Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[C@H:3]([CH3:16])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].CS(O[CH2:29][CH:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])(=O)=O>>[OH:1][C@@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:29][CH:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])[CH:18]=1)[C@H:3]([CH3:16])[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: CCCC(CCC)COS(C)(=O)=O
Reactant: C[C@H](CN1C(=O)c2ccccc2C1=O)[C@@H](O)c1cccc(O)c1
Product: CCCC(CCC)COc1cccc([C@H](O)[C@H](C)CN2C(=O)c3ccccc3C2=O)c1

Procedure:
2-((2R,3R)-3-Hydroxy-3-(3-hydroxyphenyl)-2-methylpropyl)isoindoline-1,3-dione (82) was reacted with 2-propylpentyl methanesulfonate following the method described for Example 72 to give 2-((2R,3R)-3-hydroxy-2-methyl-3-(3-(2-propylpentyloxy)phenyl)propyl)isoindoline-1,3-dione as a colorless oil. Yield (0.414 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.80 (m, 4H), 7.13 (t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.67-6.70 (m, 1H), 5.30 (d, J=4.3 Hz, 1H), 4.38-4.41 (m, 1H), 3.78 (d, J=5.7 Hz, 2H), 3.70 (dd, J=5.3, 13.5 Hz, 1H), 3.41 (dd, J=9.4, 13.7 Hz, 1H), 2.21-2.28 (m, 1H), 1.67-1.75 (m, 1H), 1.23-1.42 (m, 8H), 0.85 (t, J=6.7 Hz, 6H), 0.65 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:17](=O)[N:16]([CH:19]([CH3:21])[CH3:20])[N:15]=[N:14]1)([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:17](=[S:31])[N:16]([CH:19]([CH3:21])[CH3:20])[N:15]=[N:14]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1-n1nnn(C(C)C)c1=O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1-n1nnn(C(C)C)c1=S
Yield: 109.4 %

Procedure:
A mixture of 5.6 g of 1-(2,6-diisopropylphenyl)-4-isopropyl-5-oxo-2-tetrazoline and 5.1 g of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) are heated at reflux for 24 hours in 60 ml of dry toluene. After evaporating off the solvent, the residue is purified by chromatography on 500 g of silica gel with hexane/ethyl acetate (19:1) as eluant. Crystallisation from hexane yields 4.2 g of 1-(2,6-diisopropylphenyl)-4-isopropyl-5-thioxo-2-tetrazoline in the form of colourless crystals, m.p. 109°-111° C.
Reaction SMILES: Cl[C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][C:6]1[N:7]([CH3:22])[C:8]2[C:13]([C:14]=1[CH:15](O)[CH2:16][C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=[CH:10][CH:9]=2.[OH-].[Li+]>O1CCCC1>[Cl:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][CH2:5][C:6]2[N:7]([CH3:22])[C:8]3[C:13]([C:14]=2[CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:2][CH:26]=1
Reactant: COC(=O)CC(O)c1c(COc2ccc(Cl)cc2Cl)n(C)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(Cl)cc2)c(C=CC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere a round bottom flask is charged with 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[1-hydroxy-2-(methoxycarbonyl)ethyl]-1H-indole (Example 55) (0.149 g, 0.398 mmol) and 6.11 ml of dry tetrahydrofuran. To this solution is added 1.22 ml of a 2.0 N lithium hydroxide aqueous solution and the resulting mixture was stirred at room temperature for about two hours. The solvents were removed in vacuo and the residue is partitioned between methylene chloride and water. The aqueous fraction was extracted twice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was triturated with diethyl ether.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:8]([CH:26]=1)[C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)=[O:10])(=[O:3])[CH3:2].[Br-:35].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>O1CCCC1>[CH2:28]([O:27][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH2:2][Br:35])=[CH:26][C:8]=1[C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)=[O:10])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.7 %

