Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8]([NH:34][C:31]2[CH:32]=[CH:33][N:29]([CH2:28][CH2:27][O:26][CH3:25])[N:30]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 71 mg, 0.21 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 72, 32 mg, 0.23 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.11 g, 0.25 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.62 mmol) dropwise and the resulting solution stirred at room temperature over night. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium bicarbonate solution (20 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-12 g column, 50-80% ethyl acetate/hexanes) to give (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (42 mg, 43%) as an off white solid: HR-ES(+) m/e calcd for C23H27N4O3F3 [M+H]+ 465.2108, observed 465.2107; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-2.18 (m, 10H), 3.20 (s, 3H), 3.51-4.28 (m, 4H), 4.60-5.34 (m, 3H), 6.40 (d, J=1.81 Hz, 1H), 7.41-8.28 (m, 5H), 10.93 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C([O-])([O-])=O.[K+].[K+].[CH2:36](I)[CH3:37]>CN(C=O)C.Cl>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:36][CH3:37])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCI
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2CO3 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added EtI (82 mg, 0.52 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCl (50 mL) and extracted with ethyl acetate (3×25 mL). The organic layer was washed with 10% aq. NaHCO3 (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 88 mg (82%) of the title compound as an off white solid.
Reaction SMILES: C([O:3][C:4]([C@:6]12[CH2:11][C@H:10]1[CH2:9][CH2:8][NH:7]2)=O)C.[NH3:12]>CO>[C@:6]12([C:4]([NH2:12])=[O:3])[CH2:11][C@H:10]1[CH2:9][CH2:8][NH:7]2
Reactant: CCOC(=O)[C@]12C[C@H]1CCN2
Reactant: N
Solvent: CO
Product: NC(=O)[C@]12C[C@H]1CCN2

Procedure:
A mixture of (1S,5R)-2-aza-bicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester (2.5 g, prepared by the procedure of Hercouet Tetrahedron Asymmetry 1996, 7, 1267-1268.) and 7 M ammonia in MeOH (20 ml) was heated in a sealed vessel at 80° C. for 5 days. The cooled RM was evaporated and triturated with hexanes/DCM to give the title compound as a beige solid. 1H-NMR (DMSO-d6, 400 MHz): 7.15 (s, 1H), 7.04 (s, 1H), 3.00-2.91 (m, 1H), 2.67 (q, 1H), 1.94-1.83 (m, 1H), 1.74-1.67 (m, 1H), 1.64-1.55 (m, 1H), 1.38-1.31 (m, 1H), 0.90 (t, 1H)).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:24][N:23](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:22][CH2:21][N:20](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:19][CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[NH:10]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: C1CNCCNCCNCNCCNC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 36 %

Procedure:
A mixture-of 1,4,7,11,14-penta(p-toluenesulfonyl)-1,4,7,11,14-pentaazacyclopentadecane prepared as in Example 11C (26.3 g, 0.0258 mole) and concentrated H2SO4 (80 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 h. To the resulting brown solution, ethanol (160 mL) was added dropwise with stirring at 0° C. followed by ethyl ether (400 ml). The resulting tan solid was filtered and dried in vacuo over P2O5. The tarry solid was then dissolved by the addition of 10 N NaOH and the salts were removed by filtration. The solution was then extracted with CHCl3 (6×200 ml). The extracts were combined, dried (Na2SO4) and the solvent was removed in vacuo to give an oil which crystallized on standing. The crude product was dissolved in hexane and insoluble impurities were removed by filtration. Upon cooling to -20° C, 2.28 g (36% yield) of the product was obtained as colorless needles: mp 49-51° C.; 1H NMR (CDCl3) δ 1.69 (m, 4 H), 1.78 (br s, 5 H), 2.76 (m, 20 H). Exact mass: (M+H)+ : calcd., 244. 2501; Found: 244.2557 (C12H30N5).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][CH3:21])[CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[C:4]([NH:22][CH2:23][C@@H:24]([OH:26])[CH3:25])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:34][C:35]#[N:36]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][CH3:21])[CH:14]=3)=[N:10][N:11]([CH2:34][C:35]#[N:36])[CH:12]=2)[CH:5]=[C:4]([NH:22][CH2:23][C@@H:24]([OH:26])[CH3:25])[N:3]=1
Reactant: COc1cc(C)cc(-c2n[nH]cc2-c2cc(NC[C@H](C)O)nc(Cl)n2)c1
Reactant: N#CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C)cc(-c2nn(CC#N)cc2-c2cc(NC[C@H](C)O)nc(Cl)n2)c1
Yield: 43.4 %

Procedure:
In a two-necked round-bottom flask, 4-[2-chloro-6-(2(S)-hydroxypropylamino)-pyrimidin-4-yl]-3-(3-methoxy-5-methylphenyl)-1H-pyrazol (900 mg, 2.4 mmol) was dissolved in acetone (30 mL) to which finely ground potassium carbonate (1.66 g, 12 mmol) was then added and refluxed for 2 hours. Iodoacetonitrile (0.2 mL, 3.36 mmol) was dropwise added, followed by reflux for an additional 2 hours. After completion of the reaction, the solvent was removed by vacuum distillation. The reaction mixture was dissolved in water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation and the residue was purified through column chromatography to produce the title compound (430 mg, 43.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C.CS([N:27]=[N+:28]=[N-])(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[O:15])[C:10](=[N+:27]=[N-:28])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CC(=O)c1c(F)cccc1Cl
Reactant: CS(=O)(=O)N=[N+]=[N-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(=[N+]=[N-])C(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
To a solution of 5.80 g (25.1 mmol) of methyl 3-(2-chloro-6-fluorophenyl)-3-oxopropionate in 60 mL acetonitrile was added 3.9 mL (28 mmol) of triethylamine followed by 3.05 g (25.2 mmol) of methanesulfonyl azide. The mixture was stirred at room temperature for 18 h and concentrated by rotary evaporation. The resulting solid mass was washed with ethyl acetate/hexanes and the washings were filtered through a plug of silica gel. The filtrate was concentrated to give 4.90 g (76%) of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([N:24]1[CH2:25][CH2:26][CH:21]([C:18]2[CH:17]=[CH:16][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:20][CH:19]=2)[CH2:22][CH2:23]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4CCNCC4)cc3)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4CCN(C(C)=O)CC4)cc3)nc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperidin-4-yl)phenyl)quinazolin-4(3H)-one (0.16 mmol) in CH2Cl2 (10 mL) was added Et3N (0.32 mmol) and acetyl chloride (0.17 mmol). The resulting solution was stirred at 0° C. overnight. The solution was concentrated in vacuo, basified with NaHCO3, extracted with CH2Cl2, and washed with water and brine. The material was dried (Na2SO4), filtered, and concentrated to afford the title compound 13 (0.020 g, 30%). 1H NMR (300 MHz, DMSO-d6): δ 11.93 (s, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 6.73 (s, 1H), 6.53 (s, 1H), 4.42-4.64 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.06-3.21 (m, 1H), 2.77-2.94 (m, 1H), 2.54-2.68 (m, 1H), 2.03 (s, 3H), 1.73-1.91 (m, 2H), 1.56-1.73 (m, 1H), 1.36-1.56 (m, 1H), 1.06-1.36 (m, 1H). ESI MS m/z 408 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:12][C:13]1[CH:14]=[C:15]([NH:22][C:23]([C:25]2([CH3:28])[CH2:27][O:26]2)=[O:24])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]>>[OH:26][C:25]([CH3:28])([CH2:27][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1)[C:23]([NH:22][C:15]1[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:13]([CH3:12])[CH:14]=1)=[O:24]
Reactant: COCCc1ccc(O)cc1
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Product: COCCc1ccc(OCC(C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1

Procedure:
2-Hydroxy-3-[4-(2-methoxyethyl)phenoxy]-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 4-methoxyethylphenol and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1% methanol). 1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 2.71 (2H, t, J=6.8 Hz), 3.21 (3H, s), 3.45 (2H, t, J=6.8 Hz), 3.94 (1H, d, J=9.5 Hz), 4.17 (1H, d, J=9.5 Hz), 6.20 (1H, s), 6.82 (2H, d, J=7.8 Hz), 7.10 (2H, d, J=8.0 Hz), 7.89 (1H, d, J=9.0 Hz), 7.94 (1H, s), 8.03 (1H, d, J=8.8 Hz), 10.16 (1H, s).
Reaction SMILES: N[C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[N:9]([CH2:10][CH3:11])[N:8]=[C:7]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH:6]=1.N([O-])=O.[Na+]>Cl.O>[CH2:10]([N:9]1[C:5]([O:4][C:3]2[CH:2]=[CH:23][C:22]([F:24])=[CH:21][CH:20]=2)=[CH:6][C:7]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])=[N:8]1)[CH3:11]
Reactant: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(F)cc1N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(F)cc1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
3-[5-(2-amino-4-fluorophenoxy)-1-ethyl-1H-pyrazol-3-yl]benzonitrile (0.25 g, 0.78 mmol, 1 equiv) was dissolved in a mixture of 1:1 36% aq HCl: 50% aq hypophosphoric (12.7 mL) acid and then cooled to −5° C. Sodium nitrite (3 M in water, 0.27 g, 3.88 mmol, 5 equiv) was added dropwise. The resulting mixture was warmed to 22° C. and stirred for 1 hr. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride then dried over anhydrous magnesium sulfate. The drying agent was filtered and the filtrate was concentrated in vacuo. The residue (0.24 g) was purified by flash-column chromatography on silica gel (0-45% EtOAc:Hex) to give 3-[1-ethyl-5-(4-fluorophenoxy)-1H-pyrazol-3-yl]benzonitrile. Calcd (M+1)+: 308.1. Found 308.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]([O:25][Si](C)(C)C)=[C:22]([CH3:24])[CH3:23]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:18])[C:22]([CH3:24])([CH3:23])[C:21]([O:20][CH3:19])=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To solution of 1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (1.0 g, 4.16 mmol) and 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.85 mL, 4.2 mmol) in 10 mL of dry DCM at 0° C. was added TiCl4 (0.8 mL of 1.0 M DCM solution, 0.8 mmol) The reaction was stirred 2 h and then quenched with aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography eluting with 1:2 EtOAc/hexane to give 700 mg (50% yield) of methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2-dimethylpropanoate. MS found: (M+H)+=343.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:19]1[N:20]=[C:21]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:22]2[CH:27]=[C:26]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]3)[S:25][C:23]=2[N:24]=1>>[CH3:8][C:7]1[CH:6]=[C:5]([C:19]2[N:20]=[C:21]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[C:22]3[CH:27]=[C:26]([CH2:28][N:29]4[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:36])=[O:37])[CH2:33][CH2:34]4)[S:25][C:23]=3[N:24]=2)[CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: Cc1cc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cnc1C

Procedure:
2,3-Dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine was reacted with 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine in General Procedure A. Purification on silica yielded 371. NMR: (CDCl3): (400 MHz, CDCl3): 2.40 (3H, s, Me), 2.59 (3H, s, Me), 2.63-2.68 (4H, m), 2.82 (3H, s, Me), 3.29-3.31 (4H, m), 3.84 (2H, s, CH2), 3.90-3.92 (4H, m), 3.98-4.00 (4H, m), 7.17 (1H, s, Ar), 8.41 (1H, s, Ar) and 9.35 (1H, s, Ar). MS: (ESI+): MH+ 503.15
Reaction SMILES: C(O[C:4]([CH:6]1[C:14](=[O:15])[C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:16])=[O:5])C.[C:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[C:17]1([NH:27][C:4]([CH:6]2[C:14](=[O:15])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:16])=[O:5])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1C(=O)c2ccncc2C1=O
Reactant: Nc1cccc2ccccc12
Product: O=C(Nc1cccc2ccccc12)C1C(=O)c2ccncc2C1=O

Procedure:
In a similar manner to Example 1a, 5,7-dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid naphthalen-1-ylamide was obtained starting from 5,7-Dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester and naphthalen-1-ylamine. The desired product was obtained as a light brownish powder. ESI−MS: m/z 317 (MH+); 1H-NMR (DMSO-d6): δ7.38-7.67 (5H, m), 7.91 (1H, d, J=8.1 Hz), 8.38 (1H, d, J=8.7 Hz), 8.54 (1H, dd, J=1.1 Hz, 7.6 Hz), 8.57 (1H, d, J=1.1 Hz), 8.75 (1H, d, J=4.9 Hz), 11.61 (1H, brs).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O>CO.C1COCC1.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH2:9]
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(N)ccc1N

Procedure:
6-Methyl-5-nitropyridin-2-amine [CAS 22280-62-2] (0.38 g, 2.48 mmol) was hydrogenated at 50 psi with 10% Pd/C (0.35 g) in MeOH/THF (10 mL) overnight to give 6-methylpyridine-2,5-diamine as a light yellow solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]12[CH2:15][CH:12]([CH:13]=[CH:14]1)[CH:11]=[CH:10]2>C1(C)C=CC=CC=1>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH:10]2[CH2:11][CH:12]3[CH2:15][CH:9]2[CH:14]([S:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:13]3)=[CH:3][CH:4]=1
Reactant: C1=CC2C=CC1C2
Reactant: Oc1ccc(S)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc(SC2CC3CC(Sc4ccc(O)cc4)C2C3)cc1
Temperature: 25 °C

Procedure:
To the reactor of Example 1 was added 66 grams of 4-mercaptophenol, 100 ml. toluene and 24.1 grams of 2,5-norbornadiene. The mixture was reacted for 2.5 hours at 70° C. The mixture was cooled to ambient temperature and after 16 hours the white solid was filtered and washed with benzene. The product contained 17.9% sulfur and had a melting point of 142°-146° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:21][CH2:22][CH2:23][CH2:24]3)[CH2:19][NH:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CN(C(=O)OC(C)(C)C)CC34CCCC4)n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(Nc2ncc(Cl)c(NC3CNCC34CCCC4)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl 4-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (650 mg, 1.45 mmol) in DCM (20 mL) was added CF3COOH (5 mL) and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was concentrated in vacuo and adjusted to pH=8-9 with a saturated Na2CO3 solution, then the mixture was diluted with H2O (20 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), then dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1 to 5/1) to give the product as a white solid (490 mg, 97%).
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:9][CH:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][C:12](Cl)=[O:13]>O>[CH3:9][CH:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][C:12]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13]
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Reactant: CC(C)(C)OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)OOC(C)(C)C)CC(C)(C)C

Procedure:
The reaction is effected in a reactor arrangement of a first reactor of type E with a downstream reactor of type C. Before the start of the reaction, the first reactor is filled with a solution of 25.6% by weight of tert-butyl hydroperoxide and 15.0% by weight of potassium hydroxide in water. 20.2 kg/h of a solution of 70% by weight of tert-butyl hydroperoxide in water, 18.2 kg/h of a solution of 45% by weight of potassium hydroxide in water, 16.2 kg/h of water and 19.2 kg/h of 3,5,5-trimethylhexanoyl chloride are then fed to the first reactor. Cooling with cooling water keeps the internal temperature in the first reactor at 25° C. and in the second reactor at 25° C. The organic phase is removed from the reaction mixture withdrawn from the second reactor. The organic phase is washed successively with an 8% by weight solution of sodium hydroxide in water, with a solution of 10% by weight of sodium sulphite in water comprising acetic acid and with a 1% by weight solution of sodium hydrogen-carbonate in water, and then dried by stripping in a packed column at 34° C. and 47 mbar. 24.6 kg/h of tert-butyl peroxy-3,5,5-trimethylhexanoate are obtained (98.2% based on 3,5,5-trimethylhexanoyl chloride). The space-time yield is 1.98 kg/l·h.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:4]=1[C:5]([C:7]1[C:12]([O:13][CH3:14])=[CH:11][N:10]=[CH:9][C:8]=1[Cl:15])=[O:6].ClC1C=CC=C(C(OO)=[O:33])C=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:4]=1[C:5]([C:7]1[C:12]([O:13][CH3:14])=[CH:11][N+:10]([O-:33])=[CH:9][C:8]=1[Cl:15])=[O:6]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cncc2OC)c(OC)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc(C)c(C(=O)c2c(Cl)c[n+]([O-])cc2OC)c(OC)c1OC
Reaction time: 2 h
Yield: 951.7 %

Procedure:
A chloroform (60 ml) solution of 3.4 g (1 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-methoxypyridine (compound No. 244) was cooled with ice, 4.1 g (1.6 mmol) of m-chloroperbenzoic acid was added thereto, followed by stirring under cooling with ice for 2 hours, and stirring was further conducted at room temperature for 2 hours. 30 ml of a 0.5 mol/l aqueous sodium hydroxide solution was added to the mixture to terminate the reaction, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 3.5 g (yield 85%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-methoxypyridine-N-oxide (m.p. 160-166° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:12]2[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]3[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(C2=Nc3cc(N4CCOCC4)c(C(F)(F)F)cc3NC(=O)C2)ccn1

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-morpholin-4-yl-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M2) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (11 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38](Cl)=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)CO
Product: Cc1nc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-Chloro-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.22) (256 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (190 mg, 32%). MS (ISP) 604.0 [(M+H)+]; mp 216-218° C.