Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH2:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:31][CH3:32]>>[CH2:30]([S:33]([N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:35])=[O:34])[CH2:31][CH3:32]
Reactant: CCCS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Agent: Cl
Product: CCCS(=O)(=O)N1CCC[C@@H](NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-[(R)-1-(Propane-1-sulfonyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and n-propylsulfonyl chloride.
Reaction SMILES: [CH2:1]([C@@H:4]1[C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6]([CH3:16])([CH3:15])[N:5]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH:2]=C.I([O-])(=O)(=O)=[O:28].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH3:16][C:6]1([CH3:15])[N:5]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@H:4]([CH2:1][CH:2]=[O:28])[C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@H]1[C@@H](c2ccccc2)OC(C)(C)N1C(=O)OCc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)O[C@H](c2ccccc2)[C@@H](CC=O)N1C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To the crude (4R,5R)-benzyl 4-allyl-2,2-dimethyl-5-phenyloxazolidine-3-carboxylate (1.29 g, 3.66 mmol) in THF (50 mL) and water (20 mL) was added osmium tetroxide (0.45 ml, 0.0180 mmol, 4%) solution. The reaction was stirred for 10 min, after which sodium periodate (3.91 g, 18.3 mmol) was added portion wise over 1 hr. Stirring was continued for 2 h. Saturated aqueous Na2S2O3 was added and the reaction was stirred for 15 min. The volatiles were removed in vacuo and the aqueous residue extracted with Et2O (3×50 mL). The combined ether layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude residue was evaporated onto silica gel and purified via flash chromatography (0% to 20%; EtOAc in hexanes) to afford (4R,5R)-benzyl 2,2-dimethyl-4-(2-oxoethyl)-5-phenyloxazolidine-3-carboxylate. MS m/z=354 [M+1]+. Calc'd for C21H23NO4: 353.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[C:16]2[C:19]3[N:8]([N:9]([CH3:22])[CH2:10][O:11][C:12]=3[C:13](F)=[C:14]([F:20])[CH:15]=2)[CH:7]=1)=[O:5])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([N:36]2[CH2:40][C@H:39]([CH2:41][NH:42][C:43](=[O:45])[CH3:44])[O:38][C:37]2=[O:46])[CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>N1C=CC=CC=1.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:17](=[O:18])[C:16]2[C:19]3[N:8]([N:9]([CH3:22])[CH2:10][O:11][C:12]=3[C:13]([N:33]3[CH2:34][CH2:35][N:30]([C:29]4[CH:28]=[CH:27][C:26]([N:36]5[CH2:40][C@H:39]([CH2:41][NH:42][C:43](=[O:45])[CH3:44])[O:38][C:37]5=[O:46])=[CH:25][C:24]=4[F:23])[CH2:31][CH2:32]3)=[C:14]([F:20])[CH:15]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCN2C
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cn2c3c(c(N4CCN(c5ccc(N6C[C@H](CNC(C)=O)OC6=O)cc5F)CC4)c(F)cc3c1=O)OCN2C

Procedure:
A solution of 100 mg 8,9-difluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3,3a-diaza-phenalene-5-carboxylic acid ethyl ester (0.32 mmol) and 216 mg of N-[{(5S)-3[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl}-methyl]-acetamide (0.64 mmol) were dissolved in a mixture of 1 ml pyridine and 1 ml DMSO. The reaction was monitored by TLC. The DMSO was evaporated, the residue digested in water and the solid collected. The solid was purified by chromatography, using a 9/1 dichloromethane/methanol mixture as eluent.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:17]O>OS(O)(=O)=O>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
3-Hydroxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (D36) (400 mg, 1.72 mmol, 1 equiv) was heated at reflux in a mixture of MeOH (20 ml) and concentrated H2SO4 (4 drops) for 7 h. The solution was then cooled to room temperature and concentrated in vacuo to give of 3-hydroxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D37) (300 mg, 74%) as a light brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:23]=[CH:22][C:21]=1[NH:33][C:34]([NH2:36])=[NH:35].C(O)C>O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][N:36]=[C:34]([NH:33][C:21]3[CH:22]=[CH:23][C:24]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:25][C:20]=3[O:19][CH3:18])[N:35]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c(C(=O)/C=C/N(C)C)c1
Reactant: COc1cc(N2CCN(C)CC2)ccc1NC(=N)N
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)c1
Temperature: 110 °C
Yield: 57.3 %

