Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])#[CH:9]>>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]#[C:9][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1
Reactant: Cn1ccnc1I
Reactant: C#Cc1ccccc1F
Product: Cn1ccnc1C#Cc1ccccc1F

Procedure:
The title compound, MS: m/e=201.2 (M+H+) was prepared in accordance with the general method of example 1b from 2-iodo-1-methyl-1H-imidazole and 1-ethynyl-2-fluorobenzene.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:25])[C:13]3[C:14](=[C:16]([C:20]4[O:21][CH:22]=[CH:23][CH:24]=4)[N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH3:36])[CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:6][N:5]=1)[CH3:2]>[Pd].C(O)C.O>[CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:25])[C:13]3[C:14](=[C:16]([CH:20]4[CH2:24][CH2:23][CH2:22][O:21]4)[N:17]([CH3:19])[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH3:36])[CH2:31][CH2:30]2)(=[O:27])=[O:28])=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(-c3ccco3)n(C)nc2c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(C3CCCO3)n(C)nc2c(=O)[nH]1
Reaction time: 18 h
Yield: 32.6 %

Procedure:
A mixture of the title compound from example 61 (80 mg, 0.16 mmol) and 10% palladium on charcoal (10 mg) in ethanol (4.5 ml) and water (0.5 ml) was hydrogenated at 60 psi (414 kPa) and 40° C. for 18 hours. The reaction mixture was filtered through Celite®, and the filtrate evaporated under reduced pressure to afford the title compound, (27 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[NH2:20][C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([NH:20][C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CC(C)(N)CNC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CNC(=O)OCc1ccccc1)NC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 17 h
Yield: 90.7 %

Procedure:
The title compound of Example 2 (5.0 g, 17.0 mmol) in 100 mL of CH2Cl2 was combined with molecular sieves #5A (5 g), the product of Example 17 (3.8 g, 17.0 mmol), and triethylamine (Et3N, 2.4 mL, 17.2 mmol). After stirring the reaction at room temperature for 17 hours, another 3.1 g of the product of Example 17 was added and stirring was continued for another 17 hours. The reaction was filtered and the filtrate was stripped of all solvent under reduced pressure to yield a white foam solid that was purified by HPLC on silica gel to give 7.4 g of the title material as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)C.[H][H]>C(O)C.[Pd]>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]([CH3:4])=[C:2]([OH:1])[CH:9]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C)c(O)c1
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A solution of 2-hydroxy-4-methoxy-benzaldehyde (5.00 g, 32.86 mmol) and palladium under carbon (10%) (3.50 g, 3.28 mmol) in ethanol (32 mL) and acetic acid (3 mL) is stirred under 60 psi of hydrogen. After stirring overnight, the mixture is filtered off through Celite and washed with methanol. The mixture is concentrated under reduced pressure, and purified by flash chromatography by eluting with hexane:ethyl acetate 2:1 to afford the title compound (3.96 g, 87%). Rf=0.58 (hexane:ethyl acetate 2:1). δ1HNMR (300 MHz, CDCl3): 2.18 (s, 3H), 3.75 (s, 3H), 6.42 (m, 2H), 7.00(d, 1H, J=8.9 Hz).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([CH:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:7])#[N:2].[CH2:22]([Mg]Br)[CH:23]([CH3:25])[CH3:24]>O1CCCC1.CCOCC>[C:1]([CH2:3][CH2:4][O:5][C:6]([CH2:8][C:9]1([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)=[O:7])#[N:2]
Reactant: CC(C)C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)OCCC#N)CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC1(CC(=O)OCCC#N)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The process is performed according to the procedure described in Example 18 (step 18.1.). Starting with 5.00 g (16.99 mmol) of tert-butyl 4-(cyanoethoxycarbonylmethylene)piperidine-1-carboxylate (WO 2006/001 752) in 56 mL of tetrahydrofuran, and 16.99 mL (33.97 mmol) of a 2M solution of isobutylmagnesium bromide in ether, 1.46 g of pure product are obtained in the form of a wax.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.Cl.CN(C)[CH2:26][CH2:27]CN=C=NCC.C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([O:15][CH2:26][CH3:27])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C

Procedure:
5 g of Boc-Phe(4-NO2)-OH, 3.09 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 5 ml of ethanol and 2 g of dimethylaminopyridine were stirred in dichloromethane for 3 days. The obtained substance was washed with 1N hydrochloric acid, an aqueous solution of saturated sodium hydrogen carbonate and saturated NaCl solution, and dried with magnesium sulfate. The solvent was removed to obtain the title compound.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>C(O)CCC>[Cl:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([NH:15][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=2[O:11][CH3:10])[CH:28]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cc(Cl)ncn2)c(OC)c1
Temperature: 100 °C
Yield: 85.2 %

