Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](OC(=NOCCN(C)C[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2C)[C@H](O)[C@@H]1O)C)C.[C:31]([CH2:36][CH2:37][N:38]([CH3:58])[CH2:39][C@H:40]1[O:44][C@@H:43]([N:45]2[C:54]3[N:53]=[CH:52][N:51]=[C:49]([NH2:50])[C:48]=3[N:47]=[C:46]2[CH3:55])[C@H:42]([OH:56])[C@@H:41]1[OH:57])([O:33][CH2:34][CH3:35])=[O:32].CNC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2CC)[C@H](O)[C@@H]1O.ClCCC(OCC)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[C:31]([CH2:36][CH2:37][N:38]([CH3:58])[CH2:39][C@H:40]1[O:44][C@@H:43]([N:45]2[C:54]3[N:53]=[CH:52][N:51]=[C:49]([NH2:50])[C:48]=3[N:47]=[C:46]2[CH2:55][CH3:1])[C@H:42]([OH:56])[C@@H:41]1[OH:57])([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCOC(C)=NOCCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: CCOC(=O)CCCl
Agent: CCc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CNC)[C@@H](O)[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(CC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 33b was prepared by the same procedure as described for the preparation of 6a and 33a using 4b (260 mg, 0.84 mm), ethyl 3-chloropropionate (138 mg, 1.0 mm), DIEA (53 mg, 0.07 ml, 0.41 mm), and DMF (4 ml). After column chromatography (elution with 7:1:0.1 chloroform:methanol:NH4OH), a glassy sticky solid was obtained: yield 153 mg (44%), MS: m/z 409 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.10 (bs, 2H, 6-NH2), 5.71 (d, 1H, H-1′, J1′,2′=5.5 Hz), 5.32 (bd, 1H, OH-2′, J2′-2′OH=5.0 Hz), 5.16 (bd, 1H, OH-3′, J3′-3′OH=5.1 Hz), 5.12 (ddd, 1H, H-2′, J1′,2′=5.5 Hz, J2′,3′=5.7 Hz, J2′-2′OH=5.0 Hz), 4.14 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.1 Hz, J3′-3′OH=5.1 Hz), 4.01 (q, 2H, CH3—CH2), 3.91-3.98 (m, 1H, H-4′), 2.87 (q, 2H, CH2 of 8-Et), 2.71-2.79 (m, 1H, 5′-CH2), 2.51-2.65 (m, 3H, 5′-CH2, CO—CH2), 2.38 (t, 2H, NCH3—CH2), 2.16 (bs, 3H, N—CH3), 1.30 (t, 31-1, CH3 of 8-Et), 1.15 (t, 3H, OCH2—CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[CH2:45]([O:47][CH2:48][CH2:49]Cl)[CH3:46].N12CCCN=C1CCCCC2.CO.C(OCC)(=O)C>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:30]([CH2:46][CH2:45][O:47][CH2:48][CH3:49])[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCCl
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1 H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine (0.81 g, 1.36 mmol), 2-chloroethyl ethyl ether (0.59 g, 5.44 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.66 g, 10.88 mmol) in acetonitrile (16 mL). Heat to reflux. After 18 hours, cool to ambient temperature and dilute the reaction mixture with ethyl acetate. Extract twice with saturated aqueous solution of ammonium chloride, 5% aqueous solution of sodium bicarbonate, water, and saturated aqueous solution of sodium chloride. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 1/5 methanol/ethyl acetate to give the title compound: mp; 65-70° C.; Rf=0.28 (silica gel, 1/5 methanol/ethyl acetate). Elemental Analysis calculated for C39H48N4O6·0.70 H2O: C 68.74; H 7.31; N 8.22; Found: C 68.93; H 7.18; N 8.22.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[CH:16]=[CH:17][CH2:18][NH:19][O:20]C2CCCCO2)=[CH:4][CH:3]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=2[CH:16]=[CH:17][CH2:18][NH:19][OH:20])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Sc2cccc(F)c2C=CCNOC2CCCCO2)cc1
Agent: Cl
Solvent: CO
Product: ONCC=Cc1c(F)cccc1Sc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[3-[2-(4-fluorophenylthio)-6-fluorophenyl]prop-2-enyl]-O-tetrahydropyranyl hydroxylamine (1.26 g, 3.34 mmol) is dissolved in 17 ml of methanol and cooled in an ice bath. Concentrated HCl (1.7 ml) is then added dropwise and the reaction mixture is stirred overnight at room temperature. The reaction mixture is evaporated to dryness and then slurried in saturated NaHCO3 solution and extracted twice with diethyl ether. The extracts are washed with water and then brine and dried over K2CO3 to afford the subtitle compound.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:36])[C@H:12]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=CC=1)([O-])=O.Cl.[NH2:38][C@H:39]([C:41]([NH2:43])=[O:42])[CH3:40].C(N(CC)CC)C>CN(C)C=O>[C:14]([NH:13][C@H:12]([C:11]([NH:38][C@H:39]([C:41]([NH2:43])=[O:42])[CH3:40])=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: C[C@H](N)C(N)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O
Yield: 95.4 %

Procedure:
Referring to Scheme 6, a solution of 5.0 g (0.010 mol) of Nα-BOC-Nε-CBZ-L-lysine p-nitrophenyl ester and 1.5 g (0.012 mol) of L-alanine amide hydrochloride and 1.67 ml (0.012 mol) of triethylamine in anhydrous N,N-dimethylformamide (50 mi) was stirred at room temperature for 16 hours before the solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate (200 ml) and washed with 3M NaOH (3×100 ml), water (3×100 ml), 1M HCl (2×100 ml) and finally with brine (100 ml). After drying over anhydrous sodium sulfate, the solution was filtered and concentrated in vacuo to give 4.3 g (96% yield) of Nα-BOC-Nε-CBZ-L-lysyl-L-alanine amide (6a) as a white solid. TLC: Rf 0.32 (chloroform-isopropanol 9:1); 1H NMR (d6 -DMSO) δ 1.20(d,3H), 1.35(bm, 6H), 1.37(s,9H), 2.97(m,2H), 3.86(m,1H), 4.21(m,1H), 5.00(s,2H), 6.95(d,1H), 7.06(s, 1H), 7.24(t,1H), 7.34(m,6H), 7.78(d,1H); 13C NMR (d6 -DMSO) δ 18.6, 22.8, 28.2, 29.2, 31.4, 40.1, 47.8, 54.5, 65.2, 78.2, 127.8, 128.4, 137.3, 155.5, 156.1, 171.7, 174.2.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].CS(C)=O.[BrH:18].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Br:18][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of 2,6-diisopropylaniline (25 g, 0.141 moL) in toluene (25 mL) was added dimethyl sulfoxide (12.1 g, 1.1 equivalents), and the mixture was heated to 90° C. 48% Aqueous hydrobromic acid solution (26.1 g, 1.1 equivalents) was added dropwise to the mixture at the same temperature over 30 min. Then, the mixture was stirred at 86° C. for 3 hr and at 100° C. for 2 hr. Water (20 mL) was added to the mixture at 0° C., and 1M aqueous sodium hydroxide solution (30 mL) was added dropwise to the mixture. The mixture was partitioned, and the organic layer was washed with 1M aqueous sodium hydroxide solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered naturally, and the filtrate was concentrated under reduced pressure. The residue was distilled under reduced pressure to give 4-bromo-2,6-diisopropylaniline (29.4 g, pale-yellow liquid). 37% Formaldehyde (23.1 g, 2.5 equivalents) was added to a solution of 4-bromo-2,6-diisopropylaniline synthesized as mentioned above in formic acid (189 g, 4.11 moL) at 32° C., and the mixture was stirred under refluxing for 2 hr. Toluene (100 mL) and 8M aqueous sodium hydroxide solution (150 mL) were added to the mixture at 0° C., the mixture was partitioned, and the organic layer was successively washed with 1M aqueous sodium hydroxide solution (50 mL) and water (50 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered naturally, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (35.0 g, colorless solid). yield 95%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[I:13]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([S:11][CH3:12])=[N:9][C:10]=2[I:13])[CH:5]=[CH:6][N:7]=1
Reactant: CSc1ncc2c(Cl)nccn12
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1nc(I)c2c(Cl)nccn12
Temperature: 55 °C
Reaction time: 6 h

Procedure:
To a solution of 8-chloro-3-methylsulfanyl-imidazo[1,5-a]pyrazine (1.75 g, 0.00876 mol) in DMF (15 mL) was added N-iodosuccinimide (3.94 g, 0.0175 mol), the resulting mixture was stirred at 55° C. for 6 h. The mixture was diluted with EtOAc (200 mL), washed with sat. aq. NaHCO3 (40 mL), water (2×40 mL), brine (40 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography to give the title compound as a yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.72 (s, 3H), 7.36 (d, J=4.8 Hz, 1H), 7.76 (d, J=4.8 Hz, 1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:17])[CH2:13][O:14][CH2:15][CH3:16])[CH3:10].[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[C:28]([CH3:34])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.CCCCCCC.O1CCCC1>[CH2:9]([O:11][C:12](=[O:17])[CH:13]([O:14][CH2:15][CH3:16])[CH:30]([C:29]1[CH:32]=[CH:33][C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:27][C:28]=1[CH3:34])[OH:31])[CH3:10]
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Reactant: CCOCC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(OCC)C(O)c1ccc(OCc2ccccc2)cc1C
Reaction time: 0.5 h
Yield: 102.7 %

Procedure:
To a −78° C. cold 2 M solution of lithium diisopropylamide (305 mmol) in THF/n-heptane (152.4 ml) was added a solution of ethoxy-acetic acid ethyl ester (45.2 ml, 331 mmol) in tetrahydrofuran (240 ml) within 1.5 h under an argon atmosphere. The mixture was stirred for 30 min. A solution of 4-benzyloxy-2-methyl-benzaldehyde (30 g, 132.6 mmol) in tetrahydrofuran (420 ml) was added dropwise over a period of 50 min. The reaction mixture was stirred 2 h at −78° C., poured onto ice water/aqueous ammonium chloride solution 1/1 and extracted two times with ethyl acetate. The combined extracts were washed three times with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, n-heptane/AcOEt) to give 48.8 g (136.2 mmol) of the title compound as a mixture of stereoisomers as yellow oil.
Reaction SMILES: [O:1]=[C:2]([CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC1C=CC=CC=1)[C:3]([OH:5])=[O:4].C(Cl)C1C=CC=CC=1>O1CCOCC1>[C:14]1([CH2:6][C:2](=[O:1])[C:3]([OH:5])=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C(=O)C(Cc1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: ClCc1ccccc1
Product: O=C(O)C(=O)Cc1ccccc1
Yield: 63 %

Procedure:
By the same operation as in Example 61 except that 6 ml of 1,4-dioxane was used as the solvent, 2-oxo-3,4-diphenylbutanoic acid formed in a yield of 63 % by the reaction of 0.49 g (3 mmoles) of phenylpyruvic acid with 0.5 ml of benzyl chloride, as determined by NMR spectral analysis.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.4 %

Procedure:
A mixture of 3,4-dihydroxybenzaldehyde (1.38 g, 10 mmol), benzyl bromide (1.71 g, 10 mmol), and K2CO3 (1.24 g, 9 mmol) in 20 mL acetone was stirred at rt for 15 h under Ar atmosphere. Solid was filtered off and the filtrated was diluted with EtOAc (100 mL) and washed with NaH2PO4 (sat. 100 mL), and dried over MgSO4 and concentrated. The residue was chromatographed (hexane/EtOAc) to afford 4-(benzyloxy)-3-hydroxybenzaldehyde as a white solid (1.15 g, 50%). 1H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.44-7.40 (m, 6H), 7.04 (d, J=8.0 Hz, 1H), 5.80 (s, 1H), 5.21 (s, 2H); MS (ESI) m/z 229 (M+H+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][C:13]([F:16])([F:15])[CH2:12][NH:11]1.Br[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]2[CH:19]=1>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:14][C:13]([F:15])([F:16])[CH2:12][N:11]1[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]2[CH:19]=1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Reactant: Fc1ccc(F)c([C@H]2CC(F)(F)CN2)c1
Agent: Cl
Product: CCOC(=O)c1cnn2ccc(N3CC(F)(F)CC3c3cc(F)ccc3F)cc12

