21][CH2:20][N:19]([C:17]([O:16][CH2:15][CH3:14])=[O:18])[CH2:24][CH2:23]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C1c2ccccc2C(=O)C2OC12
Solvent: CCO
Product: CCOC(=O)N1CCN(C2=C(O)C(=O)c3ccccc3C2=O)CC1
Reaction time: 24 h
Yield: 44.9 %

Procedure:
A mixture of 1.174 g of 2,3-epoxy-2, 3-dihydro-1,4-naphthoquinone, 1.58 g of ethyl-N-piperazinocarboxylate and 100 ml of absolute ethanol was stirred for 24 hours, then evaporated. The residue was chromatographed on silica gel, eluting with 5% methanol in chloroform, giving 1.0 g of the desired product, mp 115°-118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCCC1.[F:29][C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=3)(=[O:38])=[O:37])=[CH:10][CH:9]=2)[C:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:6]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc(N)ccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Yield: 74.4 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-phenyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 1 from 0.4 g of 5-amino-N-tert-butoxycarbonyl-3-phenyl-1H-indazole, 15 ml of tetrahydrofuran, 0.36 ml of triethylamine and 0.27 g of 3-fluorobenzenesulfonyl chloride. 0.45 g of N-(N-tert-butoxycarbonyl-3-phenyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of an ochre solid melting at 100° C.
Reaction SMILES: C1([O:7][C:8](=[O:16])[C@@:9]2([C:12]([F:15])([F:14])[F:13])[O:11][CH2:10]2)C=CC=CC=1.O.[OH-].[Na+]>CO>[O:11]1[CH2:10][C@@:9]1([C:12]([F:15])([F:14])[F:13])[C:8]([OH:16])=[O:7]
Reactant: O=C(Oc1ccccc1)[C@]1(C(F)(F)F)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@]1(C(F)(F)F)CO1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Into a 100 ml three-necked round-bottomed flask equipped with a dropping funnel and a stirrer, the (S)-2,3-epoxy-2-trifluoromethylpropionic acid phenyl ester (7.2 g, 31.0 mmol) obtained in Example 7, methanol (20 ml) and water (20 ml) were charged and cooled to 0° C. on an ice bath, whereupon 3N sodium hydroxide aqueous solution (30 ml, 90 mmol) was dropwise added over a period of one hour by means of the dropping funnel, and stirring was further carried out at the same temperature for one hour. After completion of the reaction, methanol was distilled off, followed by extraction with diisopropyl ether (30 ml×twice). Then, hydrochloric acid was added to adjust the pH to 3, followed by extraction with ethyl acetate (30 ml×3 times). The obtained organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration to obtain the desired (S)-2,3-epoxy-2-trifluoromethylpropionic acid (4.17 g, 26.7 mmol, yield: 87%, optical purity: 78% ee).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:7]=2[CH2:6]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH:4]=[C:5]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[O:9][C:8]4[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:7]=4[CH2:6]3)[CH2:32][CH2:33]2)=[CH:24][CH:23]=1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: Oc1cccc2c1CC(=CCCBr)c1cccnc1O2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(F)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 23 h
Yield: 38.6 %

Procedure:
To a solution of 5-(3-bromopropylidene)-5,11-dihydro-7-hydroxy-[1]benzoxepino[2,3-b]pyridine (2.59 g) in DMF (10 ml) was added 4-(4-Fluorophenyl)-4-hydroxypiperidine (1.02 g) and triethylamine (835 μM). The solution was stirred at room temperature for 23 hours. The reaction was quenched with water, extracted with ethyl acetate, and evaporated in vacuo. The residue was purified by silica gel chromatography (87:10:3 ethyl acetate:methanol:triethylamine) to yield 0.9 g (39%) of the title compound. 1H-NMR (DMSO) d: 1.64-1.69 (2H, m), 1.74-1.85 (2H, m), 2.27-2.52 (8H, m), 4.81 (1H, s), 5.16 (2H, brs), 6.08 (1H, t), 6.62-6.71 (3H, m), 7.12 (2H, t), 7.40-7.51 (3H, m), 7.72 (1H, dd), 8.48 (1H, dd), 9.09 (1H, s).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:14]1[CH:15]=[C:16]([NH:23][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH3:13].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>ClCCl>[CH2:12]([C:14]1[CH:15]=[C:16]([NH:23][C:24]([C:25]2([CH3:27])[CH2:26][O:6]2)=[O:28])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH3:13]
Reactant: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])c(CC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Product: CCc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
3-Chloroperoxybenzoic acid (14.71 g, 0.08524 mol) was added in portions to the refluxing solution of N-(3-ethyl-4-nitrophenyl)-2-methylacrylamide (6.68 g, 0.02852 mol) and 2,6-di-tert-butyl-4-methylphenol (149 mg) in dichloromethane (180 ml). After refluxing for 5 h the reaction mixture was allowed to cool to room temperature. The precipitated 3-chlorobenzoic acid was filtered, and the filtrate was extracted three times with 1M Na2CO3 and water. The organic phase was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using dichloromethane as an eluent. 1H NMR (400 MHz, DMSO-d6): 1.20 (3H, t, 3J=7.4 Hz), 1.55 (3H, s), 2.84 (2H, q, 3J=7.4 Hz), 2.99 (1H, d, 2Jgem=5.1 Hz), 3.06 (1H, d, 2Jgem=5.1 Hz), 7.81 (1H, dd, 3J=9.0 Hz, 4J=2.3 Hz), 7.85 (1H, d, 4J=2.2 Hz), 7.97 (1H, d, 3J=9.0 Hz), 9.88 (1H, s, —NHCO—).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
To a suspension of (+)-(4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one (264 mg, 0.786 mmol), in 3.0 mL of 1,4-dioxane was added DDQ (196 mg, 1.1 equiv.) followed by bistrimethyl-silyltrifluoromethyl acetamide (911 mg, 4.5 equiv.), and the solution was stirred at room temperature for 2 h, then heated at 100° for 20 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2M sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration from ether/hexanes, 55 mg (21%) of the title compound as an orange solid. mp 205°-206°. FDMS m/e=334. α[D]589 =+57.23 (c=0.66, chloroform).