Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:15]=[C:16]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1>>[Cl:32][C:30]1[CH:29]=[C:16]([CH:15]=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:31]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(COc2cc(N)cc(Cl)c2)cc1
Product: CC(=O)Nc1ccc(COc2cc(Cl)cc(Nc3ccnc4nc(C)ccc34)c2)cc1

Procedure:
The product from Example 1d (70 mg, 0.39 mmol) was reacted with the product from Example 197d (110 mg, 0.39 mmol) for 23 h following the procedure from Example 1g giving the crude title compound which was purified by trituration with EtOAc providing the title compound (140 mg, 82%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.05 (s, 3H), 2.75 (s, 3H), 5.11 (s, 2H), 6.90 (d, J=7.0 Hz, 1H), 7.12 (br-s, 1H), 7.17 (br-s, 2H), 7.38 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.78 (d, J=8.9 Hz, 1H), 8.50 (d, J=7.0 Hz, 1H), 9.12 (d, J=8.9 Hz, 1H), 10.06 (s, 1H), 11.17 (br-s, 1H); MS (ESI+) m/z 433, 435 (M+H)+, (ESI−) m/z 431, 433 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25].[H-].[Na+].C([O-])(O)=O.[Na+].[Na+].[Cl-]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[N:12]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(Br)CC
Reactant: O=C1CC[C@@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cn2)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCC(CC)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1

Procedure:
To a degassed solution of (5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one (1.00 g, 3.11 mmol, Example 121, Step F), 3-bromopentane (6.0 ml, 48.1 mmol) and tetrabutylammonium iodide (3.45 g, 9.34 mmol) in dry DMF (5.2 ml) was added 1.25 g (31 mmol) of a dispersion of 60% sodium hydride in mineral oil at 0° C. The reaction was heated to 90° for 8 h. Sat. aq. NaHCO3/NaCl solution was added and the mixture was extracted with ethyl acetate. The organic layers were washed with water and sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 25 to 50% EtOAc/hexanes which had been sparged with NH3 gas, gradient elution) provided the title compound.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][CH3:21])[C:16]([C:22]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:15][N:14]=2)[CH2:9][CH2:8]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:25][C:23]([F:24])([F:26])[C:22]([C:16]1[C:17]([CH2:19][CH2:20][CH3:21])=[CH:18][C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][OH:4])[CH2:8][CH2:9]2)=[N:14][CH:15]=1)([O:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[C:27]([F:30])([F:29])[F:28]
Reactant: CCCc1cc(N2CCN(CCOC(C)=O)CC2)ncc1C(OCc1ccc(OC)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCc1cc(N2CCN(CCO)CC2)ncc1C(OCc1ccc(OC)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
2-(4-{5-[1,1,1,3,3,3-Hexafluoro-2-(4-methoxybenzyloxy)propan-2-yl]-4-propylpyridin-2-yl}piperazin-1-yl)ethyl acetate (479 mg) was dissolved in methanol (2.3 mL), added potassium carbonate (127 mg, 0.722 mmol), and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (chloroform/methanol). The title compound (117 mg (yield 47%)) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[C:20]([O:24][C:25]([NH:27][C:28]1[CH:39]=[CH:38][CH:37]=[CH:36][C:29]=1[CH2:30]OS(C)(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[C:20]([O:24][C:25](=[O:26])[NH:27][C:28]1[CH:39]=[CH:38][CH:37]=[CH:36][C:29]=1[CH2:30][N:4]1[C:5]2[C:10](=[CH:9][C:8]([NH2:11])=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=2)[C:2]([CH3:1])([CH3:19])[C:3]1=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccccc1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 115.6 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.55 g) is alkylated using methanesulfonic acid 2-tert-butoxycarbonylamino-benzyl ester (0.69 g; 2.09 mmol) and K2CO3 (0.99 g; 7.19 mmol) at RT for 18 h. After aqueous work-up the crude material is de-acetylated in MeOH (50 ml) using DBU (0.3 ml) at reflux. After aqueous work-up [2-(5-amino-3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-indol-1-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (1.03 g) is obtained and used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34]1([CH2:40][C:41](Cl)=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([CH2:40][C:41]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)CC3CCCCC3)CC2)cc1

Procedure:
2-Cyclohexyl-1-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-ethanone was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with cyclohexyl-acetyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 0.90-0.98 (m, 2H), 1.05-1.19 (m, 4H), 1.65-1.78 (m, 7H), 1.95-2.09 (m, 5H), 2.25-2.27 (m, 2H), 2.79-2.85 (m, 1H), 3.30 (methyl sulfonyl and water peak), 4.04-4.08 (m, 1H), 4.54-4.58 (m, 1H), 5.06-5.11 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.40 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=498.5.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].O>C1(C)C=CC=CC=1>[C:33]([N:21]1[CH2:20][CH2:19][CH:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:24])[F:25])=[CH:4][CH:5]=3)[N:10]=2)[CH2:23][CH2:22]1)(=[O:35])[CH3:34]
Reactant: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A stirred mixture of 4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 101 (15 g. 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 13 g (93%) of 1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred mixture of the indazole (4.15 g. 0.012 moles) and triethylamine (3.35 ml. 0.024 moles) in toluene (50 ml) was added acetyl chloride (0.93 ml, 0.013 moles). The reaction was stirred at ambient temperature for 2 hours and then poured into H2O. The product was extracted (CHCl3), dried (MgSO4), and concentrated to yield 4.3 g of an oil. The product was triturated with hexane and then recrystallized from CCl4 -hexane twice to yield 2.80 g of product. The product was further purified using high pressure liquid chromatography (silica gel, ethyl acetate) to yield 2.1 g (45%) of 1-acetyl-4-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine, m.p. 148°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=3)[C:15](O)=[O:16])[C:8]2=[O:21])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[O:56]1[CH:60]=[C:59]([CH2:61][NH2:62])[N:58]=[CH:57]1>CN(C)C=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][N:20]=3)[C:15]([NH:62][CH2:61][C:59]3[N:58]=[CH:57][O:56][CH:60]=3)=[O:16])[C:8]2=[O:21])=[CH:4][CH:3]=1
Reactant: NCc1cocn1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1cocn1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.8 %

Procedure:
A solution of 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid (0.35 g, 1.11 mmol), diisopropylethylamine (0.86 g, 6.66 mmol), 1-hydroxybenzotriazole monohydrate (0.39 g, 2.89 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.28 g, 1.44 mmol) in anhydrous N,N-dimethylformamide (10.0 mL) was stirred at ambient temperature for 10 minutes, followed by the addition of oxazol-4-ylmethanamine (0.23 g, 1.67 mmol). The resulting reaction mixture was stirred at ambient temperature for 17 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate (60 mL), washed with saturated aqueous sodium bicarbonate (10 mL) solution, water (2×10 mL) and brine (10 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(oxazol-4-ylmethyl)isonicotinamide as a colorless solid (0.21 g, 49%): mp 197-199° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.15 (t, J=5.6 Hz, 1H), 8.65 (s, 1H), 8.37-8.30 (m, 2H), 7.95 (s, 1H), 7.35-7.06 (m, 5H), 4.49-4.33 (m, 4H), 3.93 (t, J=8.0 Hz, 2H), 3.37-3.25 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 165.6, 163.6, 160.4, 156.8, 153.5, 152.5, 148.4, 143.3, 137.8, 136.6, 133.6, 133.6, 130.4, 130.3, 116.0, 115.7, 115.2, 110.5, 46.6, 41.6, 35.7; MS (ES+) m/z 396.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH:48]1[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([OH:59])([CH2:57][CH3:58])[CH2:55][CH3:56])[CH2:49]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:48]2[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([OH:59])([CH2:57][CH3:58])[CH2:55][CH3:56])[CH2:49]2)=[O:15])=[CH:6][CH:7]=1
Reactant: CCC(O)(CC)C1CCCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)(CC)C1CCCN(C(=O)c2cnoc2-c2ccc(C)cc2)C1
Reaction time: 2 h
Yield: 44.9 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.010 mmol, 2 equ) in DMF (0.3 mL) was added to 3-piperidin-3-ylpentan-3-ol hydrochloride (10 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C21H28N2O3: 356.2100, found 356.2099.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>C(O)C.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC=C(c2ccc(N)cc2)CC1
Temperature: 80 °C

