Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[F:9][C:10]1[CH:11]=[C:12](B(O)O)[C:13]([O:16][CH3:17])=[CH:14][CH:15]=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH2:8])[CH:11]=1
Reactant: Nc1cnccc1I
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1ccncc1N

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-pyridin-3-ylamine (CAS RN 105752-11-2) and 3-fluoro-6-methoxy-phenylboronic acid (CAS RN 179897-94-0) after a reaction time of 18 hours at reflux. The compound was purified by column chromatography eluting with a gradient of n-hexane:EtOAc (40:60 to 20:80). Yellow solid (84%). MS (ESI): m/z=219.6 [M+H]+.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-])=O)[C:11]=1[OH:20])(=[O:9])=[O:8].[H][H]>[Pd]>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:20])(=[O:9])=[O:8]
Reactant: CSCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: CSCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 91.4 %

Procedure:
N-(3- methylthiopropyl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (300 mg, 0.88 mmol) was reduced with hydrogen and 10% Pd/C (150 mg) to form the desired product (250 mg, 91%). 1H NMR (MeOD-d4): δ 6.84 (d, 1H), 6.77 (d, 1H), 2.93 (t, 2H), 2.40 (t, 2H), 1.89 (s, 3H), 1.63 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:45])[C:11](=[O:44])[CH2:12][N:13]([C:33]1[C:42]([CH3:43])=[CH:41][C:36]2[C:37]([CH3:40])=[N:38][O:39][C:35]=2[CH:34]=1)[CH2:14][C:15]([NH:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31])(=[O:23])=[O:22])=[O:16].[F:46][CH2:47][CH2:48]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(C)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:45])[C:11](=[O:44])[CH2:12][N:13]([C:33]1[C:42]([CH3:43])=[CH:41][C:36]2[C:37]([CH3:40])=[N:38][O:39][C:35]=2[CH:34]=1)[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([CH2:48][CH2:47][F:46])[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31])(=[O:22])=[O:23])=[O:16]
Reactant: OCCF
Reactant: Cc1cc2c(C)noc2cc1N(CC(=O)NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-])CC(=O)N(C)N1Cc2ccccc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(C)noc2cc1N(CC(=O)NCCN(CCF)S(=O)(=O)c1ccccc1[N+](=O)[O-])CC(=O)N(C)N1Cc2ccccc2C1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
The compound (557 mg, 0.876 mmol) of step A, 2-fluoroethanol (84 mg, 1.31 mmol) and triphenylphosphine (345 mg, 1.31 mmol) were dissolved in tetrahydrofuran (4.4 ml), and the mixture was stirred at room temperature. Thereto was slowly added a 40% diisopropyl azodicarboxylate-toluene solution (0.70 ml), and the mixture was stirred at the same temperature for 12 hr. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over sodium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (561 mg, yield 94%) as a yellow solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]#[N:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][NH2:23])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N#CCc1ccccc1OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.1 %

Procedure:
LAH (1.04 g, 0.0273 mol, 3.0 eq) was dissolved in THF (25 ml), and to this solution was added dropwise a THF solution (25 ml) of (2-benzyloxyphenyl)-acetonitrile (2.04 g, 0.0091 mol, 1.0 eq) under ice-cooling. After the completion of the dropwise addition, the mixture was stirred at room temperature for 15 minutes and refluxed under heating for 2 hours. This reaction mixture was cooled with ice-cold water, and a saturated aqueous sodium sulfate solution (about 30-40 ml) was added. After filtration through Celite, the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (chloroforn/methanol=5/1) to give 2-(2-benzyloxyphenyl)ethylamine (0.415 g, 20.0%) as a pale-yellow amorphous compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[CH2:26]Cl)[O:5][CH2:6][C:7]1[C:8]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=[N:9][O:10][C:11]=1[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[OH:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[C:8]([C:15]3[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=3[Cl:21])=[N:9][O:10][C:11]=2[CH:12]([CH3:14])[CH3:13])[CH:23]=[CH:24][C:25]=1[CH2:26][O:36][C:37]1[CH:38]=[CH:39][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:45][CH:46]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(CCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-{[3-chloro-4-(chloromethyl)phenoxy]methyl}-3-(2,6-dichlorophenyl)-5-isopropylisoxazole (50 mg, 112 μmol), potassium carbonate (16.9 mg, 122 μmol), sodium iodide (18.3 mg, 110 μmol), and methyl 4-hydroxybenzoate (16.7 mg, 110 μmol) in dimethylformamide (0.6 mL) was stirred at ambient temperature overnight. The mixture was filtered, condensed to a residue, and was chromatographed on silica gel eluting with 33% ethyl acetate/hexanes. Yield=41 mg (65%) of methyl 4-[(2-chloro-4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}benzyl)oxy]-benzoate.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[N:8][C:9]=1[S:10][CH3:11].Cl[CH:14]([F:16])[F:15]>O1CCOCC1.O.CCOCC>[F:15][CH:14]([F:16])[O:12][C:6]1[CH:5]=[C:4]([CH3:3])[C:9]([S:10][CH3:11])=[N:8][CH:7]=1
Reactant: CSc1ncc(O)cc1C
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CSc1ncc(OC(F)F)cc1C
Temperature: 25 °C
Yield: 61 %

