Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]1(=[O:15])[O:14][CH2:13][CH2:12][CH2:11]1>>[OH:3][C:1]([CH:11]1[CH2:12][CH2:13][O:14][C:10]1=[O:15])([CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=C1CCCO1
Product: CC(O)(c1ccccc1)C1CCOC1=O

Procedure:
Using the same procedure as described above, acetophenone is reacted with γ-butyrolactone to produce 2-(1-hydroxy-1-methyl-1-phenylmethyl)-γ-butyrolactone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:25])=[O:22])=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CC(=O)O)cc2F)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
To 2-(4-{4-[(t-butyl)oxycarbonyl]piperazinyl}-3-fluorophenyl)acetic acid (0.3 g, 1.0 mmol) in 2 mL methanol and 7 mL benzene was added trimethylsilyidiazomethane (0.65 mL, 1.30 mmol). After stirring at ambient temperature for 1 hour, the reaction mixture was concentrated to provide 0.36 g (99%) of the title compound. 1H NMR (CDCl3; 300 MHz) δ7.00 (m, 2H), 6.90 (t, J=8.3 Hz, 1H), 3.71 (s, 3H), 3.61 (t, J=4.9 Hz, 4H), 3.57 (s, 2H), 3.02 (t, J=5.0 Hz, 4H), 1.50 (s, 9H); ESI (M+H)+=353.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=O)[NH:10][C:9]([NH2:14])=[N:8][C:7]=2[N:6]([C@@H:15]2[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]2[O:17][C:18](=[O:20])[CH3:19])[C:5]1=[O:33])[CH:2]=[CH2:3].P(Cl)(Cl)([Cl:36])=O>>[CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9]([NH2:14])=[N:10][C:11]=2[Cl:36])[N:6]([C@@H:15]2[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]2[O:17][C:18](=[O:20])[CH3:19])[C:5]1=[O:33])[CH:2]=[CH2:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: C=CCn1c(=O)n([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c2nc(N)[nH]c(=O)c21
Product: C=CCn1c(=O)n([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c2nc(N)nc(Cl)c21
Temperature: 75 °C
Yield: 41 %

Procedure:
Compound 40 (0.65 g, 1.39 mmol) was dissolved in phosphorus oxychloride (10 mL) and heated to 75° C. for 16 h. The reaction mixture was concentrated under vacuum and the crude product dissolved in DCM. The mixture was then washed with NaHCO3 solution, brine, dried (MgSO4) and filtered. The filtrate was concentrated under vacuum and purified by flash chromatography using 10 to 50% gradient of ethyl acetate in hexanes. Removal of the solvent afforded 280 mg (41%) of the desired product 41: 1H NMR (400 MHz, CDCl3) δ 6.04 (d, J=4.0 Hz, 1H), 6.03 (t, J=5.6 Hz, 1H), 5.87 (m, 1H), 5.86 (t, J=5.6 Hz, 1H), 5.18 (m, 4H), 4.59 (d, J=8.0 Hz, 2H), 4.45 (d, J=7.6 Hz, 1H), 4.31 (m, 2H), 2.10 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H); MS (+)-ES [M+H]+ 484.2 m/z.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:37])[CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH3:36])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:38]([O:45][CH3:46])(=[O:44])/[CH:39]=[CH:40]/[C:41]([O-])=[O:42].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:2]([NH:1][C:41](=[O:42])/[CH:40]=[CH:39]/[C:38]([O:45][CH3:46])=[O:44])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])(=[O:37])[CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH3:36]
Reactant: COC(=O)/C=C/C(=O)[O-]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCC[C@H](NC(=O)/C=C/C(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
The crude (S)-tert-butyl 2-amino-6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)hexanoate, prepared above, was taken up in 40 mL acetonitrile along with monomethyl fumarate (610 mg, 4.69 mmol), DIEA (3.0 mL, 18.8 mmol) and HATU (2.4 g, 6.39 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting residue was taken up in 100 mL of EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc/pentane) afforded (S)-tert-butyl 6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)hexanoate (500 mg, 30%).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=2)[C:7](O)=[O:8])[O:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:17].C(Cl)(Cl)(Cl)Cl>C1CCCCC1>[CH2:1]1[O:12][C:11]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=2)[C:7]([Cl:17])=[O:8])[O:2]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: O=C(Cl)c1cc2c(cc1[N+](=O)[O-])OCO2

