Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[H-].[Na+].Br[CH2:17][C:18]([CH3:29])=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1.O>CN(C=O)C>[CH:26]([C:23]1[CH:22]=[CH:21][C:20]([CH:19]=[C:18]([CH3:29])[CH2:17][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:25][CH:24]=1)([CH3:28])[CH3:27]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(=Cc1ccc(C(C)C)cc1)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(C(C)C)cc1)COc1cc(C)c(NC=O)c(C)c1C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of N-(4-hydroxy-2,3,6-trimethylphenyl)formamide (3.00 g, 16.7 mmol) in DMF (30 mL) was added sodium hydride (a 60% liquid paraffin dispersion, 0.74 g, 18.4 mmol) under nitrogen atmosphere at 0° C., and the mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added 1-(3-bromo-2-methyl-1-propenyl)-4-isopropylbenzene synthesized in Reference Example 108 (4.66 g, 18.4 mmol) and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution and the product was twice extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain 3.70 g (yield 63%) of the title compound. Melting point: 153-155° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCC(CC)CC)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic ethyl ester (4.8 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4 g (87%); Semi solid; MS: 460 (M+H)+
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:32]=[C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:35]2[CH:36]=[CH:31][CH:32]=[C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[CH:34]=2)=[CH:16][CH:17]=1
Reactant: CNC(=O)Cc1cccc(Br)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNC(=O)Cc1cccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
A solution of (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11), 2-(3-bromophenyl)-N-methyl -acetamide (0.21 g, Example 12a)), 2M aqueous sodium carbonate (0.57 ml) and tetrakis(triphenylphosphine)palladium (0) (0.1 g) in toluene (5 ml) and ethanol (2 ml) was heated at 100° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml). The suspension was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ether and water. The aqueous layer was neutralised and extracted with dichloromethane (2×50 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as an oil (0.15 g).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[O:13]1[CH:17]=[CH:16][N:15]=[C:14]1[NH2:18].C1COCC1>C(#N)C>[BrH:1].[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:15]1[CH:16]=[CH:17][O:13][C:14]1=[NH:18]
Reactant: O=C(CBr)c1ccc(F)cc1F
Reactant: Nc1ncco1
Solvent: CC#N
Solvent: C1CCOC1
Product: Br
Product: N=c1occn1CC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.8 %

Procedure:
A round bottom flask was charged with 2-bromo-1-(2,4,-difluorophenyl)ethanone (74.8 g, 318 mmol), oxazol-2-amine (GL Synthesis, 22.3 g, 265 mmol), THF (400 mL), and ACN (660 mL). The resulting mixture was stirred at ambient temperature for about 20 h. The resulting suspension was filtered and the solids were washed with Et2O (150 mL) and dried under reduced pressure to give 1-(2,4-difluorophenyl)-2-(2-iminooxazol-3(2H)-yl)ethanone hydrobromide (51.4 g, 61%). A portion of this material (19.8 g, 62.0 mmol) was added in 3 g portions over about 2 h to a flask charged with polyphosphoric acid (124.4 g) at about 80° C. The thick solution was mixed at about 80-90° C. for about 22 h. The reaction mixture was slowly transferred to a mixture of water (150 mL) and 30% aqueous NaOH (150 mL) at about 5-10° C. The pH of the resulting slurry was adjusted to about 5.4 by addition of 30% aqueous NaOH and the product was isolated by filtration. The wet cake was rinsed with warm water (3×150 mL) and dried under vacuum to give the title compound (9.5 g, 69%). MS m/z 221.1 (M+H)+ FIA(APCI)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.[Br:23]N1C(=O)CCC1=O>CN(C)C=O.C(Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][C:3]=1[CH2:9][Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)ccc1Br
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CBr)c1
Temperature: 5 °C

Procedure:
4-Bromo-3-methylphenol(4.49 g, 24.0 mmol), t-butyldimethylsilyl chloride (5.43 g, 36.0 mmol) and imidazole (4.90 g, 22.0 mmol) in N,N-dimethylformamide (30 ml) were stirred at room temperature for 16 h. Water (100 ml) was added and the products extracted with ethyl acetate. Drying (MGSO4), evaporation to dryness under reduced pressure and purification by flash chromatography using hexane as eluent gave the crude silylated phenol (4.16 g, 57%), to this crude product (4.16 g, 13.77 mmol) was added N-Bromosuccinimide (2.70 g, 15.15 mmol) and carbon tetrachloride (100 ml). The mixture was heated to reflux over a 150 W light bulb for 2 h. Cooling to 5° C., filtration, evaporation of the filtrate to dryness under reduced pressure and purification by flash chromatography using hexane as eluent gave the title compound as a colourless oil: δH (CDCl3) 0.20 [6H, s, Si(CH3)2 ], 0.97 (9H, s, t bu), 4.50 (2H, s, CH2Br), 6.63 (1H, dd, J 2.9 and 8.5 Hz, 4-H), 6.91 (1H, d, J 2.9 Hz, 5-H), 7.37 (1H, d, J 8.5 Hz, 3-H); m/z (E.I.) 382 (M+, 5%), 380 (M+, 10%), 378 (M+, 5%); (Found: M+, 377.9642. C13H20Br2OS; requires M, 377.9652).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:13][CH2:14][C:3]1=2.[H][H]>N.CO.[Ni]>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:13][CH2:14][C:3]1=2
Reactant: [H][H]
Reactant: Cn1c2c(c3ccccc31)CN(CCC#N)CC2
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cn1c2c(c3ccccc31)CN(CCCN)CC2
Yield: 100 %

Procedure:
A mixture of intermediate (15) (0.06 mol) in NH3/CH3OH (400 ml) was hydrogenated at 20° C. with Raney Nickel (3 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated, yielding 14.6 g of 1,3,4,5-tetrahydro-5-methyl-2H-pyrido[4,3-b]indole-2-propanamine (intermediate 16).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:34]([F:37])([F:36])[F:35])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][C:29](=[O:31])[NH:28][C:27](=[O:32])[CH2:26]4)=[O:24])=[C:19]([CH3:33])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:38][C:39]([F:44])([F:43])[CH2:40][CH2:41]I.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:34]([F:35])([F:36])[F:37])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][C:29](=[O:31])[N:28]([CH2:41][CH2:40][C:39]([F:44])([F:43])[F:38])[C:27](=[O:32])[CH2:26]4)=[O:24])=[C:19]([CH3:33])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)CCI
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)NC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)N(CCC(F)(F)F)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed 4-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]piperazine-2,6-dione (200 mg, 0.36 mmol, 1.00 equiv), 1,1,1-trifluoro-3-iodopropane (163.5 mg, 0.73 mmol, 2.00 equiv), N,N-dimethylformamide (10 mL), potassium carbonate (100.7 mg, 0.73 mmol, 2.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 60 mL of H2O. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 4×40 mL of brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The crude product (85 mg) was purified by Prep-HPLC. This resulted in 39.5 g (17%) of 4-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]-1-(3,3,3-trifluoropropyl)piperazine-2,6-dione as a white solid. (ES, m/z): [M+CH3CN]+ 685.0; 1H NMR (300 MHz, CDCl3): δ 7.85 (s, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.28-7.23 (m, 1H), 4.79 (s, 2H), 4.19-4.10 (m, 5H), 3.75 (d, J=17.4 Hz, 1H), 2.49-2.41 (m, 2H), 2.32 (s, 3H)
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](=O)[NH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[S:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[C:6]2[C:7]([Cl:15])=[N:8][CH:9]=[C:10]([CH3:11])[C:5]=2[S:4][CH:3]=1
Reactant: Cc1c[nH]c(=O)c2c(Br)csc12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cnc(Cl)c2c(Br)csc12
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of Example 277B (10,25 g, 42.1 mmol) in POCl3 (50 mL) was stirred at reflux for 2 hours, cooled to room temperature, diluted with ice water, and stirred vigorously resulting in a precipitate which was collected by filtration. The filter cake was further purified by silica gel chromatography on silica gel with dichloromethane to provide 7.14 g (64% yield) of the desired product. MS (ESI(+)) m/e 261.9, 263.9 (M+H)+.
Reaction SMILES: Cl[C:2]([N:4]=[C:5]=[O:6])=[O:3].[OH:7][NH:8][C:9](=[O:20])[N:10]([CH:17]([CH3:19])[CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(Cl)Cl>[CH3:19][CH:17]([N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:9]([N:8]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[O:7]1)=[O:20])[CH3:18]
Reactant: CC(C)N(C(=O)NO)c1ccccc1
Reactant: O=C=NC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)n1oc(=O)[nH]c1=O)c1ccccc1
Reaction time: 2 h
Yield: 32.3 %

Procedure:
A solution of chlorocarbonyl isocyanate (5.0 g, 0.047 mol) was added dropwise to a slurry of the title compound of Step A (9.2 g, 0.047 mol) and triethylamine (5.3 g, 0.052 mol) in 200 mL of THF while maintaining the reaction temperature below 30° C. using an ice bath. After 2 hours, TLC showed the presence of starting material. Another 0.5 g of chlorocarbonyl isocyanate was added, and the reaction mixture was stirred for another hour. At that point, TLC showed still the presence of starting material. The reaction mixture was filtered to, remove solids, and the filtrate was stripped to dryness and then extracted with 1N HCl and ether. Upon evaporation of volatiles, a gummy product was obtained which was taken into methylene chloride and potassium carbonate solution. Solids were collected by a filtration, washed with methylene chloride and air dried. The solids (5.3 g) were found to be the potassium salt of the title compound. The basic aqueous filtrate was acidified with concentrated HCl and extracted with methylene chloride to afford 4 g of the title compound, an intermediate useful for the preparation of the compounds of the present invention, melting at 116-7° C. From the methylene chloride used to wash the solids, 2.6 g of the title compound of Step A was recovered. This represented a 71.7% conversion. The combined yield was therefore 96% based on the 71.7% conversion.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[C:5](=O)([O-])[O-].[K+].[K+].[NH2:11][C:12]1[C:16]([C:17]#[N:18])=[C:15]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]2)[N:14]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:13]=1[C:41]([O:43]CC)=O>N1C=CC=CC=1>[Cl:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:14]1[C:13]2[C:41](=[O:43])[N:2]([CH3:1])[C:3]([S:4][CH3:5])=[N:11][C:12]=2[C:16]([C:17]#[N:18])=[C:15]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:20]1
Reactant: CCOC(=O)c1c(N)c(C#N)c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n1Cc1ccccc1Cl
Reactant: O=C([O-])[O-]
Reactant: CN=C=S
Agent: [K+]
Solvent: c1ccncc1
Product: CSc1nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3ccccc3Cl)c2c(=O)n1C
Temperature: 130 °C

Procedure:
Under a nitrogen atmosphere, methyl isothiocyanate (71 μl) and potassium carbonate (143 mg) were added to a solution (2.5 ml) of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(2-chlorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (260 mg) in pyridine, and the resulting mixture was stirred with heating at 130° C. for 3 hours. After the reaction solution was cooled to 25° C. and then concentrated under reduced pressure, toluene (5 ml) was added thereto and the resulting mixture was concentrated under reduced pressure. This procedure was repeated three times. To the resulting residue was added acetone (2.5 ml), and the resulting mixture was cooled to 0° C. Methyl iodide (65 μl) was added dropwise thereto and the resulting mixture was warmed to 25° C. and stirred for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1) to obtain the title compound (250 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:20](=O)[CH2:21][CH2:22][CH2:23][CH3:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.C(OCC)(=O)C>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([NH:1][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:10]=[CH:9][CH:8]=2)[CH2:4][N:5]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CCCCC=O
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCNc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.3 %

Procedure:
To a stirred solution of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.52 g, 2.0 mmol) in DMF (10 ml) was added pentanal (0.26 g, 3.0 mmol), acetic acid (0.24 g, 4.0 mmol), and sodium triactoxyborohydride (0.85 g, 4.0 mmol). The reaction mixture was stirred at room temperature for 6 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml), washed with H2O (3×00 ml), brine (1×100 ml), and dried over MgSO4. The solvent was evaporated and the residue was partially purified by chromatography (ethyl acetate/hexane, 75:25) to give an off-white solid which was slurried in ethyl acetate and filtered to give 0.14 g (21%) of product as a white solid: mp 244-246° C.; 1H NMR (DMSO-d6) δ 11.00 (s, 1H), 7.28 (t, J=7.7 Hz, 1H), 6.92 (d, J=7.3 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 5.54 (t, J=5.3 Hz, 1H), 5.12 (dd, J=5.1 and 13.2 Hz, 1H), 4.24 (d, J=17.2 Hz, 1H), 4.13 (d, J=17.2 Hz, 1H) 3.15-3.07 (m, 2H), 3.00-2.86 (m, 1H), 2.65-2.59 (m, 1H), 2.39-2.23 (m, 1H), 2.08-1.99 (m, 1H), 1.61-1.57 (m, 2H), 1.41-1.32 (m, 4H), 0.89 (t, J=6.8 Hz, 3H); 13C NMR (DMSO-d6) δ 172.83, 171.19, 168.86, 143.74, 132.00, 129.15, 126.42, 111.66, 109.86, 51.46, 45.69, 42.68, 31.20, 28.80, 28.21, 22.79, 21.96, 13.89; Anal. Calcd. For C18H23N3O3: C, 65.63; H, 7.04; N, 12.76. Found: C, 65.69; H, 7.22; N, 12.55.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5](C1NC=CN=1)(C1NC=CN=1)=[S:6].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]2[N:30]=[C:29]([NH:31][CH2:32][CH2:33][C:34]3[NH:35][CH:36]=[N:37][CH:38]=3)[C:28]([Br:39])=[CH:27][N:26]=2)=[CH:20][CH:19]=1.CN(C=O)C>C1COCC1>[Br:39][C:28]1[C:29]([NH:31][CH2:32][CH2:33][C:34]2[NH:35][CH:36]=[N:37][CH:38]=2)=[N:30][C:25]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[S:6])=[CH:23][CH:22]=2)=[N:26][CH:27]=1
Reactant: NC1CC1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: S=C(Nc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1)NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
Cyclopropyl amine (0.275 mmole) was dissolved in THF (2 ml) and thiocarbonyl diimidazole (0.28 mmole) was added. The reaction was stirred at room temperature overnight and N2-(4-Amino-phenyl)-5-bromo-N4-[2-(3H-imidazol-4-yl)-ethyl]-pyrimidine-2,4-diamine (0.26 mmole) was added as a solution in THF (3 ml) and DMF (1 ml) and the reaction was stirred overnight. After removal of the solvents under reduced pressure the crude product was purified by flashmaster chromatography (dichloromethane: MeOH 9:1) to yield 12.5 mg of 1-(4-{5-Bromo-4-[2-(3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl)-3-cyclopropyl-thiourea. ESI-MS: 474.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C@@H:10]2[CH2:15][O:14][C:13]3=[N:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][N:12]3[CH2:11]2)=[N:6][CH:7]=1.[C:22]([Si](C)(C)C)#[CH:23]>CN(C=O)C.CCN(CC)CC.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)I>[C:22]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C@@H:10]2[CH2:15][O:14][C:13]3=[N:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][N:12]3[CH2:11]2)=[N:6][CH:7]=1)#[CH:23]
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(Br)cn1)C2
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc(CO[C@@H]2COc3nc([N+](=O)[O-])cn3C2)nc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
A mixture of bromide 59 (see Example 21) (0.310 g, 0.873 mmol), PdCl2(PPh3)2 (33 mg, 0.047 mmol) and copper iodide (18 mg, 0.095 mmol) in DMF (4 mL) and Et3N (4 mL) was purged with N2. Ethynyltrimethylsilane (0.61 mL, 4.3 mmol) was added and the mixture was stirred in a sealed tube at 50° C. for 18 h, and then partitioned between EtOAc and water. The residue was dissolved in THF (20 mL), cooled to 0° C. and treated with TBAF (1M in THF, 1.8 mL), and then the solution was stirred for 2 h. Removal of the solvent gave a residue which was partitioned between EtOAc and water. Column chromatography of the organic portion on silica gel using gradient elution (0-5% MeOH:EtOAc) gave (6S)-6-[(5-ethynyl-2-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (97) (0.178 g, 68%) as a tan solid: mp 135-136° C.; 1H NMR [(CD3)2SO] δ 8.61 (d, J=1.6 Hz, 1H), 8.02 (s, 1H), 7.90 (dd, J=8.0, 2.2 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 4.78 (d, J=13.8 Hz, 1H), 4.74 (d, J=13.8 Hz, 1H), 4.69 (dt, J=12.0, 2.6 Hz, 1H), 4.49 (d, J=12.0 Hz, 1H), 4.40 (s, 1H), 4.30-4.35 (m, 2H), 4.25 (dd, J=13.7, 3.5 Hz, 1H). Anal. (C14H12N4O4) C, H, N.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]([F:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]4)=[CH:30][CH:29]=3)[N:21]=2)[CH2:16][CH2:15]1>C(Cl)Cl.CN(C=O)C>[C:40]([N:37]1[CH2:38][CH2:39][N:34]([C:31]2[CH:32]=[CH:33][C:28]([NH:27][C:22]3[N:21]=[C:20]([N:17]4[CH2:16][CH2:15][CH:14]([NH:13][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:19][CH2:18]4)[C:25]([F:26])=[CH:24][N:23]=3)=[CH:29][CH:30]=2)[CH2:35][CH2:36]1)(=[O:42])[CH3:41]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(N)CC4)n3)cc2)CC1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(NC(=O)CC#N)CC4)n3)cc2)CC1
Reaction time: 0.5 h
Yield: 14.7 %

Procedure:
To a suspension of cyanoacetic acid (85 mg, 1.00 mmol) in CH2Cl2 (2 mL) (containing 2 drops of DMF) at room temperature, oxalyl chloride (0.082 mL, 0.94 mmol) was added. Gas evolved and suspension became clear. It was then stirred for 30 min. To the above solution cooled in an ice bath, a solution of 1-(4-(4-(4-(4-aminopiperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (70 mg, 0.17 mmol) and TEA (0.478 mL, 3.43 mmol) in DMF (2 mL) was added drop wise. The mixture was then stirred at room temperature for 3 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (12 mg). MS 481.5 (M+H); UV 204.7, 266.3 nm
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:31]1([CH3:43])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[S:39](Cl)(=[O:41])=[O:40]>>[CH3:43][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[S:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])(=[O:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)c(C)c1

Procedure:
2,4,6-Trimethyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2-mesitylenesulfonylchloride (52 mg, 0.239 mmol) according to general method 3 to give 50 mg of a purple solid. MS (posES-FIA) m/z=Found: 515.3. Calcd 515.17. 1H-NMR δ 7.74 (d, 2H); 7.63-7.46 (m, 3H), 6.92 (s, 2H), 6.74-6.55 (m, 3H), 3.27-3.20 (m, 8H), 2.35 (s, 6H), 2.25 (s, 3H).