Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21]Br>CC(C)=O>[Cl:18][CH2:19][CH2:20][CH2:21][O:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: ClCCCBr
Reactant: COc1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OC)c(OCCCCl)c1
Yield: 86240.9 %

Procedure:
A mixture of 2,5-dimethoxyphenol (29 g, 0.19 mmol), K2CO3 (35 g), 3-chlorobromopropane (38.5 g, 0.25 mol) and acetone (250 ml) was stirred and refluxed for 6 hours, and then stirred at ambient temperature for 16 hours. The reaction was filtered, and the filtrate was concentrated to an orange liquid. The liquid was taken up into Et2O, and the organic layer washed with 1N NaOH, H2O, dried (MgSO4) and was concentrated to yield 37.8 g of an orange solid. An 11.7 g sample of this solid was flash chromatographed on silica gel (180 g) with 5% EtOAc/CH2Cl2 as eluent. Concentration of similar fractions gave 7.2 g of white, waxy solid, which was recrystallized from petroleum ether to afford a white solid, m.p.=48°-50° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[CH2:13][C:14]#[N:15])#N.N>C(O)C.[Ni]>[O:10]1[C:6]2[C:5]3[CH2:13][CH2:14][NH:15][CH2:1][CH2:3][C:4]=3[CH:12]=[CH:11][C:7]=2[O:8][CH2:9]1
Reactant: N#CCc1ccc2c(c1CC#N)OCO2
Agent: [Ni]
Agent: N
Solvent: CCO
Product: c1cc2c(c3c1CCNCC3)OCO2

Procedure:
(5-Cyanomethyl-1,3-benzodioxol-4-yl)acetonitrile (6.00 g, 30.0 mmoles) from Example 58C was reductively cyclized with Raney-Nickel (1.21 g) under a hydrogen atmosphere and high pressure (1100 p.s.i.) in a 10% ammonia in ethanol solution (121 mL) at 100° C. for one hour. The mixture was cooled, and the catalyst filtered off and washed with hot ethanol. The mixture was concentrated under reduced pressure, and the residue purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with 7:3 methylene chloride:methanol to afford the title compound. MS (DCI) m/z 192 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]2[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:20]2[S:24][C:23]([N:25]3[CH2:31][CH2:30][CH2:29][NH:28][C:27](=[O:32])[CH2:26]3)=[N:22][CH:21]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C.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]>[CH:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:12][C:13]3[CH:14]=[C:15]([C:20]4[S:24][C:23]([N:25]5[CH2:31][CH2:30][CH2:29][NH:28][C:27](=[O:32])[CH2:26]5)=[N:22][CH:21]=4)[CH:16]=[C:17]([CH3:19])[CH:18]=3)[N:7]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: Clc1nccc(C2CCC2)n1
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: Cc1cc(Nc2nccc(C3CCC3)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 74074.1 %

Procedure:
2-Chloro-4-cyclobutylpyrimidine (50 mg, 0.297 mmol), 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 90 mg, 0.297 mmol), Pd2(dba)3 (27.2 mg, 0.030 mmol), XPhos (70.7 mg, 0.148 mmol), and potassium carbonate (82 mg, 0.593 mmol) were combined in t-amyl alcohol (0.99 ml). The mixture was purged with argon for 5 minutes, capped, and stirred at 90° C. overnight. The mixture was then cooled to room temperature and loaded directly on the column and was purified by silica gel chromatography (10% methanol/dichloromethane) to provide 98 mg (0.22 mol, 76% yield) of 4-(5-{3-[(4-cyclobutylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-1,4-diazepan-2-one as a tan solid. MS APCI: [M+H]+ m/z 435.2. 1H NMR (600 MHz, d6-DMSO) δ 9.48 (s, 1H), 8.32 (d, J=4.8 Hz, 1H), 7.92 (s, 1H), 7.55 (dd, J=4.8 Hz, 5.4 Hz, 1H), 7.43 (s, 1H), 7.38 (s, 1H), 6.88 (s, 1H), 6.66 (d, J=5.4 Hz, 1H), 4.14 (s, 2H), 3.75 (m, 2H), 3.52 (m, 1H), 3.18 (m, 2H), 2.33-2.23 (m, 4H), 2.24 (s, 3H), 2.02 (m, 1H), 1.88 (m, 1H), 1.76 (m, 2H). rhSYK activity=+++
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].[C:32]([C:35]1[S:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:34])[CH3:33]>CCCCCC.C(OCC)(=O)C>[C:32]([C:35]1[S:36][CH:37]=[C:38]([C:11]2[C:10]3[O:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=4)[C:9]=3[C:8]([CH3:29])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:31])[CH3:30])[C:24]=2[CH3:25])[CH:39]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1cc(Br)cs1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1cc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)cs1
Yield: 62 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-acetyl-4-bromothiophene, the title compound was synthesized in the same manner as in Example 107. Yield: 62%. Melting point: 133-134° C. (hexane-ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[C:23]([CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])=[N:24][CH:25]=[CH:26][CH:27]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:25]2[CH:26]=[CH:27][CH:22]=[C:23]([CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][C:30]3=[O:34])[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: O=C1CCCN1Cc1ncccc1Br
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCCC4=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.14 g, 0.48 mmol) and 1-[(bromopyridin-2-yl)methyl]pyrrolidin-2-one (0.12 g, 0.47 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:18])[CH3:17].[Br:19]Br.[OH-].[Na+]>CC(OC)(C)C.C(O)(=O)C>[Br:19][CH2:17][C:16]([C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[Cl:1])=[O:18]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[2-chloro-4-(4-chlorophenoxy)phenyl]ethanone (1000 g) was dissolved in MTBE (5000 mL) and a solution of bromine (563 g) in glacial acetic acid (400 mL) was added dropwise at room temperature. After completion of the addition the mixture was stirred for 1 h at room temperature and the pH was adjusted to 7-8 by addition of 10% NaOH solution. The organic layer was separated, extracted twice with MTBE and the combined organic phases were washed with sat. NaHCO3 solution (1×) and brine (2×). The solvent was evaporated and the crude product was used directly in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>O1CCCC1>[Cl:17][CH2:18][CH2:19][C:20]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:21]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(Cl)CCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCl)N1CCc2ccccc21
Temperature: 10 °C

Procedure:
A mixture of 2,3-dihydro-1H-indole (50 g), triethylamine (132 g) and tetrahydrofuran (1000 mL) was cooled down to 10° C. followed by the addition (over a period of 60 min) of a solution of 3-chloropropanoyl chloride (55 g) in tetrahydrofuran (400 mL). The mixture was filtered, and the remaining solution was evaporated in vacuo to dryness. The residue was purified by flash chromatography (eluent: ethyl acetate/heptane 1:3) giving the title compound as a crystalline white material (31 g).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:4]1.O[N:29]=[C:30]([NH2:32])[CH3:31]>>[CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]3[O:26][N:32]=[C:30]([CH3:31])[N:29]=3)[CH2:10]2)=[O:8])[CH2:4]1
Reactant: CC(N)=NO
Reactant: COC1CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)C1
Product: COC1CN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(C)no3)C2)C1
Yield: 23.3 %

Procedure:
250 mg (0.647 mmol) of 1-[(3-methoxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 103A) and 52.7 mg (0.712 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 1. Enantiomer separation of the racemate according to Method 16D gave 73.0 mg of the title compound from Example 311 and 64.0 mg of the title compound from Example 312 (50% of theory).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH2:16][CH2:17][OH:18])[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5]1.CN(C=O)C.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>O>[CH2:31]([O:18][CH2:17][CH2:16][O:15][C:7]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5][N:4]([CH3:3])[C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCBr
Reactant: Cn1nc(-c2ccccc2)c(OCCO)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOCCOc1c(-c2ccccc2)nn(C)c1-c1ccccc1

