Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:23])=[CH:6][C:7]([CH3:22])([CH3:21])[NH:8]2.C(N(CC)CC)C.CS([Cl:35])(=O)=O.C(OCC)(=O)C>ClCCl.[Cl-].[Na+].O.O>[Cl:35][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:23])=[CH:6][C:7]([CH3:22])([CH3:21])[NH:8]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1-c1ccc2c(c1CO)C(C)=CC(C)(C)N2
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
5-Hydroxymethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 2.00 g, 6.46 mmol) was dissolved in anhydrous dichloromethane (32 mL) and then triethylamine (1.35 mL, 9.69 mmol) and methanesulfonyl chloride (55 μL, 7.11 mmol) were added thereto at 0° C. The reaction mixturer was stirred at room temperature overnight. Ethyl acetate (500 mL), water (200 mL), and saturated brine (200 mL) were added to the reaction mixture and separated. The water layer was extracted with ethyl acetate (150 mL) and the organic layer was combined. The organic layer was washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.07 g) as a pale yellow solid. (Yield 50%)
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH2:31][CH:30]2[CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:23]([C:19]1[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[CH:18]=1)=[O:24])[CH2:31][CH:30]2[CH3:36]
Reactant: CC1CNc2ccc(F)cc21
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1CN(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)c2ccc(F)cc21

Procedure:
80 mg (0.24 mmol) 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 36 mg (0.24 mmol) 5-fluoro-3-methyl-2,3-dihydro-1H-indole, 70 μL (0.5 mmol) TEA and 90 mg (0.28 mmol) TBTU were stirred in 1.8 mL DMF overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [Na+].[Cl-].CC(C)=CC[C:7]1[C:12]([OH:13])=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[C:15]1[O:23][C:22]2[CH:21]=[C:20]([OH:24])[CH:19]=[CH:18][C:17]=2[CH:16]=1>CO>[CH:18]1[C:17]2[CH:16]=[C:15]([C:8]3[CH:9]=[C:10]([OH:14])[CH:11]=[C:12]([OH:13])[CH:7]=3)[O:23][C:22]=2[CH:21]=[C:20]([OH:24])[CH:19]=1
Reactant: CC(C)=CCc1c(O)cc(O)cc1-c1cc2ccc(O)cc2o1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Oc1cc(O)cc(-c2cc3ccc(O)cc3o2)c1

