Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1>>[CH:13]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)=[CH:11][CH:10]=3)=[O:16])[CH2:15][CH2:14]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cn[nH]c4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (39 mg, 0.200 mmol) to afford the desired product (17 mg, 36%) as an off-white solid: ESI MS m/z 476 [C27H33N5O3+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(Nc1ccccc1Br)N1CCOCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3NS(=O)(=O)N3CCOCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and N-(2-bromophenyl)morpholine-4-sulfonamide. MS (ESI): mass calcd. for C20H20FN5O3S, 429.13; m/z found, 430.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.45 (s, 1H), 8.34 (d, J=1.4, 1H), 8.14 (m, 1H), 7.63 (d, J=8.0, 1H), 7.43-7.35 (m, 1H), 7.31 (dd, J=8.0, 1.7, 1H), 7.24-7.19 (m, 2H), 6.39 (s, 1H), 3.67 (dd, J=5.8, 3.7, 4H), 3.23-3.14 (m, 4H).
Reaction SMILES: [CH3:1][NH:2]CCNC.I[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C@@H:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]([CH3:25])[CH3:24].[C-]#N.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu]I>[CH3:24][N:23]([CH2:22][C@@H:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:1]#[N:2])[CH:9]=2)[NH:13][CH:12]=1)[CH3:25]
Reactant: CNCCNC
Reactant: CN(C)C[C@@H]1CCC[C@H]1c1c[nH]c2ccc(I)cc12
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)C[C@@H]1CCC[C@H]1c1c[nH]c2ccc(C#N)cc12
Temperature: 125 °C
Yield: 82.6 %

Procedure:
N,N′-dimethylethylenediamine (5.66 mL, 53 mMol) was added to a mixture of trans [2-(5-iodo-1H-indol-3-yl)-cyclopentylmethyl]-dimethylamine (19.4 g, 53 mMol), sodium cyanide (3.1 g, 63 mMol), and copper(I) iodide (1 g, 5.3 mMol) in deoxygenated anhydrous toluene (50 mL). The resulting mixture was heated in an oil bath to 125° C. under N2 for ˜18 h. The reaction was cooled to 50° C., diluted with ethyl acetate (400 mL), and heated to reflux for 5 min. The resulting suspension was transferred to a separatory funnel and washed with aqueous NaHCO3 (400 mL and twice with 200 mL). Every aqueous layer was extracted with ethyl acetate (50 mL) to make sure no product was left in aqueous layer. The combined organic layers were dried over MgSO4. Solvent was removed in vacuo to give the crude product which was purified by silica gel chromatography using dichloromethane/2.0 M ammonia in methanol (100/0 to 93/7) as the eluent, to give trans 3-(2-dimethylaminomethyl-cyclopentyl)-1H-indole-5-carbonitrile (11.7 g, 83%).
Reaction SMILES: N1([C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[NH:7])C=CN=C1.NC1[C:19]([OH:20])=[CH:18]C=CN=1>C1COCC1>[O:20]1[C:19]2[C:9](=[N:10][CH:11]=[CH:12][CH:18]=2)[N:8]=[C:6]1[NH2:7]
Reactant: Nc1ncccc1O
Reactant: N=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Nc1nc2ncccc2o1

Procedure:
An oven dried round bottom flask was charged with di(1H-imidazol-1-yl)methanimine (500 mg, 3.10 mmol), 2-aminopyridin-3-ol (171 mg, 1.551 mmol) and anhydrous THF (20 ml) at room temperature. The resulting suspension was refluxed under N2 for 1 hr. LC/MS indicated complete consumption of starting material. The solvent was removed in vacuo and the residue was used in the next step without further purification. MS (LC/MS) R.T.=0.235; [M+H]+=136.09.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:28]=[CH:27][C:18]3[C:19]([C:23]([NH:25][CH3:26])=[O:24])=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1.CI>CC(C)=O>[Cl:7][C:8]1[N:13]=[C:12]([N:14]([CH3:1])[C:15]2[CH:28]=[CH:27][C:18]3[C:19]([C:23]([NH:25][CH3:26])=[O:24])=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(C)oc2cc(Nc3ccnc(Cl)n3)ccc12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CNC(=O)c1c(C)oc2cc(N(C)c3ccnc(Cl)n3)ccc12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
Potassium carbonate (0.75 mmol) was added to a solution of 6-(2-chloropyrimidin-4-ylamino)-N,2-dimethylbenzofuran-3-carboxamide (0.5 mmol) in 5 ml acetone. After 15 mins, methyl iodide (0.5 mmol) was added. The reaction mixture was stirred at 60° C. for 2 days before the solvent was removed in vacuo. THF was added and the residue was filtered and subjected to column chromatography to provide the 6-((2-chloropyrimidin-4-yl)(methyl)amino)-N,2-dimethylbenzofuran-3-carboxamide in a yield of 22%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].Br[C:11]1[S:12][CH:13]=[CH:14][N:15]=1.CC([O-])(C)C.[K+].CCOC(C)=O>CC(N(C)C)=O>[F:9][C:3]1[CH:4]=[C:5]([O:8][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(O)cc1F
Reactant: Brc1nccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2nccs2)cc1F
Temperature: 150 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of 427A (0.814 g, 6.41 mmol), 2-bromothiazole (1.0 g, 6.10 mmol) and t-BuOK (0.821 g, 7.32 mmol) in DMA (25 ml) was stirred at 150° C. under argon for 1 h, then cooled to rt. Treated with EtOAc (150 ml), the mixture was washed with H2O (50 ml), 3N NaOH (2×50 ml), H2O (50 ml), dried with Na2SO4. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (10%-25% EtOAc-hexanes) gave 427B (1.02 g, 80%) as a colorless oil. It has a retention time of 4.02 min (standard LC1 method, 8 min run). MS Found: (M+H)+=211.1
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14]1[N:15]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:37][CH2:38][O:39][CH3:40]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:37][CH2:38][O:39][CH3:40])[CH2:10][CH:9]1[C:14]1[N:15]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1c1nc(-c2ccc(Br)cc2)cn1COCC[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOC1CC(c2nc(-c3ccc(Br)cc3)cn2COCC[Si](C)(C)C)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.33 h
Yield: 85 %

Procedure:
2-[4-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (222 mg) was dissolved in DMF (4 mL), and NaH (25 mg) was added. The mixture was stirred over 20 min. and 1-bromo-2-methoxy-ethane was added slowly, and then stirred for 2.5 hours. The mixture was quenched with 3 mL of sat. NH4Cl and was taken up in ethyl acetate (50 mL). The organic phase was washed with saturated sodium bicarbonate (1×50 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 20-60% ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 2-[4-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-4-(2-methoxy-ethoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (209 mg, 85%) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>C(O)C>[CH2:22]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
In 200 g of ethanol were dissolved 86.5 g (0.5 mol) of 4-bromophenol and 22 g (0.55 mol) of sodium hydroxide. To the solution at 70° C., 137 g (0.55 mol) of n-dodecyl bromide was added dropwise. The solution was allowed to ripen for 4 hours and cooled to room temperature, after which 120 g of water was added. The oily matter separated therefrom was concentrated by a rotary evaporator, followed by vacuum distillation (boiling point 178-180° C./0.5 Torr), yielding 110 g of 4-n-dodecyloxyphenyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].[CH3:19][O:20][NH2:21]>>[CH3:19][O:20][NH:21][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CON
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Product: CONC(=O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
N-methoxy-3-(2-chloro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.30 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.42 mmol of O-methyl-hydroxylamine. LC/MS [8.75 min; 404 (M+1)]
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH2:3][NH2:4].[N+:6]([O-:9])([OH:8])=[O:7].C(OC(=O)C)(=O)C>>[N+:6]([O-:9])([OH:8])=[O:7].[N+:6]([O:5][C@@H:2]([CH3:1])[CH2:3][NH2:4])([O-:8])=[O:7]
Reactant: C[C@H](O)CN
Solvent: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: C[C@@H](CN)O[N+](=O)[O-]

Procedure:
The procedure described for Example 10a was used with S-(+)-1-amino-2-propanol (960 mg, 12.8 mmol), fuming nitric acid (0.62 mL) and acetic anhydride (9.7 ml) and 2.7 mL fuming nitric acid (2.7 ml) to give the title compound as a light green solid in quantitative yield. 1H NMR (CDCl3, 300 MHz) δ 8.08 (s, 3H), 5.32 (m, 1H), 3.24-3.06 (m, 2H), 1.34 (d, J=6.4 Hz, 3H). 13C NMR (CDCl3, 75.45 MHz) δ 78.1, 40.8, 15.9. LRMS (APlMS) m/z 121 (M−HNO3 +H)+.
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10](=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH2:27][OH:28]>CO>[CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10](=[N:27][OH:28])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: Cc1ccc2c(c1)C(=O)CCC2C1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc2c(c1)C(=NO)CCC2C1CCCCC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a 125 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 5.20 grams (21.49 mmol) 4-cyclohexyl 7-methyl-1,2,3,4-tetrahydronaphth-1-one, 54 mL methanol, 3.25 grams (32.23 mmol) triethylamine, and 2.22 grams (32.23 mmol) hydroxylamine hydrochloride. The reaction was stirred at room temperature for 1.5 days, evaporated, partitioned between ethyl acetate and water, and the aqueous layer extracted with fresh ethyl acetate. The combined organic layer was dried over sodium sulfate and evaporated to an oil, which was used directly.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[C:20](#[N:23])[CH:21]=[CH2:22]>O1CCOCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][CH2:22][CH2:21][C:20]#[N:23])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Reactant: C=CC#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#CCCSC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Yield: 60.6 %

Procedure:
In 15 ml of dioxane was dissolved 2.1 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindole-1-on, and 1.5 g of acrylonitrile, together with several drops of triethylamine, was added, followed by heating at 85° to 90° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and the residual, oily substance was purified by means of column chromatography with the use of silica gel (acetone:hexane=1:3), thereby producing 1.5 g of the subject compound in white crystals, m.p. 101°-103° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O.CO>[C:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:11]=1)(=[O:5])[CH:4]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CCCc1ccc(C(C)=O)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCc1ccc(C(=O)C=Cc2ccccc2)cc1
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a solution of 0.40 g of sodium hydroxide in 6 ml of water, a solution of 1.00 g of methyl 4-(4-acetylphenyl)butyrate in 2 ml of methanol was added under ice-cooling. Then, a solution of 0.48 g of benzaldehyde in 2 ml of methanol was added dropwise and stirring was continued at room temperature for 3 hours. The reaction mixture was diluted with water and acidified with dilute hydrochloric acid. Precipitated crystals were collected by filtration, washed successively with water and n-hexane to yield 0.94 g of colorless crystals. Recrystallization from 80% aqueous methanol gave colorless needles, mp 111°~112° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2C)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:21][O:22]C1C(N)=CC=CC=1>>[CH3:21][O:22][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccccc1N
Product: COc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 59 %

Procedure:
(RK1-1-27C) I This compound was prepared according to the procedure described for compound 11a except using o-anisidine. Recrystallization from DCM/Hexanes obtained the required product as white crystals, (164 mg, 59%). Mp=141-143° C.; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=8.8 Hz, 2H), 7.91 (d, J=8.8 Hz, 2H), 7.56 (dd, J=8.0, 1.6 Hz, 1H), 7.11 (td, J=7.9, 1.5 Hz, 1H), 7.02 (br s, 1H), 6.94 (td, J=7.6, 1.2 Hz, 1H), 6.74 (dd, J=8.0, 1.2 Hz, 1H), 3.62 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>CO>[C:1]1([C:7]2[N:8]([CH2:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(=O)OC
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Solvent: CO
Product: COC(=O)CCn1c(-c2ccccc2)nc2ccccc21
Temperature: 60 °C
Reaction time: 100 h
Yield: 60 %

Procedure:
A mixture of 194 g of 2-phenylbenzimidazole, 103 g of methyl acrylate and 500 g of methanol was heated and stirred at 60° C. for 100 hours. The solvent was distilled off in vacuo, followed by purification by column chromatography. There was obtained methyl 3-(2-phenyl-1H-benzimidazol-1-yl)-propionate (yield 60%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]([N:12]2[CH:13]=[N:14][N:15]=[CH:16]2)=[N:10]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(-c2cn[nH]c2-n2cnnc2)cc1
Product: CC(=O)n1cc(-c2ccccc2)c(-n2cnnc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-(4-phenyl-5-pyrazolyl)-4H-1,2,4-triazole (1.0 g) in acetic anhydride is refluxed until a clear solution is obtained. The solution is poured into ice water and stirred for 1/2 hour. The yellowish solid is collected and recrystallized from a mixture of chloroform/hexane, giving a white powder, m.p. 165° C. to 168° C. Similarly prepared is the propionyl derivative.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]1([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32](O)[CH:33]=3)[CH:28]=2)[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[O:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]1([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:11][C@H:8]4[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]4)[CH:33]=3)[CH:28]=2)[CH2:20][O:21][C:22]([CH3:26])([CH3:25])[O:23][CH2:24]1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(O)ccc3c2)COC(C)(C)OC1
Product: CC(C)(C)OC(=O)NC1(c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)COC(C)(C)OC1

Procedure:
The title compound was prepared from cis-4-tertbutylcyclohexanol and [5-(6-hydroxynaphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester in 42% yield according to the method of Example 53.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.Cl.NO.CC([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[F:21])=O>C(O)C>[F:20][C:16]1[C:15]([F:21])=[CH:14][CH:19]=[CH:18][C:17]=1[CH:6]([NH2:3])[CH3:7]
Reactant: CCN(CC)CC
Reactant: CC(=O)c1cccc(F)c1F
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC(N)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (2.66 mL) and hydroxylamine hydrochloride (712 mg) were added to a solution of 2,3-difluoroacetophenone (1 g) in ethanol (35 mL), and the reaction solution was heated to reflux for 3 hours. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. Zinc (2.29 g) was added to a solution of the resulting residue in trifluoroacetic acid (30 mL), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was made basic with a 5 N aqueous solution of sodium hydroxide, and then extracted with chloroform. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.4 g of a crude purified product containing the title compound (purity: 72 wt %). The physical properties of the compound are as follows.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[C@H:5]([OH:7])[CH3:6].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.O>CN(C)C=O>[Cl:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][O:7][C@H:5]([CH3:6])[C:4]([F:9])([F:8])[F:3])[CH:13]=1
Reactant: Clc1cccc(CBr)c1
Reactant: C[C@@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1cccc(Cl)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Under argon atmosphere, a suspension of sodium hydride (77 mg, 60 wt % oil dispersion) in N,N-dimethylformamide (2.0 ml) was cooled to 0° C., a solution of (R)-1,1,1-trifluoropropan-2-ol (213 mg) in N,N-dimethylformamide (2.0 ml) was added thereto, and the mixture was stirred for 15 minutes. Then, a solution of 1-bromomethyl-3-chlorobenzene (311 mg) in N,N-dimethylformamide (2.0 ml) was added thereto, and then the mixture was stirred at room temperature for 2.5 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=1/0 to 19/1) to give the titled compound (307 mg).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br-:13].[C:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:50])[CH2:24][N+:25]23[CH2:32][CH2:31][CH:28]([CH2:29][CH2:30]2)[C@@H:27]([O:33][C:34](=[O:49])[C@@H:35]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:26]3)=[CH:19][CH:18]=1)([OH:16])=O.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>CN(C=O)C>[Br-:13].[N:51]1([C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:50])[CH2:24][N+:25]34[CH2:32][CH2:31][CH:28]([CH2:29][CH2:30]3)[C@@H:27]([O:33][C:34](=[O:49])[C@@H:35]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:26]4)=[CH:19][CH:18]=2)=[O:16])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: CN(C)C=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
1,1′-Carbonyldiimidazole (14.0 mg, 0.09 mmol) was added to a solution of (R)-1-(2-(4-carboxyphenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (diastereomer 1 of C67) (50 mg, 0.09 mmol) in dry DMF (2 ml). The reaction mixture was stirred at room temperature for 2 hours. Then morpholine (7.52 mg, 0.09 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 1 hour. DMF was evaporated and the crude was purified by preparative HPLC (eluents: CH3CN/H2O) to obtain (R)-1-(2-(4-(morpholine-4-carbonyl)phenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (18.9 mg, 33.8% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Br:19]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([S:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)[C:5]([Br:19])=[CH:6][CH:7]=1
Reactant: Nc1cccn2nc(SCc3ccccc3)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ccc(Br)n2nc(SCc3ccccc3)nc12

Procedure:
8-Amino-2-benzylthio[1,2,4]triazolo[1,5-a]pyridine (25.6 g, 0.1 mol), N-bromosuccinimide (17.8 g, 0.1 mol) and 2 L of dichloromethane were combined with stirring for an hour. The solution was washed with dilute aqueous sodium bisulfite and then with water and the volatiles were removed by evaporation under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 25 percent ethyl acetate in hexane. The product fractions were concentrated by evaporation under reduced pressure and the solid residue obtained was extracted with ether and dried to obtain 17.5 g (52 percent of theory) of the title compound as a light tan powder melting at 125°-126° C.