Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:28]2[CH:40]=[CH:41][CH:42]=[CH:43][C:27]=2[O:26][CH2:25]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2=CC=CC=C2[C:13]1=[O:22])=[O:5])[CH3:2].[OH2:44].NN>C(O)C>[C:36]([O:44][C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[C:28]2[CH:40]=[CH:41][CH:42]=[CH:43][C:27]=2[O:26][CH2:25]1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:22])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCOC(=O)[C@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reactant: O
Agent: NN
Solvent: CCO
Product: CCOC(=O)[C@H](CCCCCNC(=O)OC(C)(C)C)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 175 %

Procedure:
A mixture of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.65 g), hydrazine hydrate (0.27 g) and ethanol (10 ml) is allowed to stand overnight at room temperature. The mixture is concentrated in vacuo, diluted with water (50 ml) and extracted with ethyl acetate (50 ml×4). To a mixture of the organic extract, water (50 ml) and sodium bicarbonate (0.65 g) are added dropwise di-tert-butyl dicarbonate (0.36 g) with stirring at room temperature. After stirring for 30 minutes, the ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is subjected to silica gel column chromatography using hexane:ethyl acetate (2:1-1:1) as an eluent to yield tert-butyl 3(S)-[6-tert-butoxycarbonylamino-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.54 g) as a colorless oil.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:34][C:35]4[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)=[N:17][CH:18]=[C:19]([C:21]([N:24]4[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]4)([CH3:23])[CH3:22])[CH:20]=3)[N:12]=[C:11]([CH3:43])[N:10]=2)=CC=1.OS(C(F)(F)F)(=O)=O.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:42][O:41][C:38]1[N:37]=[CH:36][C:35]([NH:34][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:43])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([C:21]([N:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:28][CH2:29]3)([CH3:23])[CH3:22])=[CH:18][N:17]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(C)(C)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 26.7 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(2-(4-(methylsulfonyl)piperazin-1-yl)propan-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.034 g, 0.045 mmol) in trifluoroacetic acid (1 mL) was treated with triflic acid (0.032 mL, 0.361 mmol). The light yellow reaction was sealed and heated at 80° C. After 30 min the reaction was cooled with ice and basified with 10N NaOH, then partitioned between water and DCM. The aqueous layer was extracted with DCM (3×) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This material was dissolved in DMSO and purified by prep HPLC (5-70% MeCN/H2O with 0.1% TFA). Product-containing fractions were concentrated, then treated with sat'd aq. NaHCO3 and DCM. The aq. layer was extracted with DCM (3×) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(2-(4-(methylsulfonyl)piperazin-1-yl)propan-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.006 g, 0.012 mmol, 25.9% yield) as a yellow solid. m/z (ESI, +ve ion) 514 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.70 (s, 1H); 8.83 (d, J=2.5 Hz, 1H); 8.53 (d, J=2.7 Hz, 1H); 8.45 (d, J=2.5 Hz, 1H); 8.19 (dd, J=8.9, 2.8 Hz, 1H); 7.61-7.93 (m, 2H); 6.81 (d, J=9.0Hz, 1H); 3.84 (s, 3H); 3.01-3.16 (m, 4H); 2.86 (s, 3H); 2.48-2.63 (m, 4H); 2.44 (s, 3H); 1.36 (s, 6H).
Reaction SMILES: N1CCCCC1.[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:23][CH:22]=1)=[O:19])=[O:13])([CH3:10])([CH3:9])[CH3:8].O>CN(C=O)C>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18]([NH:17][CH2:16][CH2:15][NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])=[O:19])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Solvent: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.3 %

