Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.O>C(#N)C>[C:16]1([NH:15][C:4]2[N:5]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:7]=[C:2]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[N:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1nc(Nc2ccccc2)nc(Nc2ccccc2)n1
Reactant: NCc1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: c1ccc(Nc2nc(NCc3ccncc3)nc(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A 200 mg portion of 6-chloro-N,N′-diphenyl-1,3,5-triazine-2,4-diamine was dissolved in 10.0 ml of acetonitrile, and 145 mg of 4-(aminomethyl)pyridine and 0.585 ml of diisopropylethylamine were added thereto and stirred overnight at 80° C. The reaction solution was cooled down to room temperature, and then mixed with water and extracted with chloroform. The organic layer was washed with 5% citric acid and saturated brine and then dried using anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, the thus obtained residue was applied to a silica gel column chromatography and eluted with ethyl acetate:n-hexane (2:1), and then the thus obtained crude product was crystallized from ethyl acetate/n-hexane, thereby obtaining 107 mg of N,N′-diphenyl-N″-(4-pyridylmethyl)-1,3,5-triazine-2,4,6-triamine as light red crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:3]=1C=O.[CH3:22][O:23][C:24](=[O:45])[CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:46]O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([C:11]2[C:15]([Cl:16])=[C:14]([C:17]([F:19])([F:20])[F:18])[N:13]([CH3:21])[N:12]=2)=[CH:6][C:3]=1[CH:46]=[CH:25][C:24]([O:23][CH3:22])=[O:45]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CO
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1Cl
Reaction time: 0.25 h
Yield: 74 %

Procedure:
To a solution of 2.3 g (6.8 mmole) 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzaldehyde in 25 mL methanol was added 2.27 g (6.8 mmole) methyl(triphenylphosphoranylidene)-acetate, keeping the temperature below 35° C. The reaction mixture was allowed to stir for 15 minutes and diluted with ethyl acetate, washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified chromatographically using 20% ethyl acetate in hexane as the eluent to give 2.0 g (74%) of 3-(2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorophenyl)propenoic acid, methyl ester as a white solid; mp 117° C.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1>[ClH:36].[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:31](=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][N:12]2[CH2:13][CH2:14][CH:9]([C:7]([OH:8])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[CH:29][CH:30]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCCl)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)CCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Product: Cl

Procedure:
A mixture of 32.0 g (0.12 mole) of α,α-diphenyl-4-piperidinemethanol, 38.0 g (0.15 mole) of 4'-tert-butyl-5-chlorovalerophenone, 27.8 g (0.2 mole) of potassium bicarbonate, and 200 mg of potassium iodide in about 500 ml of toluene is stirred and refluxed for 142 hours then filtered while hot. About 50 ml of ether is added to the filtrate which is then made acidic using ethereal HCl. The resulting precipitate is recrystallized from methanol-butanone to give 4'-tert-butyl-5-[4-(α-hydroxy-α-phenylbenzyl)piperidino]valerophenone hydrochloride, M.P. 209.5°-211°C.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19](O)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:43])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]([Cl:43])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCCCCCCCCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1OCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 60 h
Yield: 98.7 %

Procedure:
To a room temperature solution of 5.0 g of product from Example 104 in 80 ml of methylene chloride and 5 drops of dimethylformamide is added 1.74 g of oxalyl chloride. The reaction is stirred at room temperature for 2.5 days and concentrated in vacuo. The residue is dissolved in diethyl ether, passed through a pad of diatomaceous earth and concentrated in vacuo to give 5.1 g of the desired product as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][O:12][CH2:13][CH3:14])[C:9]2[C:8](=[O:15])[NH:7][C:6](=[O:16])[N:5]([CH3:17])[C:4]=2[N:3]=1.[H-].[Na+].[C:20]([O:23][C@H:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])(=[O:22])[CH3:21]>CS(C)=O>[C:20]([O:23][CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])(=[O:22])[CH3:21].[C:20]([O:23][C@H:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][N:7]1[C:8](=[O:15])[C:9]2[N:10]([CH2:11][O:12][CH2:13][CH3:14])[C:2]([Br:1])=[N:3][C:4]=2[N:5]([CH3:17])[C:6]1=[O:16])(=[O:22])[CH3:21]
Reactant: CCOCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(=O)O[C@H](C)CCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)OC(C)CCCCCl
Product: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 149.4 %

