Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:11][CH:12]([C:18]([F:21])([F:20])[F:19])[C:13](OCC)=[O:14])[CH2:8][CH2:9][CH3:10].[OH-].[Na+]>C1COCC1>[CH2:7]([O:11][CH:12]([C:18]([F:19])([F:20])[F:21])[CH2:13][OH:14])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOC(C(=O)OCC)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOC(CO)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of lithium aluminum hydride (0.1 g) with THF (10 ml) was stirred under ice cooling, followed by gradually dropwise adding a mixed solution of (+)-ethyl 2-butoxy-3,3,3-trifluoropropionate (0.8 g) obtained in Example 7 with THF (5 ml), followed by raising the temperature up to room temperature, stirring for one hour, again cooling with ice, dropwise adding 2N NaOH aqueous solution, filtering off deposited substance, extracting with ether (50 ml), washing with saturated NaCl aqueous solution, drying over anhydrous magnesium sulfate and removing the solvent. Yield: 0.5 g. [α] -11.7 (cl. 0, CHCl3)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](N)=[CH:9][CH:8]=[CH:7]2.N([O-])=O.[Na+].[S-:17][C:18]#[N:19].[K+]>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[S:17][C:18]#[N:19])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2cccc(Cl)c12
Reactant: N#C[S-]
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: N#CSc1cccc2cccc(Cl)c12

Procedure:
3.92 parts 8-chloro-1-naphthylamine were stirred in dilute hydrochloric at room temperature and diazotised by the careful addition of a solution of 1.52 parts sodium nitrite in water. The diazo solution was then added, at 10° C., to a stirred suspension of 3.5 parts potassium thiocyanate, 4.5 parts cuprous thiocyanate and 0.1 parts ferrous sulphate in water. After stirring the mixture for several hours, the product was filtered off and recrystallised several times from ethanol to yield 1 part of pure product, m.pt 77°-8° C. The I.R. spectrum contained a band at 2160 cm-1 due to the thiocyanate group.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O)([CH3:9])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6].[NH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH2:26][C@H:21]([NH:20][CH2:15][C:14]2[CH:17]=[C:10]([C:2]([CH3:9])([CH3:1])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6])[CH:11]=[CH:12][C:13]=2[O:18][CH3:19])[C@@H:22]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1ccc(C(C)(C)C#CC(F)(F)F)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1c1ccccc1
Product: COc1ccc(C(C)(C)C#CC(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 58 and Compound 12 in the same manner of Compound 13.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:4]#[N:5].[C:20](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.CCOCC>CN(C)C=O>[CH3:20][O:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[C:4]#[N:5]
Reactant: O=C([O-])[O-]
Reactant: N#CC(=NO)c1ccccc1Oc1ccc(Cl)cc1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON=C(C#N)c1ccccc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
α-hydroxyimino-2-(4-chlorophenoxy)phenylacetonitrile (a mixture of E- and Z-isomers) (1.36 g, 0.005 mole) was dissolved in dried dimethylformamide (10 ml) and potassium carbonate (0.90 g, 0.0065 mole) was added to the mixture. Further, dimethylsulfate (0.76 g, 0.006 mole) was added to the mixture under ice cooling, followed by stirring at room temperature for 1 hour. Then, ether (150 ml) was added to the mixture, which was washed twice with water. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and then the resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain α-methoxyimino-2-(4-chlorophenoxy)phenylacetonitrile (1.35 g, yield: 94.4%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:7]=[N:8][N:9]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[C:10](=[O:12])[CH:11]=1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[Cl:1][C:2]1[C:3]([F:26])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:7]=[N:8][N:9]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:15])[C:10](=[O:12])[CH:11]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(Cl)c2F)cc1=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4cccc(Cl)c4F)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 2-[4-(3-chloro-2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid (Intermediate 82) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 2-[4-(3-chloro-2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as an off-white solid as a mixture of diastereomers (1.24 g, 84%).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:27]([OH:28])=[CH:26][C:20]4[N:21]([CH3:25])[C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4=[CH:18][C:19]5[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=5[CH:26]=[C:27]4[O:28][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: Cn1c(=O)oc2cc(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Product: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione was obtained (40%) as a colorless solid: mp 228-229° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.42-7.28 (m, 10H), 7.15-6.96 (m, 4H), 6.60 (s, 1H), 6.55 (d, J=7.2 Hz, 1H), 6.44 (s, 1H), 5.04 (d, J=9.0 Hz, 1H), 4.77 (d, J=9.0 Hz, 1H), 3.38 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.6, 157.7, 155.3, 142.0, 137.7, 137.4, 137.2, 133.2, 132.1, 129.0, 128.9, 128.6, 128.5, 128.3, 128.2, 124.0, 123.5, 122.6, 112.6, 105.4, 92.0, 80.6, 59.1, 58.0, 28.5; MS (ES+) m/z 475.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([O:1][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=3)[CH:5]=[CH:6][CH:7]=2)=[N:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=C(Nc1cccc(O)c1)c1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1)c1cccc(C(F)(F)F)c1
Yield: 83.8 %

Procedure:
In the same method as in Example C1(v) and using N-(3-hydroxyphenyl)-3-(trifluoromethyl)benzamide (5.00 g, 17.7 mmol), 2-chloro-5-nitropyridine (2.81 g, 17.7 mmol), potassium carbonate (7.37 g, 30.6 mmol) and N,N-dimethylformamide (150 mL) as starting materials, the title compound (5.98 g, 83%) was obtained as a pale-brown powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(S)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OC(=O)C(Cl)(Cl)CC[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Br:31])C.O>CN(C)C=O>[Br:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=[CH:21][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCCCBr
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCCCCCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.7 %

Procedure:
3.46 g (25.0 mmol) potassium carbonate and 2.75 g (25.0 mmol) thiophenol were added to a solution of 10.1 g (25.0 mmol) 3 in 200 ml dimethylformamide. It was stirred for 12 h at room temperature, 300 ml water was added, it was extracted with ether, washed with water, dried over sodium sulfate and the solvent was removed on a rotary evaporator. 6.62 g (61%) 66 was obtained as a nearly colourless oil after flash chromatography of the residue (silica gel, heptane/toluene 5:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1[CH2:41][CH2:40][O:39][CH2:38]C1>C(OCC)(=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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:14]1[CH:15]=[C:6]([CH:4]=[O:3])[CH:7]=[CH:41][C:40]=1[O:39][CH3:38])=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cc(C=O)ccc1OC