Procedure:
Piperidine (9.68 mL, 97.75 mmol, 5.0 eq) is added at room temperature to a stirred solution of N-{4-[({2-[(tert-butoxy)carbonylamino]ethyl}amino)carbonylamino]-phenyl}(fluoren-9-ylmethoxy)carboxamide (10.10 g, 19.55 mmol, 1.0 eq) in DMF (140 mL). After 2 hours stirring at room temperature, water is added to the reaction mixture and precipitation occurred. The resulting mixture is filtered, and the liquid phase is concentrated to afford 6.75 g of the expected product as an orange oil:
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][O:4][CH2:5]2.[C:7]1([Mg]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Cu]I.C1COCC1>[C:7]1([C@@H:2]2[CH2:3][O:4][CH2:5][C@H:6]2[OH:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1OCC2OC12
Reactant: Br[Mg]c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: O[C@@H]1COC[C@H]1c1ccccc1

Procedure:
A second batch was obtained according to the above procedure reacting 3,4-epoxy-tetrahydrofuran (1.0 g, 11.62 mmol), phenylmagnesium bromide (3.872 mL, 11.62 mmol), CuI (155.67 mg, 0.813 mmol) and dry THF (total volume of 3.6 mL). The residues obtained from the above two batches was mixed and purified by flash chromatography (silica; DCM in MeOH 0/100 to 10/90). The desired fractions were collected and evaporated in vacuo to give I-42 (5.5 g, 74%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([OH:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)(C)C.C([O-])(O)=O.[Na+]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(O)c1cccnc1Cl
Agent: [Cr+6]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a solution of 1-(2-chloropyridin-3-yl)ethanol (XII) in dry acetone at −30° C. under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at −30° C. and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated aqueous NaHCO3 solution. The solution was filtered through a bed of Celite. The solids were washed by DCM. The organic phase of the filtrate was separated and the aqueous phase extracted with DCM (2×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield 1-(2-chloropyridin-3-yl)ethanone (XIII) as a brown liquid (0.72 g, 4.63 mmol, 77% yield). 1H NMR (CDCl3) δ ppm 2.71 (s, 3H), 7.35 (dd, J=7.63 Hz, J=4.80 Hz, 1H), 7.91 (dd, J=7.54 Hz, J=1.88 Hz, 1H), 8.55 (dd, J=4.71 Hz, J=1.88 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:12][C:13]([CH:15]=[CH:16][C:10]=2[CH:9]=[C:5]2[CH:6]=[CH:7][O:8][C:4]=12)=[O:14].[Br:17]Br>O1CCCC1>[CH3:1][O:2][C:3]1[C:11]2[O:12][C:13]([CH:15]=[CH:16][C:10]=2[C:9]([Br:17])=[C:5]2[CH:6]=[CH:7][O:8][C:4]=12)=[O:14]
Reactant: COc1c2occc2cc2ccc(=O)oc12
Reactant: BrBr
Solvent: C1CCOC1
Product: COc1c2occc2c(Br)c2ccc(=O)oc12
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
8-methoxypsoralen (4.32 g, 20.0 mmol), obtained from Aldrich Chemical Company was dissolved in tetrahydrofuran (50 mL). To the mixture was added dropwise, with stirring, elemental bromine (4.0 g, 25 mmol) over 20 min at room temperature. The reaction mixture turned red when bromine was added. Precipitate appeared in 5 min. Extra bromine was consumed by solvent tetrahydrofuran in an extended 2 hr stirring or by the addition of 10% sodium thiosulfate solution. The crude product was collected by filtration and was purified with recrystallization from ethanol to give the product 5-bromo-8-methoxypsoralen (5.38 g, 91% yield) as a white solid. mp 178-80° C. 1H--NMR (DMSO(dimethylsulfoxide)--d6, ppm): 8.22(d, J=2.2 Hz, 1H), 8.11 (d, J=9.9 Hz, 1H),7.01(d,J=2.2 Hz, 1H),6.53(d, J=9.9 Hz, 1H),4.17(s,3H).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][C:3]=1OC1C=CC=CC=1.NC1[C:40]2[C:39](=[O:41])[C:38]3[C:33](=CC=CC=3)[C:32](=O)[C:31]=2C(O)=CC=1Br.C1(O)C=CC=CC=1>[OH-].[K+]>[O:41]([C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:39]1[CH:40]=[CH:31][CH:32]=[CH:33][CH:38]=1
Reactant: Nc1c(Oc2ccccc2)cc(O)c2c1C(=O)c1ccccc1C2=O
Reactant: Nc1c(Br)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: [K+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Oc3ccccc3)cccc21

