Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.[CH2:26]([SH:30])[CH2:27][CH2:28][CH3:29].[OH-].[K+].CN1CCCC1=O.Cl>>[CH2:26]([S:30][C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCS
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCCCSc1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)nc2c1
Temperature: 150 °C
Reaction time: 4.5 h

Procedure:
5-Chloro-2-(2-hydroxy-3,5-di-tert-butylphenyl)2H-benzotriazole (21.2 g, 0.06 mol), n-butyl mercaptan (7.2 g, 0.08 mol), potassium hydroxide (6.7.1 g, 0.12 mol) and N-methylpyrrolidone (50 g, 0.5 mol) are charged to a reactor and heated to 150° C. The reaction mass is held at 150° C. for 4.5 hours at which time it then cooled to ambient temperature. A mixture of 15 g of concentrated hydrochloric acid aand 70 g of ice are then added to the reactor. The solids are filtered off and washed with water. Thirty gram of crude, wet, yellow crystals are obtained as the title compound. This product can be used “as is” in procedure of Example 33.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([NH2:28])=[O:27])[CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cc(-c2ccnn2-c2ccc(F)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: NC(=O)Nc1cc(-c2ccnn2-c2ccc(F)cc2)ccn1
Temperature: 50 °C
Yield: 73.4 %

Procedure:
To the solution of 4-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-pyridin-2-ylamine (83 mg, 0.33 mmol) in DCM (3.0 mL) is added benzoyl isocynate (96 mg, 0.65 mmol). The resulting mixture is heated at 50° C. for 1 hour. The solvent is then carefully removed in vacuum and to the residue are added K2CO3 (54 mg, 0.39 mmol) and ethanol (2 mL). The reaction mixture is then heated at 85° C. for 30 min. Solvent is again removed in vacuum and the residue is purified through a Silica column eluting with 0-100% EtOAc/Heptane to give the titled compound (72 mg).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([NH2:8])=[O:7])(N)=[O:2].[C:9]1([CH2:17][NH2:18])[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]N)[CH:10]=1>CN1CCCC1=O>[NH:5]1[C:6](=[O:7])[N:8]([CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH2:17][N:18]3[C:6](=[O:7])[NH:5][NH:4][C:1]3=[O:2])[CH:10]=2)[C:1](=[O:2])[NH:4]1
Reactant: NC(=O)NNC(N)=O
Reactant: NCc1cccc(CN)c1
Solvent: CN1CCCC1=O
Product: O=c1[nH][nH]c(=O)n1Cc1cccc(Cn2c(=O)[nH][nH]c2=O)c1

Procedure:
64.2 g of hydrazodicarbonamide and 37 g of m-xylylene diamine in 300 ml of N-methyl pyrrolidone are heated with stirring for 4 hours to 175° C. and for 30 hours to 200° C. The solvent is then distilled off in vacuo and the residue is recrystallised from chloroform, giving 58 g (70% of the theoretical) of 1,3-bis-(1,2,4-triazolidine-3,5-dione-4-yl-methyl)-benzene in the form of colourless crystals melting at 244° to 246° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.CN(C)C=O.[C-]#N.[Na+].[C:23](#[N:27])[CH:24]=[CH:25][CH3:26]>O>[CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([C:11](=[O:12])[CH:25]([CH3:26])[CH2:24][C:23]#[N:27])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC=CC#N
Reactant: Cc1nccn1-c1ccc(C=O)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1-c1ccc(C(=O)C(C)CC#N)cc1
Temperature: 30 °C

Procedure:
To a mixture of 33.6 g of 4-(2-methyl-1-imidazolyl)benzaldehyde and 400 ml of dimethylformamide under a nitrogen atmosphere was added 0.78 g of sodium cyanide and then with stirring at 30° C. 10.7 g of 2-butenenitrile was added dropwise. The reaction mixture was stirred at 25° C. under nitrogen for another 16 hours. Following the addition of one liter of water the mixture was extracted with chloroform, and the chloroform phase was washed with water, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel/chloroform) and then reprecipitated with chloroform/hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:29])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: COC1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-methoxypiperidin-1-yl)quinolin-7-yl]ethanone (0.0206 g, 0.0646 mmol) and ammonium acetate (0.0498 g, 0.646 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.16 mL, 0.16 mmol). The reaction was heated at 65° C. overnight. The resulting mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined extracts were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H23ClN3O (M+H)+: m/z=320.2; Found: 320.1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=2)[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]1=[O:25].CCN(C(C)C)C(C)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[CH2:18]([N:4]1[C:5]2[C:10](=[N:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=2)[CH2:11][CH:2]([NH:1][S:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:43])=[O:42])[C:3]1=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1Cc2nc(-c3ccccc3)ccc2N(Cc2ccccc2)C1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C(NS(=O)(=O)c2ccccc2)Cc2nc(-c3ccccc3)ccc2N1Cc1ccccc1
Reaction time: 0.08 h
Yield: 69.5 %

Procedure:
To a solution of 2B (63 mg, 0.19 mmol) in CH3CN (2 mL) at RT was added DIPEA (50 μL, 0.285 mmol), followed by benzenesulfonyl chloride (27 μL, 0.21 mmol). After 5 min, white precipitates formed. The reaction was stirred for additional 15 min. The product was collected by filtration and the solid washed with CH3CN (2-3 mL) to give the title compound as a white solid (62 mg, 70%). LC/MS (method A): RT=3.58 min, (M+H)+=470. 1H NMR (CDCl3, 400 MHz): δ 8.41 (d, J=7.4 Hz, 1H), 8.04 (d, J=7.3 Hz, 2H), 7.96 (d, J=7.3 Hz, 2H), 7.82 (d, J=8.6 Hz, 1H), 7.62-7.70 (m, 3H), 7.50 (t, J=7.3 Hz, 2H), 7.44-7.47 (m, 2H), 7.25-7.44 (m, 5H), 5.16 (s, 2H), 4.4-4.55 (m, 1H), 3.25-3.31 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:30]=[CH:29][C:5]2[N:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]5[CH2:28][CH2:27][CH2:26]5)[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH:25]1([N:22]2[CH2:21][CH2:20][CH:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]([C:7]4[N:8]([CH3:11])[C:9](=[O:10])[C:4]5[CH:3]=[CH:2][N:30]=[CH:29][C:5]=5[N:6]=4)=[CH:13][CH:14]=3)[CH2:24][CH2:23]2)[CH2:26][CH2:27][CH2:28]1
Reactant: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2cnc(Cl)cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2cnccc2c1=O
Yield: 14.9 %

Procedure:
6-Chloro-2-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (40.8 mg, 0.096 mmol) produced in Example 30 and triethylamine (77 μL, 0.48 mmol) were dissolved in ethyl acetate (0.5 mL), and 10% palladium-carbon (10 mg) was added thereto and stirred in a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered through Celite, then the Celite was washed with ethyl acetate, and the mother liquid was concentrated. The residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the entitled compound (5.6 mg, 15%) as a pale yellow solid. The resulting compound was recrystallized from ethanol-water to give a colorless solid (m.p. 147.0-148.0° C.).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][CH2:13][C:14]2[CH:19]=[N:18][NH:17][C:16](=[O:20])[CH:15]=2)=[CH:10][CH:9]=1.[OH:23][C:24]([CH3:39])([CH3:38])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[O:36][CH3:37].Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]2[CH:19]=[N:18][N:17]([C:30]3[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:24]([OH:23])([CH3:39])[CH3:38])=[C:28]([O:36][CH3:37])[CH:29]=3)[C:16](=[O:20])[CH:15]=2)=[CH:21][CH:22]=1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Reactant: O=c1cc(COc2ccc(Cl)cc2)cn[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-n2ncc(COc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O

Procedure:
Pyridine (0.123 mL, 1.52 mmol) was added in portions over 4 hr to a stirred mixture of 5-((4-chlorophenoxy)methyl)pyridazin-3(2H)-one Part B (36 mg, 0.15 mmol), copper(II) acetate (91 mg, 0.46 mmol), and 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (73.0 mg, 0.30 mmol) in CH2Cl2 (15 mL) at RT (flask left open to air). The mixture was poured into 3.0 N aqueous HCl (100 mL) and extracted with CH2Cl2. The CH2Cl2 layer was dried over Na2SO4 and concentrated. The crude product was purified by prep-HPLC (C18 column/H2O:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient) giving the title compound 5-((4-chlorophenoxy)methyl)-2-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridazin-3(2H)-one E-2 (25 mg, 38% yield) as an off-white solid. LC/MS 431 (M+H)+, tR 0.93 min (method 5); 1H NMR (500 MHz, Chloroform-D) δ ppm 7.94 (1H, d, J=1.92 Hz), 7.30 (2H, d), 7.12-7.17 (2H, m), 7.09 (1H, br. s.), 6.98 (1H, d, J=8.25 Hz), 6.91 (2H, d), 4.97 (2H, s), 3.82-3.92 (5H, m), 1.35 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9]CC)=O)[N:6]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.N>>[Cl:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:9])[N:6]=1
Reactant: CCOC(=O)c1coc(Cl)n1
Reactant: Nc1ccc(Cl)cc1
Agent: N
Product: O=C(Nc1ccc(Cl)cc1)c1coc(Cl)n1

Procedure:
Prepared from ethyl 2-chlorooxazole-4-carboxylate (83.5 mg, 0.475 mmol) and 4-chloroaniline (60.5 mg, 0.475 mmol) as described in Example 154A: 1H NMR (500 MHz, DMSO-D6) δ ppm 7.37-7.45 (m, 2H), 7.81-7.89 (m, 2H), 8.91 (s, 1H), 10.45 (s, 1H) MS (DCI/NH3) m/z=274 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]([C:11]2[C:16](=[O:17])[C:15](Br)=[C:14]([CH3:19])[N:13]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH:12]=2)=[O:10])=[N:4][N:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]([C:11]2[C:16](=[O:17])[C:15]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)=[C:14]([CH3:19])[N:13]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[CH:12]=2)=[O:10])=[N:4][N:3]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1nnc(CNC(=O)c2cn(C3CCC3)c(C)c(Br)c2=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nnc(CNC(=O)c2cn(C3CCC3)c(C)c(-c3cccc(C(F)(F)F)c3)c2=O)o1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-1-cyclobutyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amide (preparation 24, 44 mg, 0.115 mmol), 3-(trifluoromethyl)phenyl-boronic acid (26 mg, 0.137 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13 mg, 0.018 mmol) in acetonitrile (0.5 mL) is added 2 M aqueous K2CO3 solution (0.10 mL, 0.20 mmol). After stirring for 18 h at 75° C., the reaction mixture is filtered and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 40 mg (78% of theory); ESI mass spectrum: [M+H]+=447; Retention time HPLC: 1.09 min (Z003_001).
Reaction SMILES: [ClH:1].C(OC([NH:12][CH:13]([C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:38])[NH2:37])=[CH:32][CH:31]=1)[P:14]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:22])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O)C1C=CC=CC=1.[H][H]>CO.Cl.[Pd]>[ClH:1].[ClH:1].[NH2:12][CH:13]([C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:37])[NH2:38])=[CH:32][CH:31]=1)[P:14]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:22])[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N=C(N)c1ccc(C(NC(=O)OCc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C(N)c1ccc(C(N)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1

Procedure:
A sample of 1.8 g of diphenyl N-benzyloxycarbonylamino(4-amidinophenyl)methanephosphonate hydrochloride was dissolved in 150 ml of 2N HCl methanol solution and after addition of 5% Pd/C catalyst, the solution was stirred under an atmosphere of hydrogen until the theoretical amount of hydrogen was consumed. The catalyst was removed by filtration and after evaporation of the methanol, the residue was crystallized from ethanol-ether. In several experiments, the yields were 60-80%; mp. 213°-215° C.; Anal. Calcd. for C20 H22N3ClP.1/2 H2O: C,51.85; H, 4.97; N, 9.08; Cl, 15.34. Found: C, 51.73; H, 5.02; N, 9.10; Cl, 15.36.
Reaction SMILES: [CH:1]([O:3][CH3:4])=[CH2:2].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH:7]=[CH:6]1>O>[CH:1]([O:3][CH3:4])=[CH2:2].[C:5]([OH:10])(=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:3])=[O:9]
Reactant: O=C1C=CC(=O)O1
Agent: C=COC
Solvent: O
Product: O=C(O)/C=C\C(=O)O

Procedure:
Copoly(methyl vinyl ether:maleic anhydride)(50:50) (Grantrez AN-119 available from GAF)(20.6 grams) was suspended in 80 grams of water and heated on a steam bath to form a 20% solids clear solution of copoly(methyl vinyl ether:maleic acid) (50:50) in water. To 61.8 grams of the solution (containing 12.4 grams of copolymer and 8.26 grams (0.072 mole) of maleic acid)) was added 4.0 grams (0.072 mole) of potassium hydroxide in order to half-neutralize all maleic acid present. Glycerol (9.3 grams) was also added as a plasticizer. The impedance of a bioelectrode prepared with the material was 33 Kohms.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=[CH:9]1)=O)(C)(C)C.[CH3:23][O:24][CH2:25]Cl.C(=O)([O-])O.[Na+]>C(#N)C>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][C:11]1[N:10]([CH2:23][O:24][CH3:25])[CH:9]=[N:8][CH:12]=1)=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)NCCc1cn(C(=O)OC(C)(C)C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COCn1cncc1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
1-t-Butoxycarbonyl-4-{2-(t-butoxycarbonyl-amino)ethyl}imidazole (78.1 g) is dissolved in acetonitrile (500 ml), and thereto is added methoxymethyl chloride (22.2 g), and the mixture is stirred at room temperature overnight. The reaction solution is poured into 10% aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract is washed, dried, and the solvent is distilled off to give 4-{2-(t-butoxycarbonyl-amino)ethyl]-3-methoxymethylimidazole (54.4 g) as oil.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH3:19])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([O:29][C:30](=O)[C:25]=12)=[O:28])(=[O:22])[CH3:21].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:25]=1[C:30](=[O:29])[N:1]([CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH3:19])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])[C:27]2=[O:28])(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 43.3 %

Procedure:
3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid was prepared by the procedure of Example 4 from 3-amino-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (2.7 g, 13 mmol), 3-acetamido-phthalic anhydride (4.0 g, 14.5 mmol) and sodium acetate (1.2 g, 14.5 mmol) in acetic acid (50 ml) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (2.6 g, 45%) as yellowish solid. mp 89-91° C.; 1HNMR (CDCl3): δ 1.42 (t, J=7.5 Hz, 3H, OCH2CH3), 2.51 (s, 3H, CH3CO), 3.19 (dd, J=5.8, 15.5 Hz, 1H, CH2), 3.79 (dd, J=8.4, 15.5 Hz, 1H, CH2), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 5.65-5.71 (m, 1H, CHN), 6.52 (t, JH-F=75 Hz, 1H, CF2H, 7.03-7.11 (m, 3H, Ar), 7.45 (d, J=7.5 Hz, 1H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.72 (d, J=8.3 Hz, 1H, Ar), 9.46 (s, 1H, NHCO). 13C NMR (CDCl3): δ 14.6, 24.8, 35.6, 50.3, 64.7, 98.4, 99.1, 111.8, 113.5, 115.2, 115.9, 118.2, 120.1, 120.2, 122.7, 125.0, 131.0, 136.0, 136.5, 137.4, 138.1, 140.0, 140.1, 140.2, 150.6, 167.4, 169.5, 169.7, 175.1; Anal. Calcd. for C22H20F2N2O7+0.17H2O: C, 56.77; H, 4.40; N, 6.06; H2O 0.66. Found: C, 56.60; H, 4.43; N, 6.02; H2O 0.66.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH:13]=[CH:12][CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:20].C1C=C(Cl)C=C(C(OO)=[O:29])C=1>ClCCl>[O:29]1[C@H:12]2[CH2:11][CH:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@@:2]([CH2:19][CH2:18]1)([CH3:1])[C:3](=[O:20])[CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: ClCCl
Product: C[C@]12C[C@H]3O[C@H]3CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 0 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of compound 2 (320 mg, 1.17 mmol) in anhydrous dichloromethane (25 mL) was added m-CPBA (316 mg, 1.41 mmol) at 0° C. under an atmosphere of argon. The solution was stirred at 0° C. for 3 h. The solution was then diluted with dichloromethane (50 mL) and washed with an aqueous sodium bicarbonate solution (10%). The organic layer was dried with sodium sulfate and evaporated under reduced pressure. The crude compound was purified by flash chromatography (Hexanes/EtOAc: 8:2) to yield compound 22 (260 mg, 78%). 1H NMR (CDCl3) δ: 0.79 (s, 18-CH3), 0.85 (s, 19-CH3), 0.60-2.11 (residual CH and CH2), 2.43 (dd, J1=18.8 Hz, J2=8.7 Hz, 16β-H), 3.12 (t, J=5.8 Hz, 2×CH of epoxide), 3.16 (broad, s, 2×CH of epoxide).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][C:19]([NH:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:20][CH:21]=4)[N:16](COCC[Si](C)(C)C)[N:15]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][C:19]([NH:23][CH2:24][CH2:25][N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[N:20][CH:21]=4)[NH:16][N:15]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:40][CH:41]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccc(Cl)cc3)n2)c2cnc(NCCN3CCOCC3)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2cccc(-c3n[nH]c4nc(NCCN5CCOCC5)ncc34)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-[6-(4-chloro-benzylamino)-pyridin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (100 mg, 0.168 mmol) in dichloromethane (2 mL) was added TFA (2 mL). The reaction mixture was stirred for 2 hours at room temperature. The pH of mixture was then adjusted to about 8 with saturated NaHCO3 solution. The resulting mixture was extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by prep-HPLC to give {3-[6-(4-Chloro-benzylamino)-pyridin-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-(2-morpholin-4-yl-ethyl)-amine. (Yield 20 mg, 26%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:19].[CH2:20]([N:27]1[CH2:32][CH2:31][CH:30]([NH:33][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: CCc1cc(-c2ccc(S(=O)(=O)NC3CCN(Cc4ccccc4)CC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 80 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride was reacted with (1-benzylpiperidin-4-yl)amine as described in Step 5, Example 24 to give the title compound as a solid (80% yield). LC/MS: RT 2.27 min; m/e 472 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[F:39][C:40]([F:50])([F:49])[C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44][NH2:45]>C1COCC1.O>[C:1]([CH2:3][C:4]([NH:45][CH2:44][C:43]1[CH:46]=[CH:47][CH:48]=[C:41]([C:40]([F:39])([F:49])[F:50])[CH:42]=1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)NCc1cccc(C(F)(F)F)c1
Yield: 50.7 %

Procedure:
Cyanoacetic acid (297.0 mg, 3.5 mmol), N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (1.34 g, 7.0 mmol), 1-hydroxybenzotriazole hydrate (641.0 mg, 4.2 mmol) and DIPEA (1.8 g, 14.0 mmol) and 3-(trifluoromethyl)benzylamine (611.0 mg, 3.5 mmol) were suspended in THF. The mixture was heated to 60° for 18 h. Water was added to the mixture and the product extracted with EtOAc, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography, CH2Cl2/MeOH 98:2, yielding 430.0 mg (51%) of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[C:8]2[C@:15]3([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]3)[CH2:14][C@@H:13]([C:22]([OH:24])=O)[O:12][C:9]2=[CH:10][CH:11]=1>>[F:5][C:6]1[CH:7]=[C:8]2[C@:15]3([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]3)[CH2:14][C@@H:13]([C:22]([Cl:3])=[O:24])[O:12][C:9]2=[CH:10][CH:11]=1
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)O)Oc3ccc(F)cc32)N1
Reactant: O=S(Cl)Cl
Product: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1

Procedure:
To thionyl chloride (24.9 ml, 3.57 mol) was added (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxylic acid (20.0 g, 71.4 mmol). After refluxing the mixture under argon atmosphere for 22 hours, the excess thionyl chloride was evaporated in vacuo to dryness to give quantitatively crude crystals of (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride.