Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[CH:5]=[C:6]([C:12]2([C:35]([F:38])([F:37])[F:36])[CH2:16][C:15]([C:17]3[CH:30]=[CH:29][C:20]([C:21]([NH:23][CH2:24][C:25]([O:27]C)=[O:26])=[O:22])=[C:19]([C:31]([F:34])([F:33])[F:32])[CH:18]=3)=[N:14][CH2:13]2)[CH:7]=[C:8](Cl)[C:9]=1Cl>O.CCO>[F:32][C:31]([F:34])([F:33])[C:4]1[CH:5]=[C:6]([C:12]2([C:35]([F:37])([F:38])[F:36])[CH2:16][C:15]([C:17]3[CH:30]=[CH:29][C:20]([C:21]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:22])=[C:19]([C:31]([F:33])([F:34])[F:32])[CH:18]=3)=[N:14][CH2:13]2)[CH:7]=[C:8]([C:35]([F:38])([F:37])[F:36])[CH:9]=1
Reactant: COC(=O)CNC(=O)c1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CNC(=O)c1ccc(C2=NCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide (22 mg, 0.50 mmol) was added to Methyl N-{4-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-(trifluoromethyl)benzoyl}glycinate (130 mg, 0.22 mmol) in Water (1 ml) and EtOH (5 ml), and stirred at ambient temperature for overnight. 2NHCl was added into the mixture, and extracted with t-BuOMe three times, and dried over MgSO4. After evaporated, the crude product was got (120.0 mg, 94%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O>[N:1]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[O:21][CH:22]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=3)=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCOC(=O)c1coc(-c2ccc(CCl)cc2)n1
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc(-c2ccc(Cn3ncc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of indazole (0.244 g, 2.07 mmol) in DMF at 0° C. was treated with sodium hydride (0.076 g, 1.98 mmol), stirred for 10 minutes at room temperature, treated with ethyl 2-[4-(chloromethyl)phenyl]-1,3-oxazole-4-carboxylate (0.5 g, 1.88 mmol) and stirred at 80° C. overnight. The reaction mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo to give a solid residue. The resultant residue was purified by column chromatography (silica, EtOAc:hexanes, 50%) to give ethyl 2-[4-(1H-indazol-1-ylmethyl)phenyl]-1,3-oxazole-4-carboxylate as white solid. The resulting solid (0.45 g, 1.29 mmol) was dissolved in 1:1 MeOH:THF treated with 1.0 M LiOH for 3 hours at 60° C. and concentrated in in vacuo. The resulting residue was diluted with water, treated with 1.0 M HCl and filtered to afford the title product 92% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 320 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:18])CCOC[CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1.O=C1C[N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28]1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:18])[CH2:28][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)CCOCC1)n2C
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)CN(C(=O)OC(C)(C)C)C1)n2C

Procedure:
This compound (c-1) was prepared in an analogous fashion to (S)-4-(2-chloro-9-methyl-6-(3-methylmorpholino)-9H-purin-8-yl)tetrahydro-2H-pyran-4-ol, using tert-butyl 3-oxoazetidine-1-carboxylate as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 5.17 (broad d, 2H), 4.56 (dd, J=16.9, 9.48 Hz, 2H), 4.21 (dd, J=9.48. 2.56 Hz, 1H), 4.04 to 3.96 (m, 1H), 3.82 to 3.71 (m, 5H), 3.59 (td, J=11.6, 2.6 Hz, 1H), 3.47 (broad s, 1H), 2.02 (s, 1H), 1.43 (s, 9H), 1.40 to 1.36 (m, 4H); LC-MS (method A)=439/441 [M+H]+, RT=2.56 min.
Reaction SMILES: [NH:1]1[C:10](=O)[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[S:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].[OH-].[Na+]>N1C=CC=CC=1>[NH:1]1[C:10](=[S:13])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[S:3]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]c(=S)[nH]c2nc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: S=c1[nH]c(=S)c2[nH]cnc2[nH]1
Yield: 258.8 %

Procedure:
13.22 g (50 mM) of 2-thioxanthine and 13.34 g (60 mM) of phosphorus pentasulfide were heated under reflux in 160 ml of pyridine for 3 days. At 5-10° C., 66 ml (132 mM) of 2N NaOH were added. The solvents were evaporated in vacuo, the residue treated with 200 ml of water and evaporated again. The residue was again suspended in 200 ml of water and collected. The crude product was dissolved in 120 ml of 1N NaOH, treated twice with 0.14 g of charcoal, filtered and acidified with 32 ml of 5N HCl to pH 4.5. The solid was collected, washed and dried to give 14.31 g of crude dithioxanthine. This was dissolved in 300 ml of chloroform; some insoluble material was filtered off, and the solution passed through 71.5 g of silica gel in a column. Crystallization from isopropanol gave 12.17 g (86.8%) of 2,6-dithioxanthine with mp 196-200° C.
Reaction SMILES: C[S-].[Na+].C[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:21][N:19]([CH2:18][C:12]1([C:9]2[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH3:20]
Reactant: COc1ccc(C2(CN(C)C)CCOCC2)cc1
Agent: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Temperature: 130 °C
Yield: 108.4 %

Procedure:
To a suspension of Sodium thiomethoxide (49.2 g, 0.702 mol, 5 eq) in DMF (140 ml) was added {[4-(4-methoxyphenyl)-tetrahydro-2H-pyran-4-yl]methyl}dimethylamine (35 g, 0.140 mol) and the resulting mixture was heated to 130° C. Once complete, allowed to cool to ambient temperature and saturated aqueous NH4Cl (525 ml) was added. The resultant was extracted with EtOAc (3×500 ml), dried over MgSO4, filtered and concentrated in vacuo at 35° C. to provide 4-(4-dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (intermediate 3) as a yellow solid (35.7 g, 108%) containing residual DMF and EtOAc.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[CH:24][N:23]3[C:31]=2[CH3:32])[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)C1C=CC=CC=1.[H][H]>CN(C)C=O.[Pd]>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][CH2:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[CH:24][N:23]3[C:31]=2[CH3:32])=[CH:10][C:9]=1[OH:8]
Reactant: CCOc1ccn2c(C)c(C=Cc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1
Yield: 62.8 %

Procedure:
A solution of 2-[2-(3-benzyloxy-4-nitrophenyl)vinyl]-7-ethoxy-3-methylimidazo[1,2-a]pyridine (3.8 g) in N,N-dimethylformamide (80 ml) was subjected to catalytic reduction over 10% palladium on carbon (1.9 g) under atmospheric pressure of hydrogen gas at 40° to 60° C. for hours. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with a mixture of diethyl ether and diisopropyl ether and the precipitate was collected by filtration to give 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-7-ethoxy-3-methylimidazo[1,2-a]pyridine (1.73 g).
Reaction SMILES: C([NH:20][C@H:21]([C:25]([O:27][CH2:28][CH:29]([CH2:69][O:70][C:71](=[O:89])[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH2:53][O:54][C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[C:57](=[O:68])[CH:58]=[C:59]([C:65]([OH:67])=[O:66])[O:60]2)[CH2:37][O:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[C:41](=[O:52])[CH:42]=[C:43]([C:49]([OH:51])=[O:50])[O:44]2)=[O:34])=[O:26])[CH:22]([CH3:24])[CH3:23])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C>[NH2:20][C@H:21]([C:25]([O:27][CH2:28][CH:29]([CH2:69][O:70][C:71](=[O:89])[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:36]([CH2:37][O:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[C:41](=[O:52])[CH:42]=[C:43]([C:49]([OH:51])=[O:50])[O:44]2)[CH2:53][O:54][C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[C:57](=[O:68])[CH:58]=[C:59]([C:65]([OH:67])=[O:66])[O:60]2)=[O:34])=[O:26])[CH:22]([CH3:24])[CH3:23]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(CCCC(=O)OC(COc1cccc2oc(C(=O)O)cc(=O)c12)COc1cccc2oc(C(=O)O)cc(=O)c12)COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(CCCC(=O)OC(COc1cccc2oc(C(=O)O)cc(=O)c12)COc1cccc2oc(C(=O)O)cc(=O)c12)COC(=O)[C@@H](N)C(C)C
Reaction time: 2 h

Procedure:
Dibenzyl ester of 2-[5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoyloxy]-1,3-bis-(2-carboxychromon-5-yloxy)propane (238 mg, (0.17 mmol) was dissolved in ethyl acetate (1.5 ml). To the solution was added 80% acetic acid (10 ml). After two hr, the solution was evaporated and purified by column chromatography to yield 197 mg of 2-[5-(L-valyloxymethyl)-6-stearoyloxyhexanoyloxy]-1,3-bis-(2-carboxychromon-5-yloxy)propane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH3:11])=[CH:4][C:3]=1[OH:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH:59](O)[CH3:60]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH3:11])=[CH:4][C:3]=1[O:19][CH:59]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][N:53]=1)[CH3:60]
Reactant: C[C@@H](NCc1ccc(Cl)c(O)c1)c1cccc(Cl)c1
Reactant: CC(O)c1ccccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1cc(CN[C@H](C)c2cccc(Cl)c2)ccc1Cl)c1ccccn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a solution of (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenol 96 (130 mg, 439 μmol) in 5 mL of THF under N2 was added triphenylphosphine (127 mg, 483 μmol). The solution was chilled to 0° C. in an ice bath and then diisopropyl azodicarboxylate (94 μL, 483 μmol) was added dropwise to the reaction. After stirring for 15 min 0° C., a solution of 1-(pyridin-2-yl)ethanol (59 mg, 483 μmol) in THF was added to the reaction. The reaction was allowed to warm to room temperature and it was stirred for 10 h. The reaction was concentrated and diluted with EtOAc. The solution was extracted with saturated NaHCO3, water, and then brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 5% to 90% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give (1R)—N-(4-chloro-3-(1-(pyridin-2-yl)ethoxy)benzyl)-1-(3-chlorophenyl)ethanamine 98 (67 mg, 38% yield) as a colorless oil and as a mixture of diastereomers. 1H NMR (400 MHz, d4-methanol) δ ppm 1.60 (d, J=6.65 Hz, 2.1H) 1.73 (d, J=5.28 Hz, 3H) 1.83 (d, J=6.46 Hz, 3H) 3.90 (d, J=11.15 Hz, 1H) 4.16 (d, J=12.72 Hz, 1H) 4.45-4.54 (m, 1H) 5.18-5.28 (m, 0.7H) 5.99 (m, 1H) 7.05 (d, 1H) 7.48 (m, 5H) 7.63 (m, 1H) 7.99 (m, 1.7H) 8.08 (m, 0.7H) 8.20 (d, 1H) 8.59 (m, 1.7H) 8.73 (m, 0.7H) 8.83 (d, 1H). Mass spectrum: calculated for C22H22Cl2N2O 401.3. found 402.4 (M++1).
Reaction SMILES: Br[C:2]1[C:28]([F:29])=[CH:27][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[C:8]2=[O:26])=[C:4]([F:30])[CH:3]=1.[CH3:31][S:32]([O-:34])=[O:33].[Na+].[C@@H]1(N)CCCC[C@H]1N.[ClH:44]>CS(C)=O.O.CCOC(C)=O.C(Cl)Cl.CCOCC>[ClH:44].[F:30][C:4]1[CH:3]=[C:2]([S:32]([CH3:31])(=[O:34])=[O:33])[C:28]([F:29])=[CH:27][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:8]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCC(Oc3cc(F)c(Br)cc3F)C2=O)CC1
Reactant: CS(=O)[O-]
Agent: Cl
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(F)c(OC2CCCN(C3CCNCC3)C2=O)cc1F
Temperature: 110 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of tert-butyl 3-(4-bromo-2,5-difluorophenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (710 mg, 1.45 mmol) in DMSO (4 mL) was added Cu(I) triflate benzene complex (73 mg, 0.145 mmol), sodium methanesulfinate (222 mg, 2.18 mmol) and trans-cyclohexane-1,2-diamine (66.3 mg, 0.580 mmol). The reaction was heated at 110° C. overnight. The reaction was cooled to ambient temperature and diluted with water (5 mL) and EtOAc (5 mL). The organic layer was separated and the aqueous washed with EtOAc (2×10 mL). The combined organic layers were dried with MgSO4 and concentrated. The crude residue was purified over silica gel (2:1 hexanes/EtOAc) to give a clear oil. This material was then dissolved in CH2Cl2 (10 mL) and excess 2 N HCl in ether (5 mL) added. The reaction was allowed to stir overnight and then concentrated under vacuum to give 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1,4′-bipiperidin-2-one HCl salt (238 mg, 89%) was an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([OH:17])=O)[N:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=[O:33])=[CH:23][C:22]=1[F:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][C:15](=[O:17])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]4=[O:33])=[CH:23][C:22]=3[F:34])[N:10]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(O)Cn1ccc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Product: O=C(Cn1ccc(NC(=O)c2ccc(Cl)cc2)n1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
59.3 According to general method B, [3-(4-chloro-benzoylamino)-pyrazol-1-yl]-acetic acid was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) to give 4-chloro-N-(1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-1H-pyrazol-3-yl)-benzamide. White solid. MS 466.3 ([M+H]+)
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([O:13]C)[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[C:17]([CH3:34])[N:16]=3)=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br>C(O)(=O)C>[CH:1]1([NH:6][C:7]2[NH:12][C:11](=[O:13])[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[C:17]([CH3:34])[N:16]=3)=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nc(NC2CCCC2)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Br
Solvent: CC(=O)O
Product: Cc1nc(-c2cnc(NC3CCCC3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Yield: 70.3 %

Procedure:
Using the procedure of Example 6, N-cyclopentyl-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.085 g, 0.186 mmol) and HBr (0.085 mL, 0.743 mmol) were combined in acetic acid (2 mL) to afford 2-(cyclopentylamino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (58 mg, 70%). 1H NMR (400 MHz, DMSO-d6): δ 10.78 (br s, 1H), 8.67 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 8.29-8.23 (m, 2H), 7.96 (s, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.94 (br s, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 4.21-4.18 (m, 1H), 3.84 (s, 3H), 2.34 (s, 3H), 1.92-1.89 (m, 2H), 1.68-1.64 (m, 2H), 1.58-1.54 (m, 2H), 1.49-1.40 (m, 2H); MS (ESI) m/z: 444.2 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[CH:18][CH:19]=[C:13]4[NH:12][C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].[Na].Br[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25]>COCCOCCOC>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:15](=[O:16])[N:14]4[N:17]=[CH:18][CH:19]=[C:13]4[N:12]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c3[nH]c4ccnn4c(=O)c3cnc21
Reactant: CC(C)CCBr
Agent: [Na]
Solvent: COCCOCCOC
Product: CCn1ncc2c1ncc1c(=O)n3nccc3n(CCC(C)C)c12

Procedure:
7.6 g. of 3-ethyl-3,11-dihydro-6H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one (0.03 mol.) are refluxed with stirring in 100 ml. of diethyleneglycol dimethylether together with 1.4 g. of sodium (0.06 mol.). After this time, 11.5 g. of 1-bromo-3-methylbutane (0.075 mol) are added and the mixture is refluxed for 16 hours. The solvent is distilled off and the residue is crystallized with methanol, filtered and washed with water to obtain 3-ethyl-3,11-dihydro-11-(3-methylbutyl)-6H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one, yield 4.1 g. (42%); m.p. 167°-168° (isopropanol).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH3:7][C:8]1([CH2:13][CH2:14][C:15](=O)[CH2:16][C:17](OC)=[O:18])[O:12][CH2:11][CH2:10][O:9]1>C1(C)C=CC=CC=1>[OH:18][C:17]1[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=[C:15]([CH2:14][CH2:13][C:8]2([CH3:7])[O:9][CH2:10][CH2:11][O:12]2)[CH:16]=1
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)CC(=O)CCC1(C)OCCO1
Solvent: Cc1ccccc1
Product: CC1(CCc2cc(O)n3nccc3n2)OCCO1
Temperature: 115 °C
Yield: 84.5 %

Procedure:
A toluene solution (2 ml) containing 0.90 g of 3-aminopyrazole and 1.90 g of methyl 2-methyl-β-oxo-1,3-dioxolane-2-valerate was refluxed with heating at 115° C. for 1 hour, allowed to cool and then concentrated under reduced pressure. Diethyl ether was added to the residue. The crystals precipitated were collected and washed with diethyl ether to provide 1.85 g of 7-hydroxy-5-[2-(2-methyl-l,3-dioxolane-2-yl)ethyl]pyrazolo[1,5-a]pyrimidine as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:9]([F:23])=[C:8]2[C:3]=1[C:4](=[O:32])[CH:5]=[C:6]([C:27]([O:29]CC)=[O:28])[N:7]2[CH:24]1[CH2:26][CH2:25]1.[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:9]([F:23])=[C:8]2[C:3]=1[C:4](=[O:32])[CH:5]=[C:6]([C:27]([OH:29])=[O:28])[N:7]2[CH:24]1[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1cc(=O)c2c(N)c(F)c(NCCNc3ccccn3)c(F)c2n1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(F)c(NCCNc2ccccn2)c(F)c2c1c(=O)cc(C(=O)O)n2C1CC1
Yield: 82.8 %

