Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:43])[C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]([C:17]2[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]3[O:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[C:22]([C:32](=[O:35])[NH:33][CH3:34])[C:21]=3[CH:36]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[CH2:1]([N:8]1[C:9](=[O:43])[C:10]2[N:11]=[C:12]([C:17]3[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]4[O:24][C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[C:22]([C:32]([NH:33][CH3:34])=[O:35])[C:21]=4[CH:36]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH2:44]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(C(=O)NCc4ccccc4)n3)cc12
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)C(=O)N(Cc3ccccc3)CO4)cc12
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
To a solution of N-benzyl-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-hydroxypicolinamide (100 mg, 0.17 mmol) and Cs2CO3 (117 mg, 0.33 mmol) in DMF (20 mL) was added chloroiodomethane (47 mg, 0.25 mmol) dropwise at 110° C. under N2. The mixture was stirred at 110° C. for 0.5 hour. Then the mixture was concentrated and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (DCM:CH3OH=20:1) to afford the product of 5-(3-benzyl-4-oxo-3,4-dihydro-2H-pyrido[2,3-e][1,3]oxazin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 19.6%). 1H-NMR (CDCl3, 400 MHz) δ 7.88˜7.90 (m, 3H), 7.72˜7.74 (m, 1H), 7.55 (s, 1H), 7.34˜7.39 (m, 5H), 7.25˜7.28 (m, 1H), 7.14 (t, J=7.2 Hz, 2H), 6.87 (br s, 1H), 5.19 (s, 2H), 4.76 (s, 2H), 3.14 (s, 3H), 2.93˜2.94 (m, 6H). MS (M+H)+: 615.
Reaction SMILES: [C:1]1([C:7]2[C:8]([NH2:12])=[N:9][O:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:18]CC)(=[O:17])[C:14]([CH3:16])=O>C(O)C.[Pt]>[C:1]1([C:7]2[C:8]([NH:12][CH:14]([C:13]([OH:18])=[O:17])[CH3:16])=[N:9][O:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nonc1-c1ccccc1
Reactant: CCOC(=O)C(C)=O
Agent: [Pt]
Solvent: CCO
Product: CC(Nc1nonc1-c1ccccc1)C(=O)O

Procedure:
4-Phenyl-furazan-3-ylamine (Maybridge) and ethyl pyruvate (Aldrich) were dissolved in dry ethanol. Platinum on sulfide carbon (5%) was added and the resulting mixture was hydrogenated (1000 psi, H2) at 150° C. for 8 hours. The reaction mixture was then filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using CHCl3 as the eluent to provide the title compound as its ethyl ester. The ethyl ester was then hydrolyzed using General Procedure II-A, Method B (LiOH/H2O/dioxane) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.Br[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.[Pd](Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Cl[Mg]c1ccc(Cl)cc1
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 75 %

