Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH:16]1(B(O)O)[CH2:18][CH2:17]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:9]([Si:6]([O:5][C:4]1[CH:13]=[CH:14][CH:15]=[C:2]([CH:16]2[CH2:18][CH2:17]2)[CH:3]=1)([CH3:8])[CH3:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C2CC2)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
A suspension of (3-bromo-phenoxy)-tert-butyl-dimethyl-silane (500 mg, 0.1.74 mmol), cyclopropyl boronic acid (194 mg, 2.26 mmol), K3PO4(1.3 g, 6.1 mmol), PCy3(49 mg, 0.17 mmol), and Pd(OAc)2 (20 mg, 0.087 mmol) in toluene/water (8 ml/0.4 ml) was stirred 3 hours at 110° C. and then diluted with Et2O. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (gradient 12% to 100% EtOAc in n-hexane) to give tert-butyl-(3-cyclopropyl-phenoxy)-dimethyl-silane (390 mg, 90%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C@H:9]1[O:13][C:12](=[O:14])[CH2:11][CH2:10]1.[CH3:15][CH2:16][Mg+].[Br-].CCOCC>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[OH:13][C@H:9]([CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:10][CH2:11][C:12]1([OH:14])[CH2:16][CH2:15]1
Reactant: CC[Mg+]
Reactant: O=C1CC[C@@H](COC2CCCCO2)O1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O[C@@H](CCC1(O)CC1)COC1CCCCO1
Temperature: 15 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a mixture of Ti(OiPr)4 (0.33 mL, 0.001 mol, Ardrich) and (5S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-dihydrofuran-2(3H)-one (1.0 g, 0.005 mol) in 18.7 mL of THF was added a solution of 3M EtMgBr in Et2O (4.3 mL, 0.0125 mol, Aldrich) via a syringe over 3 hrs at 15° C. After stirring for additional one hour at 15° C., the reaction was quenched with 20 mL of saturated NH4Cl solution, filtered and extracted with EtOAc (50 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography to afford 1-((S)-3-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)butyl)cyclopropanol as colorless oil (0.853 g, 74%)2.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[CH3:14][CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17].[Cl:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([C:32]3[O:33][C:34]4[CH:40]=[CH:39][C:38]([CH2:41]Cl)=[CH:37][C:35]=4[CH:36]=3)=[N:29]2)=[CH:24][CH:23]=1>CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[Cl:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([C:32]3[O:33][C:34]4[CH:40]=[CH:39][C:38]([CH2:41][C:15]([C:16]([O:18][CH3:19])=[O:17])([CH3:20])[CH3:14])=[CH:37][C:35]=4[CH:36]=3)=[N:29]2)=[CH:24][CH:23]=1
Reactant: COC(=O)C(C)C
Reactant: ClCc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)(C)Cc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 9.3 %

Procedure:
To a cooled suspension of lithium diisopropylamide {(1.45 mM tetrahydrofuran and n-hexane solution), 3.1 ml} and methyl 2-methylpropionate (0.5 g), dried hexamethylphosphoric triamide (0.5 ml) was added at -78° C. and the mixture was stirred for 10 minutes at the same temperature. Subsequently, 7-chloro-2-(5-chloromethylbenzofuran-2-yl)quinoline (6.43 g) was added to the mixture. After being stirred for 30 minutes at the same temperature, additive hexamethylphosphoric triamide (1.36 ml) was added to the mixture. The reaction temperature was gradually elevated to -10° C. for 1 hour. The resulting mixture was poured into ice-water and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (100 g) and eluted with n-hexane, successively 10% ethyl acetate in n-hexane and toluene. The fractions containing object compound were combined and concentrated under reduced pressure. The residue was dissolved in chloroform and n-hexane was added to the solution. The resulting precipitates were collected by filtration and dried to give 7-chloro-2-[5-(2-methoxycarbonyl-2-methylpropyl)benzofuran-2-yl]-quinoline (0.18 g).
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9]C)=O)=[CH:5][C:4]([C:11]([O:13][CH3:14])=[O:12])=[N:3][CH:2]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][C:17]=1[CH3:24]>CN(C=O)C>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:7]([C:6]2[N:1]=[CH:2][N:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:5]=2)=[O:9])=[CH:18][C:17]=1[CH3:24]
Reactant: Cc1cc(CN)ccc1F
Reactant: COC(=O)c1cc(C(=O)OC)ncn1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)NCc2ccc(F)c(C)c2)ncn1
Temperature: 60 °C
Reaction time: 48 h
Yield: 64.1 %

