Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]1([F:30])[O:17][C:16]2[CH:18]=[C:19]([CH3:29])[C:20]([C:22]3[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=3)=[CH:21][C:15]=2[O:14]1.CCN(C(C)C)C(C)C>ClCCl.O1CCCC1.CO.[OH-].[Na+]>[F:30][C:13]1([F:12])[O:17][C:16]2[CH:18]=[C:19]([CH3:29])[C:20]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:4](=[O:5])[C:3]4[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=4[F:11])=[N:26][CH:27]=3)=[CH:21][C:15]=2[O:14]1
Reactant: Cc1cc2c(cc1-c1ccc(N)nc1)OC(F)(F)O2
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1-c1ccc(NC(=O)c3c(F)cccc3F)nc1)OC(F)(F)O2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (32 mg, 0.2 mmol) was added to a stirred solution of 4 (24 mg, 0.1 mmol) and Hünig's base (95 μL, 70 mg, 0.5 mmol) in dichloromethane (1.0 mL) at room temperature. The reaction was stirred for 0.5 h. The solution was diluted with tetrahydrofuran (0.6 mL), methanol (0.4 mL) and 2 M sodium hydroxide solution (0.2 mL). The mixture was stirred and heated to 60° C. for 15 min then cooled to room temperature, diluted with dichloromethane (5 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-25% ethyl acetate in hexane) provided 5 (27.8 mg, 76%) as a solid: LRESIMS m/z 405.1 [M+H]+, calcd. for C20H13F4N2O3 405.1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([O:21]COC)[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([O:8][CH2:9][C@H:10]([OH:21])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCO[C@H](CCOCc1ccccc1)COCc1ccccc1
Solvent: CCO
Product: O[C@H](CCOCc1ccccc1)COCc1ccccc1

Procedure:
The (R)-isomer was prepared in an identical fashion from (R)-1,4-dibenzyloxy-2-(methoxymethoxy)-butane and had [α]D25 +7.7° (c 0.5 in ethanol).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=1[C:32](=[O:34])[CH3:33])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44].O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:26]=1[C:32](=[O:34])[CH3:33])(=[O:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1C(C)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6′-hydroxyacetophenone (0.6 g) in N,N-dimethylformamide (5 mL) were added potassium carbonate (0.26 g) and methyl bromoacetate (0.13 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (0.62 g).
Reaction SMILES: S(=O)(=O)(O)O.O[C:7]1([C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[C-]#[N:22].[K+].[ClH:24]>FC(F)(F)C(O)=O.CO.C(OCC)C>[ClH:24].[NH2:22][C:7]1([C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Cn1cc(C2(O)CCCCC2)ccc1=O
Reactant: [C-]#N
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cn1cc(C2(N)CCCCC2)ccc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Concentrated sulfuric acid (67 ml) was added dropwise over 45 minutes to a suspension of 5-(1-hydroxycyclohexyl)-1-methyl-2(1H)-pyridinone (17.2 g) and potassium cyanide (16.3 g) in 334 ml of trifluoroacetic acid at 0° C. The resulting suspension was stirred at room temperature for 18 hours, and then it was cooled to 0° C., and diethyl ether was added slowly. The solvent was decanted, and the solids were washed with diethyl ether. The product was then dissolved in methanol and neutralized with poly-4-vinylpyridine. The polymer was removed by filtration, and the filtrate concentrated to yield a foam. The foam was dissolved in methanol, acidified with ethereal hydrochloric acid and concentrated, affording 17.1 g of foam.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C([Li])CCC.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25](C(Cl)=O)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.Cl>C1COCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: -65 °C
Reaction time: 0.08 h

Procedure:
4.29 g (32.5 mmol) of monoethyl malonate is dissolved in 100 mL of THF and 42.3 mL (67.7 mmol) of butyllithium solution (1.6N in hexane) is added dropwise at −60° C. The temperature is allowed to come up to −15° C., then the mixture is cooled again to −65° C. and 3.40 g (13.5 mmol) of 4′-chlorobiphenyl-4-carboxylic acid chloride (for preparation see Gazz. Chim. Ital. 1949, 79, 453.) in 30 mL of THF is added dropwise. The mixture is kept for 5 minutes at −65° C., then heated for 2 hours to ambient temperature. The mixture is poured onto 50 mL of 1N hydrochloric acid, extracted with 300 mL of diethyl ether, and the organic phase is washed with saturated sodium hydrogen carbonate solution and water and finally dried over sodium sulfate. The solvent is eliminated, the residue is recrystallized from petroleum ether and the product is dried in vacuo. Yield: 3.10 g (76% of theory); Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate=5:2); m.p. 45° C.-50° C.; C17H15ClO3; EII mass spectrum: m/z=303/305 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(C=O)cc2)CC1