Procedure:
5-Acetyl-2-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (compound of Example 58(3); 4.81 g, 10 mmol) was dissolved in tetrahydrofuran (30 ml). Phenyltrimethylammonium tribromide (3.75 g, 10 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with aqueous sodium hydrogen sulfite, water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1), and recrystallized (ethyl acetate/n-hexane) to give the title compound (2.39 g, 42.7%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:36]=[N:35][N:34]([CH:37]([CH3:39])[CH3:38])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]3)=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13].C=O.[BH3-][C:43]#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:36]=[N:35][N:34]([CH:37]([CH3:39])[CH3:38])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:26]([CH:28]3[CH2:33][CH2:32][CH2:31][N:30]([CH3:43])[CH2:29]3)=[O:27])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCCNC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCCN(C)C4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(piperidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in methanol was added formalin (5 equiv.) stirred it at room temperature for 10 min. Then NaBH3CN (1 equiv.) was added to it Resulting reaction mixture was stirred at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (195 yield). LCMS: 546.40 (M+1)+; HPLC: 94.91% (@ 254 nm) (Rt; 7.295); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.84 (bs, 1H), 8.30 (d, 1H, J=2 Hz), 7.84 (d, 1H, J=9.2 Hz), 6.90 (s, 1H), 5.89 (s, 1H), 5.20 (m, 1H), 4.38 (d, 2H, J=4 Hz), 4.33 (bs, 1H), 4.19 (bs, 1H), 3.72 (bs, 2H), 2.90-2.65 (m, 5H), 2.20 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H), 1.91 (m, 1H), 1.80-1.70 (m, 3H), 1.61 (m, 1H), 1.50 (d, 6H, J=6 Hz), 1.28 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:12][CH:11]([O:13][CH3:14])[CH2:10]2)=[CH:4][N:3]=1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C[Si]([N-:44][Si](C)(C)C)(C)C.[Li+].Cl>C1COCC1.C(Cl)Cl.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].CCN(CC)CC.CO.C1(C)C=CC=CC=1>[CH3:14][O:13][CH:11]1[CH2:12][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:44])=[N:3][CH:4]=2)[CH2:10]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC1CN(Cc2ccc(Cl)nc2)C1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC1CN(Cc2ccc(N)nc2)C1
Reaction time: 8 h

Procedure:
To a round bottomed flask charged with 2-chloro-5-((3-methoxyazetidin-1-yl)methyl)pyridine (11.5 g, 54.1 mmol, Eq: 1.00), tris(dibenzylideneacetone)dipalladium(0) (1.24 g, 1.35 mmol, Eq: 0.025), and biphenyl-2-yldicyclohexylphosphine (948 mg, 2.7 mmol, Eq: 0.05) was added toluene (150 ml) followed immediately by lithium bis(trimethylsilyl)amide (81.1 ml, 81.1 mmol, Eq: 1.5) as a 1.0 M solution in THF. Brought quickly to reflux and stirred overnight under Argon. Next day, the reaction was checked by TLC (9:1 MC:MeOH) and the starting material was gone, replaced primarily by a single lower Rf spot. Cooled while stirring and added 5 ml of 1.0M HCl. Stirred 20 min and filtered over celite. The filtrate was diluted with ether and washed with 200 mL of 1.0M NaOH followed by water and brine. Dried the org phase over sodium sulfate, filtered and removed solvent. Obtained a dark red oil weighing 14.4 g. Took the oil up in CH2Cl2 and flashed (neat MC to 90:10 MC:MeOH:0.1 Et3N). Collected 4.4 g (42.1%) of cleanest fractions as a reddish oil for next step.
Reaction SMILES: [CH2:1](/[C:3](/[CH:11]([N+:13]([O-:15])=[O:14])[CH3:12])=[CH:4]\[C:5](=[N:9][OH:10])[C:6]([NH2:8])=[O:7])[CH3:2].[N+](=[CH2:18])=[N-].C(O)(=O)C>CO>[CH2:1](/[C:3](/[CH:11]([N+:13]([O-:15])=[O:14])[CH3:12])=[CH:4]\[C:5](=[N:9][O:10][CH3:18])[C:6]([NH2:8])=[O:7])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC/C(=C\C(=NO)C(N)=O)C(C)[N+](=O)[O-]
Solvent: CO
Solvent: CC(=O)O
Product: CC/C(=C\C(=NOC)C(N)=O)C(C)[N+](=O)[O-]

