Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2([CH:15]([OH:17])[CH3:16])[CH2:12][O:11]C(C)(C)[O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O>CO>[CH:1]1([C:7]([CH2:8][OH:9])([CH:15]([OH:17])[CH3:16])[CH2:12][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)C1(C2CCCCC2)COC(C)(C)OC1
Solvent: O
Solvent: CO
Product: CC(O)C(CO)(CO)C1CCCCC1
Reaction time: 6 h

Procedure:
5-Cyclohexyl-2,2-dimethyl-5-(1-hydroxyethyl)-1,3-dioxane (1.5 g.) and Dowex 50×8-200 ion exchange resin (H+ form) (1.0 g.) in methanol (30 ml.) and water (10 ml.) was refluxed with stirring for six hours. The mixture was filtered and the filtrate was evaporated in vacuo. 2-Cyclohexyl-2-hydroxymethyl-butan-1,3-diol was obtained as a pale yellow oil (1.2 g.) and was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24](OC)=[O:25])[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4].O1CCCC1.[NH3:33]>>[CH3:1][CH:2]([C:5]1[N:6]([CH2:17][C:18]2[N:23]=[C:22]([C:24]([NH2:33])=[O:25])[CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[C:9]([Cl:16])[CH:8]=2)[CH2:3][CH3:4]
Reactant: N
Reactant: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(=O)OC)n1
Solvent: C1CCOC1
Product: CCC(C)c1cc2cc(OC)c(Cl)cc2n1Cc1cccc(C(N)=O)n1
Reaction time: 27 h

Procedure:
To a suspension of methyl 6-[2-(butan-2-yl)-6-chloro-5-methoxyindol-1-ylmethyl]pyridine-2-carboxylate (125 mg) in ammonia (Ca. 7 mol/L methanol solution, 20.1 mL) was added tetrahydrofuran (6.7 mL) at room temperature, followed by stirring for 27 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (120 mg). 1H-NMR (CDCl3) δ ppm: 0.86 (3H, t, J=7.5 Hz), 1.25 (3H, d, J=6.9 Hz), 1.45-1.80 (2H, m), 2.65-2.80 (1H, m), 3.93 (3H, s), 5.39 (2H, s), 5.45-5.65 (1H, br), 6.30 (1H, s), 6.65-6.75 (1H, m), 7.11 (1H, s), 7.19 (1H, s), 7.60-7.80 (2H, m), 8.00-8.15 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O)=[O:4].[C:15]([C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:17])[CH3:16].N1CCCCC1>N1C=CC=CC=1>[OH:28][C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:15](=[O:17])[CH:16]=[CH:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH:8]=1
Reactant: CC(=O)c1c(O)c2ccccc2[nH]c1=O
Reactant: COC(=O)COc1cccc(C=O)c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)COc1cccc(C=CC(=O)c2c(O)c3ccccc3[nH]c2=O)c1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a mixture of 1.43 g of 3-[(methoxycarbonyl)methoxy]benzaldehyde, 0.50 g of 3-acetyl-4-hydroxy-2(1H)-quinolinone and 6 ml pyridine was added 0.1 ml of piperidine, and this was heated under reflux for 1 hour. After cooled to room temperature, precipitated crystals were filtered, and washed with tetrahydrofuran to obtain 0.63 g of 4-hydroxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone [Compound No. (7e)] as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([CH3:14])[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:25]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([CH3:14])[C:9](=[O:13])[N:10]2[CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:32])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26][CH2:25]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: COc1ccc2nc(C)c(=O)[nH]c2c1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C)c(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Yield: 10.2 %

