Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]([C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]([O:17][CH3:18])=[O:16])=[O:3].O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].C(N(C(C)C)CC)(C)C>C(#N)C>[C:35]([O:34][C:32]([CH:30]1[CH2:31][N:28]([CH2:27][C:26]2[CH:39]=[CH:40][C:23]([C:21]3[N:22]=[C:2]([C:4]4[O:8][N:7]=[C:6]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)[C:5]=4[C:15]([O:17][CH3:18])=[O:16])[O:3][N:20]=3)=[CH:24][CH:25]=2)[CH2:29]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1c(-c2ccccc2)noc1C(=O)F
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(CN3CC(C(=O)OC(C)(C)C)C3)cc2)no1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To a mixture of methyl 5-(fluorocarbonyl)-3-phenylisoxazole-4-carboxylate (99 mg, 0.397 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (121 mg, 0.397 mmol) in acetonitrile (2 mL) at rt was added diisopropylethylamine (0.083 mL, 0.477 mmol) and the reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated to afford a white solid that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford methyl 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-phenylisoxazole-4-carboxylate (128 mg, 0.248 mmol, 62.4% yield) as a white solid. HPLC retention time=1.78 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=517.22. 1H NMR (400 MHz, chloroform-d) d ppm 1.45 (s, 9H) 3.23-3.32 (m, 3H) 3.51-3.58 (m, 2H) 3.68 (s, 2H) 3.95 (s, 3H) 7.44 (d, J=8.0 Hz, 2H) 7.48-7.56 (m, 3H) 7.75 (dd, J=7.91, 1.63 Hz, 2H) 8.11 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][N:20](C(=O)C(F)(F)F)[CH2:19][CH2:18]4)[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:13]3[CH2:16][CH:15]([N:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)[CH2:14]3)=[O:12])=[CH:29][CH:30]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1CC(N2CCN(C(=O)C(F)(F)F)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1ccc(C2CCCCC2)cc1)N1CC(N2CCNCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 1i (0.95 g, 2.24 mmol) in CH3OH (16 mL) and H2O (4 mL) was added K2CO3 (0.8 g, 5.79 mmol). The mixture was stirred at room temperature for 1 h. After filtration, the solvent was removed by evaporation. The crude compound 1j was used in the next reaction without further purification. MS m/z (M+H+) 328.2.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:24]1[CH:29]=[CH:28][C:27]2=[N:30][N:31]=[C:32]([C:33]([F:36])([F:35])[F:34])[N:26]2[N:25]=1>C(O)C>[F:35][C:33]([F:34])([F:36])[C:32]1[N:26]2[N:25]=[C:24]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[CH:29]=[CH:28][C:27]2=[N:30][N:31]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 70 °C
Yield: 90.7 %

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (8.29 g, 44.5 mmol) and ethanol (90 mL) was added to a mixture of DIPEA (9.16 mL, 52.6 mmol) and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (obtained as described in Monatsh. Chem. (1972) 103(6), 1591-603) (9.0 g, 40.4 mmol) in ethanol (90 mL). The mixture was heated at 70° C. for 11 hours and then allowed to cool to ambient temperature to give a precipitate. The is precipitate was collected by filtration, washed with chilled ethanol and then with water, and dried under vacuum to afford tert-butyl 4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboxylate (13.64 g, 90.6%) as a white solid that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[CH2:29]([O:31][CH2:32][CH2:33]O)[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:30][CH2:29][O:31][CH2:32][CH3:33])=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CCOCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOCCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Yield: 75.7 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl](4-hydroxyphenyl)methanone (0.39 g, 1.00 mmol) and ethylene glycol mono ethyl ether (2 mmol) were converted to 350 mg of the title compound by the procedure of Example 1 using 520 mg (2.0 mmol) of triphenylphosphine and 2.0 mmol of diethyl azodicarboxylate the only difference being that the total reaction time was 18 hours.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([Br:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[N+:13]([CH:16]=[C:17](SC)[S:18][CH3:19])([O-:15])=[O:14]>C(#N)C>[N+:13]([CH:16]=[C:17]([S:18][CH3:19])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([Br:12])=[CH:10][CH:9]=[CH:8][N:7]=1)([O-:15])=[O:14]
Reactant: NCCSCc1ncccc1Br
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCSCc1ncccc1Br

Procedure:
A solution of 2-[(2-aminoethyl)thiomethyl]-3-bromopyridine (from the dihydrobromide, 3.0 g) and 1-nitro-2,2-bis-methylthioethylene (1.21 g) in acetonitrile (30 ml) was set aside at room temperature for 3 days. The product was chromatographed on a column of silica gel with elution by ethyl acetate, to give 1-nitro-2-methylthio-2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]ethylene (1.2 g), m.p. 79°-80° (from ethanol-ether).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12][OH:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:7]=2)[CH:3]=1.CCN(CC)CC.C(Cl)Cl.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12][O:13][S:55]([CH3:54])(=[O:57])=[O:56])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[N:7]=2)[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COC(COS(C)(=O)=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 0.236 mmol) and Et3N (0.099 mL, 0.709 mmol) in DCM (3 mL, 46.6 mmol) at 0 C was added Methanesulfonyl chloride (0.037 mL, 0.473 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was cooled to 0 , quenched by addition of saturated NaHCO3 and diluted with ether, the layers were separated and the ether layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by Biotage LC (30% EtOAc/Hex) to give 155 mg of title product as white foam (92% yield). LC/MS (HPLC method 3): tR=4.15 min, 712.3(MH)+.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[C:32]([F:35])([F:34])[F:33]>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:20]2[CH2:21][CH2:22][C:5]3([O:4][C:3](=[O:2])[N:7]([C:8]4[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=4)[CH2:6]3)[CH2:18][CH2:19]2)=[CH:26][C:25]=1[C:32]([F:33])([F:34])[F:35]
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: Cl
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4ccc(Cl)c(C(F)(F)F)c4)CC3)OC2=O)cc1

Procedure:
The title compound was prepared from methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 4-chloro-3-trifluoromethylbenzaldehyde (38.3 mg, 0.184 mmol) following essentially the same procedure described in Step 1 of Example 7-6. The title compound was obtained as a yellow solid (73 mg) that was used without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(N(CC)C(C)C)(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].CO.ClCCl>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(N)ccc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(NS(C)(=O)=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine methyl 2-methoxy-5-aminobenzoate (1.5 g, 8.3 mmol) and dichloromethane (25 mL). Cool in an ice bath. Add N,N-diisopropylethylamine (3.17 mL, 18.2 mmol) and methanesulfonyl chloride (0.71 mL, 9.1 mmol). After 30 minutes, warm to ambient temperature. After 4 hours, dilute the reaction mixture with dichloromethane and extract three times with a 1 M aqueous hydrochloric acid solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3% methanol/dichloromethane/0.1% concentrated aqueous ammonia to give methyl 2-methoxy-5-methylsulfonamidobenzoate: mp; 82-83° C. Elemental Analysis calculated for C10H13NO5S: C, 46.32; H, 5.05; N, 5.40. Found C, 46.44; H, 4.96; N, 5.19.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[C:31]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:30]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][CH:60]=1>C(Cl)Cl>[CH3:57][O:58][C:59]1[C:64]2[C:34]3[C:29](=[CH:30][C:31]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:33]=3)[C:14]3[C:15](=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=3)[C:63]=2[C:62]([O:65][CH3:66])=[CH:61][CH:60]=1
Reactant: COc1ccc(OC)cc1
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(OCCCCCCCCCC)c(OCCCCCCCCCC)c2)cc1OCCCCCCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCOc1cc2c3cc(OCCCCCCCCCC)c(OCCCCCCCCCC)cc3c3c(OC)ccc(OC)c3c2cc1OCCCCCCCCCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Solid 3a (5.50 g, 7.06 mmol) was added to an ice cold suspension of anhydrous FeCl3 (9.16 g, 56.5 mmol) in dry CH2Cl2 (250 mL). Within 2 min 1,4-dimethoxybenzene (3.90 g, 28.2 mmol) was added to the green reaction mixture. The reaction mixture was allowed to warm slowly to room temperature and then stir for an additional 12 h. The reaction mixture was quenched with anhydrous MeOH (30 mL). The volume of the mixture was reduced to 50 mL under reduced pressure and MeOH (200 mL) was added to the resulting oil. The slightly violet product was called on a frit and washed with MeOH. The product was further purified by column chromatography using a 50% CH2Cl2/50% hexane solvent mixture to afford 4a (RF=0.24) as a colorless solid in 84% yield (mp 69-70° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](Cl)(=[O:16])[CH3:15].[OH-].[K+].O>C(O)C>[C:14]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Oc1ccc(C(C)=O)cc1[N+](=O)[O-]

Procedure:
A mixture containing 36.2 g (0.2 mole) of 4'-hydroxy-3'-nitroacetophenone, 15.7 g of acetyl chloride, 22 mL of 50% KOH solution, 200 mL of H2O and 300 mL of 95% ethanol is stirred and heated to reflux for 18 hours. The mixture is evaporated to remove ethanol, and the aqueous mixture is extracted with CHCl3 to solubilize the product. The CHCl3 extract is evaporated to dryness to afford 4'-acetoxy-3'-nitroacetophenone, which is brominated with an equimolar quantity of Br2 in CHCl3 (100 mL) to afford 2-bromo-4'-acetoxy-3-nitroacetophenone. This phenacyl bromide is then reacted in 100 mL of ethanol with 2 equivalents of isopropylamine to afford 4'-acetoxy-3'-nitro-2-isoproylaminoacetophenone, which isolated as the hydrochloride by the procedure reported by Larson et al. in Journal of Medicinal Chemistry, 10, 467 (1967) for a related compound. This ketoamine is then hydrogenated in 90% aqueous ethanol with 0.5 g of 10% Pd-C/3.5 kg/cm2H2 pressure in a Parr hydrogenator until the uptake of H2 is completed. The mixture is filtered, and the filtrate is evaporated to dryness to afford the crude title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:9][CH3:11])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(O)c(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C)c(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
4-Bromo-2-fluoro-5-methylphenol (40 g, 0.19 mol), cesium carbonate (75 g, 0.23 mol), and iodomethane (15 ml, 0.23 mol) were combined in 100 ml of DMF and stirred at RT for one hour (exothermic). The solution was diluted with ethyl acetate and filtered. The solution was washed with water twice, dried with anhydrous sodium sulfate, filtered, and concentrated. The product was purified via silica gel column chromatography (RediSep 330 g column) using 0-50% ethyl acetate in hexane to afford 1-bromo-5-fluoro-4-methoxy-2-methylbenzene (38 g, 89% yield) as a colorless liquid. No [M+H] peak by LCMS. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.24 (s, 3H) 3.76 (s, 3H) 6.73 (d, J=8.80 Hz, 1H) 7.13 (d, J=10.56 Hz, 1H)
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[C:19]2[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=2[N:21]=[CH:22][N:23]=1>CS(C)=O.O>[CH3:32][Si:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][O:28][CH2:27][N:24]1[C:20]2[N:21]=[CH:22][N:23]=[C:18]([O:1][C@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)[C:19]=2[CH:26]=[CH:25]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.6 %

Procedure:
To a solution of (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0.4 g, 2.0 mmol) in DMSO (5 mL) under nitrogen, was added NaH (60% suspension in mineral oil, 79 mg, 2.0 mmol). After the reaction was stirred for 1.5 h at rt, a solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (564 mg, 2.0 mmol) in DMSO (5 mL) was added dropwise at rt and the mixture was heated at 50° C. for 2 h. The reaction mixture was cooled to rt, diluted with water (10 mL) and extracted with EtOAc (4×60 mL). The combined organic layer was washed with water (50 mL), dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography (silica gel, gradient EtOAc in Hexanes) to give (750 mg, 85%) of the titled intermediate.
Reaction SMILES: [NH:1]1[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C[Si](N[Si](C)(C)C)(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C(O[C@@H:34]1[O:46][C@H:45]([CH2:47][O:48]C(=O)C)[C@@H:40]([O:41]C(=O)C)[C@H:35]1[O:36]C(=O)C)(=O)C>C(#N)C>[C@@H:34]1([N:1]2[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]2=[O:3])[O:46][C@H:45]([CH2:47][OH:48])[C@@H:40]([OH:41])[C@H:35]1[OH:36]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1nc[nH]c(=O)n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 2.5 °C
Reaction time: 20 h

Procedure:
A mixture of 5-azacytosine, HMDS, and TMSC1 in acetonitrile is heated to reflux for 20 hours under an inert atmosphere. TMS-triflate and 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose are then added directly to the silylated 5-azacytosine in acetonitrile. The addition is performed at ambient temperature and under an inert atmosphere. The reaction mixture is maintained under stirring for 20 hours, then the acetonitrile is removed under vacuum. The solids are then dissolved in dichloromethane, and the mixture is poured over a pre-cooled (0-5° C.) sodium bicarbonate solution (10%). The resulting mixture is extracted with dichloromethane. The combined organic extract is washed with cooled (0-5° C.) 10% sodium bicarbonate and brine, then dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuum to dryness. The off-white foam is dissolved in methanol and treated with a solution of 25% sodium methoxide in methanol. The suspension is stirred at ambient temperature for 15 hours, then the solid is filtered off, washed with methanol and anhydrous ether, then dried in vacuum. The crude 5-azacytidine is further purified from DMSO and methanol (for details see Example 4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:18]([O:17][C:15]([C:14]1[CH:20]=[N:1][C:2]2[C:3]([C:13]=1[OH:12])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)=[O:16])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cn1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1O

Procedure:
3-Amino-6-methoxypyridine (12.41 g) and diethyl ethoxymethylene malonate (20.2 ml) in Dowtherm A (400 ml) was heated at reflux, under argon for 1 h. The cooled reaction mixture was poured onto pentane (1 litre). The precipiated solid was collected by filration, washing with pentane. Drying afforded the title compound (24.78 g, crude).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:17]Br>CC(O)=O>[Br:17][C:8]1([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[C:9]1=[O:12]
Reactant: BrBr
Reactant: CC(C)(C)C1CCc2ccc(Br)cc2C1=O
Solvent: CC(=O)O
Product: CC(C)(C)C1(Br)CCc2ccc(Br)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
step b—To a solution of 109 (3 g, 10.7 mmol) and HOAc (40 mL) stirred at RT under N2 was added dropwise via cannula a solution of bromine (1.88 g, 605 μL, 11.7 mmol) in HOAc (20.0 mL) over 20 min. The solution was stirred for 1 h at RT then warmed reaction to 50° C. and stirred 1 h. An aliquot of neat bromine (100 μL) was added and heating continued. The total heating time was 2.5 h. The reaction mixture was poured over ice, partitioned between EtOAc and H2O and aqueous phase was neutralized with satd. aq. NaHCO3. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The product was purified by SiO2 chromatography eluting with hexanes to afford 3.8 g (quantitative) of 110.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH3:16])[C:4](=[O:17])[N:3]1[CH3:18].[Cl:19]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>[Cl:19][C:5]1([C:8]2[C:9]([CH3:16])=[CH:10][C:11]([CH3:15])=[CH:12][C:13]=2[CH3:14])[C:6](=[O:7])[N:2]([CH3:1])[N:3]([CH3:18])[C:4]1=[O:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C)c(C2C(=O)N(C)N(C)C2=O)c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(C)c(C2(Cl)C(=O)N(C)N(C)C2=O)c(C)c1
Yield: 78.4 %

Procedure:
There was refluxed with heating a mixture of 0.50 g (2.0 mmols) of 1,2-dimethyl-4-(2,4,6-trimethylphenyl)pyrazolidine-3, 5-dione, 0.32 g (2.4 mmols) of N-chlorosuccinic acid imide, 19 mg (0.08 mmol) of benzoyl peroxide and 20 ml of carbon tetrachloride for 30 minutes. Water was added to the reaction mixture, followed by extraction with chloroform. The extract was washed with an aqueous solution of saturated sodium hydrogencarbonate and a saturated solution of sodium chloride and was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then the residue was washed with hexane, thereby obtaining 0.44 g (yield 78%) of 4-chloro-1,2-dimethyl-4-(2,4,6-trimethylphenyl)pyrazolidine-3,5-dione in the form of yellowish white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=O)[CH:2]=1.Cl.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.C(O)(=O)C>C(O)C>[Br:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[NH:19][CH:9]=[C:8]2[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=CCCc1cccnc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Brc1ccc2[nH]cc(Cc3cccnc3)c2c1

Procedure:
A mixture of 3-pyridin-propionaldehyde (1 g; 0.0074 mol) and of 4-bromophenylhydrazin hydrochloride (1.8 g; 0.0074 mol) with acetic acid (4.44 ml) in absolute ethanol (50 ml) was refluxed for 3 hours. The reaction was then quenched with a saturated solution of aqueous sodium carbonate and the product was extracted with ethyl acetate. The organic extract was dried (MGSO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol (98/2), the desired compound was obtained.