Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.[P:11]([OH:14])([OH:13])[OH:12].P(Cl)(Cl)Cl>C(#N)C>[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH2:7][C:8]([P:11]([OH:14])([OH:13])=[O:12])([P:11]([OH:14])([OH:13])=[O:12])[OH:10])[CH:4]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Solvent: CC#N
Product: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 72.5 °C
Reaction time: 2 h

Procedure:
3-Pyridine acetic acid (100 g) added to acetonitrile (1.0 L). To the reaction mixture was added phosphorous acid (142 g). The reaction mass was heated up to reflux temperature (70-75° C.). To this phosphorous trichloride (271 g) was added slowly at 70° C. and the reaction mass was refluxed for 5.0 hours. The solvent was distilled off completely under vacuum. Demineralized water (400 ml) was added to the reaction mass at ambient temperature and charcoalised. The filtered mass was refluxed for 4.0 hours at 85° C. The reaction mass was cooled to 0-5° C. and stirred for 2 hours. It was filtered and washed with demineralized water to get risedronic acid as a white crystalline solid. The wet material was dissolved in demineralized water (300 ml) and 50% sodium hydroxide solution was added to reaction mass to make the pH basic, charcoalised and acidified with concentrated hydrochloric acid. The reaction mass was stirred further for 1.0 hour. The solid was filtered, washed with demineralized water to get the pure risedronic acid (160 g, yield 77.33%) having purity of 99.25% by HPLC.
Reaction SMILES: [NH:1]1[C:9](=O)[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.CN(C)C1C=CC=CC=1.[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].P(Cl)(Cl)([Cl:27])=O>>[CH3:20][S:21]([OH:24])(=[O:23])=[O:22].[Cl:27][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[N:5]2
Reactant: O=c1[nH]cnc2nc[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Agent: CS(=O)(=O)O
Solvent: CN(C)c1ccccc1
Product: Clc1ncnc2nc[nH]c12
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 5 g (0.0368 mole) of hypoxanthine, 12.5 ml of N,N-dimethylaniline and 150 ml of phosphorus oxychloride was refluxed for 40 minutes. Excess phosphorus oxychloride was removed by vacuum distillation with an external oil bath having a temperature below 70° C. and 200 ml of methylene chloride were added to the oily residue. The red methylene chloride solution was cooled in an ice bath and 6 g (0.063 mole) of methanesulfonic acid were added slowly. The mixture was left in an ice bath with stirring for 1 hour and then filtered to give 7.20 g (78% yield) of 6-chloropurine methanesulfonate as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[OH-].[K+]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=1)([O-:3])=[O:2]
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3)c2c1

Procedure:
Using the procedure of Example 1, a mixture of 0.8 g of 5-nitro-1H-indole, 1.53 g of the hydrate of 4-piperidone hydrochloride and 16 ml of 2 N methanolic potassium hydroxide was reacted to obtain 0.86 g of raw product which was crystallized from isopropanol to obtain 0.74 g of 5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 250° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[NH:10][C:11](=[O:19])[C:12]([C:17]#[N:18])=[C:13]([S:15][CH3:16])[N:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].O>COCCOC>[C:17]([C:12]1[C:11](=[O:19])[N:10]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:9]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:14][C:13]=1[S:15][CH3:16])#[N:18]
Reactant: CSc1nc(C2CCCCC2)[nH]c(=O)c1C#N
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cn1c(C2CCCCC2)nc(SC)c(C#N)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a cooled (0° C.), stirred suspension of NaH (50% dispersion in mineral oil, washed with hexane, 2.2 g, 0.047 mol) in DME (350 mL) was added 2-cyclohexyl-1,6-dihydro-4-(methylthio)-6-oxo-5-pyrimidinecarbonitrile (9.5 g, 0.038 mol) in several portions. After 1 hour, methyl bromoacetate was added and the resulting solution was heated at 95°-100° C. for 2 days. The solution was cooled and water (300 mL) was added. The mixture was extracted with ethyl acetate and the combined extracts were washed with water, dried (MgSO4), and concentrated to give a beige powder (12.2 g, 99%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1>Cl.O1CCOCC1>[CH3:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(C)CCNCC1

Procedure:
A solution of Example 532B (2.1 g, 8.0 mmol) in 4M HCl in dioxane (10 mL) at room temperature was stirred for 3 hours and concentrated to provide the desired product. MS (DCI) mne 171 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[Br:30]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Br:30])[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(n2cnc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reaction time: 4 h