Procedure:
To N-t-butyloxycarbonylpiperidin-4-ylmethanol (7.87 g, 36.5 mmol), p-hydroxybenzaldehyde (4.46 g, 36.5 mmol) and PPh3 (9.59 g, 36.5 mmol) in THF (100 mL) at -20° C. was added DEAD (5.75 mL, 36.5 mmol) in THF (50 mL) according to Example 1, Part B, affording 8.14 g (70%); mp: 115.6°-116.8° C.; 1H NMR (300 MHz, CDCl3) δ 9.86 (s, 1H), 7.81 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.15 (bd, J=13.2 Hz 2H), 3.87 (d, J=6.6 Hz, 2H), 2.74 (dt, J=12.4, 1.8 Hz, 2H), 1.97 (m, 1H), 1.81 (bd, J=12.8 Hz, 2H), 1.45 (s, 9H), 1.27 (dq, J=12.1, 4.0 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(#N)C>[CH:13]1([NH:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A solution of 4-chloro-3-nitrobenzonitrile (5.28 g, 28.9 mmol), cyclohexylamine (5.0 mL, 43.7 mmol), and triethylamine (6.0 mL, 43.0 mL) in acetonitrile (75 mL) was stirred at 50° C. for 15 h. The reaction mixture was cooled to rt and then poured into 100 mL ice water. The solid precipitate was filtered, washed with water, and dried to afford compound 3 as a yellow solid (6.42 g, 90%). ESI-MS m/e 246.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2([C:15]3[CH:14]=[CH:13][S:12][C:11]=3[CH2:10][CH2:9][CH2:8]2)[N:4]=[C:3]1SC.[I-].[NH4+:19].N>CO>[NH2:19][C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]2([C:15]3[CH:14]=[CH:13][S:12][C:11]=3[CH2:10][CH2:9][CH2:8]2)[N:4]=1
Reactant: CSC1=NC2(CCCc3sccc32)C(=O)N1C
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CO
Product: CN1C(=O)C2(CCCc3sccc32)N=C1N

Procedure:
1′-Methyl-2′-(methylthio)-6,7-dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazol]-5′(1′H)-one (1.5 g, 5.63 mmol), ammonium iodide (4.89 g, 33.78 mmol) and 7 N ammonia in methanol (20 mL) were heated at 90° C. for 12 h. The solvent was then evaporated under reduced pressure and the residue was partitioned between water and dichloromethane. The dichloromethane extracts were combined, dried over magnesium sulphate and evaporated under reduced pressure to give an oil. This consisted of the title compound as the major component and its minor regioisomer in a 2:1 ratio. The oil was loaded onto a Biotage SNAP cartridge and eluted with dichloromethane-dichloromethane/7N ammonia in methanol (9:1). The appropriate fractions were combined and evaporated under reduced pressure to give 2′-amino-1′-methyl-6,7-dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazol]-5′(1′H)-one as a foam (800 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:4]=2[N:3]=1.Cl>CCO.O1CCOCC1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCOC)cc3C)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Reaction time: 3 h

Procedure:
Ethyl 3-(5-amino-2-(4-(methoxymethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-12) (1.0 equiv.) was dissolved in EtOH (0.2 M), then added a solution of 4M HCl in dioxane (0.2 M). The product precipitated out as a yellow salt. After stirring for 3 hours, the reaction was poured into a stirring solution of ether. The mixture was stirred for 10 minutes, then filtered and washed with ether. Ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-13) was obtained as a yellow solid which was dried on vacuum overnight (bis-HCl salt). Alternatively, the crude product was purified by Combiflash using 0-5% MeOH in DCM to give the free base.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1)#[N:20]>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2ccc(C#N)cn2)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=386.2 [M+H]+.
Reaction SMILES: [F:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:3][OH:4].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:11][C:7]1[CH:6]=[C:5]([C@H:2]([F:1])[CH2:3][O:4][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:10]=[CH:9][CH:8]=1
Reactant: OC[C@H](F)c1cccc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](F)c2cccc(Br)c2)cc1
Temperature: 25 °C

