Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[N:21]([CH2:22][CH3:23])[N:20]=[C:19]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C@@H:32]4[CH2:36][O:35]C(C)(C)[O:33]4)=[O:31])[CH2:26][CH2:25]3)[N:18]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][N:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[N:21]([CH2:22][CH3:23])[N:20]=[C:19]([CH:24]3[CH2:29][CH2:28][N:27]([C:30](=[O:31])[C@@H:32]([OH:33])[CH2:36][OH:35])[CH2:26][CH2:25]3)[N:18]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]([CH3:15])([CH3:16])[CH3:14])=[N:11][N:12]=1
Reactant: CCn1nc(C2CCN(C(=O)[C@@H]3COC(C)(C)O3)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nc(C2CCN(C(=O)[C@@H](O)CO)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Reaction time: 16 h
Yield: 48 %

Procedure:
To a mixture of 3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (257 mg, 0.50 mmol, TFA salt), potassium (S)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (101 mg, 0.55 mmol) and EDCI (105 mg, 0.55 mmol) in DCM (5 mL) were added 1-hydroxy-1H-benzotriazol hydrate (85 mg, 0.56 mmol) and DIPEA (194 mg, 1.50 mmol). The mixture was stirred for 16 hours at room temperature. Water was added to the mixture and the mixture was extracted with DCM. The organic layers were washed with brine and dried over Na2SO4, filtered and concentrated to give (S)-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)(2,2-dimethyl-1,3-dioxolan-4-yl)methanone (320 mg). Mass Spectrum [M+H]+=526. To a mixture of (S)-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)(2,2-dimethyl-1,3-dioxolan-4-yl)methanone (320 mg) in DCM (10 mL) at r.t was added dropwise TFA (1.6 ml, 20.77 mmol). The mixture was stirred for 16 h at r.t, concentrated and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as the eluant. The fractions containing the desired compound were evaporated to dryness to afford the title compound (142 mg, 48%) as a white solid. 1H NMR Spectrum (400 Hz, DMSO-d6, 30° C.): 1.45 (12H, m), 1.56 (1H, m), 1.70 (1H, m), 1.98 (2H, m), 2.85 (1H, m), 3.00 (1H, m), 3.20 (1H, m), 3.45 (1H, s), 3.55 (1H, s), 4.05 (1H, m), 4.35 (2H, m), 4.60 (2H, m), 4.70 (1H, m), 4.85 (1H, m), 7.90 (2H, m), 8.85 (1H, s); Mass Spectrum [M+H]+=486.
Reaction SMILES: [C:1]([C:4]1[C:13]([OH:14])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)(=[O:3])[CH3:2].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:14][C:13]1[C:4]([C:1](=[O:3])[CH3:2])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(=O)c1nc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4nc3C(C)=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
2-Acetyl-3-quinolinol (22 mg), 4-chloro-6,7-dimethoxyquinoline (54 mg), and 4-dimethylaminopyridine (88 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (6 mg, yield 13%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[C:15]2[S:20]([OH:23])(=O)=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>ClCCl>[C:1]([NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[C:15]2[S:20]([Cl:26])(=[O:23])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2c(S(=O)(=O)O)cccc12)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1cccc2c(S(=O)(=O)Cl)cccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 5-benzoylamino-napthalene-1-sulfonic acid (1.5 g, 3.51 mmol) in dichloromethane (5 ml), was added thionyl chloride (0.359 ml, 4.92 mmol). The resultant solution was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was quenched by pouring into ice water and extracting with ethyl acetate. The organic extracts were washed with brine, dried over MgSO4 and concentrated to provide the crude intermediate 44 as a yellow oil that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:22]1([CH:28]([N:35]=[C:36]=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH:28]([NH:35][C:36]([N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1)=[O:37])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCC(C(c2ccc(Cl)cc2)N2CCNCC2)CC1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN1CCC(C(c2ccc(Cl)cc2)N2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 1-((4-chlorophenyl)(1-methylpiperidin-4-yl)methyl)piperazine 0.1 g (0.325 mmol) dissolved in methylene chloride (20 ml) was added diphenylmethyl isocyanate 0.07 μg (0.325 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 0.14 g of desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:10]1[O:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:24])[CH:21]([CH3:23])[CH3:22]>C(O)(C)C>[OH:12][C@H:10]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:24][CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Solvent: CC(C)O
Product: CC(C)CNC[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
To a solution of 3(S)-(t-butyloxycarbonyl)amino-1,2(S)-epoxy-4-phenylbutane (200 mg, 0.76 mmol) in 2 mL of dry isopropanol was added isobutylamine (0.38 mL, 3.8 mmol) and the mixture was stirred for 5 h at 50° C. The mixture was concentrated under reduced pressure and dried in vaccuo to give 230 mg of 2(S)-hydroxy-3(S)-(t-butyloxycarbonyl)amino-1-isobutylamino-4-phenylbutane
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[OH-].[K+].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:26])([F:28])[F:27]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cc(Cl)ccc2Cl)c(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2,5-dichloroaniline (1.6 g.) in dry dimethylformamide (10 ml.) potassium hydroxide (1.0 g.) was added in small portions over 5 minutes, and stirring continued for a further 15 minutes. To the resultant solution was added 2-chloro-3,5-dinitrobenzotrifluoride (2.7 g.) in small portions over 5 minutes. When the addition was complete the mixture was stirred for 30 minutes at 20° C, after which concentrated hydrochloric acid was added to acidify the mixture. Industrial methylated spirit (10 ml.) was then added, the mixture stirred for further 15 minutes and then poured into water (150 ml.) The solid precipitate was collected by filtration, washed with water and dried to yield 2(2,5-dichloroanilino)-3,5-dinitrobenzotrifluoride, melting point 125°-126° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[C:14]([OH:16])[C:13]([CH3:17])=[CH:12][CH:11]=1>CCO>[NH2:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([OH:16])[CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(N)cc1O
Reactant: Nc1nccc(Cl)n1
Solvent: CCO
Product: Cc1ccc(Nc2ccnc(N)n2)cc1O
Temperature: 90 °C
Yield: 94 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-amino-4-chloropyrimidine (70 mg, 0.5 mmol) and 5-amino-o-cresol (67 mg, 0.5 mmol) in 10% aqueous EtOH (2 mL) was heated at 90° C. for 18 h. The title compound was obtained in 94% yield a (110 mg) and used for the next step without additional purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:52])(=O)=O)=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]([F:52])[C:16]([C:22]3[CH:23]=[C:24]([Cl:29])[CH:25]=[C:26]([Cl:28])[CH:27]=3)([C:18]([F:20])([F:19])[F:21])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2F)ccc1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 38.5 %

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (preparation of similar compounds described in, for example, EP 1,731,512) (500 mg) in tetrahydrofuran (6 ml) that was stirred at −78° C. for 15 minutes under argon, was slowly added lithium bis(trimethyl-silyl)amide (“LiHMDS”) (1M in hexane) (1.1 ml). The reaction mixture was stirred at −78° C. for 1.5 hours. Then N-fluorobenzenesulfonimide (“NFSI”) (433 mg) was added quickly and the reaction mixture was stirred at −78° C. for 2 hours. The reaction was quenched by addition of aqueous ammonium chloride (saturated) at −78° C. tent-Butyl methyl ether (“TBME”) was added and the phases were separated. The organic layer was washed successively with aqueous ammonium chloride (saturated) and brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/heptane 1:2) to give 4-[5-(3,5-dichloro-phenyl)-4-fluoro-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (200 mg) as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]2[O:14][CH2:13][C@H:12]3[C@:10]([CH2:15]O)([CH2:11]3)[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[N:26]=[C:25]([NH2:27])[N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][NH:22]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC1CCCO1>[Cl:17][C:18]1[N:26]=[C:25]([NH2:27])[N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:15][C@:10]12[CH2:11][C@H:12]1[CH2:13][O:14][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:8][CH2:9]2
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: OC[C@@]12COC(c3ccccc3)OC[C@@H]1C2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC1CCCO1
Product: Nc1nc(Cl)c2ncn(C[C@@]34COC(c5ccccc5)OC[C@@H]3C4)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a reactor, a mixture of [(1S,7R)-4-phenyl-3,5-dioxabicyclo[5.1.0]octan-1-yl]methanol (750 g, 3.4 mol) (5c), 6-chloro-9H-purin-2-amine (7c) (479 g, 2.8 mol) and triphenylphosphine (930 g, 3.5 mol) in 2-methyltetrahydrofuran (7.4 L) was stirred at room temperature for 30 minutes, and then heated to 65° C. (+/−5° C.). To this mixture was dosed a solution of DIAD (711 g, 3.5 mol) in 2-methyltetrahydrofuran (740 mL) over a period of 1 hour. The mixture was stirred during 1 hour at reflux and then allowed to cool to room temperature overnight. Solids were removed by filtration. The reactor was rinsed with 2-methyltetrahydrofuran (740 mL) and this liquid was used to wash the solids on the filter. The filtrate was submitted as such in the next step (6′).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].O.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[O:21])=[CH:18][CH:17]=1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(Cl)cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 g (0.296 mol) of 4-hydroxypiperidine, 260 ml of CHCl3, 57.3 g (0.414 mol) of K2CO3 and 260 ml of water are placed in a one liter Erlenmeyer flask, 51.8 g (0.296 mol) of p-chlorobenzoyl chloride, dissolved in 50 ml of CHCl3, are added in the course of 15 minutes, whilst cooling with a bath of iced water. The mixture is stirred overnight at ambient temperature. The organic phase is decanted, the aqueous phase is extracted with CHCl3 and the CHCl3 extract is washed with water until the pH is 6-7. It is dried over MgSO4, filtered and concentrated. The product is recrystallised from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[F:19].O.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O>[ClH:12].[F:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: Fc1cnccc1Cl
Reactant: Nc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1cnccc1Nc1c[nH]c2ccccc12
Reaction time: 3 h
Yield: 121.7 %

