Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:36]=[C:35]([CH2:37]P(OCC)(OCC)=O)[CH:34]=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1.CO>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH:18]=[CH:37][C:35]4[CH:34]=[CH:33][C:31]5[N:32]=[C:28]([C:25]6[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=6)[O:29][C:30]=5[CH:36]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: CCOP(=O)(Cc1ccc2nc(-c3ccc(OC)cc3)oc2c1)OCC
Reactant: COc1ccc(-c2nc3ccc(C=O)cc3o2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(-c2nc3ccc(C=Cc4ccc5nc(-c6ccc(OC)cc6)oc5c4)cc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A solution of 5.06 g (0.02 Mole) of 2-p-methoxyphenyl-6-formylbenzoxazole of the formula ##STR33## (melting point: 161.5°-162.5° C.) and 7.50 g (0.02 mole) of 2-(p-methoxyphenyl)-6-(diethylphosphonomethyl)-benzoxazole of the formula ##STR34## (melting point: 85°-88° C.) in 150 ml of dimethyl formamide is heated to 50° C. and 2.1 g of sodium tert.butylate are added in small amounts to the solution over the course of 15 minutes. The reaction mixture is stirred at room temperature overnight, then poured into 400 ml of methanol with stirring. The product is collected by filtration, washed with water and then with 140 ml of methanol, and subsequently recrystallised from chlorobenzene with the addition of fuller's earth, affording 7.1 g (75% of theory) of 1,2-bis-(2-p-methoxyphenyl-benzoxazol-6-yl)-ethylene of the formula ##STR35## in the form of pale yellow crystals with a melting point of over 300° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O>S(Cl)(Cl)=O>[N:3]1[CH:4]=[CH:5][N:1]2[C:6](=[O:8])[C:2]3=[N:1][CH:5]=[CH:4][N:3]3[C:6](=[O:8])[C:2]=12
Reactant: O=C(O)c1ncc[nH]1
Solvent: O=S(Cl)Cl
Product: O=c1c2nccn2c(=O)c2nccn12

Procedure:
11.2 g (0.1 mol) of imidazole-2-carboxylic acid [which could be prepared, for example, in accordance with the method of J. Am. Chem. Soc., 71, 383 (1949)] were stirred under reflux with 100 ml of thionyl chloride for 5 hours. After cooling the mixture, the solid was filtered off, washed with a little petroleum ether and dried. 5H, 10H-diimidazo[1,2-a:1',2'-d]pyrazine-5,10-dione was thus obtained in virtually quantitative yield in the form of a yellow powder. The substance still did not melt at 290° C. It could be sublimed into yellow crystals at 200°-250° C./0.01 mm Hg without decomposition. IR (KBr): 3137, 1735, 1522, 1445, 1387, 1331, 1274, 1161, 1059, 1018, 810, 800, 748, 699 and 651 cm-1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CCN(CC)CC.COC(C)(C)C>[CH3:12][N:13](/[CH:15]=[CH:2]/[C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)=[O:3])[CH3:14]
Reactant: CC(=O)c1cnccn1
Reactant: COC(OC)N(C)C
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CN(C)/C=C/C(=O)c1cnccn1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of acetylpyrazine (5 g, 40.9 mmol) in N,N-dimethylformamide dimethyl acetal (10.9 mL, 81.8 mmol) and Et3N (5.7 mL) was heated at 110° C. for 16 h. The heating was stopped and a precipitate was formed while it was allowed to cool down to room temperature. The suspension was diluted with tert-butyl methyl ether; the solid was separated by filtration and washed with tert-butyl methyl ether. This material was triturated with the same solvent, filtered off and dried to afford the title compound 23a as a yellow solid (5.9 g, 33.3 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.09 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.66 (dd, J=2.4, 1.6 Hz, 1H), 7.84 (d, J=12.4 Hz, 1H), 6.30-6.20 (m, 1H), 3.19 (s, 3H), 2.93 (s, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.Br[CH2:23][CH:24]=[CH2:25]>C1COCC1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:25][CH:24]=[CH2:23])[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
Step AA (1): NaHMDS (1.0 M in THF, 46.7 mL, 46.7 mmol) was added to a stirred solution of 2-(4-fluorophenyl)acetic acid (3.6 g, 23.4 mmol) in THF (50 mL) at 0° C. The resulting mixture was stirred for 20 min at 0° C. and neat 3-bromoprop-1-ene (2.02 mL, 23.4 mmol) was added. The mixture was allowed to warm to rt. After 16 hr, the reaction was quenched with water (3 mL). The crude mixture was concentrated in vacuo. Aqueous NaOH (1 M, 150 mL) was added to the residue and the resulting mixture was extracted with Et2O (2×100 mL). The basic layer was acidified with aqueous HCl (1 M, 200 mL) and the resulting solution was extracted with Et2O (2×100 mL). The combined organic layers from the acidic extraction were washed with mixture of brine/1N HCl/sodium sulfite, dried (MgSO4), filtered, and concentrated in vacuo. The residue was dissolved in toluene (˜50 mL) and left to sit at rt for 3 days. A white solid was collected by vacuum filtration. The solid was dried under high vacuum to afford 2-(4-fluorophenyl)pent-4-enoic acid (2.03 g, 10.1 mmol, 43% yield) as an off-white crystalline solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.28-7.34 (m, 2 H) 6.99-7.07 (m, 2 H) 5.71 (dddd, J=17.09, 10.22, 6.87, 6.71 Hz, 1 H) 5.08 (dd, J=17.09, 1.53 Hz, 1 H) 5.01-5.05 (m, 1 H) 3.65 (t, J=7.63 Hz, 1 H) 2.75-2.87 (m, 1 H) 2.52 (dt, J=14.27, 7.06 Hz, 1 H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: O=S(=O)(Nc1nccnc1-c1ccc(COc2ccc(F)cc2)cc1)c1ccccc1C(F)(F)F
Yield: 67 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 4-fluorophenol, the title compound was isolated as a yellow solid in 67% yield (95% purity by HPLC).
Reaction SMILES: O.[CH2:2](I)I.[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]=1[CH2:14][OH:15]>CC(O)=O.[Zn]>[CH3:13][C:8]1([CH3:12])[CH2:9][CH2:10][CH2:11][C:6]2([CH3:2])[C:7]1([CH2:14][OH:15])[CH2:5]2
Reactant: CC1=C(CO)C(C)(C)CCC1
Reactant: ICI
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CCCC2(C)CC12CO
Temperature: -5 °C
Reaction time: 0.05 h

Procedure:
A solution of 0.4 g of Cu(OAc2).H2O in 20 mL of hot HOAc was treated with 8.8 g (0.13 g-atom) of Zn dust with shaking for 3 min, and the acid was decanted. The Zn-Cu couple was washed by decantation with 30 mL of 1:1 HOAc/Et2O, followed by Et2O (6×30 mL). Next, 20 mL of Et2O was added together with a crystal of I2. A mixture of 18.8 g (70 mmol) of CH2I2 and 3.08 g (20 mmol) of β-cyclogeraniol (l) was added dropwise over a 20-min period, with warming to maintain a gentle reflux. Heating at reflux was continued for an additional 2 h. The cooled solution was decanted, the residue was washed with Et2O, and the total Et2O volume was brought to 200 mL. The solution was cooled in ice/H2O, and pyridine (8 to 9 mL) was added dropwise until no further ZnI2 -pyridine complex separated. The reaction was cooled to -5° C. overnight, filtered twice, and evaporated. Further complex separated on evaporation. TLC (9:1 hexane/EtOAc) demonstrated a single product. The crude oil was eluted through a 3×25 cm silica gel column by 9:1 hexane/Et2O, followed by 1:1 hexane/Et2O. The spectrally pure, colorless oil weighed 3.4 g (quant): IR (film) 3400 (OH), 1460, 1385, 1365, 1155, 1035, 1010, 705 cm-1 ; 1H NMR (CDCl3) δ0.22 (d, J=4.5 Hz, 1, cyclopropyl H), 0.49 (d, J=4.5 Hz, 1, cyclopropyl H), 0.99 (s, 3, CH3), 1.21 (s, 3, CH3), 1.26 (s, 3, CH3), 1.0-1.8 [m, 7, (CH2)3, OH], 3.51 and 3.92 (d, J=12 Hz, 1, and dd, J=12 and 3.5 Hz, 1, CH2O); 13C NMR (CDCl3), 65.8, 38.0, 35.5, 31.9, 31.3, 29.2, 27.4, 23.9, 22.5, 21.7, 18.0 ppm; MS calcd for C11H20O 168.1514, found 168.1521.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.O>CS(C)=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: BrCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(OCCCCCCBr)cc1
Reaction time: 0.08 h
Yield: 71.4 %

Procedure:
To a solution of 232 g of ethyl 4-hydroxybenzoate [XII; Alk=C2H5 ] in 1.2 liters of dimethylsulfoxide was added 100 g of potassium hydroxide. The mixture was stirred for five minutes, 678 g of 1,6-dibromohexane was then added, and the mixture stirred for four hours during which an exothermic reaction occurred (max. temp. 46° C.). The reaction mixture was added to 1500 ml of water and extracted three times with 800 ml of cyclohexane. The cyclohexane layer was washed with 800 ml of water, 200 ml 2N potassium hydroxide and 800 ml concentrated sodium chloride solution, then filtered and concentrated in vacuo. The residue was triturated with ether to give 328.1 g of ethyl 4-(6-bromohexyloxy)benzoate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cccc(CO)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: N#Cc1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
3-(Hydroxymethyl)benzonitrile (5.00 g; 37.6 mmoles) and 3,4-Dihydro-2H-pyran (3.77 mL; 41.4 mmoles) were dissolved in methylene chloride (25 mL) under nitrogen and the solution was cooled to 5° C. p-Toluenesulfonic acid monohydrate (74 mg; 0.37 mmoles) was added and the mixture was stirred for 2 hours at 25° C. The reaction mixture was diluted with methylene chloride (25 mL). The solution was washed with aqueous sodium bicarbonate solution (30 mL) and aqueous sodium chloride solution (30 mL). The solution was dried over sodium sulfate and filtered. The solvent was removed under vacuum to give the product, 3-[(tetrahydro-2H-pyran-2-yloxy)methyl]benzo-nitrile (7.34 g; 89%) as an oil. 1H NMR (400 MHz) CDCl3 δ 7.68–7.70 (1H, m), 7.54–7.61 (2H, m), 7.42–7.48 (1H, m), 4.82 (1H, d, J=12.5 Hz), 4.72 (1H, t, J=3.3 Hz), 4.53 (1H, d, J=12.5 Hz), 3.84–3.92 (1H, m), 3.53–3.60 (1H, m), 1.60–1.95 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>>[Cl:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:6]2[CH:5]=[C:4]([CH3:26])[N:3]=[C:2]([NH:1][C:31]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[O:32])[N:7]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:23])[F:25]
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)nc(N)n1
Reactant: O=C(Cl)C1CCC1
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)nc(NC(=O)C2CCC2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-6-methylpyrimidine-4-carboxamide (20 mg, 0.05 mmol, Step-1, single enantiomer) and cyclobutanecarbonyl chloride (27 mg, 0.26 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc(B(O)O)c(F)c1
Reactant: N#Cc1cc(Cl)c2ccc(Cl)cc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(C#N)nc3cc(Cl)ccc23)c(F)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
To a stirred solution of 4,7-dichloroquinoline-2-carbonitrile (6 g, 26.9 mmol), (2-fluoro-4-methoxyphenyl)boronic acid (5.03 g, 29.6 mmol), 2M sodium carbonate (29.6 ml, 59.2 mmol) in 10:1 toluene (48.9 ml) ethanol (4.89 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.777 g, 0.672 mmol). The mixture was stirred at 75° C. under N2 for 18 hours. The reaction was allowed to cool to ambient temperature. The cooled reaction mixture was diluted with EtOAc and then washed with H2O, brine, dried (MgSO4) and concentrated. The residue was mostly dissolved in warm EtOAc (100 ml), added 100 ml of Et2O, allowed to stand at ambient temperature for 1 hour. The solid was collected and washed with cold Et2O (50 ml) to give 7-chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carbonitrile (4.4 g, 14.07 mmol, 52.3% yield) as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C2CCCCO2)[CH:12]=1.Cl.C(=O)([O-])O.[Na+]>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([NH:24][CH:25]1[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]1)[C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1
Reactant: CN1CCC(NC(c2cccc(OC3CCCCO3)c2)c2nc3ccccc3[nH]2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN1CCC(NC(c2cccc(O)c2)c2nc3ccccc3[nH]2)CC1

Procedure:
A solution of {(1H-benzimidazol-2-yl)[3-(tetrahydropyran-2-yloxy)phenyl]methyl}(1-methylpiperidin-4-yl)amine (example 120, 500 mg) in ethanol (5 mL) is treated with aqueous 37% hydrochloric acid at room temperature for one night. The mixture is then neutralized with an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (gradient dichloromethane/methanol/ammonia from 90/10/0.5 to 80/20/0.5) to give 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-ylamino)methyl]phenol as a white solid melting at 230° C.
Reaction SMILES: [CH:1]1([OH:4])[CH2:3][CH2:2]1.[H-].[Na+].F[C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([O:4][C:8]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:3][CH2:2]1
Reactant: OC1CC1
Reactant: N#Cc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(F)cc1OC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution cyclopropanol (1.9 g, 29 mmol) in 20 mL dioxane was added dropwise to a 0° C. solution of Sodium hydride (60% dispersion in mineral oil, 1.04 g, 26 mmol) in 80 mL dioxane. The reaction mixture was allowed to warm to room temperature, 2,4-difluorobenzonitrile (3.48 g, 25 mmol) was added portionwise, and reaction temperature raised to 95° C. The reaction solution was cooled to room temperature after stirring for 18 hours, diluted with ethyl acetate, washed twice with water and twice with brine, dried over MgSO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (0-10% EtOAc/hexanes) afforded 2-cyclopropoxy-4-fluorobenzonitrile. 1H-NMR (400 MHz, Chloroform-d) δ 7.52 (dd, J=8.6, 6.2 Hz, 1H), 7.05 (dd, J=10.5, 2.3 Hz, 1H), 6.73 (td, J=8.2, 2.3 Hz, 1H), 3.87-3.76 (m, 1H), 0.87 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:14])[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][N:8]=2.O[C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:14][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:5]1[CH2:4][CH2:3][CH2:2][O:1][C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1
Reactant: Cn1c(CCCO)nc2cccnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(CCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 750 mg of 2-(3-hydroxypropyl)-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 34), 1.83 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.98 ml of tributylphosphine, 990 mg of 1,1'-(azodicarbonyl)dipiperidine and 20 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 0:1 by volume as the eluent, to give 550 mg of the title compound, melting at 76°-81° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: COc1cccc(CN)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CNC(=O)c2ccc(Br)c(C)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-3-methylbenzoic acid (100 mg, 0.465 mmol) in DCM (2 mL) were added (3-methoxyphenyl)methanamine (70.2 mg, 0.512 mmol), DIEA (0.244 mL, 1.395 mmol) and HATU (212 mg, 0.558 mmol) at RT. The reaction was stirred under argon at RT for 1 h. The crude product was purified by normal phase chromatography. 58A was obtained as white solid (155 mg, 0.464 mmol, 100% yield). LCMS (ESI) m/z: 336.0 (M+H)+; 1H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (d, J=2.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.46-7.39 (m, 1H), 7.30-7.24 (m, 1H), 6.92 (dd, J=7.6, 0.6 Hz, 1H), 6.88 (t, J=1.8 Hz, 1H), 6.84 (dt, J=8.1, 1.3 Hz, 1H), 6.38 (br. s., 1H), 4.60 (d, J=5.7 Hz, 2H), 3.80 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20](=[O:29])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)[N:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:10]=1)=[O:5])C.[OH-].[K+].Cl>C1COCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:20]([CH2:19][N:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[N:8]2)=[O:29])=[N:23][CH:24]=1
Reactant: CCOC(=O)c1cc(OCCOCCOC)nn1CC(=O)Nc1ccc(Cl)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOCCOc1cc(C(=O)O)n(CC(=O)Nc2ccc(Cl)cn2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1.2 g 2-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-[2-(2-methoxy-ethoxy)-ethoxy]-2H-pyrazole-3-carboxylic acid ethyl ester in 5 ml THF 10 ml of a aqueous KOH solution (10%) were added and the reaction mixture was stirred for 4 h at RT. Then the mixture was acidified with half concentrated hydrochloric acid to pH 3 and the precipitate collected by filtration and washed with 10 ml of water The product was obtained as a white solid which was dried under reduced pressure.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:18]=1[C:19]#[N:20]>>[CH2:1]([N:8]1[C:12]([C:13]([NH:16][C:17]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)[C:18]=2[C:19]#[N:20])=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(c2cccc(N)c2C#N)CC1
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Product: CN1CCN(c2cccc(NC(=O)c3nnnn3Cc3ccccc3)c2C#N)CC1

Procedure:
In a manner similar to Example I, 1-benzyl-1H-tetrazole-5-carbonyl chloride is condensed with 2-amino-6-(4-methyl-1-piperazinyl)benzonitrile to give 1-benzyl-N-[2-cyano-3-(4-methyl-1-piperazinyl)phenyl]-1H-tetrazole-5-carboxamide.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:3][C@H:2]([CH3:4])[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:14][CH:13]=1
Reactant: C[C@H](O)C(=O)OC(C)(C)C
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
To a stirred solution of known tert-butyl L-(+)-lactate (217 mg), 4-chlorophenol (219 μl) and triphenylphosphine (584 mg) in dry tetrahydrofuran (8 ml) on an ice bath, diethylazodicarboxylate (350 μl) was added dropwise over about 10 minutes. After the addition, the ice bath was removed and the mixture was further stirred at room temperatures for 24 hours. The reaction mixture was evaporated with a rotary evaporator (water bath temperaure 38° C.). The residue thus obtained was purified by silica gel chromatography [silica gel 50 g, eluant:ethyl acetate-hexane (1:10)] to give tert-butyl (2R)-(+)-2-(4'-chlorophenoxy)propionate (256 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[N+:8]([O-:22])=[C:9]1[C:14](=[N+:15]2[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]1.[CH3:23][NH:24][CH3:25]>C(=O)=O.CC(C)=O>[CH3:23][N:24]([CH3:25])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:7]=1[N+:8]([O-:22])=[C:9]1[C:14](=[N+:15]2[O-:20])[C:13]([OH:21])=[CH:12][CH:11]=[CH:10]1
Reactant: [O-][n+]1c2cccc(OCCCCl)c2[n+]([O-])c2cccc(O)c21
Reactant: CNC
Agent: O=C=O
Solvent: CC(C)=O
Product: CN(C)CCCOc1cccc2c1[n+]([O-])c1cccc(O)c1[n+]2[O-]
Temperature: 25 °C
Reaction time: 70 h

Procedure:
Into a sealed tube was placed 2.0 grams of 6-(3-chloropropoxy)-1-phenazinol 5,10-dioxide. The tube was cooled in dry-ice-acetone and 80 ml of dimethylamine was condensed into the tube. The tube was sealed and shaken at room temperature for 70 hours. The tube was then opened and excess dimethylamine allowed to evaporate at room temperature. The residue was dissolved in CHCl3 solution, was washed with water and was then extracted with 3 × 150ml 10 percent aqueous HCl. The combined acid extracts were made basic with sodium carbonate, extracted with CHCl 3 and the combined CHCl3 extracts were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from acetone/ether to yield 6-(3-dimethylaminopropoxy)-1-phenazinol 5,10-dioxide, mp. 103°C (dec.).