Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C@@H:21]([CH2:32][C:33]1[NH:34][CH:35]=CN=1)[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[CH3:38][N:39]1CCOCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH2:25]([O:24][C:22](=[O:23])[C@@H:21]([O:18][C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:32][C:33]1[N:34]=[CH:35][NH:39][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H](O)Cc1ncc[nH]1
Reactant: CN1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O[C@@H](Cc1c[nH]cn1)C(=O)OCc1ccccc1
Reaction time: 144 h
Yield: 13 %

Procedure:
1.99 g of N-t butoxycarbonyl-L-phenylalanine and 1.58 g of benzyl (S)-α-hydroxyimidazolepropionate were suspended in 25 ml of methylene chloride and stirred. After stirring at room temperature for 15 minutes, 305 mg of 4-dimethylaminopyridine were added and the reaction mixture was cooled to -15°. After the dropwise addition of 2 ml of N-methylmorpholine and a solution of 6.6 g of propanephosphoric acid anhydride in 5 ml of methylene chloride, the reaction mixture was stirred at -15° for an additional 2 hours and left to stand at -18° for 6 days. After the addition of a few drops of water, the reaction mixture was evaporated under reduced pressure and the oily residue was triturated for 2 hours with 100 ml of ethyl acetate and 25 ml of water. The organic phase was then washed in succession with aqueous sodium bicarbonate solution (5%) water and 1.5M citric acid. The colorless oil obtained after evaporation of the solvent under reduced pressure was chromatographed on silica gel using a 95:5 mixture of methylene chloride and methanol as the eluting agent, to obtain (S)-α-[[N-(t-butoxycarbonyl) 3-phenyl-L-alanyl] oxy]imidazole-4-propionic acid benzyl ester as a yellow oil in 13% yield, MS: 494 (M+H)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4]CC1.Cl>O1CCCC1.C(OCC)(=O)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]1
Reactant: N#CC1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CC1CCC(=O)CC1
Yield: 50.8 %

Procedure:
A solution of 1,4-Dioxa-spiro[4.5]decane-8-carbonitrile (2.0 grams, 12.8 mmole) and 2 N hydrochloric acid (21.0 grams, 42.0 mmole) in tetrahydrofuran (30 ml) at room temperature was stirred over night. The mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 10% ethyl acetate/hexane as eluent to give an oil (0.800 g). MW 123.15.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].C1(C)C=CC(S([N:20]=[N+:21]=[N-])(=O)=O)=CC=1.C(NCC)C>CCOCC>[N+:20](=[C:5]([C:4](=[O:10])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH3:9])=[O:7])=[N-:21]
Reactant: COCC(=O)CC(=O)OC
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCNCC
Solvent: CCOCC
Product: COCC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
Methyl 4-methoxy-3-oxobutanoate (4.28 g, 0.029 mol) was dissolved in ether (20 mL). The solution was cooled in an ice bath. To the solution was added p-toluenesulfonyl azide (5.78 g, 0.029 mol) followed by N-ethylethanamine (2.0 mL, 0.019 mol). The solution was stirred at 0° C. for 15 minutes, then at rt for 30 minutes. Upon evaporation, the tosyl amide bi-product solidified. This was filtered off and the filtrate was purified by flash chromatography to give the desired product (4.5 g, 89%) as a light oil. 1H NMR (400 MHz, CDCl3): δ 4.55 (s, 2H), 3.83 (s, 3H), 3.45 (s, 3H). MF═C6H8N2O4. LCMS calculated for C6H9N2O4 (M+H)+: m/z=173.0.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2[CH:17]=[CH:18][S:19][C:13]=2[C:12]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:11]1.O.Cl.[C:26]1([CH:36]=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>O1CCCC1>[OH:37][CH:36]([C:18]1[S:19][C:13]2[C:12]([CH2:20][CH:21]([CH3:23])[CH3:22])=[N:11][N:10]([CH3:9])[C:15](=[O:16])[C:14]=2[CH:17]=1)[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)Cc1nn(C)c(=O)c2ccsc12
Reactant: O=Cc1cccc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cc1nn(C)c(=O)c2cc(C(O)c3cccc4ccccc34)sc12
Reaction time: 2 h

Procedure:
Lithium diisopropylamide (6.75 mmol) in tetrahydrofuran (8 ml) and 1-naphthaldehyde (0.7 ml) in tetrahydrofuran (5 ml) were added alternately to a solution of 5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one (1 g) prepared in b) above in tetrahydrofuran (20 ml) at 0° C. After 2 hours, water (10 ml) was added, the reaction mixture was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The organic phase was washed once with dilute hydrochloric acid, twice with saturated sodium hydrogen carbonate solution and once with brine, before being dried and evaporated. Purification by chromatography eluting with isohexane/ethyl acetate (1:1), and subsequent HPLC eluting with the same gave the title compound (0.4 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH:18]([NH2:20])[CH3:19])=[C:8]([N:11]3[CH2:17][C:13]4([CH2:16][O:15][CH2:14]4)[CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24](Cl)[N:23]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24]([NH:20][CH:18]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:17][C:13]3([CH2:16][O:15][CH2:14]3)[CH2:12]2)[CH3:19])[N:23]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CC2(COC2)C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CC2(COC2)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a 10 mL vial were added 1-(1-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (81 mg, 0.30 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (50.4 mg, 0.297 mmol) and Et3N (0.083 mL, 0.60 mmol) in DMF (2 mL). The resulting yellow solution was heated to 90° C. and stirred for 5 hours. The reaction mixture was diluted with EtOAc and washed with saturated NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The desired compound was precipitated with ether, filtered, and purified by silica gel column chromatography, eluting with 1:1 EtOAc/hexane to 100% EtOAc to 9:1 EtOAc/MeOH gradient. The resulting yellow foam was further purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium bicarbonate). The fractions containing the product were combined and lyophilized to give the title compounds (racemate) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28-1.40 (m, 3 H), 3.71-3.82 (m, 3 H), 3.96-4.07 (m, 2 H), 4.14-4.25 (m, 2 H), 4.72-4.85 (m, 4 H), 5.44-5.58 (m, 1 H), 6.37-6.45 (m, 1 H), 6.45-6.55 (m, 2H), 6.55-6.66 (m, 2 H), 6.68-6.79 (m, 1 H), 7.08-7.16 (m, 1 H), 7.37-7.45 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H23N9O, 406.2; found 406.5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:18][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 69.6 %

Procedure:
N-tert-butoxycarbonyl glycine (10.57 g, 60.33 mmol) and glycine methyl ester hydrochloride (7.58 g, 60.4 mmol) were dissolved in DMF (60 mL). N,N-diisopropylethyl amine (7.80 g, 60.4 mmol) and HOBt hydrate (9.24 g, 60.3 mmol) dissolved in DMF (40 mL) were added. The solution was cooled to 0° C. (icebath) and EDC hydrochloride (12.72 g, 66.35 mmol) added in small portions. The reaction mixture was stirred for 15 hours before the solvent was evaporated. The residue was taken up in EtOAc (300 mL) and washed with 2 M aqueous H2SO4 (3×50 mL), 7.5% (w/w) aqueous K2CO3 (3×50 mL) and saturated brine (50 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a clear liquid (10.34 g, 70%) with spectral characteristics in accordance with literature data8; δH (300 MHz; d6-DMSO) 8.17 (1H, t, J 6, NH(Gly2)), 6.97 (1H, t, J 6, NH(Gly1)), 3.85 (2H, d, J 6, CαH2(Gly2)), 3.62 (3H, s, OCH3), 3.57 (2H, d, J 6, CαH2(Gly1)), 1.38 (9H, s, (CH3)3); δC (75 MHz; d6-DMSO) 170.2, 169.9, 155.7, 78.0, 51.6, 42.9, 40.4, 28.1; m/z (ESI) 269.1110 ([M+Na]+; C10H18N2O5 requires 269.1113)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[N:22]([C:23]([C:25]4[C:26]([CH3:30])=[N:27][O:28][CH:29]=4)=[O:24])[CH2:21][CH2:20][N:9]2[C:10](=[O:19])[C:11]2[N:12]([C:14]([CH2:17][OH:18])=[CH:15][CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[N:22]([C:23]([C:25]4[C:26]([CH3:30])=[N:27][O:28][CH:29]=4)=[O:24])[CH2:21][CH2:20][N:9]2[C:10](=[O:19])[C:11]2[N:12]([C:14]([CH:17]=[O:18])=[CH:15][CH:16]=2)[CH2:13]3)=[CH:6][CH:7]=1
Reactant: Cc1nocc1C(=O)N1CCN2C(=O)c3ccc(CO)n3CC12c1ccc(Cl)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3ccc(C=O)n3CC12c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 92.6 %

Procedure:
10a-(4-chlorophenyl)-8-(hydroxymethyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (26 mg, 0.061 mmol) in CH2Cl2 (50 mL) was added MnO2 (26.5 mg, 0.30 mmol) and the reaction mixture was heated at 50° C. for 18 h. LCMS analysis after this time showed complete conversion of the starting material alcohol to the target aldehyde. The reaction mixture was filtered twice with a syringe filter and the filtrate was concentrated in vacuo to give 10a-(4-chlorophenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-8-carbaldehyde as a white solid (24 mg, yield 92%) The crude product was used in the next step without further purification. ESI-MI m/z [M+H]+ 425.1.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:24]=2)=[CH:17][CH:16]=1.N1C=CC=CC=1>ClCCCl.C1COCC1>[CH3:21][C:19]1[C:18]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH:24]=2)=[CH:17][CH:16]=[C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])[N:20]=1
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(N)ccc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1nc(NC(=O)NC(=O)C(C)(C)C)ccc1Oc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
A suspension of 2,2,2-trimethylacetamide (0.192 g, 1.897 mmol) in DCE (5 mL) was treated with oxalyl chloride (0.160 mL, 1.897 mmol), stirred at RT for 10 min, then heated at 80° C. for 1 h. The mixture was cooled to RT, added to a solution of tert-butyl (4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)carbamate (0.400 g, 1.264 mmol) and pyridine (0.112 mL, 1.391 mmol) in THF (10 mL) and stirred at RT overnight. The mixture was concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford tert-butyl (4-((2-methyl-6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (367 mg, 65%). MS (ESI) m/z: 444.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[OH:10].P(Br)(Br)[Br:12]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:12])=[CH:4][C:3]=1[OH:10]
Reactant: OCc1ccc(Br)c(O)c1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: Oc1cc(CBr)ccc1Br
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a suspension of 2-bromo-5-hydroxymethylphenol 71 (5.17 g, 25.5 mmol) in chloroform (100 mL) at 0° C. was added a solution of PBr3 (1.21 g 12.7 mmol) in chloroform (60 mL) over 30 min. The resultant solution was stirred at 0° C. for 1 h, and then was warmed to room temperature and stirred for an additional 1.75 h. After this time, the reaction mixture was poured into ice water and extracted with dichloromethane (2×). The organic layers were dried over Na2SO4, filtered, and the filtrate was purified by silica gel chromatography (eluent: dichloromethane:EtOAc, 95:5) to give 72. 1H NMR (400 MHz CDCl3) δ: 4.40 (s, 2H), 5.52 (s, 1H), 6.85 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.06 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H). MS (EI) m/z (M−H−) 263.
Reaction SMILES: O1[CH2:9][C@@H:2]1[C@@H:3]([CH3:8])[CH2:4][C:5]([O-:7])=[O:6].[CH3:10][C:11]([CH3:14])=[CH:12]Br.[Mg]>O1CCCC1.[Cu](Br)Br>[CH3:8][C@@H:3]1[C@@H:2]([CH2:9][CH:10]=[C:11]([CH3:14])[CH3:12])[O:7][C:5](=[O:6])[CH2:4]1
Reactant: CC(C)=CBr
Reactant: C[C@@H](CC(=O)[O-])[C@H]1CO1
Agent: Br[Cu]Br
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)=CC[C@H]1OC(=O)C[C@@H]1C
Temperature: -20 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
500 mg (3.47 mmol) of the epoxide obtained in Example 2 [C'] were dissolved in 10 ml of anhydrous tetrahydrofuran. To the resultant solution, 49.8 mg (0.35 mmol) of copper bromide were further added. To the obtained mixture, Grignard reagent which had been prepared by utilizing 2-methyl propenyl bromide (2.34 g, 17.4 mmol) and magnesium (842 mg, 34.7 mmol) was slowly added dropwise under an argon atmosphere with cooling at -20° C. When the disappearance of the epoxide was confirmed by a gas chromatography, dropwise addition of the Grignard reagent was terminated. The reacted solution was poured into a saturated aqueous ammonium chloride solution, followed by extraction with diethyl ether. The obtained extract was washed with water and saturated sodium chloride aqueous solution, in this order, and dried with anhydrous sulfate. The extract was then filtered, and the filtrate was concentrated. The obtained residue wa dissolved in 10 m of methanol. The resultant solution was added to 10 ml of 10% aqueous sodium hydroxide solution, followed by stirring at room temperature for three hours. Next, methanol in the solution was distilled off under reduced pressure, and the obtained residue was extracted twice with diethyl ether and then the organic layer was separated from the obtained extract. Also, the obtained aqueous layer was acidified with dilute hydrochloric acid, and extracted five times with diethyl ether. The obtained extract was combined with the organic layer obtained before. The combined organic layer was dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. This crude product was purified via silica gel column chromatography (n-hexane:ethyl acetate=10:1 to 5:1), and distilled under reduced pressure to obtain 430 mg of (3S,4R)-3,7-dimethyl-6-octen-4-olide (eldanolide) (yield: 73.8%). This product exhibited the following physical properties:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][CH:41]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)nc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)nc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 28.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(1-propylimidazol-5-yl)methyl]sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.4 g) was dissolved in methylene chloride (42 ml), and a solution of m-chloroperbenzoic acid (0.65 g) in methylene chloride (28 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(1-propylimidazol-5-yl)methyl]sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 297) (0.41 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[N:14][CH:15]=3)[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]([O:30][C:31]([NH:33][CH:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)=[O:32])([CH3:29])[CH3:28].CCN(CC)CC>CC(O)C>[C:27]([O:30][C:31](=[O:32])[NH:33][CH:34]1[CH2:35][CH2:36][CH:37]([NH:40][C:13]2[N:12]=[C:11]3[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:9]=[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=4)[C:16]3=[CH:15][N:14]=2)[CH2:38][CH2:39]1)([CH3:29])([CH3:26])[CH3:28]
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)n2)c2cnc(Cl)nc21
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)n4)nn(COCC[Si](C)(C)C)c3n2)CC1
Temperature: 25 °C

Procedure:
The mixture of 3-(6-bromo-pyridin-2-yl)-6-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 31 supra) (2.65 g, 6.01 mmol), tert-butyl (1r,4r)-4-aminocyclohexylcarbamate (1.53 g, 7.14 mmol) and Et3N (1.4 mL, 9.7 mmol) in IPA (60 mL) was heated at reflux for 16 hours. After cooling to room temperature, the reaction mixture was filtered and solid dried to give {4-[3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester as white powder. (Yield 3.3 g, 89%).
Reaction SMILES: Br.[C:2]1([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:17][C:14]2[S:15][CH:16]=[C:12]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=3)[N:13]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Nc1nc(-c2cccc3ccccc23)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc4ccccc34)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A mixture of 0.5 g of 4-(1-naphthyl)-thiazol-2-ylamine hydrobromide with 0.34 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and extracted twice with 40 ml of ethyl acetate each time. The organic extracts were combined, dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 60 ml of 50% ethanol yielded 0.46 g of 4-methyl-N-(4-naphthalen-1-yl-thiazol-2-yl)-benzenesulfonamide as colorless crystals.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(CC)CC>C1COCC1>[CH:19]1([NH:24][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCC1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C(#Cc1cnc(NC2CCCC2)nc1)c1ccccc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
2-Methanesulfonyl-5-phenylethynyl-pyrimidine (100 mg, 3.11 mmol), cyclopentylamine (80 μl, 6.22 mmol) and Et3N (110 μl, 6.22 mmol) were suspended in 1 ml THF and stirred for 1 hour at 65° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography by directly loading the crude material onto a silica gel column and eluting with (heptane:ethyl acetate 100:0→0:100). The desired compound was obtained as a white solid (85 mg, 83%), MS: m/e=264.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH3:15][O:16][C:17]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:18]=1/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)cc3OC)nc2n(CC)c1=O
Yield: 19.7 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.89 g (13.9 mmol) of 2,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/ethanol to give 0.92 g (yield 20%) of Compound 77 as yellow crystals.