Procedure:
A solution of 3-aminoindole (7 g) and 4-chloro-3-fluoropyridine hydrochloride (13 g) in 200 mL of 1-methyl-2-pyrrolidinone was stirred at 75°-80° C. for two hours, after which additional 4-chloro-3-fluoropyridine hydrochloride (5 g) was added. After stirring a total of three hours the mixture was cooled, stirred with water, basified with sodium carbonate and extracted with ethyl acetate. The dried (anhydrous magnesium sulfate) organic layer was filtered and concentrated to 20 g of a dark oil. Elution through silica gel first with dichloromethane and then with 50% ethyl acetate in dichloromethane via flash column chromatography yielded 17 g of a dark oil. This oil was eluted through silica with ether via flash column chromatography to yield 10.6 g of a dark oil. This oil was eluted through silica with 20% ethyl acetate in dichloromethane via HPLC to yield 8 g of a dark oil. A six gram portion was converted to the hydrochloride salt in methanol/ether to yield 3.5 g of a solid, m.p. >250° C. Recrystallization from 30% methanol in ether yielded 2.7 g of crystals, m.p. 256°-258° C. (dec.).
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][CH2:8][C@H:9]([NH:13]C(OC(C)(C)C)=O)[C:10](O)=[O:11])(C)(C)C.CCN=C=NCCCN(C)C.[ClH:33].[CH2:34]([N:38]1[CH:42]=[C:41]([NH:43][C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][C:54]([F:57])([F:56])[F:55])=[CH:49][CH:48]=2)=[O:45])[N:40]=[C:39]1[C:58]([NH:60][CH2:61][CH2:62][OH:63])=[O:59])[CH2:35][CH2:36][CH3:37]>CN(C=O)C.CN(C1C=CN=CC=1)C>[ClH:33].[NH2:13][C@H:9]([C:10]([O:63][CH2:62][CH2:61][NH:60][C:58]([C:39]1[N:38]([CH2:34][CH2:35][CH2:36][CH3:37])[CH:42]=[C:41]([NH:43][C:44]([NH:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][C:54]([F:55])([F:56])[F:57])=[CH:51][CH:52]=2)=[O:45])[N:40]=1)=[O:59])=[O:11])[CH2:8][CH2:7][C:6]([OH:21])=[O:5]
Reactant: CCCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCCO
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCCOC(=O)[C@@H](N)CCC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
91 mg (0.30 mmol) of (2S)-5-tert-butoxy-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid are dissolved in 5 ml of DMF and, after addition of 58 mg (0.3 mmol) of EDCI×HCl and 37 mg (0.30 mmol) of DMAP, stirred at room temperature for 10 minutes. Then 70 mg (0.15 mmol) of 1-butyl-N-(2-hydroxyethyl)-4-[({[4-(trifluoromethoxy)phenyl]amino}-carbonyl)amino]-1H-imidazole-2-carboxamide (Example 81) are added, and the mixture is stirred at room temperature overnight. The reaction mixture is purified by preparative HPLC. The product-containing fractions are evaporated in vacuo.
Reaction SMILES: [OH:1][C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]>O.CO>[CH2:11]([OH:12])[C@@H:9]([OH:10])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C:3]([CH:2]=[O:1])=[O:4]
Reactant: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CO
Solvent: O
Product: O=CC(=O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
To a solution of α-D-glucose (4.5 g) in water (10 ml), a solution of cupric acetate (20 g) in methanol (250 ml) was added, and the resultant mixture was heated on a water bath for 1 hour. The reaction mixture was cooled, and the precipitated cuprous oxide was eliminated by filtration. Hydrogen sulfide gas was introduced into the filtrate for about 1 minute to precipitate the unreacted cupric acetate in the form of cupric sulfide. After elimination of the precipitate by filtration, the filtrate was treated with a small amount of activated charcoal and concentrated under reduced pressure to give glucosone in a syrupy state.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:5]=1[NH2:14].O1CCO[CH2:18][CH2:17]1>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>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:17]#[CH:18])[C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:5]=1[NH2:14]
Reactant: C1COCCO1
Reactant: COC(=O)c1cc(I)c(C(C)C)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C#Cc1cc(C(=O)OC)c(N)cc1C(C)C
Yield: 72 %

Procedure:
A solution of 2-amino-5-iodo-4-isopropyl-benzoic acid methyl ester (1.5 g, 4.7 mmol), Bu3SnCCH (1.5 mL, 5.17 mmol) and (Ph3P)4Pd (271.6 mg, 0.235 mmol) in dioxane (80 mL) was heated at 120° C. for 1.5 h. The solvent was removed in vacuo. The residue was purified by two successive flash chromatographies (160 g silica gel, hexanes→EtOAc:hexanes (3:7 to 1:1), then (50 g silica gel, hexanes→EtOAc:hexanes (1:9)) to provide 2-amino-5-ethynyl-4-isopropyl-benzoic acid methyl ester (738 mg, 72%) as a yellowish oil. API-ES: m/z 218 [M+H]+, rt 5.45 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH3:19][N:20]([CH3:40])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30](C2C=CC=CC=2)=[C:29]([CH:37]=O)[NH:28][C:27]=1[CH3:39])=[O:25]>>[CH3:19][N:20]([CH3:40])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[CH2:30][C:29]([CH:37]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])=[N:28][C:27]=1[CH3:39])=[O:25]
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCN(C)C
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=CC1=NC(C)=C(C(=O)NCCN(C)C)C1
Yield: 51.8 %

Procedure:
6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (53 mg, 0.22 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (65 mg) to give 0.05 g (44%) of the title compound as an orange gum.
Reaction SMILES: [N+]([O-])(O)=O.[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[C:6]1=[O:15])[CH2:12]2.[OH-:16].[Na+]>OS(O)(=O)=O>[OH:16][C:11]12[CH2:13][CH:7]3[CH2:8][CH:9]([CH2:14][CH:5]([C:6]3=[O:15])[CH2:12]1)[CH2:10]2
Reactant: [OH-]
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: O=C1C2CC3CC1CC(O)(C3)C2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a mixture of H2SO4 (96%; 150 ml) and HNO3 (70%; 15 ml), cooled to 0° C. is added tricyclo[3.3.1.13,7 ]decan-2-one (10 g; 0.067 mole) and the mixture stirred at room temperature for 5 hrs. The reaction mixture is then poured over ice, basified to pH 8 using 50% NaOH, extracted into ether, dried over MgSO4 and evaporated to dryness. The resultant product is recrystallized from carbon tetrachloride to obtain 5-hydroxytricyclo[3.3.1.13,7 ]decan-2-one [(m.p. 314° C. (dec.)] which is used directly in step B.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(Cl)Cl.CO>[CH3:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:3]=[N:4][C:5]([CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:20][CH:19]=1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(Nc2nnc(Cc3ccncc3)c(C)c2C)cc1

Procedure:
The compound is prepared from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.129 g para-methylaniline in the manner described in Example 82A. Title compound is obtained after FC in CH2Cl2/Methanol 19/1; m.p. 68-70° C. 1H-NMR (250 MHz,CDCl3): δ=8.45 (s, wide, 2H); 7.45 (d, 2H); 7.10 (“d”, wide, 4H); 6.10 (s, wide, 1H); 4.25 (s, 2H); 2.30 (s, 3H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 305 (M+H).
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.[OH-].[NH4+].Cl[CH2:14][C:15]([NH:17][C:18]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)=[O:16].N>C(O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:18]2[NH:17][C:15](=[O:16])[CH2:14][N:2]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]=2[CH:28]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: N
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 167 %

Procedure:
A mixture of ethanol (1100 ml), hexamethylenetetramine (70.0 g., 0.5 mol), 26% ammonium hydroxide (58 ml) and 2-chloroacetamido-5-chlorobenzophenone (308.2 g., 1.0 mol) was stirred and slowly heated to reflux with ammonia bubbling into the mixture. Reflux was continued for 5 hours, the flow of ammonia was interrupted, and the reaction mixture distilled to dryness in vacuo. The residue was heated to reflux for 30 minutes in a mixture of toluene (500 mls) and water (500 mls) and then allowed to cool slowly to room temperature. The crystalline material was filtered, washed with toluene (100 mls) and hot water (2 × 250 mls) and dried to constant weight. The product, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (226 g) obtained corresponded to a yield of 83.5%, melting point 210° C.