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 5-formal-2-methoxylphenylboronic acid (100 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(5-formyl-2-methoxy-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][O:4][C:5]1[C:10]([O:11][CH:12]([F:14])[F:13])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:15]=[CH:16]/[C:17]1[N:18]=[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]2[C:25]=1[C:26]([OH:28])=O.[CH:31]1([C:34]2[N:35]=[C:36]([NH2:39])[S:37][CH:38]=2)[CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH3:1][C:2]([CH3:29])([CH3:30])[CH2:3][O:4][C:5]1[C:10]([O:11][CH:12]([F:13])[F:14])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:15]=[CH:16]/[C:17]1[N:18]=[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]2[C:25]=1[C:26]([NH:39][C:36]1[S:37][CH:38]=[C:34]([CH:31]2[CH2:33][CH2:32]2)[N:35]=1)=[O:28]
Reactant: CC(C)(C)COc1c(/C=C/c2nc3ccccn3c2C(=O)O)cccc1OC(F)F
Reactant: Nc1nc(C2CC2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3ccccn3c2C(=O)Nc2nc(C3CC3)cs2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 13 (100 mg, 0.240 mmol) with 4-cyclopropyl-1,3-thiazol-2-amine (37 mg, 0.264 mmol) in the presence of EDCI hydrochloride (91 mg, 0.480 mmol) and DMAP (27 mg, 0.240 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 35 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 0.79-0.85 (m, 2H), 1.05 (s, 9H), 1.20-1.26 (m, 2H), 1.95-2.01 (m, 1H), 3.58 (d, J=5.4 Hz, 2H), 6.60-6.71 (m, 1H), 6.90-6.98 (m, 1H), 7.10-7.27 (m, 3H), 7.38-7.46 (m, 1H), 7.50-7.56 (m, 2H), 7.63-7.70 (m, 1H), 7.92 (d, J=15.6 Hz, 1H), 7.99 (d, J=15.0 Hz, 1H), 13.03 (br s, 1H); APCI-MS (m/z) 539.45 (MH)+.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:35])[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:17]2[C:22]([C:23]=1[CH3:24])=[CH:21][C:20]([Cl:25])=[CH:19][CH:18]=2)=[O:13])[CH3:10]>CS(C)=O>[CH2:9]([O:11][C:12]([C:14]12[CH2:24][C:23]1([CH3:4])[C:22]1[C:17]([N:16]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[C:15]2=[O:35])=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(C)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C12CC1(C)c1cc(Cl)ccc1N(Cc1ccc(OC)cc1)C2=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
A suspension of sodium hydride in anhydrous DMSO was treated in two portions with trimethylsulfoxonium iodide (0.33 g, 1.50 mmol). The reaction mixture was stirred for 30 min, treated with 3 (0.29 g, 0.752 mmol), and heated to 80° C. for 12 h. The resulting amber solution was allowed to cool to room temperature and poured over ice water. The milky suspension was extracted with CH2Cl2, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography provided 4 (0.22 g, 72%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.45 (d, J=2.3 Hz, 1H), 7.13 (d, J=8.6 Hz, 2H), 7.05 (dd, J=2.2, 9 Hz, 1H), 6.84 (d, J=8.6 Hz, 3H), 5.12 (m, 2H), 4.31 (m, 2H), 3.76 (s, 3H), 2.11 (d, J=6.6 Hz, 1H), 1.58 (s, 3H), 1.31 (t, J=7.2 Hz, 3H), 1.08 (d, J=6.6 Hz, 1H).
Reaction SMILES: [CH:1]1([C:9]([O:11]C(C)(C)C)=[O:10])[CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(O)C.C([O-])(O)=O.[Na+]>O>[CH:1]1([C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)C1CCC=CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCC=CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.9 %

Procedure:
A 100 mL round bottom flask was charged with t-butyl cyclooct-4-ene carboxylate (1.0 g, 4.8 mmol) and trifluoroacetic acid (2 mL) and stirred at room temperature for two days. A 4:1 ethanol:water mixture (10 mL) was then added and the pH of the resulting mixture was adjusted to ˜4.0 with aqueous saturated NaHCO3. The mixture was then extracted with 4×25 mL portions of ethyl ether and the ether phases were combined and concentrated. The liquid was then purified by flash chromatography on silica (3:7 ethyl acetate:hexanes mobile phase) to afford cyclooct-4-ene carboxylic acid (0.051 g, 69%). The material was crudely dried immediately before polymerization by dissolving the material in benzene and carrying out azeotropic distillation using a rotary evaporator (three cycles). IR (film on NaCl): 3017, 2932, 2859, 1736 (C═O), 1467, 1449, 1392, 1334, 1165, 747, 714 cm−1 (O—H stretch not assigned due to weakness). 1H NMR (300 MHz, CDCl3): δ 11.6 (br, 1H), 5.6-5.8 (m, 2H), 2.30-2.54, (m, 2H), 2.02-2.24 (m, 4H), 1.84-1.96 (m, 1H), 1.50-1.82 (m, 3H), 1.32-1.48 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 184.34, 130.45, 129.34, 43.10, 31.28, 29.10, 27.65, 25.75, 23.92 ppm. HRMS-FAB for C8H14O2: Theoretical: 126.1045; Found: 126.1048.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:28][CH3:29])[C:5]([NH2:27])=[C:6]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[CH:30](OCC)(OCC)OCC>CC#N>[Br:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2[N:27]=[CH:29][N:28]([CH3:30])[C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CNc1cc(Br)cc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)c1N
Solvent: CC#N
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Br)cc3c2ncn3C)cc1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-N,N-bis-(4-methoxy-benzyl)-N″-methyl-benzene-1,2,3-triamine (170 mmol) was dissolved in a mixture of HC(OEt)3 (100 mol) and MeCN (500 mL). The mixture was stirred at 85° C. for 0.5 h and then at room temperature for approximately 16 h. The mixture was combined with another one obtained following the same procedure described above. The resulting mixture was concentrated and the residue was purified by flash column chromatography (SiO2, 15:85 to 60:40 EtOAc/petroleum ether) to obtain the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:11])(=[O:10])[NH2:9])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[Br:16]Br.[OH-].[K+]>CC(O)=O>[NH2:1][C:2]1[C:7]([Br:16])=[CH:6][C:5]([S:8](=[O:10])(=[O:11])[NH2:9])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13]
Reactant: Nc1ccc(S(N)(=O)=O)cc1S(N)(=O)=O
Reactant: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1c(Br)cc(S(N)(=O)=O)cc1S(N)(=O)=O
Temperature: 70 °C
Yield: 62.6 %

Procedure:
A stirred solution of 2-amino-5-sulfamoylbenzenesulfonamide (3.77 g; 15 mmol) in AcOH (50 ml) was added a solution of Br2 (0.78 ml; 15 mmol) in AcOH (10 ml). The reaction mixture was heated to 70° C. for 6 days, evaporated to dryness, resuspended in MeOH (85 ml) and added solid KOH (3.8 g; 68 mmol). The reaction mixture was heated to 60° C. for 2.5 h (hydrolysis of 3-methyl-, 3-bromomethyl-, 3-dibromomethyl and 3-tribromomethyl-1,2-dihydro-1,2,4-benzothiadiazine isomers formed in situ), filtered, neutralized and evaporated to dryness. Column chromatography gave 3.1 g (63%) product.
Reaction SMILES: Cl.[C:2]1([NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[C:10](O)(=O)[CH2:11][OH:12]>>[OH:12][CH2:11][C:10]1[NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:9]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)CO
Agent: Cl
Product: OCc1nc2ccccc2[nH]1

Procedure:
To 150 ml. of 4N hydrochloric acid were added 10.8 gms. (100 mmoles.) of o-phenylenediamine and 11.4 gms. (150 mmoles.) of glycolic acid. The mixture was refluxed for 40 minutes. The solution then was cooled, filtered, and neutralized by the addition of concentrated ammonium hydroxide. The title compound precipitated and was filtered and dried to obtain 4 gms. of product.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[CH2:9]([OH:15])[CH2:10][O:11][CH2:12][CH2:13]O>[Pd]>[OH:15][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:5][CH:4]([CH3:6])[CH2:3][CH2:2][C:1]([O:8][CH2:13][CH2:12][O:11][CH2:10][CH2:9][OH:15])=[O:7]
Reactant: CC(=O)CCC(=O)O
Reactant: OCCOCCO
Agent: [Pd]
Product: CC(CCC(=O)OCCOCCO)OCCOCCO
Temperature: 230 °C
Yield: 23.4 %

Procedure:
Levulinic acid (11.6 g; 0.1 mol), diethylene glycol (63.6 g; 0.6 mol), and 2.32 g of 10% Pd/C from Aldrich (20 wt % relative to levulinic acid) are charged to a Parr reactor, purged with nitrogen three times, heated to 230° C. with stirring, and reacted with 1000 psi of hydrogen for 65 hrs. GC analysis reveals that the reaction is complete. Diethylene glycol is distilled off at 70-72° C./0.06 mm to give 15.6 g of the crude product, which is chromatographed on silica gel using at first neat methylene chloride and then methylene chloride-methanol from 30:1 to isolate 6.9 g of 2-(2-hydroxyethoxy)ethyl 4-(2-(2-hydroxyethoxy)ethoxy)pentanoate. 1H NMR (δ, ppm, CDCl3): 1.16 d (3H, CH3), 1.81 m (2H, CH2), 2.46 m (2H, CH2CO), 3.1 (broad, 2H, OH), 3.50 m (3H, CH2O, CH), 3.61 m (14H, 7CH2O), 4.25 m (2H, COOCH2). 13C NMR (δ, ppm, CDCl3): 19.30 (CH3); 30.01; 31.27 (CH2 groups); 61.38; 61.54; 63.22; 67.64; 68.88; 70.48; 72.33; 72.37 (CH2O groups), 74.68 (CH), 173.57 (COO). Mass spectrum: m/e 294 (M+).
Reaction SMILES: O.[CH2:2]([NH:9][CH:10]([CH3:12])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C1C=CC=CC=1>[CH2:2]([N:9]([CH:10]([CH3:12])[CH3:11])[C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)NCc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)N(Cc1ccccc1)C(=O)C(C)(C)C

Procedure:
A one-liter reaction flask fitted with a power stirrer, heating mantle, dropping funnel, thermometer, water-cooled condenser and drying tube was charged with 149.2 g (1.0 mole) N-benzyl-N-isopropylamine, 350 ml of benzene and 111.1 g (1.1 mole) of triethylamine. The dropping funnel contained 126.6 g (1.05 mole) of pivalyl chloride which was added dropwise to the stirred reaction mixture. After the addition was completed, the reaction mixture was stirred and heated at 75-80° for 18 hours. The mixture was cooled and the amine-salt was collected on a vacuum filter. The filtrate was transferred to a separatory funnel and extracted with water which was followed by dilute aqueous hydrochloric acid. The organic phase was dried over sodium sulfate. After removing the drying agent, the solvent was evaporated. The liquid residue was transferred to a pot which was appropriately fitted for a simple vacuum distillation. The forecut material proved to be mainly trimethylacetyl chloride and trimethylacetic acid. The product fraction weighed 188.6 g, b.p. 86-87/0.07 mm, nD25 1.5074.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]([C:22]#[N:23])=[C:11]2[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)(=O)C.CO.[OH-].[Na+].O>O1CCCC1>[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]([C:22]#[N:23])=[C:11]2[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1
Reactant: CC(=O)OCCOc1ccc2nc(CC(C)C)c(C#N)c(-c3ccc(C)cc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(OCCO)cc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of 2-{[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}ethyl acetate (4.0 g, 9.9 mmol) in tetrahydrofuran (20 ml)-methanol (20 ml) was added 2N aqueous sodium hydroxide solution (20 ml). The obtained mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give 6-(2-hydroxyethoxy)-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (3.2 g, yield 89%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[CH2:14]([O:13][P:12]([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cccc([N+](=O)[O-])c1)OCC
Temperature: 140 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
A mixture of 3-nitrobenzyl bromide (648 mg, 3.00 mmol) and triethyl phosphite (0.669 mL, 3.90 mmol) was stirred at 140° C. under nitrogen for 16 h. The excess triethyl phosphite was removed under reduced pressure and the residue purified by chromatography over silica gel eluting with 2% MeOH in dichloromethane to afford diethyl(3-nitrobenzyl)phosphonate, 0.80 g (yield: 98%). 1H-NMR (CD3OD, 400 MHz): δ=1.27 (t, J=6.8 Hz, 6H), 3.43 (d, J=22.0 Hz, 2H), 4.08 (q, J=6.8 Hz, 4H), 7.58 (t, J=8.0 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H). MS (ES+): m/z 273.99 (MH+). HPLC: tR=2.92 min (ZQ3, polar—5 min).