Procedure:
Sodium hydride (0.89 g, 57%, 0.02 mole) is added to a solution of 2-[(1-methyl-3,5-diphenyl-4-pyrazolyl)oxy]ethanol (5.9 g, 0.02 mole) and dry DMF (50 ml). The reaction mixture is stirred and heated to 80°-90° C. The stirred mixture is allowed to cool. This mixture is added to a solution of 1-bromoheptane (9 g, 0.05 mole) and dry DMF (75 ml). After heating at 80°-90° C for 4 hours, the stirred reaction mixture is poured into water.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:12]1[CH2:16][C:15]([Br:17])=[CH:14][CH:13]=1)=[CH:5]\[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CC(C[AlH]CC(C)C)C>>[Br:17][C:15]1[CH2:16][C:12](/[C:4](=[CH:5]/[CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)/[CH2:3][OH:2])=[CH:13][CH:14]=1
Reactant: COC(=O)/C(=C\C1CCCCC1)C1=CC=C(Br)C1
Agent: CC(C)C[AlH]CC(C)C
Product: OC/C(=C\C1CCCCC1)C1=CC=C(Br)C1
Yield: 36.3 %

Procedure:
According to method 16e was used (Z)-2-(4-bromo-cyclopenta-1,3-dienyl)-3-cyclohexyl-acrylic acid methyl ester (116.9 g, max. 0.338 mol), DIBALH (750 ml, 20% in toluene, 0.887 mol) to get 105 g crude product. Purify by silica gel chromatography, eluting with gradient 10:0 to 6:4 hexane:TBME to get 34.7 g pure compound. MS (m/e): 301.0/303.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[C:10]([CH3:15])=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C(Cl)Cl>[CH3:15][C:10]1[C:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:7][N:6]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Cc1ncccc1Oc1ccc(N)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncccc1Oc1ccc(NC(=O)Oc2ccccc2)cn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
5-Amino-2-(2-methylpyridin-3-yloxy)pyridine (D9, 60.3 g, 0.3 mole) in dry CH2Cl2 (2.5L) was cooled to −20° C. under argon. Triethylamine (46 ml, 0.33 mole) was added, followed dropwise by phenyl chloroformate (41 ml, 0.33 mole) and the mixture was stirred at −20° C. for 1 hour. After warming to ambient temperature, the mixture was washed with dil. aq. NaHCO3, dried (Na2SO4) and evaporated in vacuo. The residue was recrystallised from ethyl acetate/60-80° petroleum ether to afford the title compound (53.7 g, 56%) as a pink solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:15]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].Cl>C(Cl)Cl>[C:38]([O:31][CH2:30][CH2:29][NH:28][C:26]([C:15]1[N:14]=[N:13][N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[O:27])(=[O:40])[CH3:39]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCO)c2COc2cccc(F)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCOC(C)=O)c2COc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]phenyl}-5-[(3-fluorophenoxy)methyl]-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (500 mg) obtained in Example 498 in methylene chloride (10 ml) were added pyridine (0.2 ml) and acetic anhydride (0.17 ml), and the mixture was stirred at room temperature for 10 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/2 to 1/1) and recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (480 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[CH2:10]1[O:18][C:17]2[C:12](=[C:13]([S:19]([NH:22]C(OC(C)(C)C)=O)(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=2)[O:11]1.FC(F)(F)C(O)=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[CH2:10]1[O:18][C:17]2[C:12](=[C:13]([S:19]([NH2:22])(=[O:20])=[O:21])[CH:14]=[CH:15][CH:16]=2)[O:11]1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)c1cccc2c1OCO2
Agent: COCCNCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 199.4 %

Procedure:
Boc methylenedioxybenzenesulfonamide bis-methoxyethylamine tethered product (18) (0.023 g, 0.033 mmol) was dissolved in DCM (1 mL). Trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo, and the resultant orange oil was dissolved in DCM (1 mL) and the solution cooled to 0° C. using an ice bath. Diisopropylethylamine (0.173 mL, 0.99 mmol) was added dropwise with stirring, followed by (3R,3aS,6aR) hexahydrofuro[2,3-b]furan-2-yl 4-nitrophenyl carbonate (0.012 g, 0.040 mmol) in one portion as a solid. After 5 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature with stirring overnight. The solvent was removed in vacuo, and the resultant yellow oil was purified by flash column:chromatography (4:1 ethyl acetate/hexane to ethyl acetate to 9:1 DCM/methanol) to give bis-THE methylenedioxybenzenesulfonamide bis-methoxyethylamine tethered product (51) (0.022 g, 89%) as a yellow foam: Rf=0.50 (9:1 DCM/methanol); 1H NMR (CDCl3): 7.33 (1H, dd, J=8.2, 1.8 Hz), 7.17 (1H, d, J=1.8 Hz), 7.13 (2H, d, J=8.6 Hz) 6.89 (1H, d, J=8.2 Hz), 6.80 (2H, d, J=8.6 Hz), 6.09 (2H, s), 5.65 (1H, 8, J=5.2 Hz), 5.08-4.98 (2H, m), 4.35-4.24 (2H, m), 4.00-3.90 (1H, m), 3.90-3.63 (6H, m), 3.61-3.49 (2H, m), 3.42-3.31 (2H, m), 3.35 (6H, s), 3.16-3.07 (2H, m), 3.05-2.88 (4H, m), 2.88-2.74 (2H, m), 1.83 (1H; septet, J=6.6 Hz), 1.74-1.54 (1H, m), 1.48-1.35 (5H, m); 0.92 (3H, d, J=6.6 Hz), 0.88 (3H, d, J=6.6 Hz), OH signal not observed; coupled LCMS showed the product as a single major peak with m/z 752 [M+H]+; HPLC (205 nm) showed the material as a single major peak at RT of 1.92 min. (purity=91%).
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12]CC)=[O:11])(=O)C.[Cl-].[Na+].[BrH:23]>>[Br:23][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(CCCCOC(C)=O)c1ccccc1
Reactant: Br
Agent: [Cl-]
Agent: [Na+]
Product: O=C(O)C(CCCCBr)c1ccccc1
Temperature: 130 °C
Yield: 75 %

Procedure:
Ethyl 6-acetoxy-2-phenylhexanoate (22 g) was dissolved in 47% aqueous hydrobromic acid (100 ml), and the solution was heated at 130° C. for 4 hours. After the completion of the reaction, the solution was cooled, and aqueous sodium chloride (300 ml) was added, followed by extraction of the product with isopropyl ether. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, and development was effected with isopropyl ether to give 6-bromo-2-phenylhexanoic acid (16 g, 75%).
Reaction SMILES: [C:1]([O:6][CH:7]([CH:30]=[CH2:31])[C@H:8]1[O:12][C@@H:11]([N:13]2[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:10][C@@H:9]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])([O:3][CH2:4][CH3:5])=[O:2].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:6][CH:7]([CH:30]=[CH2:31])[C@H:8]1[O:12][C@@H:11]([N:13]2[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[N:16]([C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:14]2=[O:15])[CH2:10][C@@H:9]1[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(OC(=O)OCC)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CC(OC(=O)OCC)[C@H]1O[C@@H](n2cc(C)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 15 h