Procedure:
7-Methoxy-3-methylquinoxalin-2(1H)-one (Intermediate 161, 500 mg, 2.60 mmol) was deprotonated with sodium hydride (60% in oil, 2.90 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (3.9 mmol) as described for Intermediate 2. Chromatography on silica gel with 70% ethyl acetate in hexanes, followed by a second chromatography on silica gel with 20% acetone in hexanes gave 110 mg (10%) of the product as a colorless solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C[O-].[K+].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].O>CN(C)C=O>[CH3:1][N:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])[S:3]([CH3:6])(=[O:5])=[O:4]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CNS(C)(=O)=O
Agent: C[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccccc1[N+](=O)[O-])S(C)(=O)=O
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To 3.2 g of N-methyl methanesulfonamide in 50 ml of dry dimethylformamide is added 1.47 g of potassium methoxide. The mixture is stirred for 15 minutes. 2.8 g of 2-Fluoronitrobenzene is added and the mixture is heated to reflux for two hours. The dimethylformamide is removed on a rotary evaporator. The concentrated reaction mixture is poured into water. The crude product is extracted with CH2Cl2. The crude extracts are dried with MgSO4, filtered and concentrated on a rotary evaporator. The crude product is purified by recrystallization from butyl chlorideethyl acetate. 3.4 g of product with m.p. 144°-145° C. is obtained.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH:14]=[O:15])=[CH:7][C:6]=1[O:16][CH3:17].[CH2:18](OS(C1C=CC(C)=CC=1)(=O)=O)[C:19]#[C:20][CH2:21][CH3:22]>CO>[CH3:17][O:16][C:6]1[CH:7]=[C:8]([CH2:11][CH2:12][NH:13][CH:14]=[O:15])[CH:9]=[CH:10][C:5]=1[O:4][CH2:18][C:19]#[C:20][CH2:21][CH3:22]
Reactant: COc1cc(CCNC=O)ccc1O
Reactant: CCC#CCOS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC#CCOc1ccc(CCNC=O)cc1OC

Procedure:
41 ml of a 30% solution of sodium methylate in methanol are added to a solution of 31.5 g (180 mmol) N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-formamide in 880 ml methanol. 48.1 g (184 mmol) toluene-4-sulfonic acid pent-2-ynyl ester are added and the mixture is refluxed for 4 hours. After evaporation the residue is taken up in ethyl acetate and washed with water. After evaporation the residue is submitted to flash-chromatography and crystallisation in ether to give the N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-formamide.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:21])[CH2:17][CH2:18][CH:19]=[O:20])=[CH:12][CH:11]=2)=[C:7]([OH:24])[CH:6]=1)[CH3:4].C(O)(=O)C>CO.O>[CH2:3]([C:5]1[CH:23]=[CH:22][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:21])[CH2:17][CH2:18][CH2:19][OH:20])=[CH:14][CH:15]=2)=[C:7]([OH:24])[CH:6]=1)[CH3:4]
Reactant: CCc1ccc(Oc2ccc(C(=O)CCC=O)cc2)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc(Oc2ccc(C(=O)CCCO)cc2)c(O)c1
Temperature: -5 °C
Reaction time: 5 h

Procedure:
To a suspension of NaBH4 (0.052 mmol; 2 mg) in dry methanol, under argon at −78° C., (0.5 mL) was added 4-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]-4-oxobutanal (0.040 mmol; 12 mg). The reaction was stirred 5 hours with gradual warming to −5° C., and treated with acetic acid. The mixture was diluted with water and extracted with ethyl acetate. Combined organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a clear oil (7.6 mg; 63%) after purification on preparative TLC (cyclohexane/ethyl acetate: 5/5).
Reaction SMILES: COC1OCC(COC2C=CN=C(C[S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])C=2C)CO1.[Na:30].COC1OCC(COC2C=CN=C(CS(C3NC4C=CC=CC=4N=3)=O)C=2C)CO1.[CH3:60][C:61]1([CH3:79])[O:66][CH2:65][CH:64]([CH2:67][O:68][C:69]2[CH:74]=[CH:73][N:72]=[C:71]([CH2:75]O)[C:70]=2[CH2:77][CH3:78])[CH2:63][O:62]1>>[Na:30].[CH3:60][C:61]1([CH3:79])[O:66][CH2:65][CH:64]([CH2:67][O:68][C:69]2[CH:74]=[CH:73][N:72]=[C:71]([CH2:75][S:18]([C:20]3[NH:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)=[O:19])[C:70]=2[CH2:77][CH3:78])[CH2:63][O:62]1
Reactant: CCc1c(OCC2COC(C)(C)OC2)ccnc1CO
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Agent: [Na]
Product: CCc1c(OCC2COC(C)(C)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 25 %

Procedure:
The same procedure as in the steps (6d), (6e), and (6f) of Example 6 was repeated using the (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3-ethylpyridin-2-yl)methanol obtained in the step (92d) above to obtain the title compound (159 mg, overall yield: 25%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6].[CH:32]([C:35]1[CH:36]=[CH:37][C:38]([S:41](Cl)(=[O:43])=[O:42])=[N:39][CH:40]=1)([CH3:34])[CH3:33]>C1(C)C=CC=CC=1.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[O:12][C:11]1[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][S:41]([C:38]1[CH:37]=[CH:36][C:35]([CH:32]([CH3:34])[CH3:33])=[CH:40][N:39]=1)(=[O:42])=[O:43]
Reactant: COC(=O)c1cc(N)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C(C)C)cn2)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.12 g of methyl 3-amino-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in a mixture of toluene/pyridine (20 ml/30 ml) treated dropwise while cooling with ice with a solution of 1.05 g of 5-isopropylpyridine-2-sulphonyl chloride in toluene (30 ml) and subsequently stirred at room temperature for 24 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was washed with water and dried over magnesium sulphate. After removing the solvent there was obtained the desired methyl 4-(2-chloro-5-methoxy-phenoxy)-3-(5-isopropyl-pyridine-2-sulphonylamino)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH2:15][CH2:16][CH:17]1[O:22][CH2:21][CH2:20][CH2:19][O:18]1)[C:10]([O:12]CC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1CO.O>[CH2:1]([NH:8][CH:9]([CH2:15][CH2:16][CH:17]1[O:18][CH2:19][CH2:20][CH2:21][O:22]1)[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCC1OCCCO1)NCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: OCC1CCCO1
Solvent: O
Product: O=C(O)C(CCC1OCCCO1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.5 %

Procedure:
A mixture of ethyl 2-benzylamino-4-(1,3-dioxan-2-yl)butyrate (77.5 g, 0.252 mol) and lithium hydroxide monohydrate (15.87 g, 0.378 mol) in tetrahydrofuran-methanol-water (1:3:1; 1 L) was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the aqueous residue was diluted with water (200 mL), washed with diethyl ether (200 mL) and freeze dried. The residue was purified by flash chromatography (silica gel, 20-30% MeOH/CH2Cl2) to give 59.5 g (85%) of the title compound as a white solid. δH (360 MHz, d6 -DMSO/D2O) 1.29 (1H, br d, J=13.4 Hz), 1.54 (2H, m), 1.63 (2H, m), 1.79 (1H, m), 3.05 (1H, t, J=6.0 Hz), 3.64 (2H, m), 3.80 (1H, d, J=13.1 Hz), 3.91-3.94 (3H, m), 4.44 (1H, t, J=5.1 Hz), 7.32-7.39 (5H, m), m/e (ES+) 280 (M+H)+, 204 (M-C6H5 +2H)+.
Reaction SMILES: CCCN1[C@@H]2CC3C4C(=CC=CC=4NC=3)[C@H]2C[C@@H](CSC)C1.C1[C:33]2[C:28](=[CH:29][C:30]([OH:36])=[C:31]([OH:35])[C:32]=2Cl)[CH:27](C2C=CC=CC=2)[CH2:26][NH:25]C1>>[NH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:35])=[C:30]([OH:36])[CH:29]=1
Reactant: Oc1cc2c(c(Cl)c1O)CCNCC2c1ccccc1
Agent: CCCN1C[C@H](CSC)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Product: NCCc1ccc(O)c(O)c1

Procedure:
HEK cells were transfected with a DNA construct encoding D1-NLS-GFP (1.5 micrograms of DNA), and incubated with the agonist pergolide (10 micromolar) for 48 hours. At 6, 22, 30 and 42 hours after transfection, the cells were treated with fresh medium containing SKF-81297 (final concentration 10 micromolar). The cells were examined by confocal microscopy.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>C1COCC1>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(C(F)(F)F)cc2)CC1
Reaction time: 1 h
Yield: 76.3 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (1.88 g, 9.34 mmol) was dissolved in THF (20 ml). Sodium hydride (411 mg, 10.3 mmol) was added to this solution while cooling in an ice-bath, and the mixture was stirred for 1 hour. 4-(Trifluoromethyl) benzylbromide (2.23 g, 9.34 mmol) was added to the mixture, which was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was extracted with methylene chloride. The extract was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-(4-trifluoromethylbenzyloxy)piperidine-1-carboxylate (2.56 g, yield 76%) as a pale yellow oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][S:2]1.CO.[C:13]([C:15]1C(=O)C(Cl)=C(Cl)[C:17](=O)[C:16]=1C#N)#N.O>C(Cl)Cl>[CH2:1]1[C:10]2[CH:9]=[C:8]3[C:7](=[CH:6][C:5]=2[CH:4]=[CH:3][S:2]1)[CH:17]=[CH:16][CH:15]=[CH:13]3
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: c1ccc2c(c1)CCSC2
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C1=Cc2cc3ccccc3cc2CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
The thioisochroman from step 1 (Example 13) (100.0 mg,0.40 mmmol) was dissolved in CH2Cl2 (12 ml) and MeOH (4 ml) followed by the addition of DDQ (109.0 mg,0.48 mmol,1.2 eq [2]) at R.T. The resulting mixture was stirred at room temperature overnight. H2O was added and it was extracted with CH2Cl2. The combined organic phases were washed with water, dried over MgSO4, filtered and concentrated in vacuum. The crude obtained was flash chromatographed using toluene:ethylacetate (95:5) to give the trans titled compound (65.0 mg,0.23 mmol) in 58% yield (MP: 84° C.).
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[C:31]([C:36]([O:38]C)=[O:37])[N:32]=[CH:33]4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][N:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[C:31]([C:36]([OH:38])=[O:37])[N:32]=[CH:33]4)=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc2ccc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CCC4)cc3)cc2cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CCC4)cc3)cc2cn1
Temperature: 120 °C
Yield: 60.1 %

Procedure:
To a solution of methyl 7-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate (39 mg, 0.070 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.10 mL, 0.10 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. The solution was concentrated under a nitrogen stream and 1 N aqueous hydrochloric acid (0.10 mL, 0.10 mmol) was added. The solution was concentrated further under an nitrogen stream and water was added followed by ethyl acetate. A solid precipitated. The water layer was removed and ether was added and the solid was isolated by filtration. The solid was dried under a nitrogen stream at 45° C. to afford 7-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylic acid (23 mg, 60%). 1H-NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.81 (s, 2H), 8.60 (s, 1H), 8.43 (s, 1H), 8.25-8.10 (m, 2H), 7.75 (d, J=9 Hz, 2H), 6.89 (d, J=9 Hz, 2H), 4.93 (s, 2H), 4.08-3.99 (m, 1H), 2.50-2.40 (m, 4H), 2.15-2.05 (m, 1H), 2.00-1.90 (m, 1H). HRMS (ESI) C29H21Cl2N3O4 calculated: 546.0982 [M+H]+, found: 546.0981 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14]>C(Cl)Cl.N1C=CC=CC=1>[C:12]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])(=[O:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)=CCC/C(C)=C/CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/COC(=O)C(C)C
Yield: 31.2 %

Procedure:
A mixture of geraniol (355 mg, 2.3 mmol) and isobutyryl chloride (407 mg, 3.8 mmol) was refluxed for 4.5 hours in 9.5 ml of methylene chloride (CH2Cl2) and 2 ml of pyridine. After the reflux, the reaction mixture was quenched over ice/water, extracted with hexane, washed, and dried over magnesium sulfate. The reaction mixture was concentrated under vacuum at 32° C. to yield 161 mg of oil, which was then purified by open column chromatography using ethyl acetate/hexane (5/95) as an eluant to afford 119 mg (yield: 33%) of a pale yellow oil having the following physical properties.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:29])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[CH:15]=2)[CH:8]=1)[CH3:2].[BH4-].[Na+].O.ClCCl>CO>[CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:30])([CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:23])[CH3:22])[CH:15]=2)[OH:29])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1cccc(C(=O)c2cccc(CC(C)(C)C(=O)OCC)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1cccc(C(O)c2cccc(CC(C)(C)C(=O)OCC)c2)c1
Reaction time: 5 h
Yield: 99.8 %

Procedure:
Under Ar atmosphere, to a solution of 3-{3-[3-(2-ethoxycarbonyl-2-methyl-propyl)-benzoyl]-phenyl}-2,2-dimethylpropionic acid ethyl ester (12.37 g, 28.2 mmol) in methanol (240 mL) was added sodium borohydride (0.45 g, 13.7 mmol) under cooling with an ice water bath. The mixture was stirred for 5 h and water (480 mL) and dichloromethane (200 mL) were added. The aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic layers were washed with saturated NaHCO3 solution (150 mL and saturated NaCl solution (150 mL), dried over MgSO4, and concentrated under vacuum to give 3-(3-{[3-(2-ethoxycarbonyl-2-methylpropyl)-phenyl]-hydroxymethyl}-phenyl)-2,2-dimethylpropionic acid ethyl ester (12.4 g, 100%) as a colorless oil, which was used for the next step without further purification. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.20-7.18 (m, 4 H), 7.10 (s, 2 H), 7.00-6.98 (m, 2 H), 5.69 (d, 1 H, J=3.2 Hz), 4.02 (q, 4 H, J=7.1 Hz), 2.97 (d, 1 H, J=3.2 Hz), 2.81 (s, 4 H), 1.19 (t, 6 H, J=7.1 Hz), 1.13 (s, 12 H). 13C NMR (75 MHz, CDCl3=77.23 ppm): δ (ppm): 177.6, 143.8, 138.2, 129.3, 128.5, 128.1, 124.8, 76.1, 60.5, 46.3, 43.6, 25.1, 25.0, 14.3. HRMS (LSIMS, gly): Calcd for C27H35O4 (M+H—H2O): 423.2535, found: 423.2542.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]2[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:21][O:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:29]Br.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:29][C:28]2[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:26]([C:25]([F:24])([F:38])[F:39])[CH:27]=2)[C:14]2[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:21][O:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@@H]1C[C@H](Nc2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ((2S,4S)-4-(5-bromo-pyrimidin-2-ylamino)-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.84 mmol; 1.1 g), 3,5-bis(trifluoromethyl)benzyl bromide (4.3 mmol; 0.78 mL) and sodium hydride (60% dispersion in mineral oil, 4.3 mmol; 0.17 g) in DMF (9 mL) is stirred for 1 hour at room temperature under nitrogen. The reaction mixture is quenched with water then saturated ammonium chloride solution. The product is extracted twice with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is passed though silica pad (eluent: n-hexane/EtOAc) to give (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester. To a mixture of (2S,4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, 1-methylpyrazol-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (7.1 mmol, 1.48 g), tetrakis(triphenylphosphine)palladium(0) (0.43 mmol, 490 mg) and 2M aqueous sodium hydrogen carbonate (3.6 mL) in 1,2-dimethoxy-ethane (4 mL) is allowed to warm to 95° C. and stirred for 3 hours. The mixture is cooled to room temperature and then added water. The mixture is extracted with CH2Cl2, and the combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2S,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.3 g, 74% overall yield for 2 steps); ESI-MS m/z: 615 [M+1]+, Retention time 2.12 min (condition A).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C[O-].C([Sn+](CCCC)CCCC)CCC.C([O:33][C:34]([CH3:36])=[CH2:35])(=O)C.[F-].[K+]>C1(C)C=CC=CC=1>[O:7]([C:8]1[CH:13]=[CH:12][C:11]([CH2:35][C:34](=[O:33])[CH3:36])=[CH:10][CH:9]=1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Brc1ccc(Oc2ccccc2)cc1
Reactant: C=C(C)OC(C)=O
Agent: CCCC[Sn+](CCCC)CCCC
Agent: C[O-]
Agent: [F-]
Solvent: Cc1ccccc1
Product: CC(=O)Cc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
75.0 g of 4-bromodiphenyl ether, 129 ml of tributyltin methoxide, 45.0 g of isopropenyl acetate and 2,47 g of dichlorobis{tri(o-tolyl)phosphine}palladium, were dissolved in 300 ml of toluene and refluxed under heating for 3 hours. The reaction solution was left to cool to room temperature, and then, a saturated potassium fluoride aqueous solution was added, followed by stirring for one hour. Then, the product was subjected to celite filtration and washed with ethyl acetate. The filtrate and washing liquid were put together. Then, the organic layer was separated and washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1→10/1) to obtain 56.3 g (yield: 83%) of the above identified compound as yellow solid.