Procedure:
The title compound (Int-72) was prepared by the method similar to that for Int-84 using (R)-2-(2,5-difluorophenyl)-4,4-difluoropyrrolidine hydrochloride and Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate to afford as yellow solid. LCMS (ESI): m/z 408.1 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[N:25]#[C:26][NH2:27]>O1CCOCC1>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][C:16]([NH:15][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:26]([NH2:27])=[NH:25])[CH:4]=2)[CH:14]=[CH:13][CH:12]=1)=[O:24])([OH:23])=[O:22]
Reactant: N#CN
Reactant: Nc1cccc(-c2cccc(NC(=O)CCCCC(=O)O)c2)c1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1cccc(-c2cccc(NC(=O)CCCCC(=O)O)c2)c1

Procedure:
Prepared by refluxing 3-amino-3'-[(5-carboxyvaleryl)amino]biphenyl hydrochloride with cyanamide in dioxane for 3 hours.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].S(=O)(=O)(O)O.O>C(#N)C>[C:18]([O:17][C:6]1[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.50 kg (6.35 mol) of 2,6-di-tert-butyl-4-methoxyphenol and 658 mL (6.98 mol) of acetic anhydride dissolved in 1.2 L of acetonitrile, 3 mL of conc. sulfuric acid was added and the mixture was stirred overnight at room temperature. To the mixture, a great excess of water was added and the resulting solids were filtered and dried. The obtained 4-acetoxy-3,5-di-tert-butylanisole was used in the next reaction without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:13]([O:21][CH3:22])=[CH:12][C:4]=1[O:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8])=O.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24].C[O-].[Li+].Cl>CN(C)C=O.CO.O>[C:7]([C:6]([CH3:11])([O:5][C:4]1[CH:12]=[C:13]([O:21][CH3:22])[C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:15][C:3]=1/[CH:1]=[CH:24]/[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[O:25])[CH3:10])([OH:9])=[O:8]
Reactant: COc1cc(OC(C)(C)C(=O)O)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC(C)(C)C(=O)O)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
2-(2-Formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propionic acid (Ex-59B, 0.12 g, 0.39 mmol) and 4-acetylbenzoic acid (0.064 g, 0.39 mmol) were dissolved in a dimethylformamide-methanol solution (2.7 mL, 7:3). After complete dissolution, lithium methoxide (0.060 g, 1.6 mmol) was added and the resulting bright orange slurry was stirred in the dark at room temperature for 2 h. Upon completion, as determined by HPLC, the mixture was diluted with water (15 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethyl alcohol (5 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.15 g (85%) of the title compound as a dark yellow solid, mp 223–225° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.23 (d, 2H, J=8.1 Hz), 8.10 (d, 2H, J=8.1 Hz), 8.06 (s, 1H), 7.95 (d, 1H, J=16.2 Hz), 7.69 (d, 1H, J=3.0 Hz), 7.55 (d, 1H, J=5.1 Hz), 7.14 (dd, 1H, J=5.1, 3.0 Hz), 6.58 (s, 1H), 3.88 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z=467 ([M+H]+, 100%). Anal. Calcd. for C25H22O7S.⅓H2O: C, 63.55; H, 4.84; S, 6.79. Found: C, 63.39; H, 5.02; S, 6.53.
Reaction SMILES: CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4:17].[CH2:18]([C:20]([CH2:25][OH:26])([CH2:23][OH:24])[CH2:21][CH3:22])[OH:19].[CH2:27]([OH:45])[CH2:28][CH2:29][CH2:30]CCCCCCCCCCCCCC.C(O)CCC>>[CH2:18]([C:20]([CH2:25][OH:26])([CH2:23][OH:24])[CH2:21][CH3:22])[OH:19].[CH2:27]([OH:45])[CH2:28][CH2:29][CH3:30].[Ti:17]
Reactant: [Ti+4]
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: CC(C)[O-]
Agent: CCC(CO)(CO)CO
Solvent: CCCCO
Product: [Ti]

Procedure:
A liquid mixture of 28.4 g (0.1 mole) of tetraisopropyl titanate, 4.5 g (0.033 mole) of trimethylolpropane, 0.1 g (0.0004 mole) of stearyl alcohol and an excess amount, i.e., 100 g (1.37 moles) of butanol was heated under reflux to dissolve the solid substance completely. The resultant isopropyl alcohol and butanol were then distilled off to obtain trimethylolpropane-butyl alcohol-titanate (polyol titanate). The polyol titanate was then cooled by ice, followed by an addition of butanol which contained 1.8002 g (0.10 mole) of water. After heating the resultant mixture to form a uniform solution, butanol was removed by distillation. Under cooling, butanol with 0.9005 g (0.05 mole) of water incorporated therein was added again. The resultant mixture was heated to effect polymerization and crosslinking. Butanol was then removed thoroughly under reduced pressure. After heating the residue again at 100° C. for 30 minutes in water-containing butanol, the product was dried under reduced pressure to obtain 12.2 g of a solid substance. This solid substance had such properties that it showed water repellency when water was added thereto but its surface was wet immediately when an alcohol was added thereto.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][OH:7])#[N:2].[H-].[Na+].[F:10][C:11]([F:27])([F:26])[CH2:12][N:13]=[C:14]([NH2:25])[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18](S(C)=O)[N:17]=1>C(O)(C)(C)C>[F:27][C:11]([F:10])([F:26])[CH2:12][N:13]=[C:14]([NH2:25])[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[N:17]=1
Reactant: N#CCCCCO
Reactant: CS(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: N#CCCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 2 h
Yield: 67.2 %

Procedure:
4-Cyanobutanol (10 g.) was added to sodium hydride (2.75 g.) in t-butanol (95 ml.) and the solution warmed to 40°. 4-[2-(2,2,2-Trifluoroethyl)guanidino]-2-methylsulphinylpyrimidine (11.24 g.) was added over 10 minutes and the solution kept at 40° for 2 hours then at room temperature for 18 hours. The solvent was removed under vacuum and the residue washed with water, then ether to give 5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yloxy]valeronitrile (8.5 g.), m.p. 134°-136°.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])(=O)C.[OH-].[K+]>CO.O>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(=O)Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Yield: 87.1 %

Procedure:
A solution of 7-acetamido-4-(3-bromoanilino)-6-nitroquinazoline (1.50 g, 3.73 mmol) and KOH (2 g) in MeOH (190 mL) and H2O (10 mL) is heated under reflux for 30 min, and the solvent volume is reduced to give 7-amino-4-(3-bromoanilino)-6-nitroquinazoline (1.17 g, 87%). 1H NMR (DMSO) δ10.17 (1H, brs), 9.43 (1H, s), 8.43 (1H, s), 8.15 (1H,m brs), 7.86 (1H, d, J=7.1 Hz), 7.42 (2H, brs), 7.40-7.31 (2H, m) , 7.12 (1H, s).
Reaction SMILES: [Li]CCCC.N(C(C)C)C(C)C.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].[NH4+].[Cl-]>C1COCC1>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: ClCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C1(CCCCCl)CC1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 52.4 %

Procedure:
Under an Ar atmosphere at 0° C., BuLi (2.5M in hexanes, 37 mL, 92.5 mmol) was added drop wise to a solution of iPr2NH (12.3 mL, 88 mmol, distilled from NaOH) in dry THF (150 mL) in 10 min. The reaction mixture was stirred for 20 min, cooled to −70° C. and then, tert-butyl cyclopropanecarboxylate (prepared according to Kohlrausch, K. W. F.; Skrabal, R., Z. Elektrochem. Angew. Phys. Chem., 1937, 43, 282-285, 12.5 g, 88 mmol) was added drop wise in 20 min. After 3 min, 1-bromo-4-chlorobutane (13.7 mL, 20.1 g, 117 mmol) was added drop wise in 15 min. The reaction mixture was allowed to reach rt, poured into a mixture of aqueous saturated NH4Cl (200 mL) and ice (50 mL) and extracted with Et2O (1×200 mL, 1×100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The remaining oil, was purified by fractional distillation to give tert-butyl 1-(4-chlorobutyl)-1-cyclopropanecarboxylate (10.73 g, 52%) as a colorless oil. bp: T=57-61° C. (p=0.001 mbar). 1H NMR (CDCl3): δ=3.52 (t, J=6.6 Hz, 2H), 1.76 (quintet, J=6.8 Hz, 2H), 1.64-1.54 (m, 2H), 1.51-1.46 (m, 2H), 1.42 (s, 9H), 1.12 (dd, J=6.6, 3.9 Hz, 2H), 0.60 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR (CDCl3): δ=173.9, 80.0, 45.1, 33.6, 32.9, 28.2 (3×), 25.3, 24.2, 15.4 (2×). HRMS calcd for C12H22ClO2 (MH+): 233.1308, found: 233.1308.