Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2C=CC=CC=2[P+](C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:3]=1.C([Li])CCC.[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=O)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]>O1CCCC1.CCCCCC>[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=[CH:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)C(C)(C)CC(CC=O)CCCCO[Si](C)(C)C(C)(C)C
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1-c1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CC(CC=Cc1cccnc1)CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 8.8 g (22.6 mmol) 3-pyridyl-methyltriphenylphosphonium chloride in 40 mL dry tetrahydrofuran at 0° C. is added slowly 9.0 mL (22.5 mmol) of 2.5 M n-butyllithium in hexane. After stirring the resulting deep red solution at room temperature for 0.5 hour, a solution of 3.23 g (9 mmol) of methyl 2,2-dimethyl-4-(formylmethyl)-8-(t-butyldimethylsiloxy)octanoate in 10 mL dry tetrahydrofuran is added slowly and then stirred for 16 hours. The reaction is quenched by addition of saturated ammonium chloride solution and then extracted thrice with ether. The combined organic extracts are washed with water and brine, dried, filtered and concentrated. The residue is taken up in ether and the resulting precipitate is removed by filtration. The filtrate is evaporation and the residue is purified by silica gel chromatography using 1:1 hexane, ether to give methyl 2,2-dimethyl-4-[3-(3-pyridyl)-2-propenyl]-8-(t-butyldimethylsiloxy)octanoate; NMR (CDCl3): delta 5.7-6.4 (m,2H), 3.63 and 3.60 (two s,3H), 1.2 and 1.15 (two s,6H).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[ClH:29]>C(O)(C)C>[ClH:29].[OH:1][CH:2]([CH2:16][N:26]1[CH2:27][CH2:28][N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1)[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1CCc2cc(OCC3CO3)ccc2N1
Agent: Cl
Solvent: CC(C)O
Product: O=C1CCc2cc(OCC(O)CN3CCN(c4ccccc4)CC3)ccc2N1

Procedure:
4.4 grams of 6-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril and 3.4 g of 4-phenylpiperazine are dispersed in 80 ml of isopropanol and reacted at 50°-60° C. for 3 hours under stirring conditions, then 5 ml of concentrated hydrochloric acid are added thereto and concentrated under reduced pressure to dryness. The thus obtained residue is recrystallized from hot water to obtain 6.1 g of 6-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril monohydrochloride.1/2 hydrate in the form of colorless needle-like crystals with a melting point of 223°-224° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([OH:22])=O)[CH:17]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[N:15]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:30][C@H:31]1[CH2:36][O:35][CH2:34][CH2:33][NH:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][C@@H:31]4[CH3:30])=[O:22])[CH:17]=[C:16]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])[N:15]=3)=[CH:10][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1
Reactant: C[C@H]1COCCN1c1cc(C(=O)O)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1C(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-[4-(Cyclopropylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylic acid (95 mg) was dissolved in DMF (3 mL) and (3S)-3-methylmorpholine added. DIPEA (0.125 mL) and HATU (137 mg) were added and the reactions stirred at RT for 3 h before being concentrated in vacuo and partitioned between DCM (25 mL) and water (25 mL). The organic layer was dried over magnesium sulphate, filtered and evaporated to dryness to give the desired material as a solid (88 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:21](O)=[O:22])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C)C=O>[C:58]1([NH:57][C:21]([C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[C:12]([NH:11][S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)(=[O:9])=[O:10])[CH:13]=3)[NH:17][N:16]=2)=[O:22])[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: O=C(O)c1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1)c1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 12.7 %

Procedure:
N-Phenyl-5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxamide can be obtained as described in Example 18 from 0.45 g of 5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxylic acid, 11 ml of dimethylformamide, 0.56 g of 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 0.38 g of diisopropylethylamine and 0.14 g of aniline. 70 mg of N-phenyl-5-(3-fluorobenzenesulfonylamino)-1H-indazole-3-carboxamide are thus obtained in the form of a brown solid melting above 260° C. (Analysis: C20H15FN4O3S.0.73H2O % calculated C, 58.54; H, 3.68; F, 4.63; N, 13.65; O, 11.69; S, 7.81. % found C, 58.09; H, 3.18; N, 13.58; S, 7.43).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19]C)=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[I-].[Na+].Cl[Si](C)(C)[CH3:25]>C(#N)C.O>[CH3:25][C:10]1[NH:11][C:12](=[O:19])[C:13]2[C:18]([C:9]=1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: COc1ncc(-c2cccc(C#N)c2)c2ccccc12
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1[nH]c(=O)c2ccccc2c1-c1cccc(C#N)c1
Yield: 82.6 %

Procedure:
To a solution of 4-(3-cyanophenyl)-1-methoxyisoquinoline (200 mg, 0.73 mmol) in acetonitrile (6 mL) is added sodium iodide (219 mg, 1.46 mmol) followed by chlorotrimethylsilane (186 μL, 1.46 mmol) and the mixture is heated at reflux for 1.5 hr. The cooled reaction is diluted with water (15 mL) and the solids are collected by filtration, washed with water and dried to give 3-(3-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)benzonitrile (157 mg, 83% yield). 1H NMR (δ ppm) 11.55 (1H, s), 8.22 (1H, d), 7.95 (1H, d), 7.82 (1H, s), 7.72 (1H, t), 7.66 (1H, m), 7.60 (1H, m), 7.47 (1H, t), 6.94 (1H, d), 1.99 (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]2)=[O:8].[OH:25]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]2)(=[O:25])=[O:8]
Reactant: O=c1ccc2cc(OCCCCS(=O)c3ccccn3)ccc2[nH]1
Reactant: OO
Product: O=c1ccc2cc(OCCCCS(=O)(=O)c3ccccn3)ccc2[nH]1

Procedure:
Prepared analogous to Example 124 from 6-[4-(2-pyridylsulfinyl)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH:29]([CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[N+:33](C1C=CC(C(Cl)=O)=CC=1)([O-])=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[NH2:33][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: OCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1C[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of {3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol (46.52 g, 105.5 mmol) and 4-nitrobenzoyl chloride (23.55 g, 126.9 mmol) in methylene chloride (260 mL) was added N,N-diisopropylethyl amine (55.17 mL, 316.7 mmol). The mixture was stirred at rt for 15 h. Yellow precipitates were collected by filtration, washed with ethyl acetate, and dried to afford the title compound; 1H NMR (CDCl3, 400 MHz) δ 2.70-2.78 (m, 4H), 2.96-3.02 (m, 1H), 3.81-3.86 (m, 1H), 4.41 (d, J=4.8 Hz, 2H), 7.37 (d, J=5.2 Hz, 1H), 7.44-7.48 (m, 1H), 7.51-7.55 (m, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.88-7.96 (m, 5H), 8.16-8.19 (m, 2H), 8.26-8.29 (m, 2H), 8.33 (d, J=8.8 Hz, 1H), 8.54 (s, 1H); MS (ES+): m/z 590 [MH+]; HPLC: tR=4.37 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([NH:6][C:7](=[O:11])OCC)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([NH:19][C:7]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: C=C(C)C(=O)NC(=O)OCC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NC(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 42.6 %

Procedure:
A reaction vessel was charged with 78.5 g of ethyl N-methacryloylcarbamate and 53.5 g of benzylamine to which 100 g of toluene were added and heated at 100° C. for 30 minutes, The resulting mixture was condensed under reduced pressure and isolated by column chromatography to obtain 46.4 g of N-benzyl-N'-methacryloyl urea having a melting point of 96°-98° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:33]=[CH:32][C:11]([O:12][C:13]2[C:14]([C:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27]C(C)(C)C)=O)[CH2:21][CH:20]=3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=1.[C:34](Cl)(=O)C>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[C:14]([C:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:34])[CH2:21][CH:20]=3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Reactant: CC(=O)Cl
Product: CC(=O)N1CC=C(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1

Procedure:
During a resynthesis of Example 279 (Step 1) an incomplete hydrogenation resulted in a small fraction of tert-butyl 4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Example 278) to be carried forward through Example 279 (Step 2), which was subsequently treated in similar fashion using acetyl chloride. The impurity was separated from the major product by SFC using MeOH (1% diethyl amine) to give 1-(4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a white solid. MS (ESI, pos. ion) m/z: 388.1 (M+1). IC50 (uM) 0.00234.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([NH:18][CH2:19][C:20](O)=[O:21])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([O:13][C:11]([NH:18][CH2:19][C:20]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:21])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 4-nitrophenol (1.0 g, 7.19 mmol) in DCM (20.0 mL) was added N-Boc glycine (1.38 g, 7.91 mmol) and EDC HCl (2.05 g, 10.785 mmol) and the reaction was stirred at RT for 24 h. The reaction mixture was diluted with DCM and washed with water and saturated brine solution. The separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound as a light brown gummy material that was used in the next step without further purification (1.1 g): 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=9.2 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 5.07 (br, 1H), 4.20 (s, 2H), 1.47 (s, 9H); ESIMS m/z 296.27 ([M+H]+).
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][CH2:16][NH2:17])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[O-:21][C:22]#[N:23].[K+]>O.Cl>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][CH2:16][NH:17][C:22]([NH2:23])=[O:21])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: N#C[O-]
Reactant: CCCN(CCC)C1CCc2cccc(CCN)c2C1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(CCNC(N)=O)c2C1
Reaction time: 1 h

Procedure:
1.1 g (4 mmol) of 2-dipropylamino-8-(2-aminoethyl)-1,2,3,4-tetrahydronaphthalene were dissolved in 8 ml of water and 8 ml of 1N hydrochloric acid, and heated to +60° C. A solution of 3.24 g (40 mmol) of potassium cyanate and 15 ml of water was added dropwise at this temperature. The mixture was stirred for 1 h at +60° C. The mixture was then cooled and filtered under suction. The product was recrystallized from petroleum ether/diisopropyl ether with activated charcoal.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:6]1[CH:7]=[C:8]([S:13](Cl)(=[O:15])=[O:14])[CH:9]=[CH:10][C:11]=1[OH:12])(=[O:5])[CH3:4]>C(#N)C>[CH3:1][NH:2][S:13]([C:8]1[CH:9]=[CH:10][C:11]([OH:12])=[C:6]([C:3](=[O:5])[CH3:4])[CH:7]=1)(=[O:15])=[O:14]
Reactant: CC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Reactant: CN
Solvent: CC#N
Product: CNS(=O)(=O)c1ccc(O)c(C(C)=O)c1
Reaction time: 0.08 h

Procedure:
A saturated solution of monomethyl amine in acetonitrile cooled to 0° C. was treated with 3-acetyl-4-hydroxy-benzenesulfonyl chloride. The mixture was stirred 5 min, concentrated .in vacuo to an oil, disolved in ethyl acetate and treated with 1N aqueous HCl. The organic portion was separated, concentrated, filtered through silica gel (eluted with ethyl acetate) to provide N-methyl-3-acetyl-4-hydroxy-benzenesulfonic acid amide after concentration.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.C(#N)C>CCOCC>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CC#N
Solvent: CCOCC
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NC1CCN(Cc2ccccc2)CC1
Temperature: 120 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
250 mg. (1.06 mmol) 3-(1,6-dihydro-6-oxo-9H-purin-9-yl) propionic acid, ethyl ester (AIT-0027) was added to a 10 ml round bottom flask equipped with a magnetic stirring bar, reflux condenser and CaCl2 drying tube. Then, 604 mg (3.17 mmol) 4-amino-1-benzyl-piperidine and 1 ml acetonitrile were added and the solution was brought to reflux. Reflux was continued for 17 hours. Aacetonitrile was evaporated and the mixture was heated at 120° C. for eight hours to yield a dark viscous oil. The oil was treated with ether while stirring. The solution was filtered and the orangebrown solid was washed with additional ether. Upon drying, 385 mg of a brown solid was obtained. The solid was stirred in acetone, filtered, washed with acetone and then with ether. This yielded 200 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(1-benzylpiperidin-4-yl)propanamide (AIT-0033) as a tan solid. Analysis by HPLC indicated that the product was 65% pure.
Reaction SMILES: [F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:4]([C@H:5]3[C@:13]([CH3:26])([CH2:14][C@@H:15]2[OH:25])[C@@H:8]([C:9](=[O:12])[CH:10]=[O:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1.FC(F)(F)C[OH:31]>C(Cl)(Cl)Cl>[F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:4]([C@H:5]3[C@:13]([CH3:26])([CH2:14][C@@H:15]2[OH:25])[C@@H:8]([C:9](=[O:12])[C:10]([OH:31])=[O:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)C=O
Reactant: OCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)C(=O)O

Procedure:
1.0 g. of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-al is reacted, under the conditions described in Example 46 but with 2,2,2-trifluoroethanol, thus obtained the 2,2,2-trifluoroethyl ester of 6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-oic acid, m.p. 192.9° C. [α]D25 = +130° (chloroform). UV: ε242 = 17,000 (methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:14][S:15]([NH2:18])(=[O:17])=[O:16].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:18][S:15]([CH3:14])(=[O:17])=[O:16])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)NS(C)(=O)=O
Yield: 79.5 %

Procedure:
The title compound was prepared in the same way as that described in Example 11, Step 1, using 2-methyl-5-nitrobenzoic acid (5 g, 27.6 mmol), methyl sulphonamide (2.63 g, 27.6 mmol), 4-dimethylaminopyridine (3.37 g, 27.6 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (5.29 g, 27.6 mmol) and anhydrous dichloromethane (200 ml). The title compound (5.67 g, 79%) was afforded as a colourless solid. mp 180° C. (dec.). 1H NMR (360 MHz, D6-DMSO) δ 2.50 (3H, s), 3.42 (3H, s), 7.61 (1H, d, J=8.5 Hz), 8.28 (1H, dd, J=8.4 and 2.5 Hz), 8.36 (1H, d, J=2.5 Hz), 12.46 (1H, brs).
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:34]=[CH:33][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:38][O:39][NH2:40].Cl>N1C=CC=CC=1>[CH3:38][O:39][N:40]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:33][CH:34]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4ccccc4)ccc32)cc1
Temperature: 0 °C

Procedure:
A solution of the compound obtained in Step A (500 mg) and O-methylhydroxylamine hydrochloride (165 mg) in 15 ml of pyridine is heated at reflux for 3 hours. The reaction mixture is hydrolysed using 100 ml of ice-cold water, acidified using 6N HCl and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is then purified on silica gel, eluant AcOEt/PE 2/8, to yield the title compound in the form of a white oil (wax).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](Cl)=[O:43])=[CH:38][CH:37]=1>N1C=CC=CC=1.ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:42](=[O:43])[C:39]4[CH:40]=[CH:41][C:36]([O:35][C:34]([F:33])([F:45])[F:46])=[CH:37][CH:38]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.450 g, 1.03 mmol) in pyridine (8 mL) at −5° C. was treated with a solution of 4-(trifluoromethoxy)-1-benzenecarbonyl chloride (0.231 g, 1.03 mmol) in dichloromethane (2.5 mL) drop-wise. The reaction mixture was stirred at −5° C. for 30 min. The ice bath was removed and the reaction mixture was stirred at room temperature for 3 h. 1 N sodium hydroxide solution (10 mL) was added, and stirred for 1 h. The organic solvent was removed under reduced pressure. Dichloromethane (10 mL) was added and the layers were separated using an Empore extraction cartridge. The organic solvent was removed under reduced pressure and the crude compound was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as eluent to give 0.430 g (67%) N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide. A hot solution of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide (0.430 g, 0.688 mmol) in ethyl acetate (15 mL) was treated with a hot solution of maleic acid (0.240 g, 2.07 mmol) in ethyl acetate. A precipitate was formed, filtered under nitrogen, and dried under high vacuum to give N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide tris-maleate salt.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[C:11]2[S:18][CH:17]=[CH:16][C:12]=2[N:13]=[CH:14][N:15]=1.[I:19]I.O>C1COCC1>[Cl:9][C:10]1[C:11]2[S:18][C:17]([I:19])=[CH:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: Clc1ncnc2ccsc12
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ncnc2cc(I)sc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
To a solution of LDA (1.8M, 20.6 mL, 37.1 mmol) in THF (65 mL) at −78° C. was added 4-chloro-thieno[3,2-d]pyrimidine (5.26 g, 31 mmol) in THF (50 mL) dropwise over 1 hour. After stirring for 20 minutes, I2 (12.7 g, 50 mmol) in THF (40 mL) was added to the mixture at −78° C. dropwise. The mixture was stirred at the same temperature for 20 minutes and then warmed up to room temperature for 2 hours. The mixture was poured into water (100 mL) and stirred for 30 minutes. The solid was filtered and washed with water and Hexane-Hexanes/DCM (50:1) to afford the product 4-Chloro-6-iodothieno[3,2-d]pyrimidine (6.86 g, 75%). 1H NMR (DMSO, 400 Hz) δ 8.97 (s, 1H), 8.15 (s, 1H).