Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24].[NH4+].[Cl-]>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[Cl:20])[OH:24]
Reactant: O=Cc1ccccc1Cl
Reactant: Brc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1ccncc1Br
Temperature: -70 °C
Reaction time: 4 h

Procedure:
Add n-BuLi (48.2 mL, 77.1 mmol, 1.6N in hexane) to a −70° C. solution of diisopropylamine (10.8 mL, 77.1 mmol) in THF (130 mL) in a flame-dried flask. After 30 minutes add 3-bromo-pyridine (2.48 mL, 25.7 mmol) dropwise and stir the mixture at −70° C. After 4 hours, add 2-chloro-benzaldehyde (2.95 mL, 26.2 mmol) dropwise, stir at −70° C. After 1 hour, warm reaction to RT, quench reaction with dropwise addition of 60 mL saturated NH4Cl solution. Extract with Et2O (3×), wash with brine, dry the combined organic layers over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-40% EtOAc/hexane to afford the title compound: MS(IS) 299 (M+1); TLC (50% EtOAc/hexanes) Rf=0.23.
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[NH:4][C:3](=[O:8])[NH:2]1.C[Si](C)(C)N[Si](C)(C)C.[CH2:18]([NH2:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>S([O-])([O-])(=O)=O.[NH4+].[NH4+].O1CCOCC1>[CH2:18]([NH:28][C:5]1[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C1CONC(=O)N1
Reactant: CCCCCCCCCCN
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CCCCCCCCCCNC1=NC(=O)NOC1
Yield: 91.1 %

Procedure:
A solution of 5.0 g (0.043 mole) of 6H-1,2,4-oxadiazin-3,5(2H,4H)-dione, 0.025 g of ammonium sulfate, 35 ml of hexamethyldisilazane and 19.5 g (0.123 mole) of n-decylamine in 200 ml freshly distilled dry dioxane is refluxed for 17 hours. After cooling, the dioxane and hexamethyldisilazane are removed in vacuo and the syrupy residue is dried on a vacuum pump for 2 hours. The resulting semi-solid residue is triturated with 100 ml of petroleum ether and filtered to yield approximately 10 g (92 percent) of 5-decylamino-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: Cl.[CH2:2]1[O:12][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[CH:17]=[N:16][N:15]=1.C(N(CC)CC)C>C(O)C>[CH2:4]1[O:5][C:6]2([CH2:11][CH2:10][N:9]([C:17]3[C:18]4[C:23](=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=4)[CH:14]=[N:15][N:16]=3)[CH2:8][CH2:7]2)[O:12][CH2:2][CH2:3]1
Reactant: C1COC2(CCNCC2)OC1
Reactant: COc1cc2cnnc(Cl)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2cnnc(N3CCC4(CC3)OCCCO4)c2cc1OC
Yield: 71.5 %

Procedure:
4-Piperidone trimethylene ketal hydrochloride (20 g), 1-chloro-6,7-dimethoxyphthalazine (10 g), triethylamine (50 ml) and ethanol (300 ml) were heated together under reflux for 70 hours. The resulting mixture was evaporated in vacuo and the residue was partitioned between chloroform (2×100 ml) and water (60 ml). The chloroform extracts were combined, dried (MgSO4) and evaporated in vacuo to give a crude brown oil which on trituration with ethyl acetate (100 ml) at boiling point gave 1-[6,7-dimethoxyphthalazin-1-yl]piperid-4-one trimethylene ketal (11 g), m.p. 194°-6°. A second crop of the product (3 g) was obtained by evaporating the ethyl acetate trituration liquors.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[OH:6][CH2:7][C:8](=O)[CH3:9]>C(O)C.O=[Pt]=O>[NH:1]([CH:8]([CH3:9])[CH2:7][OH:6])[CH:2]([CH3:5])[CH2:3][OH:4]
Reactant: CC(N)CO
Reactant: CC(=O)CO
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(CO)NC(C)CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Aminopropan-1-ol (5 g, 66.57 mmol) and 1-hydroxypropan-2-one (5.77 g, 77.89 mmol) were dissolved in ethanol (115 mL) and 50 mg of PtO2 was added. The reaction mixture was stirred at 50 psi H2 pressure at room temperature for 24 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was used without further purification in the following step. Crude yield: 79%. 1H NMR (400 MHz, CDCl3) δ 4.45 (bs, 2H), 3.42-3.43 (m, 1H), 3.16-3.22 (m, 4H), 2.65-2.69 (m, 2H) 0.87-0.91 (m, 6H): LCMS m/z 133.99 [M+H]+, tR: 4.077 min.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.C([Li])CCC.C([O:21][B:22](OC(C)C)[O:23]C(C)C)(C)C>O1CCCC1>[F:9][C:7]1([F:10])[O:6][C:5]2[CH:11]=[CH:12][C:2]([B:22]([OH:23])[OH:21])=[CH:3][C:4]=2[O:8]1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)OC(F)(F)O2
Reaction time: 5 h
Yield: 117.9 %

Procedure:
A solution of the title compound of Step A (15 g, 63 mmol) in tetrahydrofuran (approximately 200 mL) was cooled to -78° C. under a nitrogen atmosphere. A solution of n-butyllithium (40 mL of a 1.6M solution in hexanes) was added dropwise while maintaining the reaction temperature below -55° C. The reaction mixture was stirred at -78° C. for 20 min before a solution of triisopropylborate (29.4 mL, 127 mmol) in tetrahydrofuran (approximately 50 mL) was added dropwise over 30 min. The reaction was allowed to come to room temperature while stirring for 5 h. The reaction mixture was then partitioned between diethyl ether and 1M hydrochloric acid solution. The organic layer was separated, dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound of Step B as a brown oil (15 g) which was used without further purification.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][CH:23]3[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21][CH2:22]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: Nc1ccc(-n2cnnn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(-n3cnnn3)cc2)CC1
Reaction time: 20 h
Yield: 98.3 %

Procedure:
To a solution of 4-(1H-tetrazol-1-yl)aniline (2 g, 12.4 mmol) and 1-tert-butoxycarbonyl-4-piperidone (3.71 g, 18.6 mmol) in THF (15 ml) were added acetic acid (1.42 ml, 24.8 mmol) and sodium triacetoxyborohydride (4 g, 18.6 mmol), successively, under ice cooling, and the mixture was stirred for 20 hours. To the mixture was added sodium triacetoxyborohydride (4 g, 18.6 mmol), and the mixture was stirred at room temperature for 20 hours. To the mixture was added saturated aqueous solution of sodium hydrogencarbonate (100 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate (100 ml), and the organic layer was washed with saturated sodium chloride solution (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the concentrate was added diisopropyl ether (20 ml), and the resulting precipitates were collected by filtration to give the titled compound (4.2 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH3:12][CH2:13]O>>[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4]1
Reactant: CCO
Reactant: NC1CCCC(C(=O)O)C1
Agent: Cl
Product: CCOC(=O)C1CCCC(N)C1

