Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].C(OC([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=O)(C)(C)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:47]3[CH2:48][CH2:49][N:44]([S:51]([CH3:50])(=[O:53])=[O:52])[CH2:45][CH2:46]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27]
Reactant: O=C1c2c(-c3ccc(F)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCN(c2cc(-c3ccc(F)cc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Yield: 24 %

Procedure:
In a similar manner to Example 6, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 16; 80.0 mg) was reacted with 1-(t-butoxycarbonyl)piperazine (70.0 mg) and methylsulfonyl chloride (60 μL) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-9-[4-(methylsulfonyl)piperazine-1-yl]-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (23.5 mg, 24%).
Reaction SMILES: C([O:9][CH:10]1[CH2:13][C:12]([C:15]#[C:16][C:17]2[C:18]([F:34])=[CH:19][C:20]3[O:26][CH2:25][CH2:24][N:23]4[CH:27]=[C:28]([C:30](=[O:32])[NH2:31])[N:29]=[C:22]4[C:21]=3[CH:33]=2)([OH:14])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Li+]>CO.O.ClCCl>[OH:14][C:12]1([C:15]#[C:16][C:17]2[C:18]([F:34])=[CH:19][C:20]3[O:26][CH2:25][CH2:24][N:23]4[CH:27]=[C:28]([C:30]([NH2:31])=[O:32])[N:29]=[C:22]4[C:21]=3[CH:33]=2)[CH2:11][CH:10]([OH:9])[CH2:13]1
Reactant: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CC(OC(=O)c4ccccc4)C3)c(F)cc1OCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)CC(O)C3)c(F)cc1OCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.8 %

Procedure:
A suspension of 3-((2-carbamoyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-10-yl)ethynyl)-3-hydroxycyclobutyl benzoate (190 mg, crude product), lithium hydroxide (96 mg, 4.01 mmol) in methanol (0.5 mL) and water (1 mL) was stirred at room temperature overnight. The resulting solution was diluted with 20 mL of dichloromethane and 10 mL water. The organic layer was washed with 10 mL of brine. The organic was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:10). This resulted in 7 mg of the titled compound as a light yellow solid. This compound was isolated as a single unassigned diasteromer.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:34][CH2:35][CH:30]([C:27]4[CH:26]=[CH:25][C:24]([NH2:23])=[CH:29][CH:28]=4)[CH2:31][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Nc1ccc(C2CCNCC2)cc1
Agent: Cl
Product: Nc1ccc(C2CCN(C(=O)Oc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 4-(4-aminophenyl)piperidine, hydrochloride, praeparative HPLC (Method C) (30%, light yellow crystals). HPLC-MS m/z=458.2 (M+1), Rt: 3.42 min.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[CH:12]/[C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CN1CC[O:35][CH2:34][CH2:33]1.C(OC(=O)C)(=O)C>ClCCl>[C:34]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[CH:12]/[C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[C:17]([F:18])([F:19])[F:20])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:35])[CH3:33]
Reactant: CN1CCOCC1
Reactant: NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
150 mg of (2E)-3-(1-amino-2,3-dihydro-1H-inden-5-yl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)-phenyl]ethyl}acrylamide were dissolved in 5 ml of dichloromethane, admixed with 71 mg of N-methylmorpholine and 36 mg of acetic anhydride, and stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator to obtain 165 mg of (2E)-3-(1-acetamido-2,3-dihydro-1H-inden-5-yl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}acrylamide (100%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:18]([CH2:38][CH2:39][CH2:40][CH3:41])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29](=O)[CH:28]=2)=[C:21]([O:36][CH3:37])[CH:20]=1)[CH2:15][CH2:16][CH3:17].O>O1CCCC1>[CH2:38]([N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29](=[CH:5][C:3]#[N:4])[CH:28]=2)=[C:21]([O:36][CH3:37])[CH:20]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCCCN(CCCC)c1ccc(C=CC2=CC(=O)CC(C)(C)C2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=CC2=CC(=CC#N)CC(C)(C)C2)c(OC)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To 0.23 g (9.6 mmol) of sodium hydride, 20 ml of tetrahydrofuran was added. To this mixture, 1.39 g (7.85 mmol) of diethyl cyanomethylphosphonate was added dropwise under ice cooling. To the mixture, 1.21 g (3.15 mmol) of 3-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]-5,5-dimethyl-2-cyclohexenone in tetrahydrofuran was added dropwise. After the reaction mixture was stirred at 50° C. overnight, water was added thereto and extraction with ethyl acetate was performed. The extract was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 1.05 g of an orange oily matter (yield: 82.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][NH2:15])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][NH:15][C:23](=[O:25])[CH3:24])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)Cl
Reactant: NCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(3,4-dichlorophenyl)-1H-imidazole-4-methanamine (0.20 g, 0.83 mmol) in THF (30 ml) was added triethylamine (0.079 g, 0.78 mmol) and acetyl chloride (0.082 mg, 1.0 mmol). The reaction mixture was stirred at rt for 12 h. After evaporation of the solvent, the residue was dissolved in AcOEt and washed with H2O. The organic phase was dried (Na2SO4), concentrated and the obtained crude product was chromatographed [silica, elution with gradient CH2Cl2 to 100% (CH2Cl2/MeOH=9:1)]. The title compound was obtained as an off-white crystalline material (0.17 g, 74%). Mp. 177-180° C. (MeOH/CH2Cl2), MS: m/e=284 (M+H+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C@@H:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.I[C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:21]2[CH:30]=[CH:31][C:18]([N:13]3[C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=4)[CH2:10][CH2:11][C:12]3=[O:14])=[CH:19][CH:20]=2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(Oc2ccc(I)cc2)cc1
Reactant: O=C1CC[C@H](c2cccc(C(F)(F)F)c2)N1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1CC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 110 °C

Procedure:
To a 10 mL reaction tube fitted with a screw cap is charged with (R)-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (90 mg, 0.39 mmol) and 1,4-dioxane (3 mL). 1-(4-iodophenoxy)-4-chlorobenzene (157 mg, 0.47 mmol) is then added, followed by copper iodide (15 mg, 0.078 mmol), N,N′-1,2-trans-dimethylcyclohexane-1,2-diamine (11.2 mg, 0.078 mmol), and K3PO4 (167 mg, 0.78 mmol). The system is degassed with argon then sealed and heated to 110° C. for 28 h. The reaction is cooled to room temperature, dissolved in ethyl acetate and washed with water and brine. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. Purification on silica gel (0-30% ethyl acetate in hexane) gave (R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one as a slightly yellow oil (102 mg, 60%). 1H NMR (CDCl3) δ (ppm) 7.60-7.50 (m, 1H), 7.49-7.37 (m, 3H), 7.34-7.28 (m, 2H), 7.27-7.21 (m, 2H), 6.91-6.67 (m, 4H), 5.28 (dd, J=6.8, 5.6 Hz, 1H), 2.84-2.59 (m, 3H), 2.07-1.94 (m, 1H). HPLC-MS calculated for C23H17ClF3NO2 (M+H+) 432.09, found 432.10.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:18](=O)[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>O.CO>[C:1]1([C:7]2[C:8]3[C:18](=[N:21][OH:22])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C1c2ccccc2-c2[nH]nc(-c3ccccc3)c21

Procedure:
A mixture of 3-phenylindeno[1,2-c]pyrazol-4(1H)-one (1.28 g, prepared as described in JP60-130521), hydroxylamine hydrochloride (0.5 g), sodium acetate (0.8 g), water (10 ml) and methanol (100 ml) was boiled under reflux for 66 hours. More hydroxylamine hydrochloride (0.5 g), sodium acetate (0.8 g) and water (10 ml) were added and the mixture was boiled under reflux for a further 16 hours. Further hydroxylamine hydrochloride (0.5 g) and sodium acetate (0.8 g) were added and the mixture was boiled under reflux for a further 20 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure until crystallization began. The mixture was cooled and filtered to give a solid which was washed with water and dried to give 3-phenylindeno[1,2-c]pyrazol-4(1H)-one oxime, m.p. 280° C. (with decomposition).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([NH2:14])=[O:13])[CH:3]=1.Cl[C:16]([S:18]Cl)=[O:17].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[O:13][C:16](=[O:17])[S:18][N:14]=2)[CH:3]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1cc(Br)c2ccccc2c1
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1oc(-c2cc(Br)c3ccccc3c2)ns1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 4-bromonaphthalene-2-carboxylic amide (1.10 g) in toluene (11.0 mL) was added chlorocarbonylsulfenyl chloride (0.73 mL), and the mixture was stirred at 100° C. for 18 hours. To the reaction solution was added water (50 mL), and the precipitated solid was collected by filtration. The obtained solid was washed with water and hexane to give 5-(4-bromonaphthalene-2-yl)-[1,3,4]oxathiazole-2-one (1.13 g). This compound (1.13 g) was dissolved in dichlorobenzene (18 mL). To the solution was added ethyl propiolate (1.52 mL), and the mixture was stirred at 160° C. for 18 hours. The reaction solution was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give the title compound (0.66 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15](O)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC.B>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][OH:16])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](C(=O)O)C1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](CO)C1
Temperature: 40 °C
Yield: 96 %

Procedure:
Racemic trans 3-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1 g, 4.11 mmol) was dissolved in THF (30 mL) and borane dimethylsulfide 2M in THF (3 mL, 6 mmol) was added slowly. The resulting colorless solution was stirred at 40° C. After 4 hours the reaction mixture was cooled to 0° C., quenched by addition of saturated aqueous NaHCO3, and extracted twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered and evaporated to give 0.905 g of crude racemic trans 3-hydroxymethyl-cyclohexyl-carbamic acid tert-butyl ester as a colorless oil (>95% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:24])[CH:18]=2)[C:14]([OH:16])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].[O:40]1CC[CH2:42][CH2:41]1>>[N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:33](=[O:35])[CH3:34])=[C:19]([O:24][C:41](=[O:40])[CH3:42])[CH:18]=2)[C:14]([OH:16])=[O:15])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCOC1
Reactant: O=C(NC(C(=O)O)c1ccc(O)c(O)c1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(NC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)O)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
DL-2-(4-Nitrobenzyloxycarbonylamino)-2-(3,4-dihydroxyphenyl) acetic acid (1.81 g, 5 m mole) was dissolved in dry tetrahydrofuran (19 ml). The solution was cooled to 0° C. and stirred while dry pyridine (1.30 ml, 3 equivalents) and acetic anhydride (1.18 ml, 2.5 equivalents) were added. The solution was allowed to regain room temperature and stirred for 3 h, further acetic anhydride (0.5 ml) being added after 1 h. The tetrahydrofuran was then removed by evaporation, the residue was partitioned between ethyl acetate and water and the pH raised to 7.5. The aqueous phase was separated and again washed with ethyl acetate, the organic phases being discarded, then acidified to pH2 with 2M hydrochloric acid and extracted with ethyl acetate (2×). The total organic extract was washed with water and brine, then dried over sodium sulphate and evaporated to give crude product. Reprecipitation was effected by adding dropwise a solution of the crude material in dichloromethane to an excess of petrol, with vigorous stirring, to give the title acid as an amorphous powder which was filtered, washed with petrol and dried; it retained solvents tenaciously (1.46 g, 65%); δ (CDCl3) 8.24 and 8.26 (6H,2s,2×CH3CO), 5.15(2H,s,ArCH2O), 5.22 (1H,d,J 7 Hz, NCHCO) 7.0-7.6 (7H,m,5H on D2O exch, aryl-H+NH+OH), 8.13(2H,d,J 9 Hz, aryl-H); RF 0.50 in chloroform:methanol:acetic acid, 17:2:1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1COCC1>[CH:32]1([NH:38][C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC2CCCCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 18 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and cyclohexylamine (100 mg, 1 mmol) were combined in THF (10 mL) and stirred under Ar at 230 for 18 h. The solvents were removed in vacuo, and the residue was flash chromatographed with 50-100% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white-crystalline solid. mp 218-219° C., LC MS m/z=465 (MH+). Retention time=2.8 min.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([Cl:11])[C:8]([Cl:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]1([CH2:23][CH2:24][NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]1>CC(C)=O>[ClH:10].[N:18]1([CH2:23][CH2:24][NH:25][C:8](=[O:9])[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[Cl:11])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NCCN1CCCC1
Reactant: O=C(Cl)C(Cl)(c1ccccc1)c1ccccc1
Solvent: CC(C)=O
Product: Cl
Product: O=C(NCCN1CCCC1)C(Cl)(c1ccccc1)c1ccccc1

Procedure:
An acetone solution of 1 mol of diphenyl-α-chloroacetyl chloride is treated at 0° C. with an acetone solution of pyrrolidinoethylamine.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH:2]=[CH2:3].Br[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C1(N(C)C2CCCCC2)CCCCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16](/[CH:3]=[CH:2]/[CH2:1][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[C:5]2=[O:14])=[CH:17][C:18]=1[C:23]([F:24])([F:25])[F:26]
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Reactant: C=CCN1C(=O)C(=O)c2ccccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: O=C1C(=O)N(C/C=C/c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc21
Temperature: 80 °C

Procedure:
Six separate oven-dried sealed tubes were charged with 1-allyl-1H-indole-2,3-dione (0.100 g, 0.534 mmol), Pd(P(t-Bu)3)2 (0.0082 g, 0.016 mmol), 4-bromo-1-chloro-2-(trifluoro-methyl)benzene (0.139 g, 0.536 mmol), dry toluene (1 mL), and N-cyclohexyl-N-methyl-cyclohexanamine (0.12 mL, 0.57 mmol) under an atmosphere of N2. The tubes were heated for 16 h at 80° C. in an oil bath, and then the reactions were cooled and concentrated in vacuo. The crude material was used in the subsequent step.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[C:13](=[O:28])[C:12]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[NH:29][CH2:30][CH3:31].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23](=[O:24])[NH:1][C:2]([CH2:5][OH:6])([CH2:3][OH:4])[CH3:7])=[CH:26][CH:27]=1)[C:13](=[O:28])[C:12]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[NH:29][CH2:30][CH3:31]
Reactant: CC(N)(CO)CO
Reactant: CCNC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)O)cc2)c2ccc(Cl)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)NC(C)(CO)CO)cc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
A solution of 0.172 g of 2-amino-2-methylpropane-1,3-diol in 2 ml of DMF is added at RT to a mixture of 0.374 g of the compound obtained in step B of EXAMPLE 241, 0.25 g of triethylamine, 0.364 g of BOP and 5 ml of DCM and the reaction mixture is stirred for 3 hours at RT. It is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed twice with a 5% solution of potassium carbonate, with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using an AcOEt/DCM mixture (80/20; v/v) as the eluent to give 0.18 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=138°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>C(#N)C>[Br-:26].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:18][CH2:19][N+:14]([CH2:27][C:28](=[O:29])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccc(Cl)cc1)N1CCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccc(Cl)cc1)N1CCCCC1)C2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
(R)-quinuclidin-3-yl 2-(4-chlorophenyl)-2-(piperidin-1-yl)acetate (100 mg, 0.28 mmol) and 2-bromo-1-phenylethanone (60.3 mg, 0.30 mmol) were dissolved in acetonitrile (4 ml) and stirred at room temperature for 16 hours. The solvent was evaporated and the resulting residue was purified by flash chromatography (DCM/MeOH=9/1) to obtain (3R)-3-(2-(4-chlorophenyl)-2-(piperidin-1-yl)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (98 mg, 63.3% yield) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:34]=[CH:33][NH:32][N:31]=3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[C:35]([O-])([O-])=O.[K+].[K+].CI.O>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=3)=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3cc[nH]n3)cc2)n1-c1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CI
Product: Cn1ccc(-c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)n1
Temperature: 60 °C
Yield: 99.2 %

Procedure:
To a solution of 5-(4-chloro-phenyl)-1-phenyl-6-[4-(1H-pyrazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (4 mg, 0.008 mmol) in MeCN (0.5 mL) is added K2CO3 (5 mg) followed by MeI (0.05 mL). The mixture is heated to 60° C. for 16 h and then cooled down to room temperature. The reaction mixture is then treated with water (3 mL) and extracted with EtOAc. The combined extracts is concentrated and purified by preparative thin layer chromatography (silica gel, 30% EtOA/hexane) to provide the title compound 5-(4-chloro-phenyl)-6-[4-(1-methyl-1H-pyrazol-3-yl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as white solid (3.8 mg, 92%). 1H NMR (CDCl3) δ (ppm) 8.33(s, 1H), 8.17(d, 2H), 7.70(d, 2H), 7.51(t, 2H), 7.38 (m, 4H), 7.11(d, 2H), 6.54(d, 1H), 3.97(s, 3H). HPLC-MS calculated C27H19ClN6O (M+1+): 479.1. Found: 479.1.