Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(S(OCC#C)(=O)=O)[CH:6]=CC=C[CH:2]=1.[CH:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH2:6][C:1]#[CH:2])[CH:14]=1
Reactant: Cc1cccc(O)c1
Reactant: C#CCOS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cccc(C)c1
Reaction time: 48 h

Procedure:
A mixture of propargyl benzenesulfonate (1.0 g, 5.1 mmol), m-cresol (0.55 mL, 5.1 mmol) and potassium carbonate (1.1 g, 7.65 mmol) in acetone (40 mL) was stirred at about 56 C for about 2 days. The mixture was cooled, filtered and the solvent was carefully distilled off at atmospheric pressure. The residue was purified by flash chromatography on silica gel using diethyl ether/n-pentane (1:9) as eluent to provide Example 614. 1H NMR (500 MHz, CDCl3): □ 2.33 (s, 3H), 2.50 (t, J=3.0 Hz, 1H), 4.66 (d, J=3.0 Hz, 2H), 6.77-6.82 (m, 3H), 7.15-7.21 (m, 1H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([N:13]2[CH2:17][CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH2:14]2)=[O:12])[CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([N:13]2[CH2:17][CH:16]=[C:15]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[C:35]([F:36])([F:38])[F:37])[CH2:14]2)=[O:12])[CH2:3][CH2:2]1
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC1(C)OB(C2=CCN(C(=O)N3CCOc4ccccc43)C2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(N1CC=C(c2ccc(F)cc2C(F)(F)F)C1)N1CCOc2ccccc21
Yield: 70.4 %

Procedure:
0.4 g of (2,3-dihydrobenzo[1,4]oxazin-4-yl)[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,5-dihydropyrrol-1-yl]methanone, 0.4 g of 1-bromo-4-fluoro-2-(trifluoromethyl)benzene, 1.4 ml of a 2N solution of sodium carbonate in water and 15 ml of ethylene glycol dimethyl ether are placed in a 100 ml three-necked flask equipped with a magnetic stirrer and placed under an inert atmosphere. The reaction mixture is degassed with nitrogen for 30 minutes and then the reaction mixture is heated at reflux for 14 h. After filtering and concentrating to dryness, the crude reaction product obtained is chromatographed on silica gel, elution being carried out with a gradient of ethyl acetate in dichloromethane varying from 0% to 10%. 0.31 g of (2,3-dihydrobenzo[1,4]oxazin-4-yl)[3-(4-fluoro-2-(trifluoromethyl)phenyl)-2,5-dihydropyrrol-1-yl]methanone is obtained.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].[SH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].COC(OC)(C1C=CC=CC=1)C(C1C=CC=CC=1)=O>C1(C)C=CC=CC=1>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][S:7][CH2:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: C=CC(F)(F)F
Reactant: COC(=O)CCS
Agent: COC(OC)(C(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)CCSCCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500 mL three-neck round bottom flask was charged with toluene (200 mL) and cooled to <−50° C. with a dry ice/acetone bath. 3,3,3-Trifluoropropene (21.8 g, 227 mmol) was condensed into the reaction by bubbling the gas through the cooled solvent and the ice bath was removed. Methyl 3-mercaptopropionate (26.8 g, 223 mmol) and 2,2-dimethoxy-2-phenylacetophenone (2.72 g, 10.61 mmol) were added and a UVP lamp (4 watt) that was placed within 2 centimeters of the glass wall was turned on to the long wave function (366 nanometers). The reaction reached 35° C. due to heat from the lamp. After 4 hours, all of the trifluoropropene was either consumed or boiled out of the reaction. The light was turned off and the reaction stirred at room temperature overnight. After 22 hours, more trifluoropropene (3.1 g) was bubbled through the mixture at room temperature and the light was turned on for an additional 2 hours. The reaction had converted 93% so no more trifluoropropene was added. The light was turned off and the mixture concentrated on the rotovap (40° C., 20 torr) giving a yellow liquid (45.7 g, 21.3:1 linear: branched isomer, 75 wt % pure linear isomer determined by a GC internal standard assay, 34.3 g active, 71% in pot yield).
Reaction SMILES: [C:1](O)(=O)[CH3:2].[C:5]([C:7]1[C:8]([F:27])=[C:9]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[C:10]([C:12](=[CH:18][N:19]([CH3:21])C)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11])#[N:6].C1(N)CC1.O>C1(C)C=CC=CC=1>[C:5]([C:7]1[C:8]([F:27])=[C:9]([CH:22]=[C:23]([F:26])[C:24]=1[F:25])[C:10]([C:12](=[CH:18][NH:19][CH:21]1[CH2:2][CH2:1]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11])#[N:6]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)c(C#N)c1F
Reactant: CC(=O)O
Agent: NC1CC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(C#N)c1F
Temperature: 30 °C
Reaction time: 1 h

