Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1F.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([O:20][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([F:8])[C:2]=1[Cl:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A solution of 2-chloro-1,3-difluoro-4-nitrobenzene (80 g, 415 mmol) and benzyl alcohol (47 g, 435 mmol) in DMF (500 mL) was treated with K2CO3 (120 g, 870 mmol) and stirred at RT overnight. The mixture was poured into water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography to afford 1-(benzyloxy)-2-chloro-3-fluoro-4-nitrobenzene (45 g, 39%). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (t, J=9.2 Hz, 1 H), 7.49-730 (m, 6 H), 5.40 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17](=[O:29])[NH:18][C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)([CH3:21])[CH3:20])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:12]([O:16][C:17](=[O:29])[NH:18][C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N+:8]([O-:10])=[O:9])[CH:23]=1)([CH3:21])[CH3:20])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)c1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (2.57 g, 14.6 mmols), tert-butyl[1-(3-hydroxyphenyl)-1-methylethyl]carbamate (3.21 g, 12.8 mmols), potassium carbonate (2.02 g, 14.6 mmols) and N,N-dimethylformamide (20 ml) was stirred at 100° C. for 2 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give a crystal of tert-butyl[1-[3-(5-chloro-2-nitrophenoxy)phenyl]-1-methylethyl]carbamate (3.6 g, 69%).
Reaction SMILES: C([O:4][C@H:5]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)[CH2:6][CH2:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:15][CH:14]=2)[C@@H:9]1[C:27]1[CH:32]=[CH:31][C:30]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[CH:29][CH:28]=1)(=O)C.[C-]#N.[Na+]>CO>[Si:34]([O:33][C:30]1[CH:29]=[CH:28][C:27]([C@@H:9]2[C@@H:8]([CH2:7][CH2:6][C@@H:5]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[OH:4])[C:11](=[O:12])[N:10]2[C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[CH:17][CH:18]=2)=[CH:32][CH:31]=1)([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:35])[CH3:36]
Reactant: CC(=O)O[C@@H](CC[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(F)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCNS(C)(=O)=O)cc2)cc1
Temperature: 50 °C

Procedure:
To a solution of 40 mg (0.059 mmol) (1S)-3-[(2S,3R)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-3-yl]-1-(4-fluorophenyl)propyl acetate (intermediate of step B) in 1 mL anhydrous methanol under nitrogen atmosphere was added 1 mg of sodium cyanide. The reaction mixture was heated at 50° C. for 4 hrs at which time the volatiles were removed by a nitrogen stream. The residue was purified by prep. Tlc eluting with EtOAc/hexanes (3/1) to afford the title compound. m/z (ES) 637.2 (MH+), 619.1 M−H2O+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(OCC)(=O)C.C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(N)C1=O
Reactant: O=C(OCc1ccccc1)C(Br)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1CC(c2ccco2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O