Procedure:
8.81 g (0.045 mol) of dimethyl pyrimidine-4,6-dicarboxylate were dissolved in 200 ml of DMF, after which 6.25 g (0.045 mol) of 4-fluoro-3-methylbenzylamine were added and the mixture was stirred at 60° C. for 48 hours (h). The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The organic phase was washed with a saturated solution of sodium hydrogen carbonate and 0.5 N HCl and then dried (MgSO4). After filtering, and evaporating the solvent in vacuo, the residue was stirred up in isopropanol. This resulted in 8.75 g of product, which was subjected to further reaction without any further purification.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][CH2:28][CH2:29][C:30]1[N:37]2[C:33]([S:34][CH:35]=[CH:36]2)=[CH:32][N:31]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:31]3[CH:32]=[C:33]4[S:34][CH:35]=[CH:36][N+:37]4=[C:30]3[CH2:29][CH2:28][OH:27])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: OCCc1ncc2sccn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc[n+]4c3CCO)[C@H](C)[C@H]12
Yield: 6 %

Procedure:
The same procedure as in Example 1 was repeated except that 134 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 185 mg of 5-(2-hydroxyethyl)imidazo[5,1-b]thiazole were used, thereby obtaining 8.6 mg of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:50])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[N:37]=[C:38]([CH2:42][O:43]C3CCCCO3)[S:39][C:40]=2[CH3:41])[CH:31]=1)=O)(C)(C)C>C1(C)C=CC=CC=1>[OH:43][CH2:42][C:38]1[S:39][C:40]([CH3:41])=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:50])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[N:37]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1sc(COC2CCCCO2)nc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3nc(CO)sc3C)c1)=N2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
A mixture of (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J15) (0.145 g) and 3-[3-[5-methyl-2-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K18) (0.18 g) in toluene (1.5 mL) was heated to 100° C. for 8 h. The mixture was cooled and evaporated in vacuum. A solution of the residue in a mixture of CH2Cl2 (2.5 mL) and trifluoroacetic acid (2.5 mL) was stirred for 0.5 h at 20° C. The mixture was evaporated in vacuum, the residual oil was dissolved in AcOEt and the solution was washed with saturated NaHCO3 solution and with brine, dried over Na2SO4 and evaporated in vacuum. The residue was triturated with CH2Cl2 to give the title compound (0.07 g) as white crystals.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[N:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH3:18][O:19][C:20]1[CH:41]=[CH:40][C:23]([C:24](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([O:8][CH2:7][C@H:6]2[O:9][C@@H:1]([N:10]3[CH:17]=[N:16][C:14]([NH2:15])=[N:13][C:11]3=[O:12])[C@H:2]([OH:3])[C@@H:4]2[OH:5])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:23]2[CH:40]=[CH:41][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc(N)nc3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 5-azacytidine (2.20 g, 9 mmol) in dry pyridine (45 mL) was added 4,4'-dimethoxytrityl chloride (3.15 g, 9.3 mmol) and the mixture was stirred overnight. The reaction mixture was poured into ice-water and extracted with chloroform. The combined organic extracts were dried (MgSO4) and chromatographed through a silica gel column (ethyl acetate--10% methanol/ethyl acetate) to give 2.89 g (59%) of a white product. NMR (CDCl3 +D2O); δ 3.35 (m, 2H), 3.70 (s, 6H), 4.26 (m, 3H), 5.80 (d, 1H), 6.80 (m, 4H), 7.31 (m, 9H), 8.45 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[N:26]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4]([C:13]([NH:35][CH2:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:15])=[C:3]([CH3:16])[N:2]2[CH3:1])=[CH:6][CH:7]=1
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Reactant: NCCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc2c(C(=O)NCCCN3CCOCC3)c(C)n(C)c2c1
Yield: 59 %

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid 16c (0.483 g, 2.20 mmole) with 2.0 M oxalyl chloride in CH2Cl2 (2.2 ml, 4.4 mmole) and 3-morpholin-4-ylpropylamine in a manner as previously described for example 16d to give a white solid (0.445 g, 59%). 1H NMR (300 MHz, CDCl3) δ 7.60 (1H, d, J=8.6 Hz), 6.82 (1H, dd, J=2.3, 8.6 Hz), 6.77 (1H, d, J=2.3 Hz), 6.71 (1H, s), 3.87 (3H, s), 3.62 (3H, s), 3.57 (6H, m), 2.69 (3H, s), 2.50 (2H, t, J=6.6 Hz), 2.43 (4H, m), 1.81 (2H, m); ESIMS (MH+): 346.20.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([O:20]CC3C=CC=CC=3)[C:10]([O:12]CC3C=CC=CC=3)=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:28]([NH:30][N:31]1[CH2:35][CH2:34][N:33]([S:36]([NH:39][C:40]([N:42]2[CH2:45][CH:44]([NH:46]C(=O)OCC3C=CC=CC=3)[C:43]2=[O:57])=[O:41])(=[O:38])=[O:37])[C:32]1=[O:58])=[O:29].CN([Si](C)(C)C)C(=O)C(F)(F)F.[NH2:71][C:72]1[S:73][CH:74]=[C:75](/[C:77](=[N:81]/[O:82][C:83]([CH3:101])([CH3:100])[C:84]([O:86][CH:87]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)=[O:85])/[C:78]([OH:80])=O)[N:76]=1>CN(C)C=O.[Pd]>[NH2:71][C:72]1[S:73][CH:74]=[C:75]([C:77](=[N:81][O:82][C:83]([CH3:101])([CH3:100])[C:84]([O:86][CH:87]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)=[O:85])[C:78]([NH:46][CH:44]2[CH2:45][N:42]([C:40]([NH:39][S:36]([N:33]3[CH2:34][CH2:35][N:31]([NH:30][C:28]([C:3]4[C:2](=[O:1])[N:7]5[CH:8]=[C:9]([OH:20])[C:10]([OH:12])=[CH:11][C:6]5=[N:5][CH:4]=4)=[O:29])[C:32]3=[O:58])(=[O:37])=[O:38])=[O:41])[C:43]2=[O:57])=[O:80])[N:76]=1
Reactant: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=C(NC1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3cnc4cc(OCc5ccccc5)c(OCc5ccccc5)cn4c3=O)C2=O)C1=O)OCc1ccccc1
Agent: [Pd]
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(ON=C(C(=O)NC1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3cnc4cc(O)c(O)cn4c3=O)C2=O)C1=O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of [1-[[[[3-[[[4-oxo-7,8-bis(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-3-yl]carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (1.35 g, 1.66 mmol) in 65 ml of N,N-dimethylformamide, N-methyl-N-trimethylsilyl trifluoroacetamide (1.66 g, 8.33 mmol) was added. After 20 minutes 0.45 g of palladium on carbon was added, and the mixture was hydrogenolyzed for 1 hour. The catalyst was removed by filtration, and to the filtrate (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid, 1-benzotriazole ester (0.83 g, 1.5 mmol) was added. After stirring overnight, the solvent was distilled off, and the residue triturated with 20 ml of water. The resulting solid was filtered off with suction and dried in vacuo. Yield of crude product: 1.28 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].C[CH2:14][N:15](C(C)C)C(C)C.CN>CN(C)C=O.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CN(C)C=O
Solvent: CO
Product: CNS(=O)(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of 4-bromo-3-methylbenzene-1-sulfonyl chloride (500 mg, 1.86 mmol) and DIEA (0.65 mL, 3.7 mmol) in N,N-dimethylformamide (5 mL) was added methylamine as a 2.0 M solution in methanol. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was evaporated to dryness and was dissolved in dichloromethane (3 mL). The solution was washed with 1 N HCl (2×3 mL) and a saturated solution of NaHCO3 (3 mL). The organics were dried over Na2SO4 and evaporated to dryness to give 4-bromo-N,3-dimethylbenzenesulfonamide (340 mg).
Reaction SMILES: [Na].[CH:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[N:11]=[CH:12][N:13]4[C:22]5[CH:21]=[CH:20][CH:19]=[C:18](F)[C:17]=5[C:16]5=[N:24][CH2:25][CH2:26][N:15]5[C:14]=34)[N:6]=2)[CH2:4][CH2:3]1.[CH:27]([OH:30])([CH3:29])[CH3:28]>>[CH:2]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[N:11]=[CH:12][N:13]4[C:22]5[CH:21]=[CH:20][CH:19]=[C:18]([O:30][CH:27]([CH3:29])[CH3:28])[C:17]=5[C:16]5=[N:24][CH2:25][CH2:26][N:15]5[C:14]=34)[N:6]=2)[CH2:4][CH2:3]1
Reactant: CC(C)O
Reactant: Fc1cccc2c1C1=NCCN1c1c(-c3noc(C4CC4)n3)ncn1-2
Agent: [Na]
Product: CC(C)Oc1cccc2c1C1=NCCN1c1c(-c3noc(C4CC4)n3)ncn1-2

Procedure:
Sodium (30 mg, 1.3 mmol) was dissolved in 20 ml of dry isopropyl alcohol. 5-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-12-fluoro-2,3-dihydrodiimidazo[1,5-a:1',2'-c]quinazoline (0.2 g, 0.6 mmol) was added and the mixture was heated at reflux for 10 min. Then the solvent was evaporated in vacuo and the residue was triturated with 25 ml of water. The insoluble material was filtered off and dried to give the title compound as pale crystals, m.p. 211°-214° C. Yield 0.17 g (75%). (Compound 43).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18]O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].S(Cl)([Cl:22])=O>>[Cl:22][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCO
Reactant: O=S(Cl)Cl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCl
Yield: 99.6 %

Procedure:
Using the general method of Example 19 Part A, 4-[(3-nitroquinolin-4-yl)amino]butan-1-ol (120 g, 0.459 mol) was chlorinated with thionyl chloride (109 g, 0.919 mol) to provide 127.9 g of N-(4-chlorobutyl)-3-nitroquinolin-4-amine as a yellow powder.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][C:14]1[N:15]=[C:11]([NH:10][CH2:9][CH2:8][NH2:7])[S:12][C:13]=1[CH3:17]
Reactant: Cc1nc(NCCNC(=O)OC(C)(C)C)sc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(NCCN)sc1C
Yield: 24.6 %

Procedure:
A solution of [2-(4,5-dimethyl-thiazol-2-ylamino)-ethyl]-carbamic acid tert-butyl ester (2.71 g) in methylene chloride (50 ml) was treated with TFA (5 ml) overnight at RT and 1 hour at 60° C. The solvent was evaporated. Ethyl acetate and 1N HCl were added. The separated aqueous layer was extracted under basic conditions with ethyl acetate. The obtained organic layer washed with brine, dried (MgSO4) and evaporated yielding 0.42 g of a light yellow oil.
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][OH:12])(=[O:8])=[O:7])C.Cl[C:18]1[C:19]([CH3:28])=[CH:20][C:21]2[N:22]([N:24]=[C:25]([CH3:27])[N:26]=2)[N:23]=1>>[CH2:15]([C:10]([CH2:13][CH3:14])([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:18]1[C:19]([CH3:28])=[CH:20][C:21]2[N:22]([N:24]=[C:25]([CH3:27])[N:26]=2)[N:23]=1)[CH3:16]
Reactant: Cc1nc2cc(C)c(Cl)nn2n1
Reactant: CCC(CC)(CO)CS(=O)(=O)N=CN(C)C
Product: CCC(CC)(COc1nn2nc(C)nc2cc1C)CS(N)(=O)=O

Procedure:
Using 3-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-diethyl-1-propanol and 6-chloro-2,7-dimethyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 221°-222° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])[CH:3]=[C:4]([C:9]([O:11]C)=[O:10])[C:5]([O:7]C)=[O:6].C1OCCOCCOCCOCCOCCOC1>CC[N+](CC1C=CC=CC=1)(CC)CC.[Cl-].[OH-].[Na+]>[CH3:1][CH:2]([CH2:13][CH2:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]=1[CH3:23])[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(=CC(C)CCC1=C(C)CCCC1(C)C)C(=O)OC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: CC1=C(CCC(C)C=C(C(=O)O)C(=O)O)C(C)(C)CCC1
Temperature: 25 °C
Yield: 87 %

Procedure:
Dimethyl malonate 3a (10 g, 28 mmol), TEBAC (0.33 g, 1.4 mmol) (or 18-Crown 6) and 1N NaOH (120 ml) are stirred at 100° C. for 3 days. Cooled to 25° C. the mixture is extracted with tert-butyl methyl ether and the organic phase, which contains aldehyde 5, is discarded. 100 ml 2 N HCl are added to the aqueous phase, which is extracted with tert-butyl methyl ether. The organic phase is washed with water, dried over MgSO4, filtered and evaporated to give 7.15 g of crude bis-acid 1c (87%). Analytical data: 1H-NMR (400 MHz, CDCl3): δ 0.96 (s, 6 H), 1.13 (d, 3 H), 1.35-1.6 (6 H), 1.56 (s, 3 H), 1.85-2.1 (4 H), 3.5 (m, 1 H), 7.6 (d, 1 H) ppm. 13C-NMR (400 MHz, CDCl3): δ 19.1 (q), 19.4 (t), 19.8 (q), 26.5 (t), 28.5 (2 q), 32.7 (t), 34.8 (s), 35.6 (d), 36.9 (t), 39.7 (t), 120.0 (s), 127.3 (s), 136.8 (s), 168.3 (s), 169.2 (d), 1669.7 (s). MS (DIP, EI): m/z (%) 294 (M+, 67), 279 (8), 276 (14), 261 (18), 258 (17), 243 (100), 233 (12), 215 (22), 190 (16), 187 (15), 175 (32), 151 (14), 144 (44), 135 (32), 126 (14), 123 (31), 121 (16), 107 (9), 95 (9). IR (film): 2969 (m), 2929 (m), 2867 (m), 1701 (s), 1367 (m), 1262 (m), 1237 (m), 1199 (s), 1172 (m), 1067 (m), 842 (m), 761 (m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1B(O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([C:26]3[CH:27]=[CH:28][C:29]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:30][C:25]=3[F:24])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Cl)ncc2Cl)CC1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(-c3ccc(S(C)(=O)=O)cc3F)ncc2Cl)CC1

Procedure:
The title compound is prepared from 4-(2,5-dichloro-pyridin-4-ylethynyl)-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoro-4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described for Intermediate 14. LC (method 7): tR=1.63 min; Mass spectrum (ESI+): m/z=493 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=2)[CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)=[N:17]2)=[N:10][CH:11]=1.[C:32]([NH:35][C@@H:36]([CH:40]([CH3:42])[CH3:41])[C:37](O)=[O:38])(=[O:34])[CH3:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.ClCCl.CO.O>[C:32]([NH:35][C@@H:36]([CH:40]([CH3:42])[CH3:41])[C:37]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:31]=[CH:30][CH:29]=[C:14]([CH2:15][N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[N:17]3)[CH:13]=2)=[N:10][CH:11]=1)=[O:38])(=[O:34])[CH3:33]
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCCN)cn4)c3)n2)cn1
Reactant: CC(=O)N[C@H](C(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N[C@H](C(=O)NCCOc1cnc(-c2cccc(Cn3nc(-c4cnn(C)c4)ccc3=O)c2)nc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg (0.23 mmol) of 2-{3-[5-(2-aminoethoxy)pyrimidin-2-yl]benzyl}-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one hydrochloride, 43 mg (0.25 mmol) of (S)-2-acetylamino-3-methylbutyric acid, 66 mg (0.34 mmol) of EDCI, 41 mg (0.30 mmol) of HOBt are dissolved in 2 ml of DMF, and 76 μl (0.68 mmol) of 4-methylmorpholine are added. The reaction mixture is stirred at room temperature for 18 h, water is added, and the precipitate is stirred with methanol and dichloromethane. The product is dried in vacuo.
Reaction SMILES: [OH:1][CH:2]([CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH:11]=1)[CH2:3][C:4](O)=[O:5].CN1CCOCC1.ClC(OCC)=O.B.[Li]>O1CCCC1.O>[OH:1][CH:2]([CH2:3][CH2:4][OH:5])[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:22][CH:21]=2)[CH:11]=1
Reactant: COc1ccc(C(=O)NCC(O)CC(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Agent: B
Agent: CCOC(=O)Cl
Agent: [Li]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCC(O)CCO)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
The obtained 3-hydroxy-4-{4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoylamino}butyric acid (27 mg) and 15 μL of N-methylmorpholine were dissolved in 3 mL of tetrahydrofuran under an atmosphere of nitrogen, and the solution was cooled to −15° C. Ethyl chloroformate (13 μL) was added to the solution, the mixture was stirred for 15 minutes, and then 18.4 mg of lithium boron hydride was added. After the mixture was stirred for 30 minutes at −15° C., 1 mL of water was added, and the reaction was quenched. The reaction mixture was purified by preparative high-performance liquid chromatography to obtain 21 mg (78%) of N-(2,4-dihydroxybutyl)-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzamide.