Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)(=O)C.[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1>N1C=CC=CC=1>[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:5](=[O:7])[CH3:6])=[CH:22][CH:21]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1
Reactant: Cn1c(=O)cc(N)n(Cc2ccc(N)cc2)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cn2c(N)cc(=O)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Using the general procedure for Intermediate 1, (4-nitro-benzyl)-urea [J. Med. Chem. 1996, 39, 1924] is converted into 6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidine-2,4-dione, [MH]+ 277. A solution of calcium chloride (4.94 g, 45 mmol) in water (100 ml) is added to a solution of 6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidine-2,4-dione (19.08 g, 69.0 mmol) in acetic acid (300 ml). Zinc dust (58.8 g, 900 mmol) is then added portionwise with external cooling. The reaction is stirred at room temperature for 1.5 hours, filtered through a celite plug and washed successively with ethanol and acetic acid. Evaporation of the combined filtrate and washings affords 6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt, [M−3H]− 243. Acetic anhydride (7.2 ml, 76.0 mmol) is added to a cooled (0° C.) suspension of 6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt (17.0 g, 69.0 mmol) in pyridine (260 ml). The reaction mixture is warmed to room temperature, stirred for 6 hours and the solvent evaporated. The residue is triturated with water and the solid collected by filtration and dried to afford N-[4-(6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, [MH]+ 289. Using the general procedure for Intermediate 1, this compound is converted into N-[4-(5,6-diamino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, [MH]+ 304.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[C:7](=[N:8][NH:9][CH:10]=3)[C:6]=2[CH:15]=1.[CH:16]([N:19]1[CH:23]=[N:22][N:21]=[C:20]1S(C)(=O)=O)([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[C:7](=[N:8][N:9]([C:20]4[N:19]([CH:16]([CH3:18])[CH3:17])[CH:23]=[N:22][N:21]=4)[CH:10]=3)[C:6]=2[CH:15]=1
Reactant: CC(C)n1cnnc1S(C)(=O)=O
Reactant: Brc1ccc2c(c1)-c1n[nH]cc1CCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)n1cnnc1-n1cc2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 150 °C
Yield: 43.2 %

Procedure:
To a microwave vial were charged 9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (200 mg, 0.755 mmol), 4-isopropyl-3-methanesulfonyl-4H-[1,2,4]triazole (143 mg, 0.755 mmol), cesium carbonate (246 mg, 0.755 mmol) and THF (2 mL). The reaction mixture was heated to 150° C. for 2 h then extracted with ethyl acetate (20 mL), washed with water (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 100% ethyl acetate in cyclohexane) to afford 9-bromo-2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (122 mg, 43%). LCMS RT=4.34 min, M+H+=374/376.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)NC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)N(C)C(=O)COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
(2-tert-Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.14 g; 0.54 mmol)(prepared as in example 33) was dissolved in methylene chloride (1 0 mL). 1-Hydroxy-7-azabenzotriazole (0.07 g; 0.54 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3-(1-naphthyl) propionamide (0.21 ; 0.54 mmol) was dissolved in methylene chloride (10 mL) and added. The reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (10 mL) was added. The reaction mixture was washed with water (30 mL), an aqueous solution of sodium hydrogen sulfate (10%; 20 mL) and an aqueous solution of sodium hydrogen carbonate (saturated; 20 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2×20 cm) using methylene chloride/ethyl acetate (1:1) as eluent to afford 0.27 g of (1,1-dimethyl-2-((N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamoyl)methoxy)ethyl)carbamic acid tert butylester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1.[CH3:34][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO>[CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:34])=[O:12])=[C:9]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (525 mg, 1.1615 mmol) was dissolved in methanol (20 ml), trimethylsilyl diazomethane (15.9 g, 10% solution in hexane, 13.9473 mmol) was added thereto under cooling with ice and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added acetic acid (2 ml) and the mixture was allowed to stand so as to decompose an excessive reagent. The reaction solution was concentrated to give the title compound (530 mg, 1.1373 mmol, 98%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:32]([O:39][CH2:40]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]1([CH2:16][C@H:15]([CH2:40][O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:14]([N:9]2[C@@H:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:22])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(CCC1CCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: ClCOCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](COCc1ccccc1)CC1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
