Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:23])[NH:10][C@@H:11]([CH3:22])[C@H:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[C:46]1[CH:47]=[C:48]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([O:62][CH3:63])=[O:61])=[CH:56][C:55]=2[CH3:64])[CH:49]=[CH:50][C:51]=1[O:52][CH3:53]>CC(N(C)C)=O.C1COCC1>[CH3:53][O:52][C:51]1[CH:50]=[CH:49][C:48]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([O:62][CH3:63])=[O:61])=[CH:56][C:55]=2[CH3:64])=[CH:47][C:46]=1[C:37]1[CH:38]=[CH:39][C:40]([C:42]([F:45])([F:43])[F:44])=[CH:41][C:36]=1[CH2:35][N:10]1[C@@H:11]([CH3:22])[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[O:23][C:9]1=[O:8]
Reactant: COc1cccc([C@@H](O)[C@H](C)NC(=O)OCc2ccccc2)c1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cccc(OC)c4)[C@@H]3C)c2)c(C)c1
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of benzyl[(1S,2R)-2-hydroxy-2-(3-methoxyphenyl)-1-methylethyl]carbamate (40 mg, 0.126 mmol) in DMA (1.5 mL) was added NaHMDS (0.246 mL of a 1M solution in THF, 0.246 mmol). After 5 minutes, a solution of methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (68 mg, 0.138 mmol) in DMA (2.5 mL) was added via cannula. After 5 minutes, the reaction was quenched with saturated NH4Cl solution (10 mL), diluted with EtOAc (20 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 25% acetone/hexanes), followed by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA) afforded methyl 4′-methoxy-2″-{[(4S ,5R)-5-(3-methoxyphenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS=644.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 7.94-7.86 (m, 2H), 7.71-7.62 (m, 2H), 7.43-7.36 (m, 2H), 7.31-7.22 (m, 2H), 7.3 (m, 1H), 7.08-7.05 (m, 1H), 6.85-6.83 (m, 1H), 6.75-6.68 (m, 2H), 5.45 (d, J=8.0 Hz), 5.23 (d, J=8.0 Hz), 4.89 (d, J=16.0 Hz), 4.82 (d, J=16.0 Hz), 4.20 (d, J=15.8 Hz), 3.96 (d, J=15.8 Hz), 3.91 (s, 3H), 3.85 (s, 3H), 3.77-3.75 (m, 3H), 3.72-3.69 (m, 1H), 2.31 (s), 2.08 (s), 0.54 (d, J=6.4 Hz), 0.44 (d, J=6.4 Hz).
Reaction SMILES: [CH:1]1([C:4]2[CH:33]=[CH:32][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18]([C:20]([C:22]5[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:17]4)=[CH:12][C:11]=3[O:30][CH3:31])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)(Cl)Cl>[CH3:41][S:42]([O:29][CH2:28][C:26]1[CH:25]=[CH:24][N:23]=[C:22]([C:20]([N:18]2[CH2:17][CH:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:7]4[CH:32]=[CH:33][C:4]([CH:1]5[CH2:3][CH2:2]5)=[CH:5][CH:6]=4)=[C:11]([O:30][CH3:31])[CH:12]=3)[CH2:19]2)=[O:21])[CH:27]=1)(=[O:44])=[O:43]
Reactant: COc1cc(C2CN(C(=O)c3cc(CO)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C2CN(C(=O)c3cc(COS(C)(=O)=O)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of {3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidin-1-yl}-(4-hydroxymethylpyridin-2-yl)-methanone (4.0 g) prepared in (6) in chloroform (80 mL) were added triethylamine (3.0 mL) and methanesulfonyl chloride (1.5 mL) at 0° C. The reaction mixture was stirred at RT for 30 min. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. Hexane was added to the residue. The precipitated solid was collected on a filter and dried to give the title compound (4.6 g, 99%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2].CCN(CC)CC.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:21])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2]
Reactant: CCc1ccc(O)c(C(=O)OC)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3.0 g (16.6 mmol) of methyl 5-ethyl-2-hydroxybenzoate in 100 mL of CH2Cl2 at 0° C was added 5.8 mL (41.5 mmol, 2.5 eq.) of Et3N. To this stirred solution was added dropwise 3.6 mL (21.6 mmol, 1.3 eq.) of Tf2O. Following complete addition 0.2 g (cat.) of 4-dimethylamino pyridine was added and the reaction mixture was allowed to warm to room temperature. After 4 h stirring at this temperature the reaction was judged complete, and quenched by the addition of a saturated aqueous solution of NaHCO3 (100 mL). The resulting layers were separated and the aqueous layer extracted twice with CH2Cl2 (100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue, was purified by column chromatography to yield the desired methyl 5-ethyl-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate. 1H NMR (400 MHz, CDCl3): δ=7.94 (d, J=2.3 Hz, 1 H), 7.47 (dd, J=2.3, 8.4 Hz, 1 H), 7.24 (d, J=8.4 Hz, 1 H), 4.00 (s, 3 H), 2.76 (q, J=7.6 Hz, 2 H), 1.28 (t, J=7.6 Hz, 3 H).
