Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:13][NH2:14])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[CH2:15]1[O:23][CH:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[ClH:24]>CO.CCOCC>[ClH:24].[OH:1][C:2]1([CH2:13][N:14]([CH2:15][CH:16]([OH:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:23])[CH2:3][O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH2:8]1
Reactant: NCC1(O)COc2ccccc2OC1
Reactant: c1ccc(C2CO2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: OC(CN(CC(O)c1ccccc1)CC1(O)COc2ccccc2OC1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Hydroxy-3-aminomethyl-3,4-dihydro-2H-1,5-benzodioxepin (2.30 g., 11.8 millimole) and styrene oxide (1.42 g., 11.8 millimole) are dissolved in methanol (12 ml.) and the solution then is stirred at ambient temperature for 48 hours. Evaporation of the reaction mixture gives 3.64 g. of a syrup which is chromatographed on a dry silica gel (150 g.) column which had been deactivated with about 25 ml. of water and packed in a 1 3/4 inches glass column. The first three fractions obtained upon elution with a 1:1 mixture of ether and chloroform are combined and dissolved in dry ether (50 ml.) and treated with a slight excess of ethanolic hydrogen chloride. The solid material is separated and dissolved in boiling ethanol (16 ml.) clarified with charcoal and filtered. The solvent was removed from the filtrate by evaporation yielding 3-hydroxy-3-[di-(2-hydroxy-2-phenylethyl)aminomethyl)-3,4-dihydro-2H-1,5-benzodioxepin hydrochloride, m.p. 221°-222° C. (dec.).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1>C1COCC1>[N:12]1([CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Reactant: C1CNC1
Solvent: C1CCOC1
Product: Cn1nc([N+](=O)[O-])cc1CN1CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with THF (45 mL), 20 (1.66 g, 7.54 mmol), azetidine (531 mg, 9.31 mmol) and stirred at room temperature for 24 h. After this time the reaction was concentrated to dryness under reduced pressure, and the resulting solid was diluted with a mixture of methylene chloride (15 mL) and 10% aqueous potassium carbonate (15 mL). The aqueous layer was separated and extracted with methylene chloride (2×15 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 99% yield (1.47 g) of 21 as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 6.74 (s, 1H), 3.97 (s, 3H), 3.55 (s, 2H), 3.22 (t, 4H, J=7.2 Hz), 2.10 (pentet, 2H, J=7.2 Hz); MS (ESI+) m/z 197.1 (M+H).
Reaction SMILES: [C:1]1([C:11]2([C:14](Cl)=[O:15])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][CH2:31][NH2:32])=[CH:28][C:27]=1[O:35][CH3:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][CH2:31][NH:32][C:14]([C:11]2([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:13][CH2:12]2)=[O:15])=[CH:28][C:27]=1[O:35][CH3:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)C1(c2cccc3ccccc23)CC1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(CCNC(=O)C2(c3cccc4ccccc34)CC2)ccc1OCc1ccccc1
Reaction time: 64 h
Yield: 101.5 %

Procedure:
A solution of 1-(1-naphthyl)cyclopropane carbonyl chloride (7.1 g, prepared as described in Example CL32) in ethyl acetate (50 ml) was added to a stirred mixture of 4-benzyloxy-3-methoxyphenethylamine hydrochloride (9.29 g) in ethyl acetate (150 ml). Triethylamine (25 ml) was added and the mixture stirred for a further 64 hours. The organic layer was washed with dilute hydrochloric acid, dried over sodium sulphate and the solvent removed in vacuo to yield N-[2-(4-benzyloxy-3-methoxyphenyl)-ethyl]-1-(1-naphthyl)cyclopropane carboxamide (14.1 g).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:33]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:28]3=[N:29][CH:30]=[CH:31][CH:32]=[C:27]3[CH:26]=2)=[CH:9]1>CN(C)C=O>[CH2:10]([O:2][C:1]([N:29]1[CH2:30][CH2:31][C:32]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH3:7])[CH:9]=[C:10]3[C:25]2[N:33]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:35])=[O:36])[C:28]3=[N:29][CH:30]=[CH:31][CH:32]=[C:27]3[CH:26]=2)=[CH:27][CH2:28]1)=[O:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(OS(=O)(=O)C(F)(F)F)cc34)cc3cccnc32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C5=CCN(C(=O)OCc6ccccc6)CC5)cc34)cc3cccnc32)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl 1-[3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl](2H)pyridinecarboxylate (2 g, prepared according to the procedure described by P. Eastwood, Tetrahedron Letters, 2000, 41, pages 3705-3708), dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium[II] (0.25 g,) and potassium carbonate (2.42 g), under nitrogen, was treated with a solution of trifluoro-methanesulfonic acid 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yl ester [1.6 g, Reference Example 18(a)] in dimethylformamide(76 mL). The mixture was heated at 80° C. for 4 hours (tlc indicated that starting material was still present), then treated with a further quantity of trifluoromethanesulfonic acid 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yl ester (0.15 g), then heated at reflux temperature for 4 hours and then left at room temperature overnight. A further quantity of trifluoro-methanesulfonic acid 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yl ester [0.15 g, Reference Example 18(a)] was added and the mixture was heated at reflux temperature for a further 4 hours then evaporated. The residue was partitioned between ethyl acetate and water, and the aqueous layer was extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give the title compound as a light brown viscous liquid which was used without further purification.
Reaction SMILES: Br[C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]2[O:19][CH2:20][O:21][C:3]=12.C([Li])CCC.CN([CH:35]=[O:36])C1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[CH:35]([C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]2[O:19][CH2:20][O:21][C:3]=12)=[O:36]
Reactant: Brc1c2c(cc3c1OCO3)C(c1ccccc1)CNCC2
Reactant: CN(C=O)c1ccccc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=Cc1c2c(cc3c1OCO3)C(c1ccccc1)CNCC2
Reaction time: 1 h

Procedure:
A mixture of 7.8 g (0.0225 mole) of 6-bromo-7,8-methylenedioxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine in toluene was added to a mixture of 2.2 ml (6.07 mole) of butyl lithium diluted with 100 ml of ethyl ether at -78°. Then, 10 ml of N-methylformanilide was added. After stirring for 1 hour at -78°, the cooling bath was removed and 100 ml of 10% hydrochloric acid was added. After stirring for 15 minutes, the layers were separated. The ether layer was dried and evaporated. The residue was dissolved in ethyl acetate then extracted by aqueous sodium bisulfite. The aqueous layer was removed, washed with ether and made basic with solid carbonate. After extraction with ethyl ether the extracts were evaporated. The residue was heated in 6 N hydrochloric acid for 1 hour. The solution was made basic and the product extracted into chloroform. After purification over silica with 5% methanol-chloroform, 6-formyl-7,8-methylenedioxy-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine was obtained as an oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:30]([C:29]4[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH2:25][C:23]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[O:24])[CH:28]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=Cc1cccc(OCC(=O)N2CCOCC2)c1
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OCC(=O)N4CCOCC4)c3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.87 g), 3-[4-morpholinylcarbonylmethoxy]benzaldehyde (2.1 g, 8.43 mmol) and xylenes (20 ml) was heated at 160° C. for about 2 days. The solvent was removed, then methanol was added to the residue and the product was collected by filtration. Additional product was obtained from the filtrates and the product fractions were pooled and recrystallized from CH3CN/CHCl3 to afford 1-cyclopentyl-3-ethyl-6-[3-(4-morpholinylcarbonylmethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 212-213° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:6]([C:20]#[N:21])[N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[C:20]([C:6]1[N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[C:4]([C:1]([NH2:2])=[O:3])[C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCn2c(C#N)c(-c3cccc(F)c3)c(C(N)=O)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(-c2cccc(F)c2)c(C(N)=O)c2n1CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of 1.05 g (2.73 mmol) of tert-butyl 8-carbamoyl-6-cyano-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 10 ml of dichloromethane are added slowly 2.7 ml (27 mmol) of trifluoroacetic acid. After stirring for 1 hour at room temperature, the solvent is evaporated off under reduced pressure, the residue is taken up in water and the aqueous phase is basified by addition of aqueous ammonia. The solid formed is separated out by filtration and rinsed with water, to give 0.71 g of 6-cyano-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide in the form of a white powder after drying under reduced pressure.