Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1C(=O)CCC1.[CH2:8]([O:10][C:11]1[N:12]=[CH:13][C:14]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[N:15][CH:16]=1)[CH3:9].CC(C)([O-])C.[K+].[CH3:29][C@:30]1([CH2:38][N:39]2[C:43]3[CH:44]=[C:45]([C:48]#[N:49])[CH:46]=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH2:37]CC[C@:32]2(O[CH2:33]2)[CH2:31]1>CC(O)C.O>[CH2:8]([O:10][C:11]1[N:12]=[CH:13][C:14]([N:17]2[CH2:21][C@@:20]3([CH2:33][CH2:32][CH2:31][C@@:30]([CH2:38][N:39]4[C:43]5[CH:44]=[C:45]([C:48]#[N:49])[CH:46]=[CH:47][C:42]=5[N:41]=[CH:40]4)([CH3:29])[CH2:37]3)[O:19][C:18]2=[O:22])=[N:15][CH:16]=1)[CH3:9]
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Reactant: CCOC(=O)Nc1cnc(OCC)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 10 mL flask was added NMP (7.11 mL), ethyl (5-ethoxypyrazin-2-yl)carbamate (0.863 g, 4.09 mmol) and potassium tert-butoxide (0.399 g, 3.55 mmol) at RT. After stirring for ˜5 min at RT, 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (1 g, 3.55 mmol) was added. The solution was then heated to 70° C. (oil bath) and stirred for 7 h. At 7 h, the temperature was taken to 80° C., then at 8 h, it was taken to 90° C. The mixture was allowed to stir at 90° C. for 16 h. The resulting solution was cooled to RT and added dropwise to a 50 mL solution of IPA/Water (1:1) that contained a small crystalline seed. The mixture was allowed to stir at RT overnight. The next day, the slurry was filtered, and the solids slurried in MeCN overnight. The next day, the solids were filtered off, dried under reduced pressure to give 1-(((5S,7S)-3-(5-ethoxypyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a very light yellow solid (968 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J=1.25 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.10 (d, J=1.51 Hz, 1H), 7.83 (d, J=8.53 Hz, 1H), 7.59 (dd, J=1.25, 8.28 Hz, 1H), 4.32 (q, J=7.03 Hz, 2H), 4.16 (s, 2H), 3.80-3.88 (m, 2H), 1.98 (d, J=13.80 Hz, 1H), 1.88 (d, J=14.31 Hz, 1H), 1.64-1.73 (m, 3H), 1.49-1.53 (m, 2H), 1.34-1.38 (m, 2H), 1.32-1.38 (t, J=8.0 Hz, 2H), 1.07 (s, 3H). MS (m/z) 447.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)C(C)C)C>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(Br)cn2)CC1
Yield: 78 %

Procedure:
To a stirred solution of 5-bromo-2-chloropyrimidine (10.0 g, 51.7 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (10.6 g, 51.7 mmol, 1.0 equiv) in acetonitrile (250 mL) was added at rt drop by drop N-ethyl diisopropylamine (45.2 mL 34.4 g, 266 mmol, 5.1 equiv). Then, the reaction mixture was heated to reflux for 16 h, poured into crashed ice and extracted twice with ethyl acetate. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 14.4 g (78%) of the title compound as a colorless solid. MS (ISP): 357.0 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1.[C:17](OCC)(=[O:19])[CH3:18]>[Zn]>[C:17]([O:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:14][CH:13]=1)(=[O:19])[CH3:18]
Reactant: OCc1ccc(COC2CCCCO2)cc1
Reactant: CCOC(C)=O
Agent: [Zn]
Product: CC(=O)OCc1ccc(COC2CCCCO2)cc1
Yield: 84 %

Procedure:
Under a nitrogen atmosphere, a mixture of (4-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)methanol (6 mmol), a zinc cluster Zn4O (OCOCF3)6 (0.075 mmol), and ethyl acetate (1.7 ml) was refluxed for 18 hours. As a result, 4-((tetrahydro-2H-pyran-2-yloxy)methyl)benzyl acetate was obtained in a yield of 84%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH3:37][NH:38][CH3:39]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:38]([CH3:39])[CH3:37])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CNC