Procedure:
Reaction of 31.7 g of 4,5-methylenedioxy-2-nitrobenzoic acid and 31.2 g of phosphorus pentachloride in 250 ml of cylohexane at reflux for 30 minutes followed by treatment of the crude oil twice with carbon tetrachloride gave 4,5-methylenedioxy-2-nitrobenzoyl chloride. The acid chloride was dissolved in 50 ml of tetrahydrofuran and added to a warm solution of 30.9 g of 5-aminotetrazole monohydrate in 750 ml of tetrahydrofuran and 30 ml of water. The solution was stirred for 30 minutes and then diluted with 3 liters of water. The solid which formed was separated by filtration and dried to give 4,5-methylenedioxy-2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 279° C. after recrystallization from a mixture of dimethylformamide and water.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N:16]([CH3:26])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:19])=[O:18])[CH:15]=1)[NH:12][C:11]([C:27]([OH:29])=O)=[CH:10]2.[CH2:30]([S:37][CH:38]([CH2:41][N:42]1[CH2:47][CH2:46][S:45][CH2:44][CH2:43]1)[CH2:39][NH2:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:30]([S:37][CH:38]([CH2:41][N:42]1[CH2:43][CH2:44][S:45][CH2:46][CH2:47]1)[CH2:39][NH:40][C:27]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][C:14]=2[N:16]([CH3:26])[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)(=[O:18])=[O:19])=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCC(CN1CCSCC1)SCc1ccccc1
Reactant: COCCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A mixture of 5-(3-methoxypropoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (330 mg), 2-(benzylthio)-3-thiomorpholinopropan-1-amine (200 mg), 1H-1,2,3-benzotriazol-1-ol (120 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (180 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1-1:2, volume ratio) to give the title compound (380 mg, yield 78%) as a pale-yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[S:36]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37]1>C1(C)C=CC=CC=1.[I-].[Zn+2].[I-]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:27])([F:26])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([N:20]([CH3:21])[CH:37]4[CH2:38][CH2:39][CH2:40][S:36]4)=[O:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reactant: O=S1CCCC1
Agent: [I-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)C1CCCS1
Temperature: 0 °C
Yield: 18.1 %

