Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:19]=[C:18]([NH:20][CH:21]([CH3:23])[CH3:22])[C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:24][C:25](=[N:31][NH2:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:24][C:25](=[N:31][NH:32][C:15](=[O:17])[C:14]1[C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[CH:19][C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)=[N:12][CH:13]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C(N)=NN
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(N)=NNC(=O)c1cnc(Nc2ccc3ncsc3c2)cc1NC(C)C
Reaction time: 4 h

Procedure:
To a stirred solution of 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinic acid (4) (500 mg, 3.8 mmol) and ethyl 2-amino-2-hydrazonoacetate (6) (3.8 mmol, 1 equiv.) in DMF (10 mL), HATU (7.63 mmol, 2 equiv.) and DIPEA (15.2 mmol, 4 equiv.) were added and stirred for 4 h. The reaction mixture was concentrated under reduced pressure to remove excess of DMF. The residue obtained was partitioned between water and EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent to afford the title compound.
Reaction SMILES: [C:1](=[O:12])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:13]1(O)C=CC=C[CH:14]=1.C(=O)(OCCCC)N>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4]>[C:1](=[O:12])([O:2][C:3]1[CH:14]=[CH:13][CH:6]=[CH:5][CH:4]=1)[O:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCOC(=O)OCCCC
Reactant: Oc1ccccc1
Agent: [Ti+4]
Agent: CCCCOC(N)=O
Agent: CCCC[O-]
Product: CCCCOC(=O)Oc1ccccc1
Reaction time: 0.17 h
Yield: 12.3 %

Procedure:
1795 g of the top section liquid obtained above containing 862 g of dibutyl carbonate, 932 g of phenol and 1 g of butyl carbamate and 16.8 g of titanium tetrabutoxide were charged into a round bottom flask of capacity 5 L in which a distillation column made from glass provided with a vacuum jacket (filled Sulzer Labopacking, inner diameter 50mmφ, height of filling portion 1100 mm) was connected to an upper portion thereof. The contents in the flask were heated with a mantle heater while stirring at 300 rpm with a mechanical stirrer. When the bottom section temperature became 191° C., reflux was started. All reflux was performed for 10 minutes after starting of reflux and then distillation-out was started in a reflux ratio of 30. The starting time of distillation-out was regarded as starting of the reaction. The yield (mol %) of butyl phenyl carbonate based on charged dibutyl carbonate was analyzed by gas chromatography. The yield was 12.3% in the reaction for 30 min., 18.6% in the reaction for 60 min., 22.5% in the reaction for 90 min., 27.4% in the reaction for 120 min., and 30.0% in the reaction for 150 min. The amount of distilled-out liquid was 131 g and the distilled-out liquid contained 128 g of butanol and 3 g of phenol. The bottom section temperature was 192° C. at the starting time of distillation-out and 197° C. after 150 minutes of starting of the reaction.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH3:22].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH3:22])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C(Cl)N1CCOCC1
Solvent: c1ccncc1
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)N1CCOCC1
Reaction time: 1 h
Yield: 51.1 %

Procedure:
A solution of the compound of Example 46, 1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.67 mmol) in 30 mL of pyridine was chilled in an ice water bath. With vigorous stirring, the solution was treated with 4-morpholinecarbonyl chloride (0.310 mL, 2.67 mmol). After 1 h, the reaction was concentrated to yield an off white solid. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) followed by trituration in ether gave 563 mg of N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}morpholine-4-carboxamide as a white solid.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:9]Br>C(Cl)(Cl)Cl.Br.CC(O)=O>[Br:9][CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1cccs1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1cccs1
Reaction time: 1 h
Yield: 36.9 %

Procedure:
To a solution of 500 mg (3.96 mmol) of 2-acetyl thiophene (Aldrich Chemical Co.) dissolved in 20 mL of CHCl3, was added 1 drop of 30% HBr/CH3COOH (Aldrich Chemical Co.) followed by 3.96 mmol (633 mg; 204 μL) of bromine (Aldrich Chemical Co.) added dropwise over 30 min. The reaction was allowed to stir for 1 h. The solution was concentrated to an oil and dried in vacuo. The crude product was purified on 1 mm silica prep plates eluting with neat CH2Cl2 to obtain 300 mg (37% yield) of 2-bromo-1-(2-thienyl)ethan-1-one. 1H-NMR (CDCl3; 300 MHz) δ 7.8 (m, 2H), 7.18 (m, 1H), 4.37 (s, 2H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.O.[NH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:26]3[C:21](=[N:22][CH:23]=[N:24][C:25]=3[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[NH:20][N:19]=2)=[CH:13][CH:12]=1>C1COCC1>[C:1]([CH2:2][CH2:3][C:4]([CH:10]([NH2:9])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:26]3[C:21](=[N:22][CH:23]=[N:24][C:25]=3[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)[NH:20][N:19]=2)=[CH:13][CH:12]=1)=[O:5])([OH:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC(C(=O)CCC(=O)O)c1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 25 °C

