Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([CH3:23])[CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(O)cc1
Reactant: CCCC(C)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCC(C)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
(R)-methyl 2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetate (23.00 g, 82 mmol), 2-methylpentan-1-ol (16.70 g, 163 mmol), and triphenylphosphine (36.46 g, 139 mmol) were combined in tetrahydrofuran (600 mL). After stirring 10 min, diethylazodicarboxylate (21.9 mL, 138 mmol) was added via syringe at room temperature. The reaction was mildly exothermic resulting in the temperature rising to the mid thirties ° C. during the addition. Intermittent cooling with a tap water bath was used to prevent the reaction mixture temperature from rising higher than this, but it was not cooled down to room temperature during the addition. After the addition was complete, the mixture was stirred at room temperature for 18 h. The reaction mixture was transferred to a separatory funnel containing water (400 mL). The aqueous layer was extracted with ether (3×400 mL). The combined organic layers were washed with brine (250 mL), dried over MgSO4, filtered and concentrated. The crude product was taken up in ether (ca. 800 mL) and was stirred for 30 min. The mixture was filtered through a pad of diatomaceous earth (Celite®) to remove most of the triphenylphosphine oxide and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (20% ethyl acetate in hexanes) to afford (2R)-methyl 2-(tert-butoxycarbonylamino)-2-(4-(2-methylpentyloxy)phenyl)acetate (29.43 g, 98% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.20-7.29 (m, 2H), 6.84 (d, J=8.6 Hz, 2H), 5.45 (d, J=6.5 Hz, 1H), 5.22 (d, J=7.3 Hz, 1H), 3.77 (dd, J=9.1, 5.8 Hz, 1H), 3.69 (s, 3H), 3.65-3.70 (m, 1H), 1.85-1.96 (m, 1H), 1.41 (s, 9H), 1.14-1.50 (m, 4H), 0.98 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.1 Hz, 3H); LRMS (ESI) m/e 366.4 [(M+H)+, calcd for C20H32NO5 366.2].
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH2:22]Cl)=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C)C=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH2:22][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: FC(F)(F)c1nc(NC23CC4CC(CC(C4)C2)C3)ncc1CCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nc(NC23CC4CC(CC(C4)C2)C3)ncc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of N-adamantan-1-yl-5-(chloromethyl)-4-(trifluoromethyl)pyrimidin-2-amine (170 mg) and N,N-dimethyl formamide (4 mL) were added morpholine (0.21 mL) and potassium carbonate (136 mg) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain N-adamantan-1-yl-5-(morpholin-4-ylmethyl)-4-(trifluoromethyl)pyrimidin-2-amine (160 mg) as a white solid.
Reaction SMILES: Br[CH2:2][CH:3]([CH:6]([CH3:8])[CH3:7])[CH:4]=[CH2:5].[Mg].[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:21][C:22]([CH3:37])([CH3:36])[CH2:23][CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH:19]=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:21][C:22]([CH3:36])([CH3:37])[CH2:23][CH2:24][O:25][Si:26]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:31])[CH3:32])[CH:33]([CH3:34])[CH3:35])[C@@H:19]([OH:20])[CH2:2][CH:3]([CH:6]([CH3:8])[CH3:7])[CH:4]=[CH2:5])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)[Si](OCCC(C)(C)C[C@@H](C=O)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Reactant: C=CC(CBr)C(C)C
Agent: [Mg]
Product: C=CC(C[C@H](O)[C@H](CC(C)(C)CCO[Si](C(C)C)(C(C)C)C(C)C)NC(=O)OC(C)(C)C)C(C)C

Procedure:
The title compound is prepared in a manner analogous to that described in Example 35f) starting from 23.9 g of 1-bromo-2(R,S)-isopropyl-3-butene (preparation according to D. Mesnard et al., C.R. Acad. Sci. Paris, t. 277, Series C-567), 3.3 g of magnesium powder and 11.25 g of 2(S)-tert-butoxycarbonylamino-6-triisopropylsilyloxy-4,4-dimethyl-hexanal (Example 1g). The crude product is purified by FC over 900 g of silica gel (mobile phase E) to give the title compound as a diastereomer mixture: Rf (E)=0.31.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>Cl.C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(C)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(C)(F)C(=O)N2C
Temperature: 100 °C
Reaction time: 20 h
Yield: 31.9 %

Procedure:
A mixture of 2-chloro-9-cyclohexyl-7-fluoro-5,7-dimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (330 mg, 1 mmol), 4-amino-3-methoxybenzoic acid (184 mg, 1.1 mmol), isopropanol (10 ml), and concentrated hydrochloric acid (10 drops) was stirred at 100° C. for 20 h. Solid was filtered to give 146 mg product as white solid (32%). [M+H] calc'd for C23H28FN5O4, 458. found 458.
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:24][C@H:23]([O:25][Si](CC)(CC)CC)[CH2:22][C@@H:21]([OH:33])[C:20]1=[CH2:34])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])(=O)=O>ClCCl>[Si:49]([O:33][C@H:21]1[C:20](=[CH2:34])[C@H:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:24][C:23](=[O:25])[CH2:22]1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]
Reactant: C=C1[C@H](O)C[C@@H](O[Si](CC)(CC)CC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(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=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
The compound of Example 13D (8.5 g, 17 mmol) was dissolved in 50 mL of dichloromethane; 4.4 mL of 2,6-lutidine was added, and the resultant solution was cooled to 0° C. tert-Butyldimethylsilyl trifluoromethanesulfonate (5.9 mL) was added, and the mixture was stirred for 1 hour. The reaction was quenched by the addition of saturated aqueous NH4Cl, the solvents were removed in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 1 N aqueous HCl, then brine, and dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix IntelliFlash 280™, eluting with a gradient of 2% to 5% ethyl acetate in hexanes. The product (9.3 g) was dissolved in 75 mL of ethanol; pyridinium p-toluenesulfonate (390 mg) was added, and the mixture was stirred at ambient temperature for 1 hour. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 9% to 17% ethyl acetate in hexanes. A sample of this product (5.8 of 6.8 g) was dissolved in 30 mL of dichloromethane; 3.0g of NaHCO3 was added, and the mixture was cooled to 0° C. Dess-Martin reagent (5.9 g) was added, and stirring was continued for 2 hours. The solvents were removed in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 1 N aqueous HCl, then brine, and dried over Na2SO4. The organic phase was passed through a plug of silica gel and concentrated in vacuo, giving the titled compound (5.5 g, 71%).
Reaction SMILES: [O:1](S(C(F)(F)F)(=O)=O)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].O[C:17]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][C:18]=1[O:31][CH3:32].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:32][O:31][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:17]=1[O:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(OC)c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
17.7 ml of Tf2O was added to a solution of 16.8 g of ethyl 4-hydroxy-3-(methyloxy)-5-nitrobenzoate and 11.3 ml of pyridine in 500 ml of CHCl3 at 0° C. The mixture was stirred for 30 min, then washed successively with water, HClaq, and saturated NaHCO3aq, dried over Na2SO4, and concentrated. The residual solid was washed with a mixed solvent of CHCl3 and n-hexane to give a 22.0 g of the intended compound as a pale orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][CH3:14])=[C:7](Cl)[C:6]=2[CH:16]=1.[CH2:17]([N:19]([CH2:23][CH3:24])[C:20](=[S:22])[S-:21])[CH3:18].[Na+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][CH3:14])=[C:7]([S:22][C:20](=[S:21])[N:19]([CH2:23][CH3:24])[CH2:17][CH3:18])[C:6]=2[CH:16]=1
Reactant: CCN(CC)C(=S)[S-]
Reactant: CCCc1c(Cl)c2cc(Br)ccc2oc1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(SC(=S)N(CC)CC)c2cc(Br)ccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-bromo-4-chloro-3-propyl-2H-1-benzopyran-2-one (0.5 g) in dimethylformamide (2 ml) was treated with sodium diethyldithiocarbamate (0.34 g). The mixture was stirred at room temperature under nitrogen overnight and then poured into water, extracted with diethyl ether and the extract washed with brine, dried and evaporated under reduced pressure to give 6-bromo-4-diethylthiocarbamoylthio-3-propyl-2H-1-benzopyran-2-one, m.p. 135-7°. (compound 16)
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].ClC(Cl)=C(Cl)C(Cl)=C(Cl)Cl.[CH3:16][N:17]([Si:19]([CH3:22])([CH3:21])Cl)[CH3:18]>>[CH3:16][N:17]([Si:19]([CH3:22])([CH3:21])[C:1]#[C:2][C:3]#[C:4][Si:19]([N:17]([CH3:18])[CH3:16])([CH3:22])[CH3:21])[CH3:18]
Reactant: [Li]CCCC
Reactant: CN(C)[Si](C)(C)Cl
Agent: ClC(Cl)=C(Cl)C(Cl)=C(Cl)Cl
Product: CN(C)[Si](C)(C)C#CC#C[Si](C)(C)N(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A flame dried 250 ml Schlenk flask containing TBF (20 ml) was cooled to −78° C. and n-butyl lithium (20 ml of 2.4 M in hexane, 48.0 mmol) was added by syringe. After several minutes hexachlorobutadiene (1.88 ml, 12.0 mmol) was added dropwise via syringe over a 10 minute period. After completion of addition, the cold bath was removed and the mixture stirred at room temperature for 3 hours. The resulting 1,4-dilithio-1,3-butadiyne was used without further purification. The flask was then recooled to −78° C., and dimethylaminodimethylchlorosilane (3.6 ml, 24 mmol) was added by syringe. The flask was removed from the cold bath and the reaction mixture stirred at room temperature for 16 hours. At this time 1H NMR analysis indicated complete disappearance of dimethylaminodimethylchlorosilane and formation of 1,4-bis(dimethylaminodimethylsilyl)-butadiyne. The TBF was removed in vacuo, and the mixture was taken up in a minimum amount of pentane and filtered. The pentane was removed in vacuo to give 2.91 g (96%) of 1,4-bis(dimethylaminodimethylsilyl)butadiyne.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.N1CCNCC1.[CH:17](=[O:26])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1(C)C=CC=CC=1>[OH:8][CH2:7][CH2:6][C:5]1[CH:4]=[C:3]2[C:2](=[CH:10][CH:9]=1)[O:1][CH:17]([OH:26])[CH2:18][CH:19]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=CC=Cc1ccccc1
Reactant: OCCc1ccc(O)cc1
Agent: C1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Product: OCCc1ccc2c(c1)C(c1ccccc1)CC(O)O2
Temperature: 80 °C

Procedure:
To a solution of 4-hydroxyphenethyl alcohol (Tyrosol) (5.0 g, 36 mmol, 1 equiv), piperazine (1.87 g, 22 mmol, 0.6 equiv) and toluene (50 ml) at reflux under N2 and Dean & Stark conditions was added cinnamaldehyde (6.4 ml, 51 mmol, 1.4 equiv) and the reaction mixture maintained at heat for 17 h. The reaction was cooled to 80° C. and quenched with aqueous HCl (0.7 molar, 1.3 equiv) then stirred at heat for 18 h. The biphasic mixture was allowed to cool to ambient temperature, separated, the organic phase washed with aqueous HCl and water and the organic phase concentrated to a black residue under reduced pressure. Flash chromatography eluting with 20% EtOAc/Heptane afforded the title compound as the main constituent of an approximately 80% pure yellow oil, Rf=0.37 (50% EtOAc/Heptane) and structure confirmed by 1H NMR and LC-MS (M+1=271).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(#N)C>[S:21]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:23])(=[O:22])[CH3:20]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CO)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COS(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
Combine 4-methoxybenzyl alcohol (45.4 mmol), N,N-diisopropylethylamine (12.9 g, 100 mmol), and acetonitrile (60 mL). Cool in an ice bath. Add methanesulfonyl chloride (6.76 , 49.0 mmol). After 2 hours, partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the organic layer with 1 M hydrochloric acid solution and then a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:28][CH2:29][CH:30]([OH:32])[CH3:31]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5]1[N:28]([CH2:29][CH:30]([OH:32])[CH3:31])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: CC(O)CN
Reactant: COc1cccc2c1C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1-c1c(ccn1CC(C)O)C2
Reaction time: 0.58 h
Yield: 45.3 %

Procedure:
A solution of 2.04 g of (RS)-2-(2-oxoethyl)-7-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). There was obtained 1.1 g (45%) of (RS)-1-(8-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol as a brown oil which was used directly in the next reaction.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=2)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:24]([N:3]([CH2:1][CH3:2])[C:4]1[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH3:25]
Reactant: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(diethylamino)-2-phenylquinoxaline-6-carboxylate (117 mg, 0.35 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (69.9 mg, 1.75 mmol, 5.00 equiv) in water (2 mL) dropwise with stiffing. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The crude product (110 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and methanol (70% methanol up to 90% in 10 min); Detector, UV 254 nm. This resulted in 70 mg (62%) of 3-(diethylamino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.CN1CCOCC1.[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[S:30](Cl)(=[O:32])=[O:31])#[N:20]>CC#N>[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[S:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1)(=[O:32])=[O:31])#[N:20]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: CC#N
Solvent: CN1CCOCC1