Procedure:
In a solution of 0.43 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-N-methyl benzoic acid amide synthesized similarly to Synthetic Example 29 and 0.20 g of triethylamine in 5 ml of toluene, 0.45 g of trimethyl silyl trifurate was added and stirred vigorously. 10 minutes after the stirring, the reaction mixture was cooled to 0° C., 0.10 g of tetrahydrothiophene-1-oxide and 0.06 g of zinc iodide were added with stirring, and continued to stir at room temperature further for 4 days. After the completion of the reaction, 10 ml of ice water was added in the reaction mixture, and extracted with ethyl acetate (20 ml×2), the organic phase was dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.09 g of the aimed product as white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.CN(C=O)C.S(Cl)([Cl:19])=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([Cl:19])=[O:11])=[N:7][CH:8]=1
Reactant: COc1ccc(C(=O)O)nc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5-methoxy-2-pyridylcarboxylic acid (11.9 g, 77.5 mmol) and DMF (5.4 ml, 69 mmol) in 200 ml of tetrahydrofuran (THF) at 5° is added thionyl chloride (8.4 ml, 116 mmol) over 15 minutes. After addition, the slurry is allowed to warm slowly to RT. After 3 hours, the reaction is rotoevaporated to give 5-methoxy-2-pyridylcarboxylic acid chloride. This acid chloride is gradually added, with cooling, to rapidly stirring ammonium hydroxide (40 ml, 340 mmol), and the slurry is stirred for 1 hour. The reaction is filtered and the residue is dried. To this is added dry toluene, with stirring, followed by filtration. More toluene is added, followed by rotoevaporation to give 5-methoxy-2-pyridylcarboxamide.
Reaction SMILES: C(O[C:5]([CH3:8])([CH3:7])[CH3:6])(=O)C.[CH2:9]([O:11][C:12](=[O:36])[CH:13]([OH:35])[C:14]1[C:15]([CH3:34])=[N:16][C:17]2[S:18][C:19]3[CH2:20][O:21][CH2:22][CH2:23][C:24]=3[C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)[CH3:10].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([O:11][C:12](=[O:36])[CH:13]([O:35][C:5]([CH3:8])([CH3:7])[CH3:6])[C:14]1[C:15]([CH3:34])=[N:16][C:17]2[S:18][C:19]3[CH2:20][O:21][CH2:22][CH2:23][C:24]=3[C:25]=2[C:26]=1[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)[CH3:10]
Reactant: CCOC(=O)C(O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCOC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Tert-Butyl acetate (0.8 mL) was added to a solution of hydroxy-(2-methyl-4-p-tolyl-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl)-acetic acid ethyl ester (100 mg, 0.252 mmol) in dichloromethane (0.8 mL) followed by concentrated sulphuric acid (40 μL) and the reaction stirred at room temperature for 2 hours. Sodium bicarbonate solution (10% aqueous, 2 mL) was added and the reaction evaporated in vacuo until only the aqueous remained. The aqueous was extracted with ethyl acetate (2 mL) and the organic layer washed with brine (1 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with 0-30% ethyl acetate/heptanes to afford a colourless solid (66 mg, 45%). LCMS (12 min acidic) 7.25 min, ES+/AP+ 454 (MH+) 1HNMR (400 MHz, CDCl3) δ ppm 0.98 (s, 9H), 1.20 (t, 3H), 1.55-1.65 (m, 2H), 2.43 (s, 3H), 2.77 (s, 3H), 3.57-3.61 (m, 1H), 3.78-3.82 (m, 1H), 4.06-4.20 (m, 2H), 4.79-4.82 (m, 2H), 7.16 (d, 2H), 7.32 (d, 2H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([CH2:8][OH:9])[OH:7])[CH:2]=[CH2:3].[OH-].[Na+].[C:12](=O)(OC)[O:13]C>>[CH2:1]([O:4][CH2:5][CH:6]1[CH2:8][O:9][C:12](=[O:13])[O:7]1)[CH:2]=[CH2:3]
Reactant: COC(=O)OC
Reactant: C=CCOCC(O)CO
Agent: [Na+]
Agent: [OH-]
Product: C=CCOCC1COC(=O)O1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Into a 500 ml reaction vessel equipped with a Dean-Stark trap, a Dimroth condenser and a magnetic stirrer bar, 133 g (1 mol) of 1-allylglycerin, 300 ml of dimethyl carbonate, and 3 g (0.075 mol) of sodium hydroxide pellet were charged. The mixture was heated to 60° C., stirred for 30 minutes, and the temperature was then raised to 90° C. to remove a mixture of dimethyl carbonate and the methanol out of the reaction system until any distillate has been no longer distilled. The reaction mixture was cooled, and tetrahydrofuran was added thereto. After filtering off the precipitate, the filtrate was concentrated under reduced pressure to give 150.3 g (95% yield) of 4-allyloxymethyl-1,3-dioxolan-2-one.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:37])[N:18]([C@H:28]3[CH2:31][C@H:30]([C:32]([O:34]CC)=O)[CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[C:11]([F:38])[CH:10]=1)#[N:2].[OH-].[Na+].Cl.[CH3:42][Mg]Br>O1CCCC1.C(O)C>[C:32]([C@H:30]1[CH2:29][C@H:28]([N:18]2[C:17](=[O:37])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][C:11]=3[F:38])=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:31]1)(=[O:34])[CH3:42]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(=O)OCC)C2)c2ncnn12
Reactant: C[Mg]Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(C)=O)C2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl trans-3-{6-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate (0.86 g), tetrahydrofuran (10 mL), ethanol (10 mL) and 1 M aqueous sodium hydroxide solution (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was mixed with N,O-dimethylhydroxyamine hydrochloride (0.24 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.48 g), 1-hydroxybenzotriazole (0.33 g), triethylamine (0.69 mL) and N,N-dimethylformaldehyde (10 mL), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in tetrahydrofuran (10 mL), methylmagnesium bromide (6.6 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 60%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[C:11]1(=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>C1(C)C=CC=CC=1>[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[CH:12]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C1CCc2ccccc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C(N2CCc3ccccc3C2)c2ccccc2C1
Yield: 96.9 %

Procedure:
Tetrahydroisoquinoline (Aldrich Chemical, 18.0 g, 135.1 mmol), 1-indanone (10.0 g, 75.1 mmol) and P2O5 (2.30 g, 16.1 mmol) in 150 mL of toluene were stirred under nitrogen and refluxed for 10 h with water removal via a Dean Stark apparatus. Upon cooling a large amount of fine white powder precipitated (as amine phosphate salts). The dark green solution was filtered under N2 through a medium porosity frit and assayed by NMR after tolune removal (about 85:15 mole ratio of product to ketone). Solvent was evaporated and indanone/amine (about 3.0 g) was removed in vacuo (90-160° C. at 0.5 mm Hg, 76 Pa). The process was stopped and the crude enamine residue recovered under inert atmosphere, giving 18.0 g of dark red-green oil, 95 percent yield. The crude product was analyzed by 1H and 13C NMR and showed less than 2 percent mole ketone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:10]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)=[N:18][N:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:44][C:45]1[CH:50]=[C:49]([S:51]([CH:54]([CH3:56])[CH3:55])(=[O:53])=[O:52])[CH:48]=[CH:47][C:46]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:10]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)=[N:18][N:17]=2)=[N:11][C:12]([C:46]2[CH:47]=[CH:48][C:49]([S:51]([CH:54]([CH3:55])[CH3:56])(=[O:53])=[O:52])=[CH:50][C:45]=2[F:44])=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)n2)c(F)c1
Temperature: 80 °C
Yield: 96 %

Procedure:
tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (100 mg, 0.1512 mmol) was dissolved in DMF (1 mL) and 2-(2-fluoro-4-isopropylsulfonyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (74.44 mg, 0.2268 mmol) and Pd(PPh3)2Cl2 (6.254 mg, 0.01512 mmol) were added. Na2CO3 (226.84 of 2 M, 0.4536 mmol) was added and the reaction heated at 80° C. under an atmosphere of nitrogen for 1 h in a sealed tube. The reaction mixture was partitioned between EtOAc (5 mL) and water (5 mL) and the aqueous layer extracted with EtOAc (2×5 mL). The combined organic extracts were washed with water (3×5 mL), brine (2×5 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 24 g column, eluting with 0 to 50% EtOAc/Petroleum Ether, loaded in CH2Cl2) to give the product as an off-white solid that was used without further purification (114.4 mg, 96% yield)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=1)[CH:19]=O>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH2:19][C:10]2[S:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: Fc1ccccc1-c1cccs1
Reactant: O=Cc1cc(Br)ccc1F
Product: Fc1ccc(Br)cc1Cc1ccc(-c2ccccc2F)s1

Procedure:
2-(2-Fluorophenyl)thiophene obtained in Reference Example 66-(1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 365/367 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1>O>[OH:5][CH2:4][CH2:3][O:6][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccnc1OCCO

Procedure:
Sodium hydride in oil (60%, 131 mg) is added to ethylene glycol (6.0 ml) and 2-chloro-3-nitropyridine (430 mg) is added. The mixture is stirred for 26 hours during which time additional sodium hydride in oil (60%, 100 mg) is added. Water is added, the pH is adjusted to 9 and the solution is extracted with methylene chloride (3×50 ml). The combined organic layers are dried with saline and sodium sulfate and concentrated. Chromatography on silica gel with a methylene/chloroform gradient affords the title compound, Rf =0.32 (TLC on silica gel, ethyl acetate/hexane [50/50]).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:18])[C:5]([C:19]#[N:20])=[CH:4][CH:3]=1.ClCCl.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:19]([C:5]1[C:6]([CH3:18])=[C:7]([C:2]([NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])#[N:20]
Reactant: Cc1c(C#N)ccc(N)c1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(C#N)ccc(NS(=O)(=O)c2ccccc2)c1C(=O)OCc1ccccc1

Procedure:
A mixture of Example 108B (576 mg, 2.2 mmol), anhydrous dichloromethane (22 mL), pyridine (0.4 mL) and benzenesulfonyl chloride (0.33 mL) was stirred 18 hours under nitrogen atmosphere. The mixture was concentrated, dissolved in ethyl acetate (100 mL), washed with 0.5M HCl (3×50 mL) and brine, dried (Na2SO4), filtered, concentrated, and purified on silica gel (20 g) with 50% dichloromethane in hexanes to provide the desired product. MS (ESI(+)) m/e 407 (M+H)+, 424 (M+NH4)+, 429 (M+Na)+; (ESI(−)) m/e 405 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.59 (br s, 1H), 7.77 (m, 3H), 7.64 (m, 1H), 7.56-7.37 (m, 7H), 7.24 (d, 1H), 5.31 (s, 2H), 2.32 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:35])[C:32]([CH3:34])=[CH2:33]>O1CCOCC1>[C:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)(=[O:35])[C:32]([CH3:34])=[CH2:33]
Reactant: C=C(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCOc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 45 °C

Procedure:
4-(6-Hydroxyhexyloxy)-4'-nitrobiphenyl (22 g) is dissolved in 500 ml of dry dioxane and heated to 45° C. A 14 g quantity of triethylamine is added, then a solution of 10.5 g of methacryloyl chloride in an equal volume of dioxane is added dropwise while maintaining the reaction medium temperature at 45° C.