Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Br:26][C:27]1[C:37]2[N:36](C)[C:35](=[O:39])[C:34]([CH3:41])([CH3:40])[N:33]=[C:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[F:48])[C:31]=2[CH:30]=[C:29]([N+:49]([O-:51])=[O:50])[CH:28]=1>>[Br:26][C:27]1[C:37]2[NH:36][C:35](=[O:39])[C:34]([CH3:41])([CH3:40])[N:33]=[C:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[F:48])[C:31]=2[CH:30]=[C:29]([N+:49]([O-:51])=[O:50])[CH:28]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Br)c21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Br)c2NC1=O

Procedure:
From 21.8 g (0.054 mol) of 9-bromo-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in paragraph (c) of Example 1, 9-bromo-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 180° (ether/petroleum ether).
Reaction SMILES: [C:1]([C:3]1([C@H:8]([NH:10][S@](C(C)(C)C)=O)[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[ClH:17]>CO>[ClH:17].[NH2:10][C@@H:8]([C:3]1([C:1]#[N:2])[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:9]
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)C1(C#N)CCCC1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)C1(C#N)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-2-Methyl-propane-2-sulfinic acid [(R)-1-(1-cyano-cyclopentyl)-ethyl]-amide (1.96 g, 8.07 mmol) was dissolved in MeOH (16 mL) and HCl (4.0 M in 1,4-dioxane, 4.0 mL, 16.0 mmol) was added. The reaction mixture was stirred at room temperature for 30 min then concentrated to give 1-((R)-1-amino-ethyl)-cyclopentanecarbonitrile hydrochloride as an off-white solid which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(OB(OC(C)C)OC(C)C)(C)C.[Li]CCCC.Cl[C:27]1[N:32]=[N:31][C:30]([NH:33][CH2:34][C:35]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)([CH3:37])[CH3:36])=[CH:29][CH:28]=1.P(C(C)(C)C)(C(C)(C)C)(C(C)(C)C)=O.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1.C1(C)C=CC=CC=1.C1COCC1>[F:44][C:41]1[CH:40]=[CH:39][C:38]([C:35]([CH3:37])([CH3:36])[CH2:34][NH:33][C:30]2[N:31]=[N:32][C:27]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:28][CH:29]=2)=[CH:43][CH:42]=1
Reactant: Brc1ccccn1
Reactant: CC(C)(CNc1ccc(Cl)nn1)c1ccc(F)cc1
Agent: [Pd]
Agent: CC(C)(C)P(=O)(C(C)(C)C)C(C)(C)C
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)(CNc1ccc(-c2ccccn2)nn1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 6.2 %

Procedure:
To a 25 mL round bottom flask was added 2-bromopyridine (500 mg, 3.2 mmol, 1.0 equiv), triisopropylborate (654 mg, 3.5 mmol, 1.1 equiv), and an 80% toluene/THF mixture (16 mL). The mixture was cooled to −78° C. After stirring for 10 min, n-BuLi (1.7 mL, 3.48 mmol, 1.1 equiv of a 2.0 M/hexanes solution) was slowly added over an hour. After the addition was complete, the reaction mixture was stirred for 30 min and allowed to warm to rt and stirred overnight. The reaction was then concentrated at 100° C. and dried in vacuo for 2 h. To 100 mg of this crude solid in a microwave vial was added 6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (70 mg, 0.25 mmol), Pd2 dba3 (10 mg, 0.011 mmol), PO(tBu)3 (5 mg, 0.030 mmol), potassium fluoride (43 mg, 0.75 mmol), and dioxane (0.75 mL). The reaction was degassed with nitrogen for 5 minutes and then heated in a microwave reactor at 160° C. for 15 min. The reaction was then concentrated, dissolved in EtOAc (25 mL), washed with water, dried over Na2SO4, filtered, concentrated, and purified by reverse phase column chromatography to give 5 mg of N-(2-(4-fluorophenyl)-2-methylpropyl)-6-(pyridin-2-yl)pyridazin-3-amine as a white solid. m/z=323.1 [M+H]+.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[N:22]([CH3:24])[CH:21]=[C:20]2[CH:25]=O.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[N:22]([CH3:24])[CH:21]=[C:20]2[CH2:25][NH:6][CH3:5]
Reactant: Cn1cc(C=O)c2cccc(F)c21
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2c(F)cccc12
Yield: 72 %

Procedure:
According to the procedure of Preparation 11 (c), except substituting 7-fluoro-1-methyl-1H-indole-3-carboxaldehyde (0.23, 1.3 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.18 g, 72%) was prepared as a viscous oil: MS (ES) m/e 193 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10]O)[C:5]=2[CH:6]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[Br-].[Li+].[OH-].[K+].Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:10][C:7]2[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[NH:9][CH:8]=2)[CH2:22][CH2:21]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: OCc1c[nH]c2ccccc12
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Br-]
Solvent: CCO
Product: COc1ccccc1N1CCN(Cc2c[nH]c3ccccc23)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
One mole (147 g) of indole-3-carbinol and one mole (192 g) of 1-(2-methoxyphenyl)piperazine were dissolved in 1.5 liters of ethanol 60%. One mole (87 g) of lithium bromide and 0.1 mole (5.6 g) of potassium hydroxide were added, then the reaction medium was heated at reflux under stirring for 24 hours. After the reaction medium had cooled to 60° C., hydrochloric acid was added until persistence of an acidic pH. Then 189 g of the dihydrochloride salt of the title product was allowed to crystallize by cooling at 0° C. overnight, producing a global yield of 59% (m.p. 188°-190° C. with decomposition.)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:15]=1)([O-])=O>[Pd].C1COCC1>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:15]=1
Reactant: CC(C)(C)OC(=O)n1cc(Cn2ccc3c([N+](=O)[O-])cccc32)c2cccnc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(Cn2ccc3c(N)cccc32)c2cccnc21
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A round-bottom flask was charged with 3-[(4-nitro-1H-indol-1-yl)methyl]-1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridine (510 mg, 1.3 mmol), Pd/C (50 mg, 10%) and THF (30 mL). The mixture was then stirred under a hydrogen atmosphere for 2 h, filtered, and concentrated under reduced pressure to afford 3-[(4-amino-1H-indol-1-yl)methyl]-1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridine (470 mg).
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[CH:16]=2)[O:11]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][CH2:9][C@H:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=3)[CH:16]=2)[O:11]1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CNC(=O)OC(C)(C)C)O3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CN)O3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
To a solution of methyl 4-((2R)-2-{[(tert-butoxycarbonyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl) benzoate (Example 18, 0.94 g, 2.37 mmol) in 5 mL 1,4-dioxane was added 1 mL of 4M hydrochloric acid in 1,4-dioxane dropwise. The resulting solution was allowed to stir at room temperature for 16 hours, followed by concentration in vacuo. At this point, diethyl ether was added and the solid was collected to provide 587 mg of product as a white solid. m/z=298.2 [MH+].
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6](=[O:16])[CH2:5]1.[CH3:17][C:18]1([CH3:42])[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:21]([CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:20][O:19]1>CN(C=O)C>[CH3:3][N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]([CH2:30][C@@H:21]2[CH2:20][O:19][C:18]([CH3:17])([CH3:42])[N:22]2[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C:6](=[O:16])[CH2:5]1
Reactant: CN1CC(=O)Nc2ccccc2C1=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(=O)N(C[C@@H]2COC(C)(C)N2C(=O)OC(C)(C)C)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.3 %

