Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]2[NH:32][CH:33]=[CH:34][N:35]=2)=[CH:25][CH:24]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COc1ccc(NCc2ncc[nH]2)cc1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Product: COc1ccc(N(Cc2ncc[nH]2)[C@@H]2c3cc([N+](=O)[O-])ccc3O[C@](C)(C(OC)OC)[C@H]2O)cc1
Yield: 27.5 %

Procedure:
The title compound (280 mg, 28%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (591 mg, 2.10 mmol) and 4-methoxyphenyl-1H-imidazol-2-ylmethylamine (427 mg, 2.10 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:14])=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl.CCOC(C)=O.O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=2)=[O:14])=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)c2ccc(N)cc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)c2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
Methanesulfonyl chloride (0.15 mL, 1.94 mmol) was slowly added to an ice-cooled solution of (4-amino-phenyl)-(4-methoxy-phenyl)-methanone (178) (0.4 g, 1.76 mmol) and pyridine (0.16 mL, 1.94 mmol) in dry dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 20 h then diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give 0.5 g (93%) of compound 179 as a solid. 1H NMR (400 MHz, DMSO-d6): δ 3.11 (s, 3 H), 3.84 (s, 3 H), 7.06 (d, J=8.8 Hz, 2 H), 7.30 (d, J=8.6 Hz, 2 H), 7.68-7.72 (m, 4 H), 10.31 (s, 1 H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[C:41]=1B(O)O>>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:41]5[C:42]([OH:46])=[CH:43][CH:44]=[CH:45][C:40]=5[F:39])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Reactant: OB(O)c1c(O)cccc1F
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5c(O)cccc5F)c4)nn23)CC1
Yield: 75 %

Procedure:
Prepared from (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate and (2-fluoro-6-hydroxyphenyl)boronic acid using the same procedure as intermediate 168 in 75% yield. 1H NMR (400 MHz, CDCl3) δ 8.19-7.99 (m, 2H), 7.61 (t, J=7.8 Hz, 1H), 7.46 (br. s., 1H), 7.25 (d, J=6.5 Hz, 1H), 6.92-6.74 (m, 3H), 6.13-5.78 (m, 2H), 5.59-5.47 (m, 1H), 5.39 (dd, J=17.2, 1.6 Hz, 1H), 5.20-4.99 (m, 1H), 4.00 (d, J=4.8 Hz, 2H), 3.76 (s, 3H), 2.72-2.54 (m, 3H), 2.05-1.87 (m, 3H), 1.79-1.64 (m, 1H), 1.35 (s, 3H), 1.25 (s, 9H). LCMS (M+1)=617.35.
Reaction SMILES: [CH:1]([N:4]([CH:20]([CH3:22])[CH3:21])[CH2:5][CH2:6][N:7]1[C:12]2[N:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=2[CH2:10][NH:9][C:8]1=[O:19])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:20]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][N:7]1[C:12]2[N:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=2[CH:10]=[N:9][C:8]1=[O:19])([CH3:22])[CH3:21]
Reactant: Cc1cc(C)c2c(n1)N(CCN(C(C)C)C(C)C)C(=O)NC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cc(C)c2cnc(=O)n(CCN(C(C)C)C(C)C)c2n1
Yield: 59.6 %

Procedure:
A solution of 1-(2-diisopropylaminoethyl)-5,7-dimethyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-2-one (3.5 g, 11.1 mmol) in methylene chloride (100 ml) containing activated manganese dioxide (9.0 g) is heated at reflux for 16 hours. The solution is filtered hot to remove the manganese dioxide and the manganese dioxide is extracted twice with hot chloroform. The organic extracts are combined, dried and evaporated to give 3.6 g of crude product which is crystallized from cyclohexane to give 2.0 g of pure title product; m.p.: 148°-150° C.
Reaction SMILES: [NH2:1][C:2]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][N:4]1[C:11](=[O:27])[C:12]([OH:26])=[C:13]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:16])[N:14]=[C:3]21.[F:28][CH2:29][CH2:30][N:31]([CH3:37])[C:32](=[O:36])[C:33](O)=[O:34].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C=O)C.Cl>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][NH:17][C:15]([C:13]2[N:14]=[C:3]3[C:2]4([NH:1][C:33](=[O:34])[C:32]([N:31]([CH2:30][CH2:29][F:28])[CH3:37])=[O:36])[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]4)[CH2:5][N:4]3[C:11](=[O:27])[C:12]=2[OH:26])=[O:16])=[CH:24][CH:23]=1
Reactant: CN(CCF)C(=O)C(=O)O
Reactant: NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCF)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.1 %

Procedure:
A mixture of 10-amino-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (0.05 g, 0.122 mmol), 2-((2-fluoroethyl)(methyl)amino)-2-oxoacetic acid (0.036 g, 0.245 mmol), diisopropyl ethylamine (0.128 mL, 0.734 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.093 g, 0.245 mmol) and 4-(dimethylamino)pyridine (DMAP) (2.99 mg, 0.024 mmol) in DMF (1.2 mL) was stirred at room temperature for 16 h. The mixture was diluted with 1N HCl and extracted with ethyl acetate. Solids precipitated out of the biphasic mixture and were collected by filtration to give the title compound as white needles (0.0394 g, 60% yield). 1H NMR (500 MHz, CDCl3) δ: 11.92-12.05 (1 H, m), 8.16-8.68 (2 H, m), 7.28-7.42 (2 H, m), 6.91-7.10 (2 H, m), 4.37-4.75 (4 H, m), 4.16 (2 H, t, J=4.58 Hz), 3.94-4.08 (1 H, m), 3.50-3.65 (1 H, m), 2.91-3.43 (3 H, m), 2.53-2.66 (2 H, m), 2.45-2.52 (1 H, m), 1.88-2.11 (4 H, m), 1.61-1.78 (2 H, m). LCMS (M+H) calcd for C24H28F2N5O5: 504.20; found: 504.02.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=3)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:30][NH2:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:31][CH3:30])[CH:23]=3)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CC(C)(C)OC(=O)NCC(c1cccc(C=O)c1)C1(c2ccc(Cl)cc2)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNCc1cccc(C(CNC(=O)OC(C)(C)C)C2(c3ccc(Cl)cc3)CCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl {2-[1-(4-chlorophenyl)cyclobutyl]-2-(3-formylphenyl)ethyl}carbamate (0.19 g, 0.459 mmol) was dissolved in dichloromethane and methylamine (1.15 ml, 2.295 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (0.146 g, 0.689 mmol) was added. The reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with sodium hydroxide (1 N) and extracted with ethyl acetate. The combined extracts were dried (magnesium sulfate), concentrated in vacuo and the crude product purified by flash chromatography (silica, dichloromethane, methanol). Yield: 0.11 g (0.256 mmol, 56%)
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)([CH3:8])[C:3]([O:5]CC)=O.[NH2:20][CH2:21][CH:22]([OH:34])[CH2:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1>CCO>[CH2:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][N:24]1[CH2:23][CH:22]([OH:34])[CH2:21][NH:20][C:3](=[O:5])[C:2]([CH3:1])([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)[CH3:8]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)C(C)(C)Oc1cccc2cccnc12
Solvent: CCO
Product: CC(C)(Oc1cccc2cccnc12)C(=O)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
To a solution of ethyl 2-methyl-2-(quinolin-8-yloxy)propanoate (120 mg, 0.46 mmol) in EtOH (0.5 ml) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (0.46 mmol) at 29° C. The mixture was stirred for 1 hour at 120° C. under microwave heating. The solvent was removed and the residue purified by prep-HPLC to afford the title compound (19.5 mg, Yield 10.1%). 1H NMR (400 MHz, MeOD): δ 8.95-8.93 (m, 1H), 8.34 (dd, J=8.4, 1.6 Hz, 1H), 7.69 (d, J=8 Hz, 1H), 7.56-7.52 (m, 2H), 7.39 (d, J=7.6 Hz, 1H), 7.11-7.02 (m, 3H), 6.94 (d, J=6.4 Hz, 1H), 4.13-4.10 (m, 1H), 3.70-3.53 (m, 2H), 3.48-3.43 (m, 2H), 2.91-2.81 (m, 4H), 2.79-2.64 (m, 2H), 1.57 (s, 6H) ppm; ESI-MS (m/z): 420.3 [M+1]+.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([SH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na].S([O-])([O-])(=O)=O.[Zn+2:15]>>[N+:1]1([O-:8])[C:2]([SH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Zn:15]
Reactant: [Zn+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na]
Agent: [O-][n+]1ccccc1S
Product: [Zn]
Reaction time: 0.5 h

Procedure:
The pH of the filtrate from A (contains about 0.20 mole sodium pyridine-2-thiol-N-oxide) was adjusted to 6.5 and a 20% zinc sulfate solution added until no free sodium 2-thiol-N-oxide was detected (via a ferric chloride test). The mixture was stirred 0.5 hours, filtered and washed with water. The "wet cake" was used for color determination using a Hunter Lab Color/Difference Meter D 25DZ, according to AATCC test method 110-1972. A portion was dried and analyzed via titration.
Reaction SMILES: C([O:8][CH:9]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:11][CH2:10]1)C1C=CC=CC=1.[H][H]>O1CCCC1.[C].[Pd]>[OH:8][CH:9]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:11][CH2:10]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(OCc1ccccc1)CO2
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)CO2
Reaction time: 8 h
Yield: 89.1 %

