Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[C:2]#C.Cl[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:7][CH2:6][C:1]#[CH:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCOCc1ccccc1
Reactant: C#CCO
Product: C#CCOCc1ccccc1

Procedure:
Propargyl alcohol is allowed to react with chloromethylbenzyl ether to obtain 1-benzyloxy-2-propyne (1). Then, this is allowed to react with Grignard reagent and a trifluoroacetic acid ester to obtain 5-benzyloxy-1,1,1-trifluoro-3-pentyne-2-one (2). Then, this is allowed to react with hydride of boron or aluminum to obtain 5-benzyloxy-1,1,1-trifluoro-3-pentyne-2-ol (3). This is acetylated or isobutylated and thereafter lipase or lipase-producing microorganism is allowed to act thereon to obtain optically active (R)-5-benzyloxy-1,1,1-trifluoro-3-pentyne-2-ol [(R)-(3)] and optically active (S)-5-benzyloxy-1,1,1-trifluoro-2-acetoxy (or butoxy)-3-pentyne [(S)-(4)].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(OC(Cl)=O)C(C)C.O[NH:33][C:34](=[NH:47])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[O:16][N:47]=[C:34]([CH2:35][O:36][C:37]3[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=3)[N:33]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CS(=O)(=O)c1ccc(OCC(=N)NO)cc1
Agent: CC(C)COC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)no2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.06 g, 9 mmol), NEt3 (1.2 g, 12 mmol) in toluene (150 mL) was added isobutylchloroformate (1.23 g, 9 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 hours. N-hydroxy-2-(4-methanesulfonyl-phenoxy)-acetamidine (1.5 g, 6 mmol) was added to the mixture. The mixture was heated under reflux overnight, cooled and the mixture was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed. The residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.98 (2H, m), 7.14 (2H, m), 5.24 (2H, s), 4.2-4.05 (2H, m), 3.14 (1H, m), 3.03 (3H, s), 2.95 (2H, m), 2.12˜2.04 (2H, m), 1.80 (2H, m), 1.46 (9H, s).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]1[CH2:64][CH2:63][CH2:62][C@@H:61]([NH2:65])[CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][C@@H:61]5[CH2:62][CH2:63][CH2:64][N:59]([CH3:58])[CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC[C@@H](N)C1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-methylpiperidin-3-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.26 (m, 2 H) 1.29-1.46 (m, 3 H) 1.55-1.73 (m, 5 H) 1.75-1.90 (m, 6 H) 2.17 (s, 3 H) 2.63-2.69 (m, 1 H) 2.78-2.84 (m, 1 H) 3.31 (s, 3 H) 3.90-4.01 (m, 1 H) 3.94 (s, 3 H) 4.06 (t, J=12.63 Hz, 2 H) 4.41-4.51 (m, 1 H) 7.47 (dd, J=8.46, 1.64 Hz, 1 H) 7.51 (d, J=1.77 Hz, 1 H) 7.91 (s, 1 H) 8.09 (d, J=8.08 Hz, 1 H) 8.21 (s, 1 H) 8.27 (d, J=8.32 Hz, 1 H). [M+H] calc'd for C28H37F2N7O3 558; found 558.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([CH2:38][CH3:39])=[N:29][N:30]3[CH:33]3[CH2:37][CH2:36][CH2:35]C3)=[CH:26][CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([CH2:38][CH3:39])=[N:29][N:30]3[CH:33]3[CH2:35][CH2:36][CH2:37]3)=[CH:26][CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ncccn1
Reactant: CCc1nn(C2CCCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4ncccn4)[C@@H](Cc4ccccc4)C3)ccc12

Procedure:
Prepared by the method outlined for Example 189 using pyrimidin-2-yl-acetic acid and 6-((S)-3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole (Example 56, Compound 144) as starting materials. Product as an oil. LC/MS (Method B) 2.46 min, [M+1]+ 495. Potency class C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:28](=[O:29])[CH2:27][C:26](=[O:30])[NH:25][C:24]3[C:31]4[C:36]([CH:37]=[CH:38][C:23]2=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:18][CH:17]=1>ClC(Cl)C>[Cl:1][C:2]1[C:3]([C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:28](=[O:29])[CH2:27][C:26](=[O:30])[NH:25][C:24]4[C:31]5[C:36]([CH:37]=[CH:38][C:23]3=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:18][CH:17]=2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ncccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 44.9 %

Procedure:
3-Chloropyridine-2-carboxylic acid (47 mg, 0.3 mmol) was treated with thionyl chloride in dichloroethane, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63 mg, 0.2 mmol) obtained in Example 1, (3), the title compound (41 mg, yield 45%) was obtained as pale brown crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])[C:5]([CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)=[C:4]([CH3:28])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])[C:5]([CH2:17][CH2:18][CH2:19][NH2:20])=[C:4]([CH3:28])[N:3]=1
Reactant: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1CCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1CCCN
Yield: 70.5 %

Procedure:
The product from step (viii) (76 mg) was dissolved in DCM (5 mL) and TFA (5 mL) and the mixture stirred at rt for 1 h. The solvent was evaporated and the crude material dissolved in MeOH (5 mL) and purified by SCX. The product was dissolved in THF (10 mL) then lithium hydroxide (12.2 mg) in water (5 mL) was added. The reaction mixture was heated to reflux for 1 h, the solvents were evaporated and the crude product purified by RPHPLC to afford the subtitle product 40 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:17]O>>[CH3:17][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)=[O:16]
Reactant: O=C(O)CCCC(=O)c1ccc(O)c(O)c1
Reactant: CO
Product: COC(=O)CCCC(=O)c1ccc(O)c(O)c1

Procedure:
A solution of 5.6g of 5-(3,4-dihydroxyphenyl)-5-oxopentanoic acid in 300 ml of methanol is stirred together with 15g of Amberlyst 15 for 16 hours at room temperature. The reaction mixture is filtered on diatomaceous earth, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/ethyl acetate (20-60%). 3.7 g of 5-(3,4-dihydroxyphenyl)-5-oxo-pentanoic acid methyl ester of melting point 104°-106° C. is obtained.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>>[CH:19]([C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: CC(C)c1ccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 4-isopropylaniline as the starting materials.
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.[CH2:28]([Li])[CH2:29][CH2:30][CH3:31].C[C:34]1[O:35][C:36]([C:43](OC)(OC)[CH2:44]C)=[C:37](C)[C:38](=[O:41])[C:39]=1[CH3:40]>CCOCC>[CH3:28][CH:29]1[CH:30]([CH3:31])[C:34](=[O:35])[C:39]([CH3:40])=[C:38]([CH:37]=[CH:36][CH2:43][CH3:44])[O:41]1
Reactant: CCC(OC)(OC)c1oc(C)c(C)c(=O)c1C
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCC=CC1=C(C)C(=O)C(C)C(C)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
40.4 g (0.1 moles) of methyltriphenylphosphonium iodide were suspended in 400 ml of anhydrous ether under argon gas flow. After cooling the mixture to 0° C., 90 ml (0.15 moles) of a hexane solution of n-butyl lithium were dripped. 19.6 g (0.1 moles) of 2,3-dihydro-2,3,5-trimethyl-6-(2-methyl-1-oxoethyl)-4H-pyran-4-on obtained in Example 3 were added dripwise to the mixture solution, and the mixture was agitated for 1 hour to obtain 10.1 g of 2,3-dihydro-2,3,5-trimethyl-6-(3-methyl-1-propenyl)-4H-pyran-4-one. The yield was 56%.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4].Br[CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22].Cl>O.C(O)C>[C:3]([C:7]1[CH:12]=[C:11]([S:13][CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCCCC(Br)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A base solution (22 grams of NaOH in 41 milliliters (ml) of water) was added to a solution of 2,6-di-t-butyl-4-mercaptophenol (64.3 grams; 0.27 mole) in 540 ml. of absolute ethanol with stirring while cooling the reaction mixture under nitrogen. Following the base addition, a solution of 2-bromohexanoic acid (52.8 grams; 0.27 mole) in 27 ml. of ethanol was added and the resulting reaction mixture was stirred at room temperature for about 6 hours and left standing overnight. The reaction mixture was then diluted with about 400 ml. of water and acidified with cold 6N HCl. The yellow brown precipitate resulting from the acidification was obtained by filtration, washed with water and recrystallized from a methylenechloride-hexane mixture. As a result of these operations, the desired 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid compound was obtained as a white crystalline solid having a melting point of 140°-142° C. Analysis calculated for C20H32O3S: C, 68.15; H, 9.14; S, 9.10. Found: C, 68.14; H, 9.34; S, 8.86.
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].[OH-].[Na+].C(O[CH:11]1[NH:14][C:13](=[O:15])[C@H:12]1[C@H:16]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:17])(=O)C>O.CO>[CH2:1]([S:4][C@H:11]1[NH:14][C:13](=[O:15])[C@@H:12]1[C@H:16]([O:18][Si:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:17])[CH:2]=[CH2:3]
Reactant: CC(=O)OC1NC(=O)[C@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCS[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.14 ml of allyl mercaptan and 0.4 g of sodium hydroxide in 25 ml of water under an argon atmosphere was added a solution of 2.87 g of 4-acetoxy-3(S)-[1(R)-{dimethyl-{2-methylprop-2-yl}silyloxy}ethyl]azetidin-2-one in 10 ml of methanol. After 30 minutes, the mixture was partitioned between dichloromethane and water. The separated organic layer was washed with water, was dried over magnesium sulphate, evaporated to dryness, and then chromatographed on silica gel. Elution with ethyl acetate/hexane mixtures afforded 1.8 g of the title compound as white crystals.
Reaction SMILES: C1([C@H]([NH:9][C@@H:10]2[C:19]3[CH2:18][O:17][CH:16]=[CH:15][C:14]4=[CH:20][NH:21][CH:22]=[C:12]([C:13]=34)[CH2:11]2)C)C=CC=CC=1.[H][H]>O1CCCC1.[OH-].[Pd+2].[OH-]>[CH:22]1[NH:21][CH:20]=[C:14]2[CH:15]=[CH:16][O:17][CH2:18][C:19]3[C@@H:10]([NH2:9])[CH2:11][C:12]=1[C:13]2=3
Reactant: C[C@@H](N[C@H]1CC2=CNC=C3C=COCC1=C32)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: N[C@H]1CC2=CNC=C3C=COCC1=C32
Yield: 86 %