Procedure:
4-chlorophenylmagnesium chloride (114 g, 18% solution in tetrahydrofuran) is added dropwise over seven hours to a refluxing solution of 4-bromobenzonitrile (20 g), palladium (II) chloride (0.78 g ) and triphenylphosphine (2.3 g) in tetrahydrofuran (100 ml). [HPLC: yield 75-79%]. After cooling to room temperature tetrahydrofuran is removed under vacuum. The residue is taken up in toluene/water (1:1) (200 ml) and filtered. The aqueous phase is separated off, and the solvent removed by distillation. The crude product is recrystallised from isopropanol/ethanol to give 4'-chlorobiphenyl-4-carbonitrile as a solid, m.pt. 128-130° C. 1H NMR (CDCl3): 2.41(s,3H), 7.46(d,2H), 7.53(d,2H), 7.65(d,2H), 7.74(d,2H).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1.Cl.C1C[O:38]CC1>>[OH:38][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Reactant: C1CCOC1
Agent: Cl
Product: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)Nc3ccc(O)nc3)nc3c2CCC3)n[nH]1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of N-(6-fluoro-3-pyridyl)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (500 mg, 1.111 mmol) in THF (10 mL) was added HCl (1 mL) and reaction mixture was stirred at 60° C. for 16 h. The progress of reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum to obtain crude product which was purified by reverse HPLC to afford N-(6-hydroxy-3-pyridyl)-1-[4-[(5-isopropyl-1H-pyrazol-3-yl)amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (249 mg). 1H NMR (400 MHz, CD3OD) δ (ppm): 1.17-1.30 (m, 6H), 2.17-2.37 (m, 4H), 2.38-2.50 (m, 1H), 2.79-2.95 (m, 3H), 3.00-3.10 (m, 2H), 3.22-3.38 (m, 2H), 3.58-3.70 (m, 1H), 3.80 (brs, 1H), 4.81 (dd, 1H), 6.22 (s, 1H), 6.68 (d, 1H), 7.60 (d, 1H), 7.98 (s, 1H). Separation by chiral HPLC provides enantiomers 63a and 63b.
Reaction SMILES: N(C(OCCCC)=O)=NC(OCCCC)=O.[CH3:17][O:18][C:19]([C:21]1[NH:22][CH:23]=[N:24][CH:25]=1)=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[NH:49][C:48](=[O:56])[C:47]1([CH3:58])[CH3:57]>C1COCC1>[CH3:17][O:18][C:19]([C:21]1[N:22]=[CH:23][N:24]([CH:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49][C:48](=[O:56])[C:47]2([CH3:58])[CH3:57])[CH:25]=1)=[O:20]
Reactant: COC(=O)c1cnc[nH]1
Reactant: CC1(C)C(=O)Nc2ccccc2C1O
Agent: CCCCOC(=O)N=NC(=O)OCCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cn(C2c3ccccc3NC(=O)C2(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of di-butyl azodicarboxylate (145 mg, 0.6275 mmol) in 2 mL of dry THF is added dropwise to a suspension of 3H-Imidazole-4-carboxylic acid methyl ester (79 mg, 0.6275 mmol), PPh3 (165 mg, 0.6275 mmol), and 4-Hydroxy-3,3-dimethyl-3,4-dihydro-1H-quinolin-2-one (80 mg, 0.418 mg) in 3 mL of dry THF at 0° C. The resulting mixture is slowly warmed up to room temperature, and stirred for 2 h. The reaction is quenched with 2 M HCl and stirred for another 0.5 h. After concentration, the residue is dissolved in HCl (2 M) and extracted with ethyl acetate (20 mL×3). The aqueous layer is adjusted to pH 8-9 by addition of saturated NaHCO3 solution. Subsequently, the mixture is extracted with ethyl acetate (20 mL×3). The combined extracts are washed with brine, and dried over anhydrous Na2SO4. After concentration, the residue is purified by flash column first then by reverse phase HPLC and gives two title regioisomers.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].BrCCOC1CCCCO1.[CH2:17]([O:24][C:25]1[C:26]([CH2:56][CH3:57])=[C:27]([CH2:40][C:41]2[O:45][C:44](=[O:46])[N:43]([CH2:47][CH2:48][O:49]C3CCCCO3)[N:42]=2)[C:28]([Br:39])=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CO.CN(C)C=O>[CH2:17]([O:24][C:25]1[C:26]([CH2:56][CH3:57])=[C:27]([CH2:40][C:41]2[O:45][C:44](=[O:46])[N:43]([CH2:47][CH2:48][OH:49])[N:42]=2)[C:28]([Br:39])=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCc1c(OCc2ccccc2)cc(OCc2ccccc2)c(Br)c1Cc1nn(CCOC2CCCCO2)c(=O)o1
Agent: BrCCOC1CCCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1c(OCc2ccccc2)cc(OCc2ccccc2)c(Br)c1Cc1nn(CCO)c(=O)o1
Yield: 75 %