Procedure:
Ya. B. Shteinberg and S. S. Tkachenko, Zh. Prikl. Khim. 49 (1976) 4, 904-905, describe a process for the preparation of 1-amino-2-phenoxy-4-hydroxyanthraquinone in an aqueous medium. In this process, 1-amino-2-bromo-4-hydroxyanthraquinone is reacted with phenol in aqueous potassium hydroxide solution in the presence of dispersants at 150° C. The authors claim yields of 87-90%. On repeating this process with various dispersants, we were unable to obtain a phenoxyanthraquinone derivative which could be used as a dye. In every case, the content of 1-amino-2-phenoxy-4-hydroxyanthraquinone in the products was less than 80%.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(Cl)(Cl)=[NH2+].[Cl-].[C:24]([O:28][C:29](=[O:46])[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][C@@H:33]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:32]1=[O:45])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[C:24]([O:28][C:29](=[O:46])[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:13](=[O:15])[C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH:33]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:32]1=[O:45])([CH3:25])([CH3:27])[CH3:26]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Agent: [Cl-]
Agent: [NH2+]=C(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
In 20 ml of dimethylformamide was dissolved 1.25 g of carbobenzyloxy-L-proline. The solution was cooled to -10° C., then there was added 810 mg of phosgene iminium chloride, and the mixture was stirred for 2 hours. To the mixture were added dropwise 5 ml of dimethylformamide containing 1.8 g of (S)-2-oxopiperazine-1,3-diacetic acid di-t-butyl ester synthesized in Working Example 3, then 2 ml of triethylamine. The mixture was stirred for one hour. The reaction mixture was diluted with ethyl acetate and was poured into ice-water. The organic layer was washed with a 5% potassium hydrogensulfate and a saturated aqueous solution of sodium hydrogenphosphate. The extract solution was dried over anhydrous magnesium sulfate and was concentrated under reduced pressure to give a crude product. The crude product was purified by s silica gel chromatography (ethyl acetate) to afford 1.0 g of the title compound as amorphous powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[NH:5][C@@H:6]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14](=[O:25])[NH:15][C:16]1[N:17]=[C:18]2[N:22]([CH:23]=1)[CH:21]=[C:20](Br)[S:19]2)=[O:8])[CH3:2].[CH3:33][O:34][C:35](=[O:68])[NH:36][C@H:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]1[NH:49][C:50]([C:53]2[CH:58]=[CH:57][C:56](B3OC(C)(C)C(C)(C)O3)=[CH:55][CH:54]=2)=[CH:51][N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39]>>[CH3:33][O:34][C:35](=[O:68])[NH:36][C@H:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]1[NH:49][C:50]([C:53]2[CH:54]=[CH:55][C:56]([C:20]3[S:19][C:18]4=[N:17][C:16]([NH:15][C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[C:7](=[O:8])[C@H:6]([NH:5][C:4]([O:3][CH2:1][CH3:2])=[O:32])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:25])=[CH:23][N:22]4[CH:21]=3)=[CH:57][CH:58]=2)=[CH:51][N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39]
Reactant: CCOC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Product: CCOC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]4)cc3)sc2n1)c1ccccc1
Yield: 11 %