Procedure:
tert-Butyl 4-(4-nitrophenyl)cyclohex-3-enylcarbamate (2.55 g, 8.01 mmol) was suspended in ethanol (30 ml) followed by addition of sodium sulfide, nonahydrate (10.37 ml, 80 mmol) dissolved in water (30 ml). The mixture was heated to 80° C. for 1.5 h and extracted with dichloromethane; the organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(Cl)Cl.C(OC(=O)[NH:17][C@H:18]([C:39]1[CH:44]=[C:43]([F:45])[C:42]([F:46])=[C:41]([F:47])[CH:40]=1)[C@H:19]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:20])(C)(C)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Si:22]([O:21][C@H:19]([CH3:20])[C@H:18]([NH2:17])[C:39]1[CH:44]=[C:43]([F:45])[C:42]([F:46])=[C:41]([F:47])[CH:40]=1)([C:35]([CH3:36])([CH3:37])[CH3:38])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](N)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 91.1 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a methylene chloride solution (2 mL) of [(1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propyl]carbamic acid tert-butyl ester (370 mg). The resulting reaction solution was stirred at room temperature for 11 hr, and a saturated sodium hydrogencarbonate aqueous solution and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated sodium hydrogencarbonate aqueous solution and with saturated saline in this order, and concentrated under reduced pressure to give 275 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[C:5]#[C:6][C:7](=O)[CH2:8][CH3:9])[CH3:2].[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].CO.C([O-])([O-])=O.[Cs+].[Cs+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[CH3:19][O:18][C:14]([C:15]1[S:16][C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:11][CH2:12][CH3:13])=[CH:6][C:7]=1[CH2:8][CH3:9])=[O:17]
Reactant: COC(=O)CS
Reactant: CCOC(C#CC(=O)CC)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc(CC)c(C(=O)OC)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 6,6-Diethoxy-hex-4-yn-3-one (1.46 g, 6.66 mmol) in THF (25 ml) was cooled to 0° C. (ice bath). Methyl thioglycolate (0.71 ml, 6.66 mmol) was added in one portion and the mixture was stirred at 0° C. for 1 h. Methanol (4 ml) and Cs2CO3/MgSO4 (1.5 g/3 g, pre-dried at 200° C. in vacuum) were added at 0° C. The mixture was stirred at 0° C. for 15 min and then at rt for 15 h. The reaction mixture was quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-10% EtOAc in hexane to afford the desired product (1.76 g, 82% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][C:14]=2[N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22]C(=O)O)[CH2:17]2)N(C)[C:8]1=[O:27])#[N:2].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH2:22][CH:18]1[CH2:19][CH2:20][CH2:21][N:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]3[C@@H:32]([CH3:33])[C:8](=[O:27])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([CH:30]=[CH:29][CH:28]=4)[C:1]#[N:2])[C:15]=23)[CH2:17]1
Reactant: Cn1c(=O)n(Cc2cccc(C#N)c2)c2c(N3CCC[C@@H](NC(=O)O)C3)ccnc21
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C(=O)N(Cc2cccc(C#N)c2)c2c(N3CCCC(N)C3)ccnc21
Yield: 50 %

Procedure:
The operation referred to the step (6) described in Example 1. 290 mg (R)-1-[1-(3-cyanobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]piperidin-3-yl carbamic acid ter.-butyl ester (0.63 mmol) and 1.0 mL trifluoroacetic acid were charged to afford 150 mg titled product with a yield of 50%.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N+:18]([O-])=O)=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=1.[NH4+].[OH-]>CCO>[NH2:18][C:10]1[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][C:11]=1[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(Cl)cc1N1CCCC1
Temperature: 70 °C
Yield: 89.8 %

Procedure:
Add pyrrolidine (0.97 g, 13.67 mmol) to a solution of 4-chloro-2-fluoro-1-nitrobenzene (2 g, 11.40 mmol) in 8 mL anhydrous DMSO under N2. Stir the reaction mixture at 80° C. for 1 h. Cool the mixture, pour into ice-H2O and extract with Et2O (3×30 mL). Wash the organic phase with water and brine, dry over MgSO4, filter, and concentrate. Chromatograph the residue on silica gel using hex/EtOAc 9:1 as eluent to afford 2.29 g (89%) of 1-(5-chloro-2-nitro-phenyl)-pyrrolidine as a yellow solid. Add tin chloride (10 g, 44.15 mmol) to a solution of 1-(5-chloro-2-nitrophenyl)pyrrolidine (2 g, 8.83 mmol) in 25 mL of EtOH under nitrogen. Heat the reaction mixture at 70° C. for 3 h. After cooling, pour the mixture into ice-water, basify (pH=9) with NH4OH, and extract with EtOAc (3×100 mL). Dry the organic phase over MgSO4, concentrate, and purify the residue by silica gel chromatography using hex/EtOAc 8:2 as eluent to obtain 1.56 g (88%) of 1-(2-amino-5-chlorophenyl)pyrrolidine as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12.[CH3:36][C:37]1[O:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][CH2:41][C:40]4[O:43][C:37]([CH3:36])=[CH:38][CH:39]=4)=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1N
Reactant: Cc1ccc(C=O)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
A mixture of benzyl 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (3.0 g, 0.0063 mol), 5-methylfurfural (0.77 g, 0.007 mol), and acetic acid (1.15 g, 0.019 mol) in dichloroethane (100 mL) was stirred at room temperature under an atmosphere of nitrogen for 1.5 hrs. Sodium triacetoxyborohydride (4.1 g, 0.0195 mol) was added to the mixture and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 18 hours. The reaction was quenched with an aqueous 5N solution of sodium hydroxide. The solvents were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×200 mL), and the combined organic layer was washed with water and brine, and dried over magnesium sulfate. The solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica gel using 2%-5% methanol/dichloromethane as mobile phase to yield benzyl 4-[4-amino-3-(3-methoxy-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (2.63 g, 0.0046 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.59 min. MS: MH+ 568.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.O.[NH2:11][NH2:12].O>C(O)C>[NH:11]([C:3]1[N:4]=[N:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])[NH2:12]
Reactant: Nc1cc(Cl)nnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nnc(Cl)cc1N

Procedure:
A stirred solution of 2.0 grams of 4-amino-3,6-dichloropyridazine and 2.5 ml of hydrazine hydrate in 20 ml of ethanol is heated under reflux for three hours. After this time water is added to the reaction mixture and the resultant precipitate collected by filtration. The filter cake is recrystallized from ethanol to yield 2.3 grams of 3-hydrazino-4-amino-6-chloropyridazine; m.p. 190° C.
Reaction SMILES: [C:1]([N:5]=[C:6]=[S:7])([CH3:4])([CH3:3])[CH3:2].[CH:8]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]([NH:5][C:6]([NH:13][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCCC1
Reactant: CC(C)(C)N=C=S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=S)NC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of tert-butyl isothiocyanate (5.0 mL; 39.4 mmoL) in DCM (200 mL) was added cyclopentylamine (4.67 mL; 47.3 mmoL) followed by DIPEA and the reaction mixture was stirred at R.T. for 2 h. The mixture was diluted with EtOAc, and washed with a 10% aqueous solution of citric acid (2×), saturated NaHCO3 (2×), H2O (2×) and brine (1×). The organic layer was dried over anhydrous MgSO4, filtered and evaporated to yield N-tert-butyl-N′-cyclopentylthiourea as a white solid (3.70 g; 47% yield). The N-tert-butyl-N′-cyclopentylthiourea (3.70 g) was dissolved in concentrated HCl (46 mL). The dark yellow solution was heated at a gentle reflux. After 40 min the reaction mixture was allowed to cool to R.T. and thereafter cooled in ice and rendered basic to pH 9.5 with solid and a saturated aqueous solution of NaHCO3. The product was extracted into EtOAc (3×). The combined EtOAc extracts were washed with H2O (2×) and brine (1×). The organic layer was dried (MgSO4), filtered and concentrated to yield a beige solid (2.46 g crude). Trituration of the crude material in hexane/EtOAc 95/5 provided, after filtration, the N-cyclopentylthiourea 8a as a white solid (2.38 g; 90% yield).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[C:11]1[C:12](=[O:18])[CH2:13][CH:14](OC)[CH:15]=1)([O:3][CH3:4])=[O:2].[SH:19][CH2:20][CH2:21][OH:22].C[O-].[Na+]>CO>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[C:11]1[C:12](=[O:18])[CH2:13][CH:14]([S:19][CH2:20][CH2:21][OH:22])[CH:15]=1)([O:3][CH3:4])=[O:2]
Reactant: OCCS
Reactant: COC(=O)CCCC/C=C\C1=CC(OC)CC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCC/C=C\C1=CC(SCCO)CC1=O
Reaction time: 0.83 h

Procedure:
To a stirred solution of 7.57 g (30 mmols) of 2-(6-carbomethoxy-2-cis-hexenyl)-4-methoxycyclopent-2-en-1-one (Example 283) and 2.46 g (31.5 mmols) of β-mercaptoethanol in 150 ml of methanol is added 15 ml of N/10 sodium methoxide in methanol solution. After 50 minutes at room temperature the solution is acidified with 0.27 ml of gl. acetic acid and partitioned with ether-brine. The ether extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to column chromatography on silica-gel to provide an oil.