Procedure:
(±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (1.32 g, 2.98 mmol) in dry N, N-dimethylformamide (6 mL) was heated to 60° C. Portions (ca. 1 mmol each) of N-bromosuccinimide (1.59 g, 8.93 mmol) were added over 5 hours. Heating was continued for an additional 4 hours. Volatiles were removed in vacuo and the residue chromatographed on silica gel. Title compound eluted with 1:1 hexane-ethylacetate as a tan powder (1.1 g, 69%), 1H-NMR identical with recrystallized sample. Such a sample was recrystallized from ethanol-water to a white powder, m.p. 156°-159° C.; 1H-NMR (DMSO-d6)δ: 8.34, 7.97 (both s, 1 each, 2 benzimidazole CH), 5.6 (m, 1, OCH), 5.3 (m, 1, OCH), 5.2-5.0 (m, 1, NCH), 4.4-4.2 (m, 2, OCH2), 2.7-2.5 (m, 1, CH), 2.4-2.0 (m) overlapping 2.1 and 2.07 (both s, total 8, CH2 and 2CH3CO), 1.92 (s, 3, CH3CO); mass spectrum (CI): 527 (6.6), 525 (45), 523 (100), 521 (65, M+1), 257 (48, M-B).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[C:4](Cl)[N:3]=1.CS(C)=O.[NH3:19]>C(OCC)(=O)C>[NH2:19][C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]=1[O:12][CH3:13]
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1OC
Reactant: N
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)nc(N)c1OC
Temperature: 2.5 °C
Reaction time: 0.21 h
Yield: 50 %

Procedure:
A solution comprising the reaction mixture prepared by Example 8, which reaction mixture contained the methyl 2,6-dichloro-5-methoxy-pyrimidine-4-carboxylate (25 g, 0.1 mol), and dimethyl sulfoxide (DMSO) was prepared. To this solution was added, at 0-5° C., a solution of ammonia in DMSO (2 eq). This mixture was stirred at the same 0-5° C. temperature for 10 to 15 minutes. Later, the mixture was diluted with ethyl acetate, and the resulting solid was filtered. The filtrate was washed with a brine solution. The organic layer was dried over sodium sulfate. Upon concentration, the crude product was obtained. The crude product was stirred in a minimum amount of ethyl acetate and filtered to obtain the pure compound. The resulting filtrate, after concentration, was column purified. This produced the title compound (11 g, 50% yield): mp 158° C.; 1H NMR (DMSO-d6) δ 3.71 (s, 3H), 3.86 (s, 3H), 7.65 (brs, 1H), 8.01 (brs, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[OH:23])[CH:19]([CH2:24][C:25]([OH:27])=[O:26])[CH2:18][CH2:17]2)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[CH3:29]O>>[CH3:29][O:26][C:25](=[O:27])[CH2:24][CH:19]1[C:20]2[C:16](=[CH:15][C:14]([C:6](=[O:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[C:22]([OH:23])[CH:21]=2)[CH2:17][CH2:18]1
Reactant: O=C(O)CC1CCc2cc(C(=O)c3ccccc3)c(O)cc21
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CC1CCc2cc(C(=O)c3ccccc3)c(O)cc21

Procedure:
0.5 ml of concentrated sulphuric acid is added to a solution of 1.4 g of 5-benzoyl-6-hydroxy-indane-1-acetic acid in 300 ml of absolute methanol and the mixture is heated to the reflux temperature for 8 hours, with exclusion of water. The reaction mixture is then evaporated in vacuo to a volume of 5 ml and partitioned between 20 ml of water and twice 20 ml of ether. The organic phases are combined, washed until neutral, dried over sodium sulphate and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum gives, in the fraction boiling at 180° C./0.04 mm, 5-benzoyl-6-hydroxyindane-1-acetic acid methyl ester as a yellow oil which is identical with the product described in Example 22.
Reaction SMILES: [C:1]([C:9](=[CH:12]N(C)C)[C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:20][C:21]([NH2:23])=[NH:22].C[O-].[Na+]>CO>[NH2:22][C:21]1[N:23]=[CH:12][C:9]([C:10]#[N:11])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:20]=1
Reactant: CN(C)C=C(C#N)C(=O)c1ccccc1
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Product: N#Cc1cnc(N)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
Following the method of Earley et al. (J. Het. Chem. 1983, 20, 1195), to a stirred solution of 6.9 g (34.4 mmol) 2-benzoyl-3-dimethylaminoacrylonitrile and 20.6 g (114 mmol) guanidine carbonate in 50 ml methanol was added 43 ml (232 mmol) sodium methylate (5.4 M in methanol) and the mixture stirred at room temperature for 2 h. The reaction mixture was then concentrated in vacuo. The residue was resuspended in ethyl acetate and water, and the aqueous phase acidified to pH 8 by addition of hydrochloric acid. The phases were separated and the aqueous phase extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was triturated in a mixture of ethyl acetate, ether, dichloromethane and ethanol, and the resulting crystals were then additionally recrystallised from ethanol/ether to afford 2.83 g (41%) 2-amino-5-cyano-6-phenylpyrimidine as a light yellow crystalline solid. EI-MS m/e (%): 196 (M+, 100), 195 ([M—H]+, 40), 170 ([M—CN]+, 36).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCOCC1>[CH2:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCC1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCCCC1CCO
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
2-Piperidine ethanol (39.6 ml, 0.31 mol) was dissolved in 5M aq NaOH (62 ml, 0.31 mol) and dioxan (100 ml). The mixture was cooled to 0° C. and treated with benzyl chloroformate (45.3 ml, 0.32 mol) and 5M NaOH (62 ml, 0.31 mol). Stirring was continued at room temp. for 18 hours. Dioxan was removed in vacuo and the aqueous phase extracted with ether before acidifying with 5N HCl and extracting again with ether. The organic phase was dried and evaporated in vacuo and the residue purified by chromatography on silica gel to give the title compound (77.2 g. 95%). MH+ 264.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:20])([F:19])[CH2:17][OH:18]>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:18][CH2:17][C:16]([F:20])([F:19])[F:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: OCC(F)(F)F
Product: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B1(b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example B1(a)) and 2,2,2-trifluoro-ethanol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 297.0 ([M−H]−, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([N:16]1[CH2:21][CH2:20][C:19]([OH:22])([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
The starting material can be produced in the following manner: In a manner analogous to that described in Example 6, 100 g of p-bromotoluene and 110 g of N-benzyl-4-piperidone are reacted to give N-benzyl-4-hydroxy-4-(4-methylphenyl)-piperidine, b.p.0.05 =185°.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:38])[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N+:33]=3[O-:9])=[CH:28][CH:27]=2)=[O:38])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccccn3)cc2)CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3cccc[n+]3[O-])cc2)CC1
Reaction time: 24 h

Procedure:
At −10° C., metachloroperbenzoic acid (789 mg) was added to a solution of 1-tert-butoxycarbonyl-4-[4-(2-pyridyl)benzoyl]piperazine (517 mg) in dichloromethane (dichloromethane: 8 ml). The resulting mixture was stirred for 24 hours, followed by dilution with dichloromethane. A small amount of an aqueous sodium thiosulfate solution and saturated saline were added to the dilute solution. The organic layer so separated was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane:methanol=20:1), whereby the title compound (415 mg, 77%) was obtained.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[N-:13]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([S:2]([CH3:1])(=[NH:13])=[O:3])=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: CS(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
23.65 g (127.7 mmol) (RS)-1-(methylsulfinyl)-4-nitrobenzene in 130 ml chloroform are treated with 9.32 g (143.4 mmol) sodium azide. The mixture is slowly treated with 32.4 ml of concentrated sulfuric acid at 0° C. and then slowly heated to 45° C. After 16 hrs, the mixture is cooled to room temperature, treated with ice-water and extracted with chloroform. This organic phase is discarded. The aqueous phase is basified with 2N NaOH solution and extracted with DCM. The combined organic phases are washed with saturated NaCl solution, dried (Na2SO4), filtered and concentrated. 17.17 g (88.4 mmol, corresponding to 63% of theor.) of the product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:23])([CH2:17][O:18]S(C)(=O)=O)[CH2:10]OC(=O)C(C)C.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:23][CH2:10]1)[CH2:17][OH:18]
Reactant: CC(C)C(=O)OC[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC[C@@]1(c2ccc(F)cc2F)CO1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
In 14 ml of methanol was dissolved 4.06 g of (S)-2-(2,4-difluorophenyl)-1-isobutyryloxy-3-methane-sulfonyloxy-2-propanol obtained in Example 44. After a temperature of the resulting liquid was kept at 5° C, 14 ml of aqueous solution of 2N sodium hydroxide was added dropwise thereto with cooling at 15° C. or below. After dropping, the resulting liquid was stirred at a temperature of 10° to 15° C. for 2 hours. Thereto 1N hydrochloric acid was added until the liquid was adjusted to pH 7 and methanol was removed under reduced pressure. To the residue was added ethyl acetate to extract. The resulting organic layer was washed with saturated aqueous solution with sodium chloride. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent n-hexane/ethyl acetate=1/1) to give 2.04 g of oily (S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-propanol. An optical purity thereof was determined in the same manner as in Example 35. (Elution time: 9.24 minutes ((S)-form) and 10.7 minutes ((R)-form)).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[NH:16])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6].CN(C)[CH:20]=[CH:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=O>>[N+:5]([C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:17]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:16]=2)[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Yield: 69.7 %