Procedure:
To (E)-4-ethyl-2-hydroxyimino-5-nitro-3-hexenamide (37 mg) in methanol (5 ml) was added excess etheral diazomethane at -20° C. The resulting mixture was allowed to stand at 0° C. for an hour and then acetic acid was added thereto until the yellow color of the solution was discharged. The resulting reaction mixture was evaporated under reduced pressure to give an oil which was purified by preparative thin layer chromatography, developing with chloroform containing 5% methanol to give (E)-4-ethyl-2-methoxyimino-5-nitro-3-hexenamide (21.5 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH:12][CH2:13][C:14]1[C:15]([NH:22][CH2:23][CH3:24])=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1.[H-].[Na+].[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>CN(C=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[N:12]1[CH2:13][C:14]2[C:15](=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=2)[N:22]([CH2:23][CH3:24])[C:27]1=[O:28]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCNc1nc(SC)ncc1CNc1cc(OC)cc(OC)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2Cl)Cc2cnc(SC)nc21
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Into a solution of 1.00 g (2.71 mmol) of {5-[(2-chloro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}-ethyl-amine in 7 mL of dry DMF cooled to 5° C. was added 0.271 g (6.78 mmol) of sodium hydride as a 60% mineral oil suspension. The ice bath was removed, and the reaction was stirred for 1 hour. To the reaction was then added 1.32 g (8.13 mmol) of 1,1′-carbonyldiimidazole. After stirring a further 2 hours, the reaction was concentrated in vacuo. The residue was partitioned between dichloromethane and a saturated solution of ammonium chloride. The aqueous layer was washed twice with dichloromethane. The dichloromethane layers were combined, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in dichloromethane, added silica gel, and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane/ethyl acetate (9:0.5 v/v), to give 0.7507 g (70%) of the title compound: mp 189-191° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:21][O:22][CH3:23])[CH:9]=[O:10]
Reactant: COCCl
Reactant: COc1cc(C=O)ccc1O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C=O)cc1OC
Temperature: 0 °C
Yield: 83 %

Procedure:
In 320 ml of dimethylformamide was dissolved 3.2 g of vaniline, and 44.8 g of N,N-diisopropylethylamine was added to the solution and the mixture was stirred. The liquid mixture was cooled to 0° C. and 18.1 ml of chloromethyl methyl ether was added to the liquid mixture. The temperature was elevated to room temperature and the mixture was stirred for 5 hours. After the reaction, a large quantity of water was added to the reaction mixture, and the mixture was extracted with diethyl ether and the solvent was removed from the extract by distillation. The obtained residue was allowed to stand under ice cooling, and the obtained solid was washed with petroleum ether and recovered by filtration to obtain 34.0 g (yield=83%) of intended 3-methoxy-4-methoxymethoxybenzaldehyde.
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH2:3][NH2:4].N1C=CN=C1.[Si:11](OS(C(F)(F)F)(=O)=O)([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][CH3:13].O>C1COCC1>[CH2:12]([Si:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[O:5][CH:2]([CH3:1])[CH2:3][NH2:4])[CH3:13]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: CC(O)CN
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC[Si](CC)(CC)OC(C)CN
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a 50 mL round bottomed flask, 1-methyl-2-aminoethanol (500.0 mg, 6.66 mmol) and imidazole (498.8 mg, 7.326 mmol, 1.1 equiv.) were dissolved in THF (3 mL). The mixture was cooled down to −78° C. and then TESOTf (1.76 g, 6.66 mmol, 1.0 equiv.) was added at the same temperature. The mixture was allowed to warm to room temperature. After stirring for 1 h, water (30 mL) was added to the mixture and the whole was extracted with EtOAc (30 mL×3). Combined organic layers were washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give the O-silylated aminoalcohol as a colorless oil (2-(triethylsilyloxy)propan-1-amine, 2.34 g). Obtained product was immediately used for the subsequent step.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[CH:5][C:6]([OH:16])=[C:7]([NH:9][C:10](=O)[C:11](F)(F)F)[CH:8]=1.BrCC=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][CH2:11][CH:10]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:9][C:7]=2[CH:8]=1
Reactant: CCOC(=O)C=CCBr
Reactant: O=C(Nc1cc(F)ccc1O)C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC1COc2ccc(F)cc2N1
Temperature: 0 °C

Procedure:
370 ml of ethanol are introduced into a 1 l reactor, with magnetic stirring, cooled to 0° C., and 3.5 g (0.146 mol) of sodium are introduced slowly, in small portions, followed by successive dropwise addition of 32.54 g (0.146 mol) of N-(5-fluoro-2-hydroxyphenyl)trifluoroacetamide and 28.18 g (0.146 mol) of 75% pure ethyl 4-bromo-2-butenoate, and the mixture is heated at 80° C. for 3 h.
Reaction SMILES: [CH2:1]([CH:3]([CH:7]([CH3:10])[CH2:8][CH3:9])[C:4](Cl)=[O:5])[CH3:2].S(Cl)(Cl)=O.[NH2:15][C:16]([NH2:18])=[O:17]>C(#N)C>[CH2:1]([CH:3]([CH:7]([CH3:10])[CH2:8][CH3:9])[C:4]([NH:15][C:16]([NH2:18])=[O:17])=[O:5])[CH3:2]
Reactant: NC(N)=O
Reactant: CCC(C)C(CC)C(=O)Cl
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCC(C)C(CC)C(=O)NC(N)=O

Procedure:
2-Ethyl-3-methyl-pentanoylchloride (0.057 mol), was prepared using thionylchloride according to a published method [24], and dissolved in dry acetonitrile (50 ml). The 2-ethyl-3-methyl-pentanoylchloride solution was slowly added to a boiling solution of urea (0.14 moles) in dry acetonitrile (100 ml) and was allowed to reflux for 2 hours. Thereafter the organic solvent was evaporated under reduced pressure and the product was dissolved in 100 ml ethyl acetate and washed three times with 20 ml of distilled water. The organic fraction was dried over MgSO4, filtered and evaporated under reduced pressure. The product was purified by crystallization from ethyl acetate.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][Cl:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>ClCCl>[Cl:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][Cl:15])[S:17]([CH3:16])(=[O:19])=[O:18]
Reactant: ClCCNCCCl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)N(CCCl)CCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
8.6 ml (62 mmol) of triethylamine are added to a solution of 5 g (28 mmol) of bis(2-chloroethyl)amine hydrochloride in 60 ml of dichloromethane. The triethylammonium chloride salts precipitate and are filtered off. 2.4 ml (31 mmol) of methylsulfonyl chloride are then added to the filtrate obtained, and the reaction medium is stirred at ambient temperature for 3 h. After the addition of water, the product is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. 5.8 g (94%) of N,N-bis(2-chloroethyl)methanesulfonamide are obtained in the form of a beige solid.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:28])=[CH:5][N:6]=3)=[C:16]([C:17]([F:18])([F:20])[F:19])[O:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 97 %

Procedure:
As described for example 137, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) was converted, using isopropylamine instead of methylamine, to the title compound (104 mg, 97%) which was obtained as an off white solid. MS: m/e=424.1 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(O[C@@H:14]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]1[O:16][C:17](=[O:19])[CH3:18])(=O)C.P([O-])(OC1C=CC([N+]([O-])=O)=CC=1)(OC1C=CC([N+]([O-])=O)=CC=1)=O>C1C=CC=CC=1>[CH3:9][O:8][C:6]([C:3]1[N:4]=[CH:5][N:1]([C@@H:14]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]2[O:16][C:17](=[O:19])[CH3:18])[N:2]=1)=[O:7]
Reactant: COC(=O)c1nc[nH]n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=[N+]([O-])c1ccc(OP(=O)([O-])Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: c1ccccc1
Product: COC(=O)c1ncn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)n1
Reaction time: 0.29 h

Procedure:
A mixture of methyl 1,2,4-triazole-3-carboxylate (12.7 g., 0.10 mol) and 1,2,3,5-tetra-O-acetyl-β -D-ribofuranose (31.8 g., 0.10 mol) was heated in an oil bath maintained at 160-165° until the sugar had melted. Bis(p-nitrophenyl) phosphate (250 mg.) was added and heating at 160-165° was continued with stirring under diminished pressure for 15-20 min. The residue was dissolved in hot benzene, the solution was filtered and cyclohexane was added to the filtrate to give the crystalline product (30.0 g., 77.8%) with M.P. 107-109°.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI>CC(C)=O>[CH2:1]([C:5]1[N:6]([CH3:14])[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1nc(C(=O)OC)c[nH]1
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCCc1nc(C(=O)OC)cn1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into flask containing a solution of methyl 2-butyl-1H-imidazole-4-carboxylate (1.2 g, 6.6 mmol) in acetone (40 ml), Cs2CO3 (6.5 g, 19.8 mmol) and methyl iodide (0.5 ml, 6.6 mmol) were added. The reaction mixture was stirred at RT for 4 h and the solvent was evaporated. The residue was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified with flash chromatography. Yield 500 mg. 1H-NMR (400 MHz; CDCl3): δ 0.937 (t, 3H), 1.35-1.44 (m, 2H), 1.68-1.75 (m, 2H), 2.69 (t, 2H), 3.62 (s, 3H), 3.86 (s, 3H), 7.50 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=O.N1CCCCC1>C(Cl)(Cl)Cl>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[O:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:17][C:16]1[CH:19]=[CH:20][C:21]([O:22][C:23]([F:24])([F:25])[F:26])=[C:14]([Cl:13])[CH:15]=1
Reactant: O=Cc1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c(C(=O)C=Cc2ccc(OC(F)(F)F)c(Cl)c2)c(=O)o1
Temperature: 25 °C
Yield: 10.7 %

Procedure:
A mixture of 1.85 g of 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one, 2.25 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 20 ml of chloroform and 0.7 ml of piperidine was heated under refluxing for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography. Resulting crystals were washed with 40 ml of t-butyl methyl ether to obtain 0.40 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (1a-6]) as a yellow crystal.
Reaction SMILES: I[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[C:14]([F:16])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[C@H:5]([OH:17])[C@@H:4]1[OH:18].C(NC(C)C)(C)C>C(O)C.C(O)(C)C.[Pd]>[F:16][C:14]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:6]1[O:7][C@H:3]([CH3:2])[C@@H:4]([OH:18])[C@H:5]1[OH:17]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2O)cc1F
Agent: [Pd]
Solvent: CC(C)O
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reaction time: 14 h
Yield: 89 %

Procedure:
To a suspension of 20 g (0.053 m) of 5′-deoxy-5′-iodo-5-fluoro uridine in a mixture of 60 ml of ethanol and 40 ml of isopropanol, 15.2 ml (0.108 m) of diisopropylamine are added, then 3 g of 5% Pd/C are added thereinto and the mixture is hydrogenated at about 1-bar pressure for 14 hours. After removal of the catalyst by filtration, the solution is concentrated under vacuum until a solid residue is obtained, which is crystallized with a mixture ethanol/isopropanol=60/40 v/v; after 8 hours the product is filtered, washed with said mixture and dried at 45° C. for 15 hours. Thus, 11,6 g (yield—89% of the theoretical) of 5′-deoxy-5-fluorouridine M.p.=187÷188° C., puritya (HPLC)=99,75% and [α]D=+18.2° (c=0.42, H2O).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[O:14])=[N:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1.[ClH:28].CCOC(C)=O>>[ClH:28].[N:15]1([C:13](=[O:14])[CH2:12][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[N:4][N:3]=[N:2]3)=[CH:11][N:10]=2)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(-n2cnnn2)cn1)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 4-{[5-(1H-tetrazol-1-yl)pyridin-2-yl]acetyl}piperazine-1-carboxylate (30 mg, 0.08 mmol) in HCl/EtOAc (5 mL) was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduce pressure to give 1-(piperazin-1-yl)-2-[5-(1H-tetrazol-1-yl)pyridin-2-yl]ethanone hydrochloride. MS m/z 274 (M+1)+.