Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](=[O:27])[CH2:5][C:6]([C:8]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.[CH:28](OCC)(OCC)[O:29][CH2:30][CH3:31].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:27])[C:5](=[CH:28][O:29][CH2:30][CH3:31])[C:6]([C:8]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(CC(=O)C1CC1)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O)C(=O)C1CC1
Temperature: 110 °C

Procedure:
A suspension of 1-cyclopropyl-3-(1,6-dihydro-6-oxo-1,2-diphenyl-5-pyrimidinyl)-1,3-propanedione (i.e. the product from Example 6, Step A) (165 mg, 0.46 mmol), triethyl orthoformate (0.23 mL, 1.4 mmol), and acetic anhydride (0.92 mL) was heated at 110° C. under a nitrogen atmosphere for 4 h. The residue was dissolved in toluene (5 mL) and the resulting solution was concentrated under reduced pressure at 50° C. The residue was re-dissolved in toluene (5 mL) and the resulting solution was concentrated at 50° C. to give 181 mg of the title compound as a brown oil that was used in the next step without further purification. 1H NMR analysis showed the product to contain a mixture of Z- and E-olefin isomers.
Reaction SMILES: [CH:1]1[C:6](O)=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].C1([S:15]Cl)C=CC=CC=1.[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)(Cl)Cl>[CH3:8][C:2]1[CH:1]=[C:6]([SH:15])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(O)c1
Reactant: Oc1ccccc1
Reactant: ClSc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(S)ccc1-c1ccccc1

Procedure:
To a solution of 22.4 g. (0.21 mole) of m-cresol in 100 ml. of carbon tetrachloride is added dropwise with stirring, 30.0 g. (0.21 mole) of phenyl sulfenyl chloride at 0°-5° C. over a period of 30 minutes. The light pink solution is stirred overnight at room temperature and then concentrated in vacuo to give 44.8 g. of the impure phenol. The crude product is taken up in 100 ml. of 10% sodium hydroxide, and extracted twice with 50 ml. portions of ether, which are discarded. The basic solution is neutralized with concentrated hydrochloric acid and then extracted twice with 50 ml. portions of chloroform. The organic extracts are combined, dried over sodium sulfate and concentrated in vacuo to give 34.9 g. of yellow oil. Fractional distillation yields 19.9 g. (b.p. 125°-135° C./ 0.1 mm) of the desired phenol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:39]([CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH3:40])=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[N:3]=1
Reactant: CNCCN(C)C
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccnc(C(=O)N(C)CCN(C)C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61B starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61B, Step 2) and N,N,N′-trimethylethylenediamine (Aldrich, Cat. No. 127124). LCMS (M+H)+: m/z=544.2.
Reaction SMILES: [Na+].[I-:2].Br[CH2:4][CH2:5][CH2:6][CH:7]=[C:8]1[C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:27][CH3:28])=[C:21]([O:25][CH3:26])[CH:22]=3)[C:17](=[O:29])[N:16]([CH3:30])[C:15]=2[C:14]2[CH:13]=[C:12]3[O:31][CH2:32][O:33][C:11]3=[CH:10][C:9]1=2>CC(C)=O>[I:2][CH2:4][CH2:5][CH2:6][CH:7]=[C:8]1[C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:27][CH3:28])=[C:21]([O:25][CH3:26])[CH:22]=3)[C:17](=[O:29])[N:16]([CH3:30])[C:15]=2[C:14]2[CH:13]=[C:12]3[O:31][CH2:32][O:33][C:11]3=[CH:10][C:9]1=2
Reactant: [I-]
Reactant: COc1cc2c3c(n(C)c(=O)c2cc1OC)-c1cc2c(cc1C3=CCCCBr)OCO2
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc2c3c(n(C)c(=O)c2cc1OC)-c1cc2c(cc1C3=CCCCI)OCO2
Yield: 91.6 %

Procedure:
NaI (217 mg, 1.45 mmol) was added to a suspension of bromide 19 (70 mg, 0.15 mmol) in acetone (15 mL). The reaction mixture was heated at reflux for 12 h, after which the resulting orange precipitate was collected by vacuum filtration and purified by flash chromatography (silica gel, CHCl3) to provide 24 (73.0 mg, 95%) as an orange solid: mp 173-174.5° C.; IR (KBr) 2944, 1612, 1522, 1481, 1254, 1033 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 7.43 (s, 1H), 7.40 (s, 1H), 7.36 (s, 1 H), 6.84 (t, J=7.22 Hz, 1H), 6.05 (s, 2H), 4.08 (s, 3H), 4.04 (s, 3H), 4.00 (s, 3H), 3.35 (t, J=6.69 Hz, 2H), 2.95 (q, J=7.32 Hz, 2H), 2.19 (m, 2H); ESIMS m/z (rel intensity) 532.1 (100, MH+). Anal. Calcd for C24H22INO5: C, 54.25; H, 4.17; N, 2.64. Found: C, 54.64; H, 4.25; N, 2.60.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1.Cl.[NH2:19]O.[CH2:21]([OH:23])C>>[CH3:21][O:23]/[N:19]=[C:9]1\[CH:4]([CH2:3][O:2][CH3:1])[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8]\1
Reactant: NO
Reactant: COCC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CCO
Agent: Cl
Product: COCC1CN(C(=O)OC(C)(C)C)CC/C1=N/OC
Temperature: 78 °C

Procedure:
1,1-dimethylethyl 3-[(methyloxy)methyl]-4-oxo-1-piperidinecarboxylate D31 (1.2 g) and hydroxylamine hydrochloride (410 mg, 4.9 mmol) were dissolved in ethanol (60 ml). The reaction mixture was heated to 78° C. for 4 hours. Solvent was removed and dichloromethane (excess) was added. The organic layer was washed with water (3×), brine, collected and solvent removed to afford a yellow oil of the desired product D32 in 1.3 g. LCMS [M-56+H] 217.1@ 1.68 min (5 min run)
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH:11]1([O:16][C:17](=[O:24])[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[NH2:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClC(Cl)C>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:19][C:18]1([C:17]([O:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:24])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: NC1(C(=O)OC2CCCC2)CCCC1
Reactant: O=Cc1cccc(CBr)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(OC1CCCC1)C1(NCc2cccc(CBr)c2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a solution of 3-(bromomethyl)-benzaldehyde (0.467 g, 2.44 mmol) in dichloroethane (20 mL) was added cycloleucine cyclopentyl ester (0.802 g, 4.06 mmol) and sodium triacetoxyborohydride (1.18 g, 5.56 mmol). The mixture was stirred at room temperature for 3 hours, then poured into ethyl acetate (200 mL) and washed with saturated ammonium chloride solution (3 times 50 mL). The organic fraction was dried (MgSO4), concentrated and purified by flash column chromatography (SiO2, 7:3 heptane:ethyl acetate) to yield the desired product (0.568 g, 61% yield). LC/MS: m/z 380/382 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([CH3:26])=[CH2:25]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:25][C:24]([CH3:26])=[CH2:23])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CCl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1ccc(OCc2ccccc2)cc1
Temperature: 58 °C
Reaction time: 24 h
Yield: 67.7 %

Procedure:
A mixture of 4-(benzyloxy)phenol (2.01 g, 10.1 mmol), K2CO3 (1.60 g, 11.6 mmol) and 3-chloro-2-methylpropene (93) (2.00 mL, 20.4 mmol) in anhydrous acetone (2.5 mL) was stirred in a sealed vial at 58° C. for 24 h. The resulting mixture was filtered, washing with CH2Cl2, and then the filtrate was evaporated to dryness and the residue was chromatographed on silica gel. Elution with petroleum ether firstly gave foreruns, and then further elution with 25% CH2Cl2/petroleum ether gave 1-(benzyloxy)-4-[(2-methyl-2-propenyl)oxy]benzene (94) (Karrer, F. DE 2312518) (1.74 g, 68%) as a white solid: mp (CH2Cl2/hexane) 62-64° C.; 1H NMR (CDCl3) δ 7.45-7.29 (m, 5H), 6.90 (dt, J=9.3, 2.8 Hz, 2H), 6.85 (dt, J=9.3, 2.8 Hz, 2H), 5.08 (m, 1H), 5.01 (s, 2H), 4.79 (m, 1H), 4.38 (s, 2H), 1.82 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]3[N:17]=[CH:18][CH:19]=[C:20]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:15]3=[N:14][C:13]=2/[CH:27]=[CH:28]/[C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[Li+].[OH-].O.Cl>C1COCC1.CO>[OH:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]3[N:17]=[CH:18][CH:19]=[C:20]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:15]3=[N:14][C:13]=2/[CH:27]=[CH:28]/[C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1O
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Compound 6a (80 mg, 0.16 mmol) was suspended in THF/MeOH (1:1 v/v, 8 mL) and treated with 1 N LiOH solution (0.8 mL, 0.8 mmol). The mixture was stirred at 90° C. for 30 min, allowed to cool to rt, and treated with water (20 mL). The pH of the mixture was adjusted to ca. pH 3 using 1 N HCl solution. The reaction mixture was then extracted with 20% MeOH in DCM (4×200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound 63 as an orange solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.60 (br. s., 1H), 8.55-8.67 (m, 1H), 8.20 (d, J=5.6 Hz, 1H), 8.12-8.18 (m, 1H), 8.04-8.12 (m, 2H), 8.00 (d, J=8.1 Hz, 1H), 7.88 (m, 3H), 7.69 (br. s., 1H), 7.37 (d, J=1.2 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 6.49 (d, J=5.9 Hz, 1H), 4.10 (m 4H), 3.88 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H23N5O4: 494.2 (M+H). Found 494.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:3]1.[O:17]1[CH2:22][CH2:21][N:20]([S:23]Cl)[CH2:19][CH2:18]1.Cl.N1C=CC=CC=1.O>N1C=CC=CC=1>[CH3:15][N:14]([S:23][N:20]1[CH2:21][CH2:22][O:17][CH2:18][CH2:19]1)[C:12](=[O:13])[O:11][C:8]1[C:9]2[O:10][C:2]([CH3:16])([CH3:1])[CH2:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: ClSN1CCOCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CN(SN1CCOCC1)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A mixture of 6.6 g of carbofuran and 4.8 g of morpholinosulfenyl chloride in 40 ml of pyridine was allowed to stand at room temperature for about 18 hours. The mixture, which contained solid pyridine hydrochloride, was poured into water and the aqueous mixture extracted with diethyl ether. The ether extract was washed with dilute acid, then with water and with saturated sodium chloride solution and dried. Evaporation of the ether gave 6.1 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (methyl)(morpholinosulfenyl)carbamate, m.p. 75° -78° . Recrystallization from hexane-diethyl ether increased the melting point to 89° .
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29](=O)[CH2:30]Cl)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O.C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C:29]1[NH:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:8][CH:30]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: N=C(N)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1cnc(-c2ccc(Br)cc2)[nH]1
Temperature: 65 °C
Yield: 44.7 %

Procedure:
A mixture of 4-Bromo-benzamidine (0.202 g) and potassium carbonate (0.237 g) in H2O (0.286 mL) and THF (1.1 mL) was heated to 65° C. 2-(2-Chloro-acetyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.106 g) in THF (0.7 mL) was added over 1 hour and reaction mixture heated at 65° C. for 18 hours. Reaction mixture was concentrated to ˜0.5 mL and extracted with ethyl acetate. Organic layer was washed with H2O, brine and dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexanes) to give 2-[2-(4-Bromo-phenyl)-3H-imidazol-4-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.075 g) as an orange film: LCMS-ESI−: calc'd for C18H23BrN3O2: 393.30 (M+H+). Found: 391.8, 393.83 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:24])/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:25]2[CH2:26][C:27]([CH3:34])([CH3:33])[O:28][C:29]([CH3:32])([CH3:31])[CH2:30]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:24])/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C/C(=C\c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C/C(=C\c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1)C(=O)O
Yield: 94.8 %

Procedure:
The general hydrolysis protocol, described for 195 was followed. Thus, 1,1-dimethylethyl(2E)-3-{4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methyl-2-propenoate (212) (0.190 g, 0.41 mmol) was treated with TFA in CH2Cl2 to afford 0.158 g (95%) of the title compound 213 as an off-white solid. 1H NMR (300 MHz, CD3OD): δ 7.68 (s, 1H), 7.40 (d, J=7.8 Hz, 2H), 7.23 (d, J=7.8 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.1 Hz, 2H), 2.83 (d, J=5.7 Hz, 4H), 2.11 (s, 3H), 1.22 (s, 12H). LCMS (ESI): m/z 405 (M−H)−. Anal. Calcd for C26H30O4, C, 76.82; H, 7.44; Found: C, 74.81; H, 7.42.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][CH:9]=[C:10]([CH3:17])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1)[CH3:2].[Na].C(C1C=CC(O)=CC=1)C.C(Br)/C=C(/CCC=C(C)C)\C>C(O)C>[CH2:8]([O:7][C:6]1[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)/[CH:9]=[C:10](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:17]
Reactant: CCc1ccc(OCC=C(C)CCC=C(C)C)cc1
Agent: CC(C)=CCC/C(C)=C/CBr
Agent: CCc1ccc(O)cc1
Agent: [Na]
Solvent: CCO
Product: CCc1ccc(OC/C=C(\C)CCC=C(C)C)cc1

Procedure:
For the synthesis of the two compounds the intermediate, 1-(p-ethylphenoxy)-3,7-dimethyl-2,6-octadiene, was prepared as described by R. E. Redfern et al., Journal of Economic Entomology, 64, 374-376 (1971). The procedure is essentially as follows: The sodium salt of p-ethylphenol was refluxed with geranyl bromide (1-bromo-3,7-dimethyl-2,6-octadiene) in ethanol for several hours to form the p-ethylphenyl geranyl ether which was worked up and distilled in the usual manner; b.p. 122-124/0.06 mm Hg.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:39])[C:11](=[O:38])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][C:31]=1[CH3:37])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16].[NH:40]1[CH2:44][CH2:43][CH2:42][C:41]1=[O:45].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:39])[C:11](=[O:38])[CH2:12][N:13]([C:30]1[CH:35]=[CH:34][C:33]([N:40]2[CH2:44][CH2:43][CH2:42][C:41]2=[O:45])=[CH:32][C:31]=1[CH3:37])[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH3:22])=[O:16]
Reactant: O=C1CCCN1
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(I)cc1C)C(=O)OC(C)(C)C
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1ccc(N2CCCC2=O)cc1C)C(=O)OC(C)(C)C
Yield: 89.3 %

Procedure:
The compound (650 mg, 1.00 mmol) of Example 293, step A, 2-pyrrolidone (128 mg, 1.50 mmol), copper iodide(I) (19 mg, 0.10 mmol), N,N′-dimethylethylenediamine (0.022 ml, 0.20 mmol) and potassium phosphate (425 mg, 2.00 mmol) were dissolved in toluene (4.0 ml), and the mixture was heated under reflux for 7 hr. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was extracted. The organic layer was washed with saturated brine and dried over sodium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (542 mg, yield 89%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([O:4][C:5]([NH:7][C@H:8]([C:19]([NH:21][C@@H:22]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:25])[CH3:23])=[O:20])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18])=[O:6])[CH3:3].CN1CCOCC1.[CH2:44]([O:51][C:52](Cl)=[O:53])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CCCCCC>C(Cl)Cl>[CH3:36][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:19]([NH:21][C@@H:22]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:25])[CH3:23])=[O:20])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:52]([O:51][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:53])=[CH:12][C:11]=1[CH3:18])=[O:6])[CH3:3]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CN1CCOCC1
Product: Cc1cc(OC(=O)OCc2ccccc2)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1
Temperature: -20 °C
Yield: 98.1 %

Procedure:
To N[(1,1-dimethylethoxy)carbonyl]-2,6-dimethyl-L-tyrosyl-N-(3-phenylpropyl)-D-alaninamide (1.0 g, 2.0 mmol) dissolved in 75 ml of CH2Cl2 and cooled to -20° C. was added 264 mg (0.3 mmol) of N-methylmorpholine. The reaction was then cooled to -78° C. and maintained under an argon atmosphere. Benzylchloroformate (445 mg, 2.5 mmol) was then added to the stirred reaction mixture. The reaction was allowed to slowly warm to room temperature an stir overnight. The mixture was then filtered and the filtrate diluted with CH2CL2 (150 ml). This filtrate was washed 3 times with 75 ml aliquots of 0.5N KHSO4 and once with 75 ml of brine before it was dried over Na2SO4. The organic layer was then stripped of all solvent under reduced pressure to yield a pale yellow solid which by TLC was a mixture of product and starting material. This material was redissolved in 40 ml of CH 2 CL2 and then retreated with N-methylmorpholine and benzylchloroformate in a manner identical to the reaction disclosed above. This second reaction was worked up as described for the original reaction yield a pale yellow solid which was then triterated with hexane containing 5% diethylether to give 1.24 g of the titled product.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:9](Br)[CH3:10].C[O-].[Na+]>>[C:3]([CH:2]([CH2:9][CH3:10])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: CCBr
Agent: C[O-]
Agent: [Na+]
Product: CCC(C(C)=O)C(=O)OC
Yield: 56.8 %

Procedure:
465 g of methyl acetoacetate and then 458 g of ethyl bromide were added under nitrogen to 720 g of 30% sodium methylate solution. The reaction mixture was subsequently boiled at reflux. After distilling off the methanol the residue was poured onto ice-water. The mixture was then extracted with n-hexane and water. The organic phases were combined and dried. After evaporation of the solvent and distillation there were obtained 328 g of methyl 2-acetylbutyrate, b.p. 77°-79°/15 Torr.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([CH3:12])=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3]1.[Br:14]Br.C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[Br:14][C:9]1[C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=[C:5]2[C:10]=1[C:2]([CH3:13])([CH3:1])[CH2:3][CH2:4]2
Reactant: BrBr
Reactant: Cc1cc2c(cc1O)C(C)(C)CC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc2c(c(Br)c1O)C(C)(C)CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a 25 mL one necked round bottom flask, 3,3,6-trimethylindan-5-ol was dissolved in acetic acid (10 mL). The solution was cooled down to 0° C. followed by slow addition of bromine (290 μL, 5.65 mmol). The reaction was slowly warmed up to room temperature. After 3 h of stirring, the reaction was completed. Excess acetic acid was removed by rotavap, and the residue was quenched with ascorbic acid solution. The content was extracted with sodium bicarbonate and brine. Plugged column with silica gel 5:95 ethyl acetate:hexane gave colorless oil, 4-bromo-3,3,6-trimethylindan-5-ol (82% yield). 1H NMR (300 MHz, CDCl3): δ 1.42 (s, 6H), 1.98(dd, 2H, J=15.11, 7.55 Hz), 2.24 (s, 3H), 2.54 (s, 3H), 2.57 (s, 3H), 2.85(d, 2H, J=7.55 Hz), 3.89 (s, 3H), 5.12(d, 1H, J=3.40 Hz), 6.31 (s, 1H), 6.95(m, 1H), 7.01 (s, 1H), 7.12(d, 1H, J=3.40) 8.34 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])=S.CI>C(O)C>[ClH:19].[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[NH:12][C:10]1[NH:9][C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccc(F)cc1NC(=S)Nc1c(Cl)cccc1Cl
Solvent: CCO
Solvent: CI
Product: Cl
Product: Fc1ccc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2-Amino-5-fluorophenyl)-3-(2,6-dichlorophenyl)-thiourea was dissolved in ethanol and treated with 8 equivalents of methyl iodide. The mixture was heated to reflux for 6 h. The solvent was distilled off, the residue was treated with water, then the mixture was rendered weakly alkaline by addition of saturated aqueous sodium hydrogencarbonate solution, and extracted. After distilling off the solvent, the residue was purified by column chromatography on silica gel using a mixture of methylene chloride and methanol (10:1). After distilling off the solvent under reduced pressure, the residue was dissolved using EA, and the solution was treated with excess ethereal hydrochloric acid. The mixture was stirred at RT for approximately 30 minutes, and the crystalline substance was filtered off and recrystallized from a mixture of EA and ethanol. Colorless crystalline product, m.p.: 294-296 ° C.