Reaction SMILES: C1C2C(=CC=CC=2)C=C1.CCC(C[O:16][C:17](C(N(CC[NH+](C)C)C)=O)([C:24]1[CH:29]=CC=CC=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC.[Cl-].[Br:40]Br>O>[Br:40][C@@H:24]1[CH2:29][C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:17]1[OH:16]
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Reactant: BrBr
Agent: C1=Cc2ccccc2C1
Agent: [Cl-]
Solvent: O
Product: O[C@@H]1c2ccccc2C[C@H]1Br

Procedure:
43.5 g of indene (92 wt %; 0.345 mol), 0.7 g of Triton X-100 and 100 ml of water were put into a 500-ml 3-mouthed flask, and mixed by stirring. Mixing was continued at 60° C. as 27.5 g of bromine (0.172 mol, 0.5 mol/mol of indene) was added dropwise over approximately 3 hours. After this, stirring at 60° C. was continued. The reaction mixture was extracted with ethyl acetate directly after dropwise addition of bromine, and after mixing for a further 1 hour. Yields of trans-2-bromoindan-1-ol were calculated from the hydrogen bromide concentrations in the aqueous phase (by gravimetric titration using silver nitrate), and the quantity of indene in the extraction layer was found by GC by means of a calibration line and used to calculate percent conversion.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:16])([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9].C(N(CC)CC)C.[F:25][C:26](=[CH2:30])[C:27](Cl)=[O:28]>C(OCC)C>[F:25][C:26](=[CH2:30])[C:27]([O:16][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:17])([C:12]([F:13])([F:14])[F:15])[C:8]([F:11])([F:10])[F:9])=[O:28]
Reactant: Cc1ccccc1C(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(F)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(F)C(=O)OC(c1ccccc1C)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A solution of 21 g (0.081 mol) of 2-tolylhexafluoro-2-propanol and 8.2 g (0.08 mol) of triethylamine in 25 ml of dry diethyl ether was added dropwise with stirring at a temperature of 20° C. to a solution of 9.8 g (0.09 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 25 ml of dry diethyl ether in the course of 40 minutes. The reaction mixture was then stirred at a temperature of 20° C. for a further 4 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.02 g of hydroquinone monomethyl ether. 19.6 g (73 percent of theory) of 2-tolylhexafluoro-2-propyl α-fluoroacrylate having a boiling point of 58° to 60° C. (under 0.27 mbar) were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)[S:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[OH:20][C:21]1[CH:25]=[C:24]([N:26]2[C:30]3[CH:31]=[N:32][CH:33]=[CH:34][C:29]=3[N:28]=[CH:27]2)[S:23][C:22]=1[C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+].[Cl:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH:52](Cl)[CH3:53]>CN(C)C=O>[Cl:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH:52]([O:1][C:2]1[CH:6]=[C:5]([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)[S:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:53].[Cl:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH:52]([O:20][C:21]1[CH:25]=[C:24]([N:26]2[C:30]3[CH:31]=[N:32][CH:33]=[CH:34][C:29]=3[N:28]=[CH:27]2)[S:23][C:22]=1[C:35]([O:37][CH3:38])=[O:36])[CH3:53]
Reactant: CC(Cl)c1ccccc1Cl
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OC(C)c1ccccc1Cl
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OC(C)c1ccccc1Cl

Procedure:
In a similar manner as described for example B3, 300 mg of an isomeric mixture of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate (example C1) and 181 mg K2CO3 and 206 mg 1-chloro-2-(1-chloroethyl)benzene in 5 ml N,N-dimethylformamide yield methyl 3-[1-(2-chlorophenyl)ethoxy]-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and methyl 3-[1-(2-chlorophenyl)ethoxy]-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate.
Reaction SMILES: [CH3:1]/[C:2](/[CH:6]=[CH:7]/[C:8](/[F:21])=[C:9](\[CH3:20])/[CH:10]=[CH:11]/[C:12]1[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:13]=1[CH3:19])=[CH:3]\[CH2:4][OH:5].O1CCC[CH2:23]1.[H-].[Na+].CN(C)C=O>O>[CH3:1]/[C:2](/[CH:6]=[CH:7]/[C:8](/[F:21])=[C:9](\[CH3:20])/[CH:10]=[CH:11]/[C:12]1[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:13]=1[CH3:19])=[CH:3]\[CH2:4][O:5][CH3:23]
Reactant: C1CCOC1
Reactant: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC/C=C(C)/C=C/C(F)=C(C)/C=C/c1c(C)sc(C)c1C
Temperature: 23 °C
Reaction time: 14 h
Yield: 52 %

Procedure:
A solution of 0.400 g. (1.31 mmole) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraen-1-ol in 5 ml. of tetrahydrofuran was added to a suspension of 0.11 g. (2.6 mmole) of a 56% sodium hydride dispersion in a mixture of 10 ml. of dry tetrahydrofuran and 20 ml. of dry dimethylformamide. This reaction mixture was stirred at 23° C. for 14 hours, poured into water and extracted with ether-hexane (1:1 parts by volume). The extracts were washed with water, dried with magnesium sulfate, filtered and evaporated to give an orange product which was crystallized from ether-hexane (1:4 parts by volume) to give 220 mg. (52% yield) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-1-methoxy-2,4,6,8-nonatetraene as a light orange solid, m.p. 117°-118° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[C:26](C1NC=CN=1)(=[O:28])[CH3:27]>O1CCCC1.CCCCCC>[C:26]([CH:21]1[CH2:20][CH:19]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH2:24][CH2:23][C:22]1=[O:25])(=[O:28])[CH3:27]
Reactant: O=C1CCC(c2ccncc2)CC1
Reactant: CC(=O)c1ncc[nH]1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)C1CC(c2ccncc2)CCC1=O
Temperature: -78 °C
Yield: 66.5 %

Procedure:
To a solution of 3.2 ml of diisopropylamine dissolved in 40 ml of tetrahydrofuran, there was added 14.2 ml of 1.6M solution of n-butyl lithium in hexane at -20° C. Then, a solution of 2 g of 4-(4-pyridyl)cyclohexanone dissolved in 40 ml of tetrahydrofuran was added at -40° C. The reaction mixture was cooled to -78° C., and 2.5 g of acetylimidazole dissolved in 40 ml of tetrahydrofuran was added. The reaction mixture was stirred at room temperature, poured into ice water, and then washed with ether. The aqueous layer was saturated with ammonium chloride and extracted with methylene chloride. Thus, there was obtained 1.65 g of 2-acetyl-4-(4-pyridyl)cyclohexanone.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:19]([CH3:36])[C:20]([C:34]#[N:35])=[C:21]2[C:25]=1[O:24][C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[C:28](=[O:33])[CH2:27]1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:19]([CH3:36])[C:20]([C:34]#[N:35])=[C:21]3[C:25]=2[O:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[C:28](=[O:33])[CH2:27]2)=[N:22]3)[CH2:4]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CCN(C)C(=O)C3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CCN(C)C(=O)C3)nc2c1C#N
Temperature: 130 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (67.9 μl, 0.535 mmol) and triethylamine (86.1 μl, 0.618 mmol) were added to a dimethyl sulfoxide (5 ml) solution of 7-fluoro-5-methyl-2-(4-methyl-3-oxopiperazin-1-yl)-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-188) (150 mg, 0.412 mmol), followed by stirring in an oil bath at 130° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (50 ml), washed with saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=10:1) to obtain the entitled compound (109 mg, 54.5%) as a colorless foamy substance.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:22][C@H:23]([CH2:27][CH3:28])[C:24]([NH2:26])=[O:25])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:26][C:24](=[O:25])[C@H:23]([NH:22][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:27][CH3:28]
Reactant: CC(=O)O
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc(-c3ccncc3)cc2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc(-c3ccncc3)cc2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(5-cyano-6-(4-(pyridin-4-yl)phenylamino)pyrazin-2-ylamino)butanamide (57 mg, 0.152 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (31 mg). MS 392.3 (M+H); UV 204.2, 244.4, 281.2, 360.0 nm; t 0.404 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][CH2:10][C:11]1[NH:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)(=O)C.[CH3:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]>CN(C=O)C>[C:25]([O:24][C:22]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10][C:11]1[N:15]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26].[CH2:45]([N:15]1[C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:12][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:14]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCCCCCC
Reactant: CC(C)(C)OC(=O)N(CCc1nc(-c2ccccc2)n[nH]1)C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCc1nc(-c2ccccc2)nn1Cc1ccccc1)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCCc1nc(-c2ccccc2)nn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.2 %
Yield: 34.6 %

Procedure:
To a solution of 5-[2-bis(tert-butoxycarbonyl)aminoethyl]-3-phenyl-[1,2,4]triazole (232 mg, 597 μmol; example 22, step 1) in DMF (2.83 mL) was added sodium hydride (55%, 25 mg, 574 μmol) at 0-5° C. The resulting suspension was stirred for 30 min. Then benzylbromide (102 mg, 71 μL, 597 μmol) was added at 0-5° C. and after 45 min the ice bath was removed and stirring was continued for 1 h. The reaction mixture was extracted with ethyl acetate (40 mL) and washed with water (3×20 mL) and brine (1×20 mL). The aqueous layers were back-extracted with ethyl acetate (40 mL) and the combined organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) to obtain 5-[2-bis(tert-butoxycarbonyl)aminoethyl]-1-benzyl-3-phenyl-[1,2,4]triazole (115 mg, 240 μmol, 73.2%, MS: M=479.3 (M+H)+) and tert-butyl 2-(1-benzyl-3-phenyl-1H-1,2,4-triazol-5-yl)ethylcarbamate (43 mg, 114 μmol, 34.6%, MS: M=379.4 (M+H)+) both as colorless oils which were combined for the next step.
Reaction SMILES: O.[OH-].[Li+:3].C[O:5][C:6]([C:8]1[O:9][C:10]2[CH2:11][N:12]([CH3:17])[CH2:13][CH2:14][C:15]=2[N:16]=1)=[O:7]>O1CCCC1>[CH3:17][N:12]1[CH2:13][CH2:14][C:15]2[N:16]=[C:8]([C:6]([O-:7])=[O:5])[O:9][C:10]=2[CH2:11]1.[Li+:3]
Reactant: COC(=O)c1nc2c(o1)CN(C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)[O-])oc2C1
Reaction time: 0.17 h
Yield: 107.6 %

Procedure:
Water (6.0 ml) and lithium hydroxide (99.7 mg) were added to a solution of 2-methoxycarbonyl-5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine (800 mg) in tetrahydrofuran (24 ml) at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (825 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[S:22]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23]1>O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][S:22][CH:23]=2)[CH:7]=1
Reactant: OB(O)c1ccsc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(-c4ccsc4)c3)cc21

Procedure:
Prepared from 6-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-thiophene boronic acid according to procedure B. A brownish-orange solid: mp 200-203° C.; 1H-NMR (CDCl3) δ 8.62 (s, 1H), 7.53 (q, 1H, J=1.4 Hz), 7.50 (d, 1H, J=1.5 Hz), 7.49 (d, 1H, J=2.0 Hz), 7.45-7.40 (m, 1H), 7.35 (d, 1H, J=1.8 Hz), 7.27-7.24 (m, 2 H), 7.15 (dt, 1H, J=5.8, 2.0 Hz), 6.94 (d, 1H, J=8.2 Hz), 1.80 (s, 6H); MS ((−)APCI) [M−H]−@m/z 352. Anal. Calc. For C20H16FNO2S.0.50 H2O: C, 66.28; H, 4.73; N, 3.87. Found: C, 66.54; H, 5.03; N, 3.52.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH:9]1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[C:17]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:23]1[N:18]2[CH:19]([CH3:30])[C:20](=[O:29])[NH:21][N:22]=1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][CH:28]=2)[O:25][CH2:24][C:23]2[N:18]3[CH:19]([CH3:30])[C:20](=[O:29])[NH:21][N:22]=2)[CH:9]1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1C(=O)NN=C2COc3ccc(N)cc3N21
Reactant: CC1C(=O)CN1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1C(Nc2ccc3c(c2)N2C(=NNC(=O)C2C)CO3)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
To a mixture of 2-methyl-3-oxo-azetidine-1-carboxylic acid tert-butyl ester (crude, 1.17 mmol) in MeOH (5 mL) and AcOH (0.5 mL) was added 6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #2, Step E, 0.050 g, 0.215 mmol). The reaction mixture was stirred at ambient temperature for 0.5 h then NaBH3CN (0.068 g, 1.076 mmol) was added. The mixture was stirred at ambient temperature overnight then concentrated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 24) to give 2-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.016 g, 18%). LC/MS (Table 1, Method 5) Rt=1.087 min; MS m/z: 424 [M+23]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:17][O:16]2)=[CH:11][CH:10]=1>CC(N(C)C)=O>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:16])([CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:17][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:13][CH:14]=1
Reactant: c1nc[nH]n1
Reactant: C[Si](C)(C)CC1(c2ccc(F)cc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CC(O)(Cn1cncn1)c1ccc(F)cc1
Temperature: 0 °C
Yield: 55.2 %

Procedure:
0.237 g (6.18 mmole) of a 60% w/v dispersion of sodium hydride in mineral oil was added to 10 ml of dimethylacetamide. The mixture was then cooled in an ice-water bath, after which 0.854 g (12.37 mmole) of 1,2,4-triazole was added, whilst stirring. The reaction mixture was stirred for 30 minutes, and then 1.4 g (6.24 mmole) of 2-(4-fluorophenyl)-2-trimethylsilylmethyloxirane (prepared as described in Example 66) were added. The mixture was stirred for a further 2 hours at 80° C., after which it was cooled, and the mixture was poured into 50 ml of ice water and extracted with 100 ml of ethyl acetate. The organic extract was washed twice, each time with 50 ml of a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to obtain crude crystals These crystals were recrystallized from diisopropyl ether, to give 1.01 g (yield 55%) of the title compound, as crystals, melting at 118°-119° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(C)C)(=O)C>O.CN(C)C=O>[OH:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[CH:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OC(=O)c2ccccc2)c1
Temperature: 47 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a flask fitted with thermometer, condenser, overhead stirrer, pH probe and nitrogen line was added methyl-3,5-dihydroxybenzoate (1.0 eq), 325 mesh potassium carbonate (3.0 eq) and dimethylformamide (DMF) (4 vols) under a nitrogen atmosphere. The mixture was heated to 47° C. for 1 hour, then benzoyl chloride (1.0 eq) was added slowly drop-wise via syringe pump over approximately 2 hours. Further benzoyl chloride was added (0.1 eq) over 20 minutes via syringe pump. The reaction mixture was held for 1.5 hours, then water (10 vols) and iso-propyl acetate (6 vols) were added. The reaction mixture was agitated for 30 minutes and then the layers were separated. The aqueous layer was re-extracted with a further charge of iso-propyl acetate (6 vols). The batch was separated, and the combined organic layers were washed with saturated brine (6 vols), then with a solution of 0.1N hydrochloric acid/brine. The iso-propyl acetate was distilled to dryness on the rotary evaporator. Iso-propyl acetate (6 vols) was added, and distilled to dryness on the rotary evaporator. Toluene (6 vols) was added and distilled to dryness on the rotary evaporator. Toluene (3.5 vols) was added and the reaction slurried for 30 minutes. The solid was filtered off and dried at 20° C.-40° C. to give the desired product as a solid (corrected yield 72%).