Procedure:
1.1 g of sodium hydride dispersion (60%) are suspended in 50 ml of DMF. 5.23 g of 4-methyl-3H-1,4-benzodiazepine-2,5(1H, 4H)-dione are added thereto so that the temperature does not exceed 35° C. and the mixture is stirred at room temperature for 90 minutes. Subsequently, a solution of 5.3 g of t-butyl (S)-2,2-dimethyl-4-(p-tolylsulfonyloxymethyl)-3-oxazolidinecaboxylate (Example 6a) in 50 ml of DMF is added thereto and the mixture is stirred at 50° C. overnight. The reaction mixture is evaporated and the residue is taken up in ethyl acetate, washed with water and dried. After evaporation of the solvent the residue is purified over silica gel with ethyl acetate/hexane (1:1). There are obtained 1.85 g of t-butyl (R)-(2,3,4,5-tetrahydro-4-methyl-2,5-dioxo-1H-1,4-benzodiazepin-1-ylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[CH3:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(C)ccc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-methyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 314.1 ([M−H]−).
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:18][CH:17]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:31]1([C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:31]1([C:41]2[CH:46]=[CH:45][C:44]([C:2]3[C:3]4[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=4)[C:9]([C:16]4[CH:17]=[CH:18][C:19]([C:22]5[O:23][C:24]6[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=6[N:26]=5)=[CH:20][CH:21]=4)=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:43][CH:42]=2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Brc1c2ccccc2c(-c2ccc(-c3nc4ccccc4o3)cc2)c2ccccc12
Reactant: OB(O)c1ccc(-c2cccc3ccccc23)cc1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc2c(-c3ccc(-c4c5ccccc5c(-c5ccc(-c6nc7ccccc7o6)cc5)c5ccccc45)cc3)cccc2c1
Yield: 95.1 %

Procedure:
In a 50 mL three-neck flask, 0.97 g (2.2 mmol) of 2-[4-(10-bromo-9-anthryl)phenyl]benzoxazole, 0.57 g (2.3 mmol) of 4-(1-naphthyl)phenylboronic acid, 0.46 g (4.3 mmol) of sodium carbonate, 15 mL of toluene, 3 mL of ethanol, and 3 mL of water were placed. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. To the mixture, 35 mg (0.030 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was stirred under nitrogen stream at 100° C. for 18 hours. After a certain period, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extracted solution and the organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and the organic layer was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a solid. The solid was purified by silica gel column chromatograghy (toluene:hexane=2:1) and recrystallized with toluene/hexane, giving 1.2 g of the target white powder in a yield of 94%.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]1([P:14]([OH:16])[OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[CH2:18][NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C>[C:20]([NH:19][CH2:18][P:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:16])[OH:15])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OP(O)c1ccccc1
Reactant: O=C(NCO)c1ccccc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(NCP(=O)(O)c1ccccc1)c1ccccc1
Yield: 72.7 %

Procedure:
43.2 g (0.424 mol) of acetic anhydride were cooled to 10° C. A solution of 28.2 g (0.2 mol) of benzenephosphonous acid in 40 ml acetic acid were then added dropwise at 15° C., with stirring and cooling. After this, 30.2 g (0.2 mol) of N-hydroxymethylbenzamide were added in portions in the course of 10 minutes at 15° C., with cooling. After this, the cooling was removed, during which process the internal temperature rose to 35° C. After this, the mixture was refluxed for 3 hours and subsequently cooled. 175 ml of water were then added; during this process, the temperature rose to 35° C. The mixture was refluxed again, and finally cooled again, with stirring. After crystallisation, a total of 40 g (73% of theory) of benzoylaminomethylphenylphosphinic acid of a melting point of 158°-160° C. were obtained. CHNP analysis revealed:
Reaction SMILES: N1CCCCC1.[CH3:7][C:8]1[N:9]=[CH:10][NH:11][C:12]=1[N+:13]([O-:15])=[O:14].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O.CN(C=O)C>CC(O)C>[N+:13]([C:12]1[NH:11][CH:10]=[N:9][C:8]=1/[CH:7]=[CH:21]/[C:17]1[S:16][CH:20]=[CH:19][CH:18]=1)([O-:15])=[O:14]
Reactant: O=Cc1cccs1
Reactant: Cc1nc[nH]c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=[N+]([O-])c1[nH]cnc1/C=C/c1cccs1
Temperature: 100 °C
Yield: 67.8 %