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[C@@H:17]1[N:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:52])[C@@H:36]([NH:38][C:39](=[O:51])[C@@H:40]([NH:44][C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:41]([CH3:43])[CH3:42])[CH3:37])=[CH:30][CH:29]=2)=[O:25])[C:22]2[CH:53]=[C:54]([O:59][Si:60]([CH:67]([CH3:69])[CH3:68])([CH:64]([CH3:66])[CH3:65])[CH:61]([CH3:63])[CH3:62])[C:55]([O:57][CH3:58])=[CH:56][C:21]=2[C:20](=[O:70])[N:19]2[CH:71]=[C:72](/[CH:74]=[CH:75]/[CH3:76])[CH2:73][C@@H:18]12.N1C(C)=CC=CC=1C>C(Cl)Cl>[Si:1]([O:8][C@@H:17]1[N:23]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:52])[C@@H:36]([NH:38][C:39](=[O:51])[C@@H:40]([NH:44][C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:41]([CH3:42])[CH3:43])[CH3:37])=[CH:32][CH:33]=2)=[O:25])[C:22]2[CH:53]=[C:54]([O:59][Si:60]([CH:61]([CH3:63])[CH3:62])([CH:67]([CH3:69])[CH3:68])[CH:64]([CH3:65])[CH3:66])[C:55]([O:57][CH3:58])=[CH:56][C:21]=2[C:20](=[O:70])[N:19]2[CH:71]=[C:72](/[CH:74]=[CH:75]/[CH3:76])[CH2:73][C@@H:18]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(COC(=O)N2c3cc(O[Si](C(C)C)(C(C)C)C(C)C)c(OC)cc3C(=O)N3C=C(/C=C/C)C[C@H]3[C@@H]2O)cc1)C(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(COC(=O)N2c3cc(O[Si](C(C)C)(C(C)C)C(C)C)c(OC)cc3C(=O)N3C=C(/C=C/C)C[C@H]3[C@@H]2O[Si](C)(C)C(C)(C)C)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.5 %

Procedure:
Tert-butyldimethylsilyltrifluoromethane sulfonate (0.46 g, 1.74 mmol, 3.0 eq) was added to a solution of secondary alcohol 16 (0.5 g, 0.58 mmol, 1.0 eq) and 2,6-lutidine (0.25 g, 2.32 mmol, 4.0 eq) in dry DCM (10 mL) at 0° C. under an atmosphere of nitrogen. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for a further 120 mins. The organic phase was then washed successively with water (10 mL), saturated sodium bicarbonate (10 mL) and brine (5 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 50/50 v/v n-hexane/EtOAc) to afford the product as a white solid (0.320 g, 57%). LC/MS (4.415 min (ES+)), m/z: 976.52 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.31 (br s, 1H), 7.48 (d, 2H, J=8.0 Hz), 7.21 (s, 1H), 7.14 (d, 2H, J=8.3 Hz), 6.89 (s, 1H), 6.65 (s, 1H), 6.38 (d, 1H, J=7.3 Hz), 6.25 (d, 1H, J=14.6 Hz), 5.93 (m, 1H), 5.85 (d, 1H, J=8.8 Hz), 5.50 (m, 1H), 5.34 (m, 1H), 5.24 (m, 2H), 5.15 (d, 1H, J=12.5 Hz), 4.86 (d, 1H, J=12.2 Hz), 4.62 (m, 3H), 4.01 (m, 1H), 3.86 (s, 3H), 3.78 (m, 1H), 3.04 (m, 1H), 2.56 (m, 1H), 2.20 (m, 1H), 1.84 (dd, 3H, J=6.6, 0.7 Hz), 1.48 (d, 3H, J=6.8 Hz), 1.20 (m, 3H), 1.05 (d, 9H, J=2.9 Hz), 1.03 (d, 9H, J=2.9 Hz), 0.99 (d, 3H, J=6.8 Hz), 0.95 (d, 3H, J=6.8 Hz), 0.88 (s, 9H), 0.27 (s, 3H), 0.14 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:18]([C:20]1[C:21]([OH:30])=[C:22]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][C:25]=1O)[CH3:19]>>[C:27]([C:22]1[CH:23]=[CH:24][C:25]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)=[C:20]([CH2:18][CH3:19])[C:21]=1[OH:30])(=[O:29])[CH3:28]
Reactant: CCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1ccc(Sc2cccc(CO)c2)cn1
Product: CCc1c(OCc2cccc(Sc3ccc(C#N)nc3)c2)ccc(C(C)=O)c1O
Yield: 77.5 %

Procedure:
Using the method of Preparation 166 using 5-(3-(hydroxymethyl)phenylthio) picolinonitrile (1.70 g, 7.02 mmol) and 1-(3-ethyl-2,4-dihydroxyphenyl)ethanone (1.26 g, 7.02 mmol) affords the title compound (2.20 g, 78%). MS (APCI-neg) m/z (rel intensity): 403 (M−H, 100%).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18].Cl.O>C1COCC1>[N+:17]([C:5]1[CH:6]=[CH:7][C:8]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][C:4]=1[CH:3]=[O:2])([O-:19])=[O:18]