Procedure:
A solution of ethyl 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-2-carboxylate (317 mg, 0.715 mmol) and 1M aq. NaOH (1.4 mL) in EtOH (7 mL) was stirred at room temperature for over night. The solvent was removed and the residue was dissolved in water. The solution was acidified to pH 7 with 2M HCl and the resulting precipitate was removed by filtration, washed with CH3CN, and dried to yield 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-2-carboxylic acid (246 mg, 83%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH:8]=[N:7][C:6]([N:13]=[C:14]=S)=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH2:24][CH2:25][C@@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH:8]=[N:7][C:6]([NH:13][C:14]1[O:34][C@:26]3([CH2:25][N:24]=1)[CH:31]1[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]1)[CH2:27]3)=[CH:5]2
Reactant: S=C=Nc1cc2cc(Cl)cc(Cl)c2cn1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Clc1cc(Cl)c2cnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)cc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
To 6,8-dichloro-3-isothiocyanatoisoquinoline (0.17 g, 0.67 mmol) in DMF (10 mL) was added cesium carbonate (0.543 g, 1.67 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.15 g, 0.67 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The product was treated with N,N′-diisopropylcarbodiimide (0.31 mL, 2.0 mmol). The reaction was heated to 90° C. for 4 hours. The reaction was cooled to room temperature and concentrated to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was taken up in a small amount of ethyl acetate, which resulted in the formation of a precipitate. It was filtered off, washed with a small amount of ethyl acetate, and dried in a vacuum oven to yield (R)—N-(6,8-dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.094 g, 0.24 mmol, 36.6% yield) as a white powder. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.23 (s, 1H), 8.71-8.83 (m, 1H), 7.90-8.00 (m, 1H), 7.57-7.67 (m, 1H), 7.13-7.24 (m, 1H), 3.79-3.90 (m, 1H), 3.53-3.64 (m, 1H), 2.93-3.04 (m, 2H), 2.72-2.82 (m, 2H), 2.61-2.70 (m, 2H), 1.99 (s, 1H), 1.90 (s, 1H), 1.59 (d, J=4.78 Hz, 2H), 1.40-1.50 (m, 1H). MS (LC/MS) R.T.=1.68; [M+H]+=377.1.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:10])[NH2:9])=[CH:4][CH:3]=1.[NH:11]([C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[NH:20][C:21](=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=O)N>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:21]([NH:20][C:19]2[CH:18]=[CH:17][S:16][C:15]=2[C:13]2[NH:11][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=3)[N:10]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(CC(=O)Nc2ccsc2C(=O)NN)cc1
Reactant: N=C(N)c1ccncc1
Agent: Cl
Product: COc1ccc(CC(=O)Nc2ccsc2-c2nc(-c3ccncc3)n[nH]2)cc1

Procedure:
The title compound was prepared from pyridine-4-carboximidamide hydrochloride (157 mg, 1.00 mmol) and N-(2-(hydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide (Example 1.11.1., 204 mg, 0.668 mmol) according to the procedure described in Example 1.11.2., above. Retention time (min)=2.511, method [7], MS(ESI) 392.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.87 (d, J=4.5 Hz, 2H), 8.08-8.16 (m, 2H), 7.94 (d, J=5.0 Hz, 1H), 7.67-7.70 (m, 1H), 7.31 (d, J=8.6 Hz, 2H), 7.88 (d, J=8.6 Hz, 2H), 3.88 (s, 2H), 3.67 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10](Cl)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:20]([NH:24][NH2:25])(=O)[CH2:21][CH3:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:20]([CH2:21][CH3:22])=[N:24][N:25]=2)=[CH:12][CH:13]=1
Reactant: CCC(=O)NN
Reactant: COc1ccc(N=C(Cl)c2ccc(OC)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1nnc(-c2ccc(OC)cc2)n1-c1ccc(OC)cc1
Yield: 72.1 %

Procedure:
Using the procedure of Step B, of Example 4, 3.46 g of the product of Step A, 2.21 g of propionic acid hydrazide, 1.74 ml of triethylamine and 50 ml of toluene were reacted to obtain 2.8 g of 3,4-bis-(4-methoxyphenyl)-5-ethyl-4H-1,2,4-triazole melting at 122° C.