Procedure:
Conc. HCl (1 mL) was added to a solution of 3-aminocyclohexanecarboxylic acid (500 mg, 3.49 mmol) in EtOH (20 mL) and stirring was continued at reflux temperature for 3 h. The reaction mixture was concentrated under reduced pressure to afford the crude, which was washed with 10% aqueous NaHCO3 solution, extracted with DCM, dried over anhydrous sodium sulphate to afford 300 mg of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.[CH2:42]([CH2:44][NH2:45])[OH:43]>C(Cl)Cl>[OH:43][CH2:42][CH2:44][NH:45][C:30]([C:29]1[CH:33]=[CH:34][C:26]([C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:13]3[C:12]([NH:11][CH:8]([CH3:9])[CH3:10])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:19][CH2:20]2)=[O:25])=[N:27][CH:28]=1)=[O:31]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: NCCO
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCO)cn2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Triethylamine (0.54 ml) was added to 6-[1-[3-(isopropylamino)-2-pyridyl]piperazine-4-yl-carbonyl]nicotinic acid (1.3 g) in methylene chloride (40 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (0.45 ml) at 0° C.˜5° C., the reaction mixture was stirred at 5° C. for 2 hours. With the addition of triethylamine (0.6 ml) and ethanolamine (0.25 ml), the mixture was stirred at 5° C.˜10° C. for 3 hours. The solution was washed with aqueous sodium bicarbonate and water twice. The separated organic layer was concentrated under reduced pressure. The concentrated residue was treated with ether for crystallization and recrystallized with ethanol and isopropyl ether to give a desired compound of 1.2 g (yield: 83%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:22])[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: CCOC(=O)c1cc2cccc(N(CCOC)S(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of ethyl 7-[(2-methoxyethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.54 g), 2N aqueous sodium hydroxide solution (2.2 mL), tetrahydrofuran (4 mL) and methanol (4 mL) was stirred at 50° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.46 g, yield 92%) as colorless crystals. melting point 216-217° C.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][C:13]1[S:17][C:16]2=[N:18][CH:19]=[C:20]([CH:21]=[O:22])[N:15]2[C:14]=1[CH3:23].[Cl-].[NH4+]>CCOCC>[CH3:12][C:13]1[S:17][C:16]2=[N:18][CH:19]=[C:20]([CH:21]([CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[OH:22])[N:15]2[C:14]=1[CH3:23]
Reactant: Cc1sc2ncc(C=O)n2c1C
Reactant: BrCCCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1sc2ncc(C(O)CCCc3ccccc3)n2c1C
Yield: 31.7 %

Procedure:
Magnesium (0.29 g) in ether was treated with 1-bromo-3-phenylpropane (2.38 g) and reacted for 5 hours. Solid 2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxaldehyde (Formula A-6) (0.72 g) was added and the viscous mixture was reacted for 1.5 hours. The thick suspension was diluted with ether and poured into cold 5% ammonium chloride solution. The mixture was extracted with ethyl acetate, the extract was dried and evaporated to a semi-crystalline residue (1.6 g). The residue, containing unreacted 2,3-Dimethylimidazo[2,1-b]thiazole-5-carboxaldehyde (Formula A-6), was triturated with ether, filtered and the filter cake (0.50 g) was recrystallized from acetonitrile to yield pure 2,3-Dimethyl-α-(3-phenylpropyl)imidazo-[2,1-b]thiazole-5-methanol (Formula A-9) (0.38 g), m.p. 167-169°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=1)=[O:5])[CH3:2].Cl.[F:24][C:25]([F:37])([F:36])[C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][NH:31][CH2:32]2)=[O:27].N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:31]3[CH2:32][CH:33]4[N:28]([C:26](=[O:27])[C:25]([F:36])([F:37])[F:24])[CH:29]([CH2:35][CH2:34]4)[CH2:30]3)=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(Cl)c(F)cc2c1=O
Reactant: O=C(N1C2CCC1CNC2)C(F)(F)F
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CC4CCC(C3)N4C(=O)C(F)(F)F)c(F)cc2c1=O
Temperature: 60 °C
Yield: 22.1 %

Procedure:
A mixture of 653 mg (2 mmoles) 1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-7-chloro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester and 732 mg (3 mmoles) 8-trifluoroacetyl-3,8-diazabicyclo[3.2.1]octan,hydrochloride and 985 mg (6.48 mmoles) 1,8-diazabicyclo[5.4.0] undec-7-ene in 30 mL acetonitrile was heated at 60° C. for 72 hours. The solution was cooled and evaporated to dryness. The residue was worked up with dichloromethane and water. The organic layer was dried over magnesium sulfate and evaporated to give an oil. Purification was achieved by silicagel column chromatography to obtain 220 mg of 7-(8-trifluoroacetyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-1-(1,1-dimethylethyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester. MP 205° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10](Cl)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:17][C:16](=[O:24])[CH:15]=1>>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:15]2[C:16](=[O:24])[O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:14]=2[OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCCC1CCCCC1
Reactant: O=c1cc(O)c2ccccc2o1
Product: O=c1oc2ccccc2c(O)c1CCCCC1CCCCC1

