Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccc(Cl)c1
Yield: 92.3 %

Procedure:
Prepared according to the procedure described for Example 121 using 3-chlorobenzenesulfonyl chloride (2.27 g, 10 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3.846 g); m.p. 197-199° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:5][CH:4]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)[CH:6]=[N:5][CH:4]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(c1ccccc1)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Using a procedure similar to that of Example 4, 2.35 g (0.010 mole) of 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride is dissolved in 20 ml saturated aqueous sodium carbonate solution and treated with 2 ml benzoyl chloride. After stirring 10 minutes at room temperature, the crude product is extracted with toluene and recrystallized from n-butyl-chloride-cyclohexane (charcoal treatment) to give colorless crystals of the title compound, mp 104.5°-105° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17](=[O:31])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[NH2:30])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[C:12]([O:16][C:17](=[O:31])[CH2:18][N:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[NH2:30])[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CNCc1ccc([N+](=O)[O-])cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN(Cc1ccc([N+](=O)[O-])cc1N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
Benzyl chloroformate (6.8 mL, 48 mmol) was added slowly to a solution of (2-amino-4-nitro-benzylamino)-acetic acid tert-butyl ester (9.08 g, 32 mmol) and triethylamine (13.5 mL, 97 mmol) in dry methylene chloride (300 mL) at 0° C. The mixture was stirred for 2 h and warmed to room temperature for another 1 h. The mixture was concentrated and chromatograph with hexanes and ethyl acetate to give [(2-amino-4-nitro-benzyl)-benzyloxycarbonyl-amino]-acetic acid tert-butyl ester (8.39 g) as a yellow solid (62%): 1H NMR (300 MHz, CDCl3) δ 7.58 (br, 1H), 7.5 (d, 1H), 7.3 (br, 5H), 7.12 (d, 1H), 5.15 (s, 2H), 4.55 (s, 2H), 3.78 (s, 2H), 1.33 (s, 9H); MS (m/e): 416.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Cl:1][C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][C:3]=1[C:17]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([F:14])[CH:16]=1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: COc1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(-c2ccc(OC)c(F)c2)c(Cl)c1

Procedure:
Ethyl 5,6-dichloronicotinate (1 g, 4.54 mmol), 3-fluoro-4-methoxyphenylboronic acid (0.965 g, 5.68 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.371 g, 0.454 mmol), cesium carbonate (3.26 g, 10.00 mmol) and THF (30 mL) were refluxed in an 80° C. oil bath under N2 for 2.5 hrs. Volatiles were removed under reduced pressure. The pot residue was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to afford a dark mixture. The resulting crude mixture was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated to afford a white fluffy solid as the titled compound. LCMS calc.=309.06. found=310.01 (M+H)+.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:14]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27](C)[C:28](=O)OC(C)(C)C)=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[CH:13][C:12]([C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH:45]([CH3:47])[CH3:46])(=[O:44])=[O:43])=[CH:38][N:37]=2)=[CH:11][N:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:45]([S:42]([C:39]1[CH:40]=[CH:41][C:36]([C:12]2[CH:13]=[C:14]([C:15]3[O:19][C:18]([C:20]4[CH:21]=[CH:22][C:23]([CH2:26][NH:27][CH3:28])=[CH:24][CH:25]=4)=[N:17][N:16]=3)[C:9]([NH2:8])=[N:10][CH:11]=2)=[N:37][CH:38]=1)(=[O:43])=[O:44])([CH3:47])[CH3:46]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2nnc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N)o2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16 %

