Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:15]([OH:16])=[C:14]([CH2:17][CH3:18])[CH:13]=[C:12]2[C:4]=1[C:5](=O)[CH2:6][C:7]1([O:11]2)[CH2:10][CH2:9][CH2:8]1)[CH3:2].Cl.[CH3:21][O:22][NH2:23].C([O-])(=O)C.[Na+]>CO>[CH3:21][O:22]/[N:23]=[C:5]1\[CH2:6][C:7]2([O:11][C:12]3[C:4]\1=[C:3]([CH2:1][CH3:2])[C:15]([OH:16])=[C:14]([CH2:17][CH3:18])[CH:13]=3)[CH2:10][CH2:9][CH2:8]2
Reactant: CON
Reactant: CCc1cc2c(c(CC)c1O)C(=O)CC1(CCC1)O2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1cc2c(c(CC)c1O)/C(=N/OC)CC1(CCC1)O2
Yield: 69.7 %

Procedure:
A mixture of 5,7-diethyl-6-hydroxyspiro[chroman-2,1′-cyclobutan]-4-one (400 mg), methoxyamine hydrochloride (385 mg), and sodium acetate (379 mg) in methanol (10 mL) was refluxed for 16 hours. The methanol was removed by distillation and the residue was treated with sodium bicarbonate solution and ethyl acetate. The organic phase was washed with water and brine. Evaporation and chromatography (silica gel, hexane-ethyl acetate, 3.5%) gave 310 mg of (E)-5,7-diethyl-6-hydroxyspiro[chroman-2,1′-cyclobutan]-4-one O-methyl oxime. 1H-NMR (300 MHz, CDCl3) δ=6.62 (s, 1H), 4.61 (s, 1H), 4.01 (s, 3H), 3.08 (q, J=7.5 Hz, 2H), 3.01 (s, 2H), 2.61 (q, J=7.5 Hz, 2H), 2.30-1.65 (m, 6H), 1.30-1.20 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=150.5, 149.4, 146.2, 133.1, 128.0, 115.7, 115.4, 77.0, 62.0, 33.3, 33.0, 23.3, 21.2, 13.4, 12.2 ppm. MS (m/z)=290 (100, M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][CH3:27])=[CH:3][CH:4]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc(Cn2nc(C(C)C)c(O)c(C(=O)NCC(=O)O)c2=O)cc1
Yield: 35.1 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 40 mg, 0.094 mmol), 2-methoxyphenyl boronic acid (17.2 mg, 0.10 mmol), potassium carbonate (40 mg, 0.290 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 5 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes, diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (15.0 mg, 0.033 mmol, 35% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.88 (s, 1H), 12.97 (s, 1H), 10.21 (t, J=5.94 Hz, 1H), 7.41-7.47 (m, 2H), 7.31-7.37 (m, 3H), 7.26 (dd, J=7.58, 1.77 Hz, 1H), 7.10 (d, J=7.58 Hz, 1H), 7.01 (dt, J=7.45, 1.01 Hz, 1H), 5.28 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.74 (s, 3H), 3.20 (m, 1H), 1.23 (d, J=6.82 Hz, 6H). MS (ES+) m/e 452 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:31])[O:29][CH3:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:28](=[O:31])[O:29][CH3:30])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: COC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 14 mg, 38 μmol) and methyl chlorocarbonate (11 mg, 114 μmol). Yield 14 mg (90%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:22]=[CH:21][C:13]3[NH:14][C:15](=O)[C:16]([CH3:19])([CH3:18])[O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(OCC)(=O)C>[C:1]1([S:7]([C:10]2[CH:22]=[CH:21][C:13]3[NH:14][CH2:15][C:16]([CH3:18])([CH3:19])[O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)Oc2cc(S(=O)(=O)c3ccccc3)ccc2NC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CNc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A solution of 7-benzenesulfonyl-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (0.570 g., 1.79 mmol) in 10 mL freshly distilled THF was cooled to 0° C., and borane-THF complex (5.39 mL of a 1 M solution in THF, 5.39 mmol) was added dropwise over 2 minutes. The resulting solution was warmed to reflux and stirred for 1 hour. Ethanolic hydrogen chloride (4 mL of 2 N solution, 8 mmol) was then added dropwise and the reaction was heated at reflux for an additional hour. The reaction mixture was cooled to room temperature and added to a mixture of 100 mL each ethyl acetate and 10% aqueous sodium bicarbonate. Potassium carbonate was added until the pH of the aqueous phase was roughly 7. The organic layer was separated, washed with 50 mL water and 50 mL brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude oil was purified by flash chromatography (10 to 45% ethyl acetate in hexanes) to give 520 mg (94%) of 7-benzenesulfonyl-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine as a white powder. MS: 304 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[NH:57][C:56](=[O:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49]2)=[CH:44][C:43]=1[O:59][CH3:60]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[CH2:10]2)[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[O:28][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[NH:57][C:56](=[O:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49]2)=[CH:44][C:43]=1[O:59][CH3:60]
Reactant: COc1cc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NO2)cc(OC)c1O
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1c(OC)cc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NO2)cc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 78.3 %