Reactant: COC(OC)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(dimethoxymethyl)-1-nitro-4-phenoxy-benzene (7.4 g, 0.0256 mol) in THF (80 mL) was added 12 N HCl (10 mL) and water (20 mL). The resulting mixture was stirred at room temperature for 2 days. Water was then added, and the mixture was extracted with diisopropyl ether. The organic layer was separated, washed with 10% aqueous NaHCO3 solution and then with water, dried (MgSO4), filtered, and concentrated to yield a yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[Br:14][C:15]1[S:19][C:18]2=[N:20][C:21]([C:23](O)=[O:24])=[CH:22][N:17]2[CH:16]=1>>[Br:14][C:15]1[S:19][C:18]2=[N:20][C:21]([C:23]([NH:11][CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=3)=[O:24])=[CH:22][N:17]2[CH:16]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: NCc1cccc(OC(F)(F)F)c1
Product: O=C(NCc1cccc(OC(F)(F)F)c1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (3-(trifluoromethoxy)phenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1>C1COCC1>[F:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([OH:12])[CH3:1])=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(F)nc1
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Add methylmagnesium bromide (3 M in ether, 12 mL, 36 mmol) at 0° C. under nitrogen to a solution of 6-fluoro-pyridine-3-carbaldehyde (3 g, 24 mmol) in THF (20 mL). Continue to stir the mixture overnight at RT. Quench the mixture with 1 N HCl, followed by basification with diluted ammonium hydroxide to ˜pH 9. Extract the product with chloroform/IPA (3/1). Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (10% methanol in DCM) to give the title compound as a colorless oil (2.3 g, 68%). MS (ES) m/z 142 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:23]=[CH:22][C:21](B4OC(C)(C)C(C)(C)O4)=[CH:20][CH:19]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1.Br[C:40]1[CH:41]=[N:42][C:43]([CH3:46])=[N:44][CH:45]=1>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:19]=[CH:20][C:21]([C:40]4[CH:41]=[N:42][C:43]([CH3:46])=[N:44][CH:45]=4)=[CH:22][CH:23]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1
Reactant: Cc1ncc(Br)cn1
Reactant: Cc1nnc(CC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)C(=O)O2)o1
Product: Cc1ncc(-c2ccc([C@H](C)N3CC[C@](CCc4nnc(C)o4)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-2-methylpyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.035 min, m/z=484.1; 1H NMR (CD3OD) 1.57 (m, 3H), 2.29 (m, 2H), 2.38 (m, 1H), 2.41 (s, 3H), 2.47 (m, 1H), 2.50 (m, 1H), 2.63 (m, 1H), 2.72 (s, 3H), 2.96 (m, 1H), 3.15 (m, 1H), 5.58 (m, 1H), 7.12 (m, 2H), 7.33 (m, 3H), 7.38 (m, 2H), 7.47 (m, 2H), 8.88 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([N:17]=[C:18]=[S:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[Br:8][C:4]1[N:3]=[C:2]([NH:1][C:18]([NH:17][C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[S:19])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Br)n1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cccc(Br)n1)c1ccccc1
Temperature: 65 °C
Yield: 99.5 %

Procedure:
2.604 g (14.75 mmol) 2-amino-6-bromopyridine was dissolved in 20 mL acetone, and 2.02 mL (14.75 mmol) undiluted benzoyl isothiocyanate was then added dropwise. The solution turned a brown color. The reaction mixture was then heated for 2 hr at 65° C. (oil bath temperature) with stirring. The light yellow solid which formed was filtered under vacuum and washed with pentane. The solvent of the mother liquor was also removed under vacuum. The resulting solids from the crystallizate (1.338 g) and from the mother liquor (3.595 g) were identical according to thin-layer chromatography (silica gel, eluents: dichloromethane/methanol (9:1)). A total of 4.933 g (14.67 mmol, 99.5%) N-{[(6-bromopyridin-2-yl)amino]carbonothioyl}benzamide was isolated.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8]([C:18]([NH:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:19])=[C:9]2[C:14](=[CH:15][CH:16]=1)[N+:13](O)=[CH:12][CH:11]=[CH:10]2>>[Cl:3][C:12]1[CH:11]=[CH:10][C:9]2[C:8]([C:18]([NH:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:19])=[C:7]([Cl:6])[CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(NCCC1CCCCC1)c1c(Cl)ccc2c1ccc[n+]2O
Product: O=C(NCCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Temperature: 60 °C

Procedure:
Phosphorous oxychloride (2 mL) was added to 6-chloro-5-[[(2-cyclohexylethyl)amino]carbonyl]-1-hydroxy-quinolinium Example 94(c)) (0.089 g) and the mixture heated at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and added to water. The aqueous was extracted with ethyl acetate and the combined organics dried filtered and evaporated give the sub titled compound as a solid (0.079 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH:10]([CH3:12])[CH3:11])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>O>[CH2:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccc(C(O)C(C)C)cc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1.9 g 1-(4-methoxy-phenyl)-2-methyl-propan-1-ol are dissolved in 30 ml dissolved, cooled to 0° C. and mixed with 3.37 ml triethylsilane. The mixture is stirred for 10 minutes and then 1.62 ml trifluoroacetic acid are added. Within 1 hour the mixture is heated to 10° C., then the reaction is stopped by the addition of water and the phases are separated. The organic phase is washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 95:5 to 80:20).
Reaction SMILES: [C:1]12[C:12](O)=[CH:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.P(Cl)(Cl)([Cl:16])=O>O1CCOCC1>[Cl:16][C:12]1[C:1]2[C:2]3[CH2:3][CH2:4][CH2:5][C:6]=3[S:7][C:8]=2[N:9]=[CH:10][CH:11]=1
Reactant: Oc1ccnc2sc3c(c12)CCC3
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Clc1ccnc2sc3c(c12)CCC3
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution of 7-thia-9-azatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-ol (280 mg, 1.46 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) was added phosphoroyl trichloride (1.12 g, 7.30 mmol, 5.00 equiv) at room temperature under nitrogen. The resulting solution was stirred for 2 h at 90° C. in an oil bath and concentrated under reduced pressure. The pH value of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate and extracted with 3×30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to afford 12-chloro-7-thia-9-azatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraene (0.25 g, 81%) as a white solid. MS (ES): m/z 210 and 212 (M+H)+.
Reaction SMILES: C12OC3CC([O:9]1)C(C=C3)C2.C(=O)(O)[O-].[K+].[C:16](#[N:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OO>CO.C(Cl)Cl>[C:16]([NH2:23])(=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccccc1
Reactant: C1=CC2CC3OC1CC2O3
Agent: O=C([O-])O
Agent: OO
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1ccccc1
Reaction time: 10 h

Procedure:
To a solution of 165 mg of racemic 9,10-dioxatricyclo[4,3,1,03,8 ]dec-4-ene in 4 ml of methanol are added, with stirring and at room temperture 865 mg of potassium bicarbonate and 750 mg of benzonitrile. To this mixture are added at intervals of 8 hours 5 positions each of 0.3 ml of 30% hydrogen peroxide and stirring is continued for 10 hours. methylene chloride (25 ml) is then added to the reaction mixture, which is washed with 2% sodium hydrogen carbonate solution, dried over sodium sulphate and concentrated, Benzamide which has formed is removed by crystallisation from methylene chloride/pentane. The residual oil can be used directly in the next reaction, or chromatographed on 22 g of basic aluminium oxide (activity level IV). Elution with petroleum ether/benzene (7:3) yields the racemic mixture of 4β, 5β-epoxy-9,10-dioxatricyclo[4,3,1,03,8 ]decane of the formula ##SPC18##