Procedure:
Needles; UV (MeOH) λmax (log ε) 328 (4.36), 315 (4.44), 215 (4.45) nm; IR (NaCl) γmax 3339, 1612, 1442, 1292, 1151, 1000 cm−1; 1H NMR (CD3OD, 500 MHz) δ 6.25 (1H, t, J=2.2 Hz, H-4′), 6.73 (1H, dd, J=2.2, 8.4 Hz, H-5), 6.76 (2H, d, J=2.2 Hz, H-2′ and 6′), 6.90 (1H, d, J=1.8 Hz, H-7), 6.91 (1H, s, H-3), 7.34 (1H, d, J=8.3 Hz, H-4); 13C NMR (CD3OD, 125 MHz) δ 98.4 (C-7), 102.2 (C-3), 103.5 (C-4′), 103.9 (C-2′ and C-6′), 113.2 (C-5), 122.0 (C-4), 123.0 (C-9), 133.8 (C-1′), 156.1 (C-6), 156.8 (C-2), 157.2 (C-8), 159.9 (C-3′); EIMS m/z 242 (M+, 100), 213 (9), 121 (10).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[CH:48]=[N:47][C:46]([CH3:49])=[C:45]2[NH:50][CH:51]=[CH:52][C:44]=12>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[CH3:40][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:12][C:11]([C:43]4[CH:48]=[N:47][C:46]([CH3:49])=[C:45]5[NH:50][CH:51]=[CH:52][C:44]=45)=[N:10][C:9]=3[CH:26]=2)[CH2:31][CH2:32]1)([CH3:41])[C:37]([NH2:39])=[O:38]
Reactant: Cc1ncc(Br)c2cc[nH]c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(C)(C)C(N)=O)CC4)cc3n2)c2cc[nH]c12
Yield: 46.8 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]isobutyramide (197 mg, 0.28 mmol), 4-bromo-7-methyl-1H-pyrrolo[2,3-c]pyridine (60 mg, 0.28 mmol), copper(I) 2-thiophene carboxylate (11 mg, 0.056 mmol), and Pd(PPh3)4 (32 mg, 0.028 mmol) in dioxane (3 mL) was placed in a microwave tube which was sealed and evacuated. The reaction vessel was degassed and purged with argon (×3). The reaction mixture was irradiated at 140° C. for 20 min. The cooled mixture was then poured onto an Isolute® SCX-II cartridge and the cartridge was washed with MeOH (100 mL). The product was eluted with 2 M NH3 in MeOH. The pooled fractions were evaporated and the product was further purified by chromatography on silica (Si—PPC), using MeOH in DCM (0-10%) as eluent. The pooled product-containing fractions were evaporated and the residue was crystallized from hot EtOAc to afford 132 as a white crystalline solid (70 mg, 46%). LCMS: (Method F): RT 5.02 min; [M+H]+ 535.2. 1H NMR (DMSO, 400 MHz): δ 11.71 (s, 1 H); 9.02 (s, 1 H); 7.66 (t, J=2.7 Hz, 1 H); 7.44 (s, 1 H); 7.38 (dd, J=2.9, 1.9 Hz, 1 H); 7.08 (d, J=3.5 Hz, 1 H); 6.95 (d, J=3.5 Hz, 1 H); 3.99 (t, J=4.6 Hz, 4 H); 3.86 (s, 2 H); 3.85-3.80 (m, 4 H); 2.73 (s, 3 H); 2.62-2.53 (m, 4 H); 2.47 (s, 4 H); 1.08 (s, 6 H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([CH3:30])([C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])=[N:16][N:15]=2)[CH3:13])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C1C=CC2N(O)[N:38]=[N:37]C=2C=1.O.NN>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([CH3:13])([C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:27])[F:28])=[N:16][N:15]=2)[CH3:30])=[C:6]([CH:10]=1)[C:7]([NH:37][NH2:38])=[O:8]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: NN
Solvent: O
Solvent: CC#N
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NN
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (1.00 g) was suspended in acetonitrile (10 ml), and WSC•monohydrochloride (654 mg) and HOBt (461 mg) were added to thereto, followed by stirring at room temperature for 30 minutes. A mixture of hydrazine monohydrate (1.1 ml) and acetonitrile (10 ml) was ice-cooled and the above reaction solution was added thereto, followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure and water and saturated aqueous sodium bicarbonate solution were added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=100:1 to 99:5). The resulting solid was washed with diisopropylether to obtain, as a white solid, 5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzohydrazide (817 mg).
Reaction SMILES: [Cl:1][C:2](=[CH2:12])[CH2:3][C:4]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6][CH2:5]1.OC(C(F)(F)F)=O.[NH2:20][C@@H:21]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)[C:22]([N:24]([CH2:26][C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)[CH3:25])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:36]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=[CH:34][C:33]([CH2:32][C@H:21]([NH:20][C:9]([C:4]2([CH2:3][C:2]([Cl:1])=[CH2:12])[CH2:5][CH2:6][CH2:7][CH2:8]2)=[O:11])[C:22]([N:24]([CH2:26][C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)[CH3:25])=[O:23])=[CH:38][CH:37]=1
Reactant: C=C(Cl)CC1(C(=O)O)CCCC1
Reactant: CN(Cc1ccco1)C(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(Cl)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)N(C)Cc2ccco2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of 1-(2-chloroallyl)cyclopentanecarboxylic acid (80 mg, 0.42 mmol) in CH2Cl2 (3 mL) and DMF (3 mL) with (S)-2-amino-3-(biphenyl-4-yl)-N-(furan-2-ylmethyl)-N-methylpropanamide TFA salt (199 mg, 0.59 mmol) was added TEA (0.41 mL, 2.97 mmol) and HATU (161 mg, 0.42 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was quenched with aq. NaHCO3 and extracted with EtOAc. The organic layer was washed with water (seven times), brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography using 10% EtOAc/heptane to 100% EtOAc/heptane to give (S)—N-(3-(biphenyl-4-yl)-1-((furan-2-ylmethyl)(methyl)amino)-1-oxopropan-2-yl)-1-(2-chloroallyl)cyclopentanecarboxamide (151 mg). HPLC retention time=1.89 minutes (condition B); MS (m+1)=505.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.61-1.80 (m, 12H), 1.96-2.19 (m, 4H), 2.54-2.83 (m, 6H), 2.74 (s, 3H, major rotamer), 2.95 (s, 3H, minor rotamer), 2.01-3.13 (m, 2H), 4.23 (d, J=16.7 Hz, 1H, minor rotamer), 4.28 (d, J=15.2 Hz, 1H, major rotamer), 4.44 (d, J=16.7 Hz, 1H, minor rotamer), 4.77 (d, J=15.2 Hz, 1H, major rotamer), 5.06 (s, 1H, minor rotamer), 5.12 (d, J=1.3 Hz, 1H, major rotamer), 5.15 (d, J=1.3 Hz, 1H, minor rotamer), 5.19 (d, J=1.3 Hz, 1H, major rotamer), 5.17-5.28 (m, 1H, major rotamer), 5.39 (q, J=7.2 Hz, 1H, minor rotamer), 6.17 (d, J=2.8 Hz, 1H, minor rotamer), 6.24 (d, J=3.3 Hz, 1H, major rotamer), 6.30 (dd, J=3.3, 1.8 Hz, 1H, minor rotamer), 6.37 (dd, J=3.2, 1.9 Hz, 1H, major rotamer), 6.57 (d, J=8.1 Hz, 1H, minor rotamer), 6.68 (d, J=7.8 Hz, 1H, major rotamer), 7.21-7.65 (m, 18H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([C:24]([O:26]CC)=[O:25])[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([C:24]([OH:26])=[O:25])[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c(n1S(=O)(=O)c1ccc(OC)cc1)CN(C(C)=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)n2c(C(=O)O)cc3c2CN(C(C)=O)CC3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39 %

Procedure:
To a solution of ethyl 6-acetyl-1-[(4-methoxyphenyl)sulfonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate obtained in Example 2 under step c) (500 mg, 1.23 mmol) in ethanol (22.5 mL) at room temperature was added sodium hydroxide solution (590 mg, 14.76 mmol, 12 eq., in 22.5 mL H2O). The reaction mixture was stirred at rt for 48 hours and partitioned between 1 N HCl and EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. Purification by preparative HPLC followed by lyophilisation gave the title compound (183 mg, 39%).
Reaction SMILES: N1([CH:10]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[C:11]([CH3:14])([CH3:13])[CH3:12])C2C=CC=CC=2N=N1.ClC1C=CC(N)=CC=1.[C:33]([O-])([O-])=[O:34].[K+].[K+]>CO.C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][CH:10]([O:34][CH3:33])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:24])=[CH:18][CH:19]=1
Reactant: CC(C)(C)C(NC(=O)c1ccc(Br)cc1)n1nnc2ccccc21
Reactant: O=C([O-])[O-]
Agent: Nc1ccc(Cl)cc1
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(NC(=O)c1ccc(Br)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-(1-(1H-benzo[d][1,2,3]triazol-1-yl)-2,2-dimethylpropyl)-4-bromobenzamide 120 as a white solid (2.38 mmol), 4-chloroaniline (0.64 g, 5.0 mmol), and K2CO3 (1 g, 7.23 mmol) in methanol (20 mL) and THF (2 mL) was stirred for 18 h at room temperature. The reaction was quenched with 2M HCl and extracted with ether. The organic solution was concentrated onto silica gel and chromatography (9:1 hexanes:ethyl acetate) and gave 4-bromo-N-(1-methoxy-2,2-dimethylpropyl)benzamide and the title product. The product was titrated with ether to give pure 4-bromo-N-(1-(4-chlorophenylamino)-2,2-dimethylpropyl)benzamide (Compound-38) (104 mg, 11%). 1H NMR (300 MHz, d6-DMSO): δ=8.34 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 6.71 (J=8.7 Hz, 2H), 5.81 (d, J=6.6 Hz, 1H), 5.19 (t, J=3.9 Hz, 1H), 1.03 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([F:26])[CH:32]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: [Na+]
Product: CN(Cc1cc(-c2cccc(F)c2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (3-fluorophenyl)boronic acid (195 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 280 mg, 90%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:25]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11]([N:24]4[CH2:28][CH2:27][CH:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH2:25]4)[C:12]=3[C:14]([F:15])([F:17])[F:16])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1ccc(C2CCNC2)nc1
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(N3CCC(c4ccccn4)C3)c(F)cc2c1=O
Yield: 74 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylic acid (1.33 g, 4.0 mmol) and 2-(3-pyrrolidinyl)pyridine, a procedure analogous to that given Example 1 provided the title compound (1.36 g, 74%) as a yellow solid, mp 210°-212° C.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([O:27][C:28]([O:30][CH3:31])=[O:29])[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:34][CH3:35])C1C=CC=CC=1>CN(C=O)C.CO.ClC(Cl)Cl.[Pd]>[ClH:1].[F:33][C:22]1[CH:23]=[C:24]([CH3:32])[C:25]([O:27][C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:34][CH3:35])[CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(O)c(OC)cc23)c(F)cc1C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A mixture of 7-benzyloxy4-(2-fluoro-5-methoxycarbonyloxy4-methylanilino)-6-methoxyquinazoline hydrochloride (700 mg, 1.4 mmol) and 10% palladium-on-charcoal (100 mg) in DMF (10 ml), methanol (10 ml) and trichloromethane (10 ml) was stirred under hydrogen at 1 atmosphere pressure for 1 hour. The catalyst was removed by filtration through diatomaceous earth and the solvent was removed by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (570 mg, 98%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@H:17]([OH:18])[CH2:16][C@H:15]2[C@@H:11]1[CH2:12][C:13](=[O:19])[O:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CCOCC.C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]1[C@H:17]([O:18][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)[CH2:16][C@H:15]2[C@@H:11]1[CH2:12][C:13](=[O:19])[O:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: O=C1C[C@@H]2[C@@H](COCc3ccccc3)[C@H](O)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@@H](COCc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1

Procedure:
A solution of 14.5 g. of (1S,5R,6S,7R)-6-benzyloxymethyl-7-hydroxy-2-oxabicyclo[3,3,0]octan-3-one, 6 ml. of dihydropyran, and 40 mg. of p-toluenesulfonic acid in 300 ml. of absolute methylene chloride as agitated for one hour at 5°. Then the solution is diluted with ether, shaken with 4% sodium bicarbonate solution, washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum. Yield: 21 g. of the tetrahydropyranyl ether as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([I:11])=[CH:9][N:10]=1)[C:5](O)=[O:6].ClC1C(CO)=CC(F)=C(Cl)N=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[C:8]([I:11])=[CH:9][N:10]=1
Reactant: O=C(O)c1cc(Cl)ncc1I
Agent: OCc1cc(F)c(Cl)nc1Cl
Product: OCc1cc(Cl)ncc1I
Yield: 51.3 %

Procedure:
Compound 25C (0.38 g, 51%) was prepared from 25B (0.78 g, 2.75 mmol) using a procedure similar to the synthesis of 1A. HPLC Rt=1.74 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[C:12]([NH2:24])[C:11]=1[N+:25]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([O:8][C:9](=[O:28])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[C:12]([NH2:24])[C:11]=1[NH2:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1[N+](=O)[O-]
Solvent: CCO
Product: Nc1cc(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1N

Procedure:
3.0 g (7.9 mmol) of 3-amino-5-benzyloxy-2-nitro-benzoic acid benzyl ester was reduced by 5.4 g (23.7 mmol) of SnCl22H2O in 30 mL of ethanol at 80° C. for 3 h to produce 2,3-diamino-5-benzyloxy-benzoic acid benzyl ester. LCMS: 350 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[CH:8]=[C:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2)=[O:6].Br[CH:28]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>ClCCl.O>[CH2:40]([C:37]1[CH:36]=[CH:35][C:34]([CH:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=2)[C:5]([C:7]2[CH:8]=[C:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)=[O:6])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:39][CH:38]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: CCCCCC(Br)c1ccc(CC(C)C)cc1
Reactant: CCOC(=O)CCCc1cc(C(=O)c2cccc(N)c2)c2ccccn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCCCC(Nc1cccc(C(=O)c2cc(CCCC(=O)OCC)n3ccccc23)c1)c1ccc(CC(C)C)cc1
Yield: 60.1 %

Procedure:
A mixture of ethyl 4-[1-(3-aminobenzoyl)indolizin-3-yl]butyrate (175 mg), 1-bromohexyl-4-isobutylbenzene (177 mg) and diisopropylethylamine (194 mg) in dichloromethane (3 ml) was refluxed for 20 hours. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated and washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with n-hexane and ethyl acetate (3:1) to give ethyl 4-[1-[3-[1-(4-isobutylphenyl)hexylamino]benzoyl]indolizin-3-yl]butyrate (170 mg) as an oil.
Reaction SMILES: C(O)C.[C:4]([N:8]1[C:13](=[O:14])[C:12]([CH:15]([F:17])[F:16])=[C:11](Cl)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1>C(N(CC)CC)C>[C:4]([N:8]1[C:13](=[O:14])[C:12]([CH:15]([F:17])[F:16])=[C:11]([NH:26][CH2:25][C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: NCc1ccncc1
Reactant: CC(C)(C)n1ncc(Cl)c(C(F)F)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)n1ncc(NCc2ccncc2)c(C(F)F)c1=O

Procedure:
20 ml of an absolute ethanol solution of 0.71 g of 2-tert-butyl-5-chloro-4-difluoromethylpyridazin-3-(2H)-one, 0.33 g of 4-picolylamine and 0.33 g of triethylamine, was reacted for 5 hours under heating and refluxing and left to cool. Then, the mixture was extracted with ethyl acetate, then washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was subjected to column chromatography, and using an eluent (n-hexane:ethyl acetate=1:2), 0.32 g of the desired product (Compound No. 12) having a melting point of from 142° to 143° C. and 0.04 g of amorphous 2-tert-butyl-5-(4-pyridylmethylamino)-4-(4-pyridylmethyliminomethylidenyl)pyridazin-3-(2H)-one (Compound No. 2) as a by-product, were obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)(=O)C>[C:13]1([NH:12][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(O)cc1Nc1ccccc1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
14 g of 3-fluoro-4-nitrophenol and 24 ml of aniline were mixed and stirred for 3 hours at 140° C. After cooling, it was dissolved in ethyl acetate and extracted six times with 2N aqueous hydrochloric acid. The organic phase was washed with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was crystallized from diisopropyl ether. 20.8 g was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[NH:16][CH:15]=[N:14][C:13]=3[C:12](=[S:18])[N:11]3[CH2:19][CH2:20][N:21]=[C:10]23)=[CH:4][CH:3]=1.O.[OH-].[Na+].[CH3:25]I>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:13]([N:14]=[CH:15][N:16]=3)=[C:12]([S:18][CH3:25])[N:11]3[CH2:19][CH2:20][N:21]=[C:10]23)=[CH:4][CH:3]=1
Reactant: S=C1c2nc[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCN12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC1=C2N=CN=C2N(Cc2ccc(Cl)cc2)C2=NCCN21
Reaction time: 3 h

Procedure:
The product of Procedure 75, 6.65 g. (0.021 mole), was dissolved in a mixture of 100 ml. of water and 15 ml. of ethanol containing 1.0 g. (0.025 mole) of sodium hydroxide. Methyl iodide, 7.09 g. (0.05 mole) was then added whereupon a precipitate commenced to form and developed into a thick slurry within 3 hrs. The solid was collected, air dried, and recrystallized from DMF with charcoal treatment, m.p. 254.0°-256.0° dec.