Procedure:
3-Nitrophenyl-guanidine nitrate (28 g, 0.12 mol) and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (16.9 g, 0.09 mol) were reacted according to the same procedure as Step 1.3 of Preparation 1 to give N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (18.4 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[C:13](=[O:14])[CH2:12][CH2:11][CH:10]1[C:15]#[N:16].[CH2:17](O)[CH2:18][OH:19].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:15]([CH:10]1[CH2:11][CH2:12][C:13]2([O:19][CH2:18][CH2:17][O:14]2)[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])#[N:16]
Reactant: N#CC1CCC(=O)C1CCCCCCCO
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: N#CC1CCC2(OCCO2)C1CCCCCCCO
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile (20 g.), ethylene glycol (5.6 g.), p-toluenesulphonic acid (1 g.) and benzene 160 ml.) was heated to reflux for 210 minutes with continuous removal of water. The mixture was cooled to ambient temperature, anhydrous sodium carbonate was added and, after filtration through a bed of sodium carbonate, the solvent was removed under reduced pressure. The residue was distilled under reduced pressure to give 7-cyano-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (19.3 g.), b.p. 166° C-182° C./0.1 mm.Hg. This material was used as a starting material in the next stage, as aliquot being redistilled to b.p. 177°-179° C./0.1 mm.Hg for elemental analysis:
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO>[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Yield: 86.9 %

Procedure:
To a solution of 10.38 gm (185 mMol) potassium hydroxide in 200 mL methanol were added 10.0 gm (61.7 mMol) 5-nitro-1H-indole followed by 13.96 gm (123 mMol) 1-methyl-4-piperidone. The mixture was heated to reflux for 4 days under a nitrogen atmosphere. The reaction mixture was then allowed to cool to ambient and the solid which formed filtered and washed with methanol This solid was dried under vacuum at 50° C. The combined filtrates were then concentrated under reduced pressure and the residue subjected to flash chromatography, eluting with 92.5:7.5 dichloromethane:methanol. Fractions shown to contain product were combined and concentrated under reduced pressure. This solid was combined with that isolated directly from the reaction mixture to give 13.79 gm (87%) 5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[Na+].[C:25]([Cl:28])(=[O:27])[CH3:26].Cl>CC(C)=O>[ClH:28].[C:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:22])[CH2:16][NH:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:27])[CH3:26]
Reactant: CC(C)(C)NCC(O)COc1ccc(O)c2c1CCC(=O)N2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(OCC(O)CNC(C)(C)C)c2c1NC(=O)CC2
Yield: 45.5 %

Procedure:
0.7 g of 8-hydroxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril was suspended in 20 ml of acetone, and 3.0 ml of 1 N NaOH was added to the suspension to form a homogeneous solution. 0.2 g of acetyl chloride dissolved in a small amount of acetone was added dropwise to the solution under ice-cooling and stirring. After the mixture was allowed to stand under ice-cooling for 30 minutes, 2 ml of 1 N hydrochloric acid was added to the mixture, and the solvent evaporated under reduced pressure. The residue was purified by silica gel column chromatography using chloroform:methanol (8:1 by volume) as an eluent. The solvent was evaporated, and the residue was recrystallized from methanol-diethyl ether to obtain 0.4 g of 8-acetoxy-5-(3-t-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril hydrochloride as colorless flake-like crystals having a melting point of 247°-248° C. (with decomposition).
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[N+:18]([O-])=O)[C:4]([NH2:6])=[O:5])#[N:2]>[Fe].C(O)(=O)C.CN(C)C=O>[CH3:15][O:14][C:12]1[CH:13]=[C:8]2[C:9](=[CH:10][C:11]=1[O:16][CH3:17])[N:18]=[C:1]([NH2:2])[C:3]([C:4]([NH2:6])=[O:5])=[CH:7]2
Reactant: COc1cc(C=C(C#N)C(N)=O)c([N+](=O)[O-])cc1OC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc2cc(C(N)=O)c(N)nc2cc1OC
Temperature: 90 °C

Procedure:
Iron powder (65.2 g., 1.22 moles) is added over a period of one-half hour to a slurry of α-cyano-β-(2-nitro-4,5-dimethoxyphenyl)acrylamide (75.0 g., 0.271 mole) in a 50% solution of acetic acid-N,N-dimethylformamide (750 ml.) at 75° C. When addition of the iron powder is complete, the mixture is heated to 90° C. for four hours and then filtered while hot. The filter cake is washed with hot acetic acid (150 ml.). The dark red filtrate is gradually added to IN hydrochloric acid (1500 ml.) and the pink precipitate recovered by filtration and recrystallized from an excess (10%) of aqueous sodium hydroxide. The solid is filtered, washed with cold isopropanol and dried to give the title product as yellow crystals: Yield = 57.1 g. (83.5%), mpp. 274°-275° C.