Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[NH:7][C:6]2=[C:8]([C@@H:11]3[NH:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[CH:9]=[N:10][C:5]2=[C:4]([OH:20])[N:3]=1>FC(F)(F)C(O)=O>[OH:20][C:4]1[N:3]=[CH:2][NH:7][C:6]2=[C:8]([C@@H:11]3[NH:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[CH:9]=[N:10][C:5]=12
Reactant: OC[C@H]1N[C@@H](c2cnc3c(O)nc(O)[nH]c2-3)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H]1N[C@@H](c2cnc3c(O)nc[nH]c2-3)[C@H](O)[C@@H]1O
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A solution of the product from Example 1.6 (66 mg) in trifluoroacetic acid (3 ml) was allowed to stand at room temperature overnight. The solution was concentrated and a solution of the residue in water was washed (×2) with chloroform and then evaporated. The residue was dissolved in methanol and treated with Amberlyst A21 base resin until the solution was pH˜7. The solids and solvent were removed and the residue was dissolved in water, treated with excess aqueous HCl and then lyophilized. Trituration of the residue with ethanol gave (1S)-1,4-dideoxy-1-C-(4-hydroxypyrrolo[3,2-d]pyrimidin-7-yl)-1,4-imino-D-ribitol (7) hydrochloride salt as a white solid (25 mg). Recrystallised from 90% ethanol, the crystalline solid darkened but did not melt below 300° C. NMR (300 MHz, D2O with DCl, δ ppm): 13C (relative to internal acetone at 33.2 ppm) 58.1 (C-1′), 61.4 (C-5′), 68.8 (C-4′), 73.3 (C-3′), 76.7 (C-2′), 107.5 (q), 121.4 (q), 133.5 (C-2), 135.0 (q), 148.0 (C-6) and 155.4 (q); 1H (relative to internal acetone at 2.20 ppm), 3.90 (H-4′), 3.96 (m, H-5′,5″), 4.44 (dd, H-3′, J2′,3′ 5.4 Hz, J3′,4′ 3.2 Hz), 4.71 (dd, J1′,2′ 9.0 Hz, H-2′), 5.00 (d, H-1′), 8.00 (s, H-6) and 9.04 (s, H-2)
Reaction SMILES: [Cl-].[Cl-].[C:3]1([N:9](B)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>>[C:3]1([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]([OH:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: BN(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCCCN(CCCC)CCCC
Product: OC(c1ccccc1)c1ccccc1Nc1ccccc1
Yield: 22.4 %

Procedure:
Using diphenylaminoborane dichloride (200 mg), benzaldehyde (85 mg) and tri-n-butylamine (147 mg), the reaction is effected as in Example 7, whereby 2-phenylaminobenzhydrol (49 mg) is obtained. This substance is recrystallized from benzene-hexane to give crystals melting at 111° to 112° C. Anal. Calcd. for C19H17ON: C, 82.88; H, 6.62; N, 5.09. Found: C, 82.67; H, 6.28; N, 5.03.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26])=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(COCCO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of the product of Example 5A (544.5 mg, 2.59 mmol) in anhydrous DMF (26 mL) was added imidazole (264 mg, 3.89 mmol) and TBDMS-Cl (586 mg, 3.89 mmol). The reaction mixture stirred at room temperature overnight and was quenched with water. The aqueous layer was extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified using silica gel chromatography (4:1 pentane:ethyl acetate) to provide the desired product (677.5 mg, 2.19 mmol) in 84% yield. 1H (CDCl38.01, 600 MHz): δ (2H, d, J=8.3 Hz), 7.42 (2H, d, J=8.4 Hz), 4.63 (2H, s), 3.91 (2H, s), 3.82 (2H, t, J=5.0), 3.58 (2H, t, J=5.1 Hz), 0.91 (9H, s), 0.07 (6H, s); 13C(CDCl3166.5, 143.5, 129.2, 128.8, 126.5, 72.1, 71.6, 150 MHz): δ 62.3, 51.5, 25.4, 17.9, −5.8.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[S:21]([CH3:24])(=[O:23])=[O:22])[C:3]=1[CH3:25].[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[C:37]([NH2:38])=[CH:36][C:35]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:34][N:33]=2)[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[C:37]([NH:38][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=4[S:21]([CH3:24])(=[O:23])=[O:22])[C:3]=3[CH3:25])=[CH:36][C:35]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:34][N:33]=2)[CH2:28][CH2:27]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(5-methyl-2-(methylsulfonyl)phenyl)quinoline (50.0 mg, 0.13 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(5-methyl-2-(methylsulfonyl)phenyl)-quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.07 (1H, d, J=8.0 Hz), 7.83 (1H, d, J=12.5 Hz), 7.42-7.58 (3H, m), 7.21 (1H, br. s.), 7.05 (1H, ddd, J=13.6, 8.6, 2.6 Hz), 6.53 (1H, br. s.), 3.84-4.04 (4H, m), 3.78 (4H, d, J=4.3 Hz), 3.41 (2H, br. s.), 2.85-3.21 (9H, m), 2.50 (3H, s), 1.93 (3H, s). Mass Spectrum (ESI) m/e=610.3 (M+1).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[CH:34]=[C:33]([F:35])[C:32]([NH:36][C:37](OC)=[O:38])=[CH:31][C:17]=1[O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].Cl>CN(C)C=O>[Cl:15][C:16]1[CH:34]=[C:33]([F:35])[C:32]([N:36]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:37]2=[O:38])=[CH:31][C:17]=1[O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)COc1ccccc1Oc1cc(NC(=O)OC)c(F)cc1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 0 °C

Procedure:
To ethyl 3-amino-4,4,4-trifluorocrotonate are added N,N-dimethylformamide and sodium hydride and the mixture is stirred at 0° C. Thereafter, to the reaction solution is added a mixture of methyl [2-(2-chloro-4-fluoro-5-methoxycarbonylaminophenoxy)phenoxy]acetate [Intermediate compound A9-22] and N,N-dimethylformamide, and the mixture is stirred at 80° C. Then reaction solution is cooled to room temperature, then, poured into a mixture of hydrochloric acid and ice water, and the deposited crystal is collected by filtration to obtain methyl [2-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O.[OH-].[Na+].Cl>CO.O>[C:1]1([CH:7]2[O:25][CH:8]2[C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)C(Cc2ccc(C(=O)/C=C/c3ccccc3)cc2)S1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1NC(=O)C(Cc2ccc(C(=O)C3OC3c3ccccc3)cc2)S1
Yield: 79.2 %

Procedure:
To a solution of title product of Example 39 (0.5 g, 1.5 mmol) in methanol (4 ml), cooled to 0° C., was added 30% H2O2 (0.5 ml, 4.8 mmol), followed by 2N NaOH (1.6 ml, 3.2 mmol). After 30 minutes at 0° C. the solution was acidified with 2N HCl, diluted with water (15 ml) and extracted with ethyl acetate (2×15 ml). The combined extracts were washed with brine (15 ml), dried over magnesium sulfate and concentrated in vacuo, leaving present title product as an oil (420 mg, 80%).
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7]CC)=O)[NH2:3].[N:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])=[C:11]=[S:12].C(N(C(C)C)CC)(C)C>ClCCl>[NH2:3][N:2]1[CH2:4][C:5](=[O:7])[N:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=[O:17])[CH:14]=2)[C:11]1=[S:12]
Reactant: CCOC(=O)CNN
Reactant: O=C(O)c1cccc(N=C=S)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NN1CC(=O)N(c2cccc(C(=O)O)c2)C1=S
Reaction time: 96 h
Yield: 19.9 %

Procedure:
Ethyl hydrazinoacetate hydrochloride (155 mg, 1.00 mmol) was added to a stirred solution of 3-isothiocyanatobenzoic acid (179 mg, 1.00 mmol) and di-isopropylethylamine (523 uL, 3.00 mmol) in dichloromethane (4 mL). The mixture was stirred for 96 h, evaporated under reduced pressure and partitioned between aqueous acetic acid and ethyl acetate. The organic extracts were washed with water, saturated aqueous sodium chloride, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was chromatographed (silica gel, 5-15% methanol/ethyl acetate, then 20% methanol/ethyl acetate ±0.5% acetic acid) to give 1-amino-3-(3-carboxyphenyl)-2-thioxoimidazolidin-4-one (50 mg, 51%) contaminated with 6% uncyclised by-product, suitable for the next step. A solution of 1-amino-3-(3-carboxyphenyl)-2-thioxoimidazolidin-4-one (50 mg, 0.199 mmol) and 1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazole-4-carbaldehyde (55 mg, 0.239 mmol) in ethanol/methanol (2:1, 15 mL) was allowed to stand a room temperature for 96 h. The solid was filtered off, washed with ether and dried to give the title compound (42 mg, 46%) as a powder. LCMS, m/e 464 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:38]=[CH:37][CH:36]=[C:31]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)c1
Temperature: 160 °C

Procedure:
A suspension of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.00 g, 2.64 mmol), methyl 3-bromobenzoate (0.581 g, 2.70 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.054 g, 0.066 mmol), 1,4-dioxane (10 mL), and aqueous sodium carbonate (2 M, 2.64 mL, 5.27 mmol) was placed under an argon atmosphere by performing 6 vacuum/argon cycles. The reaction mixture was then heated to 160° C. for 10 minutes in a microwave reactor. The resulting suspension was diluted with ethyl acetate (75 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The layers were separated, and the organic layer was washed with water (10 mL) and then brine (25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to afford methyl 3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carboxylate. MS ESI calc'd. for C20H17F3N3O2 [M+H]+ 388, found 388.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([NH:15][C@H:16]([CH3:52])[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:25]2=[O:49])=[CH:21][CH:20]=1)=O)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:15][C@H:16]([CH3:52])[CH2:17][O:18][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:49])=[CH:21][CH:20]=1
Reactant: C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
500 ml of trifluoroacetic acid were added dropwise, whilst ice-cooling, to a solution of 85.5 g of 5-{4-[2(R)-t-butoxycarbonylaminopropoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in step (e) above] in 700 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was freed from the methylene chloride solvent and the trifluoroacetic acid by distillation under reduced pressure, and a mixture of benzene and a small amount of ethyl acetate was added to the residue. The crystals which precipitated were collected by filtration and were recrystallized from a mixture of methanol and ethyl acetate, to give the title compound as crystals, melting at 162°166° C. [α]D23 -13.0° (c=0.885, methanol)
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].O>CS(C)=O>[CH2:19]([N:7]1[C:8](=[O:9])[C:10]([CH3:11])=[CH:12][N:4]([CH3:3])[C:5]1=[O:6])[CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: Cc1cn(C)c(=O)[nH]c1=O
Reactant: C=CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCn1c(=O)c(C)cn(C)c1=O
Reaction time: 0.25 h
Yield: 90 %

Procedure:
3-(5,6-Oxidohexyl)-1-methylthymine was synthesized as follows: A mixture of sodium hydride (343 mg, 14 mmol) and 1-methylthymine (2.00 g, 14 mmol) in dimethylsulfoxide (30 ml) was stirred for 15 minutes, and then 6-bromo-1-hexene (2.30 g, 14 mmol) was added. After stirring for 69 hours, the reaction mixture was poured into water (100 ml) and extracted with dichloromethane (4×50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (40 ml), dried over sodium sulfate, and then the solvent was evaporated under vacuum to give a residue which was recrystallized (dichloromethane-ethyl ether) to give 3-(5-hexenyl)-1-methylthymine (2.80 g, 88% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].I[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].Cl>O.CC(=O)CC>[CH:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])([CH3:14])[CH3:13]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(C)Oc1cccc(C(=O)O)c1

Procedure:
Combine 3-hydroxybenzoic acid (100 mmol), 2-iodopropane (500 mmol), K2CO3 (300 mmol), and 2-butanone (300 mL). Heat at reflux for 72 h. Concentrate in vacuo to obtain a residue. Add water (500 mL) and cool in an ice bath. Adjust to pH 1 by dropwise addition of concentrated HCl. Extract with dichloromethane (3×200 mL). Extract the combined organic layers with water (200 mL), dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([CH3:11])[CH:3]=1.Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:9]2=[S:10])=[C:4]([CH3:11])[CH:3]=1
Reactant: CCOC(=O)CNC
Reactant: Cc1cc(Cl)ccc1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1N1C(=O)CN(C)C1=S
Yield: 58.9 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 9.18 g of 4-chloro-2-methylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 12.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the title compound (7.5 g) as an off-white solid, m.p. 113°-115° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.72; H, 4.17; N, 10.88. Mass spectrum (EI, M.+) m/z 254/256.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:25])([CH3:24])[C:15]([C:17]4[CH:18]=[N:19][C:20](F)=[CH:21][CH:22]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:25])([CH3:24])[C:15]([C:17]4[CH:18]=[N:19][C:20]([N:30]5[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]5)=[CH:21][CH:22]=4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(F)nc1
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(N2CCC(O)CC2)nc1
Temperature: 100 °C

