Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)N[C@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: CCO
Product: CC(=O)N[C@H]1CCN(c2ccc(N)cc2)C1

Procedure:
The title compound was prepared by the procedure of Method 43 starting from N-[(3S)-1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide (Method 48). NMR: 1.79 (s, 3H), 1.69-1.88 (m, 1H), 2.07-2.20 (m, 1H), 2.82-2.93 (m, 1H), 3.01-3.14 (m, 1H), 3.16-3.38 (m, 2H), 4.25-4.36 (m, 1H), 6.31 (d, 2H), 6.51 (d, 2H), 8.08 (d, 1H)+EtOH.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[O:42]=[C:43]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:44][NH:45][C:46](=[O:60])[C:47]1[CH:52]=[CH:51][C:50]([O:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1>CN(C=O)C.O>[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:64]1[CH2:65][CH2:66][N:61]([C:43](=[O:42])[CH2:44][NH:45][C:46](=[O:60])[C:47]2[CH:48]=[CH:49][C:50]([O:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[CH:51][CH:52]=2)[CH2:62][CH2:63]1)=[O:15]
Reactant: O=C(O)c1ccccc1F
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2F)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
DIPEA (0.106 mL, 0.62 mmol) was added drop wise to 2-fluorobenzoic acid (34 mg, 0.25 mmol) in DMF (5 mL). EDCI (98 mg, 0.51 mmol) and HOBT (33 mg, 0.25 mmol) were added consecutively and, after 10 mins, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (77 mg, 0.25 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 70:30 EtOAc:hexane as eluent) afforded N-{2-[4-(2-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide in 42% yield. LC-MS purity: 97%, 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.5 (m, 4H), 7.3 (m, 2H), 7.2 (t, 1H), 7.1 (m, 4H), 4.2 (dd, 2H), 3.6 (m, 4H), 3.5 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N+:4]([O-])[C:5]([CH3:8])=[CH:6][CH:7]=1.[C:12]([O:15][C:16](=O)C)(=[O:14])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:12]([O:15][CH3:16])=[O:14])=[N:4][C:3]=1[O:10][CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(Br)ccc(C)[n+]1[O-]
Product: COC(=O)Cc1ccc(Br)c(OC)n1

Procedure:
step c—A solution of 52b (0.47 g) and acetic anhydride (4.0 mL) was heated at 120° C. for 2 h, The reaction mixture was concentrated in vacuo and purified on a SiO2 column eluting with 5% EtOAc/hexane to afford methyl 5-bromo-6-methoxy-pyridin-2-yl-acetate (52c).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH:15]([C:21]1([CH3:26])OCC[O:22]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]2=[O:27])([O-:3])=[O:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH:15]([C:21](=[O:22])[CH3:26])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]2=[O:27])([O-:3])=[O:2]
Reactant: CCOC(=O)C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O)C(C)=O

Procedure:
Ethyl 2-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (263 mg, 27%) in the same manner as described in the above example 6 (20) from ethyl 3-(5-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (1.11 g, 2.96 mmol) and p-toluenesulfonic acid monohydrate (100 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.[NH:19]([C:21]([S:23][CH3:24])=[NH:22])[NH2:20]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:20]=[N:19][C:21]([S:23][CH3:24])=[N:22][C:10]=2[OH:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CSC(=N)NN
Reactant: O=C(O)C(=O)c1cc(Cl)cc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CSc1nnc(-c2cc(Cl)cc(Cl)c2)c(O)n1
Temperature: 78 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
(3,5-Dichlorophenyl)(oxo)acetic acid (28.0 g 129.0 mmol) was dissolved in ethanol (280 mL) and treated successively with a catalytic quantity of sulfuric acid and methyl hydrazinecarbimidothioate (20.5 g, 193.5 mmol). The resulting mixture was stirred for 1 hr at 78° C. After completion of the reaction (TLC), the mixture was concentrated in vacuo, poured into water (150 mL), and extracted with DCM (3×250 ml). The combined organic extracts were then dried over Na2SO4, concentrated in vacuo, and purified by gradient flash chromatography, affording 6-(3,5-dichlorophenyl)-3-(methylthio)-1,2,4-triazin-5-ol (19 g, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[NH2:10].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:11]([NH:19][C:20]([NH:10][C:3]1[C:2]([Br:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[Br:9])=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1c(Br)cc(F)cc1Br
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(NC(=S)Nc1c(Br)cc(F)cc1Br)c1ccccc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
A mixture of 2,6-dibromo-4-fluoro-phenylamine (1.00 g, 3.72 mmol), benzoyl isothiocyanate (0.600 ml, 4.46 mmol), dimethyl-pyridin-4-yl-amine (45.0 g, 0.370 mmol), and toluene (5 ml) was stirred at 23° C. for 16 hours. The resulting precipitate was collected by filtration and washed with hexane to yield titled compound (1.37 g, 85%). MS (ESI/CI): mass calcd. for C14H9Br2FN2OS, 429.9; m/z found, 430.9 [M+H]+. 1H NMR (400 MHz, CD3OD-d4): 8.05-7.98 (m, 2H), 7.73-7.66 (m, 1H), 7.62-7.55 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[N:9][C:5]2=[N:6][C:7]=1[Cl:8].[C:13]1([S:19]([NH2:22])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:8][C:7]1[N:6]=[C:5]2[N:9]=[CH:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:22][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Clc1nc2cccnc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1nc2cccnc2nc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 17.1 %

Procedure:
2,3-dichloro-pyrido(2,3-b)pyrazine (300 mg; 1.5 mmol; 1 eq.), benzenesulfonamide (235.8 mg, 1.5 mmol, 1 eq.) and K2CO3 (207.3 mg, 1.5 mmol, 1 eq.) are taken up in anhydrous DMA (10 ml) under argon. The reaction mixture is stirred at room temperature for 7 days. The solvent is evaporated and the residue obtained is purified by prep HPLC using a gradient of H2O, TFA 0.1%/ACN, TFA 0.1%, to afford 82.1 mg (17%) of the title compound. 1H NMR (DMSO-d6) δ 8.67 (dd, J=5.7, 1.5 Hz, 1H), 8.57 (dd, J=7.9, 1.5 Hz, 1H), 8.08 (dd, J=8.0 Hz, 1.8 Hz, 2H), 7.57 (dd, J=7.9, 5.7 Hz, 1H), 7.54-7.46 (m, 4H). HPLC (max plot) 94%; Rt 1.96 min. LC/MS: (ES+): 321.0, (ES−): 319.0.
Reaction SMILES: C(OC[C:5]([CH2:27]OCC)([OH:26])[CH:6]([NH:18]C(OC(C)(C)C)=O)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)C.[ClH:31]>>[ClH:31].[NH2:18][C@H:6]1[CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C@H:27]([Cl:31])[C@H:5]1[OH:26]
Reactant: CCOCC(O)(COCC)C(Cc1cccc2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Product: N[C@H]1Cc2c(ccc3ccccc23)[C@H](Cl)[C@H]1O
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
A suspension of α,α-diethoxymethyl-β-tert-butoxycarbonylamino-1-naphthalenepropanol (252 mg), isomer B was stirred in 37% aqueous hydrochloric acid at 0° C. for 50 minutes. The resulting suspension was then stirred at 100° C. for 3 minutes. The reaction flask was cooled at 0° C. and the precipitate was filtered, washed with water and dried in vacuo. The title compound (156 mg) was obtained as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>>[CH2:2]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: c1c[nH]cn1
Product: c1ccc(CCn2ccnc2)cc1
Yield: 59.1 %

Procedure:
β-Bromoethylbenzene (10 g) and 10.6 g of imidazole were reacted at 200° C. for 5 hours, and the reaction mixture was extracted with 200 ml of chloroform. After being washed with a 10% sodium hydrogen carbonate aqueous solution and then with water, the resultant chloroform layer was separated and dried over salt cake. The solvent was then distilled off under reduced pressure and the residue was purified by distillation under reduced pressure to give 5.50 g (yield 45%) of N-phenethylimidazole as an oily material. B.P. 158° to 159° C./5 mmHg. A solution of 0.43 g of the obtained N-phenethylimidazole in 5 ml of ether was then added to a solution of 2.14 g of α-cyclodextrin in 50 ml of water, and the mixture was stirred at room temperature for 3 hours. The mixture was then lyophilized to give a colorless powder which in turn was washed twice with 50 ml of ether and dried under reduced pressure at 50° C. The product was dissolved in deuterium oxide, and it was confirmed from the proton integration ratio of the proton nuclear magnetic resonance spectra that the product was a clathrate compound of α-cyclodextrin and N-phenethylimidazole in a molar ratio of 1 to 1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:48][C:49]([F:60])([F:59])[C:50]1[N:54]2[CH2:55][CH2:56][NH:57][CH2:58][C:53]2=[N:52][N:51]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:57]1[CH2:56][CH2:55][N:54]2[C:50]([C:49]([F:60])([F:48])[F:59])=[N:51][N:52]=[C:53]2[CH2:58]1)=[O:5]
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(nnc2C(F)(F)F)C1
Reaction time: 12 h
Yield: 10.6 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (150 mg, 0.50 mmol, prepared according to a known method disclosed by “patent application WO2004080976”) was dissolved in 2 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (284 mg, 0.75 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 1b (138 mg, 0.60 mmol, prepared according to a known method disclosed by “patent application WO2004080958”) and N,N-diisopropylethylamine (0.2 mL, 1 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 1 (25 mg, yield 10.6%) as a white solid.
Reaction SMILES: Br[C:2]1[C:15]([CH3:16])=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][C:3]=1[CH3:17].CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>O1CCCC1>[Si:7]([O:6][C:5]1[CH:14]=[C:15]([CH3:16])[C:2]([B:29]([OH:34])[OH:30])=[C:3]([CH3:17])[CH:4]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1B(O)O
Temperature: -78 °C
Yield: 53.5 %

Procedure:
To a solution (250 mL) of (4-bromo-3,5-dimethylphenoxy)(tert-butyl)dimethylsilane (39.2 g, 124 mmol) in tetrahydrofuran was added n-butyllithium hexane solution (1.6 M, 90.0 mL, 144 mmol) under stirring at −78° C. The reaction mixture was stirred at the same temperature for 2 hr, and triisopropyl borate (40.0 mL, 173 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 3 hr. To the reaction mixture was added 2 M hydrochloric acid (180 mL), and the mixture was stirred for 6 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/4) to give the title compound (18.6 g, yield 53%) as pale-yellow prism crystals.
Reaction SMILES: S(=O)(=O)(O)O.O.[C:7]([C@:9]1([OH:31])[C:14](=[CH2:15])[CH2:13][C@H:12]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:10]12[CH3:11])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[C:18](=[CH2:30])[CH2:17]3)#[CH:8].C1C[O:35]CC1.C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[C:7]([C@:9]1([OH:31])[C:14](=[CH2:15])[CH2:13][C@H:12]2[C@H:16]3[C@H:26]([CH2:27][CH2:28][C@:10]12[CH3:11])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[C:18](=[CH2:30])[CH2:17]3)(=[O:35])[CH3:8]
Reactant: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3CC(=C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC(=C)[C@@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Reaction time: 8 h

Procedure:
Mercuric oxide red (0.32 g) was mixed with sulfuric acid/water (sulfuric acid, 0.4 ml; water, 6.0 ml) and let stand overnight. 17α-Ethynyl-17β-hydroxy-6,16-dimethyleneandrosta-4-en-3-one (Example 4, 5.0 g) is mixed with THF (15 ml). The mercuric sulfate solution is added the reaction heated to 41°-49° over a period of 6 hrs at which time TLC indicates the reaction is completed. Sodium carbonate (0.79 g) in water (10 ml) is added and the mixture stirred for 5 min. Celite (5 g) is added and the mixture stirred 1/2 hr at 20°-25°. The mixture is filtered through Celite (5 g), the solids washed with methanol/THF; 1/1 (2×10 ml) and once with THF (10 ml), followed by methylene chloride (10 ml). The filtrate and washings are concentrated under reduced pressure to about 35 ml, at which point crystals begin forming. Methanol (50 ml) is added and the mixture again concentrated under reduced pressure and permitted to sit overnight at 20°-25° under nitrogen atmosphere. Water (500 ml) is added, slowly at first, with stirring over a period of 15 min. The mixture is filtered, the solids washed with water (3×20 ml), and hexane (2×10 ml). The solids were dried under nitrogen to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH:22]([C:28](=[O:34])[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([O:25]CC)=[O:24])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH:22]([C:28](=[O:34])[CH2:29][CH2:30][CH:31]([CH3:32])[CH3:33])[C:23]([OH:25])=[O:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)CCC(C)C)C1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCC(=O)C(C(=O)O)C1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 0 °C
Yield: 42.5 %

Procedure:
A solution of 23 g of ethyl 2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl]-6-methyl-3-oxoheptanoate in 235 cm3 of 98% sulphuric acid is stirred for 20 hours at a temperature of approximately 20° C. and is then poured into 1.5 kg of ice. The precipitate obtained is separated by filtration, washed with water to a pH=6 and dried in air. The solid obtained is taken up in 3.8 liters of distilled water and 480 cm3 of a 0.1N aqueous sodium hydroxide solution. The insoluble product is separated by filtration, the filtrate is acidified to a pH=3 by addition of a 0.1N aqueous hydrochloric acid solution. The precipitate obtained is separated by filtration, washed with distilled water and then with isopropyl ether and dried at 20° C. under reduced pressure (0.07 kPa). 9.2 g of (±)-2-[2-(7-chloro-1,8-naphthyridin-2-yl)-3 -oxo-1-isoindolinyl]-6-methyl-3-oxoheptanoic acid, melting at 176° C., are thus obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH3:31][O:32][CH2:33][C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]([Cl:12])([Cl:11])[C:3]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)=[O:4].[Br:13]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:13][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:11])[Cl:12])[N:6]([CH3:10])[CH:7]=1
Reactant: Cn1cccc1C(=O)C(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1cc(Br)cc1C(=O)C(Cl)(Cl)Cl
Yield: 68.7 %

Procedure:
Under an ice cooling, N-methylpyrrole (8.10 g, 100 mmol) was dissolved in methylene chloride (100 ml), and trichloroacetyl chloride (20.00 g, 115 mmol) was added thereto. Thereafter, the mixture was stirred at a room temperature for 16 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the mixture. The organic phase was collected by separation, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off. Thus, 2,2,2-trichloro-1-(methyl-1H-pyrrol-2-yl)ethanone (16.3 g, 72%) was obtained. The resulting 2,2,2-trichloro-1-(methyl-1H-pyrrol-2-yl)ethanone (15.0 g, 66.7 mmol) was dissolved in chloroform (150 ml), and N-bromosuccinimide (12.5 g, 70.2 mmol) was added thereto at a room temperature. The mixture was heated under reflux for 16 hours. After the mixture was allowed to cool, a saturated sodium hydrogen carbonate aqueous solution was added to the mixture. The organic phase was collected by separation, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give the title compound (14.0 g, 69%).
Reaction SMILES: Cl.[I:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24](=[O:28])[CH2:25][CH2:26]Br>>[CH3:22][O:23][C:24](=[O:28])[CH2:25][CH2:26][N:17]1[CH2:16][CH2:15][N:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:20]=[CH:21][C:3]([I:2])=[CH:4][CH:5]=3)=[CH:13][CH:12]=2)[CH2:19][CH2:18]1
Reactant: COC(=O)CCBr
Reactant: Ic1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Agent: Cl
Product: COC(=O)CCN1CCN(c2ccc(Oc3ccc(I)cc3)cc2)CC1
Yield: 91 %

Procedure:
The title compound (280 mg, 91%) was prepared from the compound from Example 14 (300 mg, 0.66 mmol) and 3-bromo-propionic acid methyl ester (153 mg, 0.92 mmol) by the procedure described step 1 of Example 1 MS (ESI) m/z 467 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.56 (t, J=7.2 Hz, 2H), 2.64 (t, J=4.8 Hz, 4H), 2.75 (t, J=7.2 Hz, 2H), 3.15 (t, J=4.8 Hz, 4H), 3.69 (s, 3H), 6.70 (dd, J=0.8, 8.8 Hz, 2H), 6.92 (m, 4H), 7.56 (dd, J=0.8, 8.4 Hz, 2H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[S:12](=[O:15])(=[O:14])[N:11]=[C:10]([C:16]3[C:17](=[O:34])[C@@:18]([CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:27])[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:9][C:8]=2[S:7][CH:6]=1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][C:5]1[C:13]2[S:12](=[O:15])(=[O:14])[N:11]=[C:10]([C:16]3[C:17](=[O:34])[C@@:18]([CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:27])[C:19]4[C:24]([C:25]=3[OH:26])=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:9][C:8]=2[S:7][CH:6]=1
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN=[N+]=[N-])csc3N2)=C(O)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN)csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.7 %

Procedure:
A solution of Example 186A (17 mg, 0.03 mmol) in 2 mL of ethanol was degassed, treated with palladium on carbon (˜1 mg, 10%), put under an atmosphere of hydrogen, stirred for 4 h at room temp, filtered through a plug of celite, and concentrated to afford a yellow solid. The crude material was chromatographed on silica gel with a gradient of methanol in dichloromethane (0-10%) to afford the title compound (8.2 mg, 51% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.44 (m, 1 H) 0.70 (s, 9 H) 0.79 (m, 1 H) 1.39 (s, 3 H) 1.74 (m, J=3.31 Hz, 1 H) 2.15 (td, J=12.41, 4.23 Hz, 1 H) 4.12 (s, 2 H) 7.22 (s, 1 H) 7.33 (m, 1 H) 7.48 (m, 2 H) 8.04 (d, J=7.35 Hz, 1 H) 8.17 (br. s., 2 H) 16.99 (s, 1 H); MS (APCI+) m/z 474 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:23][CH:24]([CH3:26])[CH3:25])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][N:4](CC2C=CC=CC=2)[C:3]1=[O:22].C(OC(N1CCN(CC2C=CC=CC=2)C(=O)C1CCSC)=O)(C)(C)C>>[CH3:1][C:2]1([CH2:23][CH:24]([CH3:26])[CH3:25])[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][NH:4][C:3]1=[O:22]
Reactant: CC(C)CC1(C)C(=O)N(Cc2ccccc2)CCN1Cc1ccccc1
Agent: CSCCC1C(=O)N(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Product: CC(C)CC1(C)C(=O)NCCN1Cc1ccccc1

Procedure:
Following the general procedure of Example 43 and making non-critical variations, but sustituting 3-methyl-3-(2-methylpropyl)-1,4-bis(phenylmethyl)piperazinone (XXI, Example 51) for 4-t-butoxycarbonyl-3-[2-(methylthio)ethyl]-1-(phenylmethyl)piperazinone there is obtained the title compound, m.p. 158°-161°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][C:30]([CH3:31])=[C:25]3[N:24]([CH3:32])[C:23]2=[O:33])=[CH:18][CH:17]=1.CC(C)([O-])C.[K+]>CC(N(C)C)=O.CO>[CH3:32][N:24]1[C:25]2[C:26](=[N:27][CH:28]=[CH:29][C:30]=2[CH3:31])[N:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:21][CH:20]=2)[C:23]1=[O:33]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Cc1ccnc2c1n(C)c(=O)n2-c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: Cc1ccnc2c1n(C)c(=O)n2-c1ccc(Oc2nc3cccnc3n2C)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (600 mg) was added to a solution of 3-(4-hydroxyphenyl)-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (725 mg) and potassium tert-butoxide (351 mg) in DMA (4 ml) at 20° C. The mixture was stirred at 150° C. under a dry atmosphere for 30 min. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1,7-dimethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (150 mg) as colorless crystals.