Procedure:
To a suspension of 5-((E)-3-Dimethylamino-acryloyl)-1H-pyrrole-3-carboxylic acid ethyl ester (1.7 g, 7.20 mmol) in 30 mL of ethanol N-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-guanidine (1.9 g, 7.20 mmol) was added. The mixture was heated to 110° C. overnight. The resulting mixture was cooled at room temperature and diluted with water (70 mL). The solid was isolated by filtration, washed with 10 mL of water, dried in a vacuum oven at 40° C. affording to give 1.8 g (57% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:40][CH:41]([CH3:45])[CH2:42][CH2:43][NH2:44]>CN(C)C=O>[F:1][C:2]1[C:3]([C:8]([NH:44][CH2:43][CH2:42][CH:41]([CH3:45])[CH3:40])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1F
Reactant: CC(C)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)CCNC(=O)c1ncccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of 3-fluoro-pyridine-2-carboxylic acid (0.50 g, 3.54 mmol) in dimethylformamide (6 ml) are added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (3.41 g, 10.63 mmol) and N-methylmorpholine (1.56 ml, 14.2 mmol) at 0° C. followed by the addition of 3-methyl-butyl-amine (0.61 ml, 5.32 mmol). The reaction mixture is stirred at RT for 2 h. After completion of the reaction, the mixture is poured onto ice-water, extracted with EtOAc (3×50 ml). The combined organic layers are washed with brine (50 ml), dried over sodium sulfate and evaporated to dryness to yield the crude product, which is purified by column chromatography (silica gel, 50% EtOAc/hexane) affording 3-fluoro-N-(3-methyl-butyl)-pyridine-2-carboxylic acid amide (0.31 g, 1.47 mmol, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:35][CH2:34]1>>[CH2:39]([N:36]1[CH2:37][CH2:38][CH:33]([NH:32][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)[CH:19]=2)[CH2:34][CH2:35]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-amino-1-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=619.96 (M+H+); retention time=0.62 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])[N:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])[N:3]=1
Reactant: Cc1cccc(N2C(=O)c3ccccc3C2=O)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Yield: 39.8 %

Procedure:
A mixture of N-(2-methylpyridin-6-yl)phthalimide (16.7 g), N-bromosuccinimide (15.0 g) and benzoyl peroxide (300 mg) in chloroform (150 ml) was refluxed for 5 hours with stirring under ultraviolet irradiation, and then additional N-bromosuccinimide (12.5 g) and benzoyl peroxide (300 mg) were added thereto. The mixture was further refluxed for 18 hours with stirring under ultraviolet irradiation. The reaction mixture was evaporated to dryness and the residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was subjected to column chromatography on silica gel eluting with a mixed solvent (toluene:ethyl acetate=20:1) to give N-(2-bromomethylpyridin-6-yl)phthalimide (8.85 g). mp: 169°-170° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:18]([O:22][C:23](=O)[O-:24])([CH3:21])([CH3:20])[CH3:19].O>O1CCOCC1>[C:18]([O:22][C:23]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)[CH2:2][CH2:3]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)[O-]
Reactant: c1cc2[nH]ncc2cc1N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]ncc3c2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
To a solution of 5-Piperazin-1-yl-1H-indazole (0.34 g, 1.3 mmol) in 1,4-dioxane (5 mL) was added 3N NaOH (0.42 mL, 1.3 mmol). After cooling to 0° C., a solution of tert-butylcarbonate (0.25 g, 1.3 mmol) in 1,4-dioxane (1 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight and then poured into water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was purified by column chromatography (EtOAc:hexanes, 1:1) to give 4-(1H-Indazol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.31 g, 82%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 10.01 (s, 1H), 7.80 (s, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.21 (dd, J=9.2 Hz, J=2.0 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 3.62 (m, 4H), 3.09 (m, 4H), 1.50 (s, 9H). LCMS (APCI+) m/z 303 [M+H]+; Rt=2.50 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][C:12]1([CH3:19])[O:16][C@H:15]([CH2:17]O)[CH2:14][O:13]1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:17][C@@H:15]1[CH2:14][O:13][C:12]([CH3:19])([CH3:11])[O:16]1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@@H](COc2ccc(C=O)cc2Cl)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of 3-chloro-4-hydroxybenzaldehyde (4.21 g, 27 mmol) in degassed toluene (100 mL) is added ((4R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (5.35 g, 40.5 mmol), 1,1′-(azodicarbonyl)dipiperidide (13.63 g, 54 mmol) followed by tributylphosphine (10.93 g, 54 mmol). The mixture becomes slightly warm and a precipitate forms. The reaction mixture is diluted with degassed toluene (500 mL) and is stirred at rt for 2 h, then at 60° C. for further 18 h before it is washed with 1 N aq. NaOH (3×150 mL) and water (150 mL). The organic phase is dried over MgSO4, filtered and concentrated to leave a dark brown oil which is chromatographed on silica gel eluting with hexane/EA 4:1 to give the title compound (4.30 g) as yellow oil. 1H NMR (CDC3): δ 9.82 (s, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.74 (dd, J=1.8, 8.2 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 4.56-4.43 (m, 1H), 4.23-4.17 (m, 2H), 4.14-4.08 (m, 1H), 4.06-4.00 (m, 1H), 1.47 (s, 3H), 1.41 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:2]1.Br[CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:21][CH2:22][OH:23])=[CH:2]1
Reactant: OCCBr
Reactant: c1ccc(CCCCCCNCc2ccoc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN(CCCCCCc1ccccc1)Cc1ccoc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 2.538 g (9.861 mmol) of N-(3-furylmethyl)-6-phenylhexylamine and 7.39 g (59.2 mmol) of 2-bromoethanol in 50 ml of N,N-dimethylformamide, 13.6 g (98.6 mmol) of potassium carbonate was added, followed by overnight stirring at 90° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to yield the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([CH3:15])([CH3:14])[CH3:13].[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17].N#N>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:12]([NH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1C#C[Si](C)(C)C
Temperature: 70 °C
Yield: 15.7 %

Procedure:
To a solution of (2-bromo-4-nitro-phenyl)-tert-butyl-amine (0.6 g, 2.2 mmol) in Et3N (10 mL) was added Pd(PPh3)2Cl2 (70 mg, 0.1 mmol), CuI (20.9 mg, 0.1 mmol) and ethynyl-trimethyl-silane (0.32 g, 3.3 mmol) successively under N2 protection. The reaction mixture was heated at 70° C. overnight. The solvent was removed under vacuum and the residue washed with EtOAc (10 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to afford tert-butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine (100 mg, 16%). 1H-NMR (CDCl3, 400 MHz) δ 8.20 (d, J=2.4, Hz, 1H), 8.04 (dd, J=2.4, 9.2 Hz, 1H), 6.79 (d, J=9.6 Hz, 1H), 5.62 (brs, 1H), 1.41 (s, 9H), 0.28 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16][CH2:17][CH2:18]O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C([Br:35])C=C.C(OCC)C>C(#N)C>[Br:35][CH2:18][CH2:17][CH2:16][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2
Reactant: C=CCBr
Reactant: COc1nc2cc(Cl)cc(CCCO)c2nc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: CC#N
Product: COc1nc2cc(Cl)cc(CCCBr)c2nc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
0.5 g (1.77 mmol) of 3-(7-chloro-2,3-dimethoxy-quinoxalin-5-yl)-propan-1-ol and 0.287 g (1.77 mmol) of 1,1'-carbonyidiimidazole are placed in 5 ml of acetonitrile under N2. 0.75 ml of allyl bromide is added, and the mixture is then stirred at room temperature for 30 minutes and at reflux for 2 hours. The reaction mixture is cooled to room temperature, diethyl ether is added and extraction is carried out with water, 0.1N hydrochloric acid, saturated sodium hydrogen carbonate solution and brine. The aqueous phases are then washed with diethyl ether. The organic phases are combined, dried over sodium sulfate, filtered over a layer of silica gel and concentrated. 0.438 g (79.9%) of 5-(3-bromopropyl)-7-chloro-2,3-dimethoxy-quinoxaline is obtained in the form of a yellow oil which is used further without further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[N:12]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][NH2:12])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCCCc1ccc(NN)cc1
Reaction time: 0.75 h
Yield: 83.9 %