Procedure:
A solution of (R)-2-fluro-2-(3-bromophenyl)-1-ethanol (5 mmol) and p-toluenesulfonyl chloride (5.1 mmol) in CH2Cl2 at ice bath temperatures is treated with stirring with pyridine. The reaction mixture is heated at reflux temperature under a nitrogen atmosphere for 16 h, cooled to room temperature, washed with 10% HCl, saturated NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to give toluene4-sulfonic acid (S)-2-(3-bromophenyl)-2-fluoro-ethyl ester.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:9][CH:8]=1.C1COCC1.O>CO>[N:15]1([C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:20])=[O:5])=[CH:8][CH:9]=2)=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(C(=O)N2CCCC2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
DIPEA (1.26 g, 9.7 mmol) was added to a stirred solution of terephthalic acid monomethyl ester (500 mg, 2.77 mmol) in DMF (3 mL) followed by HOBt (410 mg, 3.0 mmol) and EDCI (1.32 g, 7.0 mmol). After 2 minutes of stirring, pyrrolidine (215 mg, 3.0 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with cold water, the precipitate was collected to afford 53 mg (81.9% Yield) of 4-(pyrrolidine-1-carbonyl)-benzoic acid methyl ester. LiOH.H2O (285 mg, 6.8 mmol) was added to a solution of 4-(pyrrolidine-1-carbonyl)-benzoic acid methyl ester (530 mg, 2.27 mmol) in a mixture of methanol (2 mL), THF (6 mL) and H2O (2 mL). The reaction mixture was stirred at ambient temperature for 3 hrs. The reaction mixture was concentrated, the residue was diluted with water, and acidified with conc. HCl. The solid was filtered and dried to afford 41 mg (82.32% Yield).
Reaction SMILES: [CH:1]([NH:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].Br[CH2:9][CH2:10][CH2:11][Cl:12]>CC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH3:5]
Reactant: ClCCCBr
Reactant: CNC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)N(C)CCCCl
Yield: 57.3 %

Procedure:
Isopropylmethylamine (4 g, 56 mmol), acetone (12 ml, 3 vol), 5M NaOH solution (13.44 ml, 1.2 eq.) and 1-bromo-3-chloropropane (13.22 g, 84 mmol, 1.5 eq.) were reacted together according to general procedure A to give the title compound (4.8 g, 66%) as a colourless oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:13][CH2:14][C@H:15]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(O)cc3)CC2)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(OC(C)=O)cc3)CC2)CC1

Procedure:
8 g of acetyl chloride is added to a solution of 30 g of trans-1-p-hydroxyphenyl-4-(trans-4-propylcyclohexyl)-cyclohexane and 20 ml of pyridine in 300 ml of toluene and the mixture is warmed to 80° for 1 hour. After cooling and customary working up, trans-1-p-acetoxyphenyl-4-(trans-4-propylcyclohexyl)-cyclohexane is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])[C:3]([OH:5])=[O:4].[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:16]([O:11][C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][CH2:6][C:2]([CH3:15])([CH3:1])[C:3]([OH:5])=[O:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(CCCC(C)(C)C(=O)O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(CCCC(C)(C)C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 35.5 %

Procedure:
At room temperature, 34 mg of p-toluenesulfonic acid was added to a mixture of 4.33 g of 2,2,6,6-tetramethylpimelic acid (mfd. by Tokyo Kasei (TCI), Japan), 4.24 g of benzyl alcohol and 16 ml of toluene. By equipping with a Dean-Stark type dehydration tube, this was stirred for 60Hours while heating under reflux, and then cooled down to room temperature. The insoluble matter was removed by filtration, the filtrate was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (methanol-chloroform) to obtain 2.18 g of 7-(benzyloxy)-2,2,6,6-tetramethyl-7-oxoheptanoic acid as a colorless oily substance. FP: 307.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=1[CH3:22])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>>[C:25]([O:21][C:17]1[CH:16]=[C:15]([CH3:22])[C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11])=[C:19]([CH3:20])[CH:18]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1cc(C)c(CC(NC(=O)OC(C)(C)C)C(=O)O)c(C)c1
Reaction time: 2 h

Procedure:
To a solution of 0.77 g (2.5 mmol) of 2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid and 3 mL of 3N sodium hydroxide solution, cooled in an ice bath, was added 0.89 mL (9.4 mmol) of acetic anhydride dropwise over about 30 seconds. After stirring for 2 hours, the mixture was acidified with addition of 4.5 mL of 2N hydrochloric acid. The mixture was extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate and concentrate to a clear oil. The title product was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][N:3]=1.[C:11]([NH:14][NH2:15])(=[O:13])[CH3:12].C(O)C>CCCCCC>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=[N:15][NH:14][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(=O)NN
Reactant: CC(=O)c1ccc(C)nc1
Solvent: CCO
Solvent: CCCCCC
Product: CC(=O)NN=C(C)c1ccc(C)nc1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
A mixture of 6.76 gm (0.05 mole) of 2-methyl-5-acetylpyridine, 3.7 gm (0.05 mole) of acetic acid hydrazide and 100 ml of ethanol was refluxed 5 hr. The solution was diluted with Skellysolve B until cloudy. The mixture was cooled to room temperature and then chilled in the freezer. The product was collected, washed with Skellysolve B and dried to afford 7.93 gm (83%) of the title compound having a melting point of 178.5° C.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH2:20][CH3:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.C(=O)([O-])O.[Na+].[CH2:27]([NH2:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:20]([C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]2[CH:3]1[CH2:2][N:33]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:6]2=[O:8])[CH3:21]
Reactant: CCCCCCN
Reactant: CCOC(=O)C1C(CCl)C1(CC)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCCN1CC2C(C1=O)C2(CC)c1cccc([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 33.1 %

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-ethyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 16, 4.0 g, 12.8 mmol), was added sodium hydrogen carbonate (1.3 g, 15.4 mmol) and hexylamine (15.3 g, 20 ml, 151 mmol). The mixture was heated to 150° C. for 12 h, then cooled to room temperature and partitioned between hydrochloric acid (2N, 500 ml) and ethyl acetate (2×500 ml). The combined organic layers were washed with water (500 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (200 g) column chromatography eluting with a gradient of dichloromethane/ethyl acetate 100:0 to 90:10. Product-containing fractions were combined and concentrated in vacuo to give the title compound as an orange oil (1.4 g, 32%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C:6]1[CH:16]=[C:13]([O:14][CH3:15])[C:11]([OH:12])=[C:8]([O:9][CH3:10])[CH:7]=1)[C:2]#[CH:3].[CH2:18](Br)/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21]>>[CH2:1]([O:4][C:5](=[O:17])[C:6]1[CH:16]=[C:13]([O:14][CH3:15])[C:11]([O:12][CH2:18][CH:19]=[C:20]([CH3:21])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[C:8]([O:9][CH3:10])[CH:7]=1)[C:2]#[CH:3]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: C#CCOC(=O)c1cc(OC)c(O)c(OC)c1
Product: C#CCOC(=O)c1cc(OC)c(OCC=C(C)CCC=C(C)C)c(OC)c1

Procedure:
By utilizing the procedure of Example 1 by reacting syringic acid propargyl ester with geranyl bromide, there is obtained 4-[(3,7-dimethyl-2,6-octadienyl)oxy]-3,5-dimethoxy benzoic acid propargyl ester; nD21 = 1.5320
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23]([C:28]([NH:30][CH:31]2[CH2:33][CH2:32]2)=[O:29])[N:22]=[N:21]1)C1C=CC=CC=1>CO.[C].[Pd]>[CH:31]1([NH:30][C:28]([C:23]2[N:22]=[N:21][N:20]([C:10]3[CH:11]=[CH:12][C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:9]=3[OH:8])[C:24]=2[CH2:25][CH2:26][CH3:27])=[O:29])[CH2:33][CH2:32]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCC)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCC)cc1O
Yield: 87.7 %

Procedure:
1-{2-(Benzyloxy)-4-[(ethylamino)carbonyl]phenyl}-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide compound (582 mg, 1.30 mmol) obtained in Example 312 was dissolved in methanol (20 ml), and the mixture was stirred at room temperature for 4 hr in the presence of 10% palladium carbon (wet, purity 50%, 116 mg) under a hydrogen atmosphere. The reaction mixture was filtrated to removed the catalyst, and the filtrate was concentrated to dryness to give a yellow oil. This was subjected to column chromatography (elution solvent, ethyl acetate-hexane=1:2-7:3) on silica gel (manufactured by E. Merck, Art.7734, 10 g), and the object fraction was concentrated and diluted with ethyl acetate-diethyl ether. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (409 mg, 1.14 mmol, 88.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:16])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(O)ccc1-c1ccccc1
Reactant: OCCCCCCCCBr
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCCCCCCCCO)ccc1-c1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
3-Nitro-4-phenylphenol (860 mg, 4.0 mmol) was dissolved in N,N-dimethylformamide (40 mL), followed by addition of 8-bromo-1-octanol (1.86 g, 6.0 mmol). After stirring at 50° C. for 5 hours, the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 8-(3-nitro-4-phenylphenoxy)octan-1-ol (1.23 g).