Procedure:
30 g of glacial acetic acid are added dropwise to the crude product from step e at 20° C. Then a solution of 15.75 g of cyclopropylamine in 30 ml of toluene is added dropwise. The reaction mixture is stirred at 30° C. for 1 hour. After the addition of 200 ml of water the mixture is stirred for 15 minutes. The organic phase is separated, extracted with 100 ml of water, dried with Na2CO3 and concentrated in vacuo. The crude product is used for the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][C:37]=2[CH3:38])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[N:34][CH:35]=[CH:36][C:37]=4[CH3:38])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccc3C)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cnccc3C)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M211) (304 mg, 0.545 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (177 mg, 74%).
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.[CH2:22]([Li])CCC.CI>CCOCC>[CH3:17][Si:16]([CH3:19])([CH3:18])[C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:5](=[CH:4][C:3]([Si:2]([CH3:21])([CH3:20])[CH3:1])=[CH:15][CH:14]=3)[CH:6]([CH3:22])[C:7]=2[CH:8]=1
Reactant: C[Si](C)(C)c1ccc2c(c1)Cc1cc([Si](C)(C)C)ccc1-2
Reactant: [Li]CCCC
Solvent: CI
Solvent: CCOCC
Product: CC1c2cc([Si](C)(C)C)ccc2-c2ccc([Si](C)(C)C)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a solution of 1.0 g of 2,7-bis(trimethylsilyl)fluorene in 15 mL of dry ether was added dropwise 2.8 mL of 1.3 M n-butyllithium at 0° C. The mixture was stirred at room temperature for 3 hours, cooled to 0° C., and treated with a solution of 0.25 mL of methyl iodide in 5 mL of dry ether over a period of 5 minutes. The mixture was stirred at room temperature for 8 hours and washed with 2% Na2S2O3 (10 mL) and water (2×10 mL). The pooled aqueous layer was extracted with ether (2×15 mL). The combined organic extracts were dried over MgSO4 and the solvent was evaporated under reduced pressure to give 1.03 g (98.7%) of the crude 2,7-bis(trimethylsilyl)-9-methylfluorene as a yellow oil which was chromatographed on silica gel (230-400 mesh, 2×40-cm packed column) with an eluant consisting of Skelly B--dichloromethane (6:1) to give 0.78 g (74.7%) of the crude hydrocarbon as a colorless oil. Crystallization from 95% ethanol gave 0.69 g (66.1%) of the pure 2,7-bis(trimethyl-silyl)-9-methylfluorene as white needles, m.p. 107°-108.5° C.; 1H NMR (CDC13): δ 0.34 (s, 18H, SiMe3), 1.58 (d, 3H, CH3), 3.96 (q, 1H, CH), 7.40-7.90 (m, 6H, aryl).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[C:36]([O:48][CH3:49])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:59])=[C:36]([O:48][CH3:49])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(OC)c2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OC)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(pyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.55 g) was dissolved in dichloromethane (25 ml), and to the solution was added 3-chloroperbenzoic acid (0.26 g) under ice-cooling and the mixture was stirred overnight at room temperature. An aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate and the solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.44 g) as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH:10]([CH3:18])[C:11]([O:16][CH3:17])=[CH:12][C:13](Cl)=[O:14])=[CH:7][CH:6]=1.[CH3:29][NH2:30]>C1COCC1>[CH3:29][NH:30][C:13](=[O:14])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]([O:9][C:8]1[CH:19]=[CH:20][C:5]([O:4][C:3]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:24][C:2]=2[Cl:1])=[CH:6][CH:7]=1)[CH3:18]
Reactant: CN
Reactant: COC(=CC(=O)Cl)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Solvent: C1CCOC1
Product: CNC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reaction time: 1 h

Procedure:
A mixture of 4-[4-(2-chloro-4-trifluoromethylphenoxy) phenoxy]-3-methoxy-2-pentenoyl chloride (15 mm) and THF (15 ml.), at 0°, is prepared and then slight excess of methylamine introduced. The reaction mixture is allowed to stand under nitrogen for about one hour. Then the reaction is allowed to rise to RT and solvent removed. The residue is taken up in methylene dichloride, washed, dried and solvent removed under vacuum to yield N-methyl 4-[4-(2-chloro-4-trifluoromethylphenoxy) phenoxy]-3-methoxy-2-pentenamide.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:10]=[C:11]4[N:20]([CH3:21])[CH:19]=[CH:18][C:12]4=[N:13][C:14]=3[C@@H:15]([NH2:17])[CH3:16])=[CH:7][CH:6]=[N:5]2)[CH2:3][CH2:2]1.Cl[C:23]1[N:31]=[C:30]([NH2:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(C(C)C)C(C)C)C>C(#N)C>[CH:1]1([N:4]2[C:8]([C:9]3[CH:10]=[C:11]4[N:20]([CH3:21])[CH:19]=[CH:18][C:12]4=[N:13][C:14]=3[C@@H:15]([NH:17][C:23]3[N:31]=[C:30]([NH2:32])[N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH3:16])=[CH:7][CH:6]=[N:5]2)[CH2:2][CH2:3]1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1-c1ccnn1C1CC1
Temperature: 120 °C
Yield: 9.4 %