To a solution of (4S)-benzyl-3-(3-cyclopentylpropanoyl)oxazolidin-2-one (42.4 g, 141 mmol) in dichloromethane (500 mL) at 0° C. under nitrogen was added titanium (IV) chloride (1 M in DCM, 155 mL, 155 mmol) in a slow steady stream. After 5 min, diisopropylethylamine (27 mL, 155 mmol) was added dropwise. After stirring at 0° C. for 1 h, benzyloxymethylchloride (TCI-America) (39 mL, 280 mmol) was added in a slow steady stream to the resulting titanium enolate, and the mixture was maintained at 0° C. for 3.5 h. The reaction mixture was then quenched with water (400 mL). The aqueous layer was extracted with dichloromethane (150 mL×2). The organic extracts were washed with saturated NaHCO3, were dried (MgSO4) and were evaporated. The residue was washed with ether (2×), and then was triturated with hexanes/ether to provide 2 crops of (4S)-3-((2R)-3-cyclopentyl-2-{[(phenylmethyl)oxy]methyl}propanoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one as a pale yellow solid (42.7 g, 72%). LCMS: (M+H)+: 422.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CO>[N:10]1([CH2:9][CH2:8][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:14][CH2:13][NH:12][C:11]1=[O:15]
Reactant: O=C1NCCN1CCCl
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=C1NCCN1CCN1CCNCC1
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
A mixture of piperazine (86 g, 1.0 mol), 1-(2-chloroethyl)-imidazolidin-2-one (74 g, 0.5 mol) and sodium carbonate (159 g, 1.5 mol) in ethanol (500 ml) was refluxed with stirring for 1.5 hours. A solution of 1-(2-chloroethyl)-imidazolidin-2-one (74 g, 0.5 mol) in methanol (75 ml) was then added in the course of 1.5 hours, at reflux temperature, whereupon the reaction mixture was refluxed for 18 hours. After cooling, the reaction mixture was filtered and evaporated in vacuo. The residue was dissolved in hot ethanol (100 ml), whereupon ethyl acetate (200 ml) was added. The crystals were filtered and dried to give 1-(2-(2-imidazolidinon-1-yl)ethyl)piperazine (60 g) mp. 136°-140° C. Additional 22 g could be obtained from the mother liquor.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=C)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.[N:15]1([C:21](=[O:34])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:25][CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:18]2[CH2:17][CH2:16][N:15]([C:21](=[O:34])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH:33]=[N:32][N:31]=[N:30]4)=[CH:27][CH:28]=3)[CH2:20][CH2:19]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: C=CCc1ccc(C#N)c(OC)c1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(CCN2CCN(C(=O)Cc3ccc(-n4cnnn4)cc3)CC2)ccc1C#N
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2-Methoxy-4-(prop-2-en-1-yl)benzonitrile (100 mg, 0.577 mmol) was dissolved in methanol (13 mL) and the resulting solution was cooled to −78° C. Ozone was bubbled through the solution until a blue color appeared (˜15 minutes). 1-(Piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride (178 mg, 0.577 mmol) was added, followed by sodium cyanoborohydride (363 mg, 5.77 mmol). After stirring the reaction mixture for ˜5 minutes 3 drops of acetic acid were added and the mixture was permitted to warm to rt and stir for 2 h. The reaction mixture was concentrated to dryness, dissolved in EtOAc (40 mL) and washed with brine, saturated NaHCO3 solution. The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue was then purified by mass directed HPLC to afford the title compound. LC/MS: [(M+1)]+=432.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH:7]=O)[CH:4]=[C:3]([CH:9]=O)[CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH3:29].[BH4-].[Na+].[OH-].[Na+]>CCOC(C)=O.CO>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH2:7][NH:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:4]=[C:3]([CH2:9][NH:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:2]=1
Reactant: CCCCNCCCNCCCN
Reactant: O=Cc1cc(C=O)cc(-c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCNCCCNCCCNCc1cc(CNCCCNCCCNCCCC)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[1,1′-Biphenyl]-3,5-dicarbaldehyde (0.66 g, 3.15 mmol) and MeOH (50 mL) were added to a round-bottom flask. To the solution was added N1-(3-aminopropyl)-N3-butylpropane-1,3-diamine (1.18 g, 6.31 mmol) and the reaction mixture was stirred at rt for 24 h. Sodium borohydride (0.48 g, 12.62 mmol) was added and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aq. NaOH (10%, 100 mL) and EtOAc (100 mL) were added and the reaction mixture stirred for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a clear oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[C:3]([C:4]([N:17]2[CH2:18][CH2:19][N:14]([CH:11]([CH3:13])[CH3:12])[CH2:15][CH2:16]2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)c1cccnc1Cl
Product: CC(C)N1CCN(C(=O)c2cccnc2Cl)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Step A of Example 9 using 2-chloro-nicotinic acid and 1-isopropyl-piperazine.