Procedure:
The residue from Method F Step 2 was dissolved in DCM (10 mL) and TFA (2 mL, 25.96 mmol) was added. The reaction was stirred at ambient temperature for 15 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as an off-white solid (11.4 mg, 16% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.23 (d, J=6.8 Hz, 6H), 2.30 (s, 3H), 3.56 (sept, 1H), 3.77 (s, 2H), 7.60 (d, 2H), 7.91 (s, 2H), 8.16 (d, 2H), 8.29 (dd, 1H), 8.36 (d, 1H), 9.00 (d, 1H), 9.03 (d, 1H) and 9.12 (d, 1H) ppm; MS (ES+) 465.3.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][C@H:14]2[CH2:16][C@@H:15]2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=2)=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:33]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][CH:34]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:15]2[CH2:16][C@@H:14]2[CH2:13][O:12][C:3]2[C:2]([C:35]3[CH2:36][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:33][CH:34]=3)=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][N:9]=3)[N:4]=2)=[N:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2C2=CCCN(C(=O)OC(C)(C)C)C2)nc1
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-1,5-naphthyridine (LL2) (50 mg, 0.13 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (52 mg, 0.17 mmol), tripotassium phosphate (55 mg, 0.26 mmol), S-Phos (5.3 mg, 0.01 mmol), and Pd(OAc)2 (1.5 mg, 0.006 mmol) in THF (0.6 mL) and water (0.1 mL) was heated at 100° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (5 mL), washed with sodium bicarbonate (1 mL) and brine (1 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier) to afford the title compound. 1H NMR (500 MHz, DMSO): δ 8.79 (dd, J=4.3, 1.6 Hz, 1 H), 8.18-8.06 (m, 3 H), 7.66 (dd, J=8.4, 4.2 Hz, 1 H), 7.24 (s, 2 H), 6.26 (s, 1 H), 4.54 (m, 1 H), 4.44 (m, 1 H), 4.26 (brs, 2 H), 3.77 (s, 3 H), 3.49-3.40 (m, 2 H), 2.27 (s, 2 H), 2.24-2.19 (m, 1 H), 1.80 (s, 1 H), 1.41 (s, 9 H), 1.23-1.15 (m, 2 H), 1.08 (dt, J=8.7, 4.6 Hz, 1 H); HRMS m/z (M+H) 489.2486 found, 489.2496 required.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:23][CH2:24]Br>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11]3=[N:12][C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[N:15]3[CH2:24][CH2:23]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCCBr
Reactant: O=[N+]([O-])c1ccc(Nc2nc3ccccc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCn3c2nc2ccccc23)cc1
Reaction time: 0.08 h
Yield: 5.7 %

Procedure:
A mixture of N-(4-nitrophenyl)-1H-benzimidazol-2-amine (1.00 g) in DMF (20 mL) at ambient temperature was treated with a 60% dispersion of sodium hydride in mineral oil (393 mg) then stirred for 5 min. The mixture was treated with a solution of 1,2-dibromoethane (738 mg) in DMF (1 mL) then stirred at ambient temperature for 1 h. After this time, the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (80 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with 5% aqueous lithium chloride (2×50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 1:1 ethyl acetate/heptane) to afford 1-(4-nitrophenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (63 mg) as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][N:11]3[CH2:16][CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[CH2:13][CH2:12]3)[CH2:5]2)[CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([N:4]2[CH2:9][CH2:8][CH2:7][C@H:6]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CCN(C[C@H]2CCCN(C3CC3)C2)CC1
Agent: [Pd]
Solvent: CCO
Product: C1C[C@H](CN2CCNCC2)CN(C2CC2)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 97.8 %

Procedure:
Benzyl 4-{[(3R)-1-cyclopropylpiperidin-3-yl]methyl}piperazine-1-carboxylate (45 mg) was dissolved in ethanol (6 ml). 10% Palladium on carbon (Degussa) (72 mg) was added and the mixture stirred for 60 hours at room temperature under an atmosphere of hydrogen. A further amount of catalyst (60 mg) was added and the mixture stirred for 40 hours at room temperature under an atmosphere of hydrogen. The reaction mixture was filtered through a pad of Celite, washed with ethanol and the filtrate concentrated in vacuo to give the title compound as a white solid (27.5 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH:5]=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35]>>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([OH:35])=[C:20]([O:19][CH3:18])[CH:25]=2)[CH:3]=[N:4][CH:5]=1
Reactant: Clc1cncc(NCc2ccc(Cl)c(Cl)c2)n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2cncc(NCc3ccc(Cl)c(Cl)c3)n2)ccc1O
Yield: 57 %

Procedure:
In a procedure analogous to Example 22, reaction of 6-chloro-N-(3,4-dichlorobenzyl)pyrazin-2-amine and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol furnished the product (57%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:28][C:29]1[S:33][N:32]=[C:31]([CH2:34]Cl)[N:30]=1>CC(C)=O.CC(=O)CC>[Cl:28][C:29]1[S:33][N:32]=[C:31]([CH2:34][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[N:30]=1
Reactant: ClCc1nsc(Cl)n1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: O=C1N(Cc2nsc(Cl)n2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a stirred solution of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.33 g, 4.73 mmol) in acetone (50 mL) and 2-butanone (10 mL) were added cesium carbonate (3.10 g, 9.46 mmol) and 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole (1.00 g, 5.92 mmol). The reaction was stirred at ambient temperature for 16 h, then filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (15% to 50% gradient) to afford 1′-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.43 g, 22%) as a colorless solid: mp 114-116° C.; 1H NMR (300 MHz, DMSO-d6) δ7.29 (dd, J=7.7, 7.7 Hz, 1H), 7.21 (d, J=7.0 Hz, 1H), 7.08-7.03 (m, 2H), 6.71 (s, 1H), 6.32 (s, 1H), 5.93 (d, J=3.0 Hz, 2H), 5.24 (ABq, 2H), 4.78 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.2, 174.2, 170.6, 155.7, 148.8, 142.4, 142.2, 132.2, 129.3, 124.1, 123.7, 120.4, 109.8, 103.5, 101.9, 93.8, 79.9, 57.9, 41.6; MS (ES+) m/z 414.1 (M+1), 416.1 (M+1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:28]5[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: OC1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCC(O)CC3)cc1OCC2
Yield: 42 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 4-hydroxypiperidine, the crude product was recrystallised from methanol to give 340 as a white solid (106 mg, 42%). LCMS: RT=2.48 min, [M+H]+=396. 1H NMR 400 MHz (DMSO-d6) δ: 9.09 (1H, s), 7.88 (1H, d, J=0.64 Hz), 7.83 (1H, s), 6.33 (1H, s), 5.97-5.88 (1H, m), 4.69 (1H, d, J=4.26 Hz), 4.49-4.48 (4H, m), 4.03-3.99 (2H, m), 3.75-3.67 (1H, m), 3.14-3.13 (2H, m), 1.80-1.71 (2H, m), 1.47 (6H, d, J=6.60 Hz), 1.34-1.33 (2H, m)
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.C1(C)C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[C:25]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 9 °C
Yield: 100.4 %

Procedure:
To 157.21 g (1 mol) of ethyl isonipecotate (A) were added 79.10 g (1 mol) of pyridine and 1 l of toluene. After cooling the mixture to 9° C., thereto was added dropwise 147.6 g (1.05 mol) of benzoyl chloride at 10° to 20° C. over 30 minutes with cooling. The reaction mixture was further stirred with cooling with ice for 1 hour and at room temperature for 1 hour. Then, thereto was added 500 ml of water to separate an organic layer. The organic layer was washed with 100 ml of water and 200 ml of a 5% aqueous solution of sodium hydrogencarbonate, succesively. Then, thereto was added 10 g of anhydrous magnesium sulfate. After drying, the solvent was removed by distillation to obtain 262.48 g of ethyl N-benzoylisonipecotate (B). The NMR spectrum of the obtained compound was measured. The result is shown below.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:20]2[CH:21]=[CH:22][S:23][C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([C:24]#[N:25])=[CH:14][C:13]=2[N:12]=1.O>CN(C=O)C>[O:7]([C:11]1[C:20]2[CH:21]=[CH:22][S:23][C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([C:24]#[N:25])=[CH:14][C:13]=2[N:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc2c(c1)nc(Cl)c1ccsc12
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)nc(Oc1ccccc1)c1ccsc12

Procedure:
Phenol (2.0 eq, 85 mg) was dissolved in anhydrous DMF. 60% sodium hydride (2.0 eq, 36 mg) was added and the reaction mixture stirred for a few minutes. 4-chlorothieno[3,2-c]quinoline-7-carbonitrile (1.0 eq, 110 mg) was added to the mixture and the whole reaction was stirred at 100° C. for two days. Water was added and the solid was filtered and dried. 4-phenoxythieno[3,2-c]quinoline-7-carbonitrile was isolated as a solid (114 mg). LCMS (ES)>95% pure, m/z 303 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][CH2:12][C:13]3[C:18]([C:9]=2[N:8]([CH3:20])[C:7]=1C(O)=O)=[N:17][C:16]([NH2:19])=[N:15][CH:14]=3)=[O:5])[CH3:2].C([O-])(O)=O.[Na+].[I:29]I.[I-].[K+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH2:11][CH2:12][C:13]3[C:18]([C:9]=2[N:8]([CH3:20])[C:7]=1[I:29])=[N:17][C:16]([NH2:19])=[N:15][CH:14]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2c(n(C)c1C(=O)O)-c1nc(N)ncc1CC2
Reactant: II
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c2c(n(C)c1I)-c1nc(N)ncc1CC2
Temperature: 50 °C
Yield: 30 %

Procedure:
To a solution of 8-amino-1-methyl-4,5-dihydro-1H-1,7,9-triaza -cyclopenta[a]naphthalene-2,3-dicarboxylic acid 3-ethyl ester N7 (3.16 mmol) in a mixture of DCM (10 mL) and water (10 mL), under vigorous stirring at 50° C., NaHCO3 (9.48 mmol) and an aqueous solution (4 mL) of iodine (4.1 mmol) and potassium iodide (7.58 mmol) was added. The mixture was heated at 50° C. for 3 h, cooled to rt and the organic layer was separated and washed with aq NaHSO3. The organic phase was dried (Na2SO4) and evaporated to dryness. Chromatography on silica gel (eluant: AcOEt/hexane 7:3) afforded the title compound (30% yield). ESI (+) MS: m/z 399 (MH+). 1H NMR: 1.32 (t, J=7.07, 3H), 2.65 (t, J=7.68, 2H), 2.91 (t, J=7.68, 2H), 4.21 (s, 3H), 4.24 (q, J=7.07, 2H), 6.34 (bs, 2H), 8.02 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Li]C(C)(C)C.[I:14]I>CCOCC>[Cl:8][C:5]1[C:4]([I:14])=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: Clc1ccc(Cl)c(I)n1
Temperature: -65 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
To a solution of 2,5-dichloropyridine (95 g, 0.64 mol) in 1 L of dry ether was added dropwise t-BuLi (1.3 M, 500 mL, 0.65 mol) at −65° C. After addition, the mixture was stirred at −65° C. for 2 hrs, then the mixture was poured into a solution of iodine (180 g, 0.71 mol) in dry ether (700 mL) cooled at −60° C. Then the mixture was stirred at −65° C. for 1 hour and warmed to room temperature for another 1 hour. The mixture was quenched with H2O (400 mL), then extracted with EtOAc (200 mL). The organic phase was washed with sat. Na2SO3 (250 mL×3), sat. NaCl and dried over Na2SO4. Concentrated and the residue was purified via silica gel column (petroleum ether) to give title compound (57 g, ˜77% purity, 25% yield) as a light yellow solid, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[Br:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=1>C1COCC1>[Br:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:24]([C:16]2[C:17]3[O:21][C:20]([CH3:22])([CH3:23])[CH2:19][C:18]=3[C:12]3[NH:11][C:10]([NH:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:14][C:13]=3[CH:15]=2)=[O:26])=[CH:57][CH:56]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Reactant: Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(Br)cc3)cc3nc(Nc4c(Cl)cccc4Cl)[nH]c23)O1
Yield: 13.5 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(2,6-dichlorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-6, 0.080 g, 0.204 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.130 g, 0.400 mmol), TEA (1.5 mL), DMF (1.5 mL), THF (7.0 mL) and 4-bromo aniline (0.070 g, 0.400 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.30-1.45 (m, 3H), 1.46-1.56 (m, 3H), 3.08 (s, 2H), 7.39 (m, 2H), 7.53 (d, J=8.7 Hz, 4H), 7.68 (d, J=8.7 Hz, 2H), 9.78 (s, 1H), 11.50-12.00 (s, 2H); MS [M+H]+: 547.16.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:22]([C:24](/[CH:27]=[CH:28]/[C:29](=[O:31])[NH2:30])=[CH:25][N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:20][C:21]4[N:22]([C:24](/[CH:27]=[CH:28]/[C:29]([NH2:30])=[O:31])=[CH:25][N:26]=4)[N:23]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4c(/C=C/C(N)=O)cnc4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)/C=C/c1cnc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nn12

Procedure:
162 mg Crude (1-{4-[3-((E)-2-carbamoyl-vinyl)-7-phenyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester were stirred in 10.2 mL 4M hydrogen chloride in dioxane for 16 hours at room temperature. After evaporation of the solvent the residue was dissolved in methanol and given on a PoraPak Rxn CX column. The column was washed with 100 mL methanol and the product was eluted with methanol/NH3 yielding 34 mg (13%) of the title compound which was however strongly contaminated.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](Cl)=[O:23]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:22](=[O:23])[CH:21]([F:20])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)C(F)c1ccccc1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O)C(F)c1ccccc1

Procedure:
The product of Example 86A and 2-fluoro-2-phenylacetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.22 (s, 1H), 8.39-8.45 (m, 1H), 7.90-8.07 (m, 2H), 7.69-7.78 (m, 1H), 7.61-7.68 (m, 6H), 7.46-7.53 (m, 3H), 6.26 (d, J=47.1 Hz, 1H); MS (ESI+) M/Z 408 (M+H)+.