Procedure:
Piperidine (1.7 g, 0.02 mol) was added to a suspension of 4-methyl-5-nitroimidazole (5 g, 0.04 mol) and 2-thiophenecarboxaldehyde (22 g, 0.2 mol) and heated at 100° C. for 15 hours. After cooling, DMF (5 mL) and IPA (15 mL) were added and the precipitate filtered from solution and washed with IPA (50 mL) to leave the product as a yellow solid (6.0 g, 69%). δH (DMSO-d6) 13.56 (1H, bs, NH), 7.90 (1H, s), 7.66 (1H, d, J=16.4), 7.66 (1H, d, J=5.0), 7.40 (1H, d, J=16.4), 7.35 (1H, d, J=3.6), 7.15 (1H, dd, J=3.6, 5.0).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Br)[CH:16]=1.C(OCC)C.O>CN(C)C=O>[Br:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:21][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: BrCc1cccc(CBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
0.57 g of potassium phthlimide was suspended in 20 ml of dimethylformamide, and 2.42 g of α,α'-dibromo-m-xylene was added. The mixture was stirred overnight at room temperature, and then ethyl ether and water were added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=10/1] to give 0.52 g of N-(3-bromomethylbenzyl)phthalimide as a white crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40].C(N(CC)CC)C>ClCCl>[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[S:39]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:12][CH:13]=1)(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(O)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(OS(=O)(=O)c5cccc(Cl)c5Cl)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.4 %

Procedure:
A solution containing cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol (100 mg, 0.245 mmol), 2,3-dichlorobenzenesulfonyl chloride (180 mg, 0.735 mmol) and triethylamine (0.34 mL, 2.45 mmol) in dichloromethane (8 mL) was stirred at ambient temperature for 17 h. Additional dichloromethane was added (20 mL) and the reaction was washed with brine (10 mL), saturated aqueous NaHCO3 (10 mL), dried (Na2SO4) and concentrated under reduced pressure to afford cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl 2,3-dichloro-1-benzenesulfonate as a white solid (135 mg, 90%); RP-HPLC 11.787 min, 97% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z (MH+)=616.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(S)cc1
Reactant: Fc1ccc(I)c(Br)c1
Product: Fc1ccc(Sc2ccc(F)cc2Br)cc1

Procedure:
Prepared from 4-fluoro-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1.O=S(Cl)[Cl:19]>C(Cl)Cl>[Cl:19][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(CCl)ccn1

Procedure:
tert-butyl (4-(hydroxymethyl)pyridin-2-yl)carbamate (600 mg, 2.679 mmol) was first treated with SOCl2 (3 ml) in CH2Cl2 (5 ml) at rt for 2 hrs. The solvent was removed to get a crude tert-butyl (4-(chloromethyl)pyridin-2-yl)carbamate. Then following General Procedure A, the title compound (667 mg, 68%) was prepared from 2-amino-4-chlorobenzenethiol (641 mg, 4.019 mmol), K2CO3 (1.8 g, 13.39 mmol) in DMF (20 ml).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH2:5]([O:7][C:8]([C:10]1N=C(Br)N2[C:22]3[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=3)[N:16]([CH3:27])[C:15](=[O:28])[C:14]=12)=[O:9])[CH3:6]>>[CH2:5]([O:7][C:8]([C:10]1[N:1]=[C:2]([SH:3])[N:4]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([F:25])([F:24])[F:26])=[CH:20][CH:21]=3)[N:16]([CH3:27])[C:15](=[O:28])[C:14]=12)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1nc(Br)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Reactant: NC(N)=S
Product: CCOC(=O)c1nc(S)n2c1c(=O)n(C)c1cc(C(F)(F)F)ccc12
Temperature: 25 °C
Yield: 43.8 %

