Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)CC1.BrC1C=CC2[O:17][C:18]([CH3:21])([CH3:20])[O:19]C=2C=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[CH3:20][C:18]1([CH3:21])[O:19][C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=2[O:17]1
Reactant: CC1(C)Oc2ccc(Br)cc2O1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC1(C)Oc2ccc(C=O)cc2O1
Yield: 83 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 420 mg of 5-bromo-2,2-dimethyl-benzo[1,3]dioxole [CAS 73790-19-9] (1.83 mmol), 1.38 ml of a 1.6 molar solution of n-BuLi in hexane (2.20 mmol) and 712 μl of DMF (9.17 mmol). The isolated residue was purified by flash column chromatography (1:9 ether/pentane) to give 270 mg of 2,2-dimethyl-benzo[1,3]dioxole-5-carbaldehyde (83%) as a light yellow liquid. 1H NMR (CDCl3, 300 MHz): δ 1.72 (s, 6H), 6.84 (d, J=7.8 Hz, 1H), 7.26 (s, 1H), 7.87 (dd, J=8.0 and 1.7 Hz, 1H), 9.97 (s, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.[OH-].[K+]>CN(C=O)C.O.[Cu-]=O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)c1c(C)cc(I)cc1C
Agent: O=[Cu-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Sc2cc(C)c(C(C)=O)c(C)c2)cc1
Yield: 89.1 %

Procedure:
A mixture of 1-(4-iodo-2,6-dimethylphenyl)ethanone (1.5 g, 5.5 mmol, 1.0 equiv), 4-methoxybenzenethiol (1.01 mL, 8.2 mmol, 1.5 equiv), copper(I) oxide (39.2 mg, 0.3 mmol, 0.05 equiv), and potassium hydroxide (614.1 mg, 11.0 mmol, 2.0 equiv) in DMF (4.4 mL) and H2O (1.1 mL) was heated at reflux for 20 h. The mixture was quenched with H2O (10 mL) and extracted with ether (2×20 mL). The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to provide 1-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)ethanone (1.41 g, 4.9 mmol) as yellow oil in 90% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.39 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 6.79 (s, 2H), 3.82 (s, 3H), 2.43 (s, 3H), 2.13 (s, 6H); ESI-MS: m/z 287.6 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][N:14]=3)[CH:11]=2)[N:6]([C:27](=[O:29])[CH3:28])[C@@H:5]([CH3:30])[CH2:4]1.Br[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([NH:2][C@H:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[O:20])=[CH:15][N:14]=4)[CH:11]=3)[N:6]([C:27](=[O:29])[CH3:28])[C@@H:5]([CH3:30])[CH2:4]2)=[CH:33][CH:34]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 120 °C
Yield: 10.7 %

Procedure:
1-((2S,4R)-4-amino-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone hydrochloride (for a preparation see Intermediate 65) (120 mg, 0.278 mmol), 1-bromo-4-chlorobenzene (107 mg, 0.557 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (21.9 mg, 0.056 mmol), tris(dibenzylideneacetone)dipalladium(0) (25.5 mg, 0.028 mmol) and sodium tert-butoxide (37.5 mg, 0.390 mmol) were combined in 1,4-dioxane (2 mL) and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 120° C. for 25 mins. The reaction mixture was partitioned between water (50 mL) and DCM (3×50 mL). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue which was purified by MDAP (HpH) to give 1-((2S,4R)-4-((4-chlorophenyl)amino)-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (15 mg, 0.030 mmol, 10.7% yield).
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([C:29]([O:31][CH2:32]C)=[O:30])[C:8]2[CH2:9][CH2:10][N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)[C:12](=[O:19])[C:13]=2[C:14]=1[O:15]C(=O)C)(=O)C.C[O-].[Na+].Cl>CO.O1CCCC1>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[CH2:20][N:11]1[CH2:10][CH2:9][C:8]2[C:7]([C:29]([O:31][CH3:32])=[O:30])=[N:6][C:5]([OH:4])=[C:14]([OH:15])[C:13]=2[C:12]1=[O:19]
Reactant: CCOC(=O)c1nc(OC(C)=O)c(OC(C)=O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 3,4-bis(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (27.8 g, 58 mmol) and sodium methoxide (41.8 mL, 232 mmol; 30% by weight solution of NaOMe in MeOH) in anhydrous methanol (300 mL) was heated at 40° C. for 5 hours. The volume of the reaction mixture was reduced by a half under vacuum, diluted with anhydrous tetrahydrofuran (400 mL), and treated with an additional solution of sodium methoxide in methanol (33 mL). The reaction mixture was stirred at room temperature overnight and then warmed to 50° C. for four hours. The product mixture was acidified with dilute hydrochloric acid to pH 3 and extracted with chloroform several times. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as oil.
Reaction SMILES: O=[C:2]([CH2:8]CC)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[CH3:7][C:6]1([CH:11]=[CH2:12])[O:5][C:3](=[O:4])[CH2:2][CH2:8]1
Reactant: C=C[Mg]Br
Reactant: CCCC(=O)C(=O)OCC
Solvent: C1CCOC1
Product: C=CC1(C)CCC(=O)O1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To a solution of ethyl 2-ketopentanoate (10 mL, 71 mmol) in 100 mL of THF at −78° C. was added dropwise a solution of 1.0 M vinyl magnesium bromide (80 mL, 80 mmol). After completion of the addition, the mixture was stirred for two more hours, the cooling bath was removed and the mixture was gradually warmed to ambient temperature. After the removal of the most of the solvent, the residue was poured to 2N HCl aqueous solution, extracted with ethyl acetate and dried over MgSO4. Purification by lash column chromatography on silica gel with DCM as elute afforded 4.80 grams of 5-methyl-5-vinyl-dihydro-furan-2-one. 1H-NMR (300 MHz, CDCl3) δ (ppm): 5.824-5.917 (dd, 1H); 5.29 (d, 1H); 5.13 (d, 1H); 2.50-2.56 m, (2H); 2.07-2.18 (m, 2H); 1.48 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15](=[O:32])[NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(OC(=O)C(C)(OC1C=CC([O:60][C:61]([F:64])([F:63])[F:62])=CC=1)CC1C=CC(O)=CC=1)C>>[CH3:1][C:2]([O:33][C:34]1[CH:35]=[CH:36][C:37]([O:60][C:61]([F:64])([F:63])[F:62])=[CH:38][CH:39]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:32])[NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(Cc1ccc(OCC(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)(Oc1ccccc1)C(=O)O
Product: CC(Cc1ccc(OCC(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)(Oc1ccc(OC(F)(F)F)cc1)C(=O)O

Procedure:
The title compound was prepared using same method for 2-Methyl-2-phenoxy-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionic acid from 3-(4-Hydroxy-phenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionic acid ethyl ester.
Reaction SMILES: BrC1C=C(Cl)C=C(Cl)C=1F.FC(F)(F)C(B(O)O)=C.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([C:35]([F:38])([F:37])[F:36])=[CH2:34])[C:30]([F:39])=[C:29]([Cl:40])[C:28]=1F>O1CCCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[Cl:40][C:29]1[CH:28]=[C:27]([Cl:26])[CH:32]=[C:31]([C:33]([C:35]([F:36])([F:37])[F:38])=[CH2:34])[C:30]=1[F:39]
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1F)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=C(B(O)O)C(F)(F)F
Agent: Fc1c(Cl)cc(Cl)cc1Br
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C=C(c1cc(Cl)cc(Cl)c1F)C(F)(F)F
Reaction time: 3 h

Procedure:
1-bromo-3,5-dichloro-2-fluorobenzene (10 g), (3,3,3-trifluoroprop-1-en-2-yl)-boronic acid (7.5 g) and potassium carbonate (13.6 g) were dissolved in tetrahydrofuran (41 ml) and water (20 ml), and then deaerated. Dichlorobis(triphenylphosphine)palladium (II) (1.4 g) was added thereto and the mixture was stirred for 3 hours under reflux under argon atomosphere. After cooling the mixture to the room temperature, water and n-hexane were added, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the solvent was distilled off under reduced pressure, and the residue was roughly purified by silica gel chromatography (n-hexane) to obtain a mixture containing 1,3-dichloro-2,4-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene and hexane.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[I-].[Na+].Cl[CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]([S:43][C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][C:33]([O:41][CH3:42])=[C:34]([O:39][CH3:40])[CH:35]=3)[CH2:30]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>CN(C)C=O.C(OCC)(=O)C>[N:1]1([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH:22]([S:43][C:44]3[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=3)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:38][CH2:37][C:36]4[C:31](=[CH:32][C:33]([O:41][CH3:42])=[C:34]([O:39][CH3:40])[CH:35]=4)[CH2:30]3)[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1cc2c(cc1OC)CN(CCCCCCC(Sc1ccc(C)cc1)c1ccc(OC)c(OCCCl)c1)CC2
Agent: [H-]
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(CCCCCCC(Sc1ccc(C)cc1)c1ccc(OC)c(OCCn3ccnc3)c1)CC2
Yield: 16452 %

Procedure:
To 0.76 g of imidazole in 5 mL of 4A sieve-dried N,N-dimethylformamide is added 0.18 g of 60% sodium hydride in oil. When the effervescence subsides, 0.26 g of sodium iodide is added, followed by 1.12 g of 2-[7-[3-(2-chloroethoxy)-4-methoxyphenyl]-7[(4-methylphenyl)thio]heptyl]-1,2,3,4-tetrahydro-6,7dimethoxyisoquinoline in 5 mL of N,N-dimethylformamide. An additional 2 mL of N,N-dimethylformamide is used as wash. After letting the tan solution stand for 48 hours, it is concentrated in vacuo, and the residue is distributed between ethyl acetate and water. The organic layer is extracted with 1N hydrochloric acid, the acid layer basified with aqueous ammonia, and the resulting oil extracted into ethyl acetate. After drying (sodium sulfate), the extract is concentrated in vacuo to 0.53 g of tan oil. Flash chromatography of the oil on silica gel (gradient elution: hexane to chloroform to methyl alcohol) gives an oil which is taken up in ethyl acetate, passed through a pad of hydrous magnesium silicate, and concentrated to leave 0,194 g of the desired product as a yellow gum.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12](=[O:20])[C:11]([C:21]([OH:23])=[O:22])=[CH:10]2)=[CH:4][CH:3]=1.[CH3:24][S-:25].[Na+]>CS(C)=O>[F:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[N:9]([CH2:8][C:5]1[N:6]=[N:7][C:2]([S:25][CH3:24])=[CH:3][CH:4]=1)[CH:10]=[C:11]([C:21]([OH:23])=[O:22])[C:12]2=[O:20]
Reactant: O=C(O)c1cn(Cc2ccc(Cl)nn2)c2c(F)cccc2c1=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ccc(Cn2cc(C(=O)O)c(=O)c3cccc(F)c32)nn1

Procedure:
To a solution of 1-[(6-chloropyridazin-3-yl)methyl]-8-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.050 g, 0.15 mmol) in 1 mL of DMSO was added sodium thiomethoxide (0.032 g, 45 mmol). The reaction mixture was irradiated in the microwave at 100° C. for 10 minutes, and purified via reverse phase HPLC to provide 8-fluoro-1-{[6-(methylthio)pyridazin-3-yl]methyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 346.1 for M+H+.
Reaction SMILES: C(OC([N:6]=[S:7]([CH2:33][CH3:34])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:31][CH3:32])[CH:10]=1)=[O:8])=O)C.CCCCCC.C(OCC)(=O)C.CO>CO.ClCCl.CO>[CH2:33]([S:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][CH:28]([CH3:29])[CH3:30])=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:31][CH3:32])[CH:10]=1)(=[NH:6])=[O:8])[CH3:34]
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(NC(C)C)c3cc2OC)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCS(=N)(=O)c1cccc(COc2cc3ncnc(NC(C)C)c3cc2OC)c1
Yield: 82 %

Procedure:
According to GWP 6, the conversion of (RS)-N-(ethoxycarbonyl)-S-ethyl-S-[3-({[4-(isopropylamino)-6-methoxyquinazolin-7-yl]oxy}methyl)phenyl]sulphoximide (64 mg, 0.13 mmol) and chromatographic purification (silica gel, hexane, ethyl acetate/methanol: 0→10% methanol, followed by dichloromethane/methanol: 0→15% methanol) gives the desired product in 82% yield (45 mg).
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][CH:54]([O:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=2)[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[O:10]=[C:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:17]=[CH:18][C:19]([C:20]([NH:47][CH2:48][C:49](=[O:50])[N:51]2[CH2:52][CH2:53][CH:54]([O:57][C:58]3[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:65])([F:66])[F:67])[CH:59]=3)[CH2:55][CH2:56]2)=[O:22])=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1ccc(N2CCCC2=O)cc1
Reaction time: 0.03 h
Yield: 56.62 %

Procedure:
DIPEA (200 mg, 1.55 mmol) was added to a stirred solution of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid (70 mg, 0.34 mmol) in DMF (5 mL) followed by HOBt (50 mg, 0.37 mmol) and EDCI (163 mg, 0.85 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (127 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the precipitate was filtered off. The solid obtained was purified by column chromatography (using 60-120 silica gel and 70% ethyl acetate in hexane as eluent) to afford 94 mg (56.62% Yield) of 4-(2-oxo-pyrrolidin-1-yl)-N-{2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-benzamide. LC/MS [M+H]+: 490.19, 98.95%. 1H NMR (300 MHz, DMSO-d6): δ 8.6 (t, 1H), 7.94 (d, 2H), 7.8 (d, 2H), 7.6 (t, 1H), 7.38 (t, 3H), 4.8 (m, 1H), 4.2 (d, 1H), 4.0 (t, 3H), 3.8 (d, 1H), 3.5 (d, 1H), 3.3 (bs, 1H), 2.5 (bs, 2H), 2.1 (m, 2H), 2.0 (d, 2H), 1.7 (d, 2H).
Reaction SMILES: [C:1](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:10]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)[C:2]1[CH:9]=[CH:8][C:5]([O:6][CH3:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:34]([OH:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>N1C=CC=CC=1>[CH3:7][O:6][C:5]1[CH:8]=[CH:9][C:2]([C:1]([O:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][OH:41])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: OCCCCCCO
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(OCCCCCCO)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 4 h
Yield: 33.3 %

Procedure:
To a solution of 3.38 g (10 mmol) of DMTr-Cl and 3.45 mL (20 mmol) of diisopropylethylamine in 50 mL of dry pyridine was added 5.91 g (50 mmol) of 1,6-hexanediol. After stirring for 4 h, the mixture was quenched with 85 mL of 5% sodium bicarbonate and extracted with 2×100 mL of methylene chloride. The organic phase was washed with 2×100 mL of water and 100 mL of brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (3.5×17 cm silica) using methylene chloride. The fractions containing pure product were combined and concentrated to give 1.40 g of 37 as a yellow syrup.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[CH:23][C:24]=1[Cl:25].[Cl-].[NH4+]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:26][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: C#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccc(Cl)c(Cl)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 40 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.21 g of 3,4-dichlorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.14 g of 4-(3,4-dichlorophenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (23)), m.p.: 109.2° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([CH:7]=[C:8]([S:19]([CH3:22])(=[O:21])=[O:20])[C:9]3[O:10][C:11](=[O:18])[C:12]([CH3:17])([CH3:16])[C:13]=32)=[CH:5][C:4]=1[S:23]([CH3:26])(=[O:25])=[O:24].[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>C(#N)C.O>[S:19]([C:8]1[C:9]2[O:10][C:11](=[O:18])[C:12]([CH3:16])([CH3:17])[C:13]=2[C:14]2[C:6](=[CH:5][C:4]([S:23]([CH3:26])(=[O:24])=[O:25])=[C:3]([CH2:2][N:27]3[CH:31]=[N:30][CH:29]=[N:28]3)[CH:15]=2)[CH:7]=1)([CH3:22])(=[O:20])=[O:21]
Reactant: c1nc[nH]n1
Reactant: CC1(C)C(=O)Oc2c(S(C)(=O)=O)cc3cc(S(C)(=O)=O)c(CBr)cc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CC1(C)C(=O)Oc2c(S(C)(=O)=O)cc3cc(S(C)(=O)=O)c(Cn4cncn4)cc3c21

Procedure:
A solution of 8-bromomethyl-4,7-dimesyl-1,1-dimethyl-2(1H)-naphtho[2,1-b]furanone in acetonitrile (5 ml) was treated with 1,2,4-triazole (0.2 g) and potassium carbonate (0.14 g), and the mixture was stirred under reflux for 18 h. The mixture was diluted with water, neutralised with glacial acetic acid and extracted with ethyl acetate, and the ethyl acetate extract was dried and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography, using methanol:ethyl acetate, 1:99 v/v as eluant, to give 4,7-dimesyl-1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone, m.p. 263°-264° after recrystallisation from ethyl acetate.
Reaction SMILES: C(OC(Cl)=O)(C)C.C(N(CC)CC)C.[CH2:15]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:31](O)=[O:32])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1.O>[C:38]([O:37][C:35]([NH:34][C@H:30]([CH2:31][OH:32])[CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:23](=[O:24])[O:22][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)CCCCNC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 68.6 %

Procedure:
A solution of 150.0 mL (150.0 mmol) of 1 M isopropylchloroformate in toluene was added dropwise to a solution of 20.9 mL (150.0 mmol) of triethylamine and 57.06 g (150.0 mmol) of (2S)-6-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]hexanoic acid in 500 mL of anhydrous tetrahydrofuran at 0° C. After 2 h, the resulting mixture was filtered to remove solids, rinsing with 100 mL of anhydrous tetrahydrofuran. The filtrate was then added dropwise to a stirred solution of 11.35 g (300.0 mmol) of sodium borohydride in 500 mL of 0° C. water. The cold bath was removed, and the resulting mixture was stirred for 18 h. It was then diluted with 800 mL of ethyl acetate and 300 mL of saturated aqueous sodium bicarbonate. The two layers were separated, the aqueous layer was extracted with two 250 mL aliquots of ethyl acetate, and the extracts were combined with the original ethyl acetate layer. The combined ethyl acetate phase was washed with three 100 ml portions of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under vacuum. The yellow oil was further purified by column chromatography on silica gel, eluting with 4:1 ethyl acetate:hexane to afford 37.70 g (68%) of benzyl (5S)-5-{[t-butyloxycarbonyl]amino}-6-hydroxyhexylcarbamate. 1H NMR (300 MHz, DMSO-d6) δ 7.43-7.30 (m, 5H), 7.25 (t, J=5 Hz, 1H), 6.45 (d, J=8 Hz, 1H), 5.02 (s, 2H), 4.57 (br s, 1H), 3.35-3.29 (m overlapping water peak, 2H), 3.26-3.16 (m, 1H), 3.04-2.93 (m, 2H), 1.39 (s, 9H), 1.57-1.16 (m, 6H). ES-LCMS m/z 389 (M+Na).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][C:5]1[C:6]([O:11][CH3:12])=[N:7][CH:8]=[N:9][CH:10]=1.C(O)C.O.[OH-].[Li+]>O>[CH3:12][O:11][C:6]1[C:5]([CH2:4][C:3]([OH:13])=[O:2])=[CH:10][N:9]=[CH:8][N:7]=1
Reactant: COC(=O)Cc1cncnc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ncncc1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 0.21 g (1.14 mmol) of methyl (4-methoxy-5-pyrimidinyl)acetate from Step A above in 0.5 mL of water and 1.5 mL of ethanol was added 81 mg (1.9 mmol) of lithium hydroxide hydrate. The reaction mixture was stirred at ambient temperature for 2 h then concentrated in vacuo to remove all volatiles. The residue was diluted with 3 mL of 2.0 M aqueous hydrogen chloride and then concentrated in vacuo to remove all volatiles to yield the title compound as an off white solid (191 mg, 90%). 1H-NMR (500 MHz, CD3OD) δ: 8.72 (s, 1H), 8.35 (s, 1H), 4.01 (s, 3H), 3.57 (s, 2H). LC-MS: m/z (E/S) 169 (MH)+.