Procedure:
2,6-Dimethoxy-4-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-phenol (11b) (389.40 mg, 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.31 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (16d) (570 mg, 80% yield).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH3:24][NH:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:26]([N:25]([CH3:24])[C:19](=[O:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:22])([F:23])[F:1])=[N:4]2)=[CH:13][CH:14]=1)[CH2:27][CH2:28][CH3:29]
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CCCCNC
Product: CCCCN(C)C(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and N-methylbutylamine using a similar procedure to that described for Example 13, but purified by flash column chromatography eluting from 0-66% ethyl acetate in hexane.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([CH:13]1[CH2:15][NH:14]1)#[N:12].C(OCC)(=O)C>O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]2[CH2:15][CH:13]2[C:11]#[N:12])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: N#CC1CN1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C(=O)N2CC2C#N)cc1

Procedure:
This compound is obtained in the form of an oil in a yield of 1.8 g. from 1.54 g. p-methylbenzoyl chloride and 0.68 g. 2-cyanoaziridine. It still contains a little ethyl acetate and water. The analytical results (elementary analysis, NMR and mass spectra) confirm the structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@:4]([NH2:14])([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][OH:6].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[CH3:1][O:2][C:3](=[O:15])[C@:4]([NH2:14])([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:5][O:6][S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@](N)(CO)C(=O)OC(C)(C)C
Product: COC(=O)[C@@](N)(COS(C)(=O)=O)C(=O)OC(C)(C)C

Procedure:
Commercially available (S)-2-BOC-amino-3-hydroxy-propionic acid methyl ester and methanesulfonylchloride were reacted according to the same procedure as Step B of Preparation 29 to give the title compound.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N+:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([O-:16])=[O:15].C(N(CC)CC)C>CC(C)=O>[C:1]12([C:11]([NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N+:14]([O-:16])=[O:15])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1[N+](=O)[O-])C12CC3CC(CC(C3)C1)C2
Reaction time: 22 h
Yield: 76.5 %

Procedure:
A solution of 1-adamantanecarbonyl chloride (17.95 g) in acetone (60 ml) was dropped into a solution of 2-nitroaniline (10.4 g) and triethylamine (12.6 ml) in acetone (50 ml), at ° under a nitrogen atmosphere. The mixture was stirred at 23° for 22 h; then further acetone (50 ml) was added. The mixture was heated at 70° for 3 h. The mixture was allowed to cool to 23°, then filtered; the brown solid obtained was crystallized from acetone to give the title compound as a yellow solid (17.3 g). T.l.c. CH-EA (10:2), Rf 0.67. M.p. 111°-4°.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[CH3:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>S(=O)(=O)(O)O>[CH3:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([N+:1]([O-:4])=[O:2])=[CH:11][CH:10]=2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc2ccccc2[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
A solution of 17.0 g (0.2 mol) of sodium nitrate in 150 mL of sulfuric acid was added dropwise to 26.9 g (0.205 mol) of 2-methyl-1H-indole in 150 mL of sulfuric acid keeping the temperature at -10° to 0° C. with an ethanol-water bath. After 0.25 hours, the mixture was poured onto ice, extracted with EtOAc, the EtOAc solution washed with water, Na2 CO3 solution and dried (Na2SO4). After concentrating at reduced pressure, the residue was crystallized from EtOH to give 20.86 g (59% yield) of 2-methyl-5-nitro-1H-indole, mp, 163°-165° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:17]1([N:21]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[S:22]([C:25]2[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:20][CH2:19][CH2:18]1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:28]2[CH:29]=[CH:30][C:25]([S:22](=[O:23])(=[O:24])[N:21]([CH:17]3[CH2:18][CH2:19][CH2:20]3)[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=S(=O)(c1ccc(F)cc1)N(c1cccc(F)c1)C1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(S(=O)(=O)N(c3cccc(F)c3)C3CCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 105.6 %

Procedure:
To a solution of tert-butyl-4-hydroxy-1-piperidinecarboxylate (137 mg, 681 mmol) in anhydrous THF (5 mL) was added NaH (60% dispersion in mineral oil, 30 mg, 743 mmol) and the reaction was stirred at room temperature for 15 minutes. N-Cyclobutyl-4-fluoro-N-(3-fluoro-phenyl)-benzenesulfonamide (200 mg, 619 μmol) was added and the reaction was heated at 90° C. for 4 hours. The reaction was left to cool to room temperature, water added and extracted with EtOAc, washed with brine, dried with Na2SO4 then concentrated and purified by silica gel column chromatography (0-50% EtOAc in cyclohexane) to give 4-{4-[cyclobutyl-(3-fluoro-phenyl)-sulfamoyl]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (330 mg). LCMS (m/z, Method A) ES+ 527 [M+23]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[NH3:16]>CCO>[NH2:16][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: N
Reactant: O=C(c1ccccc1)c1ccc(Cl)nc1
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccccc2)cn1
Temperature: 145 °C

Procedure:
The 2-chloro-5-benzoylpyridine (100 g, 0.460 mol) was dissolved in 500 ml of 3A EtOH and 400 ml of anhydrous ammonia, placed in a bomb, then heated at 145° C. for 16 hours. The solvents were removed in vacuo and the remaining tan solid was recrystallized from EtOH/H2O yielding 77.4 g (85%) of product as a tan solid. EA, MS(FD).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[S:20][C:11]3[NH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:10]=3[CH:9]=2)=O)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:8]2[S:20][C:11]3[NH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:10]=3[CH:9]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cc2cc(C(=O)c3ccc(Cl)cc3)sc2[nH]1
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Cc3ccc(Cl)cc3)sc2[nH]1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
Under a N2 and at rt, to a 40-mL scintillation vial fitted with a magnetic stir bar was added ethyl 2-(4-chlorobenzoyl)-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.203 g, 0.61 mmol) in solution in 5 mL in THF. AlCl3 (0.22 g, 1.67 mmol, 2.75 equiv) and NaBH4 (0.116 g, 3.0 mmol, 5 eq.) are added in the same time. The mixture was heated to reflux for 2 h. The reaction was cooled to rt and solvent was evaporated. The crude product was purified via ISCO Companion (0-30% EtOAc/heptane over 30 min) to give ethyl 2-(4-chlorobenzyl)-6H-thieno[2,3-b]pyrrole-5-carboxylate (0.050 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.39 (t, J=7.13 Hz, 3H) 4.11 (s, 2H) 4.37 (q, J=7.13 Hz, 2H) 6.71 (s, 1H) 7.00 (d, J=1.76 Hz, 1H) 7.18-7.23 (m, 2H) 7.27-7.32 (m, 2H) 9.41 (s, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[O:20][C:21]([CH3:24])=[CH:22][N:23]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[O:20][C:21]([CH3:24])=[CH:22][N:23]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ncc(C)o3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cc1cnc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)o1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A mixture of 125b (114 mg, 0.20 mmol) and lithium hydroxide (120 mg, 5.0 mmol) in i-propanol/THF/water (2:2:1, 10 mL) was stirred at 35° C. for 30 mins. The mixture was concentrated under reduced pressure and the residue was diluted with water (5 mL). The resulting mixture was extracted with dichloromethane three times. The combined organic layer was then concentrated under reduced pressure and the resulting residue was purified by reverse-phase prep-HPLC to afford 125 (52 mg, 49%). MS-ESI: [M+H]+ 530.9. 1H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.53 (d, J=3.0 Hz, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.90 (d, J=1.0 Hz, 1H), 7.78 (dd, J=1.0, 13.0 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.50 (d, J=5.0 Hz, 1H), 6.64 (d, J=1.5 Hz, 1H), 4.92 (bs, 1H), 4.40 (d, J=7.0 Hz, 2H), 3.60 (s, 3H), 2.22 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[CH2:16]([N:18](CC)CC)[CH3:17].C(N)C>C(O)C>[CH2:16]([NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1)[CH3:17]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1c(Cl)nc(C(F)(F)F)nc1Cl
Agent: CCN
Solvent: CCO
Product: CCNc1nc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Reaction time: 4 h
Yield: 97.9 %