Procedure:
To 300 ml of concentrated hydrochloric acid was added a solution of 4-n-butylaniline (20.0 g, 134.2 mmole) in 200 ml 1 N hydrochloric acid at ice bath temperature. To the resulting slurry was added a solution of sodium nitrite (21.6 g, 313 mmole) in 90 ml of water. The resulting brown solution was stirred at ice bath temperature for 45 minutes and treated dropwise with a solution of tin (II) chloride dihydrate (82.0 g, 363.0 mmole) in 90 ml of concentrated hydrochloric acid. The reaction was stirred for 1 hour at 5° C. and the hydrazine hydrochloride salt was collected by filtration. This was then dissolved in 300 ml of 3N sodium hydroxide solution and the aqueous solution was extracted with diethyl ether (2×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give 18.5 g (84% crude yield) of the titled hydrazine as brown solid which melts around room temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:47])[CH2:9][CH2:10][C@H:11]2[C:14](=[O:15])[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C@H:34]([OH:45])[C@H:35]4[O:41][CH:39]([OH:40])[C@H:38]([OH:42])[C@@H:37]([OH:43])[C@@H:36]4[OH:44])[CH:29]=3)=[CH:24][C:23]=2[OH:46])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(#N)C.O.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([OH:47])[CH2:9][CH2:10][C@H:11]2[C:14](=[O:15])[N:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:12]2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C@H:34]([OH:45])[C@@H:35]([OH:41])[C@@H:36]([OH:44])[C@H:37]([OH:43])[C@@H:38]([OH:42])[CH2:39][OH:40])[CH:29]=3)=[CH:24][C:23]=2[OH:46])=[CH:6][CH:7]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc([C@H](O)[C@H]4OC(O)[C@H](O)[C@@H](O)[C@@H]4O)c3)cc2O)N1c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc([C@H](O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO)c3)cc2O)N1c1ccccc1
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
(6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucopyranose (7.1 mg, 0.01 mmol) was dissolved in 80:20 acetonitrile-water (1 mL). Sodium borohydride (0.4 mg, 0.01 mmol) was added at room temperature and the reaction was stirred for 30 min monitoring by LCMS. Upon completion, the reaction was diluted with 80:20 acetonitrile:water (3 mL) then filtered through a Whatman 0.45 μM glass microfiber filter and purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) to afford (6S)-6-C-(4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl)-D-glucitol (1.4 mg, 22% yield). 1H NMR (300 MHz, CDCl3/CD3OD) δ 7.37-6.89 (m, 16H), 5.08 (d, J=2.4 Hz, 1H), 4.97-4.95 (m, 1H), 4.60 (t, J=6.0 Hz, 1H), 3.92 (m, 1H), 3.76-3.56 (m, 6H), 2.01-1.82 (m, 4H) ppm; MS [M−OH]+ 629.8.
Reaction SMILES: I[C:2]1[N:3]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:4]=[C:5]([C:7]([NH:9][C@H:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:8])[N:6]=1.[C:40]([NH:46][C:47]1[N:48]=[C:49]([OH:59])[C:50]2[CH:56]=[C:55]([C:57]#[CH:58])[CH:54]=[N:53][C:51]=2[N:52]=1)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42].C(N(CC)CC)C>C(#N)C>[C:40]([NH:46][C:47]1[N:48]=[C:49]([OH:59])[C:50]2[CH:56]=[C:55]([C:57]#[C:58][C:2]3[N:3]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:4]=[C:5]([C:7]([NH:9][C@H:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:8])[N:6]=3)[CH:54]=[N:53][C:51]=2[N:52]=1)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Reactant: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(I)n1)C(=O)OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CC[C@H](NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)n1)C(=O)OC
Yield: 66 %

Procedure:
Following the procedure of Example 1, dimethyl N-(2-iodo-1-triphenylmethylimidazol-4-ylcarbonyl)-L-glutamate (638 mg, 1.0 mmol), 2-pivaloylamino4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine (541 mg, 2.0 mmol), Pd(PPh)2Cl2 (35 mg, 0.05 mmol), cuprous iodide (19 mg, 0.1 mmol), triethylamine (0.7 mL), and acetonitrile (50 mL) yield dimethyl N-(2-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethynyl]-1-triphenylmethylimidazol-4-ylcarbonyl}-L-glutamate [515 mg, 66% after flash column chromatography (ethyl acetate:hexanes, 2:1), mp 93-95° C]: 1H NMR (CDCl3) δ 12.05 (br s, 1H), 8.43 (br s, 1H), 8.26 (s, 1H), 7.93 (d, 1H, J=2.2 Hz), 7.61 (s, 1H), 7.54 (d, 1H, J=7.6 Hz), 7.33-7.28 (m, 9H), 7.18-7.12 (m, 6H), 4.77 (m, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 2.45 (m, 2H), 2.32 (m, 1H), 2.05 (m, 1H), 1.30 (s, 9H). HRMS calcd for C44H41N7O7 779.3067, found 779.3088.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[NH:7][CH:8]=1.Br[CH:12]([CH3:14])[CH3:13]>CN(C)C=O>[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[N:7]([CH:12]([CH3:14])[CH3:13])[CH:8]=1
Reactant: CC(C)Br
Reactant: O=Cc1cc(I)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)cc1C=O
Temperature: 25 °C
Yield: 43.2 %

Procedure:
Sodium hydride (860 mg, 55% in mineral oil, 19.7 mmol) was added to a solution of 4-iodo-pyrrole-2-carbaldehyde (3.0 g, 13.2 mmol) in dry dimethylformamide at ambient temperature under a nitrogen atmosphere. After stirring for 15 min 2-bromopropane (3.87 mL, 40.9 mmol) was added and the reaction mixture heated at reflux for 16 h. The mixture was allowed to cool to ambient temperature, quenched with water and extracted with diethyl ether. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude residue. Purification by column chromatography over silica gel (60-120 mesh) using 2% ethyl acetate in petroleum ether afforded 4-iodo-1-isopropyl-pyrrole-2-carbaldehyde (1.5 g, 43%) as a brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:9][CH3:10])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccccc2)cc1OC
Yield: 95.7 %

Procedure:
The process of Step 1, Example 4 was followed except that 292 grams of 1,2-dimethoxy benzene, 297 grams of benzoyl chloride, and 281 grams of aluminum chloride were used to yield 490 grams of 3,4-dimethoxy benzophenone.