Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:29])[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4ccccc4Cl)c3O2)cc1
Product: CNCC1Cc2cc(C)cc(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.060 g, 28%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2-chlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.22 g, 0.50 mmol) and methylamine (0.155 g, 5.0 mmol). mp 194-196° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:30][C:31](=[O:43])[C:32]([NH:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:33])[CH:26]=[CH:27][C:28]=1[OH:29]>CN(C1C=CN=CC=1)C.BrC1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:29][C:28]3[CH:27]=[CH:26][C:25]([NH:30][C:31](=[O:43])[C:32]([NH:34][CH2:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:33])=[CH:24][C:23]=3[F:22])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: O=C(NCCc1ccccc1)C(=O)Nc1ccc(O)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: COc1cc2c(Oc3ccc(NC(=O)C(=O)NCCc4ccccc4)cc3F)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxyquinoline (30 g, 100 mmol), N-(3-fluoro-4-hydroxyphenyl)-N′-(2-phenylethyl)ethanediamide (32 g, 106 mmol), DMAP (125 g, 1.02 mol) and bromobenzene (500 mL) was heated to reflux for 6 h. The mixture was cooled to room temperature and the bromobenzene was removed under reduced pressure. Methanol (500 mL) was added to the residue and the mixture was stirred at room temperature for 2 h. The resulting solid was filtered, washed with methanol and dried to give N-{4-[(7-benzyloxy-6-methoxyquinolin-4-yl)oxy]-3-fluorophenyl}-N′-(2-phenylethyl)ethanediamide (34 g, 61%). 1H NMR (400 MHz, d6-DMSO): δ 11.05 (s, 1H), 9.15 (s, 1H), 8.47 (d, 1H), 8.05 (d, 1H), 7.84 (d, 1H), 7.56-6.36 (m, 13H), 6.46 (d, 1H), 5.32 (s, 2H), 3.97 (s, 3H), 3.47 (q, 2H), 2.86 (t, 2H); 13C NMR (100 MHz, d6-DMSO): δ 160.5, 160.2, 159.9, 159.5, 155.2, 152.7, 152.2, 150.3, 149.6, 146.9, 139.7, 137.4, 137.3, 137.2, 137.1, 129.3, 129.2, 129.1, 129.0, 128.9, 128.7, 128.6, 126.9, 124.8, 117.9, 115.3, 109.9, 102.8, 99.8, 70.6, 56.5, 41.3, 35.2; IR (cm−1): 1657, 1510, 1481, 1433, 1416, 1352, 1310, 1252, 1215, 1609, 986, 891, 868, 850, 742, 696; LC/MS (M+H=566).
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:22]([C:24]([O:26]CC)=[CH2:25])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].CC(C)=O.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[C:24]([C:22]1[CH:21]=[CH:20][C:3]([C:4]([NH:6][CH2:7][C:8]2[S:9][C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)=[O:5])=[C:2]([NH2:1])[N:23]=1)(=[O:26])[CH3:25]
Reactant: C=C(OCC)c1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a mixture of 2-amino-6 (1-ethoxy vinyl)-N-(5-phenoxy-thiophene-2-ylmethyl)-nicotinamide described in Preparation Example A+-14 (2.0 mg, 0.0051 mmol) and acetone (2 mL) were added water (1 mL) and concentrated sulfuric acid (0.2 mL), and the solution was stirred at room temperature for 3 hours. The reaction solution was neutralized with an aqueous solution of saturated sodium bicarbonate, and ethyl acetate was added for extraction. The organic layer was washed with brine, the solvent was then evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), and the title compound (1.0 mg, 0.0027 mmol, 53%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])C(=O)[N:13]([CH2:18][CH2:19][NH:20][CH3:21])[C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH2:26](I)[CH3:27].[C:29](=[O:32])([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:29](=[O:32])[N:13]([CH2:18][CH2:19][N:20]([CH3:21])[CH2:26][CH3:27])[C:12]3[CH:22]=[CH:23][CH:24]=[CH:25][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Reactant: CCI