Reaction SMILES: [PH2](O)=O.C(N1CCCCC1)C.[CH2:12]=[CH:13][S:14]([O:17][C:18]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28])(=[O:16])=[O:15].I[CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[S:37]([C:40]1[C:45]([CH3:46])=[CH:44][C:43]([O:47][CH3:48])=[CH:42][C:41]=1[CH3:49])(=[O:39])=[O:38].C(B(CC)CC)C>C(Cl)Cl>[CH3:48][O:47][C:43]1[CH:44]=[C:45]([CH3:46])[C:40]([S:37]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]2[CH2:30][CH2:12][CH2:13][S:14]([O:17][C:18]2[C:19]([F:28])=[C:20]([F:27])[C:21]([F:26])=[C:22]([F:25])[C:23]=2[F:24])(=[O:16])=[O:15])(=[O:38])=[O:39])=[C:41]([CH3:49])[CH:42]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CI)c(C)c1
Reactant: C=CS(=O)(=O)Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCB(CC)CC
Agent: CCN1CCCCC1
Agent: O=[PH2]O
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(C)c1
Temperature: 0 °C
Reaction time: 0 h

Procedure:
1-Ethylpiperidine hypophosphite (1.184 g, 6.614 mmol) were weighed into the reaction flask under an inert gas, and methylene chloride (10 ml) was added. The solution was cooled with ice-water, and 2,3,4,5,6-pentafluorophenyl 1-ethylenesulfonate (0.218 g, 0.794 mmol) [Org. Lett.; 2002; 4(15); 2549-2551] and 2-(iodomethyl)-1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidine (0.28 g, 0.661 mmol) was added at 0° C. Triethylborane solution (0.03 ml, 1 mol/l) was added to the reaction mixture and compressed air was then passed through the mixture for 10 sec. After stirring for 5 min the addition of triethylborane solution-compressed air was repeated with the same amount. After thin layer chromatography control, the addition of triethylborane soln.-compressed air was repeated again with the same amount. The reaction mixture was washed with cooled water (10 ml) and cooled saturated sodium bicarbonate soln. (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether/methylene chloride (6:1:1) Yield: 50 mg (13%)
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1.[NH2:15][OH:16].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[N:15][OH:16])=[CH:10][C:5]=2[C:4]([CH3:14])([CH3:13])[O:3]1
Reactant: NO
Reactant: CC1(C)OB(O)c2ccc(C=O)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(O)c2ccc(C=NO)cc21
Reaction time: 3 h
Yield: 73.6 %

Procedure:
To a solution of 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (10 mg, 0.053 mmol) and NH2OH.HCl (4.4 mg, 0.063 mmol) in THF (4 mL) and H2O (1 mL) at rt was added NaOAc (6 mg, 0.074 mmol). The reaction mixture was stirred for 3 h and diluted with H2O. The mixture was extracted with EA and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to provide 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (8 mg; yield 74%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.23 (s, 1 H), 7.76 (d, J=7.6 Hz, 1 H), 7.55 (m, 2 H), 2.81 (s, 1 H,), 1.61 (s,6 H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5](I)=[C:6]([F:8])[CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[O:23][C:22]([Si](C(C)C)(C(C)C)C(C)C)=[N:21][CH:20]=2)O1>>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([C:19]2[O:23][CH:22]=[N:21][CH:20]=2)=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Reactant: Fc1cc(Br)cc(F)c1I
Product: Fc1cc(Br)cc(F)c1-c1cnco1

Procedure:
The title compound is prepared from 5-bromo-1,3-difluoro-2-iodo-benzene and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole following a procedure analogous to that described in Intermediate 27. LC (method 1): tR=1.18 min; Mass spectrum (ESI+): m/z=260 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>ClCCl>[C:14]1(=[O:19])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:17](=[O:18])[CH:16]=[CH:15]1
Reactant: CN(CCCCN)c1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: ClCCl
Product: CN(CCCCN1C(=O)C=CC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
N-(4-Aminobutyl)-N-methylaniline (7.2 g) was dissolved in dichloromethane (70 ml) and maleic anhydride (4 g) was added thereto. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off and then acetic anhydride (10 ml) was added. The resulting mixture was stirred at 100° C. for 5 hours. After concentration, an aqueous sodium bicarbonate was added to the residue to neutralize it. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (2:1) to obtain the desired compound (2.0 g) as yellow needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2.[NH:21]1[C:30]2[CH2:29][CH2:28][C:27](=O)[CH2:26][C:25]=2[CH:24]=[CH:23][C:22]1=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][CH:27]1[CH2:28][CH2:29][C:30]3[NH:21][C:22](=[O:32])[CH:23]=[CH:24][C:25]=3[CH2:26]1)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2
Reactant: NCCCNc1c2c(nc3cc(Cl)ccc13)CCCC2
Reactant: O=C1CCc2[nH]c(=O)ccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1ccc2c([nH]1)CCC(NCCCNc1c3c(nc4cc(Cl)ccc14)CCCC3)C2
Reaction time: 24 h
Yield: 36.6 %

Procedure:
To a mixture of N1-(6-Chloro-1,2,3,4-tetrahydro-acridin-9-yl)-propane-1,3-diamine (50 mg, 0.17 mmoL), 1,5,7,8-Tetrahydro-quinoline-2,6-dione (31 mg, 0.19 mmoL) in 5 mL methylene chloride, was added sodium triacetoxyborohydride (110 mg, 0.52 mmoL) and a catalytic amount of acetic acid. After stiring at room temperature for 24 h, the reaction was stopped by adding saturated sodium bicarbonate. The mixture was extracted with methylene chloride three times. The combined methylene chloride extract was dried, filtered and concentrated. Purification by column chromatography on silica gel column with 10% MeOH/1% ammonium hydroxide in methylene chloride provided the desired product (27.6 mg, 0.063 mmoL, 37%).
Reaction SMILES: C1(C)C=CC([N:7]2C(N)=CC(C3C=CC(N)=CC=3)=N2)=CC=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:7])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(-n2nc(-c3ccc(N)cc3)cc2N)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-tolyl)-3-(4-aminophenyl)-5-aminopyrazole (0.6 g, 2.27 mmol) in THF (20 mL) and H2O (8 mL) at room temperature was added 4-methoxybenzenesulfonyl chloride (0.94 g, 4.55 mmol) and potassium carbonate (0.95 g, 6.88 mmol). The mixture was stirred at room temperature overnight and was then partitioned between H2O (20 mL) and EtOAc (100 mL). The layers were separated and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparatory TLC, eluting with 2:1 hexanes/EtOAc to yield N-[4-5-amino-1-(4-methylphenyl)-1H-pyrazol-3-yl]phenyl]-4-methoxy benzenesulfonamide.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]([NH:6][CH2:7][C@@H:8]1[C@H:12]([OH:13])[CH2:11][NH:10][CH2:9]1)=[O:5].[CH:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[N:26]=2)[N:21]=[CH:20][C:19]=1[C:30]#[N:31])=[CH2:17]>C(O)C>[C:30]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:18]=1[CH2:16][CH2:17][N:10]1[CH2:11][C@@H:12]([OH:13])[C@@H:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]([F:2])([F:14])[F:15])[CH2:9]1)=[N:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)#[N:31]
Reactant: C=Cc1c(C#N)cnc2ccc(OC)nc12
Reactant: O=C(NC[C@H]1CNC[C@H]1O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: COc1ccc2ncc(C#N)c(CCN3C[C@H](CNC(=O)C(F)(F)F)[C@H](O)C3)c2n1
Temperature: 95 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
To 2,2,2-trifluoro-N-{[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}acetamide HCl (0.137 g, 0.552 mmol) was added EtOH (2.0 mL). 4-ethenyl-6-(methyloxy)-1,5-naphthyridine-3-carbonitrile (0.117 g, 0.552 mmol) was added to the mixture along with TEA (0.231 mL, 1.66 mmol) and the reaction was heated and stirred at 95 degrees C. for 18 hours, allowing the ethanol to evaporate. The solution was concentrated under reduced pressure and was chromatographed on silica gel to yield an oil (0.110 g, 47%). LCMS: m/z 424.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.[C:19]1([CH:25]2[N:29]([C:30]3[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=3)[N:28]=[C:27]([C:38]3[C:51]4[C:52]5=[C:53]6[C:48](=[CH:49][CH:50]=4)[CH:47]=[CH:46][CH:45]=[C:44]6[CH:43]=[CH:42][C:41]5=[CH:40][CH:39]=3)[CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1CCCCC1>C(O)C>[C:13]1([C:4]2[O:3][C:2]([CH:1]=[CH:34][C:33]3[CH:36]=[CH:37][C:30]([N:29]4[CH:25]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:26][C:27]([C:38]5[C:51]6[C:52]7=[C:53]8[C:48](=[CH:49][CH:50]=6)[CH:47]=[CH:46][CH:45]=[C:44]8[CH:43]=[CH:42][C:41]7=[CH:40][CH:39]=5)=[N:28]4)=[CH:31][CH:32]=3)=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(N2N=C(c3ccc4ccc5cccc6ccc3c4c56)CC2c2ccccc2)cc1
Reactant: CC1=CC(=C(C#N)C#N)C=C(c2ccccc2)O1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(C#N)=C1C=C(C=Cc2ccc(N3N=C(c4ccc5ccc6cccc7ccc4c5c67)CC3c3ccccc3)cc2)OC(c2ccccc2)=C1
Temperature: 75 °C

Procedure:
As shown in the following reaction 8, 0.24 g (1.0 mmol) of 2-(2-methyl-6-phenyl-pyran-4-ylidene)-malononitrile and 0.46 g (1.0 mmol) of 4-(5-phenyl-3-pyren-1-yl-4,5-dihydro-pyrazol-1-yl)benzaldehyde were added into 20 ml of ethanol, and 0.13 g (1.53 mmol) of piperidine was added thereto. The reaction solution was heated at 75° C. for 10 hours.