Procedure:
To a stirring suspension of 8-bromo-7-ethoxymethyl-3-methylxanthine (1.52 g, 5.0 mmol) in anhydrous dimethylsulfoxide (20 ml) was added sodium hydride (144 mg, 6.0 mmol). The mixture was stirred at room temperature for 30 min and then (R)-5-acetoxy-1-chlorohexane (983 mg, 5.5 mmol) was added and the mixture was stirred at 70-75° C. The (R) 5-acetoxy-1-chlorohexane was prepared according to methods described in U.S. Pat. No. 5,629,423 issued to Klein, J. P., Leigh, A. J., Michnick, J., Kumar, A. M., Underiner, G. E., on May 13, 1997, which is incorporated herein by reference. After 12 hours, the mixture was cooled to room temperature, quenched with saturated aqueous sodium chloride solution (100 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (2×25 ml), with saturated aqueous sodium chloride solution (25 ml) and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the product was purified by flash chromatography over silica gel eluting with ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (1.83 g, 82% yield) as a beige solid.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:26]=1[CH2:27]Br>>[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:26]=1[CH2:27][O:2][C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)=[O:3]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCc3c(Cl)cccc3Cl)(CC1)CC2
Yield: 89.4 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 2,6-dichlorobenzyl bromide (24.5 mg) were used to obtain (2S,4S)-1-[[N-[4-(2,6-dichlorobenzyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (40.0 mg).
Reaction SMILES: S([O-])([O:4][CH2:5][CH2:6]CCCCCCCCCC)(=O)=[O:2].[Na+].[CH2:19](O)[C@H]([C@H:22]([C@@H:24]([C@@H:26]([CH2:28][OH:29])O)O)[OH:23])O>>[CH3:19][O:4][CH:5]=[CH2:6].[CH:24]1[C:22](=[O:23])[O:29][C:28](=[O:2])[CH:26]=1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Product: C=COC
Product: O=C1C=CC(=O)O1

Procedure:
For this purpose, 50 mL of GANTREZ® ES 425 ethanolic solution (50 mg/mL) were mixed with 100 mL of distilled water to form GANTREZ® ES nanoparticles. Different surfactants were added to the nanoparticles hydroalcoholic suspension such as sodium dodecyl sulfate (SDS) (100 mg), PLURONIC® F68 [ethylene oxide/propylene oxide block copolymer] (100 mg) or TWEEN® 80 [polyoxyethylene (20) sorbitan monooleate] (7.5 mg). Finally, 7.5 g of mannitol were added as excipient. To obtain a dry powder of the GANTREZ® ES nanoparticles, the suspension was dried in a Mini Spray-dryer Büchi B191 (Büchi Labortechnik AG, Switzerland) under the following conditions:
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)C=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:14]=1[CH:1]=[CH2:2]
Reactant: [Li]CCCC
Reactant: O=Cc1cncc(Br)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccncc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.97 g, 8.33 mmol) in THF (45 ml) at −78° C. was added n-butyllithium (2.5 M in hexanes, 2.7 mL, 6.75 mmol). The resulting yellow reaction mixture was stirred for 30 min at −78° C. In a separate flask THF (9 mL) was added to 5-bromonicotinaldehyde (CAS#113118-81-3, 837 mg, 4.5 mmol). The resulting 5-bromonicotinaldehyde solution was the transferred, via cannula, to the phosphonium ylide mixture followed by a 2 mL THF wash. The reaction was allowed to warm to room temperature over 120 minutes and then permitted to stir for an additional 30 minutes. The reaction was then quenched with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate. The organic layer was concentrated to near dryness and the resulting residue was then diluted with ethyl acetate and 1M sodium bisulfate and the layers were separated. The organic layer was extracted two additional times with 1M sodium bisulfate. The aqueous layers were combined, diluted with dichloromethane, and neutralized via the careful addition of saturated aqueous sodium bicarbonate and solid sodium carbonate. The layers were separated and the now basic aqueous layer was extracted three additional times with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0 to 16%) to furnish 3-bromo-4-vinyl-pyridine; MS: (ES+) m/z 183.9 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH2:60])=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1>C1COCC1.C(Cl)(Cl)Cl>[O:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[C:51]1[C:59]2[S:58][C:57]([NH:60][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:56][C:55]=2[C:54]([O:61][CH3:62])=[CH:53][CH:52]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)c1

Procedure:
From 3-methoxybenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+24.3° (c=0.79, CHCl3), ES-MS m/e (%): 401 (M+H+, 100).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:12][CH2:11][C:10]([OH:14])=[O:13])=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: C=CC(=O)O
Solvent: CC(=O)O
Product: O=C(O)CCc1c[nH]c2ccccc12

Procedure:
Reaction of indole XXI with acrylic acid in the presence of acetic acid affords the indole-3-propionic acid. Esterification, alkylation of the indole nitrogen, if desired, and trifluoroacetic acid hydrolysis gives rise to indoles of Formula VII in which R is (CH2)mCO2R9, m is 2 and R2 is H or C1 -C3 alkyl. ##STR29##
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[NH:12].[C:18](Cl)(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(NC(C)C)(C)C.[Li].ClC(OC)=O>C1COCC1.C(OCC)C>[CH:11](=[NH:12])[C:10]1[CH:13]=[CH:14][CH:15]=[CH:8][CH:9]=1.[C:18]([NH:12][CH2:11][C:10]#[CH:9])(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: C[Si](C)(C)c1cccc(C=N)c1
Agent: COC(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCNC(=O)CCCCCCCCCCCCCCC
Product: N=Cc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-butyllithium in solution in hexanes is added in a dropwise manner to a solution of 3-trimethylsilyl benzylidenamine in solution in THF. After 30 min. of stirring at -70° C., palmitoyl chloride (1 eq.) in solution in THF is added thereto. The solution is stirred at -70° C. for 30 min., and lithium diisopropylamine (1 eq.) in solution in hexanes is added in a dropwise manner. After 20 min. of stirring at -70° C., a solution of methyl chloroformate in tetrahydrofuran is added thereto. The solution is stirred at -70° C. for 20 min. and poured into diethylether. The solution is then washed with water and brine, dried over sodium sulfate, and concentrated to yield palmitoyl propargylamine benzylidenamine.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[S:34]1[CH:38]=[CH:37][C:36](NC)=[CH:35]1.[CH3:41][N:42](C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C(O[Na])(C)(C)C>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>[N:20]1([CH2:19][CH2:18][NH:17][C:13]2[N:12]=[C:11]3[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([NH:42][CH2:41][C:36]5[CH:37]=[CH:38][S:34][CH:35]=5)[N:7]=4)[C:16]3=[CH:15][N:14]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CNc1ccsc1
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(NCCN3CCOCC3)nc21
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccsc3)n2)c2cnc(NCCN3CCOCC3)nc21
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A sealed tube was charged with [3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 32 supra) (320 mg, 0.60 mmol), thiophen-3-yl-methylamine (81 mg, 0.72 mmol), Pd2(dba)3 (34 mg), DavePhos (47 mg), t-BuONa (69 mg, 0.72 mmol) and dioxane (12 mL). The mixture was stirred at 105° C. under an atmosphere of N2 for 8 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 16 g, 100-200 mesh, eluting with MeOH:dichloromethane, 1:100 to 1:80) to give crude (2-morpholin-4-yl-ethyl)-[3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-amine as a yellow oil. (Yield 149 mg).
Reaction SMILES: N1CCCCC1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH2:17][C@H:18]4[CH:24]=[N:23][C:22]5[CH:25]=[C:26]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]6[C:37]([O:84][CH3:85])=[CH:38][C:39]7[C:45](=[O:46])[N:44]8[CH:47]=[C:48]([C:50]#[C:51][CH2:52][NH:53][C:54](=[O:82])[C@@H:55]([NH:57][C:58](=[O:81])[C@H:59]([NH:63]C(=O)OCC9C%10C=CC=CC=%10C%10C9=CC=CC=%10)[CH:60]([CH3:62])[CH3:61])[CH3:56])[CH2:49][C@H:43]8[CH:42]=[N:41][C:40]=7[CH:83]=6)[C:27]([O:29][CH3:30])=[CH:28][C:21]=5[C:20](=[O:86])[N:19]4[CH:87]=3)=[CH:15][C:10]=2[O:9][CH2:8]1>CN(C=O)C.C(Cl)Cl>[NH2:63][C@@H:59]([CH:60]([CH3:62])[CH3:61])[C:58]([NH:57][C@@H:55]([CH3:56])[C:54]([NH:53][CH2:52][C:51]#[C:50][C:48]1[CH2:49][C@H:43]2[CH:42]=[N:41][C:40]3[CH:83]=[C:36]([O:35][CH2:34][CH2:33][CH2:32][O:31][C:26]4[C:27]([O:29][CH3:30])=[CH:28][C:21]5[C:20](=[O:86])[N:19]6[CH:87]=[C:16]([C:14]7[CH:13]=[CH:12][C:11]8[O:7][CH2:8][O:9][C:10]=8[CH:15]=7)[CH2:17][C@H:18]6[CH:24]=[N:23][C:22]=5[CH:25]=4)[C:37]([O:84][CH3:85])=[CH:38][C:39]=3[C:45](=[O:46])[N:44]2[CH:47]=1)=[O:82])=[O:81]
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc5c(c4)OCO5)C[C@H]1C=N3)N=C[C@@H]1CC(C#CCNC(=O)[C@H](C)NC(=O)[C@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(C)C)=CN1C2=O
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc5c(c4)OCO5)C[C@H]1C=N3)N=C[C@@H]1CC(C#CCNC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)=CN1C2=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Excess piperidine was added (0.01 mL, 0.1 mmol) to a solution of SEM-dilactam 11d (1 mg, 0.0009 mmol) in DMF (0.1 mL). The mixture was allowed to stir at room temperature for 20 min, at which point the reaction had gone to completion (monitored by LC/MS). The reaction mixture was diluted with CH2Cl2 (1 mL) and the organic phase was washed with H2O (3×1 mL) until complete piperidine removal. The organic phase was dried over MgSO4, filtered and excess solvent removed by rotary evaporation under reduced pressure to afford crude material 12d. LC/MS (1.917 min (ES+)). m/z: 872.2 [M+H]+
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>C(O)C>[Cl:12][C:11]1[C:2]([NH:17][CH2:16][CH:15]([O:18][CH3:19])[O:14][CH3:13])=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: COC(CN)OC
Reactant: Clc1nc2ccccc2nc1Cl
Solvent: CCO
Product: COC(CNc1nc2ccccc2nc1Cl)OC

Procedure:
A mixture of 5.0 g of 2,3-dichloroquinoxaline and 5.5 ml of aminoacetaldehyde dimethyl acetal in 75 ml of ethanol is refluxed for 4 h. After concentrating under vacuum, the resulting mixture is added with water and extracted with ethyl acetate. The organic extracts are then washed with saturated NaCl, dried and evaporated. The residue is finally chromatographed on SiO2 (eluent: CH2Cl2), thereby obtaining 5.0 g of 2-chloro-3-(2,2-dimethoxyethylamino)quinoxaline (IR (KBr): 3347, 2936, 1580, 1523, 1129 cm-1). 4.5 g of this product are then treated with 20 ml of 48% HBr and the mixture is refluxed for 4 h. After cooling down, the mixture is neutralized with aqueous NaOH and the resulting precipitate is filtered under vacuum and dried to obtain 3.2 g of imidazo[1,2-a]quinoxalin-4(5H)-one (m.p. >300° C.)
Reaction SMILES: Cl.N[OH:3].[C:4]1([C:10]2[O:14][C:13]([CH:15]=[N:16]N3CC(=O)NC3=O)=[N:12][CH:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C>C(O)(=O)C>[C:4]1([C:10]2[O:14][C:13]([CH:15]=[N:16][OH:3])=[N:12][CH:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NO
Reactant: O=C1CN(N=Cc2ncc(-c3ccccc3)o2)C(=O)N1
Agent: C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: ON=Cc1ncc(-c2ccccc2)o1

Procedure:
Hydroxylamine hydrochloride (54 g, 0.78 mole) and 1-[[[5-phenyl-2-oxazolyl]methylene]amino]-2,4-imidazolidinedione (105 g, 0.39 mole) were refluxed with stirring in a solution of water (100 ml) and glacial acetic acid (1.0 l.) for five hrs. An additional 54 g of hydroxylamine hydrochloride was added while the mixture was refluxed another five hrs. The hot solution was treated with Darco, filtered and poured into water (5.0 l.). The solid was again refluxed in a mixture of hydroxylamine hydrochloride (50 g), acetic anhydride (800 ml) and water (80 ml) for four hrs. The solution was cooled, poured into water (3.0 l.) and the resulting solid was collected and dried (48 g, 65%). Recrystallization of a sample from acetonitrile gave product of analytical purity, m.p. 208°-210°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:22])([CH3:21])[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[N:5]=[C:4]([CH3:23])[C:3]=1[C:24]([O:26]CC)=[O:25].[OH-].[Na+].Cl>CCO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:21])([CH3:22])[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[N:5]=[C:4]([CH3:23])[C:3]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC(C)C)c2c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cccc(OCC(C)(C)C(=O)NC(C)C)c2c(N)c1C(=O)O
Temperature: 90 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
To a solution of ethyl 4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylate (Example 134a, 14.0 g, 36.2 mmol) in EtOH (140 mL) was added aqueous NaOH solution (2.0 N, 46 mL) at room temperature. The reaction mixture was stirred at 90° C. for 4 hrs. The resulting solution was neutralized at 0° C. to pH 7 with 6 N HCl, and concentrated under reduced pressure. The residue was re-dissolved in EtOH (400 mL) and water (25 mL), and treated with charcoal (200 mg) at 65° C. for 30 minutes. After removal of the charcoal by filtration, the filtrate was concentrated, and the resultant white solid was purified by re-crystallization from EtOH/H2O and dried under vacuum at 70° C. to give the title compound as a white solid (11.5 g, 89%). M.p.: 216-218° C. 1H NMR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.4 Hz, 6H), 1.24 (s, 6H), 2.75 (s, 3H), 3.86-3.93 (m, 1H), 4.17 (s, 2H), 7.01 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 8.83 (brs, 1H), 12.34 (brs, 1H), 12.78 (brs, 1H). MS 360 (MH+).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.C(Cl)Cl.[CH3:24][C:25]1[CH:38]=[C:37]2[C:28]([S:29][C:30]3[CH:31]=[C:32]([C:40](Cl)=[O:41])[CH:33]=[CH:34][C:35]=3[C:36]2=[O:39])=[CH:27][CH:26]=1>O>[CH2:1]([O:13][C:40]([C:32]1[CH:33]=[CH:34][C:35]2[C:36](=[O:39])[C:37]3[C:28]([S:29][C:30]=2[CH:31]=1)=[CH:27][CH:26]=[C:25]([CH3:24])[CH:38]=3)=[O:41])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCO
Reactant: Cc1ccc2sc3cc(C(=O)Cl)ccc3c(=O)c2c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)c1ccc2c(=O)c3cc(C)ccc3sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
1.5 g (8.06 mmoles) of dodecan-1-ol and 1.0 g (9.90 mmoles) of triethyl amine are added to a CH2Cl2 solution containing 2.26 g (7.41 mmoles) of 7-methyl 9-oxo-thioxanthene-3-carbonyl chloride. After approximately 1 hour at room temperature under stirring, the mixture is poured in water, the organic phase is separated and washed again with water. The organic phase is then separated, dehydrated and after purification on a flash column (SiO2— eluent: CH2Cl2:AcOEt 8:2) it is dried, obtaining 1.62 g (49.8%) of a yellow solid with the following spectral properties: