Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]([O:35][C:36](=[O:42])[NH:37][CH2:38][CH2:39][CH2:40]Br)([CH3:34])([CH3:33])[CH3:32].CCOC(C)=O>CN(C=O)C>[F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:42])[O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCCCNC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol (511 mg, 1.55 mmol, 1.0 eq.) and potassium carbonate (428 mg, 3.1 mmol, 2.0 eq.) in dry DMF (10 mL) was added tert-butyl(3-bromopropyl)carbamate (480 mg, 2.01 mmol, 1.3 eq.). The mixture was stirred for 3 h at 90° C. and then cooled to RT. EtOAc was added and the organic phase was washed three times with water. The organic phase was dried over MgSO4 and solvents were removed in vacuo. The desired product R1 was obtained as brown oil and was used without further purification in the next step. MS (ES) C24H26FN3O7 requires: 487. Found: 488 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:5][C:4]=1[N+:17]([O-])=O.C(O)C.Cl.C(=O)([O-])O.[Na+]>O>[NH2:17][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C=C2SC(=O)NC2=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=C2SC(=O)NC2=O)cc1N
Yield: 85.4 %

Procedure:
5-[(4-Methoxy-3-nitrophenyl)methylidene]thiazolidine-2,4-dione (841 mg, 3.00 mmol), ethanol (20 mL) and concentrated hydrochloric acid (10 mL) were mixed, and tin chloride(II) dihydrate (2.26 g, 9.01 mmol) was added little by little at room temperature under stirring. After stirring for 8 hours at room temperature, the reaction mixture was poured into water and neutralized with saturated aqueous sodium hydrogencarbonate, which was extracted with ethyl acetate. The extracted solution was washed with water, then dried over anhydrous sodium sulfate and concentrated to obtain 641 mg (85%) of the title compound as yellowish orange powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[O:55]1[CH:59]=[CH:58][N:57]=[C:56]1[C:60](O)=[O:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:56]2[O:55][CH:59]=[CH:58][N:57]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1ncco1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ncco2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1,3-oxazole-2-carboxylic acid as starting materials in 31% yield. LCMS for C28H28ClN8O3 (M+H)+: m/z=559.2.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1([CH2:9][C:10]#[C:11][C:12]#[N:13])[CH2:8][CH2:7][CH2:6][CH2:5]1.CCO>[OH-].[Na+].CCOCC>[CH:4]1([CH2:9][C:10]2[O:3][N:2]=[C:12]([NH2:13])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: N#CC#CCC1CCCC1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: Nc1cc(CC2CCCC2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydroxylamine HCl (20.3 mmol) was dissolved in 14.9 mL of 2.5 M aqueous NaOH solution at rt and 4-Cyclopentyl-but-2-ynenitrile (16.9 mmol) was added in solution with 50 mL EtOH. The cloudy suspension was stirred at rt for 2 hours. The reaction material was then diluted with 200 mL of Et2O and washed with two 50 mL portions of water, followed by 50 mL of aqueous saturated sodium chloride solution. The organics were then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were then purified through flash chromatography to give 5-Cyclopentylmethyl-isoxazol-3-ylamine.
Reaction SMILES: [Cl-].[Li+].C(O[C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1)CCCCCCC.[CH2:21]([C:27]1[CH:35]=[CH:34][C:30]([CH:31]2[O:33][CH2:32]2)=[CH:29][CH:28]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:28]([C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:32][CH:31]([C:30]3[CH:34]=[CH:35][C:27]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)[O:33][C:19]2=[O:20])=[CH:16][CH:17]=1)[CH2:27][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCOc1ccc(N=C=O)cc1
Reactant: CCCCCCc1ccc(C2CO2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(N2CC(c3ccc(CCCCCC)cc3)OC2=O)cc1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
4 mg of lithium chloride and 1.0 ml of DMF were placed in a 20 ml-three necked flask. Under refluxing and stirring in nitrogen atmosphere, a solution of 0.97 g (3.92 mM) of 4-octyloxyphenyl isocyanate and 0.80 g (3.92 mM) of (-)-4-hexylstyrene oxide in 1.8 ml of DMF was added dropwise to the mixture in 5 minutes, followed by refluxing for 5 minutes under stirring. After the reaction, the reaction mixture was cooled to room temperature and poured into ice water to precipitate a crystal. The crystal was recovered by filtration, washed with water and dissolved in a toluene-ethyl acetate mixture solvent, followed by drying with anhydrous sodium sulfate and evaporation under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography and recrystallized from an acetone/methanol mixture solvent to obtain 0.25 g of optically active 3-(4-octylphenyl)-5-(4-hexylphenyl)-2-oxazolidinone (Yield: 14.1%). This compound showed the following phase transition series.
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:25][C:26]1[S:30][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:27]=1>C(Cl)Cl>[C:14]([O:13][C:11]([N:8]1[CH2:7][CH2:6][CH:5]([CH:2]([NH:1][S:31]([C:29]2[S:30][C:26]([Cl:25])=[CH:27][CH:28]=2)(=[O:33])=[O:32])[CH2:3][OH:4])[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H](N)CO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(CO)NS(=O)(=O)c2ccc(Cl)s2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a stirred mixture of tert-butyl 4-[(1S)-1-amino-2-hydroxyethyl]-1-piperidinecarboxylate (0.107 g, 0.44 mmol), triethylamine (0.046 g, 0.46 mmol) and methylene chloride (5 mL) cooled to 0° C., was added 5-chlorothiophene-2-sulfonyl chloride (0.095 g, 0.44 mmol) as a solution dissolved in 2 mL methylene chloride, dropwise by pipet. After 15 min, the ice bath was removed and the reaction allowed to attain 25° C. and stir overnight. The reaction was quenched by pouring it into saturated sodium bicarbonate solution (25 mL) and additional methylene chloride (15 mL). The organic phase was separated and washed sequentially with 1N HCl solution, H2O, brine and dried over MgSO4. The organic phase was filtered and evaporated to produce a crude oil that was flash chromatographed using ethyl acetate-hexane, 1—1 as eluent. This produced the title compound as a solid (0.109 g, 58%). MS (+APCI) 442.18 ([M+NH4]+); 386.08; 357.01; 325.07; 307.01; 285.06. Anal. Calc'd for C16H25ClN2O5S2: C, 45.22; H, 5.93; N, 6.59; Found: C, 45.31; H, 5.87; N, 6.4
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O>C(O)C>[C:2]1([C:1]2[N:8]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:8]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCO
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
Benzonitrile (5.2 g, 0.05 mol) was added dropwise over a period of 100 sec to 20 ml (34 g, 0.23 mol) of stirred trifluoromethanesulfonic acid with the temperature being allowed to rise as high as 91°C. When the reaction mixture cooled to 25°C, the yellow solution was poured into 100 ml cold ethanol. The yellow color disappeared and a white flocculent precipitate formed. Recrystallization of this precipitate from 150 ml chloroform afforded 3.43 g (66 percent yield) of 2,4,6-triphenyl-s-triazine (white crystals, m.p. 235°-237°C) (Lit. m.p. 232°C, J. Chem. Soc., 1941, 278). The 3.43 g sample of product exhibited no nitrile bands in the infrared spectrum but the infrared spectral band characteristic of the triazine structure was very strong at 6.6μ.
Reaction SMILES: Br.[Br:2][C:3]1[NH:4][C:5]2[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:7]3[N:8]([CH2:13][CH2:14][N:15]=3)[C:9](=[O:12])[C:10]=2[N:11]=1.I[CH3:25]>>[Br:2][C:3]1[N:11]([CH3:25])[C:10]2[C:9](=[O:12])[N:8]3[CH2:13][CH2:14][N:15]=[C:7]3[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:5]=2[N:4]=1
Reactant: O=C1c2nc(Br)[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCN12
Reactant: CI
Agent: Br
Product: Cn1c(Br)nc2c1C(=O)N1CCN=C1N2Cc1ccc(Cl)cc1

Procedure:
The product of Procedure 17 is allowed to react with iodomethane under alkaline conditions according to the method of Procedure 67 to give the desired product, m.p. 206°-207°.
Reaction SMILES: [N:1]#CBr.[CH3:4][N:5]1[C:9]2[CH2:10][CH2:11][C:12]3[C:19]4([CH3:22])[CH:20]([CH3:21])[CH:6]1[CH2:7][C:8]=2[C:13]=3[CH:14]=[CH:15][CH2:16][N:17]=[CH:18]4.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:4]([N:5]1[C:9]2[CH2:10][CH2:11][C:12]3[C:19]4([CH3:22])[CH:20]([CH3:21])[CH:6]1[CH2:7][C:8]=2[C:13]=3[CH:14]=[CH:15][CH2:16][N:17]=[CH:18]4)#[N:1]
Reactant: N#CBr
Reactant: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C#N
Temperature: 25 °C
Yield: 70 %

Procedure:
To a stirred solution of 0.50 g of cyanogen bromide and 20 ml of chloroform was added, at room temperature with stirring, a solution of 1.0 g of 1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 40 ml of chloroform. The mixture was heated at reflux for 2.6 hr, under nitrogen, and then cooled to room temperature. Dilute aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was washed with sodium bicarbonate solution. The combined aqueous layers were back extracted with ether, and the combined organic layers were washed with brine, dried over anhydrous potassium carbonate and filtered. The fitrate was concentrated. The residue was purified by flash chromatography (silica gel, 2% triethylamine/ether) to afford 0.73 g (70%) of 3-cyano-6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine, which was combined with 0.39 g of the product from a previous reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[C:24]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][C:26]2[O:31][CH2:30][CH:29]([C:32](O)=[O:33])[O:28][C:27]=2[CH:35]=1>>[OH:22][C:23]1[C:24]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:25][C:26]2[O:31][CH2:30][CH:29]([C:32]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:33])[O:28][C:27]=2[CH:35]=1
Reactant: CC(C)(C)c1cc2c(cc1O)OC(C(=O)O)CO2
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Product: CC(C)(C)c1cc2c(cc1O)OC(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)CO2
Yield: 72 %

Procedure:
That compound is obtained in a yield of 72% starting from 1-[bis(4-fluorophenyl)methyl]piperazine and 7-hydroxy-6-tert-butyl-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:22]3[CH:23]=[CH:24][NH:20][CH:21]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1cc[nH]c1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1cc[nH]c1
Yield: 74 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 74% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>CCOCC>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[CH:3][CH:4]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc(Br)cn1
Solvent: CCOCC
Product: OC1(c2ccc(F)nc2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 5-bromo-2-fluoro-pyridine (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:18]=[C:19]=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>CN(C)C=O.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:19](=[O:20])[NH:18][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCN=C=O
Reactant: Oc1ccc2ncccc2c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)Oc1ccc2ncccc2c1

Procedure:
Mixture of quinolin-6-ol (1.16 g., 8 mmol), hexyl isocyanate (1.37 ml, 9.6 mmol) and of dry triethylamine (0.1 ml) in dry dimethylformamide (1 ml) was heated at 50° C. for 5 hours. Reaction mixture was diluted with water (5 ml), extracted with ethyl acetate (2×5 ml), dried over sodium sulphate. The combined ethyl acetate fractions were concentrated under vaccum and crystallized with ether to give 1a, yield: 1.2 g. (55.14%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]([CH3:30])([CH3:29])[CH2:26][CH2:27]O.COC(C)(C)CC=O.Cl.[OH:40][NH2:41]>C(OCC)(=O)C.N1C=CC=CC=1.C(Cl)(Cl)Cl>[OH:40][N:41]=[CH:27][CH2:26][C:25]([O:24][CH3:23])([CH3:30])[CH3:29]
Reactant: COC(C)(C)CCO
Reactant: NO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: COC(C)(C)CC=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(C)(C)CC=NO
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
Dess-Martin reagent (15.0 g) was added to a chloroform solution (35 ml) of 3-methoxy-3-methyl-1-butanol (3.3 g) under ice cooling and stirred at room temperature for 5 hours. Chloroform was added to the reaction mixture and the organic layer was washed with an aqueous solution of 20 wt. % sodium thiosulfate, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure, thereby obtaining a crude product containing 3-methoxy-3-methylbutanal. Hydroxyamine hydrochloride (3.5 g) was added to a pyridine solution of the obtained crude product (30 ml) under ice cooling and stirred at room temperature overnight under nitrogen atmosphere. Ethyl acetate was added to the reaction mixture and the organic layer was washed with water, 1M-hydrochloric acid aqueous solution and saturated brine. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (KP-Sil, Biotage, ethyl acetate/n-hexane=10 to 50%), thereby obtaining (N-hydroxy-3-methoxy-3-methylbutan-1-imine (1.4 g) as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][C:29]=3[N+:30]([O-])=O)[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)Cl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][C:29]=3[NH2:30])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: Nc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To a solution of 18 mg (0.042 mmol) of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-3-nitro-pyrazolo[1,5-a]pyrimidine in 3 mL of ethyl acetate (EtOAc) was added 40 mg (0.21 mmol) of tin (II) chloride (SnCl2) and the resulting mixture was stirred at 80° C. under argon for 8 h when analysis by TLC indicated only 75% conversion of starting material to product. Therefore, 40 mg (0.21 mmol) of tin (II) chloride (SnCl2) was added, the reaction mixture was heated at 80° C. for 8 h when analysis by TLC indicated complete conversion of starting material to product. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water, brine, dried over sodium sulfate and evaporated to give (after lyophilization) 6 mg (36% yield) of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidin-3-ylamine as a yellow solid as indicated by 1H NMR; LC-MS—calcd for C25H26N4O [M++H]+: 399.21, found: 399.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:25][C:26]1[N:30]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[N:28][CH:27]=1)[C:13]([CH:15]([NH:20][CH2:21]/[CH:22]=[CH:23]/[CH3:24])[C:16]([O:18]C)=[O:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[Na+].Cl>CO.CCOC(C)=O.C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:25][C:26]1[N:30]([C:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:29]=[N:28][CH:27]=1)[C:13]([CH:15]([NH:20][CH2:21]/[CH:22]=[CH:23]/[CH3:24])[C:16]([OH:18])=[O:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C/CNC(C(=O)OC)C(=O)C(Cc1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C/C=C/CNC(C(=O)O)C(=O)C(Cc1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
A solution of methyl 2-[2-[(benzyloxy)carbonyl]amino-3-(1-trityl-1H-5-imidazolyl)propanoyl][(E)-2-butenyl]aminoacetate (2.23 g, 3.4 mmol) in MeOH (20 mL )/dioxane (15 mL) was treated with 2 N NaOH (7.0 mL, 14.0 mmol) and stirred at room temperature for 0.5 hour. After adding 2 N HCl (7.0 mL, 14.0 mmol), the mixture was stripped to a solid. This was mixed with EtOAc/THF and filtered to remove NaCl. Removal of the solvent under reduced pressured left 2.06 g (94.5% yield) of the product as a white solid foam. MS, rn/z 643 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]=2[CH:31]=1.C(O)(=O)C.[CH3:36][N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH:42]=O.C([BH3-])#N.[Na+]>CO>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]=2[CH:31]=1)[CH2:42][C:38]1[N:37]([CH3:36])[CH:41]=[CH:40][N:39]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2n1CCC
Temperature: 0 °C
Reaction time: 48 h

Procedure:
The compound (64.0 mg) obtained in Example 4-1 was dissolved in methanol (1.3 ml) and added with acetic acid (0.065 ml) and 1-methyl-2-imidazole carboxaldehyde (16.6 mg) and the whole was cooled to 0° C. Then, the solution was added with sodium cyanoborohydride (14.2 mg) and stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. After washing with a 1 mol/l sodium hydroxide aqueous solution, the solution was subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate.
Reaction SMILES: ClC1C=CC=CC=1O[C:5]1[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][CH:6]=1.[Na].[C:18](O)(=[O:20])C>C[O-].[Na+].CO>[N:10]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=1[C:11](=[NH:12])[O:20][CH3:18]
Reactant: CC(=O)O
Reactant: N#Cc1cccc(Oc2ccccc2Cl)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=N)c1ccccn1
Reaction time: 8 h

Procedure:
6-o-Chlorophenoxy-2-cyanopyridine (10 g) was dissolved in a solution of sodium methoxide in methanol prepared from methanol (150 ml) and metallic sodium (0.50 g). After the solution was left to stand overnight, acetic acid (1.3 g) was added thereto, followed by concentration under reduced pressure. The resulting residue was dissolved in ether (200 ml) and insoluble materials were filtered out. The filtrate was concentrated under reduced pressure to obtain methyl 2-picoline imidate derivative.
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH:10]=3)[C:5](=[O:21])[C:4]=2[CH:3]=1.N([O-])=[O:23].[Na+].O>S(=O)(=O)(O)O>[OH:23][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH:10]=3)[C:5](=[O:21])[C:4]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ccc2oc3cc(-c4nnn[nH]4)ccc3c(=O)c2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=c1c2ccc(-c3nnn[nH]3)cc2oc2ccc(O)cc12
Temperature: 15 °C
Reaction time: 1 h

Procedure:
The aminoxanthone from step (C) (14.4 g) was dissolved in concentrated sulphuric acid (250 ml) and to the stirred solution at 10°-15° C. was added in portions sodium nitrite (3.6 g). The solution was then stirred at 15° C. for 1 hr, poured on to ice (2 kg) and water (2.5 l). The mixture was slowly brought to the broil and boiled under reflux for 1 hr. The resulting yellow product was filtered off, washed well with water and dried.