Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:12]([NH:22][CH:23]([CH2:27]O)[CH:24]([CH3:26])[CH3:25])[N:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:9][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:12]([N:22]2[CH:23]([CH:24]([CH3:26])[CH3:25])[CH2:27][O:8][CH:7]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:11]=1
Reactant: CC(C)C(CO)Nc1cc(C(F)(F)F)c(C#N)c(Cl)n1
Reactant: O=Cc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)C1COC(c2ccccn2)N1c1cc(C(F)(F)F)c(C#N)c(Cl)n1

Procedure:
Pyridine-2-carboxaldehyde (207 mg, 1.9 mmol) was added to a toluene solution (15 mL) of 2-chloro-6-[[1-(hydroxymethyl)-2-methyl-propyl]amino]-4-(trifluoromethyl)pyridine-3-carbonitrile (400 mg, 1.3 mmol) (Compound 13) followed by a catalytic amount of para-toluene sulfonic acid (50 mg). The reactants were refluxed for 6 hours in a Dean-Stark apparatus, concentrated under reduced pressure, adsorbed onto silica and purified using a neutral alumina column, eluting with a mobile phase of 10% ethyl acetate in hexane. 2-Chloro-6-[4-isopropyl-2-(2-pyridyl)oxazolidin-3-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile (Compound 12) was isolated as a solid in 20% yield. mp 112-115° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+]>O.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(Oc2cccc(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(Oc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-(3-fluorophenoxy)benzoate (0.202 g; 0.880 mmol) was added to a mixture of NaOH in water (2 mL; 2M) and dioxane (1 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated under reduced pressure and dissolved in water. The aqueous layer was acidified with a solution of hydrogen chloride 6M and the precipitated product was collected by filtration to yield 0.200 g (quantitative) of the title compound as a grey solid which was used without further purification.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:25][B-:26]([F:29])([F:28])[F:27].[CH3:30][O+](C)C.C(O)C>ClCCl>[F:25][B-:26]([F:29])([F:28])[F:27].[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([N+:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]([CH3:30])[CH:17]=3)=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(-n2cnc3ccccc32)cc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: Cn1c[n+](-c2ccc(S(=O)(=O)c3ccccc3)cc2)c2ccccc21
Reaction time: 16 h
Yield: 80 %

Procedure:
A solution of 1-(4′-phenylsulfonylphenyl)benzimidazole (6.7 g, 20 mmol) in dichloromethane (100 ml) is admixed at −10° C. with trimethyloxonium tetrafluoroborate (3.3 g, 22 mmol) and stirred under argon for 16 h. After adding ethanol, the precipitate formed is filtered off and washed with cold petroleum ether. Yield: 80%.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2)=[C:4]([CH3:14])[N:3]=1.[CH3:15][NH2:16]>C(O)C>[CH3:14][C:4]1[N:3]=[C:2]([NH:16][CH3:15])[N:10]=[C:9]2[C:5]=1[NH:6][C:7]([CH2:11][CH2:12][CH3:13])=[N:8]2
Reactant: CN
Reactant: CCCc1nc2nc(Cl)nc(C)c2[nH]1
Solvent: CCO
Product: CCCc1nc2nc(NC)nc(C)c2[nH]1
Temperature: 110 °C

Procedure:
To a solution of 2-Chloro-6-methyl-8-propylpurine (from Step 1 of Example 32) (0.1 g, 0.47 mmol) in ethanol (2 ml) was added condensed methylamine (1 ml) at -20° C. The mixture was then placed in a steel-bomb and heated at 110° C. for 7 hours. The reaction was cooled and the mixture was concentrated in vacuo. The residue was partitioned between CHCl3 and water, and the organic layer was separated and dried over MgSO4. The crude product obtained after removal of the solvent was purified by flash-chromatography on silica-gel using 5% MeOH in CHCl3 giving the titled compound as an amorphous solid (0.115 g, quantitative).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1)CCC>>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:2]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:5]=[CH:4][CH:3]=3)=[CH:20][N:21]=[C:22]2[N:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(-c2ccccn2)n1
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4ccccn4)n3)cnc2n1
Yield: 33.7 %

Procedure:
6-Bromo-2,2′-bipyridine (0.35 g, 1.44 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-100%) and trituration with isohexane gave 6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridine (130 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 7.39-7.43 (2H, m), 7.85 (1H, d, J 8), 7.89-7.94 (1H, m), 7.99 (1H, dd, J 8 and 8), 8.31 (1H, d, J 8), 8.38 (1H, d, J 8), 8.56 (1H, s), 8.75-8.80 (1H, m), 10.53 (1H, d, J 7); m/z (ES+) 342 (M++H).
Reaction SMILES: I[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1.[CH3:12][O-:13].[Na+].[Na]>CO.C1COCC1>[CH3:12][O:13][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1
Reactant: COC(=O)c1cc(CI)on1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cc(C(=O)OC)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.34 g (5 mmole) of methyl 5-(iodomethyl)-3-isoxazolecarboxylate in 20 ml of methanol and 5 ml of THF is added to a solution of methanol and 5 ml of THF is added to a solution of sodium methoxide prepared from 0.15 g (6.5 mmole) sodium and 10 ml of methanol. The reaction mixture is stirred at room temperature for four hours, heated to reflux for 30 minutes, and then worked up as usual giving 0.65 g of product. The crude ester is recrystallized from ether-cyclohexane mixture to give 0.33 g of off-white solid, mp 47.5°-49° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)=[CH:8]2)(=[O:4])=[O:3].CN(C)C=O.[H-].[Na+].[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(OCC)(=O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:10]2[C:11]3[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=3)[CH:8]=[C:9]2[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)c1ccc2[nH]c(-c3nccs3)cc2c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1nccs1)n2S(=O)(=O)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
To a mixture of 5-methanesulfonyl-2-(thiazol-2-yl)indole (50 mg) and N,N-dimethylformamide (1.8 ml), 60% sodium hydride (10 mg) was added at 0° C. and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added 4-fluorobenzenesulfonyl chloride (52 mg) at 0° C. and the mixture was stirred at 15 to 30° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution successively, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 77 mg of the desired product in a white amorphous form.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:19][CH2:18]1)[CH3:3].[CH3:36][S:37]([C:39]1[CH:47]=[CH:46][C:45]([N:48]2[CH:52]=[N:51][N:50]=[N:49]2)=[CH:44][C:40]=1[C:41](O)=[O:42])=[O:38]>>[CH3:36][S:37]([C:39]1[CH:47]=[CH:46][C:45]([N:48]2[CH:52]=[N:51][N:50]=[N:49]2)=[CH:44][C:40]=1[C:41]([N:27]1[CH2:28][CH2:29][C:25]([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][CH:17]([NH:16][C:8]3[N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:18][CH2:19]2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26]1)=[O:42])=[O:38]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: CS(=O)c1ccc(-n2cnnn2)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4S(C)=O)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and 2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoic acid to give the title compound.
Reaction SMILES: [OH-].[K+].CO.O.C([O:9][CH:10]([CH:17]=[CH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C>>[CH:17]([CH:10]([OH:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:18]
Reactant: C=CC(OC(C)=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A second 12 L flask equipped with mechanical stirrer, condensor, and thermocouple was charged with 761.0 g (13.56 mol) KOH (potassium hydroxide), 3.5 L (86.6 mol) of MeOH (methanol), 1.1 L (58.38 mol) of water, and 703 g of vinylbenzyl acetate from the previous step producing a dark red-colored solution. The reaction was heated to reflux and followed by TLC, which indicated that the reaction was complete after 1 hour. The reaction mixture was cooled to room temperature and extracted twice with 4 L of diethyl ether. The ether layer was then washed with three times with 4 L of aqueous sodium chloride, then two times with 4 L of water. The ether layer was dried with MgSO4 (magnesium sulfate) and filtered. Ether was removed from the filtrate under reduced pressure to give a brown oil. (487.0 g, 91% yield) (94% overall). 1H NMR (DMSO-d6): δ 7.35 (m, 4H, aromatic), δ 6.70 (m, 1H, vinyl), δ 5.75 (d, 1H, vinyl), δ 5.25 (d, 1H, vinyl), δ 4.65 (d, 2H, benzyl).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19]>>[OH:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:18]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Br:10])=[O:19]
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccc(F)cc1O
Product: O=C(Nc1ccc(F)cc1O)Nc1ccccc1Br