Procedure:
To a solution of 5'-O-carbethoxy-5'-vinyl-3'-O-t-butyldimethylsilyl thymidine (1.7 g) in 20 ml of pyridine was added benzoyl chloride (2.5 eq.) and diisopropyl-ethylamine (95.0 eq.) and the resulting mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate followed by brine, and the organic layer was then dried over sodium sulfate. The title compound was purified by flash chromatography using 20% ethyl acetate/hexane.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH3:16])[O:15][C:13](=[O:14])[CH2:12][C:10](=[O:11])[O:9]1.[C:17](Cl)(=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C>C(Cl)Cl>[OH:31][C:17](=[C:12]1[C:13](=[O:14])[O:15][C:8]([CH3:16])([CH3:7])[O:9][C:10]1=[O:11])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCC(O)=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
14.3 mL of pyridine is added at 0° C., to a solution of Meldrum's acid (10.60 g, 73.5 mmol) in 70 mL of anhydrous CH2Cl2. After stirring for 15 min at this temperature, commercial tetradecanoyl chloride (18.16 g, 73.5 mmol) is added dropwise, so that the temperature remains below 10° C. After stirring for 2 h at 0° C. and for 1 h at ambient temperature, the reaction medium is washed with 50 mL of a 2N solution of HCl then 2×50 mL of water. After a last washing with a saturated aqueous solution of NaCl, the organic phase is dried over MgSO4, filtered and concentrated under vacuum. The oil obtained is crystallized by the addition of absolute ethanol then left overnight in the refrigerator. The solid is then filtered then rinsed with cold absolute ethanol before being dried in order to produce compound 17 (21.25 g, 59.9 mmol, 81%) in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][NH:7][CH3:8])[CH3:2].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:32].[N:33]1([CH2:39][CH2:40][N:41]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53]([OH:55])=O)[CH:49]=[N:50][C:44]=3[NH:43][C:42]2=[O:56])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[ClH:32].[CH2:1]([O:3][C:4]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][N:7]([CH3:8])[C:53](=[O:55])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[N:41]([CH2:40][CH2:39][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[CH2:46][C:45]=2[CH:47]=1)[CH3:2]
Reactant: CCOc1cccc(CNC)c1OCC
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CCOc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)c1OCC
Yield: 56 %

Procedure:
According to the procedure of Example 1, except substituting 2,3-diethoxy-benzyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.18 g, 56%) was prepared as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.63-10.49 (m, 1H), 10.14-10.12 (m, 1H), 8.41-8.31 (m, 1H), 8.03-7.91 (m, 1H), 7.52-7.45 (m, 1H), 7.38-7.19 (m, 1H), 7.03-6.90 (m, 2H), 6.70-6.51 (m, 1H), 4.63-4.51 (m, 4H), 4.02-3.91 (m, 6H), 3.81-3.68 (m, 4H), 3.60-3.50 (m, 2H), 3.40-3.28 (m, 2H), 3.20-2.85 (m, 5H), 1.40-1.31 (m, 6H); MS (ESI) m/e 524 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2)=[O:1]
Reactant: CC(C(=O)O)c1ccc2cc(CO)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C(=O)O)c1ccc2cc(C=O)ccc2c1

Procedure:
A mixture of 23 g. of 6-hydroxymethyl-2-naphthyl-α-methylacetic acid, 230 g. of manganese dioxide, and 2 l. of chloroform are stirred for 12 hours; the mixture is filtered and evaporated to give 6-formyl-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2].[BH4-].[Na+].Cl>CO>[F:13][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:6]=1[CH2:7][OH:8])[C:1]#[N:2]
Reactant: COC(=O)c1ccc(C#N)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(CO)c(F)c1

Procedure:
16.10 g (89.9 mmol) of methyl 4-cyano-2-fluorobenzoate are dissolved in 150 ml of methanol. Then 3.40 g (89.9 mmol) of sodium borohydride are added in portions. After the reaction has taken place (TLC check), the mixture is adjusted to pH 3 with dilute hydrochloric acid and extracted several times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution and dried with magnesium sulfate. The solvent is then removed in vacuo, and the residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 15:1→3:7). 3.70 g (27.2% of theory) of the title compound are obtained.