Procedure:
Solid sodium hydroxide (9.3 g, 232 mmol) were added in one portion to a stirred solution of 5-methyl-6-methylsulfanylpyridine-3-ol (7.2 g, 46.4 mmol) in 1,4-dioxane (75 mL) and water (25 mL) causing an exotherm to 50° C. Chlorodifluoromethane (13 g, 150 mmol) was then rapidly bubbled into the reaction over 9 minutes, causing a gradual exotherm to 75° C. After the reaction had cooled to room temperature, it was diluted with ether (100 mL) and water (100 mL) and the layers separated. The organic phase was extracted with water (6×100 mL), brine and dried (Na2SO4). Filtration and removal of solvent left a brown oil, 8.3 g, that was purified by chromatography on silica, eluting with 1:1 methylene chloride/hexanes to give product, as an orange liquid, 5.8 g, 28.3 mmol, 61 percent yield.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[CH2:5][O:4]1.[C:6]1([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH2:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH:12]([NH:13][CH2:5][CH:3]([OH:4])[CH2:2][Cl:1])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCC1CO1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CO
Product: OC(CCl)CNC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
2-(Chloromethyl)oxirane (92 g, 1 mol) was added dropwise to a solution of diphenyl-methanamine (183 g, 1 mol) in CH3OH (1 L) at 0° C. then the mixture was stirred at r.t. overnight. The mixture was then concentrated in vacuo to give the title compound (201 g, 73%) which was used in next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.OO.FC(F)(F)C(O)=[O:15]>C(O)(=O)C>[NH:1]1[C:9]2[CH:8]=[CH:7][N+:6]([O-:15])=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: c1cc2[nH]cnc2cn1
Agent: OO
Solvent: CC(=O)O
Product: [O-][n+]1ccc2[nH]cnc2c1
Temperature: 73 °C
Reaction time: 72 h

Procedure:
1H Imidazo[4,5-c]pyridine (4.0 g, 33.6 mmol) was dissolved in 60 ml of fresh acetic acid, heated to 73° C.±1° C. and to the solution was added 8.8 ml of 30% H2O2 (78 mmol). After stirring and heating at 73° C. for 24 hrs, an additional 5 ml of H2O2 was added as well as 1 ml of trifluoroacetic acid. Heating at 73° C. was continued for an additional 3 days. After concentrating, an aliquot NMR (D2O) shows a 2:1 product: starting material mixture. Concentration of the main reaction mixture was followed by trituration of the residue with 50 ml of acetonitrile. The filtered insolubles 1.6 g (35%) are pure N-oxide by TLC, (reverse phase, 9:1 H2O:THF) 200 MHz NMR (D2O, δ from TSP): 7.82 (1H, d, J=7 Hz) 8.21 (1H, d of d, J=7 Hz, J=1 Hz) 8.52 (1H, s) 8.84 (1H, d, J=1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]2[C:9]=1[N:10]=[C:11]1[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]1.[CH:17]([N:20]([CH:23](C)C)[CH2:21]C)(C)[CH3:18].Cl.ClCCN(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH3:21][N:20]([CH2:17][CH2:18][N:5]1[CH2:6][CH2:7][C:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][C:9]=2[CH:3]([CH2:2][OH:1])[CH2:4]1)[CH3:23]
Reactant: OCc1cnccc2c3ccccc3nc1-2
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)CCN1CCc2c([nH]c3ccccc23)C(CO)C1
Yield: 87 %

Procedure:
A solution of 7 g (0.0324 mol) of 5-hydroxymethylazepino[4,5-b]indole, of 10.04 g (0.0777 mol) of diisopropylethylamine, and of 5.6 g (0.0388 mol) of 1-chloro-2-dimethylaminoethane hydrochloride in 150 ml of chloroform is heated under reflux for 15 hours. The reaction mixture is then drowned in water and alkalified with a saturated aqueous solution of potassium carbonate. The organic phase is separated off and the aqueous phase is again extracted twice with 100 ml portions of chloroform. The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and evaporated to dryness under vacuum. The residue is crystallized from ethyl acetate and yields 8.1 g of product.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C@H:7]1[C:20](=[O:21])[N:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][C:10]2[C:11]3[CH:12]=[N:13][NH:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][CH2:6][C@H:7]1[C:20](=[O:21])[N:19]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][C:10]2[C:11]3[CH:12]=[N:13][NH:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8]1
Reactant: CC(=O)OCC[C@@H]1Cc2ccc3[nH]ncc3c2CN(CC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](CCO)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
(S)-2-(9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)ethyl acetate (18 mg, 0.05 mmol) was dissolved in methanol (1 mL). Potassium carbonate (20 mg, 0.14 mmol) was added to the mixture. Reaction stirred at room temperature for 1 hour. Amberlite IRC-50 ion exchange resin was added to the mixture. Reaction stirred at room temperature for 15 minutes. Mixture was filtered. Filtrate was concentrated in vacuo. The title compound was obtained as yellow residue in 94% yield. MS m/e (M+H)+=316.
Reaction SMILES: [CH3:1][C@@:2]1([OH:22])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[CH:11]([CH2:12][C@@H:13]2[O:21][C@@H:14]2[CH2:15]1)[CH2:10][CH2:9]3.O.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[CH3:1][C@@:2]1([OH:22])[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[CH:11]([CH2:12][C@H:13]([OH:21])[C@@H:14]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:15]1)[CH2:10][CH2:9]3
Reactant: C1CNCCN1
Reactant: C[C@]12C[C@H]3O[C@H]3CC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(C)O
Solvent: ClCCl
Solvent: O
Product: C[C@]12C[C@H](N3CCNCC3)[C@@H](O)CC1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@@]2(C)O
Temperature: 150 °C
Yield: 60.2 %

Procedure:
To compound 28 (103 mg, 0.34 mmol) was added water (1 mL) and piperazine (3.5 g, 41 mmol). The solution was subsequently heated at 150° C. over a period of 24 h. The resulting mixture was diluted with dichloromethane (50 mL) and washed with water, dried with Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by flash chromatography (DCM/MeOH: 9:1 containing 1.0% of TEA) to yield compound 29 (80 mg, 60%). 1H NMR (CDCl3) δ: 0.85 and 0.86 (2s, 18-CH3 and 19-CH3), 1.20 (s, 17α-CH3) 0.65-1.90 (residual CH and CH2), 2.50-3.30 (broad m, 2×CH2N, 2×CH2NH and 2α-CH), 3.85 (m, 3β-CH).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[OH-].[NH4+:13]>[O-]S([O-])(=O)=O.[Cu+2]>[CH3:11][S:8]([C:6]1[CH:7]=[C:2]([NH2:13])[CH:3]=[N:4][CH:5]=1)(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1cncc(Br)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Product: CS(=O)(=O)c1cncc(N)c1
Temperature: 25 °C
Yield: 31 %

Procedure:
A mixture of 3-bromo-5-(methylsulfonyl)pyridine (0.50 g, 2.1 mmol) and CuSO4.(H2O)5 (53 mg, 0.21 mmol) in concentrated ammonium hydroxide (3 mL) was heated in a sealed tube at 170° C. for 16 hours. The reaction was cooled to room temperature and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to give a brown solid. The solid was purified by column chromatography on silica gel using 0-5% MeOH in dichloromethane to give 5-(methylsulfonyl)pyridin-3-amine (0.11 g, 31% yield) as a tan solid. LC/MS: m/z 173.3 (M+H)+ at 0.21 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23]([C:29](O)=[O:30])=[N:22]2)=[CH:16][CH:15]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][C@H:62]([CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C@@H:63]([OH:67])[C:64]([OH:66])=[O:65].Cl.CCN(C(C)C)C(C)C>>[C:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23]([C:29]([NH:61][C@H:62]([CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C@@H:63]([OH:67])[C:64]([OH:66])=[O:65])=[O:30])=[N:22]2)=[CH:16][CH:15]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: N[C@H](Cc1ccccc1)[C@@H](O)C(=O)O
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)=O)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)N[C@H](Cc2ccccc2)[C@@H](O)C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)=O)nc1
Temperature: 40 °C
Yield: 91 %

