Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:26][CH2:25][CH2:24][NH:23][C:22]3=[O:27])[CH2:17][CH2:16]2)[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:28]1([C:38](Cl)=[O:39])[C:37]2[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=2[CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[CH2:26][CH2:25][CH2:24][NH:23][C:22]3=[O:27])[CH2:17][CH2:16]2)[CH2:10][N:11]([CH3:12])[C:38]([C:28]2[C:37]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:39])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC[C@@H](CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1cccc2c1CCCC2
Product: CN(C[C@@H](CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cccc2c1CCCC2

Procedure:
Using standard acylation conditions N-[(S)-2-(3,4-dichlorophenyl)4-[4-[tetrahydro-2-oxo-1(2H)-pyrimidinyl]-1-piperidinyl]butyl]-N-methylamine (S. C. Miller,. WO 9505377) was reacted with 5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride (Example 1) and the product was converted to the citrate salt MS: m/z 571 (M+H). Analysis for C31H40O2Cl2N4.C6H8O7.3.0H2O: calculated: C,54.34; H, 6.66; N, 6.85; found: C, 54.26; H, 5.97; N, 6.47.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([S:18][C:19]2[N:23]4[CH:24]=[C:25]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:26]=[CH:27][C:22]4=[N:21][N:20]=2)=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:35][CH2:36][OH:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:33][N:31]1[CH:32]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]3[N:23]([C:19]([S:18][C:14]4[CH:15]=[C:16]5[C:11](=[CH:12][CH:13]=4)[N:10]=[CH:9][C:8]([N:1]4[CH2:7][CH2:6][CH2:5][N:4]([CH2:35][CH2:36][OH:37])[CH2:3][CH2:2]4)=[CH:17]5)=[N:20][N:21]=3)[CH:24]=2)[CH:29]=[N:30]1
Reactant: OCCBr
Reactant: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(N6CCCNCC6)cc5c4)n3c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(N6CCCN(CCO)CC6)cc5c4)n3c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.3 %

Procedure:
A mixture of 3-(1,4-Diazepan-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline (Example 19—see in Table below) (15 mg, 0.033 mmol), 2-bromoethanol (12.33 mg, 0.099 mmol) and K2CO3 (9.08 mg, 0.066 mmol) in DMF (0.5 ml) was stirred at rt for 24 hr. The mixture was purified by prep-HPLC to give the title compound (6 mg, yield 36%). [Method 1D]
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:42][C:43]([NH:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:20]([N:22]([CH2:32][C:33]1[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[S:36][CH:37]=1)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH2:42][C:43](=[O:44])[NH:45][C:46]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:20]([N:22]([CH2:32][C:33]2[C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3[S:36][CH:37]=2)[C@@H:23]([CH3:31])[CH:24]([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 60 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[Cl:29][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccncc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccncc1
Yield: 55 %

Procedure:
A suspension of 6-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (300 mg, 1.06 mmol) in thionyl chloride (5 ml) containing DMF (50 μl) was heated at reflux for 1 hour. The mixture was allowed to cool, diluted with toluene and the volatiles were removed by evaporation. The residue was dissolved in methylene chloride and a cooled solution of aqueous sodium hydrogen carbonate was added. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-methoxy-7-(4-pyridylmethoxy)quinazoline (175 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+].[CH2:21](O)[CH3:22]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:21][CH3:22])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Br)cc1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (3.0 g) in ethanol (20 mL) was added thionyl chloride (2.0 mL) at 0° C., and the mixture was stirred overnight at 70° C. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, the mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.30 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cncnc3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrimidin-5-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A of Example 11t, and 4-chlorobenzenesulfonyl chloride, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.91 (s, 2H), 7.78 (d, 2H), 7.49 (d, 2H), 7.44 (d, 2H), 7.23 (m, 2H), 7.14 (m, 1H), 7.05 (d, 1H), 6.89 (d, 1H), 6.81 (s, 1H), 4.36 (s, 2H), 4.32 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H); MS 536 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N-:14]1.[K+].CN1C(=O)CCC1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:14]2[C:15](=[O:22])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]2=[O:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=C1[N-]C(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 200 °C
Yield: 91.5 %

