Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6]C(=O)OC(C)(C)C)[CH2:2]1.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.[ClH:23].O1CCOCC1>C(Cl)(Cl)Cl>[ClH:23].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:1]2[CH2:5][CH2:4][C@@H:3]([NH2:6])[CH2:2]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: N[C@@H]1CCN(Cc2ccc(F)cc2)C1

Procedure:
To a chloroform solution (2 mL) of tert-butyl (R)-pyrrolidin-3-yl-carbamate (500 mg, 2.68 mmol), 4-fluorobenzyl bromide (329 μL, 2.68 mmol) was added and the resultant solution was stirred at room temperature for 1 day. Subsequently, 4 M hydrogen chloride/1,4-dioxane solution (2 mL) was added to the reaction solution and the resultant mixture was stirred for 1 day. After completion of the reaction, solidified product was collected by filtration and dried under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(#N)C.[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>O>[Br:13][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[F:9]
Reactant: [Br-]
Reactant: Nc1cccc(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: Nc1ccc(Br)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
The procedure for preparing this compound was based on that described in International Patent Publication No. WO 2010/091272. To a 100 mL round bottom flask, 2,3-difluoroaniline (1 g, 0.0077 mol) and ACN (30 mL) were added. To the flask was added the solution of tetrabutylammonium tribromide (3.71 g, 0.0077 mol, in 10 mL of ACN). The reaction mixture was stirred at room temperature for 3 h. The reaction mass was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and evaporated under reduced pressure to get the crude product. The crude product was purified by column chromatography using 60-12 silica gel and 30% ethyl acetate in hexane to get the title compound [0.55 g, 34%]. The obtained product was immediately taken to the next step.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[C:24](O)=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C1(C)C=CC=CC=1>[F:27][C:2]([F:28])([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:23][CH:22]4[C:24]([N:52]=[N+:53]=[N-:54])=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(O)C1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC(=O)C1CC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-cyclopropanecarboxylic acid (C20) (2.49 g, 6.40 mmol) in toluene (30 mL) was added triethylamine (2.20 mL, 16.0 mmol), followed by diphenyl phosphorazidate (1.70 mL, 8.00 mmol). The yellow solution was stirred overnight at room temperature. The reaction was quenched with water and saturated aqueous sodium bicarbonate, extracted with 1:1 ethyl acetate/hexanes (2×), dried over anhydrous sodium sulfate, and filtered. The crude compound was adsorbed onto silica gel and purified by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent to afford the title compound as a yellow oil (1.94 g, 73%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.16-8.03 (m, 2H), 7.83-7.72 (m, 2H), 7.44-7.34 (m, 2H), 7.20 (d, J=8.2 Hz, 2H), 2.70 (ddd, J=9.3, 6.8, 4.1 Hz, 1H), 1.98 (ddd, J=8.4, 5.3, 4.1 Hz, 1H), 1.78 (dt, J=9.4, 5.0 Hz, 1H), 1.53 (ddd, J=8.3, 6.8, 4.7 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −58.03.
Reaction SMILES: [Na+].[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([C:16](=[CH2:19])[CH:17]=[O:18])[CH2:13][CH2:14][CH3:15]>C(O)(=O)C.O>[CH3:11][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:19][CH:16]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:17]=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=C(C=O)CCCC
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(C=O)CS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a stirred solution of 4-toluenesulfinate sodium salt (10.10 g, 56.68 mmol) in 35 mL of acetic acid at 50° C. is added 2-butylacrolein (10.6 mL, 79.66 mmol) slowly. The reaction mixture is kept at 50° C. for 3 hours. After cooling to room temperature, the mixture is diluted with 50 mL of water and extracted with ethyl acetate (2×25 mL). The combined extract is washed with saturated NaHCO3, water, brine, and dried with MgSO4. After removing solvents, the product is obtained as a yellow liquid in 75% yield.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[C:14]1([CH3:21])[C:15](C)=CC=[CH:18][CH:19]=1>>[CH2:19]([CH:14]1[CH2:21][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:15]1)[CH3:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccccc1C
Agent: [Na]
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CC(CC)C1
Temperature: 130 °C
Reaction time: 18 h

Procedure:
Sodium metal (7.6 g, 0.33 g/atom) was dispersed in 50 ml of dry xylene (distilled from sodium hydride) by heating to 130° C. with rapid stirring. Dry xylene (168 ml) and 47.8 g (45.2 ml, 0.298 mole) of diethyl malonate were then added thereto and the mixture was allowed to react at 120° C. To the resultant mixture there was then added 48.1 g (0.116 mole) of 2-ethyl-propyl-1,3-ditosylate (prepared in 1B) dissolved in 120 ml of dry xylene. This reaction mixture was heated to about 150° C. and stirred for 18 hr. The mixture was cooled and poured into 500 ml of water and extracted with 600 ml (3×300 ml) of ether. The aqueous material was made acidic with 10% aqueous HCl and then extracted with 600 ml (2×300 ml) of ether. The combined ether extract was washed with 200 ml of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo. Distillation of the product at reduced pressure yielded 7.0 g of the title compound having the following physical characteristics:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].[CH2:14]([O:16][C:17]([C@@:19]1([CH3:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1)=[O:18])[CH3:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:14]([O:16][C:17]([C@@:19]1([CH3:25])[CH2:24][CH2:23][CH2:22][N:21]([C:11]([C@@H:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)=[O:12])[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Reactant: CCOC(=O)[C@@]1(C)CCCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@]1(C)CCCN(C(=O)[C@H]2COc3ccccc3O2)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (6.05 g, 30.5 mmol) in DCM (20 ml) was added to a stirred mixture of (S)-3-methyl-piperidine-3-carboxylic acid ethyl ester (5.0 g, 29.2 mmol), DIPEA (5.5 ml, 31.7 mmol) and DCM (30 ml), previously cooled down to 5° C. The cooling bath was removed and stirring continued at RT for 1 h. The reaction mixture was washed twice with 1 M HCl, twice with sat. aq NaHCO3 and twice with water and dried with Na2SO4. Solvent was evaporated to give 9.66 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH3:18][S:19]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:21])=[O:20]
Reactant: O=C1CCC(=O)N1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCN1C(=O)CCC1=O

Procedure:
The N-(2-hydroxyethyl)succinimide (Aldrich, 0.19 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:20])[C:12]2[N:13]([N:15]=[C:16]([CH:18]=O)[CH:17]=2)[CH:14]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O)(=O)C.C([BH3-])#N.[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:20])[C:12]2[N:13]([N:15]=[C:16]([CH2:18][N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[CH:17]=2)[CH:14]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(Cc2cc3c(=O)[nH]c(-c4ccc(Cl)cc4Cl)cn3n2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
145 mg (0.32 mmol) of 6-(2,4-dichlorophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carbaldehyde (Example 18A) were dissolved in 6 ml of methanol, and 64 mg (0.64 mmol) of 1-methylpiperazine, 4 Å molecular sieve and 58 mg (0.96 mmol) of acetic acid were added. Finally, 40.2 mg (0.64 mmol) of sodium cyanoborohydride were added and the mixture was stirred at RT for 15 h. The crude mixture was acidified with 2N hydrochloric acid and the resulting precipitate was filtered off with suction. This gave 120 mg (96% of theory) of the product as a solid which was reacted further without any further purification.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH:3]1[O:5][CH2:4]1
Reactant: BrCC1CO1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)ccn2CC1CO1
Temperature: 60 °C

Procedure:
Epibromohydrin (0.73 ml, 8.5 mmole) was added to a stirred solution of indole (1.0 g, 8.5 mmole) and sodium hydride (0.34 g, 8.5 mmole) in anhydrous DMF (20 ml), and the mixture was heated at 60° C. under nitrogen for two hours. Water (100 ml) was added and the product extracted into CH2Cl2 (3×25 ml). The combined organics were washed with water (25 ml), brine (25 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a light yellow colored oil (1.45 g). This was purified by flash silica gel chromatography (30% ethyl acetate in hexane) to afford the titled product as a light oil (1.37 g, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[N:30]=[CH:29][NH:28][N:27]=2)=[C:4]([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:24])[S:5][CH:6]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40]O)[CH2:34][CH2:33]1>>[Cl:1][C:2]1[C:3]([C:26]2[N:30]=[CH:29][N:28]([CH2:40][CH2:39][CH2:38][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[N:27]=2)=[C:4]([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:24])[S:5][CH:6]=1
Reactant: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: CN1CCN(CCCO)CC1
Product: CN1CCN(CCCn2cnc(-c3c(Cl)csc3NC(=O)Cn3c(=O)ccc4cc(C(F)(F)F)ccc43)n2)CC1

Procedure:
The title compound was prepared from N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide (108 mg, 248 umol) and 3-(4-methylpiperazin-1-yl)propan-1-ol (350 mg, 2.21 mmol) using the procedures described in Example 1.76. HPLC purification gave N-(4-chloro-3-(1-(3-(4-methylpiperazin-1-yl)propyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide. Method [7] retention time 4.27 min by HPLC (M+=594 and 596). 1H NMR (300 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 8.22 (d, J=9.9 Hz, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.17 (s, 1H), 6.87 (d, J=9.3 Hz, 1H), 5.32 (s, 2H), 4.25 (t, J=6.6 Hz, 2H), 2.95 (broad m, 10H), 2.73 (s, 3H), 1.97 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]1CCN2C(=NCCC2)CC1.CI>C(#N)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1c(Cl)ccnc1Cl
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 48.5 %

Procedure:
To a solution of 2,4-dichloronicotinic acid (500 mg, 2.60 mmol) in acetonitrile (10 mL) cooled to 0° C. was added DBU (0.981 mL, 6.51 mmol) followed by methyl iodide (0.814 mL, 13.0 mmol). The reaction mixture was stirred at RT overnight (14 h). After the reaction completion, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (10 mL) and washed with water (1×5 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to afford methyl 2,4-dichloronicotinate (260 mg, 1.262 mmol, 49% yield) as pale yellow oil. LC/MS, (ESI) m/z 206.1 [(M+H)+, calcd for C7H6Cl2NO2 205.97]; LC/MS retention time (method D): tR=0.85 min. 1H NMR (300 MHz, CD3OD) δ ppm 8.42 (d, J=5.4 Hz, 1H), 7.59 (d, J=5.4 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:6]2[CH:13]=[CH:12][N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:7]=2[N:8]=[CH:9][CH:10]=1)=[NH:4].N1C=CC=CC=1.[C:28]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=O)#[N:29]>C(#N)C>[CH3:19][Si:18]([CH3:21])([CH3:20])[CH2:17][CH2:16][O:15][CH2:14][N:11]1[C:7]2=[N:8][CH:9]=[CH:10][C:5]([C:3]3[N:4]=[C:33]([C:32]4[CH:31]=[C:30]([CH:38]=[CH:37][CH:36]=4)[C:28]#[N:29])[O:1][N:2]=3)=[C:6]2[CH:13]=[CH:12]1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(C(=N)NO)ccnc21
Solvent: c1ccncc1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3noc(-c4cccc(C#N)c4)n3)ccnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
The crude product N-hydroxy-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine-4-carboximidamide (0.06 gm, 0.0002 mol) was dissolved in pyridine (1.0 mL, 0.012 mol) and then 3-cyanobenzoyl chloride (0.040 g, 0.00024 mol) was added at rt. This mixture was stirred for 1 h and heated to 80° C. in an oil bath. After heating for 18 h the reaction was allowed to cool to rt and then diluted with ACN and concentrated in vacuo to give 3-[3-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,2,4-oxadiazol-5-yl]benzonitrile 0.08 gm as an off white residue, LC/M S (M+H)+ 418.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][O:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2OC)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1CCO[CH2:24]1>>[CH3:24][O:23][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][O:8][C@H:9]1[CH2:10][O:11][C@@H:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:13][CH2:14]1
Reactant: COc1ccccc1C1OCC(OCc2ccccc2)CO1
Reactant: C1COCO1
Product: COc1ccccc1CO[C@H]1CO[C@@H](c2ccccc2)OC1