Procedure:
6.47 g of tert-butyl 3-(benzyloxy)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate was dissolved in 100 ml tetrahydrofuran, 1.3 g palladium carbon was added thereto, and the mixture was stirred overnight in a hydrogen atmosphere. The catalyst was filtered off from the reaction solution, 1.3 g of palladium carbon was added thereto, and the solution was stirred overnight in a hydrogen atmosphere. The catalyst was filtered off from the reaction solution, 2.6 g of palladium carbon was added thereto, and the solution was stirred overnight in a hydrogen atmosphere at 4.2 atmospheric pressure. The catalyst was filtered off from the reaction solution, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give 4.27 g of tert-butyl 3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)=[O:7])=[N:2]1.[Cl:28][C:29]1[C:34](Cl)=[N:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:28][C:29]1[C:34]([N:1]2[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C@@H:15]4[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]4)=[CH:11][CH:10]=3)=[O:7])=[N:2]2)=[N:33][CH:32]=[CH:31][N:30]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc[nH]n3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ccn(-c4nccnc4Cl)n3)cc2)C1
Reaction time: 16 h
Yield: 41.2 %

Procedure:
(S)-tert-Butyl 2-(4-(1H-pyrazole-3-carboxamido)phenyl)morpholine-4-carboxylate (90 mg, 0.24 mmol) and 2,3-dichloropyrazine (43 mg, 0.29 mmol) were dissolved in dimethylacetamide (2 ml) and potassium carbonate (67 mg, 0.48 mmol) was added. The reaction mixture was placed on a Büchi shaker for 16 hours at 80° C. To complete the reaction an additional amount of 2,3-dichloropyrazine (10 mg) was added and heating was continued for another 2 h at 120° C. After cooling the mixture, water was added followed by extraction with ethyl acetate twice. The combined organic layers was dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (silica gel, 10 g, 25% to 50% EtOAc in heptane) to yield an off-white gum (48 mg, 42%). MS (ISP): 429.3 (100%, [M−tBu+H]+), 485.4 (10%, [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:19][C:20]1[CH:25]=[C:24]([N:15]2[CH2:16][CH2:17][O:18][CH:13]([C:10]3[NH:11][CH:12]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[CH2:14]2)[N:23]=[C:22]([NH2:27])[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Clc1cccc(-c2c[nH]c(C3CNCCO3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4cccc(Cl)c4)c[nH]3)C2)n1
Yield: 140.6 %

Procedure:
A solution of 2-[4-(3-chlorophenyl)-1H-imidazol-2-yl]morpholine (600 mg, 2.0 mmol), 4,6-dichloro-2-pyrimidinamine (328 mg, 2.0 mmol) and Hunig's base (0.870 mL, 5.00 mmol) in ethanol (80 mL) was heated overnight at 85° C. The reaction mixture was filtered and concentrated to afford the crude title compound (1.1 g) as a brown oil. LC-MS (ES) m/z=391 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[N:16]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:17][CH:18]([C:19](=[O:29])[NH:20][CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH:12]12)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:23]1([CH:21]([NH:20][C:19]([CH:18]2[CH2:17][N:16]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:13]3[CH2:14][CH2:15][N:11]([C:9](=[O:10])[CH:8]([NH2:7])[CH:34]4[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]4)[CH:12]23)=[O:29])[CH3:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(NC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)C12)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(N)C3CCCCC3)C12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A solution of 30 (81 mg, 0.14 mmol) in DCM (10 mL) was treated with TFA (3 mL) at 0° C. After 1 h, the reaction mixture was warmed to ambient temperature. After 30 min, the solution was concentrated, diluted with EtOAc, washed with saturated NaHCO3, and brine. The aqueous layers were back-extracted with DCM and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to afford 31 (60 mg) as an off-white foam. 1H NMR (CDCl3, 300 MHz): δ7.42-7.27 (m, 5H), 5.10-5.01 (m, 1H), 4.57 (d, J=4.5 Hz, 1H), 4.22 (m, 1H), 3.86 (d, J=11.1 Hz, 1H), 3.78 (m, 1H), 3.64-3.46 (m, 2H), 3.19 (m, 1H), 2.96 (s, 3H), 2.62-2.56 (m, 1H), 1.77-1.67 (m, 6H), 1.53 (d, J=6.9 Hz, 3H), 1.19-1.15 (m, 6H) ppm. Mass spectrum, m/z [477.5] (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[N:19]1([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH2:34])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:34][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH2:26][CH2:25][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1OCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1OCCN1CCCCC1
Yield: 60.3 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 303 mg of 2-(2-piperidin-1-ylethoxy)phenylamine and 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of dimethylformamide. 255 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-{2-[2-(piperidin-1-yl)ethoxy]phenyl}acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[O:19]1[CH2:24][CH2:23]OCC1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([CH:23]1[C:24](=[O:19])[CH2:10][CH2:2][CH2:3][C:4]1=[O:6])=[O:6]
Reactant: C1COCCO1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)C2C(=O)CCCC2=O)c(Cl)c1
Reaction time: 0.25 h

Procedure:
42.5 g of 2-chloro-4-methylsulfonylbenzoic acid were boiled in 160 ml of dioxane with 5 drops of dimethylformamide and 25.1 ml of thionyl chloride until the evolution of gas subsided. The solvent was stripped off with the exclusion of moisture on a rotary evaporator. To the oily residue there were added at 0° C. 19.7 g of 1,3-cyclohexanedione in 250 ml of acetonitrile, and 63.1 ml of triethylamine were then added dropwise at this temperature. Stirring was continued for 15 minutes, 15.3 ml of acetone cyanohydrin were added, and the mixture was allowed to stand overnight. The reaction mixture was concentrated under reduced pressure on a rotary evaporator, the residue was taken up in ethyl acetate/water, and the organic phase was washed with 2N hydrochloric acid. The product was extracted from the organic phase using 5% K2CO3 solution, and precipitated at a pH of 2-3 using concentrated hydrochloric acid, with cooling. After filtration with suction and drying, 48.4 g of 2-[2-chloro-4-(methylsulfonyl)benzoyl]-1,3-cyclohexanedione of melting point 141°-142° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.O.[NH2:12][NH2:13]>C(O)CCC>[Br:1][C:2]1[CH:9]=[C:8]2[C:5]([C:6]([NH2:7])=[N:12][NH:13]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2cc(Br)ccc12
Temperature: 25 °C

Procedure:
4-bromo-2-fluorobenzonitrile (67.8 g), hydrazine hydrate (32.8 ml) in n-butanol (410 ml) were heated to 112° C. for five hours. The reaction mixture was allowed to cool down to r.t. The precipitated crystalline solid was filtered off and washed three times with ethylacetate (100 ml each). The product was dried in vacuo at 40° C. mp. 222-225° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[O:17]OC1C=C(C=CC=1)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N+:13]([O-:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(OOCl)c1
Reactant: Cc1ccc(OCc2ccccc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-benzyloxy-2-methyl pyridine described in Preparation Example 182 (5.99 g, 30.1 mmol) in methylene chloride (100 mL) was added 3-chloroperoxylbenzoic acid (8.79 g, 33.1 mmol, 65%) at 0° C., and the solution was stirred at room temperature for 2 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was partitioned with methylene chloride. This organic layer was separated, washed with an aqueous solution of saturated sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, and 5-benzyloxy-2-methyl-pyridine-1-oxide (7.71 g) was obtained as a crude product of a white solid. Next, acetic anhydride (77 mL) was added to 5-benzyloxy-2-methyl-pyridin-1-oxide (7.71 g), and the solution was stirred for 80 minutes at 120° C. This reaction mixture was cooled to room temperature, then, the solvent was evaporated in vacuo. Ethanol (50 mL) and an aqueous solution of 5N sodium hydroxide (7 mL) were added to the resulting residue, and the solution was stirred at room temperature for 50 minutes. The solvent was evaporated in vacuo, this residue was partitioned in brine and ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (heptane/ethyl acetate=1/1), and the title compound (4.17 g, 54%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([CH:8]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[N:6][OH:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=2)[N:33]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]([CH:8]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=3)[N:33]=2)=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=3)[N:33]=2)=[CH:11][CH:10]=1)=[N:6][OH:7])[CH3:2]
Reactant: CCOC(=O)C(=NO)C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NO)C(c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1)c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Reaction time: 18 h
Yield: 82.5 %

Procedure:
To a solution in dry DMF (20 mL) of bis(4-hydroxyphenyl)methyloximinoacetic acid ethyl ester (0.64 g, 2 mmol), prepared as in step 1, was added cesium carbonate (1.6 g, 5 mmol), the mixture was stirred for 10 mutes, and 2-bromomethyl-7-chloroquinoline (1 g, 4 mmol) was added. After stirring for 18 hours, the mixture was poured into water and the precipitated solid was collected by filtration, washed with water, and dried in vacuo. Chromatography on silica gel (hexane/EtOAC 3:1) afforded bis(4-(7-chloro-2-quinolylmethoxy)phenyl)-methyloximinoacetic acid ethyl ester (1.1 g).