Procedure:
5.25 g (0.02 mol) of 4,6-dichloro-5-nitro-2-trifluoromethyl-pyrimidine are dissolved in 100 ml of abs. ethanol and the solution is cooled to -30° C. At this temperature, 2.0 g (0.02 mol) of triethylamine and 0.9 g (0.2 mol) of ethylamine are added. The mixture is stirred first for 4 hours at -20° C to -30° C and then for 6 hours at 0° C. After it has been left to stand overnight at 20° C, the reaction mixture is concentrated to dryness. The residue is taken up in ether and the solution washed with water. The ethereal phase is dried and concentrated to yield 5.3 g of 4-ethylamino-6-chloro-5-nitro-2-trifluoromethyl-pyrimidine as a pale yellow oil; nD20 = 1.4985.
Reaction SMILES: [CH2:1]([OH:12])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1](=[O:12])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC=CC=C/C=C/CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCCC=CC=C/C=C/C=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of trans, trans, trans-2,4,6-undecatrien-1-ol (7.2 g) in chloroform (300 ml) was added manganese dioxide (50 g) and then the mixture was stirred for 15 hours at ambient temperature. The resultant mixture was filtered and the filtrate was concentrated under reduced pressure to give an oily residue, which was subjected to a column chromatography on silica gel (developing solvent: chloroform). The eluate was concentrated under reduced pressure to give oily trans, trans, trans-2,4,6-undecatrienal (5.5. g).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH3:3].[CH3:17][O:18][C:19]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:20]>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19](=[O:20])[CH:21]=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:5]=1[NH:4][CH2:1][CH2:2][CH3:3]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCNc1cc(C(F)(F)F)ccc1C=O
Solvent: Cc1ccccc1
Product: CCCNc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Yield: 69 %

Procedure:
N-Methoxy-N-methyl-2-propylamino-4-trifluoromethyl-benzamide (98.3 mg, 0.339 mmol) was reacted with 1M lithium aluminum hydride (0.6 ml) in THF (20 ml) at −40° C. for 1 hr. The reaction mixture was quenched by adding saturated potassium hydrogen sulfate solution. The mixture was stirred for 30 min. The reactions solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with CH2Cl2 (30 ml×3). The combined organic layer was dried over MgSO4 and concentrated in vacuo to yield 2-propylamino-4-trifluoromethyl-benzaldehyde (78 mg). 2-Propylamino-4-trifluoromethyl-benzaldehyde in toluene was reacted with methyl (triphenylphosphoranylidene) acetate (137 mg) at 100° C. overnight. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was extracted with ethyl acetate (30 ml×3). The combined organic layer was dried over MgSO4 and filtered. The filterate was concentrated in vacuo and purified with column chromatography to yield title compound (67 mg, 69%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=5)[C:22]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:35](=[O:38])([O-])[O-:36].[K+].[K+]>CN(C)C=O>[CH2:14]([O:36][C:35]([CH2:2][CH2:1][CH2:3][O:29][C:25]1[CH:24]=[C:23]2[C:28](=[CH:27][CH:26]=1)[N:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:12]3[O:11][C:10]([C:7]4[S:8][CH:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:6]=4)=[CH:14][C:13]=3[CH:15]=1)[CH:21]=[C:22]2[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:38])[C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:12]=1
Reactant: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(O)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(OCCCC(=O)OCc3ccccc3)cc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 110.8 %

Procedure:
A mixture of methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-hydroxyindole-3-acetate (0.474 g), benzyl 4-bromobutylate (0.34 g) and potassium carbonate (0.19 g) in N,N-dimethylformamide (5 ml) was stirred at 50° C. for 8 hours. After being cooled to room temperature, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give methyl 5-[3-(benzyloxycarbonyl)propoxy]-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-3-acetate (0.36 g).