Procedure:
A mixture of (3E)-6-fluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.15 mmol) and 4-hydroxypiperidine (50 mg, 0.49 mmL) in anhydrous DMSO (3 mL) was heated at 100° C. under nitrogen for 6 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-6-fluoro-3-{4-[6-(4-hydroxypiperidin-1-yl)pyridin-3-yl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as a yellow solid. Yield: 55 mg, 89%.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:17])[NH:12][C@@H:13]([CH3:16])[CH2:14][OH:15])[N:10]=2)[CH2:3]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C)C=O>[Si:18]([O:15][CH2:14][C@@H:13]([NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:17])[CH3:16])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.1 %

Procedure:
To a solution of 3-hydroxy-1-[4-((1S)-2-hydroxy-1-methylethylcarbamoyl)-1,3-thiazol-2-yl]azetidine (910 mg, 3.54 mmol) (obtained as described in Reference Example 35(3)) in dimethylformamide (46 ml) were added t-butyldimethylsilyl chloride (586 mg, 3.89 mmol) and imidazole (265 mg, 3.89 mmol) in an ice bath, and the reaction mixture was stirred at room temperature for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1→1:4) as the eluant to afford 1-{4-[(1S)-2-(t-butyldimethylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (935 mg, yield 71%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]C(OC(C)(C)C)=O)[C:5](N1C=CN=C1)=[O:6].[OH-].[Na+].[NH2:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45]>C(Cl)(Cl)Cl>[OH:46][CH:43]([CH2:44][OH:45])[CH2:42][NH:41][C:5](=[O:6])[C:4]1[CH:12]=[CH:13][C:14]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:2]([F:1])[CH:3]=1
Reactant: NCC(O)CO
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNc1ccc(C(=O)n2ccnc2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NCC(O)CO)cc1F
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-{3-fluoro-4-[N-(tert-butyloxycarbonyl)hexadecylamino]benzoyl}imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield light yellow crystals of N-(2,3-dihydroxypropyl)-3-fluoro-4-(hexadecylamino)benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(Cl)(=O)C(Cl)=O.[CH2:30](O)[CH2:31][CH2:32][CH3:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:30][CH2:31][CH2:32][CH3:33])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCCCO
Reactant: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Product: CCCCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Yield: 42.2 %

Procedure:
2 g of 2-[2-(4-fluorophenyl)-5-(3-thienyl)-4-oxazolyl]acetic acid, 0.5 g of potassium hydroxide, 4.2 g of oxalyl chloride and 20 ml of n-butanol are treated in the same manner as described in Example 17. One g of n-butyl 2-[2-(4-fluorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate is thereby obtained. Yield: 42.2%
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([F:17])[C:9]=1F.C(=O)(O)[O-].[Na+].O>CS(C)=O>[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([F:17])[C:9]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: Cc1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ncn(-c2c(F)cc([N+](=O)[O-])cc2F)n1
Temperature: 80 °C
Yield: 18.1 %

Procedure:
Step R (1): A mixture of 3-methyl-1H-1,2,4-triazole (8.12 g, 98 mmol), 1,2,3-trifluoro-5-nitrobenzene (17.3 g, 98 mmol), and sodium bicarbonate (8.21 g, 98 mmol) in DMSO (100 mL) was heated at 80° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (30-80% EtOAc/hexane, linear gradient) to afford a 1.7:1.0 mixture of two regioisomeric products as an orange solid. The orange solid was recrystallized from EtOAc (hot-cold) to provide 4.25 g of 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole as a white solid. The mother liquor was recrystallized from EtOAc/Hex (hot-rt) to afford 1.89 g of 1-(2,6-difluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole as a light yellow solid. The mother liquor was repeatly chromatographed under the previously stated conditions to provide two samples. One sample was partially enriched in the slightly less polar isomer, 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole. The other sample was partially enriched in the slightly more polar isomer, 1-(2,6-difluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole. Both samples were independently recrystallized from EtOAc/Hex to provide an additional 1.9 g of 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole and 1.37 g of 1-(2,6-difluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole. A combined total of 6.15 g (26% yield) of 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole and 3.2 g (13% yield) of 1-(2,6-difluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[N:6]=1)(=[O:3])[CH3:2].Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][CH2:15][CH2:14][CH2:13][N:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:6][C:7]1=[O:11]
Reactant: CC(=O)Nc1cc[nH]c(=O)n1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccn(CCCCl)c(=O)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of N-acetylcytosine, 1-bromo-3-chloropropane, and potassium carbonate in DMF was stirred at room temperature under argon for 4 days, filtered and evaporated to dryness. The crude product was purified by column chromatography and gave 1-(3-chloropropyl)-N4-acetylcytosine.