Procedure:
N,N-Diisopropylethylamine (8.10 mL, 46.50 mmol) and 2,4-dimethoxybenzylamine (2.52 mL, 16.78 mmol) were added to a solution of 4,6-dichloropyrimidine (2.50 g, 16.78 mmol) in butanol (80 mL) and reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and washed with water (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic layers were dried over anhydrous MgSO4, filtered and evaporated. The residue was triturated in heptane to give the title compound (4.00 g, 85%) as a solid.
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]2=[O:28])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]2=[O:28])=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(C(C)C)N1CCN(Cc2ccc(OCc3ccccc3)cc2)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C(C)C)N1CCN(Cc2ccc(O)cc2)C1=O
Yield: 96.9 %

Procedure:
Ethyl 2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (400 mg; 0.97 mmol) was dissolved in ethanol (20 ml). Pd(OH)2 (100 mg; 0.71 mmol) was added thereto, and hydrogenation was carried out under about 1 atm. of hydrogen for 3 h. The catalyst was filtered off through kieselguhr and washed with ethanol (2×; 20 ml). The solvent was removed under reduced pressure. Purification of the residue by column chromatography (SiO2) resulted in ethyl 2-(3-(4-hydroxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (300 mg; 0.94 mmol). MS: 321.35 (M+H); Rt: 1.24 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21].[NH2:26][C:27]1[C:31]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:30][NH:29][N:28]=1>>[F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[N:28]3[N:29]=[CH:30][C:31]([C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[C:27]3[N:26]=2)=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(OCC(F)(F)F)c(C(F)(F)F)c1
Reactant: Nc1n[nH]cc1-c1cccnc1
Product: FC(F)(F)COc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)cc1C(F)(F)F
Yield: 68.7 %

Procedure:
Reaction of 1-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-trifluoroethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (174 mg, 69%). MS (ISP) 507.5 [(M+H)+]; mp 181° C.
Reaction SMILES: O=C(CC)C[N:4]1[CH:8]=[C:7](C2C=CC=CC=2)[N:6]=[CH:5]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:6]1[C:7]2=[N:4][CH:8]=[CH:7][NH:6][CH:8]2[NH:4][CH2:5]1
Reactant: CCC(=O)Cn1cnc(-c2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=CNC2NCNC2=N1
Temperature: 20 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
2-[1(S)-{1,1-Dimethylethoxy)carbonylamino}-2-phenylethyl]-1-(2-oxo-butyl)-4-phenyl-1H-imidazole (60 mg) in a mixture of 10% TFA in DCM was stirred at about 20° C. for about 3 hours and then concentrated under reduced pressure. The resulting intermediate dihydro-imidazo-pyrazine was dissolved in methanol and borohydride supported on resin (AMBERLITE® IRA 400, Aldrich, 2.5 mmol BH4−/g; 4 eq) was added. The pH was maintained at about 5 by addition of drops of TFA. After about 2 hours of stirring at about 20° C., the mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/Heptane 7:3; Rf=0.30). The tetrahydro-imidazo-pyrazine was obtained as a single diastereoisomer in 86% yield (38 mg). NMR (1H, 400 MHz, CDCl3) δ: 7.80-7.10 (m, 11H, arom. H), 4.28 (dd, 1H, 3J=10 Hz, 3J=3 Hz, H8), 3.95 (dd, 1H, 2J=11.5 Hz, 3J=3.6 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=3.0 Hz), 3.60 (t, 1H, 2J=3J=11.5 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=10. Hz), 2.98 (m, 2H), 1.85 (s, 1H, NH), 1.55 (m, 2H, CH2), 0.95 (t, 3H, CH3). NMR (13C, 100 MHz, CDCl3): 146.3, 140.9, 138.0, 134.4, 129.4, 128.6, 128.5, 126.6, 126.5, 124.8, 113.8, 55.9, 54.4, 50.2, 40.0, 26.6, 10.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2].[Cl:21][CH2:22][C:23](Cl)=[O:24].O>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1[N:7]=[C:8]([NH:11][C:23](=[O:24])[CH2:22][Cl:21])[S:9][CH:10]=1)[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(N)n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)c1csc(NC(=O)CCl)n1
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 1.26 g of α-t-butyloxycarbonylamino-α-(2-aminothiazol-4-yl)acetic acid ethyl ester in 5 ml of N,N-dimethylacetamide is added 708 mg of chloroacetyl chloride under stirring. After the stirring for further 1 hour at room temperature, the reaction solution is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate aq. solution and then water and dried over anhydrous magnesium sulfate. The distillation of the solvent gives 1.435 g of α-t-butyloxycarbonylamino-α-[2-(chloroacetamido)thiazol-4-yl]acetic acid ethyl ester as crystals (yield, 90.8%). Melting point: 192°-193° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][S:9]([O:12][CH2:13][CH2:14][N:15]1[C:19]([NH2:20])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[N:16]1)(=[O:11])=[O:10].C(OC(C)C)(C)C>C(O)=O>[CH3:8][S:9]([O:12][CH2:13][CH2:14][N:15]1[C:19]([NH:20][CH:1]=[O:3])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[N:16]1)(=[O:10])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cnn(CCOS(C)(=O)=O)c1N
Solvent: CC(C)OC(C)C
Solvent: O=CO
Product: CCOC(=O)c1cnn(CCOS(C)(=O)=O)c1NC=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of acetic anhydride (184 ml) and formic acid (93 ml) was stirred for 30 minutes at room temperature. The mixture was cooled at 5° C. with ice-bath and added to 1-(2-methylsulfonyloxyethyl)-4-ethoxycarbonyl-5-aminopyrazole (270 g). The mixture was stirred for 3 hours under ice-cooling. The reaction mixture was evaporated to give crystals. To the crystals was added diisopropyl ether and the mixture was stirred for 1 hour. The crystals were collected by filtration to give 1-(2-methylsulfonyloxyethyl)-4-ethoxycarbonyl-5-formamidopyrazole (291.5 g).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([OH:27])=[O:26])[CH:21]=[CH:22][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([O:26][C:25](=[O:27])[CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=1)[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:46]2
Reactant: O=C(O)C(Nc1ccccc1)c1cccc(F)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
PS-DCC (982 mg, 1.31 mmol, loading: 1.33 mmol/g) is suspended in dry THF (15 mL). (3-fluoro-phenyl)-phenylamino-acetic acid hydrochloride (I98) (184 mg, 0.65 mmol), HOBT (200 mg, 1.31 mmol), and (R)-quinuclidin-3-ol (249 mg, 1.96 mmol) are added and the mixture is shaken at RT overnight. PS-DCC is filtered off and the filtrate is evaporated. The residue is dissolved in EtOAc and washed with NaHCO3, water and brine. The organic layer is dried over Na2SO4, filtered and evaporated to dryness. The crude compound is purified by filtration through a pad of silica-gel using DCM/MeOH=9/1 as the eluent. The title compound is obtained as a colorless oil (129 mg, 56% yield, mixture of diastereoisomers).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[C:15](=O)[CH3:16].[NH2:21][C:22]1[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=1>C(O)(C)C>[C:18]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:23]2[C:24](=[O:28])[NH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:15]=1[CH3:16])(=[O:20])[CH3:19]
Reactant: Nc1cc[nH]c(=O)c1
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Solvent: CC(C)O
Product: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12

Procedure:
4.00 g (14.79 mmol) of 3-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]pentane-2,4-dione and 1.63 g (14.79 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] are dissolved in 40 ml of isopropanol and heated at the reflux temperature under argon for 4 days. The mixture is then concentrated and the residue is recrystallized from methanol. 4.1 g (76% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[CH2:42]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Nc2ncnc3c2cnn3C2CCN(Cc3ccccc3)CC2)c(F)c1

Procedure:
[1-(1-Benzyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(2-fluoro-4-methanesulfonylphenyl)-amine was prepared according to General Procedure F by the reaction of 4-[4-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 1) with trifluoroacetic acid in dichloromethane followed by reaction with benzyl bromide (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.87-1.90 (m, 2H), 2.13-2.24 (m, 4H), 2.93-2.97 (m, 2H), 3.54 (s, 2H), 4.67-4.72 (m, 1H), 7.25-7.35 (m, 5H), 7.78-7.81 (m, 1H), 7.88-7.91 (m, 1H), 8.20-8.24 (m, 1H), 8.38-8.41 (m, 2H), 11.71 (s, 1H). Mass spectrum MH+=481.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][N:5]=1)([CH3:3])[CH3:2].CC([O-])(C)C.[K+].C1(P(O[NH2:36])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[NH2:36][N:6]1[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1n[nH]c(=O)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1nn(N)c(=O)c2ccccc12
Reaction time: 0.75 h
Yield: 109.2 %

Procedure:
A mixture of the product of Example 1A (30.0 mg, 0.159 mmol) and KOtBu (1 M in THF, 0.32 mL, 0.32 mmol) in THF (1 mL) was stirred for 45 minutes, and O-(diphenylphosphoryl)hydroxylamine (57.6 mg, 0.247 mmol) [Klotzer, W.; Stadlwieser, J.; Raneburger, J. Organic Syntheses 1986, 64, 96-103] was added and stirred overnight. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and concentrated to give 35.3 mg of crude product as a tan solid, which was used without purification. 1H NMR (300 MHz, DMSO-d6) δ 8.31 (dd, 1H), 8.09 (d, 1H), 7.92 (ddd, 1H), 7.84 (ddd, 1H), 6.31 (s, 2H), 3.63 (quin, 1H), 1.30 (d, 6H); LC/MS (APCI) M/Z 204.1 (M+H)+.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C1COCC1>[N:38]1([CH2:26][CH2:25][CH2:24][O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OCCCN3CCOCC3)cc12
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) and morpholine (0.45-0.75 mmol) in THF (10 mL) was stirred at 90° C. for about 2 hours in a sealed tube. After cooling to ambient temperature the reaction mixture was solvent evaporated. It was dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.5% ammonium hydroxide/5.0% methanol in chloroform. 5-(3-Morpholin-4-yl-propoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as a light yellow solid (74.4 mg, 100%) was obtained. This product was dissolved in methanol, and ethereal hydrochloride was added. Concentrating and drying in vacuo 83° C. for 24 hours yielded the hydrochloride as a yellow foam (74.5 mg, 100%); Mass Spectrum (+EI, [M+H]+) m/z 452. 1HNMR (500 MHz, DMSO-d6): δ14.15 (s, 1H), 10.56-10.62 (br, 1H), 8.75 (d, 1H, J=8.66 Hz), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.29 (d, 1H, J=2.32 Hz), 7.07-7.10 (m, 1H), 4.10 (t, 2H, J=5.86 Hz), 3.93-3.96 (m, 2H), 3.71-3.77 (m, 2H), 3.43-3.46 (m, 2H), 2.99-3.15 (m, 2H), 2.14-2.22 ppm (m, 2H). Elemental Analysis for C24H25N3O5S.1.00 mol HCl.1.30 mol H2O: Calcd: C, 56.36; H, 5.36; N, 8.22; Found: C, 56.05; H, 5.65; N, 8.09.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:40]=[CH:41][C:42]=1[O:43]CC1C=CC=CC=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:39])[C:21]=1OC(CCCCC(OCC1C=CC=CC=1)=O)=O)=[CH:18][CH:17]=[CH:16][CH:15]=2)C1C=CC=CC=1.C1COCC1>[OH-].[OH-].[Pd+2].CCO>[OH:8][C:9]1[CH:10]=[C:11]([CH:40]=[CH:41][C:42]=1[OH:43])[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:39])[CH:21]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: O=C(CCCCC(=O)Oc1c(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2ccccc2c1=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(O)c(O)c2)oc2ccccc12
Yield: 87.1 %

Procedure:
A mixture of 3′,4′-dibenzyloxy-3-(benzyloxycarbonylbutylcarbonyloxy)flavone (2.12 g, 3.16 mmol) and Pd(OH)2 (107 mg) in 9:1 THF:EtOH containing 0.05% acetic acid (50.0 mL) was treated with H2 under high pressure for 5 h. The reaction mixture was filtered (Celite) and concentrated to give a dark green solid. The green residue was purified by flash chromatography (30-90% THF/toluene+1% acetic acid) followed by crystallization from THF/petroleum spirits to yield the pure hemiadipate as a pale brown solid (0.70 g, 56%); mp=194-197° C.; 1H NMR (399.8 MHz, CDCl3); δ 1.44-1.62 (m, 4H, CH2CH2); 2.10 (t, 2H, J=6.8 Hz, CH2CO); 2.44 (t, 2H, J=6.8 Hz, CH2CO); 6.73 (d, 1H, J5′,6′=8.4 Hz, H5′); 7.09 (dd, 1H, J2′,6′=2.0 Hz, J5′,6′=8.4 Hz, H6′); 7.16-7.22 (m, 2H, H6, 2′); 732 (d, 1H, J7,8=8.0 Hz, H8); 7.48 (ddd, 1H, J5,7=1.6 Hz, J6,7=6.8 Hz, J7,8=8.0 Hz, H7); 7.94 (dd, 1H, J5,6=8.4 Hz, J5,7=1.6 Hz, H5). 13C NMR (100.5 MHz, d6-DMSO) δ 25.30, 25.62 (2C, CH2CH2CO2); 34.43, 34.81 (2C, CH2CO2); 116.59, 117.42, 119.98, 121.41, 122.06, 124.13, 126.51, 127.07, 133.32, 136.04, 146.97, 150.65, 156.35, 157.27 (14C, Ar); 171.97, 173.46, 179.95 (3C, C═O). Anal. Found; C, 68.89; H, 4.91; C21H18O6 requires C, 68.85; H, 4.95%. HRMS (ESI+) m/z 389.1000, C21H18NaO6 [M+Na]+ requires 389.1001.