Procedure:
In the same manner as in the step 1 in Example 317, a crude product of 5-[3,5-bis(benzyloxy)-6-bromo-2-ethylphenylmethyl]-3-(2-tetrahydropyran-2-yloxyethyl)-3H-1,3,4-oxadiazol-2-one was obtained from 5-[3,5-bis(benzyloxy)-6-bromo-2-ethylphenylmethyl]-3H-1,3,4-oxadiazol-2-one (1.1 g, 2.1 mmol) obtained in the above, using potassium carbonate (740 mg, 5.4 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.49 mL, 3.2 mmol) and N,N-dimethylformamide (15 mL). Thus obtained, 5-[3,5-bis(benzyloxy)-6-bromo-2-ethylphenylmethyl]-3-(2-tetrahydropyran-2-yloxyethyl)-3H-1,3,4-oxadiazol-2-one was dissolved in methanol (30 mL), then treated with methanol solution (10 mL) of 10% hydrogen chloride, and the reaction solution was concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 5-[3,5-bis(benzyloxy)-6-bromo-2-ethylphenylmethyl]-3-(2-hydroxyethyl)-3H-1,3,4-oxadiazol-2-one (0.85 g, 75%).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1
Reactant: BrCCCCCCCCBr
Reactant: O=c1cc(COC2CCCCO2)occ1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=c1cc(COC2CCCCO2)occ1OCCCCCCCCBr
Temperature: 80 °C
Yield: 78 %

Procedure:
The compound was prepared according to the example 11 procedure using 5-hydroxy-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one (1.00 g, 4.42 mmol), Cs2CO3 (1.58 g, 4.86 mmol) and 1,8-dibromooctane (4.12 mL, 22.1 mmol). The sealed tube was heated at 80° C. for 2 h 30. A white solid 5 was obtained (1.40 g, 78% yield).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[C:8]([C:21]1[O:22][CH:23]=[CH:24][CH:25]=1)[N:9]2[C:14]1[CH:15]=[CH:16][C:17](=[O:20])[NH:18][CH:19]=1.[ClH:26].N[C:28]1N=C(C#CC(O)(C)C)N=C2C=1N=C(C1C=CC=C(F)C=1)N2C1C=CC(=O)NC=1.Cl.C(N)C#CC.IC>CO>[ClH:26].[NH2:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[C:8]([C:21]1[O:22][CH:23]=[CH:24][CH:25]=1)[N:9]2[C:14]1[CH:15]=[CH:16][C:17](=[O:20])[N:18]([CH3:28])[CH:19]=1
Reactant: CC(C)(O)C#Cc1nc(N)c2nc(-c3cccc(F)c3)n(-c3ccc(=O)[nH]c3)c2n1
Reactant: Nc1ncnc2c1nc(-c1ccco1)n2-c1ccc(=O)[nH]c1
Agent: CC#CCN
Agent: C[O-]
Agent: Cl
Solvent: CO
Solvent: CI
Product: Cn1cc(-n2c(-c3ccco3)nc3c(N)ncnc32)ccc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodiummethoxide (150 mg, 2.78 mmol) was added to a methanol (8 ml) suspension of 5-[6-amino-8-(2-furyl)-9H-9-purinyl]-1,2-dihydro-2-pyridinone (400 mg, 1.36 mmol) synthesized in the same method as in Example 1 (2), (3) and (4) and Example 2, and the mixture was stirred in a nitrogen atmosphere at room temperature. After 15 minutes, iodomethane (0.26 ml, 4.18 mmol) was added thereto and further stirred for 16.5 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (eluting solvent: hexane, hexane/ethyl acetate=40:1,20:1,10:1). The crude product was suspended in ethanol, and the solid was collected by filtration and washed with ethanol and diethyl ether, to give the title compound in free form (337 mg). The resulting free compound was dissolved in methanol-4N hydrochloric acid/ethyl acetate (0.4 ml) and concentrated. The residue was crystallized from methanol/ethyl acetate/diethyl ether, and the solid was collected by filtration and washed with diethyl ether, to give the title compound (270 mg, 58%) as a pale brown solid.
Reaction SMILES: [P:1]([O-:6])([O-:5])([O:3][CH3:4])=[O:2].P([O-])([O-])([O-])=O.[Na].[F:13][C:14]1[C:19]([F:20])=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:15]=1[C:25]1[N:26]=[C:27]([NH:30][C:31](=[O:46])[CH2:32][C:33]2[C:41]3[C:40](=[O:42])[N:39]([CH3:43])[C:38](=[O:44])[N:37]([CH3:45])[C:36]=3[S:35][N:34]=2)[S:28][CH:29]=1.P(OCI)(OC(C)(C)C)(OC(C)(C)C)=O>CN(C=O)C>[P:1]([OH:6])([OH:5])([O:3][CH2:4][N:26]1[C:25]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[C:19]([F:20])[C:14]=2[F:13])=[CH:29][S:28][C:27]1=[N:30][C:31](=[O:46])[CH2:32][C:33]1[C:41]2[C:40](=[O:42])[N:39]([CH3:43])[C:38](=[O:44])[N:37]([CH3:45])[C:36]=2[S:35][N:34]=1)=[O:2]
Reactant: COP(=O)([O-])[O-]
Reactant: Cn1c(=O)c2c(CC(=O)Nc3nc(-c4ccc(C(F)(F)F)c(F)c4F)cs3)nsc2n(C)c1=O
Agent: CC(C)(C)OP(=O)(OCI)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(CC(=O)N=c3scc(-c4ccc(C(F)(F)F)c(F)c4F)n3COP(=O)(O)O)nsc2n(C)c1=O

