Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[CH:12]([Cl:15])([Cl:14])[Cl:13].[OH-].[K+]>CN(C=O)C.CO>[Cl:13][C:12]([CH:7]([OH:8])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([Cl:15])[Cl:14]
Reactant: ClC(Cl)Cl
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=[N+]([O-])c1cccc(C(O)C(Cl)(Cl)Cl)c1
Temperature: -5 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 3-nitrobenzaldehyde (200 g, 1.32 mol) and chloroform (238 ml, 2.97 mol) in 800 ml of DMF cooled to -9° C. under nitrogen was added dropwise a solution of potassium hydroxide (59.8 g, 0.92 mol) in 180 ml of methanol over a 2.7 hour period. The deep purple reaction mixture was aged for 2 hours at -8° C. before quenching over 40 minutes into 1.8 liter of lN HCl and 1.8 liter of toluene cooled to -5° C. The quench mixture was stirred and cooled for an additional 0.5 hour and then brought to ambient temperature. The toluene layer was separated and washed twice with 1.8 liter of water. After treatment with 35 g of Darco G-60 charcoal for 1 hour and filtration through Super-Cel, the organic layer was washed with 1.8 liter of aqueous 5% sodium bicarbonate solution and then 1.8 liter of water. After evaporation to 550 ml the desired product was crystallized by the addition of 450 ml of hexanes. The resulting slurry was cooled at 0° C. for 2 hours and the solid was collected by filtration and rinsed with hexanes. After drying, 320 g (90% yield) of TMBA was obtained; m.p. 91- 95° C; 1H NMR 3.75 (1H, d, J=1 Hz), 5.25 (1H, d, J=1 Hz), 7.20-8.45 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:11])[CH2:9][OH:10])=[CH:6][C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]([CH3:11])[CH:9]=[O:10])=[CH:6][C:5]([C:12]#[N:13])=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]([CH:31]2[CH2:32][CH2:33]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:17]2[N:16]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C(C)CO)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C(C)C=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 67.8 %

Procedure:
2-((2-chloro-5-cyano-3-(1-hydroxypropan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (37 mg, 0.070 mmol) was taken up in DCM (1 mL) and the solution was cooled to 0° C. Dess-Martin periodinane (35.6 mg, 0.084 mmol) was added, and the reaction was stirred at 0° C. for 1.5 h. Some SM still remaining, so an additional 0.4 eq. (12 mg) of Dess-Martin was added, and the reaction was stirred for 30 min. The reaction was quenched with 2M K3PO4 and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0%-60% EtOAc/Hex; 12 g column). 2-((2-chloro-5-cyano-3-(1-oxopropan-2-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (25 mg) was obtained as a glassy liquid.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]=1[CH3:23].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH2:37]([O:39][CH:40]([O:43][CH2:44][CH3:45])[C:41]#[CH:42])[CH3:38].N12CCN(CC1)CC2>CCCCCC.CN(C=O)C.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[CH2:37]([O:39][CH:40]([O:43][CH2:44][CH3:45])[C:41]#[C:42][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]=1[CH3:23])[CH3:38]
Reactant: C#CC(OCC)OCC
Reactant: COC(=O)c1nc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: Cl[Pd+]
Agent: C1CN2CCN1CC2
Agent: C=C[CH2-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(C#Cc1nc(C(=O)OC)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.5 %

Procedure:
Methyl 6-iodo-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (SM1, 1.2 g, 2.8 mmol), allylpalladium(II) chloride dimer (0.0072 g), 10% by weight tri(tert-butyl)phosphine in hexane (2.1 mL) and anhydrous DMF (3.0 mL) were stirred until a clear solution was obtained. Propargylaldehyde diethyl acetal (0.44 mL, 3.1 mmol) in anhydrous DMF (2.3 mL) was added, followed by 1,4-diazabicyclo[2.2.2]octane (0.63 g, 5.6 mmol) in small portions. The red solution was purged with dry argon for 5 minutes and then stirred under argon at RT. After 4 h, the solvent was evaporated off using an oil pump. The residue was taken up in acetonitrile (10 mL), filtered through glass-wool and then concentrated with silica. Chromatography on silica with ethyl acetate-heptanes (1:10 and 1:2) as eluents gave the title compound (0.46 g, 37%) as a yellow oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15]([CH3:16])=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)=[O:5].I[C:19]1[N:20]=[CH:21][N:22]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=1.CC1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1C(C1C=CC=C2C=1N=CC=C2)O.N1C2C(=CC=CC=2C=O)C=CC=1>>[CH3:16][C:15]1[C:6]([C:4]([C:19]2[N:20]=[CH:21][N:22]([C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:23]=2)=[O:5])=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: CON(C)C(=O)c1ccc2cccnc2c1C
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C(O)c1cccc2cccnc12
Agent: O=Cc1cccc2cccnc12
Product: Cc1c(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)ccc2cccnc12

Procedure:
(8-Methylquinolin-7-yl)(1-trityl-1H-imidazol-4-yl)methanone (21) was synthesized from (20) and 4-iodo-1-trityl-1H-imidazole via the procedure used in the preparation of (4) from (3) above.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[S:21]
Reactant: NNC(=O)c1cccc(I)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: NNC(=S)c1cccc(I)c1
Yield: 73.6 %

Procedure:
3-Iodobenzohydrazide (500 mg, 1.91 mmol) obtained in Step 1 of Example 52 was suspended in toluene (10 mL), and the mixture was refluxed for 1 hour after adding Lawesson's reagent (772 mg, 1.91 mmol). The mixture was then purified by silica gel column chromatography to give 3-iodothiobenzohydrazide (391 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22](C2CCCCO2)[CH:21]=[CH:20]3)[S:13][C:14]=1[CH3:15].[H-].[Na+].[CH2:34](Br)[CH2:35][CH3:36].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH2:34][CH2:35][CH3:36])[S:13][C:14]=1[CH3:15]
Reactant: CCCBr
Reactant: COc1ccc(-c2nc(Nc3ccc4c(ccn4C4CCCCO4)c3)sc2C)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(c1ccc2[nH]ccc2c1)c1nc(-c2ccc(OC)cc2Cl)c(C)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
10.9 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(1-(tetrahydropyran-2-yl)indol-5-yl)amino]-thiazole are dissolved in 110 ml of dimethylformamide. 1.06 g of 60% sodium hydride in oil and then 3.2 ml of propyl bromide are added at 0° C. After stirring for 16 hours at room temperature, the reaction mixture is poured onto 500 ml of water and extracted 3 times with 250 ml ethyl acetate. The organic phase is washed with 3 times 200 ml of water, dried over sodium sulphate and evaporated to dryness. The residue is purified by flash chromatography on silica gel eluted with a 3/1 (v/v) cyclohexane/ethyl acetate mixture. 10.17 g of the expected product (85%) are obtained. 1H NMR (CDCl3): 0.90 (m, 3H), 1.57-1.75 (m, 6H), 2.02 (s, 3H), 1.95-2.25 (m, 2H), 3.70-4.17 (m, 7H), 5.50 (dd, J=2.6, 10.0, 1H), 6.54-7.61 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][C:38]([NH2:40])=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[CH2:37][C:38]([NH2:40])=[O:39])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: NC(=O)CBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@H]1CCCN1
Product: NC(=O)CN1CCC[C@@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(2R)-2-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}pyrrolidin-1-yl]acetamide was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2R)-pyrrolidin-2-ylmethyl]-1,3-thiazolidine-2,4-dione and 2-bromoacetamide following General Procedure H.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.C[N:23](C=O)C>>[Br:1][C:2]1[N:3]=[C:4]2[N:9]([CH:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[CH3:11])[N:23]=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(Nc1nc(Br)cnc1N)c1ccc2ncccc2c1
Product: CC(c1ccc2ncccc2c1)n1nnc2ncc(Br)nc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a solution of the 5-bromo-N*3*-(1-quinolin-6-yl-ethyl)-pyrazine-2,3-diamine in anhydrous DMF (25 mL) was added isoamyl nitrile (0.98 mL, 1.2 mmol) at 0° C. The reaction was stirred at 0° C. for 5 min, then the ice bath was removed and allowed to stir at ambient temperature for 5 min. The reaction was then heated at 70° C. for 1 hour, cooled and quenched with sat. aqueous solution of Na2SO3 (10 mL). Water (50 mL) and EtOAc (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (4×100 mL). The combined organics were washed with NaHCO3 (50 mL) and water (3×50 mL), dried over Na2SO4, filtered and concentrated to give 6-[1-(6-bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)-ethyl]-quinoline (1.56 g, 72% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[N:6]=1)=[O:4].[O:18]1CC[CH2:20][CH2:19]1.C1(N=C=NC2CCCCC2)CCCCC1>C(O)CO>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([O:13][CH2:20][CH2:19][OH:18])=[O:12])[CH:8]=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[N:6]=1)=[O:4]
Reactant: C1CCOC1
Reactant: CNC(=O)c1cc(C(=O)O)cc(C(=O)NC)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: OCCO
Product: CNC(=O)c1cc(C(=O)OCCO)cc(C(=O)NC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Bis(N-methylcarbamoyl)pyridine-4-carboxylic acid (2.3 g) prepared in Example 2 was mixed with 50 ml of tetrahydrofuran and 3.1 g of ethylene glycol. After addition of 2.5 g of dicyclohexyl carbodiimide, the mixture was stirred at room temperature overnight. The mixture was then evaporated and the residue was purified by a column chromatography on silica gel, and recrystallized from dimethylformamide/benzene to give 0.3 g of 2-hydroxyethyl 2,6-bis(N-methylcarbamoyl)pyridine-4-carboxylate. m.p. 214°-215° C.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12]([CH2:13][O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6])([CH3:3])[CH3:2].[SiH3]O[SiH3]>>[CH:1]([O:4][C:5]([CH:7]1[CH:12]([CH2:13][O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:11][CH2:10][CH2:9][NH:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(C)OCc1cccnc1C(=O)OC(C)C
Agent: [SiH3]O[SiH3]
Product: CCOC(C)OCC1CCCNC1C(=O)OC(C)C

Procedure:
Hydrogenation of compound 3-(1-ethoxy-ethoxymethyl)-pyridine-2-carboxylic acid isopropyl ester, following the method used for the corresponding silyl ether as in scheme 1, gave the desired product 3-(1-ethoxy-ethoxymethyl)-piperidine-2-carboxylic acid isopropyl ester. The starting pyridine compound (5.1 g, 19.1 mmol) was dissolved in 60 mL of methanol in a pressure hydrogenation vessel to which 2 g of PtO2 was added. The vessel was shaken under 60 psi of hydrogen for 5 days. The suspension was filtered through Celite and the solution was concentrated in vacuo to provide the desired compound, 3-(1-ethoxy-ethoxymethyl)-piperidine-2-carboxylic acid isopropyl ester (5.1 g, ca. 100%). Data: MS 274 (M+1); 1H NMR (300 MHz, CDCl3): δ 5.50 (br. s, 1H, NH), 5.07 (m, 1H, CH of ester), 4.60-4.64 (overlapping q's, J=7.0 Hz, 1H), 3.41-3.73 (m, 5H), 3.10 (m, 1H), 2.69 (m, 1H), 2.30 (m, 1H), 1.80-1.95 (m, 2H), 1.41-1.63 (m, 3H), 1.19-1.30 (m, 12H); 13C NMR (CDCl3, 75 MHz): δ 172.4, 172.3, 100.0, 99.9, 68.1, 68.0, 64.4, 63.7, 61.1, 61.0, 60.4, 46.0, 45.9, 36.81, 36.76, 26.3, 26.1, 22.14, 22.07, 22.0, 21.9, 19.92, 19.85, 15.45, 15.39.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[C:29]([CH3:30])=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=1[CH3:31].N1C=CC(N)=CC=1.N1C=CC=CC=1>C1COCC1.C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:18][C:19]1[C:20]([CH3:31])=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][C:29]=1[CH3:30])=[O:9]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: CCOC(=O)c1cc(C)c(N)c(C)c1
Agent: Nc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)c(NC(=O)c2cc(Br)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 5-bromo-2-methyl-benzoic acid (1.35 g, 6.15 mmol) in THF (15 ml), CH2Cl2 (15 ml) and DMF (14.27 μl, 184.57 μmoles) is added dropwise oxalyl chloride (587.12 μl, 6.77 mmoles) at 0° C. and reaction mixture is slowly allowed to warm to ambient temperature. After 2 hours, the solvent is removed under reduced pressure. To the residue CH2Cl2 (30 ml) is added and reaction mixture is cooled to 0° C., then ethyl 4-amino-3,5-dimethyl-benzoate (1.19 g, 6.15 mmol) is added followed by 4-pyridinamine, N,N-dimethyl-(37.58 mg, 307.61 μmoles) and pyridine (1.49 ml, 18.46 mmoles). The cooling bath is removed and the clear solution is allowed to warm to ambient temperature. After 5 hours, the solvent is removed and the reaction mixture is diluted with ethyl acetate and washed with 1N HCl, saturated solution of sodium bicarbonate, and brine. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is triturated with hexanes and the resulting solids were collected by filtration to give the title compound as a white solid (1.80 g; 75.2%). Mass spectrum (m/z): 390.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[O:12][CH3:13].[CH3:14]N(C(OC)OC)C.N1CCCC1>CN(C=O)C>[CH3:13][O:12][C:3]1[C:4]([CH3:11])=[CH:5][CH:6]=[C:7]2[C:2]=1[CH:1]=[CH:14][NH:8]2
Reactant: COc1c(C)ccc([N+](=O)[O-])c1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COc1c(C)ccc2[nH]ccc12
Temperature: 125 °C
Reaction time: 3 h
Yield: 16.5 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-nitroanisole (3.26 g, 18 mmol) in dry DMF (36 ml) were added DMF dimethyl acetal (2.51 g, 19.8 mmol, 2.8 ml) and pyrrolidine (1.8 ml). The reaction mixture was stirred under N2 at 125° C. for 3 h, cooled to rt and concentrated in vacuo. The oily residue was dissolved in a mixture of toluene-acetic acid (5:3, 36 ml) and added to a stirred mixture of iron powder (18 g) and silica gel (70-230 mesh, 45 g) in a mixture of toluene-acetic acid (5:3, 234 ml). The mixture was then heated at reflux under N2 for 1 h, cooled to rt, diluted with CH2Cl2 and filtered. The filter cake was washed thoroughly with CH2Cl2 and the combined filtrates were washed successively with Na2S2O5 solution, saturated aq. NaHCO3 and brine, dried and evaporated. The residue was flash chromatographed [(CH2Cl2-hexanes (3:2)] to give 27 as a colourless viscous oil (0.48 g, 16%) which was used without further purification; δH (90 MHz) 8.10 (1 H, br s, NH), 6.88-7.08 (3 H, m, 2-, 6-, and 7-H), 6.50-6.64 (1 H, m, 3-H), 3.98 (3 H, s, OMe) and 2.32 (3 H, s, Me).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)[CH2:15][CH2:14]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]3)=[CH:24][N:23]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3cc(Cl)nn4ccnc34)nc2)CC1
Temperature: 25 °C
Yield: 101.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 104a (2.0 g, 4 mmol), 5-(4-methylpiperazin-1-yl)pyridin-2-amine (920 mg, 4.8 mmol), tris(dibenzylideneacetone)dipalladium(0) (366 mg, 0.4 mmol), XantPhos (688 mg, 1.2 mmol), Cs2CO3 (2.6 g, 8.0 mmol), and 1,4-dioxane (60 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 15 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (20:1) to afford 104b as yellow solid (1.4 g, 70%). MS: [M+H]+344.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([O-:20])(=[O:19])=[O:18])=O.[Na+:21]>CO>[C:1]1([NH:7][N:8]=[C:13]2[CH:14]=[CH:15][CH:16]=[CH:11][CH:12]2[S:17]([O-:20])(=[O:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:21]
Reactant: NNc1ccccc1
Reactant: O=Cc1ccccc1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)([O-])C1C=CC=CC1=NNc1ccccc1
Yield: 89.6 %

Procedure:
104 g of phenylhydrazine was dissolved in 800 ml of methanol, and a solution obtained by dissolving 56 g of sodium o-formylbenzenesulfonate in 200 ml of methanol was dropwise added thereto at room temperature. The resulting mixture was heated for 2 hours under reflux with stirring. After cooling, the crystal formed was separated by filtration and then washed with methanol to obtain 69 g of sodium 2-phenylhydrazonobenzenesulfonate (Intermediate A). 50 g of Intermediate A thus obtained was dissolved in 250 ml of water and then hydrogenated in an autoclave by adding palladium-carbon catalyst thereto. After the catalyst was removed by filtration, 250 ml of isopropanol was added to the hydrogenated product whereupon a colorless product precipitated out. This product was separated out by filtration and washed with isopropanol and then dried to obtain 43 g of sodium 2-phenylhydrazinobenzenesulfonate (Intermediate B). Next, 40 g of Intermediate B, 19 g of diethyl malonate, 25 g of sodium methylate (28% methanol solution) and 100 ml of n-butanol were blended and heated for 10 hours under reflux. N-butanol was concentrated and 200 ml of water was added to the residue. Next, the aqueous layer was made acidic with concentrated hydrochloric acid, whereby a crystal precipitated out. This was separated out by filtration and washed with a small amount of methanol to give 39 g of Intermediate C (1-phenyl-2-(2-sulfobenzyl)- 3,5-pyrazolidinedione sodium salt).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@H:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][C@H:11]1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C.N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@H:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][C@H:11]1[O:20][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H]1CC[C@@H](O)[C@@H]1COCc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C[C@@H]1CC[C@@H](OC2CCCCO2)[C@@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 8.52 g of (1R,2S,3S)-2-benzyloxymethyl-3-methoxycarbonylmethylcyclopentan-1-ol (prepared in Reference Example 2), 7.4 ml of 2,3-dihydropyran and 30 ml of methylene chloride was prepared and then cooled. To the mixture 370 mg of p-toluenesulphonic acid monohydrate was added, the mixture was stirred for 20 min. at 0° C., and for 30 min. at room temperature. After addition of 1 ml of pyridine, the mixture was diluted with 300 ml of diethyl ether. The diluted solution was washed with water, dilute hydrochloric acid, an aqueous solution of sodium bicarbonate and water successively, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to give 14.2 g of the title compound having the following physical characteristics.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH:5]([CH2:18][O:19]C(=O)C1C=CC=CC=1)[CH2:6][O:7][C:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[O:10][N:9]=1>CO>[NH2:4][CH:5]([CH2:18][OH:19])[CH2:6][O:7][C:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[O:10][N:9]=1
Reactant: NC(COC(=O)c1ccccc1)COc1noc2ccc(Cl)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(CO)COc1noc2ccc(Cl)cc12

Procedure:
To a solution of 4.00 g of sodium hydroxide in 77 ml of methanol is added 7.66 g of 3-(2-amino-3-benzoyloxypropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride at 20°-25° C., and they are subjected to reaction at the same temperature for ten minutes. The solvent is removed from the reaction mixture by distillation under reduced pressure, and ethyl acetate and water are added to the residue obtained, and after shaking, the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure to obtain 4.13 g of colorless, crystalline 3-(2-amino-3-hydroxypropoxy)-5-chloro-1,2-benzoisoxazole.