Procedure:
Compound (29) 609 mg was dissolved in tetrahydrofuran 20 ml. 20% Palladium(II)hydroxide 200 mg was added. A mixture was stirred in a hydrogen atomosphere for 22 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform to give the titled compound (31) as pale brown crystals, 337 mg. Yield 86%. Furthermore, this was recrystallized from methanol-isopropanol to give the titled compound (31) as pale brown crystals, m.p. 202-203° C.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:19])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[C:12]([OH:18])[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27]Cl)[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][O:17][C:16]2[C:15]3[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=3)[O:9][C:8](=[O:19])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:22][CH2:21]1
Reactant: O=c1oc2cc(O)ccc2c(O)c1-c1ccccc1
Reactant: ClCCN1CCOCC1
Product: O=c1oc2cc(O)ccc2c(OCCN2CCOCC2)c1-c1ccccc1
Yield: 77.6 %

Procedure:
Following the method of Example 30, 30.5 g. (0.12 mol) of 3-phenyl-4,7-dihydroxy-coumarin are treated with 19.5 g. (0.13 mol) of 2-morpholino-1-chloroethane. 34 g. of an oil are obtained, which cannot be crystallised. Yield 77.6% (theoretical yield 44.7 g.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30].C(OCC)C>O1CCCC1>[Br:30][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: BrCCc1ccccn1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of 2-pyridineethanol (1.00 ml) in tetrahydrofuran (20 ml) were successively added triphenylphosphine (3.51 g) and carbon tetrabromide (4.44 g) with stirring at room temperature, and the resulting mixture was stirred at room temperature overnight. After stirring, to the reaction mixture was added diethyl ether, and insoluble materials were filtered off, and the organic layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (1:3) as the eluent to afford the title compound (1.30 g, yield: 78%) as a yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Cl>>[CH:1]1[C:10]2[C@H:11]3[CH2:16][N:15]([CH2:28][CH2:27][CH2:26][C:25]([C:19]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=4[NH2:17])=[O:30])[CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Reactant: Nc1cc(F)ccc1C(=O)CCCCl
Product: Nc1cc(F)ccc1C(=O)CCCN1CC[C@@H]2[C@H](C1)c1cccc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 402 as a red oil (99 mg, 54%) from (±)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (100 mg, 0.47 mmol) and 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (152 mg, 0.70 mmol). 1H NMR (CDCl3, 300 MHz) δ 1.95–2.15 (m, 7H), 2.37–2.57 (m, 5H), 2.67–2.85 (m, 3H), 2.90–3.05 (m, 3H), 3.24–3.33 (m, 2H), 6.27–6.39 (m, 2H), 6.41–6.50 (br, 2H), 6.64 (t, J=7.3 Hz, 1H), 6.85–6.94 (m, 2H), 7.77 (dd, J=9.2, 6.6 Hz, 1H) ppm.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([OH:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+:25].[K+]>CC(C)=O.O>[CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O-:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:3])[CH3:4].[K+:25]
Reactant: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)[O-]
Temperature: 25 °C
Yield: 163.7 %

Procedure:
The (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylic acid (4.83 g) prepared in Example 6 or 7 was dissolved in acetone (23 mL), and potassium carbonate (1.11 g) dissolved in water (4.5 mL) was slowly added. The solution was stirred at room temperature until the deposited inorganic salt was dissolved. While the solution was heated at 50° C. in a bath, acetone (100 mL) was dropped and a seed crystal was placed in the solution, and then the solution was stirred for 30 minutes, Acetone (94 mL) was again dropped, and the solution was stirred for 1 hour while the temperature was kept. While gradually cooled to room temperature, the solution was stirred overnight. The precipitated crystalline product was collected by filtration, washed with a mixture of 2% water-acetone (20 mL), dried in air to obtain white solid potassium (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (4.28 g, 81.7%). The NMR data of the solid product were the same as those in Example 11.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC#N>[CH2:18]([O:11][C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH:10]=[CH:9][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCCCc1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3-hydroxypropyl)phenol (1.27 g) in MeCN (12.7 mL) were added K2CO3 (1.73 g) and benzyl bromide (1.05 mL) at ambient temperature and the mixture was stirred at 60° C. for 16 hours. Water (15 mL) was added to the mixture at ambient temperature and the resulting mixture was extracted with EtOAc (20 mL, two times). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=3:1) to afford 3-[3-(benzyloxy)phenyl]-1-propanol (1.77 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[NH:8][CH:7]=[CH:6]2.P(Cl)(Cl)([Cl:17])=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:17][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc[nH]c(=O)c2cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2ccnc(Cl)c2cc1C
Temperature: 100 °C

Procedure:
A suspension of 6-methoxy-7-methyl-2H-isoquinolin-1-one (5 g, 26.45 mmol) was treated at room temperature with phosphorus oxychloride (22 ml). The mixture was heated at 100° C. for 1 h with stirring then concentrated in vacuo to give a residue. Toluene was added to the residue which was further concentrated in-vacuo to give a residue which was taken up in toluene and slowly added to saturated aqueous sodium carbonate. The toluene layer was then separated. The aqueous layer was further mixed and extracted with toluene. The combined toluene layers were dried (MgSO4) and concentrated in vacuo to give a residue. The residue was triturated with diethyl ether then filtered and dried in vacuo to give 1-chloro-6-methoxy-7-methyl-isoquinoline (4 g, 19.32 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.[Mg+2].[Cl-].[Cl-].[CH2:16]=[O:17].Cl>C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:5]([OH:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1)[CH:16]=[O:17]
Reactant: C=O
Reactant: Cc1cc(O)c(C(C)C)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cc1c(Cl)cc(C(C)C)c(O)c1C=O
Yield: 100.7 %

Procedure:
To a solution of 4-chloro-2-isopropyl-5-methylphenol (5.00 g, 27.08 mmole) in anhydrous acetonitrile (150 mL) was added MgCl2 (3.87 g, 40.61 mmole), TEA (10.28 mL, 101.55 mmole) and paraformaldehyde (5.48 g, 182.79 mmole), and the resulting mixture was refluxed under a dry N2 atmosphere for 18 hrs. The mixture was then cooled, acidified with 2.4 N HCl and extracted with EtOAc (2×250 ml). The combined extracts were washed with brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo to give dark orange oil which was subjected to flash chromatography (silica gel) and eluted with 25% hexane/ CH2Cl2 to yield 5.8 g (99% yield) of the product as a pale yellow oil. GCMS m/z 212.0 (M+). This ester was of suitable purity to use without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([OH:8])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(O)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1(OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 43.6 %

Procedure:
1-Hydroxy-cyclopropanecarboxylic acid methyl ester (Acros; 1.00 g, 8.61 mmol) in 24 mL of THF was stirred with 516 mg (12.9 mmol) of NaH (60% in mineral oil) for 10 min. Benzyl bromide (1.13 mL, 9.37 mmol) and Bu4I (0.32 g, 0.85 mmol) were then added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with saturated NH4Cl. The wash was extracted once with EtOAc, and the combined extracts were washed with brine, dried with Na2SO4, filtered, concentrated, and chromatographed (0–50% EtOAc in hexanes) to provide 774 mg (3.75 mmol) of 1-benzyloxy-cyclopropanecarboxylic acid methyl ester that was dissolved in 14 mL of 1:1 Is EtOH/THF. Sodium hydroxide (1M, 5.63 mL) was added, and the mixture was stirred for 4 h. After concentrating, 5 mL of water was added and the solution was extracted once with Et2O. The aqueous layer was then adjusted to pH 3 with HCl, and the suspension was extracted twice with EtOAc. The extracts were washed with brine, dried with Na2SO4, filtered, and concentrated to provide 723 mg of 1-Benzyloxy-cyclopropanecarboxylic acid. To the above acid (3.76 mmol) in 10 mL of CH2Cl2 was added 2.82 mL (5.64 mmol) of 2M oxalyl chloride in CH2Cl2 and one drop of DMF. After stirring for 15 min, the mixture was concentrated and redissolved in 4 mL of MTBE and 0.15 mL of CH2Cl2 and chilled to 0° C. Ammonium hydroxide (28% in water; 0.78 mL) was added, and the mixture was stirred for 15 min when 1 mL of saturated NaHCO3 was added. The mixture was extracted twice with EtOAc, and the extracts were combined, washed with brine, dried with Na2SO4, filtered, and concentrated to provide 550 mg of 1-benzyloxy-cyclopropanecarboxylic acid amide as a yellow oil.