Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:9][CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12].Cl.[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[C:33]4[CH:42]=[CH:41][N:40]([CH2:43][CH:44]5[CH2:48][CH2:47][CH2:46][O:45]5)[C:34]=4[N:35]=[C:36]([C:38]#[N:39])[N:37]=3)=[CH:28][C:27]=2[C:49]([F:52])([F:51])[F:50])[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>CCOC(C)=O.O.C(#N)C>[ClH:9].[C:38]([C:36]1[N:37]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][CH:20]3[CH2:21][CH2:22][N:17]([CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:18][CH2:19]3)=[C:27]([C:49]([F:50])([F:51])[F:52])[CH:28]=2)[C:33]2[CH:42]=[CH:41][N:40]([CH2:43][CH:44]3[CH2:48][CH2:47][CH2:46][O:45]3)[C:34]=2[N:35]=1)#[N:39]
Reactant: N#Cc1nc(-c2ccc(OCCC3CCNCC3)c(C(F)(F)F)c2)c2ccn(CC3CCCO3)c2n1
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CN1CCC(CCOc2ccc(-c3nc(C#N)nc4c3ccn4CC3CCCO3)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (62 mg), potassium iodide (25 mg), and 2-chloro-N,N-dimethylacetamide (18 μL) were added to a mixture of 4-{4-[2-(piperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-7-(tetrahydrofuran-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (80 mg) and acetonitrile (3.2 mL) at room temperature, and the mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was diluted with EtOAc. Then, a saturated aqueous NaHCO3 solution and water were added thereto, then extraction thereof was performed using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (Hex:CHCl3=50:50 to 0:100). The obtained product was dissolved in EtOAc (1 mL), then a 4 M solution of hydrogen chloride in EtOAc (37 μL) was added thereto at room temperature, and the mixture was stirred at the same temperature for 1 hour. The precipitate was collected by filtration, whereby 2-[4-(2-{4-[2-cyano-7-(tetrahydrofuran-2-yl methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(trifluoromethyl)phenoxy}ethyl)piperidin-1-yl]-N,N-dimethylacetamide monohydrochloride (57 mg) was obtained as a pale yellow solid.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([C:24]([NH:26][CH2:27][C:28]([O:30]C)=O)=[O:25])[CH2:20][CH2:21][CH2:22][CH3:23])=O)C3C(=CC=CC=3)C=2C=CC=1.ClCCl.N1CCCCC1>ClCCl>[CH2:20]([C@H:19]1[NH:18][C:28](=[O:30])[CH2:27][NH:26][C:24]1=[O:25])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)OC
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCCC[C@H]1NC(=O)CNC1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of methyl N-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-D-norleucylglycinate from step (a) above (2 g, 4.7 mmol) in a 7:3 mixture of dichloromethane/piperidine (30 mL) was stirred at room temperature for 0.75 h. The reaction mixture was diluted with dichloromethane (200 mL) and solid which precipitated was filtered, washed with cold DCM (2×50 mL) and dried in vacuo to give the title compound as a white solid. MS (ESI, positive ion) m/z: 171 (M+1).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:17]2[C@@:13]([CH3:29])([C@@H:14]([C@@:18]3([CH3:28])[O:22][CH2:21][C@H:20]([CH2:23][C:24]([CH3:27])([OH:26])[CH3:25])[CH2:19]3)[CH2:15][CH2:16]2)[CH2:12][CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O.CCOC(C)=O>C1COCC1>[OH:26][C:24]([CH3:27])([CH3:25])[CH2:23][C@H:20]1[CH2:21][O:22][C@@:18]([C@@H:14]2[C@:13]3([CH3:29])[C@H:17]([C@@H:9]([OH:8])[CH2:10][CH2:11][CH2:12]3)[CH2:16][CH2:15]2)([CH3:28])[CH2:19]1
Reactant: CC(C)(O)C[C@H]1CO[C@](C)([C@H]2CC[C@H]3[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@@]32C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)C[C@H]1CO[C@](C)([C@H]2CC[C@H]3[C@@H](O)CCC[C@@]32C)C1
Yield: 74.3 %

Procedure:
A solution of 14 (280 mg, 0.78 mmol) in dry THF (4 mL) was treated with nBu4NF (1.05 g, 3.3 mmol). The mixture was heated at reflux. After 115 h H2O (20 mL) and EtOAc (20 mL) was added. The aqueous layer was extracted with EtOAc (4×20 mL) and the combined organic layer was dried (Na2SO4), filtered and concentrated in vacuum. The residue was purified by flash chromatography (SiO2, 2×5.5 cm, 30% EtOAc-hexanes) to give the corresponding diol 14a (180 mg, 88%, white solid, mp: 67° C.).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:37]2[CH:36]=[N:35][C:34]([N:31]3[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]3)=[CH:39][CH:38]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C)CC4)nc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (73.8 mg, 0.243 mmol), DMSO (2 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 12 mg (13%). LCMS E-S (M+H)=515.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (d, J=6.4 Hz, 6H), 2.13 (s, 3H), 2.23 (m, 6H), 2.37-2.46 (m, 4H), 3.56-3.69 (m, 4H), 4.40 (d, J=4.6 Hz, 2H), 5.30 (quin, J=6.7 Hz, 1H), 5.91 (s, 1H), 6.99 (d, J=9.1 Hz, 1H), 8.10 (s, 1H), 8.32 (s, 1H), 8.38 (dd, J=9.1, 2.5 Hz, 1H), 8.91 (br. s., 1H), 9.03 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([NH:15][NH:16]C(OC(C)(C)C)=O)=[O:14])[CH2:2][CH:3]=[CH2:4].[ClH:24]>O1CCOCC1>[ClH:24].[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([NH:15][NH2:16])=[O:14])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1ccccc1CC(=O)NNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C=CCCOc1ccccc1CC(=O)NN
Reaction time: 18 h
Yield: 71 %

Procedure:
tert-Butyl 2-(2-(2-(but-3-en-1-yloxy)phenyl)acetyl)hydrazinecarboxylate (0.28 g, 0.874 mmol, 1 equiv) was treated with 4 N HCl in dioxane (9 mL). After stirring 18 h, the reaction was concentrated in vacuo. The crude product was triturated with ether to provide the product (0.16 g, 71%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.28 (td, J=7.9, 1.8 Hz, 1H), 7.22 (dd, J=7.5, 1.3 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.93 (t, J=7.5 Hz, 1H), 5.95 (ddt, J=17.2, 10.3, 6.8 Hz, 1H), 5.18 (dd, J=17.2, 1.6 Hz, 1H), 5.11 (d, J=10.3 Hz, 1H), 4.06 (t, J=6.7 Hz, 2H), 3.63 (s, 2H), 2.56 (q, J=6.6 Hz, 2H); LCMS (ESI, M+1): 221.15.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC.Cl>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2](/[CH:12]=[CH:11]/[C:10]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: C=CC(=O)O
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CC#N
Product: N#Cc1ccc(/C=C/C(=O)O)cc1

Procedure:
3.64 g (20 mmol) of 4-bromobenzonitrile and 2.88 g (40 mmol) of acrylic acid were dissolved in 40 ml of acetonitrile. 49 mg (0.2 mmol) of palladium (II) acetate, 365 mg (1.2 mmol) of tri-o-tolylphosphine and 7.41 g (40 mmol) of tributylamine were added to the solution, and they were heated under reflux overnight. The reaction liquid was poured into 4 N aqueous hydrogen chloride solution. The precipitates thus formed were taken by the filtration, washed with 4 N aqueous hydrogen chloride solution, water and ethyl acetate, and then dried in vacuo to obtain the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([O:13][CH2:14][CH3:15])(=O)C>[Ni].C(O)C>[CH2:14]([O:13][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)[C:15]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: c1ccc2[nH]ccc2c1
Agent: [Ni]
Solvent: CCO
Product: c1ccc(COc2cccc3cc[nH]c23)cc1

Procedure:
Wet Raney nickel is added in portions to a stirred refluxing solution of 7-(benzyloxy)-3-methylthio)indole (4.0 g, 14.9 mmol) in ethyl acetate (100 ml) and ethanol (60 ml) until all the starting material has been consumed (by RP HPLC). The mixture is filtered, the filtrate evaporated and the residue chromatographed on silica in ethyl acetate-hexane (1:8) to give a pale oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2=[N:20][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:22](=[O:23])[C:12]2=[CH:11]1.[NH:31]1[C:39]2[C:34](=[CH:35][C:36](B(O)O)=[CH:37][CH:38]=2)[CH:33]=[CH:32]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[NH:31][CH:32]=[CH:33]3)[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2=[N:20][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:22](=[O:23])[C:12]2=[CH:11]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: O=c1c2cn(Cc3ccc(I)cc3F)c3ccccc3c-2nn1-c1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: CS(C)=O
Product: O=c1c2cn(Cc3ccc(-c4ccc5[nH]ccc5c4)cc3F)c3ccccc3c-2nn1-c1ccccc1F
Temperature: 25 °C

Procedure:
5-[(2-Fluoro-4-iodophenyl)methyl]-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazol[4,3-c]quinolin-3-one (51 mg, 0.10 mmol), 1H-indol-5-ylboronic acid (27 mg, 0.17 mmol, 1.7 equiv), potassium carbonate (34 mg, 0.25 mmol, 2.5 equiv), palladium(II) acetate (12 mg, 0.0010 mmol, 0.1 equiv) and 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (14 mg, 0.030 mmol, 0.3 equiv) were combined in water (0.1 mL) and dimethylsulfoxide (0.5 mL) and placed into a preheated oil bath at 85° C. for 90 minutes. The mixture was cooled to ambient temperature, filtered and purified by reverse phase HPLC (80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 11.18 (1H, s), 9.11 (1H, s), 8.22 (1H, dd, J=7.9, 1.5 Hz), 7.85 (1H, s), 7.79 (1H, d, J=8.7 Hz), 7.68 (1H, ddd, J=8.5, 7.3, 1.6 Hz), 7.62 (1H, dd, J=7.9, 1.7 Hz), 7.60 (1H, br s), 7.57 (1H, s), 7.55 (1H, d, J=7.4 Hz), 7.49 (1H, dd, J=8.1, 1.8 Hz), 7.47-7.37 (4H, m), 7.34 (1H, td, J=7.5, 1.4 Hz), 7.28 (1H, t, J=8.2 Hz), 6.48-6.47 (1H, m), 5.83 (2H, s) ppm; low resolution mass spectrometry (ES+) m/z 503.1667 [(M+H)+; calculated for C31H21F2N4O: 503.1678].
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1C=CC=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]#[C:17][NH2:18].C(O)(C(F)(F)F)=O.BrC#N>>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:18]1[C:17]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: N#CN
Agent: N#CBr
Solvent: O=C(O)C(F)(F)F
Product: N#CN1CCC1COCc1ccccc1

Procedure:
Following general procedure 12, to a cold (0° C.), stirred solution of the alcohol (44) (100 mg, 1 equiv.) in DMF (5 mL) was added NaH (60% in oil, 32 mg, 1.5 equiv.). The suspension was stirred at 0° C. for 40 minutes followed by the addition of the benzyl chloride (125 uL, 2 equiv.). The suspension was warmed to rt and stirred for 16 h. MeOH was added followed by sat. aq. NH4Cl. The aqueous phase was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution: 100% hexane to 20% EtOAc in hexane) to afford the desired benzyl ether. The N-Boc group of the benzyl ether was then converted to the cyanamide (N—CN) following general procedure 3 (i.e. successive treatment with TFA and BrCN). The crude material was purified by flash chromatography (gradient elution: 30% EtOAc in hexane to 60% EtOAc in hexane) to afford the desired product 2-[(benzyloxy)methyl]-1-cyanoazetidine (45).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([CH3:9])[CH2:3]1.O1CCOCC1.[OH-].[K+].[C:18]1([C:24](=[O:27])[CH:25]=[CH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[C:4]([CH3:9])([CH2:26][CH2:25][C:24](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3]1
Reactant: CC1CN(C)CCC1=O
Reactant: C=CC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCC(=O)C(C)(CCC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.8 %

