Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:22]([O:24][CH3:25])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>ClCCCl.CN(C1C=CN=CC=1)C>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:14]2[CH2:19][CH2:18][C:17]([F:20])([F:21])[CH2:16][CH2:15]2)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:10][C@H:9]1[C:22]([O:24][CH3:25])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](NC2CCC(F)(F)CC2)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(F)(F)CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Methyl (2S,4S)-1-BOC-4-[(4,4-difluorocyclohexyl)amino]pyrrolidine-2-carboxylate (1.03 g, 2.84 mmol) obtained in Step A was dissolved in DCE (5 mL) and TEA (5 mL) and DMAP (0.36 g, 2.84 mmol) were added thereto. Commercially available pivaloyl chloride (1.03 g, 8.52 mmol) was also added thereto. The reaction solution was heated to 90° C. and stirred for 24 hours. After the reaction was completed, the solvent was removed in vacuo and saturated NaHCO3 aqueous solution was added. The solution was extracted with EtOAc. The extracted organic solution was washed with 1N HCl solution, dried over MgSO4, concentrated in vacuo and purified by column chromatography (eluent: EtOAc/Hex=1/4) to give the title compound (1.04 g, 82%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH:17]=[CH:16][CH:15]=1)=[O:13])[CH2:8]2.CO>FC(F)(F)C(O)=O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:13])[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[N:19]=1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)NC3C4CC5CC(C4)CC3C5)n2)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
After tert-butyl 4-(6-(adamantan-2-ylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate (86 mg, 0.195 mmol) was dissolved in MC (2 ml), trifluoroacetic acid (2 ml) was added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 4 hours. The resulting reaction liquid was concentrated under reduced pressure, followed by addition of a saturated aqueous NaHCO3 solution (10 ml), and then extracted with MC (15 ml×2). The organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (10% MeOH/MC), to obtain 65 mg of colorless oil (98%). MS (ESI): 341 [M+H]+
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:33])[C:7]([CH3:32])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][NH:21][C:20](=[O:23])[N:19]2[CH3:24])=[CH:11][CH:10]=1)[CH3:4].Br[CH2:35][C:36]1[CH:49]=[CH:48][C:39]([C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:41])=[CH:38][CH:37]=1>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:33])[C:7]([CH3:32])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][N:21]([CH2:35][C:36]3[CH:37]=[CH:38][C:39]([C:40](=[O:41])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)=[CH:48][CH:49]=3)[C:20](=[O:23])[N:19]2[CH3:24])=[CH:13][CH:14]=1)[CH3:4]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(=O)c4ccccc4)cc3)C(=O)N2C)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 10.9 %

Procedure:
To a cooled (0° C.) suspension of NaH (45 mg, 1.1 mmol, 60% w/w in mineral oil) in DMF (0.5 ml) is added a solution of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (320 mg, 0.75 mmol) in DMF (1.5 ml). After 5 minutes, the reaction mixture is removed from the cooling bath and stirred while warming to ambient temperature over 30 minutes. The solution is cooled again to 0° C., and 4-(bromomethyl)benzophenone (188 mg, 0.68 mmol) is added in a single portion, the cooling bath removed, and the mixture stirred for one hour. The reaction mixture is quenched with 1N HCl and extracted with ethyl acetate (2×). The organic extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil. The crude product is purified by flash chromatography on a Biotage silica cartridge (gradient elution, 2:1 hexanes:ethyl acetate to 1:2 hexanes:ethyl acetate) to provide an oil (46 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][O:19]C4CCCCO4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]([F:43])([F:42])[F:41])[CH:34]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][OH:19])[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]([F:43])([F:41])[F:42])[CH:34]=2)=[CH:44][CH:45]=1
Reactant: Cn1c(=O)n(CCOC2CCCCO2)c(=O)c2c1nc(OCCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: CC(=O)Cl
Product: Cn1c(=O)n(CCO)c(=O)c2c1nc(OCCCOc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-8-(3-(3-(trifluoromethoxy)phenoxy)propoxy)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.09 mmol,) in ethanol (5 mL) was added acetyl chloride (0.2 mL) at 0° C. The mixture was stirred at room temperature for 1 h; then it was partitioned between ethyl acetate and water. The organic phase was separated and dried over sodium sulfate. This organic layer was then filtered and concentrated to give a crude product which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(3-(3-(trifluoromethoxy)phenoxy)propoxy)1H-purine-2,6(3H,7H)-dione (20 mg, 39.2% yield) as a white solid. 1H-NMR (DMSO-d6) δ 7.40(t, 1H), 7.28-7.33(m, 4H), 6.92(dd, 2H), 6.85(s, 1H), 5.23(s, 2H), 4.76(t, 1H), 4.62(t, 2H), 4.08(t, 2H), 3.93(t, 2H), 3.49(q, 2H), 3.33(s, 3H), 2.18-2.24(m, 2H). LCMS retention time 3.058 min; LCMS MH+ 569.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2CC(C)(C)C([O-])=O)[N:10]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:35]CC1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:18]=[CH:17][C:16]2[C:15]([OH:35])=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(C)(Cc1cccc2nc(C#Cc3ccccn3)ccc12)C(=O)[O-]
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Oc1cccc2nc(C#Cc3ccccn3)ccc12
Yield: 9 %

