Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O-:3])=[O:2].[Li+].C(N(C(C)C)CC)(C)C.C(OC(=O)C)(=O)C.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:39]3[CH:40]=[C:41]([C:45]4[N:49]([CH3:50])[C:48]5[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=5[N:46]=4)[CH:42]=[C:43]([CH3:44])[C:38]=3[N:37]=[C:36]2[CH2:55][CH2:56][CH3:57])=[CH:30][CH:29]=1.[Li+].[Cl-]>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:57][CH2:56][CH2:55][C:36]1[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]3[CH:22]=[CH:27][CH:26]=[CH:25][C:24]=3[C:1]([OH:3])=[O:2])=[CH:33][CH:32]=2)[C:39]2[CH:40]=[C:41]([C:45]3[N:49]([CH3:50])[C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=4[N:46]=3)[CH:42]=[C:43]([CH3:44])[C:38]=2[N:37]=1
Reactant: O=C[O-]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of lithium formate (262 mg, 3 eq), diisopropylethylamine (DIEA; 0.58 mL, 2 eq), acetic anhydride (0.32 mL, 2 eq) in anhydrous dimethylformamide (DMF; 2 mL) was stirred at room temperature for 1 hour. Then, 3′-(2′-iodo-biphenyl-4-ylmethyl)-1,7′-dimethyl-2′-propyl-1H,3′H-[2,5′]bibenzoimidazolyl (1 g, 1.68 mmol), Pd2(dba)3 (38 mg, 0.025 eq, dba is dibenzylideneacetone), LiCl (211 mg, 3 eq) in anhydrous DMF (4 mL) were added. The reaction mixture was stirred at 80° C. for 3 h, filtered and after cooling poured into 1.2 mL of water, stirred for 15 minutes, product filtered, washed with water and dried in vacuo to yield telmisartan.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:11](I)[CH3:12]>C(O)C>[CH2:11]([S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[CH3:12]
Reactant: Oc1ccc(S)cc1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCSc1ccc(O)cc1

Procedure:
4-(Ethylthio)phenol was prepared as follows. Sixty grams of 4-mercaptophenol were dissolved in 50 milliliters of ethanol. To the solution was added 27 grams of potassium hydroxide dissolved in 150 milliliters of ethanol. Seventy-four grams of ethyl iodide were added at 20° C. to 32° C. over a thirty minute period. The flask contents were stripped to remove the solvent. Benzene was added and the reaction product was water washed. The reaction product was stripped to remove a trace of the 4-mercaptophenol. The product weighed 66 grams.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C[Al](C)C.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>>[CH2:25]([N:22]1[CH2:23][CH2:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:11])=[CH:14][CH:15]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)[CH2:20][CH2:21]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCNCC
Reactant: COC(=O)c1ccc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)cc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN(CC)C(=O)c1ccc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of diethyl amine (1.88 mL, 18.2 mmol) in CH2ClCH2Cl (7 mL) at room temperature was added a trimethylaluminum (9.1 mL, 18.2 mmol, 2M in hexanes) dropwise. The reaction mixture was stirred at room temperature for 1 hour. A solution of of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid methyl ester (1.51 g, 3.64 mmol) in (CH2)2Cl2 (6 mL) was added and the reaction mixture was heated to reflux for 14 hours. The solution was then cooled 0° C. and sat. aqueous NaHCO3 (15 mL) was added dropwise. The mixture was filtered through celite. The celite cake was washed with CH2Cl2 (40 mL). The organic layer was separated and the aqueous layer was washed with CH2Cl2 (3×30 mL). The combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography with EtOAc to afford 1.4 g (84% yield) of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide. 1HNMR (400 MHz, CDCl3) δ 7.28-7.16 (comp, 10H), 6.84-6.80 (comp, 2H), 6.68 (dd, 1H), 3.74 (s, 3H), 3.52-3.48 (comp, 2H), 3.39 (s, 2H), 3.24-3.21 (comp, 2H), 2.47-2.42 (comp, 8H), 1.22-1.20 (comp, 3H), 1.19-1.16 (comp, 3H); MS (M+1) 457.2.
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]=1[C:11]1[NH:13][C:14]3[C:19]([C:10]=1[CH2:9][CH2:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:2].[CH2:20]=[O:21].O>CC(C)=O>[CH2:1]([C:3]1([CH2:20][OH:21])[C:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:11]=2[N:13]=[C:14]2[C:19]=3[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: C=O
Reactant: CCC1=C2c3[nH]c4ccccc4c3CCN2CCC1
Solvent: CC(C)=O
Solvent: O
Product: CCC1(CO)CCCN2CCC3=c4ccccc4=NC3=C21
Temperature: 25 °C

Procedure:
37.8 g (0.15 moles) of 1-ethyl-2,3,4,6,7,12-hexahydro-indolo[2,3-a]quinolizine are dissolved in 100 ml of acetone, 5 g of paraformaldehyde are added thereto and the mixture is stirred at room temperature for an hour and a half. Then 30 ml of distilled water are added to the mixture within 15 minutes and the stirring is continued for another hour at O° C. The precipitated title compound obtained in the form of orange-colored crystals is filtered off and washed in two portions under altogether 20 ml of acetone, at 0° C. Weight: 34.13 g (80.7%), melting point: 111°-113° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1)[CH2:14][CH3:15]
Reactant: CCCBr
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(CC(C)=O)cc1
Yield: 79.2 %

Procedure:
A suspension of 15.0 g of 1-(4-hydroxyphenyl)-2-propanone, 24.6 g of 1-bromopropane and 13.8 g of potassium carbonate in 100 ml of N,N-dimethylformamide was heated for 4 hours at 65°-70° C. After cooling, the reaction mixture was poured into water and extracted with ether. The extract was washed with water, dried and evaporated. The residue was distilled to give 15.2 g of the desired compound as a pale yellow oil, b.p.136°-138° C. (7 mmHg).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1.Cl.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:22]1[CH2:23][CH2:24][CH2:25][CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:13])[CH2:21]1
Reactant: Cc1ccccc1C1CCCNC1
Reactant: BrCC1COc2ccccc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccccc1C1CCCN(CC2COc3ccccc3O2)C1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (35 mg, 0.15 mmol), 3-(2-methylphenyl)piperidine.HCl (35 mg, 0.16 mmol) and triethylamine (38 mg, 0.38 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 140-150° C. for 12.5 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 29 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Br:23]Br>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:15])([F:16])[F:14])=[C:8]([Br:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc(C(F)(F)F)nc1N
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Intermediate B) (30 mg, 0.13 mmol) in acetic acid (5 ml), sodium carbonate (15 mg, 0.14 mmol) was added. To this mixture, half the contents of a solution of bromine (7 μL, 0.13 mmol) in acetic acid (5 ml) were added, followed by the addition of sodium carbonate ((15 mg, 0.14 mmol). The remaining solution of bromine in acetic acid was added and the reaction mixture was left to stir at RT for 2 hours. The mixture was diluted with water and the resulting yellow precipitate was filtered under vacuum to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33]CC)=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:37])([F:36])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.CO.O.[OH-].[Li+]>CC#N.Cl.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([OH:33])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:37])([F:36])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](O)CN2C1=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
To (2R,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-2-hydroxy-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 7i, 900 mg, 1.693 mmol) was added tetrahydrofuran (5.6 ml), methanol (2.80 ml) and water (2.80 ml). Lithium hydroxide monohydrate (145.44 mg, 3.47 mmol) was added at room temperature, and the reaction mixture was stirred at 40° C. for 16 h. The reaction mixture was diluted with CH3CN and neutralized with HCl (2 N, 1.7 ml). The mixture was concentrated under reduced pressure and azeotroped with chloroform followed by ethyl acetate and dried overnight at reduced pressure to provide the title compound (850 mg, quantitative yield). This material was utilized in subsequent reactions without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:31](O)[CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][OH:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][OH:39])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: OCCOCCOCCO
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCCOCCOCCO)cc4CCC3C2C2CCCC2)cc1Cl
Yield: 47 %

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and triethylene glycol according to Method E (yellow solid, 125 mg, 0.226 mmol, 47% yield). ES-HRMS m/z calc. for C30H34ClN3NaO5 (M+Na) 574.2085, found 574.2047.
Reaction SMILES: [Si]([Cl:5])(C)(C)C.[CH3:6][N:7]([CH3:36])[C:8]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:13][CH2:12][CH:11]([NH:14][C@@H:15]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[C:16]([NH:18][CH3:19])=[O:17])[CH2:10][CH2:9]1>CC(CC)=O>[ClH:5].[ClH:5].[CH3:36][N:7]([CH3:6])[C:8]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:13][CH2:12][CH:11]([NH:14][C@@H:15]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[C:16]([NH:18][CH3:19])=[O:17])[CH2:10][CH2:9]1
Reactant: C[Si](C)(C)Cl
Agent: CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC1CCC(c2ccccc2)(N(C)C)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
Me3SiCl (0.17 ml, 1.26 mmol) was added to a solution of (S)-2-(4-(dimethylamino)-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-N-methylpropanamide (210 mg, 0.5 mmol, polar diastereomer from step 3) in ethyl methyl ketone (20 ml). The solid was aspirated after a reaction time of 1 h.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[CH2:22]([C:24]([C:33]1[CH:46]=[CH:45][C:36]([O:37][CH2:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[C:35]([CH3:47])[CH:34]=1)([C:27]1[S:28][CH:29]=[C:30]([CH3:32])[CH:31]=1)[CH2:25][CH3:26])[CH3:23].CO.Cl>C1COCC1>[CH2:22]([C:24]([C:33]1[CH:46]=[CH:45][C:36]([O:37][CH2:38][CH:39]([OH:44])[C:40]([CH3:41])([CH3:43])[CH3:42])=[C:35]([CH3:47])[CH:34]=1)([C:27]1[S:28][CH:29]=[C:30]([CH3:32])[CH:31]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a mixture of (R)-2-methyl-CBS-oxazaborolidine (0.1 ml, 0.1 mmol, 1M in toluene), borane-N,N-dimethyl aniline complex (0.18 ml, 1 mmol) in THF (5 ml) is added a solution of 1-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (372 mg, 1 mmol) in THF (5 ml) over a period of m. The reaction is stirred at RT for 2 h and MeOH (2 ml) is added followed by 1N hydrochloric acid. The mixture is extracted with EtOAc and the organic phase is concentrated and chromatographed (Hex to 25% EtOAc/Hex) to give the title compound (305 mg, 82%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>O>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH2:16][CH2:17]1
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: C1COCCN1
Solvent: O
Product: CC(=O)c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
1-(4-Fluoro-3-(trifluoromethyl)phenyl)ethanone (510.0 mg, 2.5 mmol) and morpholine (724.2 mg, 8.31 mmol) were placed in a screw cap pressure tube. The tube was sealed and the mixture heated to 100° C. for 20 hours. The mixture was allowed to cool. H2O was added and the product extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (Pet. Ether/EtOAc 4:1→3:2) to give 541.0 mg (84%) of the title substance
Reaction SMILES: C(O)=O.[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C@H:12]1[CH2:24][O:25]CC1C=CC=CC=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO.[Pd]>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@H:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[C@H:12]1[CH2:24][OH:25])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Yield: 98.4 %

Procedure:
0.4 ml of formic acid were added to a solution of 800 mg (1.90 mmol) of (2R,3S)-1-t-butoxycarbonyl-2-benzyloxymethyl-3-t-butyldimethylsilyloxypyrrolidine [which had been prepared from 1-t-butoxycarbonyl-D-seline benzyl ether in a similar manner to that described by W. R. Ewing et al. in Heterocycles, 27, 2843 (1988)] in 8 ml of methanol, and the mixture was stirred for 3 hours in the presence of 400 mg of palladium black under an atmosphere of hydrogen. At the end of this time, the catalyst was filtered off, and the filtrate was freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 6:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 620 mg of the title compound as an oil.
Reaction SMILES: [C:1]1([C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Li+].[CH3:16][CH:17]([N-]C(C)C)[CH3:18].[Li]CCCC.C(NC(C)C)(C)C.BrCC=C>C1COCC1>[C:1]1([C:7](=[O:12])[CH2:8][C:9](=[O:11])[CH2:10][CH2:18][CH:17]=[CH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [H-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: C=CCBr
Product: C=CCCC(=O)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-phenylbutane-1,3-dione (5 g, 30.8 mmol) in THF (50 mL) was added sodium hydride (0.740 g, 30.8 mmol) at 0° C. After warming and stirring at room temperature for 30 min, LDA, which was made by adding BuLi (1.975 g, 30.8 mmol) to a solution of diisopropylamine (4.39 mL, 30.8 mmol) in THF (50 mL) at −45° C., was added at 0° C. After stirring for 30 min at the same temperature, 3-bromoprop-1-ene (3.73 g, 30.8 mmol) was added at 0° C. After stirring for 1 h, the reaction was quenched with 1.0 M HCl and extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure to give the title compound without further purification. LCMS m/z=203.19 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.[Br:20][C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>CN(C=O)C.N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:27][C:24]4[CH:25]=[N:26][C:21]([Br:20])=[CH:22][CH:23]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1ccc(Br)nc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)nc1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 60 °C
Yield: 47.7 %

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (9.50 g, 46.00 mmol), thionyl chloride (10.00 mL, 138.00 mmol) and DMF (4 drops) were added and the mixture was stirred and heated at 60° C. for thirty minutes. The excess thionyl chloride was evaporated under reduced pressure. A portion of the acid chloride (23.20 mmol) was dissolved in pyridine (15 mL) and was slowly added to 6-bromopyridin-3-amine (23.20 mmol) in pyridine (10 mL). The reaction mixture was stirred at 110° C. for one hour and thirty minutes. The pyridine was evaporated under reduced pressure. The resulting mixture was dissolved in dichloromethane (200 mL) and washed with 1 N NaOH (4×50 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-3-yl)cyclopropanecarboxamide (4 g, 48%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].ClCCl.C([Zn][CH2:28][CH3:29])C>CCCCCC>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH:13]1[CH2:14][CH:15]1[CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:28][CH3:29]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCC1CC1CC1CC1CCCCCCCC(=O)OC
Reaction time: 1 h

Procedure:
To a mixture of linoleic acid methyl ester (2.5 g) and dichloromethane (50 ml), a 0.99M solution of diethylzinc (103 ml) in n-hexane was added under a nitrogen atmosphere. The mixture was cooled in an ice-water bath (−5° C. to 0° C.) and stirred for 1 hour at this temperature. Diodomethane (16.4 ml) was added to the mixture, and the mixture was stirred at ambient temperature overnight. After evaporation in vacuo of the solvent, the reacting mixture was dissolved in a mixture of ethyl acetate (EA) and a saturated aqueous solution of ammonium chloride. The separated organic layer was washed with water and dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo. The obtained residue was purified by chromatography on silica gel (eluted with 1% EA in n-hexane). The fractions including 8-(2-((2-pentyl-cyclopropan-1-yl)methyl)cyclopropyl)octanoic acid methyl ester were collected and concentrated in vacuo to give 8-(2-((2-pentylcyclopropan-1-yl)methyl)cyclopropyl)octanoic acid methyl ester (2.81 g) as an oil.
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=3)[C:24]([NH2:26])=[O:25])[CH:17]=2)[O:12][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5]1.[CH:28]1([C:31]2[N:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([C:41](O)=[O:42])[CH:37]=[C:36]3[O:44][CH2:45][CH2:46][OH:47])[CH2:30][CH2:29]1.C1(C2C3C(=C(OC)C=C(C(O)=O)C=3)C=CN=2)CC1>>[CH:28]1([C:31]2[N:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([C:41]([N:9]2[CH2:10][CH2:11][C:6]4([CH2:5][C:4](=[O:3])[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([C:19]6[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=6)[C:24]([NH2:26])=[O:25])[CH:17]=5)[O:12]4)[CH2:7][CH2:8]2)=[O:42])[CH:37]=[C:36]3[O:44][CH2:45][CH2:46][OH:47])[CH2:29][CH2:30]1
Reactant: O=C(O)c1cc(OCCO)c2ccnc(C3CC3)c2n1
Reactant: NC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Agent: COc1cc(C(=O)O)cc2c(C3CC3)nccc12
Agent: Cl
Product: NC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OCCO)c5ccnc(C6CC6)c5n4)CC2)O3)c1

Procedure:
The intended compound was produced according to the procedure described in reference Example 37 but using 5-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinamide di-hydrochloride and 8-cyclopropyl-4-(2-hydroxy-ethoxy)-[1,7]naphthyridine-2-carboxylic acid in place of methyl 5-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinate di-hydrochloride and 1-cyclopropyl-5-methoxyisoquinoline-7-carboxylic acid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.99 (2.0H, dd, J=10.6, 2.1 Hz), 8.48-8.45 (1.0H, m), 8.42 (1.0H, d, J=5.6 Hz), 8.28 (1.0H, br s), 8.11 (1.0H, d, J=2.4 Hz), 8.06 (1.0H, dd, J=8.5, 2.4 Hz), 7.81 (1.0H, d, J=5.6 Hz), 7.64 (1.0H, br s), 7.38 (1.0H, s), 7.29 (1.0H, d, J=8.5 Hz), 5.06 (1.0H, t, J=5.6 Hz), 4.39-4.30 (3.0H, m), 3.90-3.81 (2.0H, m), 3.80-3.70 (1.0H, m), 3.58-3.39 (2.0H, m), 3.37-3.27 (1.0H, m), 2.98 (2.0H, s), 2.17-2.06 (1.0H, m), 2.02-1.80 (3.0H, m), 1.19-1.02 (4.0H, m). MS [M+H]+=594.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[O:9]>C(=O)([O-])O.[Na+]>[OH:9][C@H:8]([CH2:1][C:2]1[CH2:6][CH2:5][CH2:4][CH:3]=1)[C:7]([O:11][CH3:12])=[O:10]
Reactant: C=C1CCCC1
Reactant: COC(=O)C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)[C@H](O)CC1=CCCC1
Temperature: -30 °C
Yield: 91.7 %

Procedure:
A solution of an (R)-binaphthol-dibromotitanium complex which had been prepared in the same manner as in Example 6 was cooled to -30° C. and added with 82 mg (1 mmole) of methylenecyclopentane (manufactured by Aldrich Corp.) and 88 mg (1 mmole) of methyl glyoxylate, followed by reaction for 3 hours. Then, 10 ml of an aqueous sodium hydrogen-carbonate solution was added to terminate the reaction. The reaction mixture was filtered through Celite and extracted with two 20 ml portions of diethyl ether and two 20 ml portions of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Thereafter, the solvents were distilled off, and hexane was added to the residue to crystallize binaphthol. The remaining solution was purified by means of silica gel column chromatography to obtain 156 mg of methyl (R)-2-hydroxy-3-(l-cyclopentenyl)propionate. The yield was 92%.