Procedure:
Following the procedure described in Example 42(h), 0.30 g of t-butyl α-[6-amino-2-(2-furyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate [obtained as described in Example 56(f)] was N-alkylated using 0.60 g of benzyl 2-bromo-4-phenylbutyrate. The resulting product was subjected to silica gel column chromatography, using a 1:40 by volume mixture of ethyl acetate and methylene chloride as eluent, to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.[OH-].[Na+].[CH2:27]1COCC1>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH:16][CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2F)CC1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CNCC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To Ethoxycarbonylamino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (207) (1.05 g, 3 mmol) in THF (10 mL) at −78° C. was added 1M borane in THF (4.5 mL). The reaction is stirred at −78° C. for 1 h and then was allowed to warm to room temperature (2 h). 5N aqueous sodium hydroxide was then added and the reaction was allowed to stir for 2 h. The reaction mixture was then diluted with EtOAc and the layers are separated. The organic phase was dried with sodium sulfate and concentrated to dryness yielding 0.95 g (94%) product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[N:22][N:23]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:24]=3[CH:25]([CH3:27])[CH3:26])[C:16]2=[O:35])[N:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([N:23]2[C:24]([CH:25]([CH3:27])[CH3:26])=[C:20]([N:17]3[CH2:18][CH2:19][CH:15]([N:8]4[C:9]5=[N:10][CH:11]=[CH:12][CH:13]=[C:14]5[C:6]([C:2]5[NH:3][CH:4]=[CH:5][N:1]=5)=[N:7]4)[C:16]3=[O:35])[CH:21]=[N:22]2)=[CH:29][CH:30]=1
Reactant: CC(C)c1c(N2CCC(n3nc(C4=NCCN4)c4cccnc43)C2=O)cnn1-c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: CC(C)c1c(N2CCC(n3nc(-c4ncc[nH]4)c4cccnc43)C2=O)cnn1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A mixture of 3-[3-(4,5-dihydro-1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.085 g, 0.18 mmol) and Dess-Martin periodinane (0.153 g, 0.36 mmol) in DMSO (2.5 mL) was stirred at 80° C. for 1 hr. It was then cooled to room temperature, quenched with sat. aq. NaHCO3 (50 mL), and extracted with EtOAc (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, 0˜7% MeOH/EtOAc gradient elution) to give the title compound (0.070 g, 82%). 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H, br), 8.74 (dd, J=8.4, 1.6 Hz, 1H), 8.54 (dd, J=4.8, 1.6 Hz, 1H), 7.64 (s, 1H), 7.40 (dd, J=6.8, 4.6 Hz, 2H), 7.23 (m, 1H), 7.18 (dd, J=8.6 Hz, 2H), 6.94 (s, 1H, br), 5.94 (dd, J=9.2, 9.2 Hz, 1H), 3.94 (m, 3H), 3.07 (heptet, J=6.8, 1H), 2.75-2.95 (m, 2H), 1.33 (d, J=7.6 Hz, 3H), 1.28 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C25H23FN8O [M+H]+471.2. found 471.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:19]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]2[CH3:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2ccc(Cl)cc2n1C

Procedure:
The preparation is carried out as in Example 1.1, from 8.0 g (35.8 mmol) of ethyl 6-chloro-1H-indole-2-carboxylate, from 1.8 g of 60% sodium hydride and from 2.8 ml of iodomethane.
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2C=CC=C[C:10]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Br:23][C:24]1[N:29]=[C:28]([C:30]([OH:32])=O)[CH:27]=[CH:26][CH:25]=1.C(N)C.CCN(C(C)C)C(C)C>CN(C=O)C.C1COCC1.C(OCC)(=O)C.O>[CH2:10]([NH:9][C:30]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:23])[N:29]=1)=[O:32])[CH3:11]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)c1cccc(Br)n1
Reaction time: 16 h
Yield: 96 %

Procedure:
TBTU (6.5 mmol) was added to a solution of 6-bromo-pyridine-2-carboxylic acid (5.0 mmol) in DMF (30 mL). A solution of ethylamine in THF (1.0 mol/L, 5.0 mL) and DIPEA (15.0 mmol) were added and the reaction mixture was stirred for 16 h. Water (100 mL) and ethyl acetate (100 mL) were added, the layers were separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give 1.1 g (4.8 mmol, 96%) of the desired amide as a yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)([CH3:5])[C:3]#[CH:4].[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[CH3:15][C:10]1[CH:9]=[C:8]([C:7]2[O:16][C:3](=[CH2:4])[C:2]([CH3:1])([CH3:5])[N:6]=2)[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: C#CC(C)(C)NC(=O)c1cc(C)cc(C)c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C1OC(c2cc(C)cc(C)c2)=NC1(C)C
Yield: 97.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar, heating mantle, and reflux condenser was added N-(3-methylbutyn-3-yl)-3,5-dimethylbenzamide (25.00 g, 116.1 mmol), 200 mL of toluene, 50 mL of 0.5N aqueous sodium hydroxide, and 1.74 g (4.31 mmol, 3.7 mol %) of Aliquat® 336. The resulting mixture was heated at reflux for 1.5 h. After cooling, the mixture was transferred to a separatory funnel. The lower aqueous layer was discarded. The organic solution was washed with brine, dried over MgSO4, and filtered. The solution was concentrated using a rotary evaporator to afford a clear colorless oil which was distilled (86-94° C., 0.4 mm) to give 24.43 g (98%) of 2-(3,5-dimethylphenyl)-4,4-dimethyl-5-methyleneoxazoline as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 2H), 7.09 (s, 1H), 4.73 (d, J=3.2 Hz, 1H), 4.22 (d, J=3.2 Hz, 1H), 2.30 (s, 6H), 1.44 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 167.9, 160.1, 138.1, 133.3, 126.7, 125.8, 82.1, 68.9, 29.8, 21.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[C:9]2=[O:12])=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([F:1])=[C:3]([NH:33][CH:30]4[CH2:32][CH2:31]4)[CH:4]=3)[C:9]2=[O:12])=[CH:14][CH:15]=1
Reactant: NC1CC1
Reactant: O=c1c2cc(F)c(OS(=O)(=O)C(F)(F)F)cc2ccn1-c1ccc([N+](=O)[O-])cc1
Product: Nc1ccc(-n2ccc3cc(NC4CC4)c(F)cc3c2=O)cc1

Procedure:
An analogous C—N coupling procedure to that described in Example 7 was performed on trifluoro-methanesulfonic acid 7-fluoro-2-(4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl ester (Example 6) using cyclopropylamine as the nucleophile. Reduction of the nitro group was effected using the procedure outlined in Example 9. ES-MS (M+H)+=310.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH:11](Br)[C@@H:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@H:20]([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:35][C:36](=[O:38])[CH3:37])[CH2:6]1)(=[O:3])[CH3:2].CC1C=C(C)N=C(C)C=1.C1(C)C(C)=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@:31]2([CH3:32])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:26])[CH2:18][CH2:19][C@H:20]([F:25])[C:21]([OH:24])([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:35][C:36](=[O:38])[CH3:37])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC(Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CC[C@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Solvent: Cc1ccccc1C
Solvent: Cc1cc(C)nc(C)c1
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CC[C@H](F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 140 °C

Procedure:
A mixture of 0.300 g. (0.0005 mole) of [1α,3β,7ξ,24S]-7-bromo-24-fluorocholest-5-en-1,3,25-triol 1,3-diacetate, 0.3 ml. of s-collidine and 10 ml. of xylene was heated at reflux (140° C.) for 0.5 hr and cooled. The mixture was diluted with 20 ml. of toluene. This solution was washed with 10% aqueous sulfuric acid, and saturated sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by column chromatography on 0.06-0.20 mm silica gel to yield [1α,3β,24S]-24-fluorocholesta-5,7-dien-1,3,25-triol 1,3-diacetate.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:12]=2[F:19])[CH:10]=1)CCC.[C:28]([CH:30]1[CH2:33][N:32]([C:34](=[O:52])[C@H:35]([NH:39][C:40]([C:42]2[C:50]3[C:45](=[N:46][CH:47]=[C:48](Br)[N:49]=3)[NH:44][CH:43]=2)=[O:41])[CH:36]2[CH2:38][CH2:37]2)[CH2:31]1)#[N:29]>CN(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.[Cu]I>[C:28]([CH:30]1[CH2:31][N:32]([C:34](=[O:52])[C@H:35]([NH:39][C:40]([C:42]2[C:50]3[C:45](=[N:46][CH:47]=[C:48]([C:6]4[N:7]=[CH:8][N:9]([C:11]5[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:12]=5[F:19])[CH:10]=4)[N:49]=3)[NH:44][CH:43]=2)=[O:41])[CH:36]2[CH2:38][CH2:37]2)[CH2:33]1)#[N:29]
Reactant: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(Br)nc23)C2CC2)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(F)cc(F)c2F)cn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-c4cn(-c5cc(F)cc(F)c5F)cn4)nc23)C2CC2)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 5 %

Procedure:
To the crude 4-tributylstannanyl-1-(2,3,5-trifluoro-phenyl)-1H-imidazole from Step 3 was added crude 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (0.087 g, from Step 1) in 3 mL of DMF, Pd(PPh3)4 (0.032 g, 0.027 mmol) and CuI (0.021 g, 0.110 mmol). The dark yellow mixture was stirred at 80° C. for 16 h, then allowed to cool. The mixture was partitioned between 20 mL of ethyl acetate and 20 mL of a sat. aq. NH4Cl solution. The organic layer was washed with 20 mL of water+20 mL of a sat. aq. NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. Column chromatography (0-10% MeOH/EtOAc) of the residue afforded 0.005 g (5%) of 2-[1-(2,3,5-trifluoro-phenyl)-1H-imidazol-4-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a yellow solid, ca. 85% pure. MS: (M+Na)+=543.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]1[C@@H:10]([O:11]P(OP(OC[C@H]2O[C@@H](N3C(=O)NC(=O)C=C3)[C@H](O)[C@@H]2O)(O)=O)(O)=O)[O:9][C@H:8]([CH2:36][OH:37])[C@H:7]([OH:38])[C@@H:6]1[OH:39])=[O:3].C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(O[C@H]3O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]3O)([O-])=O)([O-])=O)[C@@H](O)[C@H]2O)C=1.[Na+].[Na+].[Na+]>O>[OH:11][CH:10]1[O:9][C@H:8]([CH2:36][OH:37])[C@H:7]([OH:38])[C@H:6]([OH:39])[C@H:5]1[NH:4][C:2]([CH3:1])=[O:3]
Reactant: CC(=O)N[C@H]1[C@@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CO)[C@H](O)[C@@H]1O
Agent: O=C([O-])[C@H]1O[C@H](OP(=O)([O-])OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: O
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
A reaction was performed in the same manner as that of (1) mentioned above under conditions of 30° C. and pH 7.2 for 8 hours by using CH6, UDP-GalNAc and UDP-GlcA as substrates and adding the K4CP enzyme. Then, 300 nmole of UDP-GalNAc was added again, and the reaction was performed again at 30° C. for 5 hours. Thermal inactivation was performed for 1 minute in boiling water, the reaction mixture was subjected to ethanol precipitation, and the residue was dissolved again in 200 μl of distilled water. The solution was subjected to gel filtration chromatography in a Superdex Peptide HR10/30 column using 0.2 M ammonium acetate as a developing buffer. The mixture was loaded at a flow rate of 1 ml/minute, and fractions were collected every 1 minute (1 ml). The obtained fractions were lyophilized, and each of the lyophilized fractions was dissolved again in 10 μl of distilled water. The solution was loaded on a small amount of Dowex 50 XW8 (H+ form) gel to obtain a sample for MALDI-TOF-MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25](F)=[CH:24][C:23]=1[NH:32][C:33](=[O:35])[CH3:34]>O>[F:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:24][C:23]=1[NH:32][C:33](=[O:35])[CH3:34]
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 86.6 %

Procedure:
First, 2.73 g of 2-methoxyphenol and 5.5 g of potassium carbonate were added to 20 ml of N,N-dimethylformamide, and the temperature was increased to 60° C. To the mixture was added dropwise a solution consisting of 4.3 g of N-(2,5-difluoro-4-nitrophenyl)acetamide and 30 ml of N,N-dimethylformamide at a temperature of 60° C. to 65° C. After stirring while keeping the temperature for 1 hour, the mixture was cooled to room temperature and then poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid and water, dried over magnesium sulfate, and then concentrated to give 5.52 g of N-[2-fluoro-5-(2-methoxyphenoxy)-4-nitrophenyl]acetamide.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([O-:22])=[O:21])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=Cc2cccc(C(=O)[O-])c2)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C=Cc2cccc(C(=O)O)c2)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
A mixture of (335 mg, 0.951 mmol, 1.0 eq) methyl, 3-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]ethenyl]benzoate in 8 ml methanol and 1.9 ml (1.90 mmol, 2.0 eq) of 1N NaOH was heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, poured into 100 ml H2O, basified to pH 12, and washed once with ethyl acetate. The aqueous layer was acidified to pH 4 and extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed once with H2O, once with brine, dried over NA2SO4, and concentrated to yield 295 mg of white waxy crystals. Recrystallization from ethyl acetate-hexane afforded 100 mg, 34%/, of the cis isomer as white crystals. M.P.: 93°-94° C. Elemental Analysis: Calc'd for C21H22O4 : Calc'd: C, 74.53; H, 6.55. Found: C, 74.32; H, 6.68.
Reaction SMILES: Cl.[N:2]1(N=C2CCCC(O)=C2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.Cl.[CH3:21][C:22]([OH:24])=O>>[CH:9]1[CH:8]=[CH:7][C:6]2[CH2:5][CH2:4][CH2:3][N:2]3[C:11]=2[C:10]=1[C:3]1[C:22](=[O:24])[CH2:21][CH2:6][CH2:5][C:4]=13
Reactant: CC(=O)O
Reactant: OC1=CC(=NN2CCCc3ccccc32)CCC1
Agent: Cl
Product: O=C1CCCc2c1c1cccc3c1n2CCC3
Temperature: 25 °C
Yield: 33 %

Procedure:
3-(3,4-Dihydro-1-(2H)-quinolinylimino)-1-cyclohexen-1-ol hydrochloride (4.78 g, 17 mmol) was mixed with AcOH (37 mL) and conc. HCl (6.1 mL). The reaction mixture was refluxed for 1 h and cooled to RT. The reaction mixture was concentrated in vacuo then the residue was dissolved in CH2Cl2. The organic solution was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel (hex:EtOAc 1:1) to give 5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one (1.25 g, 33%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][OH:11].Cl.C([O-])([O-])=O.[Na+].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][OH:11])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: ON=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
To a solution of 4-fluorobenzaldehyde (3.0 g, 2401 mmol) in MeOH (15 mL) was added NH2OH.HCl (2.0 g, 29.1 mmol) and Na2CO3 (1.53 g, 14.4 mmol) and the reaction stirred for 4 hours at room temperature. The reaction was concentrated under reduced pressure, extracted with DCM (2×100 mL), and the organic layer washed with water (2×50 mL) followed by brine solution (2×25 mL). The organic layer was concentrated under reduced pressure to obtain 4-fluorobenzaldehyde oxime [Brain, J. Am. Chem. Soc., 133:949-957 (2011)] as white solid (2 g, 61% yield). 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.55 (dd, 2H), 7.06 (t, 2H).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].C(NC)C>ClCCl>[CH2:12]([N:8]([CH3:9])[C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2])[CH3:11]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCNC
Solvent: ClCCl
Product: CCN(C)C(=O)n1ccnc1
Temperature: 22.5 °C
Reaction time: 2.5 h
Yield: 81.9 %

Procedure:
To the cooled (ice-water bath) suspension of 1,1′-carbonyldiimidazole (178.4 g, 1.10 moles) in dichloromethane (720 mL) was added N-ethylmethylamine (59.1 g, 1 mole) keeping the internal temperature below 10° C. during addition. The reaction mixture was stirred at 20-25° C. for 2-3 hours and then cooled to 0-5° C. The reaction mixture was quenched by slow addition of water (720 mL) keeping the IT<10° C. The aqueous and organic phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic extracts were washed with water. The organic phase was concentrated to give N-ethyl-N-methyl-1H-imidazole-1-carboxamide (138 g). 1H NMR (CDCl3) δ7.90 (s, 1H); 7.24 (s, 1H); 7.08 (s, 1H); 3.47 (q, J=7.2 Hz, 2H); 3.07 (s, 3H); 1.27 (t, J=7.2 Hz, 3H).