Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](F)[CH:13]=[C:12]([F:20])[C:11]=1[F:21].C[O-].[Na+].[C:25](OCC)(=[O:27])C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([O:27][CH3:25])[CH:13]=[C:12]([F:20])[C:11]=1[F:21]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
A stirred solution of (2-fluoro-4-iodo-phenyl)-(2,3,5-trifluoro-6-nitro-phenyl)-amine (1.23 g, 3 mmol) in dry THF (25 ml) under nitrogen was cooled to −78° C. and a solution of 25% sodium methoxide (0.68 ml, 0.3 mmol) was added slowly. The reaction mixture was allowed to warm to room temperature and stirring continued for another 16 hours. TLC indicated incomplete reaction. Ethyl acetate (100 mL) was added to the reaction mixture and the organic layer was washed with water, dried over sodium sulfate and further purified by column chromatography to provide the desired compound as a yellow solid (0.6 g, 47.6%). m/z=424 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH3:14])[CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]([C:3]([OH:2])=[O:4])[N:6]2[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc2c(C)cccc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: Cc1cccc2c1cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 4-methyl-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale yellow solid. MS: 314.1 ([M−H]−).
Reaction SMILES: Cl.C(O)C.[Br:5][C:6]1[C:7]([F:17])=[C:8]([CH3:16])[C:9]([F:15])=[C:10]([N+:12]([O-])=O)[CH:11]=1>O.[Fe]>[Br:5][C:6]1[C:7]([F:17])=[C:8]([CH3:16])[C:9]([F:15])=[C:10]([CH:11]=1)[NH2:12]
Reactant: Cc1c(F)c(Br)cc([N+](=O)[O-])c1F
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c(F)c(N)cc(Br)c1F
Temperature: 50 °C
Yield: 52.9 %

Procedure:
To a suspension of iron powder (26.6 g, 100 mesh) in water (60 ml), with vigorous stirring at 50° C., was slowly added concentrated hydrochloric acid (4 ml). After hot ethanol (120 ml) was mixed, 3-bromo-2,6-difluoro-5-nitrotoluene (40 g) was added dropwise to the suspension at 75° to 78° C. during 30 minutes. The reacting mixture was refluxed for 1 hour, insoluble materials were filtered off through Celite pad, and then the materials were washed with hot ethanol. To the filtrate and washings were added ice water (400 ml) and the resulting precipitate was recrystallized from hexane to give the title compound (18.66 g) as pale brown needles, mp 68°-68.5° C.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH3:12][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:41])[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35](I)[CH:34]=3)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:14]>>[CH3:14][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:41])[C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[C:37]([C:2]#[C:1][C:3]4[N:7]5[CH:8]=[CH:9][N:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:38]=3)[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc2cnccn12
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-a]pyrazine and N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1. The product was obtained as a solid: 544 m/z (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=2[C:8]=1[CH3:11])=[O:19]
Reactant: COc1ccc2occ(C)c2c1
Reactant: O=C(Cl)CCCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COc1ccc2oc(C(=O)CCCCCl)c(C)c2c1
Reaction time: 2 h
Yield: 76 %

Procedure:
To a mixture of 5-methoxy-3-methyl-1-benzofuran (2.00 g) synthesized in Example A104(2) above, 5-chlorovaleryl chloride (1.74 mL) and nitromethane (40 mL) was added aluminum chloride (2.47 g) at 0° C., and the mixture was stirred for 2 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to give the title object compound (2.63 g, 76%) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8](CC3C=CC(OC)=CC=3)[C:7](=[O:24])[C:6]=12.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>>[NH2:1][C:2]1[N:3]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:24])[C:6]=12
Reactant: COc1ccc(Cn2c(=O)c3c(N)n(-c4ccccc4OC)nc3c3ccccc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-n1nc2c(c1N)c(=O)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.1 %

Procedure:
A mixture of 3-amino-5-(4-methoxybenzyl)-2-(2-methoxyphenyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (370 mg), anisole (2 ml), trifluoroacetic acid (5 ml) and trifluoromethanesulfonic acid (1 ml) was stirred at room temperature for 3.5 hours. The mixture was concentrated under reduced pressure. To the mixture was added 5% sodium carbonate to adjust pH to about 9. Ethyl acetate was added to the mixture. An insoluble solid was collected by filtration, washed with water and ethyl acetate, and dried to obtain the target compound (250 mg).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C:9]1([CH2:31][CH2:32][CH3:33])[C:14]2[NH:15][C:16]3[C:21]([C:13]=2[CH2:12][CH2:11][O:10]1)=[C:20]([C:22]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:23])[CH:19]=[CH:18][C:17]=3[F:30])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:30][C:17]1[CH:18]=[CH:19][C:20]([C:22]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[O:23])=[C:21]2[C:16]=1[NH:15][C:14]1[C:9]([CH2:8][CH2:7][OH:6])([CH2:31][CH2:32][CH3:33])[O:10][CH2:11][CH2:12][C:13]2=1
Reactant: CCCC1(CCO[Si](C)(C)C(C)(C)C)OCCc2c1[nH]c1c(F)ccc(C(=O)N3CCOCC3)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC1(CCO)OCCc2c1[nH]c1c(F)ccc(C(=O)N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To a solution of {1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-5-yl}-morpholin-4-yl-methanone (350 mg, 0.693 mmol) in THF (5 mL) was added TBAF (0.832 mL of 1.0 M in THF, 0.832 mmol) at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was diluted with EtOAc (20 mL). The organic solution was washed with 0.5 N HCl (20 mL) and brine (20 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 50% EtOAc in hexanes) to give 254 mg (94%) of [8-fluoro-1-(2-hydroxy-ethyl)-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-5-yl]-morpholin-4-yl-methanone as white solid.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[H-].[Na+].[I-].[K+].[CH2:28](Br)[CH2:29][CH3:30]>CN(C)C=O>[CH2:28]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)[CH2:29][CH3:30]
Reactant: Oc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: CCCBr
Agent: Br
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCOc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 1.2 g (2.7 mmoles) of 2-(4-hydroxyphenyl)-3 (4-pyridyl)-6,7-dihydro [5H]-pyrrolo[1,2-a]imidazole dihydrobromide of Example 10 in 20 ml of dry dimethylformamide cooled in an ice bath was treated with 360 mg (9.0 mmoles) of 60% sodium hydride dispersion and allowed to warm to room temperature. 450 mg (2.7 mmoles) of powdered potassium iodide was added, followed by dropwise addition of a solution of 332 mg (2.7 mmoles) of 1-propyl bromide in 2 ml of dimethylformamide. After 2 hours an additional 83 mg (0.67 mmole) of 1-propyl bromide was added followed by another 90 mg (2.25 mmoles) of 60% sodium hydride suspension, and the mixture heated to 65° C. for 2.5 hours. After stirring overnight, the mixture was poured into 10 volumes of ice water and extracted three times with ethyl acetate. The organic phase was washed with water, dried over anhydrous potassium carbonate and concentrated in vacuo. The residue was flash chromatographed on silica and the fractions eluting with 3 to 6% methanol in chloroform were combined, concentrated in vacuo, and recrystallized from ethyl acetate to afford the titled compound, mp 148.5-150° C. Anal. Calcd. for C20H21N3O: C, 75.21; H, 6.63; N, 13.16. Found: C, 4.95; H, 6.59; N, 13.17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13](C#N)[CH2:12][CH2:11]3)[C:9](=[O:18])[NH:8][C:5]2=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:9](=[O:18])[NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: N#CN1CCC2(CC1)C(=O)Nc1ccc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: ClCCl
Product: O=C1Nc2ccc(Br)cc2C12CCNCC2
Temperature: 130 °C
Yield: 59.3 %

Procedure:
5-Bromo-1,2-dihydro-2-oxospiro[3H-indole-3,4′-piperidine]-1′-cyano 12 (3.3 g, 10.8 mmol) was suspended in ethylene glycol (10 ml). The mixture was treated in NaOH (1.8 g, 45 mmol) and heated to 130° C. for 15 min. It was diluted with methylene chloride (500 ml) and washed with 10% aqueous K2CO3 (2×100 m). The organic layer was dried (Na2SO4) and concentrated and residue purified by silica gel chromatography (30% MeOH/CH2Cl2) to gave 13 as a light ceramic white solid 1.8 g (60%), mp 256-258° C. 1HNMR (DMSO-d6, 400 MHz) δ 10.6 (br s, 1H, NH), 7.57 (d, J=1.84 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 4.05 (br s, 1H, NH), 3.06 (m, 2H), 2.84 (m, 2H), 1.64 (m, 2H), 1.55 (m, 2H), 13C NMR (DMSO-d6, 100 MHz) δ 180.93, 140.64, 137.98, 130.42, 126.75, 113.20, 111.45, 46.24, 40.92, 32.94. Anal. Calcd for C12H13BrN2O: C, 51.26; H, 4.66; N, 9.9. Found: C, 50.87; H, 4.91; N, 9.67.
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([S:7][CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:10]2(=[O:12])=[O:11])=[N:4][N:3]=1.Cl.Cl[CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27].C(N(CC)CC)C.C1CCCCC1>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([N:25]([CH2:28][CH3:29])[CH2:26][CH2:27][S:1][C:2]1[S:6][C:5]([S:7][CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:10]2(=[O:12])=[O:11])=[N:4][N:3]=1)[CH3:23]
Reactant: O=C1c2ccccc2S(=O)(=O)N1CSc1nnc(S)s1
Reactant: CCN(CC)CCCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCN(CC)CCSc1nnc(SCN2C(=O)c3ccccc3S2(=O)=O)s1

Procedure:
Following a procedure similar to that described in Example 33A, 2-(5-mercapto-1,3,4-thiadiazol-2-ylthiomethyl)saccharin is reacted with 2-chloroethyldiethylamine hydrochloride in DMF in the presence of triethylamine to give 2-(5-[2-(diethylamino)ethylthio]-1,3,4-thiadiazol-2-ylthiomethyl)saccharin, mp 93.0°-94.5° C. (from cyclohexane:ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.CCOCC.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C1C=CC=CC=1>[CH:29]([O:28][C:26]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1)=[O:27])([CH3:31])[CH3:30]
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)OC(C)C)nc(C(Cl)(Cl)Cl)n1
Yield: 58.9 %

Procedure:
To a solution of 3.0 g (0.013 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 1.4 g (0.013 mole) triethylamine, and 75 ml ether was added 1.6 g (0.013 mole) isopropyl chloroformate. The reaction mixture was refluxed one hour, filtered, and rotary evaporated to give a yellow oil. The oil was distilled (bp1.2 mm 120° C.) to give a cloudy yellow oil. This was taken up in benzene, filtered, and the solvent removed leaving 2.4 g (57% yield) of product. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[C:18]([CH:19]=O)=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2].Cl.[NH2:22][NH:23][C:24]([NH2:26])=[O:25].C([O-])(=O)C.[Na+]>C(O)C>[N+:1]([C:4]1[O:5][C:6]2[C:18]([CH:19]=[N:22][NH:23][C:24]([NH2:26])=[O:25])=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)NN=Cc1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
To a mixture of 2.1 g. (0.0079 mole) of 2-nitro-3-phenylbenzofuran-7-carboxaldehyde in 70 ml. of ethanol is added 1.34 g. (0.012 mole) of semicarbazide hydrochloride and 1.07 g. (0.013 mole) of sodium acetate. The mixture is heated to its reflux temperature and maintained at reflux for 3 hours. The precipitated product is separated by filtration, washed with water and diethyl ether. The solid is washed with hot dichloroethane, separated by filtration, then dissolved in a mixture of 650 ml. of chloroform and 100 ml. of acetone by heating. This solution is washed twice with water, once with sodium bicarbonate solution, again with water, once with dilute hydrochloric acid, and twice with water. The solution is dried and the dry solution is evaporated to provide solid 2-nitro-3-phenylbenzofuran-7-carboxaldehyde semicarbazone, m.p. 249° C. (dec.).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.C(Cl)(=O)C([Cl:17])=O>C1(C)C=CC=CC=1>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([Cl:17])=[O:13]
Reactant: O=C(O)C1CCc2ccccc2C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCc2ccccc2C1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
The suspension of 1,2,3,4-tetrahydro-2-naphthoic acid (500 mg, 2.84 mmol) in 5 ml of toluene was treated with oxalyl chloride (720 mg, 5.675 mmol). The mixture was stirred at 50° C. for 5 hrs. All volatile materials were removed in vacuo and product 1,2,3,4-Tetrahydro-2-naphthoyl chloride was obtained as a colorless oil, which was used for next step reaction without further purification.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:26][CH:27]1[O:32][CH:31]([CH3:33])[CH2:30][NH:29][CH2:28]1.O>CN(C)C=O>[CH3:33][CH:31]1[O:32][CH:27]([CH3:26])[CH2:28][N:29]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:30]1
Reactant: CS(=O)(=O)OC1CCN(c2ccc(C#N)cc2)CC1
Reactant: CC1CNCC(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(C2CCN(c3ccc(C#N)cc3)CC2)CC(C)O1
Temperature: 92.5 °C
Reaction time: 6 h
Yield: 43.8 %

Procedure:
To a solution of 4-(4-methanesulfonyloxypiperidin-1-yl)benzonitrile (4.90 g) in N,N-dimethylformamide (DMF) (50 ml) were added potassium carbonate (4.83 g) and 2,6-dimethylmorpholine (3.02 g), and the mixture was stirred at 90-95° C. for 6 hours. After cooling, the reaction mixture was poured into water (300 ml) and extracted twice with a mixture of ethyl acetate and n-hexane (100 ml:30 ml). The extracts were combined and washed in turn with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting precipitates were washed with IPE (100 ml), collected by filtration and dried in vacuo to give 4-[4-(2,6-dimethylmorpholin-4-yl)piperidin-1-yl]benzonitrile (2.29 g).
Reaction SMILES: [NH:1]1[C:10]2=[CH:11][CH:12]=[CH:13][C:8]3=[C:9]2[N:3]([CH2:4][CH2:5][C:6](=[N:15]O)[C:7]3=[O:14])[C:2]1=[O:17].[H][H].[BH4-].[Na+]>[Pd]>[NH2:15][C@H:6]1[C@H:7]([OH:14])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]3[NH:1][C:2](=[O:17])[N:3]([C:9]=23)[CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: O=C1C(=NO)CCn2c(=O)[nH]c3cccc1c32
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Product: N[C@@H]1CCn2c(=O)[nH]c3cccc(c32)[C@H]1O

Procedure:
Using the methods reported in U.S. Pat. No. 4,585,770, 5,6-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,7-[1H,4H]-dione may be reacted with an alkyl nitrite (e.g., tert-butyl nitrite or isoamyl nitrite), in the presence of a base or acid (e.g., HCl), to form 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime. The 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime, in turn, is reduced via catalytic hydrogenation (with, for example, hydrogen in the presence of palladium on carbon) and/or sodium borohydride to form racemic trans 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-jk][1]-benzazepin-2[1H]-one:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:9])[CH3:10])=[CH:4][C:3]=1[CH2:12][Br:13]
Reactant: Cc1cc(C(C)(C)O)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(O)c1ccc(Br)c(CBr)c1
Temperature: 25 °C

Procedure:
2-(4-Bromo-3-methyl-phenyl)-propan-2-ol (0.916 g, 4.0 mmol) in CCl4 (30 mL) was treated with N-bromosuccinimide (0.750 g, 4.2 mmol) and benzoyl peroxide (0.050 g, 0.2 mmol), and the reaction was refluxed under a halogen lamp for 2 hours. After cooling to room temperature, the mixture was partitioned between CH2Cl2 and H2O, and the organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]>P([O-])([O-])([O-])=O>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:23])[OH:7])[OH:22])[OH:21])[OH:20]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
To measure the enzymatic activity of the nigerooligosaccharide glucanotransferase, 0.25 ml of an enzyme solution is added in 0.75 ml of a maltose solution prepared by dissolving maltose in a 20 mM phosphate buffer (pH 7.0) in a concentration of 0.66% by weight, to carry out reaction at 37° C., where the amount of enzyme for forming 1 μmol of glucose in one minute from the substrate maltose is defined to be one unit.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=O)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a light yellow foam (239 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:9])=[C:4](O)[CH:5]=[CH:6][CH:7]=1.C1([OH:16])C=CC=CC=1.CC(=C)C.C1(O)C(C2C(O)=CC=CC=2)=CC=CC=1.[Cr]([O-])([O-])(=O)=O.[K+].[K+]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([OH:16])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cccc(O)c1C
Reactant: Oc1ccccc1
Agent: O=[Cr](=O)([O-])[O-]
Agent: C=C(C)C
Agent: Oc1ccccc1-c1ccccc1O
Solvent: CC(=O)O
Product: Cc1ccc(O)cc1C

Procedure:
dimethylphenol in two steps. The phenol was alkylated at 65° C. under 2 atmospheres of isobutylene and a catalytic amount of suilfric acid. The crude trialkylphenol was oxidized directly to the biphenol with potassium chromate in hot acetic acid. The overall yield from 3,4-dimethyl phenol was ˜50%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][CH:46]([NH2:55])[CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:55][CH:46]([CH3:45])[CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:22])=[CH:16][CH:15]=1
Reactant: CC(N)CCc1ccccc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC(C)CCc4ccccc4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 1-methyl-3-phenylpropylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(1-methyl-3-phenylpropyl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.56 min, MH+ 426.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH2:14](I)[CH3:15].O>CN(C=O)C>[CH2:14]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)[CH3:15]
Reactant: CCI
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ccc2c(C=O)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
To a solution of 1H-indole-4-carbaldehyde (2.00 g, 13.8 mmol) in anhydrous DMF (6.5 mL) was added sodium hydride (827 mg of 60% dispersion in oil, 20.7 mmol). The mixture was stirred for 30 min at room temperature. Ethyl iodide (2.22 mL, 27.5 mmol) was then added and the reaction mixture was stirred for 12 h at room temperature. Water was added (100 mL) and the mixture was extracted with ethyl acetate (3×100 mL). Combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to an orange oil. Purification by column chromatography (silica gel, gradient elution of CH2Cl2 to 5% MeOH/CH2Cl2) gave the title compound (1-ethyl-1H-indole-4-carbaldehyde) (2.43 g, 99%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.68-7.64 (m, 2H), 7.37-7.32 (m, 1H), 7.08 (d, J=3.0, 1H), 4.28 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H).