Procedure:
A solution of 1-[6-(2-acetylsulfamoylphenyl)pyridin-3-ylmethyl]-5-propyl-1H-pyrazole-3-carboxylic acid (100 mg, 226 μmol) in DMF (7.0 mL, 90 mmol) was added to HATU (85.9 mg, 226 μmol). The resulting mixture was stirred for 5 minutes before (2R,3R)-3-amino-2-hydroxy-4-phenylbutyric acid.HCl (52.4 mg, 226 μmol) and DIPEA (315 μL, 1.8 mmol) were added. The resulting solution was heated at 40° C. overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (48 mg; 91% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C31H33N5O7S, 620.21; found 620.4.
Reaction SMILES: CC1(C)[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:15])[C@H:5]2[C:10]([O:13][CH3:14])([CH3:12])[CH3:11]>C(O)(=O)C.O>[OH:9][CH2:8][CH2:7][C@H:6]1[NH:3][C:4](=[O:15])[C@H:5]1[C:10]([O:13][CH3:14])([CH3:12])[CH3:11]
Reactant: COC(C)(C)[C@@H]1C(=O)N2[C@@H]1CCOC2(C)C
Solvent: CC(=O)O
Solvent: O
Product: COC(C)(C)[C@@H]1C(=O)N[C@@H]1CCO
Temperature: 65 °C
Yield: 96.8 %

Procedure:
A solution of (6R, 7R)-2,2-dimethyl-7-(1-methoxy-1-methylethyl)-1-aza-3-oxabicylco[4.2.0]octan-8-one (345 mg) in a mixture of acetic acid (5.52 ml) and water (1.38 ml) was heated at 65° C. for 30 minutes. The mixture was cooled to ambient temperature and evaporated in vacuo. Xylene was added to the residue and the resultant suspension was evaporated in vacuo. The crystalline residue was dissolved in a mixture of methanol and xylene and the resultant solution was evaporated in vacuo. This operation was repeated once, and the crystalline residue was washed with hexane to give (3R, 4R)-4-(2-hydroxyethyl)-3-(1-methoxy-1-methylethyl)azetidin-2-one (275 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].[I-].[K+].B(Br)(Br)Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: COc1cccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)c1
Agent: BrB(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Product: N#Cc1cc(C(=O)c2cccc(O)c2)n2c1ccc1ccccc12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A mixture of 3-cyano-1-(3-methoxybenzoyl)-pyrrolo[1,2-a]quinoline (326 mg, 1 mmol), tetrabutylammonium bromide (967 mg, 3 mmol), potassium iodide (498 mg, 3 mmol), boron tribromide (1N solution in dichloromethane, 3 ml) in dichloromethane (5 ml) was refluxed for 8 h. It was cooled to room temperature and quenched with water (20 mL), the organic layer was washed with aqueous sodium bicarbonate (2×10 mL), water (2×20 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give 188 mg (60%) of title compound. 1H NMR (CDCl3): 8.06 (d, J=9.0 Hz, 1H), 7.85 (d, J=7.80 Hz, 1H), 7.74–7.40 (m, 8H), 7.20–7.14 (m, 1H), 5.15 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7](C(O)=O)[NH:8]2>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[F:17][C:2]([F:1])([F:16])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: O=C(O)c1cc2c(OC(F)(F)F)cccc2[nH]1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: FC(F)(F)Oc1cccc2[nH]ccc12
Temperature: 200 °C
Yield: 40.2 %

Procedure:
0.18 g of copper(0) is added to a solution of 1.0 g of 4-(trifluoromethoxy)-1H-indole-2-carboxylic acid in 4.5 ml of quinoline under argon. The reaction mixture is heated at 200° C. for 5 hours, and is then cooled to ambient temperature. After dilution with 30 ml of diethyl ether, the mixture is filtered through Clarcel®. The filtrate is washed successively with 6×10 ml of a 6N hydrochloric acid solution, with 10 ml of a saturated sodium hydrogen carbonate solution and then with 10 ml of saturated brine. The organic phase is dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 25 g cartridge of 15-40 μm silica, elution being carried out with a 95/5 v/v cyclohexane/ethyl acetate mixture, at a flow rate of 20 ml/min. 0.33 g of 4-(Trifluoromethoxy)indole is thus obtained in the form of an amber oil, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:17][N:18]([CH3:22])[C:19]([N:7]1[C:8]([S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:20]
Reactant: CCOC(=O)CSc1nc(C(C)(C)C)n[nH]1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)CSc1nc(C(C)(C)C)nn1C(=O)N(C)C
Yield: 85.2 %

Procedure:
To 100 g (0.411 mole) of 3-t-butyl-5-carboethoxymethylthio-1H-1,2,4-triazole, 6 g (0.05 mole) of 4-dimethylaminopyridine, and 200 ml of pyridine was added 54 g (0.50 mole) of dimethylcarbamoyl chloride. The resulting solution was refluxed for eight hours and allowed to cool overnight. The reaction mixture was concentrated under vacuum, partitioned between ether and dilute hydrochloric acid. The organic layer was washed with water, brine, dried over magnesium sulfate, and concentrated under vacuum. Distillation yielded a fraction boiling at 148°-160° C at 0.1 torr 100 g (0.35 mole) of 1-dimethylcarbamoyl-3-t-butyl-5-carboethoxymethylthio-1,2,4-triazole. m.p. 55° C.
Reaction SMILES: C(O[C:4](=O)[C:5]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH2:19])[C:11]=1[C:20]#[N:21])(C)[C:6](=O)[CH3:7])C.C(O)(=[O:25])C.OS(O)(=O)=O>O>[NH2:19][C:12]1[C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=[C:10]2[C:11]=1[C:20](=[O:25])[NH:21][C:6]([CH3:7])=[C:5]2[CH3:4]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc([N+](=O)[O-])c(N)c1C#N
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1[nH]c(=O)c2c(N)c([N+](=O)[O-])ccc2c1C
Temperature: 100 °C
Yield: 72 %

Procedure:
The ester from above (1.39 g, 4.56 mmol) was added to a mixture of acetic acid (20 mL), H2SO4 (3 mL) and water (2 mL), and the solution heated at 100° C. for 3 h. The cooled solution was diluted with water (30 mL), the precipitate was collected, washed with water and MeOH and dried to give 8-amino-3,4-dimethyl-7-nitro-2H-isoquinolin-1-one (0.76 g, 72%). mp >300° C.
Reaction SMILES: [OH-].[Na+].[S:3]=[C:4]1[NH:9][C:8](=[O:10])[N:7]2[N:11]=[CH:12][CH:13]=[C:6]2[NH:5]1.[CH3:14]I>CCO>[CH3:14][S:3][C:4]1[NH:9][C:8](=[O:10])[N:7]2[N:11]=[CH:12][CH:13]=[C:6]2[N:5]=1
Reactant: O=c1[nH]c(=S)[nH]c2ccnn12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc2ccnn2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A 1.75N NaOH solution (39.52 mmol, 22.58 ml) was added to a suspension of 2-thioxo-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one (3.32 g, 19.76 mmol) from 1b in absolute EtOH (80 mL). Methyl iodide (2.80 g, 19.76 mmol) was then added and the reaction mixture was allowed to stir for 2 hours at room temperature. The resulting precipitate was collected by vacuum filtration, suspended in water (110 mL) and acidified with 2NH2SO4. The solution was stirred at 0° C. for 5 minutes and the new precipitate was collected by vacuum filtration, washed with cold water, and then air dried to give 1.88 g (52%) of 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.[H][H]>CO.O=[Pt]=O>[NH2:12][CH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH2:10]2
Reactant: [H][H]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: O=[Pt]=O
Solvent: CO
Product: NCc1ccc2c(c1)CC(=O)N2

Procedure:
To a solution of 2-Oxo-2,3-dihydro-1H-indole-5-carbonitrile (1.3 g) in methanol (30 ml) was added 10% PtO2 (0.200 g). This was shaken under 44 psi hydrogen over night. The catalyst was removed by filtration, and the mixture was dried over Na2SO4. The solution was concentrated to give a yellow solid, (1.1 g). MW 162; MS (m/e) 162 (M+).