Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[CH:9]3[CH2:14][CH:6]([CH:7]=[CH:8]3)[C:5]=2[C:4]=1[OH:15].CCOC(C)=O.C(Cl)(Cl)Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[CH:9]3[CH2:14][CH:6]([CH2:7][CH2:8]3)[C:5]=2[C:4]=1[OH:15]
Reactant: COc1cc(O)c2c(c1O)C1C=CC2C1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(O)c2c(c1O)C1CCC2C1

Procedure:
A solution of 1,4-dihydro-6-methoxy-1,4-methanonaphthalene-5,8-diol (48, 1.30 g, 6.36 mmol) in MeOH (100 mL) was hydrogenated (Parr hydrogenator, 20 psi) over Pd (10% on C, 100 mg, Aldrich) for 15 min. TLC analysis (10% EtOAc, 90% CHCl3) indicated total consumption of the organic starting material to give a higher Rf product. The catalyst was removed by filtration through celite during which time the filtrate turned light green. Color change was attributed to trace air oxidation of the desired product to the corresponding quinone. After MeOH removal, the residue was filtered through silica gel with CHCl3 elution. Solvent removal yielded 52 as a brown gummy solid, which was found suitable for the next reaction without further purification (1.28 g, 98%, purity >95% by TLC and 1H NMR analyses); 1H NMR (CDCl3) δ1.20 (m, 2H), 1.49 (d, J=8.7 Hz, 1H), 1.70 (m, 1H), 1.88 (m, 2H), 3.42 (s, 1H), 3.62 (s, 1H), 3.80 (s, 3H), 4.37 (s, 1H), 5.17 (s, 1H), 6.19 (s, 1H).
Reaction SMILES: [C:1]([NH:20][CH:21]([CH2:26][S:27][C@@H:28]1[O:45][C@H:44]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]1[O:30][C:31](=[O:33])[CH3:32])[C:22]([O:24]C)=[O:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[I-].[Li+]>N1C=CC=CC=1>[C:1]([NH:20][CH:21]([CH2:26][S:27][C@@H:28]1[O:45][C@H:44]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]1[O:30][C:31](=[O:33])[CH3:32])[C:22]([OH:24])=[O:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NC(CS[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O)C(=O)OC
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)NC(CS[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O)C(=O)O
Yield: 80.5 %

Procedure:
In 6 mL of pyridine was dissolved 313 mg of methyl 2-(octadecanoylamino)-3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosylthio)propionate, 515 mg of lithium iodide was added to the solution and the resulting mixture was refluxed under nitrogen atmosphere for 4 hours. The reaction mixture was extracted with ethyl acetate, washed with 2 mol/L of hydrochloric acid, the ethyl acetate layer was dried over anhydrous magnesium sulfate, and then, the solvent was removed under reduced pressure. The finally obtained residue was purified by medium pressure column chromatography (Eluent; chloroform:methanol=15:1) to obtain 247 mg of 2-(octadecanoylamino)-3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosylthio) propionic acid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.[O:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[CH2:33][C:34](O)=[O:35]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[CH2:33][CH:28]3[CH2:29][O:30][CH2:31][CH2:32][O:27]3)[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Reactant: O=C(O)CC1COCCO1
Agent: Cl
Product: O=C(CC1COCCO1)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1

Procedure:
The title compound, off-white solid (81 mg, 62%), MS (ISP) m/z=455.4 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (115 mg, 0.29 mmol) and rac-(1,4-dioxan-2-yl)-acetic acid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21]>CN(C=O)C.ClCCl>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:21]
Reactant: O=Cc1ccc(O)c2ncccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C=O)c2cccnc12
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of 8-hydroxyquinoline-5-carbaldehyde (170 mg, 0.98 mmol) in DMF (5 ml) were added anhydrous potassium carbonate (150 mg) and 2-bromoacetic acid ethyl ester (0.12 ml, 180 mg, 1.08 mmol) at room temperature and the stirring was continued for 1 h. Then the reaction mixture was diluted with dichloromethane, the organic layer was washed several times with water, dried over sodium sulfate and then evaporated under vacuum. The residue was chromatographed on silica gel with ethyl acetate/cyclohexane (9:1) as eluant; to give 190 mg (74.8% yield) of pure 2-(5-formylquinol-8-yloxy)acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:28])[CH:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:30][OH:31])=[C:4]([CH3:28])[CH:3]=1
Reactant: NO
Reactant: CCOc1ccc([C@H](CC(=O)c2ccnc(C)c2)c2ccc(Cl)cc2C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ccc([C@H](CC(=NO)c2ccnc(C)c2)c2ccc(Cl)cc2C)cc1

Procedure:
In analogy to example 132, step 6, from (S)-3-(4-chloro-2-methyl-phenyl)-3-(4-ethoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as an off-white foam, MS (ESI+): m/z=409.4 ([M+H]+).
Reaction SMILES: [NH2:1][C@:2]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)([C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([F:17])[CH:8]=1)[CH2:3][C:4](O)=[O:5].CC[N:27]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>ClCCCl.C(Cl)Cl>[NH2:1][C@:2]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1)([C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[C:9]([F:17])[CH:8]=1)[CH2:3][C:4]([NH2:27])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: N[C@@](CC(=O)O)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: ClCCCl
Product: NC(=O)C[C@](N)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 50 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
(S)-3-amino-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)propanoic acid (0.047 g, 0.13 mmol, prepared as described in Procedure 29) was dissolved in DCE (5 mL) at room temperature. To the solution was added EDCI (0.035 g, 0.14 mmol), HOBt (0.025 mg, 0.14 mmol), NH4Cl (0.075 g, 1.3 mmol) and TEA (ca.0.070 g). The resulting solution was stirred for 18 h then heated to 50° C. for 8 h. On cooling the reaction mixture was diluted with DCM (ca. 10 mL) and washed with saturated NaCl solution (ca.2×10 mL). (S)-3-amino-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl) propanamide was isolated as a colorless oil (0.03 lg, 65% yield) and was used without further purification. LCMS: 1.25 min [M+1] 362.2 (2 min gradient, MeOH/H2O 0.1% TFA).
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([N:12]([C:16](=[O:18])[CH3:17])[CH2:13][CH:14]=[CH2:15])[CH:6]=1)C.[OH-].[Na+]>CO>[C:16]([N:12]([CH2:13][CH:14]=[CH2:15])[C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([Cl:11])[N:8]=1)[C:4]([OH:19])=[O:3])(=[O:18])[CH3:17]
Reactant: C=CCN(C(C)=O)c1cc(C(=O)OCC)cc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCN(C(C)=O)c1cc(C(=O)O)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.08 g 2-(acetyl-allyl-amino)-6-chloro-isonicotinic acid ethyl ester (3.82 mmol) in 15 ml MeOH is treated with 5.5 ml 1N NaOH (5.5 mmol) and stirred at 25° C. for 30 min. The reaction is quenched with 6 ml 1 N HCl and with EtOAc extracted. Crystallization from a small amount of EtOAc gives the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.[CH2:16]([O:18][C:19](=[O:37])[C@@H:20]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:17].CN1CCOCC1>C(Cl)Cl.CN(C=O)C>[C:33]([O:32][C:30]([NH:29][C@@H:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:8](=[O:10])[C:7]2[C:6]([Cl:11])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])=[CH:24][CH:23]=1)[C:19]([O:18][CH2:16][CH3:17])=[O:37])=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 108.7 %

Procedure:
A slurry of the compound of Intermediate 1 (51.2 g, 0.267 mol) in DCM (195 ml) and thionyl chloride (195 ml, 2.67 mol) was treated with DMF (5 drops) and heated to reflux for 4 h. The reaction was concentrated in vacuo and azeotroped with toluene (2×50 ml) to give a yellow solid which was used without further purification. A solution of ethyl-(S)-3-(4-aminophenyl)-2-(t-butoxycarbonylamino)propanoate (130.8 g, 0.425 mol) in DCM (800 ml) was cooled to 0° and treated with NMM (56.0 ml, 0.51 mol), stirred for 5 minutes and then a solution of the acid chloride (98.3 g, 0.468 mol) in DCM (200 ml) was added dropwise keeping the reaction temperature below 5°. The reaction was stirred for 1 h, quenched with NaHCO3 solution (500 ml), the organic layer separated, washed with NaHCO3 solution (500 ml), 10% citric acid solution (500 ml) and NaHCO3 solution (500 ml), dried (MgSO4) and concentrated in vacuo to give a yellow solid which was recrystallised (EtOAc/hexane) to give the title compound, (140 g, 69%). δH (DMSO d6), 8.8 (2H, s), 7.55 (2H, d, J 8.5 Hz), 7.23 (2H, d, J 8.5 Hz), 4.0 (3H, m), 3.4 (2H, b s), 2.9 (1H, m), 2.8 (1H, m), 1.3 (9H, s), 1.25 (3H, t); m/z (ES+, 70V) 504 (MNa+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]([N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])=[O:10].C(N(CC)CC)C>O1CCCC1.O>[C:2]1([NH:1][C:9]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCNC1=O
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1NCCN1C(=O)Nc1ccccc1
Reaction time: 1 h

Procedure:
10.2 parts by weight of aniline were first introduced into 120 parts by volume of 80% strength aqueous tetrahydrofurane at pH = 8 and 14.9 parts by weight of N-chlorocarbonyl-imidazolid-2-one were added in portions at room temperature while stirring and keeping the pH value at 7-8 by simultaneous addition of triethylamine. The mixture was further stirred until the pH was constant, 80 parts by volume of water were added, the tetrahydrofurane was stripped off in vacuo, the pH was adjusted to 2.5 and after standing for one hour in an ice bath the product which had precipitated was filtered off. It was washed with ice water and dried over P2O5 in a vacuum desiccator.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][CH:5]([CH2:7][N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[N:9]2)[CH2:4][O:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:16])[O:6][CH:5]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(Cn2cc([N+](=O)[O-])cn2)O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OCC(Cn2cc(N)cn2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A mixture of 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-nitro-1H-pyrazole (2.0 g, 9.5 mmol) and Pd/C (400 mg) in methanol (40 mL) was stirred at RT under H2 overnight. LCMS showed the reaction was completed. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to give 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-amine (1.7 g, crude) as a purple oil, which was directly used in the next step without further purification. MS (ES+) C9H15N3O2 requires: 197, found: 198 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].C(OC(N1CCCC(N(C(=O)C)CC2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)C2C=C([Br:75])C(C)=CC1=2)=O)(C)C>>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=2)[C:9]2[CH:33]=[C:34]([Br:75])[C:35]([F:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(F)ccc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(Br)cc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(F)c(Br)cc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 56 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-fluoro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate following the procedure of Example 56 for the synthesis of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. ESI MS 613 (M+H).
Reaction SMILES: [Cl:1][C:2]([Cl:35])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[CH:6]([S:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](C)(C)[O:15][SiH2]C(C)(C)C)=[CH:10][CH:9]=1.Cl.O>C(#N)C>[Cl:34][C:2]([Cl:1])([Cl:35])[CH2:3][O:4][C:5](=[O:33])[CH:6]([S:23][CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][OH:15])=[CH:12][CH:13]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid 2,2,2-trichloro-ethyl ester (5.47 g, 9.43 mmol) in anhydrous acetonitrile (200 mL) was dropwise added BF3xEt2O (1.10 mL, 9.43 mmol) at 0° C. The mixture was stirred for 30 min. 2N aq. HCl (50 mL) and H2O (100 mL) were added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4) and evaporated to give the crude product which was purified by flash chromatography using DCM/MeOH 95:5 as the eluent. The product was obtained as an (3.62 g, 82.5%). 1H NMR (400 MHz, CDCl3): δ 7.19 (d, 2H), 7.10 (d, 2H), 7.01 (m, 2H), 6.87 (t, 2H), 4.65 (d, 1H), 4.56 (m, 3H), 3.48 (dd, 1H), 3.12 (dd, 1H), 2.73-2.91 (m, 5H). Mass Spectrum: M−H+ 464.90.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:32]=[CH:31][C:12](/[CH:13]=[CH:14]/[C:15]2[N:23]([CH3:24])[C:22]3[C:21](=[O:25])[N:20]([CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH3:30])[C:17]=3[N:16]=2)=[CH:11][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[OH-].[Na+]>O1CCCC1>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:13]=[CH:14]/[C:15]2[N:23]([CH3:24])[C:22]3[C:21](=[O:25])[N:20]([CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH3:30])[C:17]=3[N:16]=2)=[CH:31][CH:32]=1
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCN=[N+]=[N-])cc3)n2C)n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCN)cc3)n2C)n(CC)c1=O

Procedure:
Compound 178 (75 mg, 0.17 mmol) obtained in Reference Example 117 was dissolved in 7.5 ml of tetrahydrofuran. To the solution was added 90 mg (0.34 mmol) of triphenylphosphine, and the mixture was heated under reflux for 3 hours. Water (5 ml) was added thereto and the mixture was heated under reflux for further one hour. After cooling, a 2N aqueous solution of sodium hydroxide was added thereto, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol/triethylamine) to give 74 mg (yield quant.) of Compound 179. The obtained crude crystals were further recrystallized from 2-propanol/water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[C:21]1([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH2:30][NH2:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:27]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:34]=[CH:33][CH:32]=[C:29]([CH2:30][NH:31][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:16])[CH:28]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1cccc(-c2ccccc2)c1
Product: O=C(NCc1cccc(-c2ccccc2)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 3-phenyl benzylamine (55 mg, 0.32 mmol). The title compound was obtained as a solid (24 mg, 17% yield). 1H NMR (400 MHz, CDCl3) δ: 8.74 (2H, m), 7.86 (1H, s), 7.55 (3H, m), 7.53 (1H, m), 7.46 (3H, m), 7.38 (1H, m), 7.26 (1H, m), 6.27 (1H, m), 4.63 (2H, m). MS m/z: 514.07, 516.04 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]1=[O:16]
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCn1cc(-c2ccccc2)[nH]c1=O
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: COCCn1cc(-c2ccccc2)n(C(=O)c2ccccc2)c1=O

Procedure:
Approximately 21.8 g. of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one, 14.5 g. of benzoyl chloride and 20 g. of tri-n-butylamine are refluxed together in 60 ml of xylene for sixteen hours. The solvent is distilled off under reduced pressure and the remaining viscous oil is dissolved in 300 ml. of benzene. The benzene solution is washed with water (2×100 ml.), dried over sodium sulfate, and the solvent removed to give a semisolid. Recrystallization from ether gives the title compound as a pale yellow solid; m.p. 114°-117° C.
Reaction SMILES: F[C:2]1[C:19]([F:20])=[CH:18][C:17]2[C:16](=[O:21])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:22])[C:4]=2[CH:3]=1.[C:23](=O)([O-])[O-:24].[K+].[K+].CO.Cl>O1CCCC1>[F:20][C:19]1[C:2]([O:24][CH3:23])=[CH:3][C:4]2[C:5](=[O:22])[C:6]3[C:15](=[CH:14][C:13]4[C:8]([CH:7]=3)=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:16](=[O:21])[C:17]=2[CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2cc(F)c(F)cc2C(=O)c2cc3ccccc3cc21
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1F)C(=O)c1cc3ccccc3cc1C2=O
Yield: 25 %

Procedure:
1 g (3.4 mmol) of 2,3-difluoronaphthacene-5,12-dione, 0.94 g (6.8 mmol) of potassium carbonate, 3.24 g of methanol and 20 ml of tetrahydrofuran (THF) are stirred at 25° C. for 18 hours and under reflux for 3 days. The mixture is cooled and dilute hydrochloric acid is added. The product is filtered off, washed with water, dried and chromatographed with methylene chloride on silica gel. Sublimation under 1.3×10-1 bar/180°-310° C. gives 0.26 g (25%) of pure product, melting point >250° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:4]2[CH:3]=1.[C:30](=[NH:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[N:8][N:5]4[CH:6]=[CH:7][C:2]([N:43]=[C:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:3][C:4]=34)[CH:16]=[CH:15][N:14]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nn3ccc(N=C(c4ccccc4)c4ccccc4)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 100 °C

Procedure:
To a solution of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.1 g, 0.25 mmol) in toluene (5 mL) was added benzophenone imine (0.13 g, 0.75 mmol), tris(dibenzylideneacetone)dipalladium (0.02 g, 0.03 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.05 g, 0.09 mmol) and sodium tert-butoxide (0.07 g, 0.75 mmol). The reaction was heated at 100° C. for 3 hours, then allowed to cool to room temperature. Aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture. The phases were separated and the organic phase was washed with brine and dried (magnesium sulfate). Filtration and concentration, followed by purification by flash chromatography (1:4 ethyl acetate-hexanes to 1:1 ethyl acetate-hexanes) gave 3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(diphenylmethylene)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine as a solid. This solid was dissolved in tetrahydrofuran (10 mL). To this solution at 0° C. was added 4N hydrochloric acid (2 mL) dropwise. Subsequently, the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate, then saturated aquous bicarbonate was added slowly until the ethyl acetate layer turned clear. The resulting mixture was stirred for 30 minutes. The organic phase was washed with water, brine and dried (magnesium sulfate). Filtration and concentration, followed by flash chromatography (ethyl acetate) gave 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-5-amine (54 mg, 57%) as a yellow foam. 1H-NMR (CDCl3): δ 8.22 (d, 1H), 7.97 (d, 1H), 7.58 (q, 2H), 7.11 (t, 2H), 6.34 (dd, 1H), 6.20 (d, 1H), 5.14 (d, 1H), 4.31 (m, 1H), 4.10 (m, 3H), 1.5–2.2 (m, 8H); 19F-NMR (CDCl3): δ −113.4; MS m/z 389 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3](=O)[C:4]([O:9][C:10]2C=CC=CC=2)=[CH:5][CH:6]=[CH:7][CH:8]=1.N.C[OH:19]>>[NH2:1][C:2]1[C:8](=[O:19])[CH:7]=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: CO
Reactant: Nc1ccccc(Oc2ccccc2)c1=O
Agent: N
Product: COc1cccc(=O)c(N)c1
Temperature: 80 °C

Procedure:
A solution of 2,4-dimethoxy-2,4,6-cycloheptatrien-1-one [described above in (b), 2.4 g] in methanol (70) is cooled to -25° C and saturated with ammonia gas. The solution is heated in a pressure bottle at 80° C for 4 hours and cooled to -70° C. The pressure bottle is opened and the solvent is evaporated to give 2-amino-4-methoxy-2,4,6-cycloheptatrien-1-one.