Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:37])[C:2]([NH:7][C:8]2[O:9][C:10]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH-].C[Sn+](C)C>ClCCCl.C(Cl)Cl>[C:1]1([CH3:37])[C:2]([NH:7][C:8]2[O:9][C:10]([C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:26][CH2:25]4)=[CH:22][CH:23]=3)=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(Nc2ccccc2C)oc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccccc1Nc1nc(C(=O)O)c(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)o1
Temperature: 80 °C
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(4-(2-(o-toluidino)-4-(ethoxycarbonyl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.042 g, 0.08 mmol) in DCE (2 ml) was added trimethyltin hydroxide (0.140 g, 0.77 mmol) and the resulting mixture was heated at 80° C. overnight. The reaction was cooled to room temperature and diluted with DCM. The organic phase was washed with water. The combined aqueous phase was extracted with DCM and the combined organic phase dried over MgSO4 and the solvent removed in vacuo to afford 2-(o-toluidino)-5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)oxazole-4-carboxylic acid (0.038 g, 0.08 mmol, 96%). LCMS (1) Rt: 1.89 min; m/z (ES+) 479.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:28])[C:26]#[N:27])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:26]3[NH:31][N:30]=[N:29][N:27]=3)[CH3:28])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C#N)CCCCCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)o1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(CCCCCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)o1)c1nnn[nH]1
Yield: 55 %

Procedure:
4.45 g of (RS)-7-[4,5-bis(4-chlorophenyl)-2-oxazolyl]-2-methylheptanenitrile in 40 cm3 of dimethylformamide are treated with twice 2.1 g of sodium azide and twice 4.4 g of triethylamine hydrochloride under the (time and temperature) conditions defined in Example 1. After treatment, the product of the reaction is chromatographed on a column 2.8 cm in diameter containing 115 g of silica gel (50 to 200μ). The column is eluted with 1.2 liters of diisopropyl ether and then with 2.8 liters of a diisopropyl ether/ethyl acetate (80:20 by volume) mixture, collecting 200 cm3 fractions. The fractions from the last eluent mixture are concentrated to dryness under reduced pressure (0.2 kPa). 2.7 g (55%) of (RS)-5-{7-[4,5-bis(4-chlorophenyl)-2-oxazolyl]-2-heptyl}-1H-tetrazole are obtained in the form of white crystals, melting point 144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([N:32]([C:25]1[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:23]([O:22][CH3:21])[CH:24]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: COc1cc(NNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Solvent: ClCCl
Product: COc1cc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2cc(CNC(=O)C(F)(F)F)ccc2Cl)ccc1[N+](=O)[O-]
Yield: 74.2 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.400 g, 4.57 mmol), tert-butyl 2-(3-methoxy-4-nitrophenyl)hydrazinecarboxylate (step-3 of Intermediate-32, 1.30 g, 4.57 mmol) and DCM 30 mL) to afford 2.0 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.33-1.46 (m, 9H), 3.87 (s, 3H), 4.40 (s, 2H), 7.06 (d, J=8.4 Hz, 1H), 7.32-7.36 (m, 3H), 7.45-7.52 (m, 1H), 7.96 (d, J=8.7 Hz, 1H), 9.92 (s, 1H), 10.07 (br s, 1H), 11.13 (br s, 1H); MS (m/z): 589.69 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C@@H:8]1[C:13]([OH:15])=O.[NH2:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:23]([OH:27])[C:24]([NH2:26])=[O:25].O[NH-].O=[N-]>>[NH2:26][C:24](=[O:25])[C:23](=[O:27])[CH:22]([NH:21][C:13]([C@H:8]1[CH2:9][CH2:10][C:11](=[O:12])[N:7]1[CH2:6][C:5]1[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(CN2C(=O)CC[C@@H]2C(=O)O)cc(OC)c1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: COc1cc(CN2C(=O)CC[C@@H]2C(=O)NC(Cc2ccccc2)C(=O)C(N)=O)cc(OC)c1

Procedure:
Coupling of (R)-1-(3,5-dimethoxy-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].[H-].[K+].C(S([C:16]1[O:17][CH:18]=[C:19]([CH3:21])[N:20]=1)=O)CCCCC.CCOCC>CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][N:2]([C:16]1[O:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:3](=[O:5])[CH3:4]
Reactant: CNC(C)=O
Reactant: CCCCCCS(=O)c1nc(C)co1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(=O)N(C)c1nc(C)co1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
N-Methyl-acetamide (1.02 g, 0.0140 m) in HMPA (10 ml) was stirred at 50° C. under nitrogen during the portionwise addition of 50% potassium hydride/oil dispersion (1.12 g, 0.0140 m). After the addition, the mixture was warmed to 100° C. and 2-n-hexylsulphinyl-4-methyloxazole (3.0 g, 0.0139 m) in HMPA (10 ml) was added and the mixture stirred at 100° C. for 5 hours. The mixture was then hydrolysed with water, solvent removed in vacuo and the product isolated by column chromatography on silica using ether. Recrystallisation from diethyl ether/hexane at -20° C. gave the title product as colourless needles, m.p. 27°-29° C.
Reaction SMILES: [C:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)#[CH:2].Cl.C[OH:26]>C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[OH:23][C@:3]1([C@:4]2([CH3:5])[C@H:6]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[CH:13][C:14](=[O:22])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:8]1)[C:1](=[O:26])[CH3:2]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Hg+2]
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 8 h

Procedure:
Starting from 3.12 g (0.01 mole) of 17α-ethynyl-17β-hydroxy-androst-4-en-3-one one proceeds as described in Example 9 but after the reaction with mercury(II)-acetate the mixture is not poured onto water but the mixture of 24 ml of concentrated hydrochloric acid and 40 ml of methyl alcohol is added thereto. The reaction mixture is stirred at a temperature of 48° to 50° C. for 8 hours, then it is poured onto water. The separated product is filtered, washed with water and dried. Thus 2.70 g of 17α-hydroxy-pregn-4-ene-3,20-dione are obtained (82.1% of the theoretical yield). The crude product is crystallized from methyl alcohol. Melting point: 212°to 217° C.; [α]D20 =+89° (CHC13, c=1%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12]CC)=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])=[CH:19][CH:18]=1)#[N:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])=[CH:19][CH:18]=1)#[N:2]
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(NC(=O)C4CC4)cc3)n(CC)c2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCn1c(-c2ccc(NC(=O)C3CC3)cc2)c(C#N)c2ccc(O)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of cyclopropanecarboxylic acid [4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide (4.4 g, 11.8 mmol) in 60 mL of DCM is added BBr3 (6.65 mL, 70 mmol) at −10° C. After the addition, the mixture is stirred for 3 h at 0° C. Then aqueous NaHCO3 is added to the mixture carefully until it becomes basic. The crude solid is collected by filtration to give 91% of cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-amide and is used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5][C:4](=O)[CH:3]=1.[NH2:15][OH:16]>NC1C=CC=CN=1.NC1C=CC=C(C)N=1>[OH:16][N:15]1[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: Cc1cc(C2CCCCC2)oc(=O)c1
Reactant: NO
Agent: Cc1cccc(N)n1
Agent: Nc1ccccn1
Product: Cc1cc(C2CCCCC2)n(O)c(=O)c1
Reaction time: 216 h
Yield: 36.6 %

Procedure:
2 g of 4-methyl-6-cyclohexyl-2-pyrone and 1 g of hydroxylamine were dissolved in a mixture of 1.5 g of 2-aminopyridine and 4.5 g of 2-amino-6-methylpyridine and stored for 9 days at room temperature. After the usual working up, there were obtained 0.79 g (37 %) of 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone melting at 143° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([OH:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:6]=1)=[O:4].[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1.CC(O)C.N(C(OCC1C=CC(Cl)=CC=1)=O)=NC(OCC1C=CC(Cl)=CC=1)=O>C(Cl)Cl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:7]1[C:8]([O:10][CH:18]([CH3:23])[CH3:19])=[CH:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6]1
Reactant: COC(=O)c1cc(O)n(-c2ccccc2F)n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C(N=NC(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: COC(=O)c1cc(OC(C)C)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
150 mg (0.635 mmol) of 1-(2-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid methyl ester, 166.6 mg (0.635 mmol) of triphenylphosphine and 38.16 mg (0.635 mmol) of 2-propanol were dissolved in 1.5 ml of DCM, and then a solution of 0.635 mmol of di(4-chlorobenzyl) azodicarboxylate in 1.5 ml of DCM was added. After stirring at room temperature for 4 h, the mixture was filtered and the solvent removed in vacuo. The obtained crude title compound was used in the hydrolysis step without further purification.
Reaction SMILES: Cl.[OH:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[O:16]1[CH2:20][CH2:19][C:18]([C:21]2[C:22]([CH3:34])=[C:23]([CH:27]=[CH:28][C:29]=2[S:30]([CH3:33])(=[O:32])=[O:31])[C:24](Cl)=[O:25])=[N:17]1.CC(C)(O)C#N>C(Cl)(Cl)Cl>[O:16]1[CH2:20][CH2:19][C:18]([C:21]2[C:22]([CH3:34])=[C:23]([CH:27]=[CH:28][C:29]=2[S:30]([CH3:33])(=[O:32])=[O:31])[C:24]([C:4]2[CH:5]=[N:6][N:7]([CH3:8])[C:3]=2[OH:2])=[O:25])=[N:17]1
Reactant: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1C1=NOCC1
Reactant: Cn1nccc1O
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1c(C(=O)c2cnn(C)c2O)ccc(S(C)(=O)=O)c1C1=NOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To 2.75 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoic acid were added 30 ml of benzene, then 1.7 ml of thionyl chloride and a drop of pyridine to heat at reflux for 3 hours. The reaction solution was cooled down. The solvent was distilled out under reduced pressure to give 2.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride. Separately 0.93 g of 5-hydroxy-1-methylpyrazole hydrochloride was dissolved in 20 ml of chloroform, and 1.60 g of triethylamine was added, while cooling with ice. Into the obtained solution was added dropwise 10 ml of a chloroform solution containing 1.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride to stir at room temperature for 30 minutes, and 0. 76 g of triethylamine and 0.16 g of acetone cyanohydrin were added to further stir overnight. The reaction solution was washed with dilute hydrochloric acid, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the residue. The obtained crystals were separated by filtration to give 1.59 g of the title compound as white crystals. m.p. 224~226° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[F:8][C:9]([F:39])([F:38])[C:10]1[CH:11]=[C:12]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31](Cl)=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:13]=[CH:14][CH:15]=1.O>CN(C=O)C>[F:8][C:9]([F:39])([F:38])[C:10]1[CH:11]=[C:12]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COCCO
Reactant: O=C(Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc2nc(C(=O)Nc3nc4cc(-c5cccc(C(F)(F)F)c5)ccc4[nH]3)cn2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-methoxy-ethanol (0.013 mL) in dry DMF (0.25 mL), sodium hydride (8 mg, 60% dispersion in mineral oil) was added, and the mixture was stirred at room temperature for 20 minutes under nitrogen. 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (30 mg) was added to the reaction mixture, and the mixture was warmed to 70° C. The reaction was monitored by LCMS for 1 hour until substantially complete. After cooling the reaction mixture, 10 mL of water was added and the reaction mixture was stirred for 10 minutes. The reaction was then filtered through a fine fritted funnel and the crude product was washed with water. After air drying, the product was purified by column chromatography (pre-packed silica column) using a gradient of 0 to 6% 2M ammonia-methanol in DCM. 20 mg of 6-(2-methoxy-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide was obtained. LCMS (m/z): 497.8. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (1H, s) 8.14 (1H, d) 7.93-8.03 (2H, m) 7.83 (1H, s) 7.67-7.74 (2H, m) 7.57-7.63 (1H, m) 7.51 (1H, dd) 7.10 (1H, d) 4.42-4.49 (2H, m) 3.70-3.76 (2H, m) 3.32-3.34 (3H, m).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](O)=[O:6].S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([Cl:22])=[O:6]
Reactant: O=C(O)C(CCBr)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)C(CCBr)(c1ccccc1)c1ccccc1

Procedure:
In 5 mL of chloroform was suspended 5.00 g (15.7 mmol) of 4-bromo-2,2-diphenylbutyric acid. Thionyl chloride (10 mL) was then added dropwise at room temperature. To the resulting mixture was added 0.1 mL of dimethylformamide, followed by heating under reflux for 5 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, whereby 4-bromo-2,2-diphenylbutyric chloride was obtained. While stirring under ice cooling, 50 mL of cold methanol was added. The temperature was allowed to rise back to room temperature, and then stirring was conducted for 30 minutes. The residue obtained by concentrating the solvent under reduced pressure was purified by chromatography on a silica gel column, whereby 5.00 g (yield: 95.7%) of methyl 4-bromo-2,2-diphenylbutyrate was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:15]=[C:5]2[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]([C:10]([NH:12][NH2:13])=[O:11])[N:4]2[N:3]=1.[CH2:16]=[C:17]1[O:21][C:19](=O)[CH2:18]1.C1COCC1>C(Cl)Cl>[NH2:1][C:2]1[N:15]=[C:5]2[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]([C:10]3[O:11][C:19]([CH2:18][C:17](=[O:21])[CH3:16])=[N:13][N:12]=3)[N:4]2[N:3]=1
Reactant: C=C1CC(=O)O1
Reactant: NNC(=O)c1cc(Br)cc2nc(N)nn12
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Cc1nnc(-c2cc(Br)cc3nc(N)nn23)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product of Step 1, 2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid hydrazide (1.0 g, 3.7 mmol), diketene (0.28 mL, 3.7 mmol) and THF (˜25 mL) were placed in a flask. The mixture was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and a solution of 9:1 CH2Cl2/MeOH. The organics were dried with MgSO4 and concentrated to give an oily yellow solid. The solid was dissolved in a small amount of CH2Cl2 and filtered through a plug of silica, eluting with CH2Cl2. The filtrate was concentrated to give 1-[5-(2-amino-7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-yl)-[1,3,4]oxadiazol-2-yl]-propan-2-one, which was used without further purification, in Step 3. MS (APCI+): m/z 337.0, 339.0.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](N)=[N:4][C:2]1=[O:3].[CH3:9][Si:10]([CH3:17])([CH3:16])[NH:11][Si:12]([CH3:15])([CH3:14])[CH3:13].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>>[CH3:9][Si:10]([N:11]([Si:12]([CH3:15])([CH3:14])[CH3:13])[C:8]1[CH:7]=[CH:5][NH:4][C:2](=[O:3])[N:1]=1)([CH3:17])[CH3:16]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C

Procedure:
Bis-trimethylsilylcytosine was prepared by combining 292 mg of cytosine with 2 ml of hexamethyldisilazane, 11 mg of ammonium sulfate and 5 ml of xylenes and refluxing the solution for one hour to form a homogenous solution. The excess xylenes and hexamethyldisilazane were removed leaving behind a molten residue of bis-trimethylsilylcytosine. 400 mg of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-α-methanesulfonate, dissolved in 2 ml of xylenes, were added to the molten bis-trimethylsilylcytosine and the xylenes were removed. The temperature of the reaction mixture was maintained at 160° C. for 15 minutes. HPLC analysis confirmed completion of the reaction. The alpha to beta anomeric ratio of blocked nucleoside product was 1:1.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]=[CH:12][C:13]([O:15]C)=[O:14])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:17].[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:17]
Reactant: COC(=O)C=Cc1cc(F)cc2c(C)c[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c[nH]c2c(/C=C/C(=O)O)cc(F)cc12
Reaction time: 15 h
Yield: 62.9 %

Procedure:
To a stirred solution of methyl 3-(5-fluoro-3-methylindol-7-yl)acrylate (1.75 kg, 7.51 mole), prepared as described in Example 1, in 23.4 L THF/MeOH (1:1) at room temperature was added 2 M aqueous sodium hydroxide (16.35 L, 32.7 moles). Stirring was continued for 15 h, then the reaction mixture was concentrated in vacuo to remove the volatile organic solvents. The solution was diluted with 20 L water, then extracted with dichloromethane (3×10 L). The aqueous layer was acidified to a pH of 2-3 with 2 M HCl, which induced precipitation of the product. The product was collected via vacuum filtration, washed with water (2×2 L), and vacuum dried at 60° C. to afford 1.036 kg (91% yield) of the desired title compound: 1H NMR (400 MHz, DMSO-d6) δ 2.23 (d, 3H, J=0.8 Hz), 6.67 (d, 1H, J=16 Hz), 7.24 (br s, 1H), 7.34 (dd, 1H, J=9.2, 2.4 Hz), 7.41 (dd, 1H, J=10.4, 2.4 Hz), 8.06 (dd, 1H, J=16, 1.2 Hz), 11.35 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)=[N:5][N:6]([CH3:12])[C:7]=1[N:8]=[CH:9]OC)#[N:2].[CH3:22][NH:23][NH2:24].C(C1C(C2N(C)C([N+]([O-])=O)=CN=2)=NN(C)C=1N=CO)#N>C(O)C>[CH3:22][NH:23][NH:24][CH:9]=[N:8][C:7]1[N:6]([CH3:12])[N:5]=[C:4]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[C:3]=1[C:1]#[N:2]
Reactant: COC=Nc1c(C#N)c(-c2ncc([N+](=O)[O-])n2C)nn1C
Reactant: CNN
Agent: Cn1nc(-c2ncc([N+](=O)[O-])n2C)c(C#N)c1N=CO
Solvent: CCO
Product: CNNC=Nc1c(C#N)c(-c2ncc([N+](=O)[O-])n2C)nn1C

Procedure:
A mixture of 1.0 g. of methyl N-[4-cyano-1-methyl-3-(1-methyl-5-nitro-2-imidazolyl)pyrazol-5-yl]formimidate, 1 ml. of methyl hydrazine, and 10 ml. of ethanol was stirred at ambient room temperature for about 1 hour. The reaction product mixture was filtered. The solid which was recovered was recrystallized from ethanol to yield product in the form of yellow needles having a melting point of about 232°-234° C. The product was identified by NMR spectrum and elemental analyses as N-[4-cyano-1-methyl-3-(1-methyl-5-nitroimidazol-2-yl)pyrazol-5-yl]formimidic acid, 2-methyl hydrazine.
Reaction SMILES: [C@@H:1]1([N:12]2[C:23]3[C:15](=[C:16]4[C:30](=[O:31])[NH:29][C:28](=[O:32])[C:17]4=[C:18]4[C:22]=3[NH:21][C:20]3[N:24]=[CH:25][CH:26]=[CH:27][C:19]4=3)[C:14]3[CH:33]=[CH:34][CH:35]=[N:36][C:13]2=3)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[K+].[K+].[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>O1CCCC1>[S:49]([O:3][C@@H:2]1[C@@H:4]([OH:5])[C@H:6]([OH:7])[C@@H:8]([CH2:10][OH:11])[O:9][C@H:1]1[N:12]1[C:23]2[C:15](=[C:16]3[C:30](=[O:31])[NH:29][C:28](=[O:32])[C:17]3=[C:18]3[C:22]=2[NH:21][C:20]2[N:24]=[CH:25][CH:26]=[CH:27][C:19]3=2)[C:14]2[CH:33]=[CH:34][CH:35]=[N:36][C:13]1=2)([C:46]1[CH:47]=[CH:48][C:43]([CH3:53])=[CH:44][CH:45]=1)(=[O:51])=[O:50]
Reactant: O=C1NC(=O)c2c1c1c3cccnc3[nH]c1c1c2c2cccnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]2n2c3ncccc3c3c4c(c5c6cccnc6[nH]c5c32)C(=O)NC4=O)cc1

Procedure:
To a solution of the compound of Example 12 (0.17 mmol) in 10 ml of tetrahydrofuran there are added 23.5 mg of potassium carbonate and 1.7 mmol of para-toluenesulphonic acid chloride. The mixture is heated at reflux for 48 hours. After evaporating off the solvent, the residue is taken up in a water/ethyl acetate mixture and is then filtered over a frit. The crystals are successively washed with ethyl acetate and then with methanol, allowing the expected product to be isolated.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH3:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.CCOC(C)=O>CN(C)C(=O)C>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]4=[N:26][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2][N:22]4[CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:27][CH:28]=1
Reactant: Cc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
2-Chloroethanesulfonyl chloride (0.885 g) in N,N-dimethylacetoamide (7.0 mL) was added dropwise to a solution of 3-[4-(4-methylphenoxy)phenyl]pyridin-2-amine (1.00 g) in N,N-dimethylacetoamide (3.0 mL) at 0° C. The mixture was stirred at 70° C. under N2 overnight. EtOAc and IPE was added dropwise to the mixture at room temperature. The solid was isolated by filtration and washed with water, IPE and EtOAc to give the title compound (1.07 g) as a gray solid.