Product: N#Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (2.98 g, 20 mmol) and NMM in MeCN (150 ml) was added 2-cyano-4-nitrobenzene-1-sulfonyl chloride (5.423 g, 22 mmol) at 0° C., then the solution was stirred at room temperature for overnight. The mixture was concentrated in vacuo at room temperature, and DCM and water was added to the residue. The organic layer was dried over Na2SO4 and concentrated to give the crude product. It was purified by prep. HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 25%-50%, 25 min) to give the title compound (2.0 g, 27.86%) as a yellow solid. 1H NMR: DMSO 400 MHz. δ11.05 (s, 1H), 9.22 (s, 1H), 8.88 (s, 1H), 8.62 (d, J=11.2 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.45 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.18 (d, J=10.0 Hz, 1H), 4.89 (s, 2H). ESI-MS m/z 360 (M+H, positive); HPLC purity: 93.07% (MaxPlot 190-370 nm), 98.72% (220 nm).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11](CC)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50](Cl)(=[O:52])=[O:51]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([S:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[Cl:43])(=[O:52])=[O:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(S(=O)(=O)c3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-chlorobenzene-1-sulfonyl chloride and isolated as brown solid. MS (m/e): 457.3 (MH+).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][OH:8].[CH2:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=1[CH:14]=O)[CH:10]=[CH2:11]>O.CO>[CH2:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=1[CH:14]=[N:7][OH:8])[CH:10]=[CH2:11]
Reactant: C=CCc1cccc(Cl)c1C=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCc1cccc(Cl)c1C=NO
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.58 g of sodium bicarbonate were added to a solution of 4.62 g of hydroxylamine hydrochloride in 50 ml of water, and the mixture was cooled to 0° C. A solution of 9.7 g (44.32 mmol) of 2-allyl-6-chlorobenzaldehyde in 50 ml of methanol was then added dropwise, and the mixture was stirred at room temperature overnight. The methanol was subsequently removed under reduced pressure and the residue was stirred into 300 ml of water. The aqueous phase was extracted with diethyl ether and the combined organic phases were washed with saturated ammonium chloride solution and dried, and the solvent was removed. This gave 8.7 g (quantitative) of 2-allyl-6-chlorobenzaldehyde oxime in the form of a viscous oil.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]=1[CH3:16])C.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH3:32])(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>CS(C)=O.O>[CH:33]1([N:31]([CH3:32])[S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][N:8]3[C:9]4[C:14](=[CH:13][C:12]([F:15])=[CH:11][CH:10]=4)[C:6]([CH2:5][C:4]([OH:3])=[O:17])=[C:7]3[CH3:16])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(F)cc12
Reactant: CN(C1CCCCC1)S(=O)(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(CC(=O)O)c2cc(F)ccc2n1Cc1ccc(S(=O)(=O)N(C)C2CCCCC2)cc1

Procedure:
To a stirring suspension of (5-fluoro-2-methyl-1H-indol-3-yl)-acetic acid ethyl ester (100 mg, 0.43 mmol) in dry DMSO (1 ml), is added NaH (29 mg, 0.73 mmol). The reaction mixture is stirred at room temperature for 15 min after which time 4-bromomethyl-N-cyclohexyl-N-methyl-benzenesulfonamide (149 mg, 0.43 mmol) is added. Reaction mixture is diluted with water (10 ml) and treated with 1N HCl aq to acidic pH. The product is extracted in 1:1 EtOAc:Et2O (20 ml), washed with brine, dried (MgSO4) and evaporated in vacuo. The crude reaction mixture is purified by preparative MS-directed HPLC to afford the title compound; [M+H]+ 474.
Reaction SMILES: C(OC([N:7]1[CH2:11][CH2:10][CH:9]([C:12]2[CH2:18][C@H:17]3[N:14]([C:15](=[O:22])[C@@H:16]3[C@H:19]([OH:21])[CH3:20])[C:13]=2[C:23]([O:25]CC=C)=[O:24])[CH2:8]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1>O1CCCC1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:21][C@@H:19]([C@H:16]1[C:15](=[O:22])[N:14]2[C@@H:17]1[CH2:18][C:12]([CH:9]1[CH2:10][CH2:11][NH:7][CH2:8]1)=[C:13]2[C:23]([OH:25])=[O:24])[CH3:20]
Reactant: C=CCOC(=O)C1=C(C2CCN(C(=O)OCC=C)C2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C3CCNC3)C[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of allyl (5R,6S)-3-(1-allyloxycarbonylpyrrolidin-3-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.94 g) in a mixture of tetrahydrofuran (14 ml) and ethanol (2 ml) were added successively triphenylphosphine (130 mg), 5,5-dimethyl-1,3-cyclohexanedione (dimedone) (0.66 g) and tetrakis(triphenylphosphine)palladium(0) (280 mg). Stirring at ambient temperature for 1 hour gave a precipitate, which was collected by filtration and washed with tetrahydrofuran to give (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-(pyrrolidin-3-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (480 mg).