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(methylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 0.96 g of ethyl iodide are dissolved in 20 ml of dimethylformamide, and 1.16 g of potassium carbonate are added thereto. The mixture is stirred at room temperature overnight. After the reaction, the mixture is poured into ice-water and then extracted with ethyl acetate. The extract is washed with water, dried and then condensed, whereby (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-ethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained as a yellow oil.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12]>CN1CCCC1=O>[N:13]1([C:11](=[O:12])[CH2:10][O:5][C:4](/[CH:3]=[CH:2]/[C:1]([OH:8])=[O:7])=[O:6])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(O)/C=C/C(=O)O
Reactant: O=C(CCl)N1CCOCC1
Solvent: CN1CCCC1=O
Product: O=C(O)/C=C/C(=O)OCC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
Following general procedure A, fumaric acid (1.00 g, 8.60 mmol) was reacted with chloro acetyl morpholine (1.4 g, 8.6 mmol) and Ag2O (4.2 g, 9.47 mmol) at ca. 100° C. in N-methylpyrrolidinone. The reaction mixture was cooled to room temperature, filtered over Celite®, and the filter cake was washed with ethylacetate (EtOAc). The combined organic filtrates were subjected to acidic aqueous work-up and the crude material was purified by mass-guided preparative HPLC to give 0.50 g (24% yield) of the title compound (47) as a white solid. 1H NMR (CD3CN, 400 MHz): δ 6.85-6.80 (m, 2H), 4.85 (s, 2H), 3.64-3.60 (m, 4H), 3.57-3.54 (t, J=4.8 Hz, 2H), 3.42-3.39 (t, J=5.2 Hz, 2H). MS (ESI): m/z 244.06 (M+H)+, 242.07 (M−H)−.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28](=[O:39])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37]Br)=[CH:31][CH:30]=1>>[CH3:26][O:27][C:28](=[O:39])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:25])[CH3:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccc(F)cc1
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2ccc(F)cc2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 57 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-pyrrolidin-2-one (296 mg, 0.809 mmol) was alkylated with 4-(3-bromo-propyl)-benzoic acid methyl ester (276 mg, 1.07 mmol) over 72 h. Purification by medium pressure chromatography (1:1 hexanes:EtOAc) provided 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (250 mg). 1H NMR (CDCl3) (selected peaks) δ7.92 (d, 2H), 7.21 (d, 2H), 7.05 (m, 2H), 6.92 (m, 2H), 3.86 (s, 3H), 3.76 (m, 1H), 3.62 (m, 1H), 3.45 (m, 1H), 0.81 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)=[C:16]([CH3:32])[CH:15]=1.C(N(CC)CC)C>ClCCCl.CC(O)(C)C.[Cl-].[Zn+2].[Cl-]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)=[C:16]([CH3:32])[CH:15]=2)[N:7]=1
Reactant: CNC(=O)c1ccc(-c2cc(OC)c(N)cc2C)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CNC(=O)c1ccc(-c2cc(OC)c(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2C)cc1
Reaction time: 0.5 h

Procedure:
To the mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (100 mg, 0.46 mmol) in 0.5 mL of DCE and 0.5 mL of t-BuOH is added zinc chloride (1.0 M in ether, 0.46 mL, 0.46 mmol), and stirred 30 min. 4′-amino-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide (111 mg, 0.414 mmol) and triethylamine (46 mg, 0.46 mmol) are added sequentially, and the reaction is stirred at room temperature overnight. The precipitate is filtered, washed by MeOH, and dried in vacuo to afford 4′-(4-Chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-5′-methoxy-N,2′-dimethylbiphenyl-4-carboxamide as a white solid; ESMS m/z 451.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9]N=C1CCCC1=O.[C:17]([O-:20])(O)=O.[Na+]>CC#N.OS(O)(=O)=O>[Cl:1][C:2]1[C:3]2[NH:9][C:3]3[C:17](=[O:20])[CH2:6][CH2:7][C:2]=3[C:4]=2[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1CCCC1=NNc1ccc(Cl)cc1Cl
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCc2c1[nH]c1c(Cl)cc(Cl)cc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-(2,4-dichlorophenyl)hydrazono)cyclopentanone (2.2 g, 8.59 mmol) in MeCN (10 mL), H2SO4 (1.4 mL, 1.8M solution) was added and the mixture stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature, basified with saturated NaHCO3 and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude title compound as an off-white solid (800 mg) which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15](Cl)(=[O:17])[CH3:16]>C(OCC)(=O)C.O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([CH3:16])=[O:17])=[CH:3][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C)cc1
Reaction time: 2 h
Yield: 77801.2 %

Procedure:
100 g (933.3 mmol) of p-toluidine and 154.8 g (1.120 mmol) of potassium carbonate were dissolved in a mixed solvent of 1,000 ml of ethyl acetate and 500 ml of water. Thereinto was dropped 87.9 g (1.120 mmol) of acetyl chloride with ice-cooling, followed by stirring for 2 hours. Extraction with ethyl acetate was carried out. The organic phase obtained was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The crude crystal obtained was washed with hexane to obtain 130 g (yield: 93%) of p-acetotoluidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.[BrH:25]>C(OCC)(=O)C.CCCCCC>[Br:25][CH2:14][C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: Br
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CBr
Temperature: 80 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (50.0 g) and 48% hydrogen bromide (130.0 mL) were added to a reactor. The reaction mixture was stirred at 80° C. for 15 hours. The reaction was monitored with thin layer chromatography (ethyl acetate/n-hexane=1:2). The reaction mixture was cooled to 20˜25° C., stirred for over 1 hour, and then filtered under reduced pressure. The resulting white solid was washed with water (500.0 mL) and then dried under reduced pressure to obtain N-[5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide as a white solid (55.3 g, yield 94%).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C:3]([C:5]1[C:6]([CH3:26])=[C:7]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[N:8]2[C:13]=1[CH:12]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:10]=[CH:9]2)=[O:4].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31].C1CCN2C(=NCCC2)CC1.O>CN(C=O)C>[CH3:28][C:2]([CH3:1])([CH3:27])[C:3]([C:5]1[C:6]([CH3:26])=[C:7]([C:17]([N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:31][CH2:30][C:29]([O:33][CH3:34])=[O:32])=[O:18])[N:8]2[C:13]=1[CH:12]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:10]=[CH:9]2)=[O:4]
Reactant: Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)Nc1ccccc1
Reactant: C=CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCN(C(=O)c1c(C)c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn12)c1ccccc1
Temperature: 50 °C
Yield: 68.3 %

Procedure:
To a stirred solution of 1-(2,2-dimethylpropanoyl)-2-methyl-N-phenyl-7-(propan-2-yl)indolizine-3-carboxamide (70 mg, 0.19 mmol) in DMF (2.0 mL) is added Triton B (8 μl, 0.02 mmol) followed by methyl acrylate (18 μl, 0.20 mmol). The reaction is stirred for 3 days at 23° C. after which time DBU (0.20 mL, 1.31 mmol) and additional methyl acrylate (0.10 mL, 1.11 mmol) are introduced. The reaction is heated at 50° C. for 18 h and then cooled to 23° C., poured into water, extracted with EtOAc, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 30% EtOAc in hexanes) gives methyl N-{[1-(2,2-dimethylpropanoyl)-2-methyl-7-(propan-2-yl)indolizin-3-yl]carbonyl}-N-phenyl-beta-alaninate (60 mg, 70%).
Reaction SMILES: [F:1][C:2]([F:17])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)[C:3]([F:6])([F:5])[F:4].[H][H]>[Ni].O1CCOCC1>[F:1][C:2]([F:17])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[C:3]([F:4])([F:6])[F:5]
Reactant: O=[N+]([O-])c1ccccc1OC(F)(F)C(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1ccccc1OC(F)(F)C(F)(F)F
Yield: 85.3 %

Procedure:
A mixture of 27.2 g of crude 2-pentafluoroethoxy-nitrobenzene, 2.6 g of Raney-nickel catalyst and 250 ml of dioxane is agitated in a hydrogen atmosphere for 24 hours at a temperature of 20°-25° C. The hydrogen consumption is 6.54 liters. After filtering off the catalyst, the solution is evaporated to dryness, yielding 20.5 g of 2-pentafluoroethoxy-aniline in form of a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[NH:45][C:46]([NH:48][C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1)=[O:47].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:34]2[CH:33]=[CH:32][C:31]([NH:45][C:46]([NH:48][C:49]3[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=3)=[O:47])=[C:30]([F:29])[CH:35]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3ccncc3)c(F)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc(NC(=O)Nc4ccncc4)c(F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (40 mg, 0.09 mmol) in dioxane (2 ml) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(pyridin-4-yl)urea (62 mg, 0.14 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (7.5 mg, 0.01 mmol) and 136 μl of a 2M aqueous solution of cesium carbonate. The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 25 mg (45% yield) as a white solid. Purity 97%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([C@@H:22]1[C@H:25](OC(=O)C)[N:24]([NH2:30])[C:23]1=[O:31])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([SH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([C@H:22]1[C@H:25]([S:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:24]([NH2:30])[C:23]1=[O:31])=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1ccccc1
Reactant: CC(=O)O[C@H]1[C@@H](C(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1N
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: NN1C(=O)[C@@H](C(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1Sc1ccccc1
Yield: 80.6 %

Procedure:
A mixture of (3S,4S)-3-(N-benzyloxycarbonyl-L-phenylalanyl)-amino-4-acetoxy-azetidin-2-one (500 mg, 1.18 mmol) obtained in example 7, thiophenol (117 mg, 1.07 mmol), and zinc acetate dihydrate (207 mg, 0.95 mmol) in a mixture of benzene (20 ml) and toluene (20 ml) was refluxed for 4 hrs using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate, containing a small volume of acetone, and water. The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent to dryness, a white solid was washed with dichloromethane and 410 mg of the title compound was obtained as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:29][O-:30].[Na+]>C1COCC1>[CH3:29][O:30][CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: C[O-]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
4-Chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (200 mg, 0.48 mmol) were suspended in THF (5 ml) and sodium methoxide (0.27 ml 5.4 M in MeOH, 1.4 mmol) were added at 0° C. The mixture was stirred at ambient temperature for 18 h. Workup and purification as described in the general procedure C afforded the title compound as light yellow solid (41%), MS: m/e=414 (M+H+).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[C:8]([C:10]1[CH:11]=[C:12]([CH:16]2[CH2:25][C:24]([CH3:27])([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28](O)=[O:29])[CH:22]=3)[NH:17]2)[CH:13]=[CH:14][CH:15]=1)#[N:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[C:8]([C:10]1[CH:11]=[C:12]([CH:16]2[CH2:25][C:24]([CH3:26])([CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:28]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:29])[CH:22]=3)[NH:17]2)[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(C#N)c2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C#N)c2)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a suspension of methanesulfonamide (160 mg, 1.65 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (66 mg, 1.65 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A33. A solution of 2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.33 mmol) and 1,1′-carbonyldiimidazole (110 mg, 0.66 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B33. Solution B33 was added to Solution A33 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(3-cyano-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (25 mg, 20%) as a white solid: MS (ESI) M+1=384.3.
Reaction SMILES: [CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[C:8]=1[CH2:17][S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])(=[O:6])=[O:5])[CH3:3].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([NH2:34])[N:27]=1>C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([NH:34][C:22]([NH:21][S:18]([CH2:17][C:8]2[C:7]([S:4]([N:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[CH:12][CH:11]=[CH:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:20])=[O:19])=[O:23])[N:27]=1
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1

Procedure:
A solution of the sulfonyl isocyanate from Example 16 (approximately 1.3 g) and 0.56 g of 4,6-dimethoxy-2-aminopyrimidine in 6 ml methylene chloride was stirred overnight at room temperature. The reaction mixture was then filtered and the filtrate concentrated in vacuo. Trituration of the residue was warm n-butyl chloride/ethyl acetate gave a cream-colored solid. The yield of the title compound, m.p. 175°-180°, was 1.1 g; IR(nujol): 1720, 1730 cm-1 ; NMR(CDCl3 /DMSO-d6): δ 2.8 (6H, s, SO2N(CH3)2), 3.7-4.0 (9H, s, CO2CH3 and OCH3 's), 5.8-6.0 (3H, two singlets, --CH2 -- and heterocyclic ring H), 7.55-8.4 (3H, m), 10.5 (1H, br s, NH), 12.5 (1H, br s, NH).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (60 mg, 0.16 mmol) in DMF (1 mL) were added morpholine (17 mg, 0.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC. HCl) (38 mg, 0.20 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, ethyl acetate) yielding the Compound 48 as a solid (20 mg).