Procedure:
The urea was prepared from 2-hydroxy 4-fluoro aniline(254 mg, 2 mmol) and 2-bromophenylisocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane(173 mg, 26%). EI-MS m/z 325 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:16]N1C(=O)CCC1=O>CC#N.CCOC(C)=O>[CH2:9]([O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:16])[CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1ncc(Br)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a stirred solution of 2-amino-3-benzyloxypyridine (42.0 g, 0.21 mol) in CH3CN (600 mL) at 0° C. was added N-bromosuccinimide (37.1 g, 0.21 mol) over 30 minutes. The mixture was stirred for 0.5 hr, after which the reaction was then diluted with EtOAc (900 mL) and partitioned with H2O (900 mL). The organic layer was washed with brine and dried (Na2SO4), filtered and concentrated to dryness under vacuum to yield 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol, 53%). 1H NMR (CDCl3, 300 MHz) δ 4.63-4.78 (brs, 2H), 5.04 (s, 2H), 7.07 (d, 1H, J, 1.8 Hz), 7.33-7.42 (m, 5H), 7.73 (d, 1H, J, 1.8 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([Cl:14])=[O:10])[CH2:4][CH2:3]1
Reactant: O=C1CCC(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C1CCC(C(=O)Cl)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-oxo-cyclohexanecarboxylic acid (commercially available) (115 mg, 0.81 mmol) in CH2Cl2 (3 ml) was added oxalyl chloride (205 mg, 1.61 mmol). The reaction mixture was stirred at RT over night, and then concentrated under vacuo. The product was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:13])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:20])(=O)=O.N>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:6][CH2:7][CH2:8][O:9][CH3:20])=[C:10]([CH3:12])[CH:11]=1
Reactant: Cc1cc(Br)cc(C)c1OCCO
Reactant: COS(=O)(=O)OC
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COCCOc1c(C)cc(Br)cc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-(4-bromo-2,6-dimethylphenoxy)ethanol (15 g) in methylene chloride (100 ml) was added to a stirred solution of sodium hydroxide (50 g) in water (50 ml) at 5° C. Dimethyl sulphate (8.6 ml) was added dropwise to the stirred solution at 5° C. over 30 minutes. The mixture was stirred at ambient temperature for 12 hours. Dimethylsulphate (5 ml) was added at ambient temperature and the mixture stirred for a further 2 hours. The mixture was cooled to 0° C. and a solution of ammonia (10 ml, density=0.88 g/cm3) was added. The mixture was stirred for 20 minutes, diluted with iced water (500 ml). The methylene chloride phase was removed and the aqueous phase extracted with methylene chloride (2×150 ml). The organic extracts were combined, washed with water (2×100 ml), saturated brine (100 ml) and evaporated. The residue was distilled using a short path distillation apparatus (furnace temperature 120° C./0.08 bar) to give 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane (11.6 g); NMR(CDCl3): 2.34(6H,s), 3.52(3H,s), 3.78(2H,m), 3.96(2H,m) and 7.2(2H,s).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH3:10].[CH2:20]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:20]([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([O:17][C:14]2[CH:13]=[CH:12][C:11]([CH:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:18][CH3:19])[CH3:10])=[CH:16][CH:15]=2)=[O:34])=[CH:36][CH:37]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CC[C@H](C)CCCCCOC(C)c1ccc(O)cc1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(C(C)OCCCCC[C@@H](C)CC)cc2)cc1