Procedure:
5-benzyloxy-2-(2-methoxyphenyl)-1,3-dioxane (b.p. 190°-195° C at 10-5 mm; VPC analysis indicated that it contained 14% cis, 31% trans, and 55% of the isomeric dioxolane);
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].[CH:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[C:24]1=[O:33])[CH2:30]2.O>O1CCCC1>[OH:33][CH:24]1[CH:23]2[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][C:25]1([CH:6]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)[CH2:26]3)[CH2:30]2
Reactant: N#Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2ncc[nH]2)C23CC4CC(CC(C4)C2O)C3)cc1
Reaction time: 0.5 h

Procedure:
5.0 g of 4-[1-(imidazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour at -60° combined With 4 3 g of 2-adamantanone, further stirred for 1 hour, and heated to 25°. Then water is added, the mixture is extracted three times with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 6.66 g of crude 4-[2-hydroxy-adamant-1-yl-1-(imidazolyl)methyl]benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:7]([C:17]([OH:19])=[O:18])=[C:8]([CH3:16])[NH:9][C:10]=1[CH:11](OC)[O:12]C)=[O:4]>Cl.CC(C)=O.C(OCC)(=O)C>[CH:11]([C:10]1[NH:9][C:8]([CH3:16])=[C:7]([C:17]([OH:19])=[O:18])[CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:12]
Reactant: COC(=O)C1=C(C(OC)OC)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)C1=C(C=O)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 6.5 h
Yield: 79 %

Procedure:
A solution of 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (7.50 g) dissolved in a mixture of 6N hydrochloric acid (22.5 ml) and acetone (90 ml) was stirred for 6.5 hours at 20° C. The resulting mixture was evaporated under reduced pressure. The residue obtained was dissolved in ethyl acetate, and washed successively with water, an aqueous sodium bicarbonate and an aqueous sodium chloride. The ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue obtained was subjected to column chromatography on silica gel (200 g) and eluted with a mixture of toluene and ethyl acetate (10:1 by volume). The fractions containing the desired compound were collected and evaporated under reduced pressure and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give yellow crystals of 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (5.23 g), mp 125° to 125.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:11]=2)=[CH:5][CH:4]=1.[CH3:26]I>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:11]=2)[CH3:26])=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2nc(-c3ccccc3)nc3ccccc23)cc1
Reactant: CI
Product: COc1ccc(N(C)c2nc(-c3ccccc3)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (4-methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-amine (51 mg, 0.16 mmol) and methyl iodide (0.07 ml, 1.09 mmol) by a procedure similar to Example 36. 1H NMR (CDCl3): 8.64-8.61 (m, 2H), 7.90 (d, J=8.4 Hz, 1H), 7.59-7.48 (m, 4H), 7.18-7.14 (m, 2H), 7.08-6.98 (m, 2H), 6.94-6.91 (m, 2H), 3.85 (s, 3H), 3.73 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1([CH3:20])[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1>C(O)(=O)C.CCO>[CH3:20][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[CH:18]=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: Cc1cccc(C=O)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(C=NNC(=O)c2ccc(O)cc2)c1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.2 g, 0.0013 mol) in abs. EtOH (10 mL) and m-tolualdehyde (0.32 g, 0.0026 mol) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.25 g, in 76% yield, mp: 241.9° C. 1H NMR (CD3OD) δ 8.27 (s, 1H), 7.83 (d, 2H), 7.67 (s, 1H), 7.59 (d, 1H), 7.31 (t, 1H), 7.24 (d, 1H), 6.88 (d, 2H), 2.37 (s, 3H). 13C NMR (CDCl3) δ 166.9, 162.8, 150.0, 139.7, 135.7, 132.2, 130.8, 129.7, 129.1, 126.1, 124.7, 116.3, 114.9, 21.3. Anal. Calcd for C15H14N2O2 ·¼ H2O: C, 69.61.; H, 5.45; N, 10.82. Found: C, 69.38; H, 5.51; N, 10.52.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:10][C:6]=2[C:5](C(=O)C)=[CH:4][CH:3]=1.C(C1C=CC2O[C:29]([C:31]([O:33]CC)=[O:32])=C(C)C=2C=1O)(=O)C>>[CH2:14]([O:13][C:11]([C:9]1[O:10][C:6]2[C:5]([O:33][C:31](=[O:32])[CH3:29])=[CH:4][CH:3]=[C:2]([OH:1])[C:7]=2[C:8]=1[CH3:16])=[O:12])[CH3:15]
Reactant: CCOC(=O)c1oc2ccc(C(C)=O)c(O)c2c1C
Reactant: CCOC(=O)c1oc2c(C(C)=O)ccc(O)c2c1C
Product: CCOC(=O)c1oc2c(OC(C)=O)ccc(O)c2c1C