Procedure:
2-(Pyridine-2-ylethynyl)quinoline-5-ol (3.7 mg, 9%) was prepared as yellow solid according to the same method as described in Example 16 except that 2-(pyridine-2-ylethynyl)quinoline-5-ylpivalate (56.8 mg, 0.17 mmol), LiAlH4 (0.43 mL, 1.0 M in THF), and THF (2.8 mL) were used.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=1.O.Cl>N1C=CC=CC=1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([NH:21][S:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:10])=[O:9])[CH3:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: C[C@@H](NS(=O)(=O)Cc1ccccc1)c1ccc(Br)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Phenylmethanesulfonyl chloride (10.5 g, 55 mmol) was added into a solution of (R)-1-(4-bromophenyl)ethanamine (10 g, 50 mmol) in pyridine (100 mL) drop wise at 0° C. The reaction mixture was stirred at 10° C. for 1 hour. The reaction was poured into water (500 mL), the pH value adjusted to 5 with 6 N aqueous HCl, extracted with EtOAc (100 mL×4). The organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound (13 g, 73% yield) as pale yellow solid which was used in the next step without further purification.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1>>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([N:13]=[C:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:12])[CH:22]=2)[CH:18]=[N:19]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C1Nc2ccccc2C1=CO
Product: O=C1Nc2ccccc2C1=C=Nc1ccc2cn[nH]c2c1
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield from 3-hydroxymethylene-1,3-dihydro-indol-2-one and 6-aminoindazole according to Procedure J: 1H NMR (DMSO-d6): δ 13.02 (s, 1H), 10.86 (d, 1H), 10.51 (s, 1H), 8.7 (d, 1H), 8.0 (s, 1H), 7.74 (d, 1H), 7.63 (d, 1H), 7.51 (s, 1H), 7.15 (dd, 1H), 7.02 (m, 1H), 6.94 (m, 1H), 6.85 (d, 1H); ESI-MS m/z 275 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:20]=[C:19]([Cl:21])[C:5]([O:6][C@H:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:10][CH3:11])=[O:9])=[C:4]([Cl:22])[CH:3]=1.[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[O:28][C:27]=2[C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:19]1[CH:20]=[C:2]([C:35]2[C:29]3[O:28][C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:31]=4[C:30]=3[CH:32]=[CH:33][CH:34]=2)[CH:3]=[C:4]([Cl:22])[C:5]=1[O:6][C@H:7]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Cl)cc(Br)cc1Cl
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Cl)cc(-c2cccc3c2oc2ccccc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
A mixture of Example 1A (944 mg, 2.34 mmol), dibenzo(b,d)furan-4-ylboronic acid (619 mg, 2.92 mmol), Pd(PPh3)4 (216 mg, 0.187 mmol), and 2M Na2CO3 (5 mL, 10 mmol) in toluene (10 mL) was heated to 78° C., stirred for 18 hours, cooled to room temperature, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide 1.05 g (91%) of the desired product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:22]4[NH:21][C:20]5C(=[CH:16][CH:17]=[CH:18][CH:19]=5)C=4C[CH2:12][N:11]3[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C[C:31]([CH3:34])([O-:33])[CH3:32].[K+].O=O>CN(C=O)C>[CH2:23]([N:11]1[CH2:12][C:34]2[C:31](=[O:33])[C:32]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[NH:21][C:22]=2[CH:10]1[C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CN2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)cc1
Reactant: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)CCO3)N(Cc1ccccc1)C2
Reaction time: 1.5 h

Procedure:
1-(2,3-Dihydrobenzofuran-5-yl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline (prepared as in Example 2) (3.10 g, 8.15 mmol) was dissolved in dry DMF (20 mL). Potassium t-butoxide (2.29 g, 20.38 mmol) was added, followed by oxygen, bubbled in via syringe needle. The solution was stirred for 1.5 h. To the reaction mixture was added a solution of HCl in ether (10 mL, 2M) and the solution dripped into rapidly stirring water. The resulting suspension was stirred overnight. A brown solid was filtered off and washed with water. The filtrate was neutralized with 1N NaOH, resulting in a yellow precipitate. The solid was filtered, washed with water, dried briefly, and partially dissolved in THF/methanol. The precipitate solid was filtered and washed with ether to yield the product as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: O=C(CBr)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccccc2)CCN(C)C1
Reaction time: 8 h
Yield: 3.1 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 5 mmol) was dissolved in NMP (1 mL). KOH (280 mg, 5 mmol) was then added to it, followed by addition of 2-bromoacetophenone (208 mg, 1 mmol). The reaction was kept overnight at RT and was monitored by TLC and LC/MS. The reaction was quenched by adding water, and the compound extracted using EtOAc, which was washed with water (2-3×). The organic layer was dried over sodium sulfate and then concentrated to yield 10 mg of dark brown crude oil, which was then purified by column chromatography using 100-200 mesh silica in 5% MeOH:DCM. 1HNMR (CD3OD, TFA salt) d (ppm): 8.15 (m, 1H), 7.70 (m, 1H), 7.60 (m, 2H), 7.28 (d, 1H), 7.20 (m, 1H), 7.0 (m, 1H), 5.80 (m, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 4.20 (m, 1H), 3.80 (m, 1H), 3.60 (m, 2H), 3.10 (s, 1H), 2.40 (s, 3H), 2.30 (m, 1H), 2.0 (m, 1H), 1.80 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([C@@H:12]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[CH2:13]3)[N:9]=[C:10]([I:11])[C:5]2=[C:4](OC(C)C)[N:3]=1.[NH3:24]>>[C@@H:12]1([N:8]2[C:6]3=[N:7][C:2]([NH2:1])=[N:3][C:4]([NH2:24])=[C:5]3[C:10]([I:11])=[N:9]2)[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[CH2:13]1
Reactant: CC(C)Oc1nc(N)nc2c1c(I)nn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: N
Product: Nc1nc(N)c2c(I)nn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Temperature: 70 °C

Procedure:
A soln. of compd. 6-amino-1-[2-deoxy-β-D-erythro-pentofuranosyl]-3-iodo-4-isopropoxy-1H-pyrazolo[3,4-d]pyrimidine 12 (F. Seela, G. Becher, Synthesis 1998, 2, 207.) (1 g, 2.3 mmol) in a aq. 25% NH3 soln. (80 ml) was heated at 70° C. for 4 d. The solvent was evaporated to dryness, the residue dissolved in hot water and crystallized. Colorless needles (640 mg, 71%). M.p. 154°. TLC (A): Rf0.2. UV (MeOH): 223 (31800), 260 (8700), 278 (9100). 1H-NMR ((D6)DMSO): 2.12 (m, Hα—C(2′)); 2.67 (m, Hβ—C(2′)); 3.38, 3.44 (m , H2—C(5′)); 3.73 (m , H—C(4′)); 4.33 (m, H—C(3′)); 4.73 (t, J=5.7, OH—C(5′)); 5.17 (d, J=4.3, OH—C(3′)); 6.27 (‘t’, J=6.5, H—C(1′)); 6.34 (br, NH2); 6.62 (br, NH2). Anal. calc. for C10H13IN6O3 (392.2): C, 30.63; H, 3.34; N, 21.43; Found: C, 30.91; H 3.61; N, 21.27.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:32]1([N:38]=[C:39]=[S:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)C>[C:32]1([NH:38][C:39]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:3]=2)=[S:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: S=C=Nc1ccccc1
Reactant: COc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=S)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
0.8 g (0.0023 mol) of 2-bromo-4-methoxy-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. While cooling the obtained solution in a dry ice-acetone bath in an argon atmosphere, 1.5 ml of a 1.69M-hexane solution of BuLi (0.0023×1.1 mol) was added thereto, followed by stirring the solution for about 10 minutes. After 0.62 g (0.0023×2.0 mol) of phenyl isothiocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the solution was removed from the bath and stirred at room temperature for about 30 minutes. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then precipitated with hexane, thereby obtaining an aimed product.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][CH2:15][CH3:16])=[CH:8][C:7]=1[OH:17])[CH:2]=[CH2:3].Br[CH2:20][C:21]1[CH:41]=[CH:40][C:24]([O:25][CH2:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:7]([O:17][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[CH:40][CH:41]=2)=[CH:8][C:9]([O:13][CH2:14][CH2:15][CH3:16])=[CH:10][C:11]=1[CH3:12])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(C)cc(OCCC)cc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1c(C)cc(OCCC)cc1OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
A mixture of the title C compound, 2-hydroxy-6-methyl-4-propoxy-benzoic acid allyl ester (400 mg, 1.6 mmol), the title C compound in Example 11, 4-[2-(4-bromomethyl-phenoxy)-ethyl]-5-methyl-2-phenyl-oxazole (595 mg, 1.6 mmol) and potassium carbonate (662 mg, 4.79 mmol) in 15 mL of DMF is stirred at RT overnight. The mixture is partitioned between EtOAc and water. The organic phase is washed with brine, dried over magnesium sulfate, and concentrated under vacuum. The residue is chromatographed on silica gel using 15% EtOAc in hexane as the eluent to obtain 2-methyl-6-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}4-propoxy-benzoic acid allyl ester as an oil: ESI-MS 542 [M+1]+.
Reaction SMILES: [OH:1][CH:2]([CH3:10])[CH:3](C)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C-:11]#[N:12].[Na+]>>[C:11]([CH2:10][CH:2]([OH:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:12]
Reactant: CCOC(=O)C(C)C(C)O
Reactant: [C-]#N
Agent: [Na+]
Product: CCOC(=O)CC(O)CC#N

Procedure:
The recombinant E. coil HB101(pNTS1G) obtained in Example 10 was inoculated in 100 ml of a 2×YT medium sterilized in a 500 ml Sakaguchi flask, and cultured with agitation at 37° C. for 13 hours. Glucose, 7.5 g, 3.2 mg of NADP, and then 4 g of ethyl 2-methyl-3-oxoacetate were added to 50 ml of the resultant culture. The culture was stirred at 30° C. while being adjusted at pH 6.5 with a 5 M sodium hydroxide solution to allow for reaction for 18 hours. After the reaction, the reaction solution was subjected to extraction using ethyl acetate, the solvent was removed under decompression, and the concentrate was purified by silica gel column chromatography, to obtain 3.5 g of ethyl 3-hydroxy-2-methylbutyrate. The optical purity of the ethyl 3-hydroxy-2-methylbutyrate was analyzed as follows and found to be 91.6% e.e. The analysis was performed in the following manner. The sample was reacted with sodium cyanide in demethyl sulfoxide at room temperature to obtain ethyl 4-cyano-3-hydroxybutyrate, which was then changed to a benzoic ester using benzoyl chloride under the presence of pyridine. The optical purity of the benzoic ester was measured by the HPLC method. 1H-NMR(CDC13)δ(ppm): 1.17(3H,t), 1.22(2H,t), 1.28(3H,t), 2.46(1H,m), 2.82(1H,br), 3.90(1H,m), 4.18(2H,q).
Reaction SMILES: [CH3:1][C:2](=[CH2:34])[C@@H:3]([N:20]1[C:26](=[O:27])[C@H:25]2[C@@H:21]1[O:22][C:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[N:24]2)[C:4]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:35]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:28]1([C:23]2[O:22][C@H:21]3[C@H:25]([C:26](=[O:27])[N:20]3[C@H:3]([C:2]([CH2:1][Cl:35])=[CH2:34])[C:4]([O:6][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:5])[N:24]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C=C(C)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21
Reactant: ClCl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21

Procedure:
A solution of 100 mg of Compound (1a) in 3 ml of methylene chloride is mixed with 0.2 ml of a 1.66 N solution of chlorine in carbon tetrachloride at 38° C. with stirring under nitrogen atmosphere to yield Compound (7) after silica gel chromatography.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[F:24]>C1COCC1>[CH2:10]([O:9][C:3]([CH:4]([C:5](=[O:6])[CH3:7])[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[F:24])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(C(=O)OC)cc1F)C(C)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 2.45 g) was added portionwise over 10 min to a solution of ethyl acetoacetate (7.5 mL) in THF (60 mL) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 10 min and a solution of methyl 4-(bromomethyl)-3-fluorobenzoate (12.1 g) in THF (40 mL) added over 10 min. The mixture was heated to 65° C. for 15 h and allowed to cool. The mixture was poured cautiously into ice/water (300 mL) and the aqueous extracted with EtOAc. The combined organic phase was dried, filtered and evaporated. The crude product was purified by chromatography eluting with to 20% EtOAc in isohexane to give the subtitle compound as a colorless oil 11.10 g.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:12])=[O:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C(C)=O)cc1

Procedure:
acylating the 4-hydroxyacetophenone with acetic anhydride to form 4-acetoxyacetophenone; and
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][CH:29]([CH3:35])[CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][CH:29]([CH3:35])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(C)CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CC(C)CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (97 mg, 91%), MS (ISP) m/z=429.4 [(M+H)+], mp 175° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-methyl-pentanoic acid.