Procedure:
4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.1 mmol) and potassium 1,3-dioxoisoindolin-2-ide (2.0 g, 10.9 mmol) were placed in microwave vial (0.5-2 ml) and NMP (12.0 ml) was added. The reaction mixture was heated at 200° C. using microwave (Biotage, Initiator) for 1 min. After cooling to rt, the reaction mixture was added dropwise to stirring water which resulted in formation of precipitate. The solid was collected, washed with water and dried under stream of nitrogen to afford the title compound (2.89 g, yield: 92%). 1H-NMR (400 MHz, CDCl3) δ 7.26 (s, 2H) 7.43 (d, 2H) 7.81-7.87 (m, 3H) 7.91 (dd, 2H) 7.95-8.05 (m, 3H) 8.33 (d, 1H)
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)(C)C>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)O
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Essentially prepared according to Procedure G using 2,4-dichloro-5,7-difluoro-3-methylquinoline (610.0 mg, 2.50 mmol) and tert-butyl piperazine-1-carboxylate in isopropanol to give tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-piperazine-1-carboxylate. Mass Spectrum (ESI) m/e=398.2 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:34])[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(OC(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccc(OC(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(4-trifluoromethoxy-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (36 mg, 0.077 mmol), β-alanine (682 mg, 7.7 mmol) and NaOMe solution (12 mL, 6.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH was about 2. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 21 mg of the title compound as a yellow solid. MS: (+) m/z 528.27 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:39][CH2:40][CH2:41][CH3:42])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[CH:35]=[N:36][NH:37][CH:38]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:50][CH2:51][O:52][CH3:53]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:39][CH2:40][CH2:41][CH3:42])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[CH:38]=[N:37][N:36]([CH2:50][CH2:51][O:52][CH3:53])[CH:35]=4)[CH:22]=3)[CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cn[nH]c2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(CCOC)c2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.1 %

Procedure:
A mixture of 4-{6-butyl-5-[4-cyclohexyloxy-3-(1H-pyrazol-4-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (0.14 mmol, 80.6 mg), potassium tert-butoxide (0.15 mmol, 17.2 mg, 98%) and THF (1 mL) was stirred at room temperature for 40 min. 1-Bromo-2-methoxy-ethane (0.17 mmol, 0.016 mL) was added and it was stirred for 2.5 h. More potassium tert-butoxide (0.30 mmol, 34.4 mg, 98%) was added and after stirring for 30 min, more 1-bromo-2-methoxy-ethane (0.34 mmol, 0.032 mL) was added. It was stirred overnight. The reaction mixture was partitioned between ethyl acetate (10 mL) and saturated aq. sodium bicarbonate solution (10 mL). The ethyl acetate layer was dried over sodium sulfate. Purification by column chromatography on silica gel using 20-100% ethyl acetate in hexanes to provide 4-(6-butyl-5-{4-cyclohexyloxy-3-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-pyridazin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless solid (59.5 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1.Cl[C:18]1[C:23]([CH2:24][CH2:25]Cl)=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[N:21]=[C:20]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:19]=1>O1CCCC1>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([C:22]2[C:23]3[CH2:24][CH2:25][N:16]([C:14]4[CH:13]=[CH:12][N:11]=[C:10]([N:7]5[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]5)[CH:15]=4)[C:18]=3[N:19]=[C:20]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:21]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Reactant: CN1CCN(c2cc(N)ccn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccnc(N3CCN(C)CC3)c2)c1
Yield: 81.3 %