Procedure:
Compound A55 was synthesized from compounds 44 (0.125 mmol) and 8 (0.187 mmol), following the procedure as described for compound A1, to give compound A55 as a lyophilized white solid in 11% yield. MS (ESI, EI+) m/z=810.2 (MH+).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:13](=[O:21])[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[C:17]([N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:21])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)N1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)N1CCNCC1=O
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 4-tert-butyl-3-oxopiperazine-1-carboxylic acid benzyl ester (0.75 g, 2.58 mmol) in EtOH (5 mL). The reaction mixture was flushed with nitrogen and 10% Pd/C (67 mg, 0.13 mmol) was added. The reaction mixture was stirred under a hydrogen atmosphere for 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-tert-Butylpiperazin-2-one as grey oil (0.276 g, 69%). 1H NMR (300 MHz, CDCl3): δ 3.50 (s, 2 H), 3.37 (t, J=5.5 Hz, 2 H), 3.06 (t, J=5.5 Hz, 2 H), 1.48-1.41 (m, 9 H)
Reaction SMILES: [BH4-].[CH:2]1([NH:5][C:6](=[O:26])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([NH:14][C:15](=[O:25])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[CH:8]=2)[CH2:4][CH2:3]1>CO.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C.[Au]>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([NH:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[CH3:13])[C:6]([NH:5][CH:2]1[CH2:4][CH2:3]1)=[O:26])=[O:25]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Au]
Agent: [Ni+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccccc1N
Temperature: 25 °C
Yield: 11.5 %

Procedure:
Nickel acetate tetrahydrate (0.119 g) was added to a suspension of Borohydride on Amerlite IRA-400 resin (8.96 g) in methanol (90 ml). Gas was evolved and the resin turned from a light gold to black. After 1 minute the N-cyclopropyl-4-methyl-3-[(2-nitrobenzoyl)amino]benzamide (1.52 g) was added in a single portion and the mixture stirred at room temperature. After 1 hour the reaction was filtered through diatomaceous earth (Celite®) and the filtrate concentrated onto silica gel (2.0 g). Purification by column chromatography (isolute silica 50 g column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using a gradient of 0% iso-propanol/iso-hexane through to 50% iso-propanol/iso-hexane to give 3-[(2-aminobenzoyl)amino]-N-cyclopropyl-4-methylbenzamide as a white solid (0.159 g); NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.26 (s, 3H), 2.85 (m, 1H), 6.40 (s, 2H), 6.59 (t, 1H), 6.76 (d, 1H), 7.21 (t, 1H), 7.33 (d, 1H), 7.63 (m, 1H), 7.72 (d, 1H), 7.78 (d, 1H), 8.36 (d, 1H), 9.70 (d, 1H); Mass Spectrum: M+H+ 310.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[S:5].Cl[CH:13]([C:19]([CH3:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]1[S:5][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:19]([CH3:21])[N:6]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1ccc(Cl)cc1Cl
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2Cl)nc1C
Yield: 63.5 %

Procedure:
In ethanol (10 ml), 2,4-dichlorothiobenzamide (378 mg) was dissolved, and ethyl 2-chloroacetoacetate (302 mg) was added thereto. The mixture was heated under reflux for 25 hours. After the mixture was allowed to cool, the precipitated crystal was separated by filtration, washed with water, and dried to give ethyl 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate (368 mg, 64%).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[O:27][CH:26]([CH2:28]O)[N:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[C:22]([F:25])[C:23]=4[CH:24]=[C:16]3[C:15]=2[N:30]=1>C(Cl)Cl.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[O:27][CH:26]([CH2:28][F:7])[N:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[C:22]([F:25])[C:23]=4[CH:24]=[C:16]3[C:15]=2[N:30]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Solvent: ClCCl
Solvent: O
Product: FCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
DAST (64 mg, 0.29 mmol) was added to a solution of (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methanol (60 mg, 0.2 mmol) in CH2Cl2 (0.5 mL) at −78° C. under N2. The mixture was stirred at −78° C. for 1 hour. The mixture was then heated to reflux and stirred for another 3 hours. The mixture was then diluted with water (30 mL) and extracted with CH2Cl2 (15 mL*3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=4:1) to provide 2-chloro-11-fluoro-6-(fluoromethyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (30 mg, yield: 50.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.29˜7.33 (m, 2H), 7.13˜7.20 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.78˜6.83 (m, 1H), 6.46˜6.51 (m, 1H), 4.35˜4.63 (m, 2H). MS (M+H)+: 307/309.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])=O.[N+](C1C=CC=CC=1C=O)([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>Cl>[NH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: O=Cc1ccccc1NC(=O)C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=Cc1ccccc1[N+](=O)[O-]
Product: Nc1ccccc1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
o-(trifluoroacetamido)benzaldehyde (4). To a suspension of o-nitrobenzaldehyde (3 g, 19.86 mmol) in 35% aqueous hydrochloric acid (35 ml) was added 21 g (93.1 mmol) of tin (II) chloride in small portions. The suspension was stirred at room temperature for 72 h, neutralized with 6N aqueous sodium hydroxide and extracted with chloroform (4×50 ml). The combined chloroform layers were dried over sodium sulphate and evaporated, yielding 1.87 g (78%) of o-aminobenzaldehyde 3. A part of this residue (1.26 g, 10.4 mmol) was dissolved in dry ethyl ether (5 ml). This solution was cooled to 0° C. and treated dropwise with trifluoroacetic anhydride (2 ml, 14.15 mmol), while magnetically stirred. The solution was stirred for 2 h at room temperature. The solvent was evaporated and the residue was chromatographed on silica gel, eluting with a 7:3 petroleum ether-dichloromethane mixture. Yield, 1.65 g (77%) of compound 4.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:30])=[O:29])[CH:23]=2)[NH:5][N:4]=1)[CH3:2].[OH:31]OS([O-])=O.[K+]>CO.O>[CH2:1]([C:3]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:30])(=[O:31])=[O:29])[CH:23]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c(CCOc2cccc(S(C)=O)c2)c1Oc1cc(C#N)cc(C#N)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1n[nH]c(CCOc2cccc(S(C)(=O)=O)c2)c1Oc1cc(C#N)cc(C#N)c1
Yield: 34.4 %