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN(C)C)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 99) (219 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in DMF according to the method described in Example 45. Obtained as a light brown solid (143 mg, 61%).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[CH3:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:19][C:7]1[O:6][C:5]([C:3]([OH:2])=[O:4])=[CH:9][C:8]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21][CH3:20])=[CH:14][CH:13]=1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Reactant: CSc1ccccc1B(O)O
Product: CSc1ccccc1-c1ccc(OCc2cc(C(=O)O)oc2C)cc1

Procedure:
Compound (105) was prepared from compound (20) and (2-methylsulphanyl-phenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.86 mins, m/z (ES−)=353 (M−H for C20H18O4S).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.CC(C)([O-])C.[K+].Br[CH2:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1[C:41]1([O:47][CH3:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>O1CCCC1>[CH3:48][O:47][C:41]1([C:32]2[CH:33]=[CH:34][C:35]([C:37]([F:38])([F:40])[F:39])=[CH:36][C:31]=2[CH2:30][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:14]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CBr)CCCCC1
Reactant: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (26 mg; 0.079 mmol) in tetrahydrofuran (0.3 mL) was added potassium t-butoxide (80 uL; 0.08 mmol; 1.0M in tetrahydrofuran). A solution of 2-(bromomethyl)-1-(1-methoxycyclohexyl)-4-(trifluoromethyl)benzene (25 mg; 0.071 mmol) in tetrahydrofuran (0.2 mL) was added. The reaction was stirred at room temperature for 3 hours. The reaction was quenched with 2 drops of water. The mixture was diluted with ethyl acetate and filtered through a column containing silica and sodium sulfate and concentrated. The residue was purified by 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-45% ethyl acetate in heptane) to give 25 mg (59%) of a colorless gum. MS (ES+): Calc: 595.5, Found: 596 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (s, 1H), 7.73 (s, 2H), 7.48 (d, J=7.47 Hz, 2H), 7.42 (d, J=8.30 Hz, 1H), 5.14 (s, 2H), 4.79 (s, 2H), 4.20 (s, 3H), 2.92 (s, 3H), 2.12 (d, J=11.62 Hz, 2H), 1.77-1.52(m, 8H).
Reaction SMILES: C(O)(=O)C.[C:5]1([CH:11]2[CH2:16][CH2:15][C:14](=[N:17]O)[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O1CCCC1>C(O)(C)(C)C>[C:5]1([C@H:11]2[CH2:12][CH2:13][C@H:14]([NH2:17])[CH2:15][CH2:16]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ON=C1CCC(c2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: N[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
Into a solution of 8.58 g. of 4-phenylcyclohexanone oxime acetate (prepared in Example 79) in 90 ml. of tetrahydrofuran and 27 ml. of t-butanol, 350 ml. of ammonia is distilled from over sodium. To this there is added 1.9 g. of lithium in three portions at a rate that the blue color just persists. When the final blue color fades, 10 g. of solid ammonium chloride is added and the solvent is then evaporated with a stream of nitrogen. The residue is dissolved in ether and aqueous N-sodium hydroxide solution. The organic layer is separated, washed with water and brine and then taken to dryness to give a residue of trans 4-phenylcyclohexylamine. The residue is dissolved in a small amount of ether and treated with an excess of 4.9N hydrogen chloride in ether. The precipitate that forms is collected on a filter to yield 7.9 g. of trans 4-phenylcyclohexylamine hydrochloride. A sample of identical material previously prepared melts above 300° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[N:7]=[C:8]([C:10](=[O:21])[NH:11][C:12]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[S:9][C:5]=2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=1.Cl.Cl.[N:31]1([C:37]2[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[Cl-].[Na+]>N1C=CC=CC=1>[CH3:13][C:12]([NH:11][C:10]([C:8]1[S:9][C:5]2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=[C:2]([NH:1][C:41](=[O:42])[C:40]3[CH:39]=[CH:38][C:37]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:45][CH:44]=3)[C:6]=2[N:7]=1)=[O:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:20]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Reactant: O=C(Cl)c1ccc(N2CCOCC2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.3 %

Procedure:
0.40 g (0.998 mmol) of tert-butyl 3-amino-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 10 ml of pyridine is placed in a 50 ml round-bottomed flask under argon. 0.25 g (0.996 mmol) of 4-(4-morpholinyl)benzoyl chloride dihydrochloride (prepared according to WO 95/04729) is then gradually added and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 50 ml of dichloromethane and 50 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography (msilica=30 g; eluent: 99/1 dichloromethane/methanol). 0.19 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-(4-morpholin-4-ylbenzoylamino)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a yellow foam. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.61 (s, 9H); 1.70 (s, 6H); 3.29 (masked m, 4H); 3.75 (m, 4H); 7.03 (d, J=8.5 Hz, 2H); 7.20 (t, J=7.5 Hz, 1H); 7.30 (t, J=7.5 Hz, 2H); 7.40 (d, J=7.5 Hz, 2H); 7.97 (d, J=8.5 Hz, 2H); 8.69 (s, 1H); 11.1 (broad m, 1H). LC-MS-DAD-ELSD: 591(+)=(M+H)(+); 535(+)=591(+)-tBu+H.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]=[C:4]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[N+:5]([O-:7])=[O:6].[NH2:16][C@@H:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:8]1([CH:4]([N+:5]([O-:7])=[O:6])[CH:3]([NH:16][CH:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[C:2]([F:14])([F:15])[F:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: O=[N+]([O-])C(=CC(F)(F)F)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(C(C1CCCCC1)[N+](=O)[O-])C(F)(F)F)C(C)(C)C
Temperature: 100 °C

Procedure:
A mixture of (3,3,3-trifluoro-1-nitroprop-1-enyl)cyclohexane (3) (0.62 gm), (S)-methyl 2-amino-3,3-dimethylbutanoate (4) (0.656 gm, 1.3 eq) and diisopropylethylamine (0.69 mL) in toluene (15 mL) was heated to 100° C. for 23 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid, water, brine and then dried over anhydrous sodium sulfate. Evaporation to dryness under reduced pressure gave crude methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-nitropropan-2-ylamino)-3,3-dimethylbutanoate as a mixture of isomers. Separation by silica gel chromatography, eluting with 8% ethyl acetate/hexane, gave two fractions, a faster eluting compound, 5A-1 (0.553 gm) and a slower eluting compound, 5B-1 (0.3 gm). The two compounds are different diastereoisomers of methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-nitropropan-2-ylamino)-3,3-dimethylbutanoate (5), although the absolute stereochemistry has not yet been established.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([CH:12]=[O:13])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:24][C:25]([CH3:27])=[CH2:26]>CN(C)C=O.O>[CH3:14][C:3]1[C:2]([O:1][CH2:26][C:25]([CH3:27])=[CH2:24])=[CH:10][C:9]([CH3:11])=[C:8]2[C:4]=1[CH2:5][CH2:6][N:7]2[CH:12]=[O:13]
Reactant: C=C(C)CCl
Reactant: Cc1cc(O)c(C)c2c1N(C=O)CC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1cc(C)c2c(c1C)CCN2C=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
2,3-Dihydro-5-hydroxy-4,7-dimethyl-1H-indole-1-carbaldehyde (5.74 g, 30 mmol) was dissolved in N,N-dimethylformamide (100 ml) and to the solution were added potassium carbonate (8.29 g, 60 mmol), potassium iodide (0.50 g, 3 mmol) and 3-chloro-2-methyl-1-propene (4.41 ml, 45 mmol). The mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into cold water (300 ml), and extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel. (hexane:ethyl acetate=6:1) to obtain 6.00 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][CH:10]=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:20]([Mg]Br)[CH:21]=[CH2:22]>C(OCC)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][CH:10]([OH:11])[CH2:22][CH:21]=[CH2:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CC=O)c1cccc(Br)c1
Reactant: C=CC[Mg]Br
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCC(O)CC(O[Si](C)(C)C(C)(C)C)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a 0° C. solution of 3-(3-bromophenyl)-3-(tert-butyldimethylsilyloxy)propanal (17.9 g, 52.1 mmol) in dry diethyl ether (150 mL) is added 1 M allylmagnesium bromide solution in ether (52.1 mL, 52.1 mmol). The resulting mixture is warmed to room temperature over 1 hour. The mixture is diluted with dichloromethane and is quenched by addition of saturated aqueous solution of ammonium chloride. The mixture is extracted three times with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a racemic diastereomeric mixture (18.8 g, 84%). 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.38-7.34 (m, 1H), 7.24-7.21 (m, 1H), 7.19-7.15 (m, 1H), 5.84-5.76 (m, 1H), 5.09-5.04 (m, 1H), 5.00 (t, J=5.3 Hz, 1H), 4.86-4.80 (m, 1H), 3.83-3.75 (m, 2H), 2.23-2.15 (m, 2H), 1.80-1.69 (m, 2H), 0.89 (d, 9H, J=6.6 Hz), 0.06-0.04 (m, 3H), −0.17 (d, J=40.4 Hz, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:8]1[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH:14]([OH:29])[CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([OH:28])=[CH:22][C:23](=[O:27])[O:24]3)=[CH:19][CH:18]=2)=[C:10]([CH2:32][CH2:33][CH3:34])[C:9]=1[OH:35])(=[O:7])[CH3:6].Cl>C(Cl)(Cl)Cl>[C:5]([C:8]1[CH:31]=[CH:30][C:11]([O:12][CH2:13][CH:14]([OH:29])[CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([OH:28])=[C:22]([N+:1]([O-:4])=[O:2])[C:23](=[O:27])[O:24]3)=[CH:19][CH:18]=2)=[C:10]([CH2:32][CH2:33][CH3:34])[C:9]=1[OH:35])(=[O:7])[CH3:6]
Reactant: CCCc1c(OCC(O)COc2ccc3c(O)cc(=O)oc3c2)ccc(C(C)=O)c1O
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCC(O)COc2ccc3c(O)c([N+](=O)[O-])c(=O)oc3c2)ccc(C(C)=O)c1O
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Fuming nitric acid (9 ml) was added to a stirred suspension of 7-(3-[4-Acetyl-3-hydroxy-2-n-propylphenoxy]-2 -hydroxypropoxy)-4-hydroxycoumarin (2.8 g) in chloroform (300 ml) over 1 hr at 0° and the dark mixture stirred for a further 0.5 hr at this temperature. Dilute hydrochloric acid (150 ml) was added and the chloroform removed in vacuo at 0°. The solid which separated was removed by filtration and recrystallised from ethanol to give 2.42 g, (78%) of yellow solid of mp 201°-203° (dec). υmax (mull) 3350 (br), 1770, 1620, 1610, 1540 cm-1 ; τ(DMSO); 9.17 (3H, t, J 6.9 Hz); 8.55 (2H, m, J ca 7 Hz); 7.43 (3H, S+2H, m); 5.78 (5H, S); 3.20 (3H, m); 2.16 (2H, exchangeable S); 2.16 (2H, near doublet); 1 low field broad exchangeable). (Found, C, 58.49; H, 5.07; N, 3.04; C23H23NO10 requires, C, 58.35; H, 4.90; N, 2.96%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)[C:30]([C:41]([OH:43])=[O:42])=[C:29]([CH3:44])[NH:28][C:27]=1[CH3:45])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:22][O:23][C:24]([C:26]1[CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)[C:30]([C:41]([O:43][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:6]=2)=[O:42])=[C:29]([CH3:44])[NH:28][C:27]=1[CH3:45])=[O:25]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(OCCBr)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCCNC(=O)OC(C)(C)C)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
8.7 g (24 mmol) of the bromine derivative obtained in step 2b), 8.0 g (24 mmol) of 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridine-dicarboxylic acid monomethyl ester and 6.6 g (48 mmol) of potassium carbonate are heated at boiling in 100 ml of acetonitrile for 20 hours while stirring and under reflux. Working up analogously to Example 1c yields 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-tertiary butoxycarbonylaminoethoxy)-phenoxy]-ethyl}-ester 5-methyl ester, which is used in the following step without being purified further.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][NH:23][C:24]([C:26]2[CH:40]=[CH:39][C:29]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:27]=2)=[O:25])=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[NH2:1][C:2]1[C:3]([C:20]2[O:25][C:24]([C:26]3[CH:27]=[CH:28][C:29]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:39][CH:40]=3)=[N:23][N:22]=2)=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=O)c3ccc(CNC(=O)OC(C)(C)C)cc3)n2)cc1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CNC(=O)OC(C)(C)C)cc4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.4 %

Procedure:
A mixture of tert-butyl 4-(2-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carbonyl)hydrazinecarbonyl)benzylcarbamate (136 mg, 0.24 mmol) and DIPEA (109.8 mg, 148.0 μL, 0.8499 mmol) in acetonitrile (3.000 mL) at 0° C. was treated portionwise with dibromo(triphenyl)phosphorane (143.5 mg, 0.3400 mmol) and the resulting mixture stirred at room temperature for 48 h. The mixture was concentrated in vacuo and pre-absorbed onto silica gel and purified by column chromatography on silica gel eluting with 50% EtOAc/CH2Cl2 to give the product (46.8 mg, 30% yield);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:29]3[CH2:34][CH2:33][CH2:32][N:31](C([O:37][C:38]([CH3:41])(C)C)=O)[CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[O:19][C:20]5[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.Cl.CC(C)=[O:45]>>[C:38]([OH:45])(=[O:37])[CH3:41].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:29]3[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[O:19][C:20]5[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:21]=5[N:22]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCCN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Reactant: CC(C)=O
Agent: Cl
Product: CC(=O)O
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCCNC5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.28 g, 0.00051 mol) in acetone (10 mL) was added an 6N aqueous solution of hydrogen chloride (3 mL) at room temperature. The mixture was stirred at 45° C. for 1 hour. The solvent was removed, and the mixture was basified with an aqueous 5N sodium hydroxide solution. The aqueous layer was extracted with dichloromethane (3×80 mL). The solvent was removed under reduced pressure, and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 20 min with 0.1 M ammonium acetate, 21 mL/min) to yield N2-{4-[4-amino-1-(3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-5,7-dimethyl-1,3-benzoxazol-2-amine acetate (0.06 g, 0.00012 mol). 1H NMR (DMSO-d6, 400 MHz) δ 10.85 (s, 1H), 8.22 (s, 1H), 7.95 (d, 2H), 7.65 (d, 2H), 7.05 (s, 1H), 6.80 (s, 1H), 4.75 (br, 1H), 3.15 (br, 2H), 2.95 (m, 2H), 2.40 (s, 3H), 2.35 (s, 3H), 2.05 (br, 1H), 2.00 (br, 11), 1.90 (s, 3H), 1.80 (br, 1H), 1.60 (br, 1H). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 9.4 min. MS: MH+ 455
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([NH:14][CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:6]=1[C:7]([OH:9])=O.[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([NH:14][CH3:15])=[CH:13][C:5]=2[O:4][CH2:3][CH:2]([F:1])[F:19])=[CH:23][CH:22]=1
Reactant: CNc1cc(OCC(F)F)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared in accordance with Example 72, step (c) using 2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzoic acid (800 mg; 2.90 mmol), 4-bromoaniline (499 mg; 2.90 mmol), HBTU (1.10 g; 2.90 mmol), TEA (587 mg; 5.80 mmol) and DMF (15 mL). Yield: 1.01 g (81%).