Procedure:
Di-tert-butyl 4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-2-{[(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-d]pyrimidin-3-yl)acetyl]imino}-1,3-thiazol-3(2H)-yl]methyl phosphate: The title compound was prepared according to the general procedure as described in step 2 of method B for the preparation of phosphate derivatives by the reaction of sodium salt of N-{4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-d]pyrimidin-3-yl)acetamide (2.0 g, 3.71 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (Intermediate 2) (1.948 g, 5.56 mol) in dry DMF (20 ml) to yield 1.035 g of product as a white solid. Alternatively the title compound was also prepared according to the general procedure as described in method A for the preparation of phosphate derivatives by coupling N-{4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-d]pyrimidin-3-yl)acetamide (500 mg, 0.967 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (Intermediate 2) (1.18 g, 3.38 mmol) in presence of sodium hydride (60% dispersion in mineral oil, 58 mg, 1.45 mmol) in dry DMF (5 ml) to yield 135 mg of product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 1.46 (s, 18H), 3.36 (s, 3H), 3.57 (s, 3H), 4.66 (s, 2H), 6.38 (s, 2H), 7.40 (t, J=7.8 Hz, 1H), 7.64 (s, 1H), 8.15 (t, J=7.5 Hz, 1H); ESI-MS (m/z) 739.06 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].ClCCl.C([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:33][C:34]4[CH:39]=[CH:38][C:37]([N:40]5[C:44]([CH3:45])=[N:43][N:42]=[N:41]5)=[CH:36][CH:35]=4)=[C:27]3[CH:26]=[N:25]2)[CH2:20][CH2:19]1)=[O:17])(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:45][C:44]1[N:40]([C:37]2[CH:36]=[CH:35][C:34]([O:33][C:32]3[N:31]=[CH:30][N:29]=[C:28]4[N:24]([CH:21]5[CH2:22][CH2:23][N:18]([C:16]([OH:17])=[O:15])[CH2:19][CH2:20]5)[N:25]=[CH:26][C:27]=34)=[CH:39][CH:38]=2)[N:41]=[N:42][N:43]=1
Reactant: Cc1nnnn1-c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnnn1-c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 98 %

Procedure:
A solution of 20% trifluoroacetic acid/dichloromethane (12 mL) was added to a solution of 4-{4-[4-(5-methyl-tetrazol-1-yl)-phenoxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (Example 84; 486 mg, 1.02 mmol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 25 min. The volatiles were evaporated and the residue held at high vacuum and then triturated with ether to give 4-{4-[4-(5-methyl-tetrazol-1-yl)-phenoxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylic acid trifluoro-acetate salt (493 mg, 98%) as a white solid. This was taken up in dichloromethane (3 mL) and diisopropylethylamine (243 μL, 1.37 mmol) was added. The mixture was cooled to 0° C., and isopropyl chloroformate (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 1 M in toluene; 458 μL, 0.46 mol) was added dropwise. The mixture was stirred at room temperature for 1.5 h. Water (5 mL) was added and the layers were separated. The organic layers was washed with brine, dried (sodium sulfate), filtered, and evaporated. The residue was purified on a Supelco 11 g column, eluting with 6% methanol/dichloromethane to give 4-{4-[4-(5-methyl-tetrazol-1-yl)-phenoxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-piperidine-1-carboxylic acid isopropyl ester (136 mg, 64%) as a white powder. 1H NMR (DMSO-d6) δ 1.20 (d, 6H, J=6.4 Hz), 1.93-2.05 (m, 4H), 2.59 (s, 3H), 2.96-3.14 (m, 2H), 4.04-4.18 (m, 2H), 4.79 (pentet, 1H, J=6.3 Hz), 4.96-5.08 (m, 1H), 7.61-7.64 (m, 2H), 7.79-7.82 (m, 2H), 8.36 (s, 1H), 8.57 (s, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:14][CH2:15][C:16](Cl)=[O:17]>>[Br:14][CH2:15][C:16]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:17]
Reactant: CC(C)Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)CBr
Product: CC(C)N(C(=O)CBr)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-isopropylamino-nitrobenzene and bromoacetyl chloride
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12.O1CCCC1>[Pd].CO>[NH2:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12
Reactant: Nc1c2c(=O)[nH]c3ccccc3c2nn1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(-n2nc3c(c2N)c(=O)[nH]c2ccccc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A mixture of 3-amino-2-(3-nitrophenyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (150 mg), 10% palladium/active carbon (50% water, 40 mg), tetrahydrofuran (10 ml) and methanol (30 ml) was stirred under hydrogen atmosphere, at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added methanol, and the precipitated solid was collected by filtration, washed with methanol, and dried to obtain the target compound (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH:21]([F:23])[F:22])[CH:19]=3)=[CH:12][C:11]([C:24](O)=[O:25])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH:21]([F:22])[F:23])[CH:19]=3)=[CH:12][C:11]([C:24]([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=[O:25])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cncc(OC(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cncc(OC(F)F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1

Procedure:
109 mg (0.28 mmol) of the compound of Example 65A is reacted analogously to the synthesis of the compound of Example 1 with 38 mg (0.31 mmol) of 4-imidazolinone-hydrochloride. 108 mg (84% of theory) of the title compound is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29](I)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCI
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(O)cc3)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)cc1

Procedure:
A mixture of 30 g of trans-1-p-hydroxyphenyl-4-(trans-4-propylcyclohexyl)-cyclohexane, 6.9 g of K2CO3, 25 g of hexyl iodide and 250 ml of DMF is heated to 80° for 16 hours, while stirring, and is then cooled and worked up in the customary manner. Trans-1-p-hexoxyphenyl-4-(trans-4-propylcyclohexyl)-cyclohexane is obtained.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([CH2:12][CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=[O:16])(=O)[CH3:10]>C(O)(=O)C>[CH3:10][C:9]1[NH:7][C:1]2[C:6]([C:12]=1[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:5][CH:4]=[CH:3][CH:2]=2
Reactant: NNc1ccccc1
Reactant: CC(=O)CCCC(=O)N1CCN(c2ccccc2)CC1
Solvent: CC(=O)O
Product: Cc1[nH]c2ccccc2c1CCC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.8 g of phenylhydrazine in 100 ml of 30 % aqueous acetic acid was added 27.4 g of 1-(γ-acetylbutyryl)-4-phenylpiperazine and the resulting mixture was stirred for 30 minutes at room temperature. The precipitate was filtered, and washed with water. The precipitate was added to 180 ml of 5 % ethanolic hydrogen chloride, and the mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure to the residue, to which was added 100 ml of water. The resulting solid substance was recrystallized from ethanol to give 1-[β-(2-methyl-3-indolyl)propionyl]-4-phenylpiperazine, melting at 120°-121°C.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CO.CN(C=O)C>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2)ccn1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccccc2)ccn1)NO
Reaction time: 24 h
Yield: 23 %

Procedure:
HONH2 (50% aqueous, 4 mL) was added to II (120 mg, 0.3 mmol) in MeOH (4 mL) and DMF (2 mL) at rt. The reaction mixture was stirred for 24 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (3×5 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:2 to 100:8) to furnish III as a yellow oil (28 mg, 23%).