Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](/[CH:13]=[CH:14]/[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(C)cc2)o1
Agent: Cl
Agent: OCCC1CCCO1
Agent: [Na+]
Product: Cc1ccc(-c2ccc(/C=C/C(=O)O)o2)cc1
Reaction time: 24 h
Yield: 66.3 %

Procedure:
To a solution of methyl (E)-3-[5—(4-methylphenyl)-furan-2-yl]acrylate (1.49 g) in tetrahydrofuran-ethanol (10-10 ml) was added 2N sodium hydroxide (4 ml) at room temperature, and the mixture was stirred for 24 hours. The reaction mixture was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to give (E)-3-[5—(4-methylphenyl)-furan-2-yl]acrylic acid (0.93 g) as colorless crystals.
Reaction SMILES: [OH:1][C@H:2]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]1.[Si:14](OS(C(F)(F)F)(=O)=O)([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].CCN(CC)CC>C(Cl)Cl>[CH:15]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:1][C@H:2]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[C:6](=[O:13])[CH2:5][CH2:4][CH2:3]1)([CH3:17])[CH3:16]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C1CCC[C@@H](O)c2ncccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](O[C@@H]1CCCC(=O)c2cccnc21)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
In a 1L round-bottomed flask was (R)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (19.14 g, 108 mmol) (azeotroped with dry benzene) in CH2Cl2 (300 mL) to give a tan solution. After cooling to 0° C., TIPS-OTf (29.3 mL, 108 mmol) and Et3N (30.1 mL, 216 mmol) were added via syringe, and the mixture was stirred at 0° C. for 1h. LCMS indicated complete conversion. Volatiles were stripped off and the residue was partitioned between NaHCO3 solution and EtOAc. The layers were separated and the organic layer was washed with brine, dried and concentrated to a tan oil (37 g). It was purified by FCC up to 20% EtOAc/hexane to afford the product as a white solid (26.3 g, 73% for two steps). MS(ESI)[M+H+]=334.37.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[C:24]([Cl:30])[CH:23]=3)[C:18]([F:21])([F:20])[F:19])=[CH:11][C:8]=2[C:9]#[N:10])[N:3]=1.C(N(CC)CC)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>C(Cl)Cl>[C:9]([C:8]1[CH:11]=[C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]2[CH:23]=[C:24]([Cl:30])[C:25]([Cl:29])=[C:26]([Cl:28])[CH:27]=2)[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][C:7]=1[N:4]1[CH:5]=[N:6][C:2]([NH:1][C:41]([CH:38]2[CH2:40][CH2:39]2)=[O:42])=[N:3]1)#[N:10]
Reactant: O=C(Cl)C1CC1
Reactant: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(N)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(NC(=O)C2CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.15 g, 0.31 mmol) in DCM at 0° C., were added triethylamine (0.1 g, 1 mmol) and cyclopropylcarbonyl chloride (0.04 g, 0.38 mmol) and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with DCM and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by column chromatography (SiO2, 100-200 mesh) afforded the title compound as a solid (66 mg, 34%): mp 109-112° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.94 (br s, 1H), 8.36 (s, 1H), 8.08 (m, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.13 (dd, J=15.6, 9.2 Hz, 1H), 6.87 (d, J=15.6 Hz, 1H), 4.92 (m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H); ESIMS m/z 540.04 ([M+H]+); IR (thin film) 3233, 2233, 1699, 1114, 807 cm−1.