Procedure:
Sodium hydride (108 mg, 60% mineral oil dispersion, 2.72 mmol) was placed in a dried flask under a nitrogen atmosphere, followed by sequential addition of anhydrous tetrahydrofuran (10 ml) and 2-(4-methylpiperazin-1-yl)pyridin-4-ylamine (62 mg, 0.32 mmol) with a syringe, and the resulting mixture was heated to reflux for 2 hours. 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]morpholine (100 mg, 0.27 mmol) was added, followed by heating to reflux for 16 hours. The reaction mixture was cooled, which was subsequently added dropwise slowly onto ice water, followed by extraction twice with ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), and dried over sodium sulfate, followed by distilling off under reduced pressure, to obtain a crude product as a red oil (107 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7]O)[CH2:3][CH2:2]1.[CH3:9][O:10][C:11]([C:13]#[C:14][C:15]([O:17][CH3:18])=[O:16])=[O:12].C1N2CCN(CC2)C1>C1(C)C=CC=CC=1>[NH:7]1[C:13]([C:11]([O:10][CH3:9])=[O:12])=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:3]2[CH2:2][O:1][CH2:6][CH2:5][C:4]1=2
Reactant: ON=C1CCOCC1
Reactant: COC(=O)C#CC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: COC(=O)c1[nH]c2c(c1C(=O)OC)COCC2
Temperature: 165 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
A suspension of dihydro-2H-pyran-4(3H)-one oxime (7 g, 60.8 mmol), dimethylacetylene dicarboxylate (9.72 ml, 79 mmol), and DABCO (2.046 g, 18.24 mmol) in Toluene (27.5 ml) were heated to 165° C. After 2 h, the reaction mixture was cooled to ambient temperature, concentrated in vacuo and purified by ISCO (0-100% EtOAc-hexanes) to afford dimethyl 1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2,3-dicarboxylate (3.2 g, 13.38 mmol, 22.00% yield) as a yellow solid. The residue was dissolved in DMF (30 mL), and treated with Cs2CO3 (5.29 g, 16.23 mmol) and 4-fluorobenzyl bromide (2.023 ml, 16.23 mmol). After 2 h, the reaction mixture was partitioned between EtOAc and sat. aq. NH4Cl. The organic layer was washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by ISCO (0-50% EtOAc-hexanes; 120 g column) to afford dimethyl 1-(4-fluorobenzyl)-1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2,3-dicarboxylate (3.92 g, 11.29 mmol, 18.56% yield) as a yellow oil. LCMS (m/z) ES+=348 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].C[O:23][C:24](=[O:39])[C:25]([CH3:38])([CH3:37])[CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1>>[CH3:36][C:29]1[CH:28]=[C:27]([CH2:26][C:25]([CH3:38])([CH3:37])[C:24]([OH:39])=[O:23])[CH:32]=[C:31]([CH3:33])[C:30]=1[C:34]1[NH:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:18]=[CH:19][C:20]=2[N:21]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Product: Cc1cc(CC(C)(C)C(=O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[nH]1

Procedure:
The title compound was prepared from 3,4-diamino-N-quinolin-2-yl-benzamide (from Example 6-17) and 3-(4-formyl-3,5-dimethylphenyl)-2,2-dimethylpropionic acid methyl ester analogous to Example 6-26. 1H NMR (Methanol-d4, 400 MHz): δ 8.45 (d, 1H), 8.38 (d, 2H), 8.04 (dd, 1H), 7.93 (m, 2H), 7.77 (m, 2H), 7.55 (m, 1H), 7.06 (s, 2H), 2.89 (s, 2H), 2.16 (s, 6H), 1.2 (s, 6H). MS (m/z) 493.2 (M+1); Retention time: 1.25 min (Method 10).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:45])[CH2:10][C:11]1[CH:44]=[CH:43][CH:42]=[CH:41][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:27]=2)[N:16]=1>C(Cl)Cl>[CH3:21][C:20]1[C:15]([CH2:14][CH2:13][C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[CH2:10][C:9]([NH2:8])=[O:45])=[N:16][C:17]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:27]=2)=[N:18][CH:19]=1
Reactant: Cc1cnc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1CCc1ccccc1CC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2cnn(C3CCNCC3)c2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
TFA (0.5 mL) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (A128) (0.040 g, 0.077 mmol) in DCM (5 mL) and the resulting mixture stirred for 18 hours at room temperature. The volatiles were evaporated under reduced pressure and the residue partitioned between 2 M NaOH (10 mL) and EtOAc (25 mL). The organic layer was separated and washed with water (25 mL), brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound 33 as an off white solid (0.015 g, 49%); 1H NMR (400 MHz, d4-MeOH) δ 8.05 (s, 1H), 7.99 (d, J=0.5 Hz, 1H), 7.56 (d, J=0.6 Hz, 1H), 7.27-7.22 (m, 1H), 7.22-7.15 (m, 3H), 4.23 (tt, J=11.7, 4.1 Hz, 1H), 3.64 (s, 2H), 3.23-3.09 (m, 4H), 3.02-2.91 (m, 2H), 2.76 (td, J=12.8, 2.5 Hz, 2H), 2.14-2.05 (m, 5H), 1.98-1.85 (m, 2H). LCMS-A: rt 3.968 min; m/z 420 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][SH:8].[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N+]([O-])=O)=[CH:18][N:17]=1)=[O:15].C(O)(=O)C>CN(C)C=O>[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([Cl:3])[CH:5]=2)=[CH:18][N:17]=1)=[O:15]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cn1
Reactant: SCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCc2cccc(Cl)c2)cn1
Reaction time: 0.25 h

Procedure:
To the stirred suspension of 1.73 g of sodium hydride in 30 ml of dimethylformamide the solution of 12.7 g of m-chlorobenzylmercaptan is added during 2 minutes and stirring is continued for 15 minutes. Thereupon the solution of 12.25 g of 5-nitro-pyridine-2-carboxylic acid methyl ester in 75 ml of dimethylformamide is added all at once. The mixture is stirred for 1 hour on the steam bath and allowed to stand at room temperature overnight. It is poured onto ice and acetic acid, the suspension obtained filtered and the residue recrystallized from 95% aqueous ethanol, to yield the 5-(m-chlorobenzylmercapto)-2-pyridinecarboxylic acid methyl ester melting at 75°-77°.
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[N:12]=[C:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[CH:14]2)[N:10]=[C:9]2[C:5]=1[NH:6][C:7](=[O:30])[N:8]2[C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]2[N:15]=[CH:14][N:13]([C:11]3[N:10]=[C:9]4[C:5]([NH:6][C:7](=[O:30])[N:8]4[C@H:23]4[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]4)=[C:4]([OH:1])[N:12]=3)[C:17]=2[CH:18]=1
Reactant: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](O)CC1
Reactant: [OH-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1[nH]c2c(O)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](O)CC1
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
An oven dried vial containing a stirbar was charged with Pd2 dba3 (2 mg, 0.002 mmol, 0.02 equiv.), 2-di-t-butylphosphino-2′,4′,6′-tri-isopropyl-1,1′-diphenyl (Strem, 3.5 mg, 0.008 mmol, 0.08 equiv.), KOH (17 mg, 0.3 mmol, 3 equiv.) and 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9-(trans-4-hydroxycyclohexyl)-7H-purin-8(9H)-one (40 mg, 0.1 mmol, 1 equiv.), followed by 1,4-dioxane (0.3 mL) and degassed water (0.3 mL). A stream of argon was passed through the reaction mixture for 3 min; the vial was then closed and heated at 100° C. After 16 h, the reaction was found to be complete. Preparative HPLC chromatography provided, after evaporation of solvent, the desired product as a white solid. 1H NMR (300 MHz, CD3OD+CDCl3) δ, ppm: 9.04 (s, 1H), 8.45 (dd, 1H), 7.80-7.65 (m, 1H), 7.15-7.08 (m, 1H), 4.42-4.30 (m, 1H), 3.84-3.77 (m, 1H), 2.70-2.60 (m, 2H), 2.25-2.11 (m, 2H), 1.97-1.83 (m, 2H), 1.62-1.40 (m, 2H); MS (EI) m/z 385.3 (MH)+.
Reaction SMILES: [Cl-].[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH2+:16][CH:17]=2)=[CH:5][CH:4]=1.[C:18]([Cl:23])(=[O:22])[CH2:19][CH2:20][CH3:21]>C(O)(C(F)(F)F)=O>[Cl-:23].[C:18]([O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:13]2[N:14]=[CH:15][NH2+:16][CH:17]=2)=[CH:5][CH:4]=1)(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: Oc1ccc2c(c1)C(CC1=C[NH2+]C=N1)CC2
Reactant: CCCC(=O)Cl
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)Oc1ccc2c(c1)C(CC1=C[NH2+]C=N1)CC2

Procedure:
4-(6-hydroxy-indan-1-ylmethyl)-1H-imidazol-1-ium chloride (100 mg, 0.399 mmol) and butyric acid chloride (510 mmol) were reacted in TFA (1 ml) and purified as described in example 1. Yield 90 mg (77%) of a white hygroscopic solid. 1H NMR (CDCl3, TMS): δ 1.02 (t, 3H), 1.70-1.79 (m, 3H), 2.18-2.24 (m, 1H), 2.52 (t, 2H), 2.73-2.86 (m, 3H), 3.18 (dd, 1H), 3.53 (qui, 1H), 6.84 (dd, 1H), 6.87 (s, 1H), 6.92 (s, 1H), 8.66 (s, 1H), 11.28 (s (broad), 2H). 13C NMR (CDCl3, TMS): δ 13.66, 18.45, 29.68, 30.52, 31.68, 36.24, 43.98, 115.79, 117.05, 120.36, 125.36, 132.32, 132.59, 141.32, 146.36, 149.51, 172.85.-HPLC-MS (EI): m/z=285.2 ((M+H)+—Cl−). Anal.—Calc. for C17H20N2O2.HCl.0.2CH2Cl2: C, 61.16; H, 6.39; N, 8.29. Found C, 61.30; H, 6.46; N, 8.22.