Procedure:
(S)-1-(6-(1-Cyclopropyl-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (166 mg, 0.590 mmol), 6-chloro-9H-purin-2-amine (100 mg, 0.590 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.31 mL, 1.8 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and was purified by preparative HPLC (acid mode) eluting with 10-15% ACN in water. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (basic mode) eluting with 25-35% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as a white solid (23 mg, 9.2%). 1H NMR (500 MHz, CD3OD) δ ppm 0.59-0.75 (m, 2 H), 0.87-1.03 (m, 2H), 1.50 (d, J=6.35 Hz, 3 H), 3.38-3.47 (m, 1 H), 3.87 (d, J=0.98 Hz, 3 H), 5.56 (br s, 1 H), 6.44 (s, 1 H), 6.70 (d, J=2.93 Hz, 1 H), 7.54-7.71 (m, 3 H), 7.83 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H22N10, 415; found 415.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:11][CH2:10][N:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:8]2[N:23]=[CH:24][CH:25]=[CH:26][C:7]=2[C:6]1=O)C.O.[NH2:29]N>CO>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([N:9]2[CH2:10][CH2:11][C:5]3[CH:4]=[N:2][NH:29][C:6]=3[C:7]3[CH:26]=[CH:25][CH:24]=[N:23][C:8]2=3)=[O:22])=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ncccc2C1=O
Reactant: NN
Solvent: O
Solvent: CO
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cn[nH]c2-c2cccnc21
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a slurry of 0.51 g of 6-[(dimethylamino)methylene]-6,7,8,9-tetrahydro-9-(4-nitrobenzoyl)-5H-pyrido[2,3-b]azepin-5-one in 17 ml of methanol under argon is added 0.14 g of hydrazine hydrate. The mixture is stirred overnight and the solvent removed under vacuum. The residue is dissolved in hot chloroform-methanol (95:5) and filtered through silica gel and washed filter pad with chloroform-methanol (95: 5). The filtrate is concentrated to dryness to give 0.48 g of yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][C:8](=O)[NH:7][C:6]=2[CH:13]=1.COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:13]=1
Reactant: O=C1CCSc2ccc(F)cc2N1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)NCCCS2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.2 %

Procedure:
7-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (76 mg, 0.38 mmol) dissolved in toluene (1 mL) and cooled to 0° C. in an ice bath. Red-Al (275 mL, 0.91 mmol) was added and then the reaction allowed to warm to room temperature. The reaction was heated at reflux for 1.5 hours. 1 N sodium hydoxide was added slowly until pH >10, this was stirred for 10 minutes, extracted with dichloromethane (3×25 mL), washed with water, and dried (sodium sulfate). The concentrated organics were purified by preparative thin layer chromatography on silica gel and eluted with 50% ethyl acetate in hexanes to give 7-fluoro-2,3,4,5-tetrahydro-1,5-benzothiazepine (30.8 mg, 93%). 1H NMR (CDCl3, 300 MHz): δ 7.32 (t, 1H, J=7.5 Hz), 6.53–6.42 (m, 2H), 4.09 (s-broad, 1H), 3.31–3.27 (m, 2H), 2.83–2.79 (m, 2H), 2.11–2.04 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].OO.C(=O)([O-])[O-:23].[Na+].[Na+]>C(O)C>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]1[O:23][CH:8]1[C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=C([O-])[O-]
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: O=C1C2OC2C(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
38 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared according to Example 1, were added slowly to a solution of 200 ml. of ethanol containing 20 ml. of 30% hydrogen peroxide and 13 g. of sodium carbonate at such a rate that the temperature was maintained at 40°-50° C. The yellow color of the dione disappeared quickly. The solution was then cooled to 10°-13° C. and a white precipitate formed. This solid was filtered and recrystallized from ethanol, m.p. 180°-181° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.Cl.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.O>CN(C=O)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([N:27]3[CH2:28][CH2:29][CH:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:30])[F:31])[CH:19]=4)[CH2:25][CH2:26]3)=[O:14])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc2nccnc2c1
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2nccnc2c1)N1CCC(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
0.48 g (2.55 mmol) of quinoxalin-6-ylacetic acid is mixed in 25 ml of DMF, and 1.07 ml of TEA, 0.68 g (2.55 mmol) of 4-(3-(trifluoromethyl)phenyl)piperidine hydrochloride and 1.13 mg of BOP are added thereto. The mixture is heated at ambient temperature overnight, 200 ml of water are added and extraction is carried out with ethyl acetate. The organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated under reduced pressure. A dark oil is thus obtained, which oil is purified by flash chromatography on a column of silica gel, elution being carried out with ethyl acetate. 0.76 g of the title product is obtained in the form of a yellow oil.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][S:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:30][C@H:29]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])[O:28][C:27]4=[O:36])=[CH:22][CH:21]=3)=[O:19])=[CH:16][N:17]=2)[CH:14]=1>O.CO>[CH3:7][S:8]([C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:30][C@H:29]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])[O:28][C:27]4=[O:36])=[CH:24][CH:25]=3)=[O:19])=[CH:16][N:17]=2)[CH:14]=1)=[O:2]
Reactant: CSc1ccc2ncc(C(=O)c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3)n2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)c3cnc4ccc(S(C)=O)cn34)cc2)C(=O)O1
Yield: 56.2 %

