Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:23][CH2:24][O:25][C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[C:29]#[N:30])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccc(OCCBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCCOc3cccc(C#N)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
616 mg (1.91 mmol) of 1-t-butoxycarbonyl-4-(4-aminophenoxy)piperidine, 432 ml (1.91 mmol) of 3-(2-bromoethoxy)benzonitrile and 634 mg (3.82 mmol) of potassium iodide were dissolved in 20 ml of dimethylformamide. 2.64 g (19.1 mmol) of potassium carbonate was added to the solution, and they were stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure. After the treatment with ethyl acetate as extractant in an ordinary manner, the crude product was obtained. This product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:55]=[CH:54][CH:53]=[CH:52][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=3)=[N:9][C:8]=2[N:7]([CH2:26][C:27]2[N:31]=[CH:30][N:29](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:28]=2)[C:6]1=[O:51].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[F:1][C:2]1[CH:55]=[CH:54][CH:53]=[CH:52][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=3)=[N:9][C:8]=2[N:7]([CH2:26][C:27]2[N:31]=[CH:30][NH:29][N:28]=2)[C:6]1=[O:51]
Reactant: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3Cc2nc[nH]n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A suspension of N-{4-[1-(2-fluoro-benzyl)-2,6-dioxo-3-(1-trityl-1H-[1,2,4]triazol-3-ylmethyl)-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-acetamide (47 mg, 0.06 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with trifluoroacetic acid (1.0 mL). The reaction was stirred at 25° C. for 1 h. At this time, the reaction was treated with triethylsilane (0.01 mL, 0.06 mmol) and then was concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford N-{4-[1-(2-fluoro-benzyl)-2,6-dioxo-3-(1H-[1,2,4]triazol-3-ylmethyl)-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-acetamide (12 mg, 26%) as a white solid: LR-MS for C24H21FN8O3 (M+H)+ at m/z=489.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.CCOCC>O1CCCC1>[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][O:20][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (3.36 g of a 50% dispersion in mineral oil) was added portionwise to a stirred solution of the product of part (i) (17.43 g) in dry tetrahydrofuran (200 ml) and the mixture was stirred at room temperature for 1 hour. 4-Fluoronitrobenzene (9.87 g) was added dropwise and the mixture was stirred for a further 18 hours and then evaporated. Water was added to the residue and the mixture was extracted several times with dichloromethane. The combined extracts were washed with water, dried (MgSO4) and evaporated to give an oil which solidified on trituration with ether. The solid was filtered off, washed with a little ether and crystallised from ethyl acetate/hexane to give the product, (13.51 g), m.p. 121°-122°.
Reaction SMILES: [CH3:1][Zn]Cl.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[C:25](Br)=[CH:24][N:23]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[C:25]([CH3:1])=[CH:24][N:23]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Reactant: C[Zn]Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Yield: 95.6 %

Procedure:
MeZnCl (2.0M in THF, 720 uL, 1.4 mmol) was added to a stirred solution 4-(7-Benzenesulfonyl-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.48 mmol) and tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.12 mmol) in THF (10 mL) at room temperature under N2. The solution was stirred and heated at reflux for 2 hours, cooled to room temperature, quenched with saturated aqueous NH4Cl, extracted into EtOAc (2×100 mL), dried over Na2SO4 and concentrated in vacuo. The product was purified on a Biotage (silica, 40% EtOAc/hexanes) to give 4-(7-Benzenesulfonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (210 mg, 94%.) LCMS (APCI+) m/z 458 [M+H]+; Rt: 3.73. 1H NMR (CDCl3, 400 MHz) δ 8.49 (1H, s), 8.18 (2H, d, J 8.2 Hz), 7.59 (1H, t, J 6.9 Hz), 7.50 (2H, t, J 7.8 Hz), 7.34 (1H, s), 3.59-3.54 (4H, m), 3.48-3.44 (4H, m), 2.35 (3H, s), 1.48 (9H, s.)
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[CH2:5]1)=[N+]=[N-].[H][H]>[Pd]>[NH2:1][C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15]([NH2:16])=[N:14][C:12]2=[O:13])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1CO
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccn([C@H]2C[C@H](N)[C@@H](CO)O2)c(=O)n1

Procedure:
An alternate synthesis of compound (XIII) involves treatment of 3,-azido-5'-0-acetyl-2',3'-dideoxyuridine (X) with 4-chlorophenylphosphorodichloridate and 1,2,4-triazole in pyridine at room temperature for 3 days to give the 4-trizolylpyrimidinone derivative. Subsequent treatment with aqueous ammonia in dioxane (1:3 v/v) for 4 hours, then saturated methanolic ammonia overnight at room temperature, yields the 3'-azido analog (XII). Compound (XII) is then reduced under 50 psi of hydrogen in the presence of 10% palladium on charcoal at room temperature for 6 hours to obtain the desired 3'amino-2',3'-dideoxycytidine derivative (XIII).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])(C)C)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].[CH3:17][CH:18]([CH3:29])[CH2:19]CCC1C=CC(Br)=CC=1>>[CH3:4][Si:2]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:16][CH2:17][CH:18]([CH3:29])[CH3:19])=[CH:11][CH:12]=1)([CH3:1])[CH3:3]
Reactant: CC(C)CCCc1ccc(Br)cc1
Reactant: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Product: CC(C)CCCc1ccc(C#C[Si](C)(C)C)cc1

Procedure:
Using the same general procedure as described for Compound 21, but using instead 4-(4-methylpentyl)bromobenzene (Compound 30), the title compound was synthesized as a colorless oil. PMR (CDCl3): & 0.32 (9H, s), 0.93 (6H, d, J-6.6 Hz), 1.18-1.29 (2H, m), 1.52-1.70 (3H, m), 2.58 (2H, t, J-7.7 Hz), 7.12 (2H, d, J-8.1 Hz), 7.43 (2H, d, J-8.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:6][NH:7]2.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+]>CN(C)C=O>[CH2:17]([N:7]1[C:8]2[C:3](=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=2)[C:4](=[O:16])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:6]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1n[nH]c2cccc(Cl)c2c1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nn(Cc2ccccc2)c2cccc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
To 1.00 g (4.2 mmol) of methyl 5-chloro-4-oxo-1,4-dihydrocinnoline-3-carboxylate and 0.86 g (5.0 mmol) of benzyl bromide in 30 mL of dimethylformamide was added 0.20 g (5.0 mmol) of sodium hydride (60% dispersion in mineral oil). The mixture was stirred for 4 h at room temperature and quenched with water. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated onto silica gel. The crude material was purified by flash chromatography eluting with a 33-50% ethyl acetate/hexanes gradient mixture to give 0.86 g (62%) of the title compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:22]=[C:21]2[C:16]([C:17]([F:23])=[CH:18][CH:19]=[CH:20]2)=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:17]1[C:16]2[C:21](=[CH:22][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1cc2cccc(F)c2n1
Product: FCc1cccc(C#CCCn2cc3cccc(F)c3n2)n1
Yield: 12.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-fluoromethylpyridine (93 mg, 0.49 mmol) and 2-but-3-ynyl-7-fluoro-2H-indazole (84 mg, 0.45 mmol). Reaction time: 6 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 17 mg (57 μmol, 13%) of 7-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:29][CH:28]=2)[CH2:25][CH2:26]1)=[O:23])[CH3:20]
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[Cl:11].Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:15]([CH3:16])[CH3:14])=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1ccc(F)cc1Cl
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)cc1Cl
Yield: 99 %

Procedure:
To a stirred solution of 4.00 g (20.6 mmol) 2-chloro-4-fluoro-benzoic acid methyl ester (Apollo) and 60 ml dimethylsulphoxid were added 2.03 g (24.7 mmol) dimethylamine hydrochloride and 5.97 g (43.2 mmol) potassium carbonate. The reaction mixture was stirred over night and is reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude product 1a was obtained in 99% yield (4.36 g, 20.4 mmol) and was used for the next step without purification.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[O:16][CH2:17][CH2:18][CH2:19][CH3:20].[Li+].[OH-]>C1COCC1.CO>[CH2:17]([O:16][C:7]1[CH:8]=[C:9]([C:12]([F:14])([F:13])[F:15])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:21])=[O:2])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1cc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1cc(C(F)(F)F)ccc1C=CC(=O)O

Procedure:
3-(2-Butoxy-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (464 mg) was reacted with 1N LiOH (10 ml) in THF and CH3OH for 1 hr as described above to yield title compound
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>CN(C=O)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCNCCO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N(CCO)CCO)cc1
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 70.7 %

Procedure:
Diethanolamine (2.70 mL, 2.5 mmol) was added to 1-fluoro-4-nitrobenzene (1.0 g, 7.09 mmol) in DMF (30 mL). The resulting mixture was stirred at 140° C. for 3.5 h. The solution was cooled to room temperature and solvent was evaporated off in vacuo. The residue was dissolved in EtOAc (30 mL) and washed with water (3×10 mL) and brine (3×20 mL) and dried (MgSO4). Solvent was evaporated off in vacuo and the product was purified by flash chromatography, eluting with EtOAc to give 67 (400 mg, 25%) as a yellow solid. H1 NMR (500 MHz, CDCl3): δ=8.06 (2H, d, J=9.50 Hz, ArH), 6.87 (2H, d, J=9.50 Hz, ArH), 4.27 (2H, t, J=5.35 Hz, 2×OH), 3.83 (4H, q, J=5.55 & 5.45 Hz, 2×CH2), 3.74 (4H, t, J=5.62 Hz, 2×CH2).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>>[C:22](=[O:23])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:19][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC(=O)OCc1ccccc1

Procedure:
Example 3 is repeated to react oleic acid with benzyl chloroformate in the presence of dry sodium carbonate.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCl.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][CH:15]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)CCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 500 ml three-necked flask provided with a mechanical agitator and a thermometer were added a solution of 22.4 g (133.2 mmol) in theoretical amount of 3-phenylpropionyl chloride which was prepared in the step 1, dissolved in 100 ml dichloromethane, 14.4 g (205.9 mmol) methylphenyl ether and 150 ml dichloromethane, the mixture was cooled in an ice salt bath to lower than −5° C., while maintaining the inside temperature at −5° C. to −10° C., 17.8 g (133.2 mmol) anhydrous AlCl3 was added portionwise, upon the completion of addition. The mixture was stirred at this temperature for 1 hour and then at room temperature for 1 hour, the resultant was poured under stirring into a mixture of 100 g ice, 100 g water and 40 ml concentrated hydrochloric acid, the organic layer was separated, and the aqueous layer was extracted with dichloromethane twice ×20 ml, the organic layers were combined and washed with saturated brine, then with saturated aqueous sodium bicarbonate solution, and then with saturated brine until neutrality, dried over anhydrous magnesium sulfate, filtrated and concentrated under a reduced pressure to obtain a crude product, which was recrystallized with petroleum ether and ethyl acetate (2:1) to obtain a 23.5 g product, the mother liquid was concentrated and recrystallized to obtain a 3.3 g product in a yield of 83.7% in total, mp: 96-97□. 1H-NMR (CDCl3, 400 MHz) δ: 3.05 (2H, t, J=8.16 Hz), 3.25 (2H, t, J=8.16 Hz), 3.86 (3H, s, OCH3), 6.92 (2H, d, J=9.00 Hz, ArH), 7.18˜7.32 (5H, m, ArH), 7.94 (2H, d, J=9.00 Hz, ArH); EI-MS m/e (%): 240.1 (M+, 37), 135 (100).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][CH:32]([O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1
Reactant: OC1CCN(c2nnc3ccc(F)cn23)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (395 mg, 1.29 mmol) was added dropwise to a solution of Intermediate 24c (254 mg, 1.07 mmol) and Et3N (0.20 mL, 1.40 mmol) in DMF (3 mL) at RT under N2. The mixture was stirred for 1 h then Et3N (0.10 ml, 0.70 mmol) and triisopropylsilyl trifluoromethanesulfonate (200 mg, 0.65 mmol) were added sequentially, and the mixture stirred for 1 h. The solvent was evaporated, the residue applied to an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo left the title compound (339 mg, 80%). LCMS (Method 1): Rt 4.74 min, m/z 393 [MH+].
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:20][CH2:19]1
Reactant: CC(C)CCBr
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(CCC(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].S(Cl)([Cl:18])(=O)=O.O>C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([Cl:18])[C:6](=[O:13])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH3:12]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(=O)C(Cl)C(=O)OCC
Temperature: -9 °C
Yield: 215.2 %

Procedure:
Dissolve 3-oxo-pentanedioic acid diethyl ester (1122 g, 5.327 mol) in CH2Cl2 (3 L) and cool to −9° C. To the above solution, slowly add a solution of sulfuryl chloride (374 g, 2.69 mol) in CH2Cl2 (3 L) over 3 h. Upon completion, add a second charge of sulfuryl chloride (374 g, 2.69 mol) in CH2Cl2 (3 L) over 4 h. Stir the resulting cooled solution for one hour, then warm to room temperature and stir overnight. Cool the solution in an ice bath and slowly add water (8 L). Stir for 15 min, then separate the layers. Extract the aqueous layer with additional CH2Cl2. Combine the organic phases and wash with saturated NaHCO3 (3 L). Dry and concentrate the organic solution to obtain 1370 g (105%) of the title compound as a colorless oil. Use the material as-is in the next reaction without further purification. ES/MS m/z (35Cl) 235 [M−1]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.[NH:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[NH2:21]>C(O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:20]1[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:21]1)[CH3:27]
Reactant: CCOC(=O)CNN
Reactant: COc1ccc(CC=Cc2ccc(Br)cc2)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CN1N=C(c2ccc(OC)cc2)CC1c1ccc(Br)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of ([1-(4-bromophenyl)-3-(4-methoxypheyl)-propene]) (3.17 g, 10 mmol) and ethyl hydrazinoacetate hydrochloride (1.54 g, 10 mmol) in ethanol (50 mL) was heated to reflux for 4 h. After cooling to room temperature, the solution was concentrated, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (5-10% ethyl acetate in heptane) provided [5-(4-bromo-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-acetic acid ethyl ester (3.25 g, 78%) as an oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([OH:39])=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:48][CH:47]=3)=[CH:42][CH:41]=2)[N:34]=1.[CH2:61](O)[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68]>O1CCCC1>[F:32][C:33]1[C:38]([O:39][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])=[CH:37][CH:36]=[C:35]([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:48][CH:47]=3)=[CH:44][CH:45]=2)[N:34]=1
Reactant: CCCCCCCCO
Reactant: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(O)c(F)n3)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(-c3ccc(OCCCCCCCC)c(F)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.02 ml (6.45 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. to 1.70 g (6.45 mmol) of triphenylphosphine in 100 ml of tetrahydrofuran and the mixture is stirred at room temperature for 30 minutes. 1.70 g (4.30 mmol) of 2-fluoro-3-hydroxy-6-[4-(4-octyloxyphenyl)phenyl]pyridine and 0.56 g (4.30 mm 1-octanol are then added. After a reaction time of 18 hours, the precipitated product is filtered off and purified by chromatography (silica gel, dichloromethane) and by recrystallization from acetonitrile, giving 1.13 g of 2-fluoro-3-octyloxy-6-[4-(4-octyloxyphenyl)phenyl]pyridine. ##STR26##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH2:9][N:10]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH2:9][NH2:10]
Reactant: O=C1c2ccccc2C(=O)N1CCSc1ncccn1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCSc1ncccn1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A mixture of N-[2-(2-pyrimidinylthio)ethyl]phthalimide (17.1 g), hydrazine hydrate (21 g) and ethanol (200 ml) was stirred for one hour under reflux. The crystals separated was filtered off, and the filtrate was concentrated under reduced pressure to obtain 2-(2-pyrimidinylthio)ethylamine (6.6 g 71%) as an oil.