Procedure:
To a stirred solution of the sulfoxide from Example 5 (34 mg, 0.08 mmol) in methanol (1 ml) was added a solution of oxone (49 mg, 0.08 mmol) in water (1 ml). After 2 hours the reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (5 ml) and water (5 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (100:0, 99:1 then 98:2, by volume) to give the title compound as a colourless oil (12 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH:22]4[CH2:31][CH2:30][C:25]5(OCC[O:26]5)[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[C:12]([F:32])[CH:11]=2)[CH2:6][CH2:5]1)[CH3:2].C(O)=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH:22]4[CH2:31][CH2:30][C:25](=[O:26])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[C:12]([F:32])[CH:11]=2)[CH2:8][CH2:9]1)[CH3:2]
Reactant: CCOC1CCC(c2ccc(C3CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: O
Product: CCOC1CCC(c2ccc(C3CCC(C4CCC(=O)CC4)CC3)c(F)c2)CC1
Temperature: 25 °C
Yield: 26.5 %

Procedure:
The compound (25) (31.4 g), formic acid (90 g) and toluene (90 ml) were put in a reaction vessel under a nitrogen atmosphere, heated under reflux for 3 hours, and cooled slowly to room temperature. Water (200 ml) and toluene (200 ml) were added and mixed thereto. The mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from a mixed solvent of toluene and heptane (toluene: heptane=1:1 by volume), and dried, giving 7.51 g of 4′-(4-(4-ethoxycyclohexyl)-2-fluorophenyl)bi(cyclohexane)-4-one (26). The yield based on the compound (25) was 26.6%.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C>O1CCCC1.CO>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[S:17][C:8]1[CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:16]=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(Cl)cc2Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(Cl)cc2Cl)c1
Reaction time: 9 h
Yield: 86.2 %

Procedure:
Sodium borohydride (0.22 g) was added portionwise to a solution of 4'-acetyl-2'-(2,4-dichlorophenylthio)methanesulfonanilide (1.5 g) in tetrahydrofuran (20 ml) and methanol (10 ml) at room temperature. The mixture was stirred for 9 hours, treated with acetic acid, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate, and dried. The solution was evaporated to dryness and the residue was recrystallized from a mixture of ethanol and water to give colorless needles of 2'-(2,4-dichlorophenylthio)-4'-(1-hydroxyethyl)methanesulfonanilide (1.3 g).