Procedure:
A solution of sodium periodate (0.067 g. 0.313 mM) in water (2.5 ml) was added to a stirred suspension of the title product from Example 37 (0.12 g. 0.283 mM) in MeOH (10 ml) and the mixture heated at gentle reflux for 3 hours. The mixture was filtered hot and allowed to cool. The solid which precipitated was filtered, washed with water and ether and purified by chromatography on a BondElut silica column with gradient elution increasing in polarity from dichloromethane to 10% MeOH/dichloromethane to give the title compound (0.07 g). MS: 441 (MH+); NMR 1.83 (3H, s); 2.9 (3H, s); 3.45 (2H, t); 3.83 (1H, m); 4.2 (1H, t); 4.75 (1H, m); 7.75 (2H, d) 7.9 (1H, m); 7.96 (2H; d); 8.05 (1H, d); 8.24 (1H, t); 8.36 (1H, s); 9.83 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][NH:23][CH2:24][CH2:25][OH:26].C1N=CN([C:38](N2C=NC=C2)=[O:39])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C@H:7]([CH2:22][N:23]2[CH2:24][CH2:25][O:26][C:38]2=[O:39])[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]1=[O:10]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CNCCO)c(OC)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN2CCOC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a solution of benzyl ((2R,3S)-1-(2,4-dimethoxybenzyl)-2-(((2-hydroxyethyl)amino)methyl)-4-oxoazetidin-3-yl)carbamate (4.47 g, 10.08 mmol) in chloroform (50 ml) was added CDI (4.90 g, 30.2 mmol). After stirring at rt for 30 min it was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-5%), affording the title compound (3.84 g, 81%) as a white foam. LCMS: Rt=0.76 min, m/z=470.1 (M+1).
Reaction SMILES: Cl.C([O:4][C:5](=O)[CH2:6][NH:7][CH3:8])C.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[S:18])[CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:8][N:7]1[CH2:6][C:5](=[O:4])[N:16]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[C:17]1=[S:18]
Reactant: CCOC(=O)CNC
Reactant: S=C=Nc1cccnc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CC(=O)N(c2cccnc2)C1=S
Yield: 39.6 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), pyridin-3-yl-isothiocyanate (6.8 g), triethyl amine (10.1 g) and chloroform (200 mL) was heated at reflux for 3.5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (300 mL) and washed with water (2×200 mL). The organic phase was dried over anhydrous magnesium sulfate. The solvent was evaporated. Crystallization from ethyl acetate afforded the title compound (4.1 g) as an off-white solid, m.p. 149°-151° C. Anal. Calcd. for C9H9N3O S: C, 52.16; H, 4.38; N, 20.28. Found: C, 52.16; H, 4.05; N, 20.06. Mass spectrum (EI, M.+) m/z 207.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(C(C)C)CC)(C)C.Cl.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[OH:29]>ClCCl>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: N[C@@H]1CCCC[C@@H]1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N[C@@H]2CCCC[C@@H]2O)ccc(C#N)c1Cl
Reaction time: 4 h
Yield: 29.6 %

Procedure:
A mixture of 2-chloro-4-fluoro-3-methyl-benzonitrile (500 mg, 2.95 mmol), diisopropylethylamine (1.29 mL, 7.37 mmol), and (1S,2R)-2-aminocyclohexanol hydrochloride (670 mg, 4.42 mmol, Acros®) is microwaved using a CEM® microwave at 190° C. for 2 h and 180° C. for 4 h. The mixture is diluted with dichloromethane and washed with 1 N HCl. The aqueous layer is extracted again with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with 2% methanol/dichloromethane. The isolated product is recrystallized with ether and hexane to yield the title compound as a white solid (231 mg, 29%). LC-ES/MS m/z 265.0 (M+1).