Procedure:
To an ethanolic solution (200 ml) of 1-bromo-5-methyl-4-oxo-7-trifluoromethyl-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (1.8 g) was added thiourea (0.4 g). The mixture was refluxed on a steam bath for two hours. After cooling to room temperature, the precipitate was collected, taken up in chloroform and put through a short silica gel dry column (5% methanol in chloroform as eluant). From column, the product was isolated as a white solid (0.7 g, 44% yield). Recrystallized from acetonitrile, m.p. 282° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([OH:13])=O)[CH:8]=[CH:9][CH:10]=2)[N:6]=1.Cl.Cl.[NH2:16][C@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@H:17]([NH:16][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]3[O:3][C:2]([CH3:1])=[N:6][C:5]=13)=[O:13])[CH2:18]2
Reactant: Cc1nc2c(C(=O)O)cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.5 %

Procedure:
A mixture of 2-methylbenzoxazole-4-carboxylic acid (75 mg, 0.42 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (84 mg, 0.42 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg, 0.84 mmol) and 1-hydroxybenzotriazole (114 mg, 0.84 mmol) in DMF (4 mL) was stirred at room temperature for 5 min, then triethylamine (0.22 mL, 1.68 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-methylbenzoxazole-4-carboxamide (39 mg, 33%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.37 (d, J=7.0 Hz, 1H), 8.14 (dd, J=7.5, 1.0 Hz, 1H), 7.60 (dd, J=8.0, 2.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 4.28-4.23 (m, 1H), 3.47 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.08-2.85 (m, 4H), 2.76 (dd, J=14.0, 4.5 Hz, 1H), 2.70 (s, 3H), 2.13-2.07 (m, 1H), 2.02-1.93 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z 286 (M+H); HPLC >99% (AUC), tR=11.14 min.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(OCC)(=O)C>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][CH2:7][NH:8][C:19](=[O:21])[CH3:20])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(CCCN)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(CCCNC(C)=O)OCC
Reaction time: 2 h

Procedure:
4,4-Diethoxybutylamine (3.0 g, 18.61 mmol) and triethylamine (7.85 ml, 55.83 mmol) were dissolved in 250 ml of ethyl acetate. At 10° C., acetic anhydride (1.75 ml, 18.61 mmol) was added, and stirring was continued for 2 h. The cooling bath was removed after 1 h. The reaction mixture was concentrated. Yield: 1.526 g. The product was directly reacted further.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[O:10][N:9]=1.C(C1[O:20][CH2:19]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:1]1[C:7]2[C:2]1=[C:3]([C:8]1[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[O:10][N:9]=1)[CH:4]=[CH:5][C:6]=2[O:20][CH3:19]
Reactant: Oc1ccccc1-c1noc2ccsc12
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2noc3ccsc23)c2c1O2
Temperature: 25 °C
Reaction time: 28 h
Yield: 73.4 %

Procedure:
A mixture of 6.3 g of 3-(2-hydroxyphenyl)thieno[2,3-d]isoxazole, 5 g of epibromohydrin and 2.6 g of potassium carbonate in 37 ml of acetonitrile was stirred under nitrogen at 70°-80° C. until completion of the reaction. The reaction was complete fter 28 hours and the mixture was left to cool to room temperature. Quenching with water, extraction with ether/ethyl acetate (1:1), washing and drying (over anhydrous magnesium sulfate) gave 6.34 g of a crude oil. The epoxide was separated by high performance liquid chromatography (HPLC hereafter) using ethyl acetate/hexane (2:1) as an eluent, yielding 5.22 g of crystal This was recrystallized from ether/hexane, m.p. 65°-67° C.