Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.C(CC(=O)C)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[NH3:27].[Cl-].[NH4+]>C(CC(=O)C)(=O)C.[Cu+2].CN1C(=O)CCC1>[CH3:9][NH:8][C:7]1[C:2]([NH2:27])=[N:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][CH:6]=1
Reactant: CNc1ccc(C(F)(F)F)nc1Cl
Reactant: N
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)CC(C)=O
Solvent: CN1CCCC1=O
Product: CNc1ccc(C(F)(F)F)nc1N
Temperature: 140 °C
Reaction time: 8 h

Procedure:
To a pressure-resistant reaction container, (2-chloro-6-trifluoromethylpyridin-3-yl)-methylamine (2.60 g), copper (II) acetylacetone (0.64 g), acetylacetone (1.23 g), cesium carbonate (7.99 g), NMP (10 ml), and 28% of aqueous ammonia (7 ml) were added, and stirred at 140° C. for 8 hours. After the mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride solution was poured thereinto, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 2.09 g of N3-methyl-6-trifluoromethylpyridin-2,3-diamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[O:10]
Reactant: OCCc1ccccc1Br
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCc1ccccc1Br
Reaction time: 15 h

Procedure:
A solution of 9.11 grams (0.045 mole) of 2-(2-bromophenyl)ethanol in 35 milliliters of methylene chloride was added to a stirred suspension of 14.62 grams (0.063 mole) of pyridinium chlorochromate in 75 milliliters of methylene chloride at ambient temperature whereupon a slightly exothermic reaction took place with the formation of a black reaction mixture. Stirring was continued for 15 hours at ambient temperature; then 150 milliliters of ether was added and the mixture filtered through silica gel on a pad of celite. The insoluble residue was washed with 100 milliliters of ether, filtered, the ether solutions combined and the solvents evaporated on a rotary evaporator to recover as residue, 8.0 grams (90 percent) of the desired 2-(2-bromophenyl)acetaldehyde intermediate as an oil. The oil had an Rf of 0.6 on silica gel when eluted with one percent methanol in chloroform.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1.BrBr.O>C(O)(=O)C>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[S:1][C:2]([NH2:3])=[N:5][C:6]2=[CH:7][CH:8]=1
Reactant: N#C[S-]
Reactant: COc1ccc(N)cn1
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2nc(N)sc2n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Potassium thiocyanate Fluka 60519 (38.8 g, 400 mmol, 8.0 equiv.) and 5-amino-2-methoxypyridine Aldrich A6, 120-9 (6.2 g, 50 mmol, 1.0 equiv.) were added to 100 mL glacial acetic acid precooled to 5° C. (semi solid) with mechanical stirring. Bromine (23.9 g, 150 mmol, 3.0 equiv.) dissolved in 30 mL glacial acetic acid was added dropwise to the reaction mixture over 1.5 hr at 0° C. The thick slurry was stirred 2 hrs at 0° C. and overnight at RT. Then 30 mL water was added to the orange suspension, which was heated to 85° C. and filtered hot. The residue was treated again with acetic acid, heated and filtered like before. The combined filtrates were cooled and neutralized with NH4OH at pH 6. The red precipitate was filtered, dissolved in ethyl acetate and washed with NaHCO3 and brine, dried over Na2SO4, evaporated and crystallized from ethyl acetate-hexane using charcoal to give 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine m/e 182.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:35]2)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[S:35]
Reactant: Nc1ncccc1C(=O)NCc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Nc1ncccc1C(=S)NCc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
A mixture of 2-amino-N-(4-benzyloxy-benzyl)-nicotinamide described in Example A-17 (220 mg, 0.67 mmol), 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (670 mg, 1.7 mmol) and toluene (8 mL) was stirred at 80° C. for 15 minutes, then, refluxed for 45 minutes. After cooling, the precipitate was filtered, and the filtrate was evaporated in vacuo. Purification was carried out by NH silica gel column chromatography (ethyl acetate), and the title compound (28 mg, 0.080 mmol, 12%) was obtained as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1.[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18].C(OCC)C>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([C:10](=[O:12])[CH2:11][C:15]([O:16][CH2:17][CH3:18])=[O:19])[CH:9]=1