Reaction SMILES: S(O[CH2:12][CH2:13][C:14]1([CH3:21])[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1)(C1C=CC(C)=CC=1)(=O)=O.[I-:22].[Na+]>CC(C)=O>[I:22][CH2:12][CH2:13][C:14]1([CH3:21])[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCCC2(C)COC(C)(C)O2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(CCI)COC(C)(C)O1
Yield: 107.4 %

Procedure:
6.5 g of 4-(2-tosyloxyethyl)-2,2,4-trimethyl-1,3-dioxolane were heated at reflux temperature for 1 hour with 50 g of sodium iodide and 500 ml of acetone, then concentrated, suspended in 100 ml of toluene and filtered. The toluene solution was washed with sodium thiosulphate solution, dried and concentrated. There were obtained 6.0 g (97%) of 4-(2-iodoethyl)-2,2,4-trimethyl-1,3-dioxolane.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[NH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[C:27]1(=[O:32])[O:31][CH2:30][CH2:29][CH2:28]1>CN(C)C1C=CN=CC=1.CO>[Cl:26][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][N:11]=[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][OH:32])[CH:4]=4)[C:18]=23)[CH:25]=[CH:24][CH:23]=1
Reactant: NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Reactant: O=C1CCCO1
Agent: CN(C)c1ccncc1
Solvent: CO
Product: O=C(CCCO)NCc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 95 °C
Reaction time: 10 h

Procedure:
A mixture of 300 mg (0.8054 mmol) of 3-(3-aminomethyl-phenylamino)4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (water content: 1.79%; see Step 90.5), 277 mg (3.22 mmol) of -γ-butyrolactone, 2 mg of 4-dimethylamino-pyridine and 5 ml of methanol is stirred for 10 hours at 95° C. and, after a further addition of 277 mg (3.22 mmol) of γ-butyrolactone and 4 mg of 4-dimethylaminopyridine, for a further 16 hours at 100° C. The reaction mixture is then concentrated by evaporation in vacuo, and the residue is stirred with ethyl acetate and filtered, and the filter residue is recrystallized from methanol, yielding 4-(3-chloro-phenylamino)-3-[3-({4-hydroxy-butyryl-amino}-methyl)-phenylamino]-1H-pyrazolo[3,4-d]pyrimidine having a water content of 0.67%; m.p. 182-184° C.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[C:20](=[O:22])=[O:21]>C1COCC1>[CH:1]1[C:14]2[CH:13]([C:20]([OH:22])=[O:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C=O
Reactant: c1ccc2c(c1)Cc1ccccc1S2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thioxanthene, 9.1 g, was dissolved in 100 mL of dry THF. The solution was cooled in an ice bath and n-BuLi (24 mL of 2.5 M solution) was added dropwise. The red solution was stirred at room temperature for one hour. Powdered CO2 was added (ca. 150 g) causing formation of a white precipitate. After stirring an additional hour the mixture was evaporated and the residue dissolved in water. The aqueous solution was extracted with CH2Cl2, and neutralized with HCl. The precipitated product was dissolved in ether, dried and evaporated producing thioxanthene-9-carboxylic acid as a white solid (8.8 g): 1H NMR (DMSO-d6) δ 5.25 (s, 1H), 7.30 (m, 4H), 7.49 (m, 4H), 12.60 (s, 1H).
Reaction SMILES: [SiH3][C-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[Fe+2:12].C[SiH](C)CCCC[C-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].[Cl:42][CH2:43][CH2:44][CH2:45][C:46](Cl)=[O:47]>[Cl-].[Al+3].[Cl-].[Cl-]>[Cl:42][CH2:43][CH2:44][CH2:45][C:46]([C-:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1)=[O:47].[CH-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[Fe+2:12]
Reactant: O=C(Cl)CCCCl
Reactant: [SiH3][c-]1cccc1
Agent: [Fe+2]
Agent: C[SiH](C)CCCC[c-]1cccc1
Agent: [Al+3]
Product: O=C(CCCCl)[c-]1cccc1

Procedure:
In a specific embodiment, a silylferrocene compound such as 4-(dimethylsilyl)butylferrocene can be prepared. The process for the preparation of 4-(dimethylsilyl)butylferrocene comprises (a) treating ferrocene with 4-chlorobutyryl chloride, in the presence of aluminum chloride catalyst and an organic solvent to obtain the acylated product, 4-chlorobutyroylferrocene; (b) reduction of 4-chlorobutyroylferrocene to yield 4-chlorobutylferrocene, using without limitation a Clemmensen type reduction; (c) treating 4-chlorobutylferrocene with a metal such as a magnesium under Grignard reaction conditions to form the corresponding Grignard intermediate compound which when reacted with chlorodimethylsilane in-situ yields 4-(dimethylsilyl)butylferrocene.
Reaction SMILES: C[C@@]12[C@H]3[C@@H](O)C[C@]4(C)[C@@](O)(C(CO)=O)CC[C@H]4[C@@H]3CCC1=CC(=[O:6])CC2.C(N(CC)C(=O)COCC(O)=O)C.[CH:40]1([N:46]=[C:47]=[N:48][CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>N1C=CC=CC=1>[C:47]([NH:46][CH:40]1[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1)([NH:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:6]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(CC)C(=O)COCC(=O)O
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a solution of hydrocortisone (5.12 g, 0.014 mole) and N,N-diethyl-3-oxaglutaramic acid (2.57 g, 0.015 mole) in 15 ml pyridine was added dicyclohexylcarbodiimide (3.06 g, 0.015 mole). After the reaction was stirred 10 minutes, 25 ml CH2CH2 was added to it to keep the suspension which had formed sufficiently fluid for stirring. The reaction was stirred overnight at room temperature then filtered. The residue was washed twice with CH2Cl2 and dried to give 2.6 g (89% yield) dicyclohexylurea. The filtrate was concentrated in vacuo to give a foam which was suspended in 20 ml hot dichloromethane and allowed to cool. The suspension was filtered and the filtrate was concentrated in vacuo to give a residue which was dissolved in 20 ml THF; the solution was then diluted to 100 ml with Et2O. Crystals formed overnight and were filtered to give 2.69 g of product which TLC showed to be contaminated with hydrocortisone. These crystals were in turn recrystallized from THF-Et2O (20:80). After 5 days, 2.14 g (29% yield) of light brown needles were filtered which were the etherate of the desired product: mp 95°-97.5° C., NMR (CDCl3) δ5.67 (s, 1, O=C--CH=), 5.07 (s, 2, O=C--CH2O--C=O), 4.48 (m, 3, CHOH,--OH), 4.35 (s, 2, --OCOCH2O--), 4.30 (s, 2, NCOCH2O--), 3.48 (q, 4, O(CH2CH3)2, J=5 Hz), 3.34 (m, 4, N(CH2CH3)2), 1.44 (s, 3, C--CH3), 1.18 (t, 6, O(CH2CH3)2, J=5 Hz), 0.93 (s, 3, C--CH3), 2.9-0.9 (m, 23, CH, CH2); IR (KBr) 3400 cm-1 (s) OH and 1730, 1710 and 1640 cm-1 (s) (C=O); TLC (silica gel, 10% MeOH/Et2O) Rf 0.36; [α]23D=+117° (C=0.5, dioxane).
Reaction SMILES: CN([CH:4]=[O:5])C.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:18][C:19]1[C:20]([Cl:46])=[N:21][C:22]2[C:27]([C:28]=1[NH:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:43]=[CH:44][CH:45]=1)[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:26][CH:25]=[CH:24][CH:23]=2>N1C=CC=CC=1>[Cl:46][C:20]1[C:19]2[N:18]=[C:4]([OH:5])[N:29]([CH2:30][C:31]3[CH:32]=[C:33]([CH:43]=[CH:44][CH:45]=3)[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:41])[CH3:39])[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNc2c(N)c(Cl)nc3ccccc23)c1
Reactant: CN(C)C=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1cccc(Cn2c(O)nc3c(Cl)nc4ccccc4c32)c1
Temperature: 80 °C

Procedure:
DMF (150 mL), pyridine (10 mL), and 1,1′-carbonyldiimidazole (16.7 g, 103 mmol) were added to tert-butyl 3-{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}benzylcarbamate (17.03 g, 41.24 mmol), and the reaction was heated at 80° C. overnight and allowed to cool. The volatiles were removed under reduced pressure. The residue was mixed with ethyl acetate, collected by filtration, and dried under vacuum for two hours to provide 12.06 g of tert-butyl 3-[(4-chloro-2-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl]benzylcarbamate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:12]1[N:16]([CH2:17][CH2:18][CH2:19][OH:20])[C:15]2[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:23]=[CH:24][C:14]=2[N:13]=1)(O)[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH3:10])[C:12]2=[N:13][C:14]3[C:15](=[C:21]([N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])[CH:22]=[CH:23][CH:24]=3)[N:16]2[CH2:17][CH2:18][CH2:19][O:20]1
Reactant: CCN(CC)c1cccc2nc(C(C)(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc3n(c12)CCCOC3(C)c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-{2-[1-(2,4-dichlorophenyl)-1-hydroxyethyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propan-1-ol (Reference example 209, 210 mg, 0.500 mmol) and triphenylphosphine (157 mg, 0.600 mmol) in tetrahydrofuran (10 mL) was added a solution of diethyl azodicarboxylate in toluene (40%, 342 μL, 0.750 mmol) at room temperature. The mixture was stirred at 40° C. for 12 h, concentrated in vacuo, and purified by column chromatography on NH silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture to give a colorless amorphous (97.6 mg, 0.233 mmol, 47%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[N:28]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1(C)C=CC=CC=1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([C:13]([F:15])([F:16])[F:14])([OH:17])[CH2:11][NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[N:28]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: COc1ccc2c(N)cccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.3 %

Procedure:
300 mg (0.97 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 202 mg (1.16 mmol) of 5-amino-2-methoxyquinoline in 10 ml of acetic acid are refluxed for 5 hours. It is allowed to cool to room temperature, 640 mg (3 mmol) of sodium triacetoxy borohydride is added thereto, and it is stirred for 15 hours at room temperature. After toluene is added, the batch is concentrated by evaporation, the residue is taken up in ethyl acetate, washed with saturated NaHCO3 solution, dried and concentrated by evaporation. Column chromatography on silica gel with hexane-ethyl acetate yields 146 mg of the product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[F:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1>>[F:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1cccc(F)c1
Product: O=Cc1cc(F)c(Oc2cccc(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-fluorophenol.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].CC1(C)[O:18][C:17](=O)[C:14]2([CH2:16][CH2:15]2)[C:13](=[O:20])[O:12]1>C(O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([N:7]2[CH2:16][CH2:15][CH:14]([C:13]([OH:20])=[O:12])[C:17]2=[O:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: CCc1ccc(N)cc1
Solvent: CCO
Product: CCc1ccc(N2CCC(C(=O)O)C2=O)cc1
Yield: 66.1 %

Procedure:
A mixture of 4-ethylaniline (1.1 mL; 8.73 mmol) and 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.5 g; 2.94 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane with 5% acetic acid) to afford 1-(4-ethylphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.453 g (67%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1conc1-c1ccc(CCl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1conc1-c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
Methyl 3-(4-chloromethylphenyl)isoxazole-4-carboxylate (7.59 g, 30.16 mmol) was dissolved in THF-water (2:1, 225 ml), lithium hydroxide monohydrate (5.06 g, 120.6 mmol) was added, and the mixture was stirred at room temperature for 6 hours. THF was evaporated under reduced pressure, 2N hydrochloric acid was added to weakly acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (7.14 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28](O)=[O:29])[CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][OH:29])[CH:23]=3)[CH2:20][CH2:21]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2CCN(c3cccc(C(=O)O)c3)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCN(c3cccc(CO)c3)CC2)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
A solution of 1.5 g (3.59 mmol) of 4-{2-[4-(3-carboxyphenyl)piperazin-1-yl]ethyl}piperidine-1-carboxylic acid tert-butyl ester in 20 mL of dry tetrahydrofuran is cooled to −10° C. under argon. An addition of 11 mL of a 1M solution of boranetetrahydrofuran complex in tetrahydrofuran is performed at −10° C. Stirring is maintained overnight at room temperature. The mixture is cooled to 0° C. and 12 mL of 1N aqueous sodium hydroxide solution are added. The product is extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is stirred with diisopropyl ether, filtered and dried under reduced pressure to give 1.0 g (69%) of 4-{2-[4-(3-hydroxymethylphenyl)piperazin-1-yl]ethyl}piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][NH:13][C:14]([C:16]2[S:20][C:19]([NH2:21])=[N:18][C:17]=2[CH3:22])=[O:15])=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]([C:16]2[S:20][C:19]([NH:21][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[N:18][C:17]=2[CH3:22])=[O:15])=[CH:23][CH:24]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccc(Cl)cc1
Reactant: O=C(Cl)C1CC1
Product: Cc1nc(NC(=O)C2CC2)sc1C(=O)NCc1ccc(Cl)cc1
Yield: 55 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use cyclopropanecarbonyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid 4-chlorobenzylamide, the title compound was obtained as a white solid in 55% yield; 1H NMR (DMSO-d6, 300 MHz) δ 8.51 (t, J=6.0 Hz, 1H), 7.36-7.25 (m, 4H), 4.32 (d, J=6.0 Hz, 2H), 2.50 (s, 3H), 1.94-1.84 (m, 1H), 0.93-0.87 (m, 4H); MS (ES+) m/z 350.1 (M+1).
Reaction SMILES: C([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.C1(N=C=NC2CCCCC2)CCCCC1.O[CH2:32][C@H:33]([CH2:46][CH2:47][O:48][C:49](=[O:67])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:34][N:35]1[CH:43]=[N:42][C:41]2[C:40](=[O:44])[NH:39][C:38]([NH2:45])=[N:37][C:36]1=2.CN(C)C=O>ClCCl.CN(C)C1C=CN=CC=1>[NH2:8][C@H:9]([C:13]([O:15][CH2:32][C@H:33]([CH2:46][CH2:47][O:48][C:49](=[O:67])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:34][N:35]1[CH:43]=[N:42][C:41]2[C:40](=[O:44])[NH:39][C:38]([NH2:45])=[N:37][C:36]1=2)=[O:14])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](COC(=O)[C@@H](N)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of N-Boc-L-valine (528 mg; 2.1 mmol) and N,N′-dicyclohexyl carbodiimide (250 mg; 1.21 mmol) in dichloromethane (20 ml) was stirred over night at room temperature, dicyclohexylurea filtered off and extracted with a small volume of dichloromethane, and the filtrate evaporated in vacuo to a small volume. (R)-9-[2-Hydroxymethyl-4-(stearoyloxy)butyl]guanine (340 mg; 0.654 mmol), 4-dimethylaminopyridine (25 mg; 0.205 mmol), and dry N,N-dimethylformamide (15 ml) were added and the mixture was stirred for 4 h at 50° C. under N2. The solvent was evaporated in vacuo to a small volume. Column chromatography on silica gel, then on aluminum oxide (ethyl acetate:methanol: water 15:2:1 as eluent) gave 185 mg (39%) pure title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16](Br)[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:30]4[CH:31]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=4[Cl:32])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cc(F)cc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Yield: 88 %

Procedure:
To a solution of [(R)-8-bromo-6-fluoro-3,4-dihydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate, prepared in Example 38, step 2 (0.40 g, 0.97 mmol) and 2,5-dichlorophenylboronic acid (0.56 g, 2.9 mmol) in dioxane (10 ml) was added a solution of potassium carbonate (0.34 g, 2.4 mmol) in water (2 mL) and the mixture purged with nitrogen for 20 minutes. Dichlorobis(tri-o-tolylphosphine)palladium (II) (20 mg, 0.029 mmol) was added and the reaction mixture heated to reflux for 1 hour. The cooled reaction mixture was then partitioned between ethyl acetate (100 mL) and 2.0 M aqueous sodium hydroxide (100 mL). The organic layer was separated, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 5 to 20% ethyl acetate in hexane gave 0.41 g (88%) of ((R)-8-(2,5-dichlorophenyl)-6-fluoro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. MS (ES) m/z 496.0 ([M+NH4]+).