Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](B4OC(C)(C)C(C)(C)O4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.Br[C:27]1[CH:28]=[C:29]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)[CH:30]=[CH:31][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([C:31]4[CH:32]=[CH:27][CH:28]=[C:29]([C:33]5[N:37]=[C:36]([CH3:38])[O:35][N:34]=5)[CH:30]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1
Reactant: Cc1nc(-c2cccc(Br)c2)no1
Reactant: Cc1ccn2c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccn2c(-c3cccc(-c4cccc(-c5noc(C)n5)c4)c3)cnc2n1
Temperature: 90 °C

Procedure:
To a degassed solution of 7-methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]imidazo[1,2-a]pyrimidine (0.1 g, 0.29 mmol) in 1,4-dioxane (3 ml) was added 3-(3-bromophenyl)-5-methyl-[1,2,4]oxadiazole (0.142 g, 0.59 mmol) (prepared as described in WO 95/27692), potassium phosphate (189 mg, 0.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 15 μmol) and the mixture heated at 90° C. for 18 h. After cooling to ambient temperature the solvent was evaporated in vacuo and the residue stirred with 10% methanol in dichloromethane. The solid material was removed by filtration and the filtrate applied to two preparative TLC plates (silica gel) and eluted with 5% methanol in dichloromethane. The appropriate band was collected and processed, affording a solid which was recrystallised from dichloromethane/ethyl acetate/isohexane to give 7-methyl-3-[3′-(5-methyl-[1,2,4]oxadiazol-3-yl)biphenyl-3-yl]imidazo[1,2-a]pyrimidine as a cream coloured solid (32 mg): δH (400 MHz, CDCl3) 2.67 (3H, s), 2.68 (3H, s), 6.79 (1H, d, J 7), 7.60-7.80 (5H, m), 7.87 (1H, s), 7.92 (1H, m), 8.10 (1H, dd, J 7 and 1), 8.32 (1H, s), 8.52 (1H, d, J 7); m/z (ES+) 368 (M++H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:17]([CH:19]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20]1)=[O:18].CCOC(C)=O>C1COCC1.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]([CH:19]2[CH2:23][CH2:22][N:21]([C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:29]=3)[CH2:20]2)=[O:18])=[CH:3][CH:4]=1
Reactant: CON(C)C(=O)C1CCN(c2ncccn2)C1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)C1CCN(c2ncccn2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To a solution of 1,4-dibromobenzene (407.5 mg, 1.727 mmol) in THF (6 ml) was added n-BuLi (2.5 M in hexanes, 0.691 ml, 1.727 mmol) at −78° C. The mixture was stirred at the temperature for 30 minutes before the addition of a solution of the above amide (203.8 mg, 0.8636 mmol) in THF (4 ml). After stirring at −78° C. for 30 minutes, the mixture was warmed to room temperature for 1 hour. EtOAc (40 ml) and water (15 ml) was added to the reaction, followed by separation of the layers. The aqueous phase was extracted with EtOAc (15 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (40% acetone/hexanes) to furnish (4-bromo-phenyl)-(1-pyrimidin-2-yl-pyrrolidin-3-yl)-methanone (182.2 mg, 64%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.32 (d, J=6.4 Hz, 2H), 7.87 (d, J=12.0 Hz, 2H), 7.63 (d, J=12.0 Hz, 2H), 6.51 (t, J=6.4 Hz, 1H), 4.07 (m, 1H), 3.98 (m, 1H), 3.86 (m, 1H), 3.74 (m, 2H), 2.38 (m, 2H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH2:13]([O:15][C:16](=[O:24])[CH:17]([C:21](=O)[CH3:22])[C:18](=O)[CH3:19])[CH3:14].N1C=CC=CC=1>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[C:18]([CH3:19])=[N:12][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[C:21]=1[CH3:22])=[O:24])[CH3:14]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc([N+](=O)[O-])c2)c1C

Procedure:
Similar to Example 1, m-nitrophenylhydrazine hydrochloride (10 mmol, 1.9 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) were mixed in a 50% solution of pyridine in ethanol. A precipitate was formed in the reaction medium, and was collected by filtration. Analysis confirmed synthesis of the named product, m.p., 107.7° C.–109.2° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+](C)([O-])=O.[CH3:9][O:10][C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH:21]=[N:20][C:19]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:18]2)=[C:13]2[NH:29][CH:30]=[CH:31][C:12]=12.Cl[C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35]>C(Cl)Cl>[CH3:9][O:10][C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH:21]=[N:20][C:19]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:18]2)=[C:13]2[NH:29][CH:30]=[C:31]([C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35])[C:12]=12
Reactant: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]ccc12
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: COC(=O)C(=O)c1c[nH]c2c(-n3cnc(NC(=O)C(C)(C)C)n3)ncc(OC)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
To an oven-dried flask in ice bath was added AlCl3 (382 mg, 2.86 mmol), then CH2Cl2 (4 mL) was introduced at 0° C. Nitromethane (10.84 μL, 0.201 mmol) was added at that temperature. Ice bath was removed and the mixture was stirred at room temperature for 30 min. N-(1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)pivalamide (90 mg, 0.286 mmol) and methyl 2-chloro-2-oxoacetate (0.079 mL, 0.859 mmol) were added at 0° C. The reaction mixture was stirred for three hours at room temperature. The reaction mixture was quenched with ammonium acetate (8 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford methyl 2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (40 mg, 45%) as white solid.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[CH:7]2.[C:14](O)(=[O:16])[CH3:15]>C(OC(=O)C)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14](=[O:16])[CH3:15])[CH:8]=[CH:7]2
Reactant: Brc1ccc2cnccc2c1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C=Cc2cc(Br)ccc2C1
Temperature: 60 °C

Procedure:
Sodium borohydride (1.12 g, 29.6 mmol) is added portionwise to a cooled (0° C.) solution of 6-bromoisoquinoline [J Chem Soc Perkin Trans 2, 1998, 437] (1.544 g, 7.42 mmol) in acetic acid (10 ml) and acetic anhydride (3 ml). After heating at 60° C. for 4 hours, the mixture is cooled, evaporated and diluted with water. After adjustment to pH10 with potassium carbonate and extraction with ethyl acetate, the combined organic phases are washed twice with 0.5N HCl and brine, then dried over sodium sulphate. Evaporation affords 1-(6-bromo-1H-isoquinolin-2-yl)-ethanone, MH+ 253. Glyoxylic acid (0.812 g, 8.80 mmol) is added to mixture of 1-(6-bromo-1H-isoquinolin-2-yl)-ethanone (1.50 g, 5.90 mmol) in 6N HCl (20 ml). The reaction is heated at 100° C. for 2 hours, cooled to RT and washed with ethyl acetate. After evaporation, the residue is taken into methanol (20 ml), concentrated sulphuric acid (10 drops) is added and the mixture heated at reflux for 14 hours. After partial evaporation of the solvent, the resultant solid is collected by filtration, washed with methanol and dried to afford (6-bromo-isoquinolin-4-yl)-acetic acid methyl ester hydrochloride, MH+ 281. Lithium hydroxide hydrate (8.5 mg, 0.20 mmol) is added to a cooled (0° C.) solution of (6-bromo-isoquinolin-4-yl)-acetic acid methyl ester (50 mg, 0.18 mmol) in 3:1 THF-water (3 ml). After 1 hour the solvent is evaporated to afford (6-bromo-isoquinolin-4-yl)-acid lithium salt, MH+ 266.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH3:8])[S:5][CH3:6])#[N:2].ClC1C=CC=C(C(OO)=[O:17])C=1>CC(C)=O>[C:1]([NH:3][C:4]([S:5]([CH3:6])=[O:17])=[N:7][CH3:8])#[N:2]
Reactant: CN=C(NC#N)SC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: CN=C(NC#N)S(C)=O
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a stirred suspension of N-cyano-N',S-dimethylisothiourea (19.4 g) in acetone (700 ml) was added dropwise a solution of m-chloroperbenzoic acid (80% purity, 38.8 g) in acetone (120 ml) at 20°-25° C. After stirring for 1 hr. at the same temperature, the reaction mixture was cooled in an ice bath for 1 hr. and the precipitate was filtered and washed with acetone to give N-cyano-N'-methyl-methylsulfinylformamidine (13.65 g). Yield 62.8%, m.p. 115.5°-116° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:10]=1O)=[O:5])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:10]=1[Cl:22])=[O:5])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nnn(Cc2cc(Cl)cc(Cl)c2)c1O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnn(Cc2cc(Cl)cc(Cl)c2)c1Cl

Procedure:
Combine 1-(3,5-dichloro-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (1 eq) with PCl5 (2 eq) in toluene and heat at 40–50° C. until reaction is complete. Concentrate the mixture, treat with aqueous NaHCO3, and extract with Et2O. Dry the combined extracts over Na2SO4, concentrate, and purify by chromatography on silica gel. MS (ES) 334.0, 336.0 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([F:33])=[C:29]([CH:32]=1)[CH2:30]Br>O1CCCC1.C(Cl)Cl>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([F:33])=[C:29]([CH:32]=1)[CH2:30][O:17][CH2:16][CH2:15][CH2:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1CCCOCc1cc(Br)ccc1F
Temperature: -40 °C
Reaction time: 0.58 h
Yield: 49.9 %

Procedure:
3-[1-(t-Butoxycarbonyl)piperidin-2-yl]propanol (800 mg, 3.29 mmol) was taken up in tetrahydrofuran (17 ml), cooled to −40° C., and treated with potassium t-butoxide (1 M in tetrahydrofuran, 3.62 ml, 3.62 mmol). The resulting mixture was stirred at −40° C. for about 35 minutes, then cooled to −78° C. To this mixture was then added 5-bromo-2-fluorobenzyl bromide (881 mg, 3.29 mmol) as a solution in tetrahydrofuran (5 ml). The resultant yellow reaction mixture was slowly warmed to 0° C. and stirred for about four hours. The reaction mixture was diluted with methylene chloride and washed with 1 M potassium carbonate and brine. The organic fraction was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by high performance liquid chromatography, yielding 707 mg (50%) of the title intermediate as a clear oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([Cl:21])[CH:20]=1)[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:15]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:21][C:19]1[CH:20]=[C:12]([C:10]#[C:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:18]=1[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=1)[CH2:15]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(C(F)(F)F)cc1
Reactant: C#CCN1CCN(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)NC(C)C
Product: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(C(F)(F)F)cc2)C3=O)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
A mixture of 1-methyl-4-prop-2-ynyl-piperazine (0.122 mL, 0.79 mmol), 5-bromo-7-chloro-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.240 g, 0.6 mmol), PdCl2(PPh3)2 (0.023 g, 0.03 mmol), and CuI (0.006 g, 0.03 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-prop-1 ynyl)-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.250 g, 90%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.34 (s, 3H), 2.32-2.54 (m, 8H), 3.57 (s, 2H), 4.20 (s, 2H), 4.81 (s, 2H), 7.34 (s, 1H), 7.41-7.63 (m, 5H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[C:19]([CH3:24])=[N:20][O:21][C:22]=3[CH3:23])[CH:16]=2)[NH:11][C:10]1=[O:25])(=O)=O.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.O>C1COCC1>[CH3:24][C:19]1[C:18]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:25])[C:9]3([CH2:8][CH2:7][CH2:6][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: C1COCCN1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(CCCOS(C)(=O)=O)(c1ccccc1)C(=O)N2
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1-c1ccc2c(c1)C(CCCN1CCOCC1)(c1ccccc1)C(=O)N2
Temperature: 80 °C
Yield: 89.2 %

Procedure:
A mixture of compound 5-(3,5-dimethylisoxazol-4-yl)-3-(3-hydroxypropyl)-3-phenylindolin-2-one (0.72 g, 2.0 mmol), DIPEA (1.05 mL, 6.0 mmol), MsCl (250 mg, 2.2 mmol) in CH2Cl2 (20 mL) was stirred at 0° C. then gradually raised to RT overnight. The contents were diluted with CH2Cl2, washed with water (2×10 mL), and concentrated. The crude was purified with flash chromatography to afford compound 3-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)propyl methanesulfonate (575 mg, 65.3%). 1H NMR (400 MHz, DMSO-d6): δH 10.73 (s, 1H), 7.24-7.38 (m, 7H), 7.02 (d, J=8.0 Hz, 1H), 4.13-4.16 (m, 2H), 3.12 (s, 3H), 2.37 (s, 3H), 2.30-2.34 (m, 2H), 2.20 (s, 3H), 1.30-1.48 (m, 2H). To a stirred solution of 3-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)propyl methanesulfonate (440 mg, 1.0 mmol) in dry THF (10 mL) was successively added triethylamine (280 μl, 2.0 mmol) and morpholine (174 mg, 2.0 mmol) at room temperature. The reaction mixture was heated at 80° C. for 15 h and then water (10 mL) was added. The aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate and filtered. After concentration of the filtrate in vacuo, the residue was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH: 95/5) to afford compound (385 mg, 89.3%) as a white solid. 1H NMR (400 MHz, CDCl3): δH 7.88 (s, 1H), 7.28-7.39 (m, 5H), 7.14-7.16 (m, 1H), 7.08 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 3.76 (m, 4H), 2.45-2.55 (m, 5H), 2.37-2.39 (m, 4H), 2.22-2.29 (m, 5H), 1.54-1.55 (m, 2H). MS (ESI) m/e [M+1]+ 432.0.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([S:9][CH3:10])([CH3:8])[CH:5]=[N:6][OH:7].[CH3:11][N:12]([S:16][N:17]([CH3:19])[CH3:18])[C:13](F)=[O:14]>C1C=CC=CC=1.C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>[CH3:11][N:12]([S:16][N:17]([CH3:19])[CH3:18])[C:13]([O:7][N:6]=[CH:5][C:4]([CH3:8])([S:9][CH3:10])[CH3:3])=[O:14]
Reactant: CSC(C)(C)C=NO
Reactant: CN(C)SN(C)C(=O)F
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CSC(C)(C)C=NOC(=O)N(C)SN(C)C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A mixture of 3.3 g powdered potassium hydroxide, 0.1 g dicyclohexyl-18-crown-6, and 6.7 g (0.05 mole) of 2-methyl-2-(methylthio)propionaldehyde oxime in 200 ml of benzene was stirred 1 hr. at room temperature. N-methyl-N-(dimethylaminosulfenyl)carbamoyl fluoride (8.0 g, 0.05 mole) was then added, and the mixture was stirred overnight at room temperature. The solution was extracted three times with water, dried (MgSO4), and concentrated in vacuo. The oily residue was recrystallized from n-hexane to give 10 g (75.5 percent yield) of 2-methyl-2-(methylthio)propionaldehyde O-[N-methyl-N-(dimethylaminosulfenyl)carbamoyl]oxime, m.p. 48°-50° C.
Reaction SMILES: [CH2:1]([N:8]([C:12](Cl)=[O:13])[C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I.[CH3:16][S:17][C:18](=[NH:24])[NH:19][N:20]=[C:21]([CH3:23])[CH3:22]>C(N(CC)CC)C>[CH2:1]([N:8]1[C:12](=[O:13])[NH:24][CH:18]([S:17][CH3:16])[N:19]([N:20]=[C:21]([CH3:23])[CH3:22])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=N)NN=C(C)C
Reactant: O=C(Cl)N(Cc1ccccc1)C(=O)Cl
Agent: I
Solvent: CCN(CC)CC
Product: CSC1NC(=O)N(Cc2ccccc2)C(=O)N1N=C(C)C

Procedure:
Analogously to Example 1, N-benzyl-bis-(chlorocarbonyl)-amine and acetone-S-methyl-isothiosemicarbazone hydroiodide, with addition of triethylamine, yielded 1-benzyl-3-isopropylideneamino-4-methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione as a pale brown powder of melting point 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[C:13]([NH:14][NH:15][C:16]([NH:18][CH3:19])=S)=[CH:12][C:10](=[O:11])[N:9]([CH2:20][CH2:21][CH3:22])[C:7]1=[O:8].CO>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[C:13]2[NH:14][N:15]=[C:16]([NH:18][CH3:19])[C:12]=2[C:10](=[O:11])[N:9]([CH2:20][CH2:21][CH3:22])[C:7]1=[O:8]
Reactant: CCCn1c(=O)cc(NNC(=S)NC)n(Cc2cccc(Cl)c2)c1=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2cccc(Cl)c2)c1=O
Yield: 71.8 %

Procedure:
A solution of 1-(3-chlorobenzyl)-6-(4-methylthiosemicarbazido)-3-propyluracil (3.81 g, 10 mM) in DMF (40 ml) was stirred at 100° C. for 20 hours. To the reaction solution was added 50% methanol (20 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol gave colorless crystals (2.49 g, 72%), m.p. 263°-265° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:12])[CH:3]=1.[CH3:13][C:14]1([CH3:28])[C:19]2[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:27])[O:15]1>>[CH3:13][C:14]1([CH3:28])[C:19]2[CH:20]=[C:21]([C:2]3[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:12])[CH:3]=3)[CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:27])[O:15]1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: CC(=O)Nc1ccc(Br)cc1F
Product: CC(=O)Nc1ccc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)cc1F

Procedure:
Prepared according to procedure B from 4′-bromo-2′-fluoroacetanilide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. Off white solid, mp 245-247° C. 1H-NMR (DMSO-d6) δ 10.3 (s, 1H), 9.79 (s, 1H), 7.95 (t, 1H, J=8.4 Hz), 7.56-7.63 (m, 3H), 7.47 (dd, 1H, J=1.64, 8.47 Hz), 6.95(d, 1H, J=8.9 Hz), 2.1 (s, 3H), 1.67 (s, 6H); MS+APCI [M+H]+m/z 329. Anal. Calc. For C18H17N2 FO3; C, 65.85; H, 5.22; N, 8.53. Found: C, 65.46; H, 5.24; N, 8.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH:9]=[CH2:10].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:32]C)C=C4)N(CC2)C1.S([O-])([O-])=O.[Na+].[Na+].[OH2:75]>CC(O)(C)C.O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C@H:9]([OH:32])[CH2:10][OH:75]
Reactant: C=Cc1cc(I)ccc1Cl
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: OC[C@@H](O)c1cc(I)ccc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-Chloro-4-iodo-2-vinylbenzene (2.43 g, 9.19 mmol) was dissolved in t-BuOH/H2O (1:1, 60 mL) and then cooled to 0° C. AD-mix-α (11 g) was slowly added. The reaction slowly warmed to rt overnight. Sodium sulfite (11 g) was added and the solution stirred at rt. After 3 h, H2O and CH2Cl2 were added and the organic layer isolated. The aqueous layer was washed with CH2Cl2 (3×) and then the combined organic extracts were combined, dried (Na2SO4), concentrated, and purified by Biotage chromatography (0%-100% EtOAc/hexanes) to afford 2.6 g of (1S)-1-(2-chloro-5-iodophenyl)ethane-1,2-diol as an oil that will solidify over time (95%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.94 (d, J=2.27 Hz, 1 H) 7.55 (dd, J=8.34, 2.02 Hz, 1 H) 7.07 (d, J=8.34 Hz, 1 H) 5.17 (dd, J=7.58, 3.03 Hz, 1 H) 3.90 (dd, J=11.24, 3.16 Hz, 1 H) 3.54 (dd, J=11.24, 7.71 Hz, 1 H) 3.49 (s, 2 H).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[CH3:17][O:18][CH2:19][CH2:20][C@@H:21]1[NH:26][CH2:25][CH2:24][N:23]([C:27]2[C:36]3[CH:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[S:33][C:32]=3[NH:31][C:30]3[CH:40]=[CH:41][CH:42]=[CH:43][C:29]=3[N:28]=2)[CH2:22]1>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[NH3:23].[CH3:17][O:18][CH2:19][CH2:20][C@@H:21]1[N:26]([CH3:1])[CH2:25][CH2:24][N:23]([C:27]2[C:36]3[CH:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[S:33][C:32]=3[NH:31][C:30]3[CH:40]=[CH:41][CH:42]=[CH:43][C:29]=3[N:28]=2)[CH2:22]1
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)cc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)cc32)CCN1C
Product: N
Reaction time: 5 h
Yield: 149.5 %

Procedure:
Add sodium triacetoxyborohydride (0.15 g, 0.71 mmol) and aqueous formaldehyde (37% w/w, 0.05 mL, 0.62 mmol) to a solution of (S)-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-2-isopropyl-4H-3-thia-4,9-diaza-benzo[f]azulene (0.18 g, 0.47 mmol) in dichloroethane (12 mL) and stir. After 5 hours, dilute with a saturated aqueous solution of sodium bicarbonate, and separate the layers. Extract the aqueous layer with dichloromethane (3×), combine organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to an oil (0.24 g). Purify the oil by flash chromatography, eluting with a gradient of a 5% solution of 2M ammonia in methanol, in dichloromethane (0-100% over 30 minutes), and then with a 5% solution of 2M ammonia in methanol, in dichloromethane to give the title compound (0.14 g, 74%): mass spectrum (APCI, m/e): 399 (M+1); NMR (1H, 300 MHz, DMSO-d6) δ 7.63 (s, 1H), 6.79 (m, 3H), 6.66 (m, 1H), 6.30 (s, 1H), 3.70 (m, 2H), 3.35-3.28 (m, 2H), 3.20 (s, 3H), 2.99-2.88 (m, 2H), 2.80-2.60 (m, 2H), 2.29-2.05 (m, 5H), 1.66 (m, 2H), 1.17 (d, 6H, J=7.5 Hz).
Reaction SMILES: C[Al](C)C.C([Al:9]([CH2:14][CH:15]([CH3:17])C)[CH2:10][CH:11]([CH3:13])[CH3:12])C(C)C.[Al].[OH2:19].[C:20]1([CH3:26])C=CC=CC=1>>[CH3:26][CH:20]1[CH2:17][CH2:15][CH2:14][Al:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[O:19]1
Reactant: Cc1ccccc1
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: O
Agent: C[Al](C)C
Agent: [Al]
Product: CC(C)C[Al]1CCCC(C)O1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a 1000 ml flask thoroughly purged with nitrogen, equipped with a stirrer and a reflux condenser, 100 ml of toluene which had been dehydrated and deoxygenated was introduced. Subsequently, 0.72 g (10 mmol) of trimethylaluminium and 1.96 g (10 mmol) of triisobutylaluminium were diluted in 50 ml of toluene in one of two dropping funnels, and toluene containing saturated water was introduced to the other funnel. The mixed aluminium solution and the toluene containing saturated water were fed to the flask at 30° C. over 3 hours in such a manner that an equimolar amount of the A1 and the H2O were fed at the same time. After the feeding was completed, the mixture was heated to 50° C., and a reaction was carried out for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, thereby giving 1.9 g of methylisobutylalumoxane as a white solid. The white solid thus obtained was dissolved in toluene, and the solution was subjected to a measurement by 27A1-NMR. As a result, a spectrum having a chemical shift at 174 ppm with a half band width of 5844 Hz was obtained.