Procedure:
A solution of 57.4 mg (0.573 mmol) of succinic anhydride in 0.5 ml of THF is added dropwise, with stirring, to a suspension, cooled to 0° C., of 200 mg (0.521 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate (see Step 77.5) in 3 ml of THF. The reaction mixture is stirred at RT for 4 hours and then a further solution of 57.4 mg (0.573 mmol) of succinic anhydride in 0.5 ml of THF is added. The mixture is stirred for a further 3 hours at 40° C., then allowed to cool to RT and filtered, and the filter residue is washed with diethyl ether. 3-[4-({3-Carboxy-propionyl}-aminomethyl)-phenylamino]-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine having a water content of 2.45% is obtained; m.p. 205-207° C.; ESI-MS: (M−H)−=464.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].[C:20]1(=[O:31])[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[CH2:21]1.O1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:31])[CH2:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([OH:26])=[O:25])[CH:16]=[CH:17][CH:18]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(/C=C/c2cccc(N)c2)n1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: C1CCOCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc(/C=C/c2cccc(NC(=O)Cc3ccccc3C(=O)O)c2)n1
Yield: 100.6 %

Procedure:
A solution of 0.5 g of (E)-2-[2-(3-aminophenyl)ethenyl]-4-thiazolecarboxylic acid ethyl ester, 0.3 g of homophthalic anhydride, 15 ml of toluene and 5 ml of tetrahydropyran was heated to reflux for 0.5 hr. Upon cooling, a solid formed which was filtered to yield 0.8 g of (E)-2-[2-[3-[2-[4-(ethoxycarbonyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 221°-223° C. from ethanol.
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:16][N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:19][C:18]2([CH3:30])[CH3:29])=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1(C)C=CC=CC=1>[C:38]([N:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[C:8]([O:16][N:17]1[C:18]([CH3:30])([CH3:29])[CH2:19][CH:20]([O:25][C:26](=[O:28])[CH3:27])[CH2:21][C:22]1([CH3:24])[CH3:23])=[N:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)NC2CCCCC2)C(C)(C)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OC1CC(C)(C)N(OC(=NC2CCCCC2)N(C(=O)c2ccccc2)C2CCCCC2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.6 %

Procedure:
To a solution of compound 1 (4.21 g, 10 mmol) [prepared according to Example 1] in toluene (25 ml) is added triethylamine (1.55 ml, 11 mmol) and benzoyl chloride (1.55 g, 11 mmol). The mixture is stirred at room temperature for 24 hours, then washed with water (2×10 ml), dried over MgSO4 and evaporated. The residue is chromatographed over silica gel with hexane-ethyl acetate (4:1) and the pure fractions are recristallized from acetonitrile to afford 0.98 g of the title compound as a white solid, mp. 147-152° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([O:7][C:8]2[S:14][CH:13]3[N:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([O:18]CC2C=CC([N+]([O-])=O)=CC=2)=[O:17])=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+:35]>O1CCOCC1.O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[S:14][CH:13]3[N:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([O-:18])=[O:17])=[CH:29][CH:30]=1.[Na+:35]
Reactant: COc1ccc(OC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)CC3S2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(OC2=C(C(=O)[O-])N3C(=O)CC3S2)cc1

Procedure:
A mixture of a solution of 60 mg of 4-nitrobenzyl 3-(4-methoxyphenoxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 15 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.[NH:29](C(OC(C)(C)C)=O)[C@H:30]([C:38]([OH:40])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C=O)C>C(Cl)Cl>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:29][C@H:30]([C:38]([OH:40])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:6])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
On the other hand, 2 mmole of Boc-Ala, the 36th amino acid in the amino acid sequence, was dissolved in 5 ml ml of DCM. In an amino acid activating vessel, 2 ml of DCC (0.5M DCM solution) was added to the resulting solution They were reacted for 5 minutes. Thereafter, the reaction product was treated in the same manner as in the Boc-Phe After addition of DMF and subsequent concentration under a nitrogen gas stream, the resulting concentrate was transferred to a reaction vessel so as to conduct a reaction for 20 minutes. The reaction mixture was then washed with 8 ml of DCM (6 times, each, for 20 seconds) and filtered to obtain Boc-Ala-Phe-resin.
Reaction SMILES: [CH3:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Br:13]Br.O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:2](=[O:12])[CH3:1]
Reactant: BrBr
Reactant: CCCCCCCCCC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCCCCCCC(Br)C(C)=O
Reaction time: 2 h