Procedure:
The title compound was prepared from 4-cyclohexylbutyryl chloride and 4-hydroxycoumarin following the same procedure used in Example 13, m.p. 160°-161° C.; NMR (CDCl3) δ0.82 (m, 2H), 1.15 (m, 5H), 1.38 (m, 2H), 1.51-1.66 (m, 8H), 2.62 (t, 2H), 7.21 (bs, 1H), 7.26-7.34 (m, 2H), 7.53 (m, 1H), 7.87 (dd, 1H).
Reaction SMILES: C(OC(=O)C)(=O)C.O[CH:9]([C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1)[CH:10]1[C:23](=[O:24])[N:14]2[C:15]3[C:20]([C:21]([CH3:22])=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3>N1C=CC=CC=1>[CH3:22][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[C:23](=[O:24])[C:10](=[CH:9][C:25]3[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:11][CH2:12][C:13]=12
Reactant: Cc1ncccc1C(O)C1CCc2c(C)c3ccccc3n2C1=O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1ncccc1C=C1CCc2c(C)c3ccccc3n2C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (2.24 g) was added to a solution of 8,9-dihydro-7-[(hydroxy)(2-methylpridin-3-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (1.35 g, a mixture of the isomers A and B) in pyridine (20 ml). After being stirred at 60° C. for 2 hours, the solution was evaporated in vacuo. The residue was diluted with chloroform, washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.27 g) were dissolved in toluene (30 ml). The solution was stirred at 60° C. for 2 hours and evaporated in vacuo. The residue was crystallized from ethyl acetate to give 8,9-dihydro-10-methyl-7-[(2-methylpyridin-3-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (0.92 g).
Reaction SMILES: [O:1]=C1CN(CC([O-])=O)C(=O)N1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[CH2:18][N:19]1[C:23](=[O:24])[C:22](=[O:25])[N:21]([CH2:26][C:27]([OH:29])=[O:28])[C:20]1=S)([O-:14])=[O:13].Cl>C(O)(=O)C>[OH:25][CH:22]1[N:21]([CH2:26][C:27]([OH:29])=[O:28])[C:20](=[O:1])[N:19]([CH2:18][C:17]2[CH:31]=[CH:32][CH:33]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:23]1=[O:24]
Reactant: O=C(O)CN1C(=O)C(=O)N(Cc2cccc([N+](=O)[O-])c2)C1=S
Reactant: O=C([O-])CN1CC(=O)NC1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)N(Cc2cccc([N+](=O)[O-])c2)C(=O)C1O
Reaction time: 2 h

Procedure:
The above-prepared dioxoimidazolidine-1-acetate product of paragraph (2) (15 g) was suspended in a mixed solvent of acetic acid and hydrochloric acid and the mixture was heated to reflux with stirring for two hours. Then the mixture was concentrated in vacuo, ether-chloroform was added thereto. The crystals were dislodged from the wall of the reaction flask with a spatula. The solid was washed with ether and recrystallized from a mixed solvent of ethanol and water to give 8.1 g of 5-hydroxy-3-(3-nitrobenzyl)-2,4-dioxoimidazolidine-1-acetic acid [Compound 15]. The melting point, MS, IR, NMR, and elementary analysis for the compound were:
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:16][CH:15]=1>CN(C=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[O:4]
Reactant: CC(C)S(=O)(=O)Nc1ccc(N)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)Nc1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 115 °C
Yield: 23.2 %

Procedure:
Isatoic anhydride (0.690 g, 4.20 mmol) was added to a solution of N-(4-aminophenyl)propane-2-sulfonamide (0.910 g, 4.20 mmol) in DMF (15 mL) and heated at 115° C. overnight. The mixture was concentrated in vacuo and purified by flash chromatography on silica gel, eluting with 6% MeOH in CH2Cl2. Further purification was effected by reverse phase chromatography, eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. The desired fractions were collected, basified, and extracted with EtOAc to afford 2-amino-N-(4-(1-methylethylsulfonamido)phenyl)benzamide (0.325 g, 23%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][OH:7])[N:3]=[N:2]1.N1C=CN=C1.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:17]([O:7][CH2:6][C:4]1[N:3]=[N:2][NH:1][CH:5]=1)([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1c[nH]nn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1c[nH]nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a solution of (1H-1,2,3-triazol-4-yl)methanol (30 g, 200 mmol) in DCM (160 mL) was added imidazole (20.4 g, 300 mmol) followed by TBDMS-Cl (33.3 g, 220 mmol) as a solid in portions. After stirring at rt for 16 h, the reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (500 mL) and washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-hexanes, 5-30%) to afford the title compound (30.2 g, 71%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:15]([OH:17])=[O:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30](O)[CH2:31][OH:32]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:15]([OH:17])=[O:16])[CH2:9][CH2:10][C:11]2([O:32][CH2:31][CH2:30][O:14]2)[CH2:12][CH2:13]1
Reactant: OCCO
Reactant: O=C1CCC(C(=O)O)(c2ccccc2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C1(c2ccccc2F)CCC2(CC1)OCCO2

Procedure:
1-(2-Fluorophenyl)4-oxocyclohexane-1-carboxylic acid (D3, 16.36 g, 69 mmol) was stirred with toluene-4-sulphonic acid hydrate (0.50 g, 3 mmol) and 1,2-ethanediol (35 ml) at reflux in toluene (500 ml), removing the immiscible 1,2-ethanediol/water distillate via a Dean-Stark trap until the distillate was homogenous. The solution was then evaporated, dissolved in ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (19.94 g, quantitative) as an amber syrup, contaminated with some unidentified materials (NMR).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([CH3:15])=O>>[CH2:18]([O:17][C:12](=[O:16])[C@H:13]([CH3:15])[NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)[CH3:19]
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1ccc2ccccc2c1
Product: CCOC(=O)[C@H](C)Nc1ccc2ccccc2c1

Procedure:
Following reductive amination General Procedure AA above and using 2-aminonaphthalene (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared as a solid having a melting point of 52-56° C. The reaction was monitored by silica gel tlc (Rf=0.50 in 25% EtOAc/hexanes). Purification was by flash chromatography with silica gel using 25% EtOAc/hexanes as the eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH2:38][CH3:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:36][CH2:37][CH2:38][CH3:39])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: CCCCBr
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: CCCCOc1ccc(OC)c2c1CCN(CC(=O)NCc1ccccn1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with butyl bromide
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[NH2:8][C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N(Cc4ccccc4)Cc4ccccc4)nc4ccccc43)nc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(N)nc4ccccc43)nc21
Temperature: 70 °C
Yield: 76 %

Procedure:
To a flask of 2-(1-((2-(2-(dibenzylamino)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (125 mg) in Ethanol (5.4 mL) was added 10% Palladium on Carbon (0.2 g) and Acetic acid (83 uL). The flask was purged with a nitrogen balloon and then placed under a Hydrogen balloon. The reaction was heated at 70° C. for 48 hours. The reaction was filtered thru celite and the celite cake was rinsed with a mixture of 1% acetic acid in methanol several times. The solvent was concentrated to dryness to give 70 mg of crude 2-(1-((2-(2-amino-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol, 70 mg of which was added to HATU (105 mg), DIPEA (0.12 mL) and acetic acid (24 uL) in DMF (0.8 mL). Upon completion, the reaction was diluted with Ethyl acetate and extracted with water. The organic layer was dried, filtered and concentrated to give crude product. The crude was purified via reverse phase HPLC to afford 11.5 mg of 517 as a white solid. MS (Q1) 548.3 (M)+