Reactant: COc1ccc(Cl)cc1C(C)=O
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.17 g, 54.2 mmol) was added portionwise to a stirred solution of 1-(5-chloro-2-methoxy-phenyl)-ethanone (10.0 g, 54.2 mmol) in THF (100 mL) at 0° C. The mixture was then stirred for 10 minutes before addition of diethyl carbonate (7.68 g, 65.0 mmol) and then for an additional 1 hour. The mixture was warmed to room temperature for 2 hours and then heated to 65° C. for 2 hours. Diethyl ether was added, the organics washed with water and brine, then evaporated to dryness. The residues were purified by flash chromatography on silica gel (50 to 100% dichloromethane in cyclohexane) to yield 3.41 g of ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate. LCMS (ESI) m+H=257.2; NMR (400 MHz, CDCl3): δ 7.59 (d, 1H); 7.38 (dd, 1H); 6.89 (d, 1H); 4.18 (q, 2H); 3.95 (s, 2H); 3.88 (s, 3H); 1.24 (t, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.C([O-])([O-])=O.[Na+].[Na+].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>CCO>[C:19]1([CH2:18][NH:3][CH:4]2[CH:9]3[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]3)[CH2:5]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC1CN2CCC1CC2
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CCO
Product: c1ccc(CNC2CN3CCC2CC3)cc1
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of 3-aminoquinuclidine dihydrochloride (8.0 g, 40.0 mmol) in EtOH (100 mL) was added excess Na2CO3 and the mixture was stirred for 1 h and then filtered. To this solution was added benzaidehyde (3.2 g, 30.0 mmol) and the reaction was stirred at room temperature for 2 h and then NaBH4 (3 pellets, 0.4 g ea.) was added and the reaction was stirred overnight at room temperature. The solvent was evaporated in vacuo and the residue was partitioned between 10% Na2CO3 and EtOAc. The organic layer was separated, dried over K2CO3, filtered and the solvent was evaporated in vacuo. The residue was chromatographed on silica (92/8 CHCl3/1.0 M NH3 in MeOH) to give N-phenylmethyl-1-azabicyclo[2.2.2]octan-3-amine (4.2 g, 76%) as an intermediate, a pale yellow oil. MH+=217. 1H NMR (CDCl3) 1.4 (m, 3H), 1.7 (m, 1H), 1.9 (m, 2H), 2.45 (2m, 1H), 2.8 (m, 5H), 3.2 (m, 1H), 3.75 (d, 2H), 7.3 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.[CH3:12][S:13][S:14][C:15]([CH3:19])([CH3:18])[CH:16]=O.[BH4-].[Na+]>C(O)C>[CH3:16][C:15]([S:14][S:13][CH3:12])([CH3:19])[CH2:18][NH:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: CSSC(C)(C)C=O
Reactant: Nc1cc(CO)cc(CO)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CSSC(C)(C)CNc1cc(CO)cc(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
(5-amino-1,3-phenylene)dimethanol (2.5 g, 16.32 mmol) and 2-(methyldithio)isobutyraldehyde (2.347 ml, 16.32 mmol) were stirred at ambient temperature in absolute ethanol (82 ml) until completely dissolved (3 hours). The mixture was cooled to 0° C. in an ice bath and sodium borohydride (0.741 g, 19.59 mmol) was added. The reaction was stirred for 1 hour at 0° C., and was then quenched slowly with cold 5% HCl solution. The mixture was diluted with dichloromethane and the pH was adjusted to pH=8 with saturated sodium bicarbonate solution then extracted with dichloromethane and then washed with brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (MeOH/DCM) yielded (5-(2-methyl-2-(methyldisulfanyl)propylamino)-1,3-phenylene)dimethanol (3g, 65%) as a white solid. 1H NMR (400 Hz, CDCl3): δ6.62 (s, 1H), 6.54 (s, 2H), 4.53 (s, 4H), 3.13 (s, 2H), 2.30 (s, 3H), 1.32 (s, 6H). See FIG. 47.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18](#[N:20])[CH3:19]>>[OH:14][CH:13]([C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([O:9][CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=1)[CH2:19][C:18]#[N:20]
Reactant: O=Cc1cccc(OCCc2ccccc2)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(OCCc2ccccc2)c1

Procedure:
Addition of acetonitrile to 3-phenethoxybenzaldehyde gave 3-hydroxy-3-(3-phenethoxyphenyl)propanenitrile as a yellow oil. Yield (0.80 g, 80%): 1H NMR (400 MHz, CDCl3) δ 7.23-7.38 (m, 6H), 6.93-6.97 (m, 2H), 6.88 (dd, J=7.6, 1.8 Hz, 1H), 5.00 (t, J=6.0 Hz, 1H), 4.18 (t, J=7.2 Hz, 2H), 3.12 (t, J=7.2 Hz, 2H), 2.75 (d, J=6.4 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>O(C(OC)C)C.O>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([CH3:12])=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([NH:14][CH3:13])=[O:16])=[CH:18][CH:19]=2)[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1Br
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Agent: COC(C)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CNC(=O)c1ccc(-c2cc(Cl)c([N+](=O)[O-])cc2C)cc1
Temperature: 90 °C

Procedure:
To a mixture of the crude product from Step 1 (400 mg, 1.6 mmol), 4-(methylcarbamoyl)phenylboronic acid (286 mg, 1.6 mmol) and sodium carbonate (340 mg, 3.2 mmol) in dimethoxylethane/water (12/4 mL), is added palladium tetrakis(triphenylphospine) (93 mg, 5% mmol). The mixture is purged with N2 for 3 min, then sealed and heated at 90° C. for 3 h. The mixture is cooled, filtered and concentrated. The residue is purified with silica gel chromatography (30% ethyl acetate in DCM) to afford 5′-chloro-N,2′-dimethyl-4′-nitrobiphenyl-4-carboxamide as yellow solid. ESMS m/z 305.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.[H-].[Na+].Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[O:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1
Reactant: OCC1(CO)CCC1
Reactant: Brc1nccs1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCC1(COc2nccs2)CCC1
Reaction time: 0.25 h
Yield: 39.6 %

Procedure:
To a solution of 0.5 g (4.31 mmol) of [1-(hydroxymethyl)cyclobutyl]methanol in 15 mL of N,N-dimethylformamide:tetrahydrofuran (1:1), was added a 60% dispersion of 0.165 g (4.31 mmol) sodium hydride in oil. After stirring for 15 min, 0.71 g (4.31 mmol) of 2-bromothiazole was added and the contents refluxed for 3 h. A saturated solution of sodium bicarbonate was added followed by ethyl acetate. The organic phase was isolated, dried with magnesium sulfate and concentrated under vacuum. The crude product was purified by silica gel chromatography eluting with ethyl acetate:hexane (4:6) to afford 0.340 g (40%) of {1-[(1,3-thiazol-2-yloxy)methyl]cyclobutyl}methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.05 (d, J=4 Hz, 1H), 6.64 (d, J=4 Hz, 1H), 4.51 (s, 2H), 3.59 (s, 2H), 2.03-1.72 (m, 6H). GC-MS m/z 200 (M+H).
Reaction SMILES: CC[O-].[Na+].[CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[OH:16])([CH3:7])[CH3:6].Cl.[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[C:21]([N:33]2[C@@H:42]3[C@@H:37]([CH2:38][CH2:39][CH2:40][CH2:41]3)[N:36]([C:43](=[O:46])[CH2:44][Cl:45])[CH2:35][CH2:34]2)[N:20]=1>C(O)C>[ClH:45].[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[C:21]([N:33]2[C@@H:42]3[C@@H:37]([CH2:38][CH2:39][CH2:40][CH2:41]3)[N:36]([C:43](=[O:46])[CH2:44][O:16][C:9]3[C:10]([O:14][CH3:15])=[CH:11][CH:12]=[CH:13][C:8]=3[CH:5]([CH3:7])[CH3:6])[CH2:35][CH2:34]2)[N:20]=1
Reactant: COc1cccc(C(C)C)c1O
Reactant: COc1cc2nc(N3CCN(C(=O)CCl)[C@@H]4CCCC[C@@H]43)nc(N)c2cc1OC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc2nc(N3CCN(C(=O)COc4c(OC)cccc4C(C)C)[C@@H]4CCCC[C@@H]43)nc(N)c2cc1OC
Reaction time: 0.5 h
Yield: 21 %

Procedure:
10 ml of a freshly prepared 0.095M EtONa solution was added to a stirred solution of 0.16 g of 2-isopropyl-6-methoxyphenol in 5 ml of ethanol and stirring was continued for 0.5 hours at room temperature. The resulting solution was added dropwise in 15 minutes into a stirred solution 0.2 g of the above intermediate 4B in 50 ml of ethanol under nitrogen atmosphere. The mixture was stirred for 5 hours at room temperature and was then refluxed for 20 hours. The residue obtained after solvent evaporation was converted into the hydrochloride salt and crystallized from i-propanol to give 0.64 g (21%) of the title compound; m.p. 208-209° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(N(CC)CC)C.CS(C)=O>O>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:9][C:6]=1[C:7]#[N:8])([O-:12])=[O:11]
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: c1nc[nH]n1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1cc(-n2cncn2)ccc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 48.9 %

Procedure:
A mixture of 5-fluoro-2-nitrobenzonitrile (3 g), 1,2,4-triazole (4.92 g), triethylamine (9.9 ml) and DMSO (50 ml) was stirred and heated to 85° C. for 16 hours. The mixture was cooled to ambient temperature and water was added. The precipitate was isolated and dried to give 2-nitro-5-(1,2,4-triazol-1-yl)benzonitrile (1.9 g) which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:17]=2)[CH:12]=[C:11]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:10]=1)C1C=CC=CC=1.Cl>C(O)C>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[C:18]3[C:13]([CH:12]=[C:11]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[N:10]=[C:9]3[OH:8])=[CH:14][CH:15]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(-c2ccc3cc(-c4cccnc4)nc(OCc4ccccc4)c3c2)c1
Agent: Cl
Solvent: CCO
Product: COc1cccc(-c2ccc3cc(-c4cccnc4)nc(O)c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of 1-(benzyloxy)-7-(3-methoxyphenyl)-3-(pyridin-3-yl)isoquinoline (200 mg, 0.48 mmol), and concentrated HCl (10 mL) in ethanol (20 mL) was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered and concentrated to afford 130 mg of lxviii-a as a yellow solid (yield 90% for two steps). LCMS m/z=329.0 (M+1) (Method B) (retention time=1.66 min).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]=[N:13][C:14]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[CH:16][C:15]=1[OH:24])([O-])=[O:4].C1(C=CC(O)=CC=1)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.N(C1C=CC=CC=1)=NC1C=CC=CC=1>O.CO>[OH:24][C:15]1[CH:16]=[CH:17][C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:19][C:14]=1[N:13]1[N+:3]([O-:4])=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=[N:12]1
Reactant: CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1

Procedure:
Example 7 of U.S. Pat. No. 4,835,284 is duplicated. 97% sodium hydroxide (14.4 g) is added to a mixture of methanol (72 ml) and water (36 ml). 2-nitro-2'-hydroxy-5'-t-butylazobenzene (15.0 g) is then added to the resultant mixture and the mixture is heated to 45°-5020 C. Hydroquinone (0.4 g) and then glucose (5.0 g) are added to the heated mixture over 30 minutes while stirring. The mixture is further stirred for one hour. As this result, the azobenzene disappears to produce 2-(2'-hydroxy-5'-t-butylphenyl)benzotriazole-N-oxide. 9-fluorenone (0.7 g) is then added to the reaction liquor thus obtained, and the liquor is heated to 55°-60° C. Thereafter, glucose (6.0 g) is added to the reaction liquor over 30 minutes, and the reaction is conducted at 75° C. (boiling point) for 6 hours. As a result, the N-oxide disappears. Thereafter, the pH of the reaction liquor is brought to 8 with 62% sulfuric acid (19.0 g) to precipitate a crystal. The precipitated crystal is separated by filtration, and the separated crystal is fully washed with water and further with methanol. The washed crystal is then dried, thus obtaining 11.6 g of 2-(2'-hydroxy-5'-t-butylphenyl)benzotriazole. One can see that the reaction using an aromatic ketone takes over 8 hours to complete. Two catalysts are also required.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=1)=[O:3].C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH3:40][C:41]([CH3:43])=[O:42]>C(Cl)Cl>[C:15]([C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:41]([OH:42])([CH3:43])[CH3:40])[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[C:7]=1[OH:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)=O
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 3,5-di-tert-butyl-4-hydroxyacetophenone (Apim Chemicals, Ltd.) (4 g) in dry methylene chloride (250 mL) is cooled to -78° C. and di-isopropyl ethylamine (7.3 mL) is added followed by trimethylsilyl trifluoromethanesulphonate (Aldrich Chemical Co.) (8.0 mL). The mixture is stirred at -78° C. for 10 minutes and is allowed to warm to ambient temperature over 1 hour. The mixture is cooled again to -78° C. and dry acetone (4.05 mL) is added dropwise. After stirring for 25 minutes, the mixture is washed with 1N aqueous hydrochloric acid and brine. The organic solution is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude product is dissolved in methanol-1N aqueous HCl mixture (10:1, v/v, 200 mL) and the homogenous solution is stirred for 1 hour at room temperature. Methanol is removed under reduced pressure; the mixture is washed with methylene chloride. The organic extracts are washed: with aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The crude product is crystallized from hexane to give 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-3-methyl-butan-1-one as orange crystals. Two additional crystallizations give product of analytical purity, mp 113°-14° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[CH3:34])[CH2:15]/[C:16](/[C:19]3[CH:20]=[CH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=3)=[N:17]\[OH:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1.C(OCC)(=O)C>CN(C)C=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH2:15]/[C:16](=[N:17]\[OH:18])/[C:19]2[CH:20]=[CH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[C:28]([CH3:34])[CH:29]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(N)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(NC(=O)CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of (E)-5-(3-(4′-aminobiphenyl-4-yl)-3-(4-fluoro-2-methylphenyl)-1-(hydroxyimino)propyl)-1-methylpyridin-2(1H)-one (0.05 g, 110 μmol, example 259) in N,N-dimethylformamide was added at room temperature succinic anhydride (12.1 mg, 121 μmol) and the resulting solution was stirred at room temperature for 26 hours. The reaction mixture was poured on water and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate and the organic layers were washed twice with water and once with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Light brown foam (0.043 g, 70%). MS (ESI+): m/z=556.2 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:27]1[C:28]2[C:35]([CH3:36])=[CH:34][S:33][C:29]=2[N:30]=[CH:31][N:32]=1>C(O)C>[O:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]([NH:2][C:27]1[C:28]3[C:35]([CH3:36])=[CH:34][S:33][C:29]=3[N:30]=[CH:31][N:32]=1)[CH2:11]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: NC1Cc2ccc(Oc3ccccc3)cc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1csc2ncnc(NC3Cc4ccc(Oc5ccccc5)cc4C3)c12
Yield: 39.4 %

Procedure:
Using 2-amino-5-phenoxyindan hydrochloride (99 mg, 0.36 mmol), ethanol (3 ml), triethylamine (92 μl, 0.66 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (61 mg, 0.33 mmol), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (51 mg, 0.13 mmol) having the following physical properties:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.O>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
5-Aminoindole (100 mg, 0.757 mmol) was dissolved in DMF (2 mL), and the solution was added with EDCI (290 mg, 1.51 mmol), HOBT monohydrate (102 mg, 0.755 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (208 mg, 0.907 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using acetonitrile to obtain 5-[1-(tert-butoxycarbonyl)piperidine-4-carbonylamino]indole (142 mg, yield 55%).