Procedure:
A solution of undecan-2-one (170 g, 1.0M) in CCl4 (500 ml) was stirred at 20°-25° C. and bromine (160 g) was added over 15 minutes. The solution decolourised rapidly and stirring was continued for 2 hours at 20°-25° C. when water (100 ml) was added. NaHCO3 (92 g) was added portion-wise and the mixture filtered. The filtrate was dried over anhydrous MgSO4 and distilled. The fraction which boiled at 142°-146° C./20 mmHg (116 g) was collected. NMR(CDCl3)=0.7-1.6 (m, 17, C8H17), 2.3 (s, 3, CH3), 4.0-4.4 (t, 1, CH).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28]2>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32]([CH:31]=[CH:30][C:29]([C:2]3[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:22])[CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:14][CH3:15])=[CH:7][C:3]=3[C:4]([NH2:6])=[O:5])=[CH:28]2)=[CH:33][CH:34]=1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Reactant: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1ccccc1
Product: CCC(C(=O)Nc1ccc(-c2ccc3ccc(OC)cc3c2)c(C(N)=O)c1)c1ccccc1

Procedure:
50 mg (0.12 mmol) of the compound from Example 5A are reacted with 37 mg (0.18 mmol) of 6-methoxynaphthalene-2-boronic acid in analogy to the synthesis of Example 1. 27 mg (44% of theory) of product are obtained.
Reaction SMILES: [CH3:1]OP(OC1C=CC(C#N)=CC=1)(OC)=S.C(C1C=C(C)C([CH2:24][N:25]2[C:30](=O)N(CC3C(C)=CC(C(C)(C)C)=C(O)C=3C)C(=O)N(CC3C(C)=CC(C(C)(C)C)=C(O)C=3C)[C:26]2=[O:61])=C(C)C=1O)(C)(C)C>>[CH3:1][C:26]([N:25]([CH3:30])[CH3:24])=[O:61].[CH3:24][N:25]([CH3:30])[C:26](=[O:61])[CH3:1]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1Cn1c(=O)n(Cc2c(C)cc(C(C)(C)C)c(O)c2C)c(=O)n(Cc2c(C)cc(C(C)(C)C)c(O)c2C)c1=O
Reactant: COP(=S)(OC)Oc1ccc(C#N)cc1
Product: CC(=O)N(C)C

Procedure:
CYANOX® 1790 1,3,5-tris(4-t-butyl-3-hydroxy-2,6-dimethyl-benzyl)-1,3,5-triazine-2,4,6(1H,3H,5H)trione antioxidant, sold by Cytec Industries.
Reaction SMILES: [C:1]([C:4](=[C:10](OCC)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C(O)(=O)C.[CH:19]([NH2:21])=[NH:20].[O-]CC.[Na+]>C(O)C>[CH3:2][C:1]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:10]([CH3:11])[N:21]=[CH:19][N:20]=1
Reactant: CCOC(=O)C(C(C)=O)=C(C)OCC
Reactant: N=CN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)ncnc1C
Temperature: 90 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
Ethyl 2-acetyl-3-ethoxybut-2-enoate (10.7 g, 0.0537 mol), formamidine acetate (5.6 g, 0.054 mol) and sodium ethoxide (2.7 M in ethanol, 20.0 mL) were mixed in ethanol (30 mL) and the mixture was stirred at 90° C. for 4 h. The reaction mixture was cooled, quenched with water and concentrated. The crude material was purified by flash chromatography on silica gel, eluting with 10%, 50% ethyl acetate/hexane to afford the desired product (7.4 g, 76%) as a yellow oil. MS (EI) 181.1 (M+1). 1H NMR (300 MHz, CDCl3) δ (ppm) 8.97 (s, 1H), 4.44 (q, 2H), 2.56 (s, 6H), 1.42 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:27]OS(C)(=O)=O)[C:13](=[O:26])[N:14]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:27][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)[C:13](=[O:26])[N:14]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Reactant: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 79.3 %

Procedure:
Following the procedure of Example 1(10), 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 79.3%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[CH2:20](Br)[CH:21]=[CH2:22]>>[CH2:22]([N:7]1[C:6](=[O:8])[C:5]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=[C:2]1[NH2:1])[CH:21]=[CH2:20]
Reactant: Nc1nc(-c2ccco2)c(-c2ccncc2)c(=O)[nH]1
Reactant: C=CCBr
Product: C=CCn1c(N)nc(-c2ccco2)c(-c2ccncc2)c1=O

Procedure:
The title compound was synthesized in a manner similar to that described for Example 3 from 2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone and allyl bromide.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[C:17]([F:30])[C:16]=1[O:31][CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=2)=[C:17]([F:30])[C:16]=1[O:31][CH3:32]
Reactant: COc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Reactant: CC(=O)Nc1cc(Cl)c(C=O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(Cl)ccc(-c2cc(NC(C)=O)ncc2C=O)c1F
Temperature: 85 °C
Yield: 33.8 %