Procedure:
The procedure of Example 26 was followed except for use of (+)-4-(1-(6-(S)-methyloctyloxy)ethyl)phenol in place of (+)-4-(1-methoxyethyl)phenol and 4-octyloxybenzoic acid chloride in place of 4'-octyloxy-4-biphenylcarboxylic acid chloride to obtain (+)-4-(1-(6(S)-methyloctyloxy)ethyl)phenyl 4-octyloxy-benzoate. [α]D20 =+44.0° (c=1, CHCl3)
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([F:22])[F:21])[CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:56]1[C:60]2=[C:61]([C:65](O)=[O:66])[N:62]=[CH:63][CH:64]=[C:59]2[CH:58]=[CH:57]1>CN(C=O)C>[C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][N:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([F:22])[F:21])[CH:14]=2)[C:65]([C:61]2[N:62]=[CH:63][CH:64]=[C:59]3[CH:58]=[CH:57][NH:56][C:60]=23)=[O:66])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)F)c2)cc1
Reactant: O=C(O)c1nccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)F)c2)C(=O)c2nccc3cc[nH]c23)cc1
Yield: 83.8 %

Procedure:
(4-tert-Butyl-benzyl)-[2-(3-difluoromethoxy-phenyl)-ethyl]-amine (90 mg, 0.27 mmol), N-methylmorpholine (74 mg, 0.73 mmol), and HBTU (139 mg, 0.37 mmol) were added at RT to a solution of 1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid (66 mg) in DMF (3 mL), then after 64 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, heptane-dichloromethane gradient) afforded the title compound (108 mg, 86% over 2 steps). Light yellow oil, MS (ISP) 478.4 (M+H)+.
Reaction SMILES: [OH:1]C(C)CC(O)=O.O[C@H:9]([CH2:14][CH2:15][CH2:16]CCC)[CH2:10][C:11]([OH:13])=[O:12]>>[OH:1][C@H:10]1[CH2:9][CH2:14][C@@H:15]([CH3:16])[O:12][C:11]1=[O:13]
Reactant: CC(O)CC(=O)O
Reactant: CCCCCC[C@@H](O)CC(=O)O
Product: C[C@@H]1CC[C@H](O)C(=O)O1

Procedure:
When the above procedures were repeated in the same manner except that β-hydroxybutanoic acid synthesized in Referential Example 2 was used instead of (R)-β-hydroxynonanoic acid, (2S,5R)-2-hydroxy-5-methyl-δ-valerolactone was obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH2:24])[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].[C:29]1([S:35][C:36]2([S:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:40][CH:39]([O:41]CC)[NH:38][C:37]2=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH:24][CH:37]3[C:36]([S:35][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)([S:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH2:40][C:39](=[O:41])[NH:38]3)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC1CC(Sc2ccccc2)(Sc2ccccc2)C(=O)N1
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4NC(=O)CC4(Sc4ccccc4)Sc4ccccc4)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 55.7 %

Procedure:
Adenosine 2',3',5'-triacetate (110 mg) and 3,3-diphenylthio-5-ethoxy-2-pyrrolidinone (155 mg) were heated in toluene (10 ml) under reflux for 5 hours, at the end of which the reaction solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform-acetone (5:1) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give crystals which were recrystallized from ethanol. By the above procedure was obtained N6 -(3,3-diphenylthio-5-oxo-2-pyrrolidinyl)adenosine 2',3',5'-triacetate as colorless needles (108 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([O:19][CH2:20][CH2:21][O:22][C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=3)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([O:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:27][OH:28])=[CH:29][CH:30]=3)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCCOc2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1ccc(OCCOc2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
(4-(2-[(5,6-Diphenyl-2-pyrazinyl)oxy]ethoxy)benzaldehyde (2.90 g) was dissolved in ethanol (30 mL), and sodium borohydride (615 mg) was added to the resultant solution under ice cooling. The mixture was stirred at room temperature for one hour. Subsequently, water was added to the reaction mixture, and the thus-formed organic matter was separated through extraction by use of methylene chloride, followed by washing sequentially by water and saturated saline. The washed product was dried over sodium sulfate anhydrate, and the residual solvent was removed through distillation under reduced pressure. The thus-yielded residue was crystallized from n-hexane, to thereby yield 2.69 g of the title compound as colorless crystals (yield 92.3%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[I:10]N1C(=O)CCC1=O>C(#N)C.CO>[Cl:8][C:6]1[C:5]([I:10])=[C:4]([CH3:9])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CO
Solvent: CC#N
Product: Cc1nc(N)nc(Cl)c1I
Temperature: 60 °C
Yield: 83.2 %

Procedure:
To a solution of 2-amino-4-chloro-6-methylpyrimidine (Aldrich, 10 g, 70 mmol) in acetonitrile (100 mL) and MeOH (140 mL) was added N-iodosuccinimide (Aldrich, 24 g, 105 mmol) at room temperature. The reaction mixture was heated to 60° C. for 5 h under a nitrogen atmosphere. After the reaction was complete, by monitoring LC/MS, it was allowed to cool to room temperature. The reaction mixture was put on a rotary evaporator and the solvent was evaporated to the half of its original volume. A precipitate was formed by addition of diethyl ether (200 mL). The precipitate was collected by vacuum filtration to afford (15.7 g, 83% yield) of the 4-chloro-5-iodo-6-methylpyrimidin-2-amine; MS (EI) for C5H5ClIN3 (272.65, M+2): analytical HPLC purity >97%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:17][C:18]([C:20]1[N:21]=[C:22]([CH2:25]Br)[S:23][CH:24]=1)=[O:19])C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:25][C:22]3[S:23][CH:24]=[C:20]([C:18]([OH:19])=[O:17])[N:21]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Product: O=C(O)c1csc(COc2ccc(-c3ccc(Br)cc3)cc2)n1

Procedure:
2-(4′-Bromo-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure B from 4-bromo-4′-hydroxybiphenyl (available from TCI America, Portland, Oreg.) and 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (Intermediate 3). Yield: 82 mg. Mass spectrum (ES) MH+=390.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:52]=[CH:51][C:36]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][C:44]([OH:50])=[C:45]([O:48][CH3:49])[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[C:35]([F:53])[CH:34]=1.[C:54]([O:58][C:59]([NH:61][CH2:62][CH2:63]O)=[O:60])([CH3:57])([CH3:56])[CH3:55]>C(Cl)Cl>[C:54]([O:58][C:59]([NH:61][CH2:62][CH2:63][O:50][C:44]1[CH:43]=[C:42]2[C:47]([C:38]([NH:37][C:36]3[CH:51]=[CH:52][C:33]([Cl:32])=[CH:34][C:35]=3[F:53])=[N:39][CH:40]=[N:41]2)=[CH:46][C:45]=1[O:48][CH3:49])=[O:60])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.4 %

Procedure:
Diethyl azodicarboxylate (0.94 ml, 6 mmol) was added dropwise to a mixture of triphenylphosphine (1.57 g, 6 mmol), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (640 mg, 2 mmol), (prepared as described for the starting material in Example 2), and N-(tert-butoxycarbonyl)ethanolamine (0.354 g, 2.2 mmol) in methylene chloride (20 ml) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 4 hours. The reaction mixture was diluted with methylene chloride, washed with aqueous sodium hydrogen carbonate solution, water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The product was recrystallised from acetonitrile, collected by filtration, washed with ethyl acetate and dried to give 7-(2-[N-tert-butoxycarbonylamino]ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (235 mg,25%).