Procedure:
Following the procedure of Example 156 but substituting Ethyl 4-hydroxy-7-acetyl-3-methylbenzofuran-2-carboxylate for the compound of Example 155. There is obtained the intermediate Ethyl-7-acetoxy-4-hydroxy-3-methylbenzofuran-2-carboxylate which is hydrolyzed in an aqueous acetic acid solution of hydrochloric acid (6 hours, 100° C.) to give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:6]2.Br.[OH-].[Na+]>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:6]2
Reactant: COc1ccc2ncc(C[C@H](N)C(=O)O)cc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H](Cc1cnc2ccc(O)cc2c1)C(=O)O
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A mixture of 0.18 g (0.74 mmol) of 3-(6-methoxy-3-quinolyl)alanine and 5.4 mL of 48% hydrobromic acid was stirred at 85°-90° C. overnight. The reaction mixture was cooled to room temperature and neutralized to pH 7.0 with 1N sodium hydroxide solution, then was concentrated under reduced pressure to give a brown solid. After filtration, the solid product was washed with a small amount of cold water and ethyl ether and then was dried in vacuo to give 57.4 mg (33.4%) of the title compound of the formula: ##STR90## NMR (DMSO-d6, CF3COOH) δ 9.05 (1H, bs), 8.9 (1H, bs), 8.2 (1H, d), 7.7 (1H, dd), 7.5 (1H, d), 4.5 (1H, m), 3.5 (2H, m); IR (KBr) ν 3400, 1630, 1500 cm-1.
Reaction SMILES: CN(P(N(C)C)(N(C)C)=O)C.[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH3:20])[O:14]1.[CH:22]([C:24]([CH3:26])=[O:25])=[CH2:23].Cl>CCOCC>[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH2:20][CH2:23][CH2:22][C:24](=[O:25])[CH3:26])[O:14]1
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: C=CC(C)=O
Agent: Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(=O)CCCC1=CC(=O)OC(C)(C)O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
In an argon gas stream, 20.6 ml of n-butyl lithium (1.6M solution in hexane) were added to 60 ml of an ether solution containing 3.53 g (0.033 mol) of diisopropylamine at -20° C. to form LDA. After stirring for 30 minutes, the solution was cooled to -78° C., and 10.4 ml (0.06 mol) of HMPA were added thereto, followed by stirring for 15 minutes. Afterward, a mixture of 4.26 g (0.03 mol) of 2,2-dimethyl-6-methyl-1,3-dioxin-4-one and 60 ml of ether as well as 60 ml of an ether solution containing 2.1 g (0.03 mol) of methyl vinyl ketone were added to the solution. After the temperature was gradually returned to room temperature, 10% hydrochloric acid was added thereto to neutralize the solution, and extraction was then carried out with ether. The resultant organic layer was dried over anhydrous magnesium sulfate. Next, the used solvent was distilled off, and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 3.16 g of 2,2-dimethyl-6-(4-oxopentyl)-1,3-dioxin-4-one.