Procedure:
A stirred solution of N-(4-chloro-5-formylpyridin-2-yl)acetamide (1.947 g, 8.72 mmol) (prepared as described in Example 18, Part D), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 g, 8.72 mmol), cesium carbonate (5.69 g, 17.45 mmol) and Pd(PPh3)4 (0.504 g, 0.436 mmol) in a mixture of dioxane (30 mL) and water (5 mL) was purged with nitrogen for 5 minutes then heated to 85° C. for 14 h. The reaction mixture was cooled to rt and diluted with water (10 mL). The mixture was extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of ethyl acetate in hexanes to yield N-(4-(4-chloro-2-fluoro-3-methoxyphenyl)-5-formylpyridin-2-yl)acetamide (1.78 g, 2.95 mmol, 34% yield) as a white solid. LCMS (ESI) m/e 322.9 [(M+H)+, calcd for C15H13ClFN2O3 323.1]; LC/MS retention time (Method F): tR=0.89 min.
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[CH3:26])[C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][C:4]=1[CH3:14].N1C=CC=CC=1.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:43][C@@H:44]([CH3:48])[C:45](Cl)=[O:46])(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClC(Cl)C>[N:9]1([C:7]2[CH:6]=[CH:5][C:4]([CH3:14])=[C:3]([CH:8]=2)[CH:2]([C:15]2[C:16]([CH3:26])=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][C:24]=2[CH3:25])[O:1][C:45](=[O:46])[C@@H:44]([NH:43][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=2)(=[O:42])=[O:41])[CH3:48])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: COC(=O)c1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c(C(OC(=O)[C@H](C)NS(=O)(=O)c2ccc(C)cc2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Yield: 100.9 %

Procedure:
Methyl (±)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate (35 g) was suspended in dichloroethane (350 ml) and pyridine (12 ml) and a solution of (S)-2-(4-methylbenzenesulfonylamino)propionyl chloride (31.4 g) in dichloroethane (70 ml) was added dropwise to the suspension over 10 minutes with stirring under ice-cooling. The mixture was stirred at room temperature for 4 hours, and the reaction mixture was washed successively with water, 5% citric acid, 5% potassium carbonate and water. The organic layer was separated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 58 g of methyl (±)-4-[5-(1-imidazolyl)-2-methyl-α-{(S)-2-(4-methylbenzenesulfonylamino)propionyloxy}benzyl]-3,5-dimethylbenzoate as a pale-yellow oil. This was crystallized from ethyl acetate (120 ml) and isopropyl ether (480 ml), and the obtained crystals were recrystallized from ethyl acetate (50 ml) and isopropyl ether (100 ml) to give 20 g of methyl (S)-4-[5-(1-imidazolyl)-2-methyl-α-{(S)-2-(4-methylbenzenesulfonylamino)propionyloxy}benzyl]-3,5-dimethylbenzoate as white crystals, melting point 103-105° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:20])=[CH:17][N:16]=1.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>C1COCC1>[CH3:30][N:21]([CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:19](=[O:20])[C:18]1[CH:28]=[CH:29][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N(C)C2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide (200 mg, 0.51 mmol) in THF (2 mL) was added at 0° C. potassium bis(trimethylsilyl)amide (0.91 M in THF, 614 μL, 0.56 mmol) over a period of 2 min. After stirring for 0.5 h at this temperature iodomethane (41 μL, 0.66 mmol) was added and the resulting suspension was stirred for 2 h at ambient temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (91 mg, 44%) as a white foam. MS: m/e=408.5 [M+H]+.
Reaction SMILES: O=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].Cl.[NH2:17][OH:18].S([O-])([O-])(=O)=O.[Na+].[Na+]>CO.O>[OH:18][N:17]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9]
Reactant: O=C(CN1CCCC1=O)c1cccnc1
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CCCN1CC(=NO)c1cccnc1
Yield: 65.2 %

Procedure:
To 0.3 g (1.47 mmol) of 1-(2-oxo-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one prepared from Example 20, 0.15 g (2.21 mmol) of hydroxylamine hydrochloride salt and 0.12 g of sodium sulfate were added in methanol/water (1.5:1). The mixture was reacted at 30˜40° C. for 12˜36 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, extracted with ethyl acetate for three times, washed with brine for two times, and dried over sodium sulfate. After concentrating under reduced pressure, it was purified by separation with silica gel column chromatography (chloroform/methanol (30:1˜10:1)) to obtain 0.21 g (66% yield) of 1-(2-hydroxyimino-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one as E/Z mixture (1.56:1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([F:25])[CH:19]=1>>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[C:20]([F:25])[CH:19]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Nc3ccc(Cl)cc3F)c2c2ccccc12
Yield: 79.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 4-chloro-2-fluoroaniline (95 mg, 0.65 mmol) to provide 195 (116 mg, 79% yield) as a white solid. LC-MS (M+H=340, obsd.=340).