Procedure:
To a stirred solution of 1,3-dimethyl-piperidin-4-one (0.1 g, 0.787 mmol) in mixture of 1,4 dioxane (2 mL) and water (0.1 mL) was added crushed KOH (44 mg, 0.787 mmol). The reaction mixture was stirred at 25° C. for 10 min. To this was added 1-phenylprop-2-en-1-one (103 mg, 0.787 mmol) dropwise. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (10 mL) and EtOAc (20 mL), the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography on neutral alumina (eluted with EtOAc:Hexanes, 1:99) to afford 1,3-dimethyl-3-(3-oxo-3-phenyl-propyl)-piperidin-4-one as an oil (22 mg).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[N+](=[CH2:30])=[N-]>CO.CCOCC>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:30])=[O:20])=[CH:15][N:14]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)O)cn2)ccc(C(C)=O)c1O
Solvent: CCOCC
Solvent: CO
Product: CCCc1c(OCCCSc2ccc(C(=O)OC)cn2)ccc(C(C)=O)c1O
Temperature: 0 °C

Procedure:
The compound of Example 1 (500 mg, 1.284 mmoles) was dissolved in mixture of CH3OH (10 ml) and ether (10 ml) cooled to 0° C. Diazomethane was added until a slight yellow color persisted. The reaction mixture was concentrated to afford the title compound, m.p. 66°-68°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17])([O-])=O>>[N:1]1([S:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH2:7])(=[O:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: Nc1ccccc1S(=O)(=O)N1CCCCC1
Yield: 58 %

Procedure:
The title compound (0.59 g, 58%) was obtained as a brown solid from piperidine and 2-nitrobenzenesulfonylchloride following the same procedure as described in preparation 2.
Reaction SMILES: C(=O)(O)[O-].[Na+:5].[C:6]([O:10][C:11](=[O:26])[CH2:12]/[C:13](=[CH:17]\[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[C:14]([OH:16])=[O:15])([CH3:9])([CH3:8])[CH3:7]>CO.O>[Na+:5].[C:6]([O:10][C:11](=[O:26])[CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]([O-:16])=[O:15])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)C/C(=C\CCc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)[O-]
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 60.8 %

Procedure:
A stirred solution of sodium bicarbonate (28.6 g, 0.34 mol), (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid (100 g, 0.34 mol) and [(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)ruthenium chloride (0.63 g, 0.68 mmol) in methanol (750 ml) and water (250 ml) was heated to 60° C., under hydrogen (60 p.s.i.), for 24 hours and then allowed to cool to 20-25° C. (enantiomeric excess 87%). The mixture was filtered through a filter aid Celite® and the solvent was stripped and replaced with acetonitrile by distillation at atmospheric pressure, at a constant volume of 500 ml. The resulting suspension was cooled to 20-25° C. and was stirred for 24 hours, then filtered. The residue was washed with acetonitrile (3×25 ml) and then dried in vacuo at 45° C. for 3 hours to leave the title compound as a colourless solid (65 g, 61% yield, enantiomeric excess=94.3%, 95% pure by NMR).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[CH:6]1([Mg]Cl)[CH2:10][CH2:9][CH2:8][CH2:7]1.O>CCCCCC.CCOCC>[CH:6]1([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cl[Mg]C1CCCC1
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(Cl)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopentanesulfonyl chloride was prepared according to the procedure of S. N. Bhattacharya, et. al., J. Chem. Soc. (C), 1265-1267 as follows. To a solution of 2.7 g (1.6 mL, 20 mmol) of sulfuryl chloride in 5 mL of hexane at 0° C. was added a solution of 5 mL (10 mmol) of 2 M cyclopentylmagnesium chloride in ether over a 15-min period. The reaction mixture was allowed to warm to room temperature and stir overnight. The mixture was recooled to 0° C. and a 5-mL portion of ether was added followed by a 10-mL portion of water. The layers were separated and the organic phase was washed with water, dried over sodium sulfate and concentrated to give 1.12 (70%) of cyclopentanesulfonyl chloride. This compound was used without further purification to prepare the title compound from the Cbz amine from Example 3 in a manner analogous to that of Example 5: 1H NMR (400 MHz, CDCl3) δ7.34-7.30 (m, 5H), 7.13 (s, 4H), 6.44 (br s, 1H), 5.07 (s, 2H), 4.74 (br, s, 1H), 3.50-3.39 (m, 3H), 2.76 (br t, 2H), 2.09-1.91 (m, 4H), 1.86-1.76 (m, 2H), 1.64-1.54 (m, 2H); FAB MS m/z 403 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=O)=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH2:30][CH2:31][CH3:32]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([N:29]([CH3:28])[CH2:30][CH2:31][CH3:32])=[O:27])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCCNC
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(OC)nc2n1
Yield: 78.3 %

Procedure:
The procedure is as in Example 44, but starting with [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (3.1 g) in anhydrous dimethylformamide (70 cc), N,'-carbonyldiimidazole (1.4 g) and N-methylpropylamine (0.6 g). After recrystallization in ethanol, [2-(7-methoxy-1,8-naphthyridin-2yl)-3-oxo1 -isoindolinyloxy]-N-methyl-N-propylacetamide (2.7 g), m.p. 160° C., is obtained.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]12([C:15](Cl)=[O:16])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2.[F:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.CCCCCCC.C1(C)C=CC=CC=1>ClCCCl>[C:5]12([C:15]([C:24]3[CH:23]=[CH:22][C:21]([OH:25])=[CH:20][C:19]=3[F:18])=[O:16])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: Oc1cccc(F)c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: O=C(c1ccc(O)cc1F)C12CC3CC(CC(C3)C1)C2
Yield: 53.8 %

Procedure:
To a mixture of AlCl3 (45 g, 0.337 mol) in 1,2-dichloroethane (DCE, 250 ml) at 0° C. was added 1-adamantyl carbonyl chloride (36.6 g, 0.228 mol) in DCE (150 ml). 3-fluorophenol (21 g, 0.183 mol) in DCE (100 ml) was added slowly at 0° C. The reaction was followed by TLC (heptane/toluene 50/50). The mixture was poured onto HCl 2N, extracted with AcOEt, washed with NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under vacuum. Purification by flash chromatography (heptane/toluene 8/2) gave 27 g of 1-adamantyl (2-fluoro-4-hydroxyphenyl)methanone (48% as solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[Br:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Br:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Reactant: Brc1cccc(N2CCNCC2)c1
Product: COc1cc2nc(NC(=O)N3CCN(c4cccc(Br)c4)CC3)c(OC)nc2cc1OC
Yield: 63 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate and 1-(3-bromophenyl) piperazine were reacted by the same way with the example 190 to obtain the titled compound (yield, 63%) H NMR (300 MHz, CDCl3) δ 3.28-3.30 (m, 4H), 3.78 (m, 4H), 3.97 (s, 3H), 3.99 (s, 3H), 4.13 (s, 3H), 6.86 (m, 1H), 7.01 (s, 1H), 7.06-7.07 (m, 1H), 7.13-7.16 (m, 2H), 7.22-7.28 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc(CBr)cc1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccc(Cl)cc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-4-chlorobenzene and isolated as white solid (5.1 mg, 31%). MS (m/e): 407.4 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CO
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred MeOH (100 mL) solution of 2-(4-nitrophenyl)acetic acid (10.0 g, 55.202 mmol, 1.0 eq) SOCl2 (6.7 mL, 110.045 mmol, 2.0 eq) was added at 0° C. for 10 min and the mixture was stirred at RT for 2 h, then excess of SOCl2 was removed under vacuum and the residue was dissolved in EtOAC (50 mL), washed with water, sat. (aq) NaHCO3, dried (Na2SO4) and the solvent was evaporated to get methyl 2-(4-nitrophenyl)acetate (10.5 g, 98%, solid; TLC system: EtOAc/PE (3:7), Rf: 0.60).