Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]=[C:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][O:25]CC3C=CC=CC=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH2:23][CH2:24][OH:25])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(OCCOCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCO)ccc21
Reaction time: 6 h
Yield: 80 %

Procedure:
3-[5-(2-benzyloxy-ethoxy)-indol-1-yl]-3-phenyl-acrylic acid ethyl ester (2.5 g, 5.6 mmol) was dissolved in 70% ethyl acetate/methanol (50 mL) and added under an argon atmosphere to a suspension of 10% palladium on carbon [10% w/w] (3.0 g) in the same solvent (50 mL). The reaction was placed in a Parr Hydrogenator for 6 h. The reaction was filtered through celite and the solvent was evaporated under vacuum. Purification of the crude mixture via column chromatography with silica gel, eluting with hexane/ethyl acetate gave the title compound (80% yield). 1H NMR (CDCl3), δ 7.14–7.32 (m, 7H), 6.82 (dd, 1H, J=2.3, 8.8 Hz), 6.45 (d, 1H, J=3.0 Hz), 6.07 (d, 1H, J=2.1 Hz), 6.01 (t, 1H, J=7.4 Hz), 4.03 (m, 4H), 3.91 (m, 2H), 3.27 (m, 2H), 1.06 (t, 3H, J=7.2 Hz).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[CH2:26]([NH2:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:32][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reactant: CCCCCCN
Product: CCCCCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), and hexylamine (2 ml) the subtitle compound was obtained (298 mg, 100%). MS 416 m/z (M+H)+.
Reaction SMILES: [OH2:1].Cl[C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([Cl:17])[C:4]=1[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[H-].[Na+].Cl>O1CCCC1>[Cl:17][C:10]1[C:4]([C:5]([N:7]([CH3:9])[CH3:8])=[O:6])=[C:3]([OH:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=1
Reactant: O
Reactant: CN(C)C(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
3.2 ml (177.6 mmol, 4.2 eq) of water and 11.04 g (41.96 mmol; 1.0 eq) of 2,6-dichloro-N,N-dimethyl-3-nitrobenzamide (41.96 mmol; 1.00 eq.) in solution in 130.00 ml of tetrahydrofuran were added to a suspension of 7.16 g (179.01 mmol; 4.3 eq) of sodium hydride in 250 ml of tetrahydrofuran cooled to 0° C. After 10 minutes, the reaction medium was stirred at ambient temperature for 19 hours. The reaction medium was hydrolyzed with a 1 N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with a 1 N aqueous hydrochloric acid solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue (11.82 g) was chromatographed on silica gel (300 g prepacked column, eluent heptane/ethyl acetate from 40 to 80% of ethyl acetate, 150 ml/min). 6.10 g of 6-chloro-2-hydroxy-N,N-dimethyl-3-nitrobenzamide were obtained in the form of a yellow solid. Yield=59%.
Reaction SMILES: [CH3:1][C:2]12[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]1=[CH:7][C:5](=O)[CH2:4][CH2:3]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25]([SH:28])[CH2:26][SH:27].O>C(O)(=O)C>[CH3:1][C:2]12[C:12](=[O:13])[CH2:11][CH2:10][CH:9]=[C:8]1[CH2:7][C:5]1([S:28][CH2:25][CH2:26][S:27]1)[CH2:4][CH2:3]2
Reactant: SCCS
Reactant: CC12CCC(=O)C=C1CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC12CCC3(CC1=CCCC2=O)SCCS3
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
To a solution of Wieland-Miescher ketone (5.87 g, 33.0 mmol) in glacial acetic acid (40 mL) was added p-toluenesulfonic acid (2.94 g) followed by dropwise addition of 1,2-ethanedithiol over a 1 hour period. The reaction mixture was stirred at room temperature for another 4 hours, poured into 30 mL water, and stirred for 15 minutes. The white solid was filtered off, washed successively with water, diluted with NaHCO3 solution and water, and then dried to yield thioketal 239 (7.33 g, 87.3 %) as a white solid. 1H NMR (CDCl3) δ 1.50-2.70 (m, 10H), 3.20-3.40 (m, 4H), 5.67 (s, 1H); 13C NMR (CDCl3) 212.92, 141.23, 128.04, 64.81, 49.43, 40.11, 39.62, 37.92, 37.57, 30.81, 30.69, 24.73, 24.57.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[C:18]([O:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:23]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:20])[CH3:19]>>[C:18]([O:21][C:22]1[CH:27]=[C:26]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[CH:25]=[CH:24][C:23]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Oc1cc(I)ccc1OCc1ccccc1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: CC(=O)Oc1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1OCc1ccccc1

Procedure:
This compound was obtained by coupling rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 5-iodo-2-(phenylmethoxy)phenyl acetate under the conditions described in Example 26. The crude product was chromatographed over the 50 fold amount of silica gel using methylene chloride. The combined fractions were evaporated and the residue was crystallized from methanol after treatment with charcoal and was recrystallized from ether/hexane for analysis to give colorless crystals with m.p. 117°-120°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1)[CH2:5][CH2:6][S:7]([CH3:10])(=O)=O.[CH2:25]([O:28][C:29]([N:31]1[CH2:35][C@@H:34]([S:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][C@H:32]1[CH2:44][NH2:45])=[O:30])[CH:26]=[CH2:27].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:25]([O:28][C:29]([N:31]1[CH2:35][C@@H:34]([S:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:33][C@H:32]1[CH2:44][NH:45][S:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12](=[O:23])[NH:11][C@H:4]([C:3]([O:2][CH3:1])=[O:24])[CH2:5][CH2:6][S:7][CH3:10])[CH:14]=1)(=[O:21])=[O:20])=[O:30])[CH:26]=[CH2:27]
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CN
Reactant: COC(=O)[C@H](CCS(C)(=O)=O)NC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CNS(=O)(=O)c1cccc(C(=O)N[C@@H](CCSC)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 15(a) (1.53 g. 4.18 mmol) in CH2Cl2 (20 mL) was added to a stirred solution of (2S,4S)-2-aminomethyl-4-BOCsulfanyl-pyrollidine-1-carboxylic acid allyl ester (15(b)) (prepared as described in International Patent Application WO 92/17480. see pages 39-41) (1.32 g. 4.18 mmol) and (iPr)2NEt (1.5 mL. 9.0 mmol) in CH2Cl2 (30 mL) at 0° C. under argon. The resulting solution was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then washed with water (100 mL), dried over MgSO4, filtered and concentrated to a viscous white gum. This was then purified by flash chromatography on 9385 SiO2. eluting with a gradient of 35-50% EtOAc/i-Hexane to give (2S,4S)-4-BOCsulfanyl-2-{[3-([1S]-1-methoxycarbonyl-3-methylsulfanyl-propylcarbamoyl)-benzenesulfonylamino]-methyl }-pyrrolidine-1-carboxylic acid allyl ester (15(c)) as a colourless foam: 2.19 g (81.3%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][N:16](CC3C=CC(OC)=CC=3OC)[C:15](=[O:30])[C:14]3[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][NH:16][C:15](=[O:30])[C:14]3[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CN2Cc3c(-c4nc(C5CC5)no4)ncn3-c3ccc(OC)cc3C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)NCc1c(-c3nc(C4CC4)no3)ncn1-2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxy-benzyl)-8-methoxy-4,5-dihydro-2,5,10b-triaza-benzo[e]azulen-6-one (5 g, 10.3 mmol) were dissolved in CH2Cl2 (30 mL), cooled to 0° C., then TFA (30 mL) was added, followed by trifluoromethanesulfonic acid (2 mL, 22.9 mmol). The mixture was stirred for 4 h at rt, evaporated, the residue dissolved in CH2Cl2 (100 mL), and extracted with 10% NaHCO3. The product precipitated upon evaporation of CH2Cl2. Yield: 3 g (86%); mp 245° C. m/z 337 (M).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]([O:15][C:16](=[O:37])[CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14]>ClCCl>[CH2:13]([O:15][C:16](=[O:37])[CH:17]=[C:10]1[CH2:11][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:9]1)[CH3:14]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CC(c2cccc(Br)c2)C1
Solvent: ClCCl
Product: CCOC(=O)C=C1CC(c2cccc(Br)c2)C1
Yield: 89 %

Procedure:
3-(3-Bromo-phenyl)-cyclobutanone (2.03 g 9.02 mmol) and Triphenyl-phosphoranylidene acetic acid ethyl ester (15.72 gms 45.12 mmol) were dissolved in dichloromethane (30 mL) inside a CEM 80 ml microwave vessel. The solution was irradiated in a CEM Discover™ microwave instrument for 30 minutes at 120° C. Pressure reached a maximum of 180 PSI. The product was purified by column chromatography (isocratic; 10% diethyl ether in hexanes) to give 2.37 gm of an oil (89%) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.1 Hz, 3H) 2.89-3.00 (m, 1H) 3.03-3.11 (m, 1H) 3.16-3.27 (m, 1H) 3.46-3.57 (m, 1H) 3.63 (q, J=8.0 Hz, 1H) 4.08 (q, J=7.0 Hz, 2H) 5.71 (q, J=2.9 Hz, 1H) 7.25-7.35 (m, 2H) 7.39-7.43 (m, 1H) 7.48-7.52 (m, 1H); MS (APPI) m/z 295 [M+H]·+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[NH:1][CH:16]1[CH2:15][CH2:14][C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]1
Reactant: NC1Cc2ccccc2C1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(NC2Cc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
2-Aminoindane (266 mg, 2 mmol) and 4-dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmol) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 490 mg N′-Indan-2-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid which, for preparation of the hydrochloride, was dissolved in 2-butanone (10 ml), and 1.85 M ethanolic HCl (2 ml) was added. The mixture of cis- and trans-N′-indan-2-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride obtained was filtered off with suction and dried (540 mg, m.p. 224-226° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH:17]=[O:18])[NH:8][C:7]=1[CH3:19])=[O:5])C.CO.[OH-].[K+]>O>[CH:17]([C:9]1[NH:8][C:7]([CH3:19])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:18]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52 %

Procedure:
5-Formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester was dissolved in water (100 mL) and methanol (45 mL) with stirring. Added KOH (2 eq. 1.9 g) and heated in 100° C. After 2.5 h, cooled to room temperature and the remaining ester was removed by extracting into ethyl acetate (200 mL), dried and concentrated. The water layer was acidified to pH=3 using 2N HCl. The white solid was removed by filtration, rinsing with water. The solid was re-concentrated from toluene, triturated with hexanes and dried to afford 2 g (52%) of an off-white solid. 1H NMR (360 MHz, DMSO-d6) δ 12.46 (br s, 1H, CO2H), 11.95 (s, 1H, NH), 9.08 (s, 1H, CHO), 7.36 (s, 5H, ArH), 2.49 (s, 3H, CH3). MS m/z (relative intensity %, ion) found 229 (100, M+); calc. 229.2.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:9])[NH:8][C:3]=1[CH:2]([F:1])[F:14]
Reactant: COC(=O)c1ccc(C(F)F)[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)c(C(F)F)[nH]c1=O
Reaction time: 2 h

Procedure:
4.1 g (20 mmol) of methyl 6-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate were dissolved in 20 ml of N,N-dimethylformamide, and 5.35 g (30 mmol) of N-bromosuccinimide were added at room temperature. After 2 hours of stirring, the reaction mixture was added to water and extracted with tert-butyl methyl ether. The extract was subsequently washed repeatedly with water. Drying and concentration finally gave 3.7 g (65% of theory) of the product.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]1[O:13][CH2:4]1
Reactant: C[S+](C)C
Reactant: COc1ccccc1C=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: COc1ccccc1C1CO1

Procedure:
A mixture of 9.7 g of sodium hydride, 38 g of trimethylsulfonium iodide and 25.2 g (0.185 mol) of o-methoxybenzaldehyde is reacted to give o-methoxystyrene oxide.
Reaction SMILES: C([C:4]1[C:5](=[O:25])[NH:6][CH:7]=[C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)[CH:9]=1)(O)=O.C>C(Cl)(Cl)Cl.CO>[O:25]=[C:5]1[CH:4]=[CH:9][C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:7][NH:6]1
Reactant: O=C(O)c1cc(-c2c(-c3ccccc3)nn3ccccc23)c[nH]c1=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)c[nH]1
Yield: 28.8 %

Procedure:
3-(3-Carboxy-2-oxo-1,2-dihydropyridin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (120 mg) was melted by an electric hot plate at 370° C. This was dissolved in a mixture of chloroform (26 ml) and methanol (13 ml), and silica gel (1 g) and charcoal (0.2 g) were added thereto and then this mixture was filtered. The solvent of the filtrate was removed and chromatographed on silica gel (3 g) with a mixture of chloroform, methanol and triethylamine (200:10:1). The fractions containing the object compound were combined and evaporated in vacuo and recrystallized from ethyl acetate to give 3-(2-oxo-1,2-dihydropyridin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (30 mg).
Reaction SMILES: [F:1][C:2]([F:12])([S:9]([O-:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].[CH2:13]([NH+:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].O.OO.S([O-])([O-])=[O:24].[Na+].[Na+]>CC(C)=O>[F:12][C:2]([F:1])([S:9]([O-:24])(=[O:11])=[O:10])[C:3]([F:7])([F:8])[CH2:4][CH2:5][OH:6].[CH2:13]([NH+:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]
Reactant: O=S([O-])[O-]
Reactant: O=S([O-])C(F)(F)C(F)(F)CCO
Agent: CC[NH+](CC)CC
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)([O-])C(F)(F)C(F)(F)CCO
Temperature: 40 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
A 500 mL reactor was charged with 65 g (93% purity, 0.194 mole/1.0 equivalent) of triethylammonium 1,1,2,2-tetrafluoro-4-hydroxy-butane-1-sulfinate obtained in Example 2-1 by purification, 200 g of water and 46 g (0.40 mole/2.1 equivalents) of 30% hydrogen peroxide at room temperature, followed by 6 hours of stirring at 40° C. Upon confirming the termination of the reaction, the reaction liquid underwent cooling, and 7.5 g of sodium sulfite was added to the reaction liquid, followed by stirring. Thereafter, 350 g of acetone was added to a liquid obtained by distilling the solvent out of the reaction liquid, followed by 1 hour of stirring at room temperature. Thereafter, filteration was performed in the use of a filter paper. An obtained filtrate was concentrated and dried, thereby obtaining 65.6 g of a target triethylammonium 1,1,2,2-tetrafluoro-4-hydroxy-butane-1-sulfonate. It exhibited a purity of 92% and a yield of 95% at this time.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:14](=[O:16])O[C:12](=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C1COCC1>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:25]2[C:12](=[O:17])[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][C:14]2=[O:16])=[CH:22][CH:21]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)O1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CC(c3ccc([N+](=O)[O-])cc3)CC2=O)cc1
Temperature: 85 °C
Yield: 669 %

Procedure:
A solution of 12.6 g (53.6 mmol) of 4-(4-nitro-phenyl)-dihydro-pyran-2,6-dione (as prepared in the previous step) in THF (160 mL) was treated with 9.04 mL (6.96 mmol) of 4-methoxy-benzylamine at RT for 2 h. Solvents were evaporated in vacuo. The residue was dissolved in 1.0 N HCl (200 mL) and extracted with EtOAc (2×250 mL). The combined organic layers were washed with water (1×200 mL), dried (MgSO4) and concentrated in vacuo. The residue was treated with acetic anhydride (200 mL) and triethylamine (30 mL), and heated to 85° C. for 1.5 h. The mixture was concentrated in vacuo, treated with 1.0 N HCl (200 mL), and extracted with EtOAc (3×200 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (1×200 mL) and water (1×200 mL), dried (MgSO4), and concentrated in vacuo. The solid was triturated with hexane using sonication, filtered and air-dried to afford 16.5 g (87%) of the title compound as light tan solid: Mass spectrum (ESI, m/z): Calcd. for C19H21N2O, 325.1 (M-OCH3+2H), found 325.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18](=[O:21])[CH:19]=[CH2:20]>CC(=O)CC>[C:18]([C:19]1[CH2:20][O:10][C:5]2[C:6]([CH:7]=1)=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:21])[CH3:17]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: C=CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)C1=Cc2cc(Br)ccc2OC1
Yield: 58 %

Procedure:
A heterogeneous solution of 100 g (497 mmol) of 5-bromo-2-hydroxybenzaldehyde and 13.8 g (10 mmol) of potassium carbonate (previously finely ground and dried at 90° C.) in 220 ml of butan-2-one is brought to reflux. A solution of 35.31 g (i.e. 42 ml, 497 mmol) of but-3-en-2-one in 40 ml of butan-2-one is then added dropwise over a period of from 15 to 20 minutes. After 4 hours' refluxing, 13.8 g (10 mmol) of potassium carbonate are added. The mixture is refluxed for 16 hours. When the reaction mixture has returned to room temperature, the solid is separated off by filtration and then washed with 2×50 ml of butan-2-one. The filtrate is then concentrated and the residue is purified by chromatography over a silica column (eluant: methylene chloride/cyclohexane, 1:1). Recrystallisation from diisopropyl ether yields 73 g of a yellowish solid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH2:13][CH2:14][OH:15])[C:11]=1[NH2:12].C(N(CC)CC)C.[C:23]([O:27][C:28]([NH:30][C:31]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=NS(C(F)(F)F)(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:12][C:11]1[N:10]([CH2:13][CH2:14][OH:15])[N:9]=[CH:8][C:7]=1[NH:6][C:31]([NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[N:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: Nc1cnn(CCO)c1N
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn(CCO)c1N
Yield: 62.5 %

Procedure:
To a suspension of 4,5-diamino-1-(2-hydroxyethyl)pyrazole sulfuric acid salt (50.0 g) in chloroform (500 ml) were added 4-(dimethylamino)pyridine (2.54 g), triethylamine (116 ml) and 1,3-bis(tert-butoxycarbonyl)-2-(trifluoromethanesulfonyl)guanidine (106 g). The mixture was stirred under reflux for 2 hours. After cooling on an ice bath, the reaction mixture was washed successively with water, 4% aqueous citric acid solution, water and aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixed solvent of ethyl acetate (50 ml) and diethyl ether (200 ml) to give 5-amino-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-1-(2-hydroxyethyl)pyrazole (50 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:13][CH2:14][O:15][C:16]3[C:17]([N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]4)=[N:18][CH:19]=[CH:20][N:21]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:35][C:36](OC(C)=O)=[O:37]>N1C=CC=CC=1>[C:36]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:13][CH2:14][O:15][C:16]3[C:17]([N:22]4[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]4)=[N:18][CH:19]=[CH:20][N:21]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:37])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc3ccc(N)nc23)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2cccc(OCCOc3nccnc3N3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product obtained in Step 1 (502 mg, 1.08 mmol) was dissolved in pyridine. Ac2O (0.42 mL 4.45 mmol) was added, and the reaction mixture seas stirred under inert atmosphere at room temperature for 5 h. Concentration in vacuo afforded a yellow oil, which was purified by column chromatography using EtOAc/Et3N (95:5) as eluent to give the title product as a yellow solid: yield 531 mg (97%); MS m/z 509 (M+H)+. Anal. (C26H32N6O5.0.4 H2O) C, H, N
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:14]=[CH:13][NH:12][C:6]=2[N:7]=[C:8]([S:10][CH3:11])[N:9]=1.[CH2:15](I)[CH3:16]>CN(C)C=O>[Cl:3][C:4]1[C:5]2[CH:14]=[CH:13][N:12]([CH2:15][CH3:16])[C:6]=2[N:7]=[C:8]([S:10][CH3:11])[N:9]=1
Reactant: CSc1nc(Cl)c2cc[nH]c2n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2c(Cl)nc(SC)nc21
Reaction time: 0.75 h

Procedure:
Sodium hydride (0.44 g, 60% dispersion in oil) was added portionwise to a stirred solution of 4-chloro-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (2 g) in N,N-dimethylformamide (30 ml) at 0° C. After 0.75 h, ethyl iodide (0.88 ml) was added, the mixture stirred for 2 h, quenched with water and partitioned between ethyl acetate and brine. The organics were washed with water, dried (MgSO4), evaporated under reduced pressure and the residue purified by chromatography on silica eluting with 15% ethyl acetate in isohexane. Yield 1.98 g