Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][N:32]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:37][C:34]4[CH:33]=[N:32][C:31]([Cl:30])=[CH:36][CH:35]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(Cc2ccc(Cl)nc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (150 mg, 0.46 mmol), prepared as described in Example 244, in DMF (3 mL) was added K2CO3 (80 mg, 0.58 mmol) and 2-chloro-5-(chloromethyl)pyridine (90 mg, 0.556 mmol). The reaction mixture was stirred at 70° C. for 15 min. After this time, the solution was cooled to RT and diluted with water (20 mL). The resulting solid was collected by filtration and the crude product was purified by reverse phase HPLC to give the title compound, 7-(4-chlorophenyl)-2-((6-chloropyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (110 mg, 52%), as a yellow solid. HPLC: 2.61 min; MS, M+H=449; 1H NMR (CDCl3) δ 8.62 (2H, d, J=5.0 Hz), 8.43 (1H, d, J=5.0 Hz), 8.19 (1H, s), 7.33 (1H, d, J=5.0 Hz), 7.29-7.31 (3H, m), 7.20 (2H, d, J=5.0 Hz), 7.08 (2H, d, J=10.0 Hz), 5.17 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([Cl:25])[CH:18]=4)[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1.O>CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:25])[CH:18]=4)[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1Cl
Agent: CS(=O)(=O)O
Solvent: O
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(-c3ccc(O)c(Cl)c3)c(=O)c12
Temperature: 145 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
7-Chloro-2-(3-chloro-4-methoxyphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (previously prepared in Example 37 1.00 g, 2.47 mM) was stirred in methanesulfonic acid (20 mL) to give a black solution. This solution was heated to 145° C. for 6 hours and cooled to room temperature. Water (60 mL) was added to give a tan suspension which was stirred for 3 hours and filtered. The collected solids were washed with water and ether to give the title compound as a gold powder (0.98 g, 76 %), mp 350-353° C.; MS(CI): 390.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12].[H-].[Na+].[NH2:15][C:16]1[C:25](Cl)=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>O1CCCC1>[NH2:15][C:16]1[C:25]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: Nc1nc2ccccc2nc1Cl
Reactant: OCc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc2ccccc2nc1OCc1ccc2ccccc2c1
Yield: 82.1 %

Procedure:
According to Step 2 of Reference Example 7-1, by use of 2-naphthalenemethanol (792 mg, 5.01 mmol), 60% sodium hydride (in oil) (200 mg, 5.01 mmol), tetrahydrofuran (6.0 mL) and 2-amino-3-chloroquinoxaline (300 mg, 1.67 mmol), the mixture was stirred and reacted at room temperature for 17 hours. Then, slurry purification was performed using diisopropyl ether, to give 2-amino-3-[(naphthalen-2-yl)methoxy]quinoxaline (Compound BC) (413 mg, yield: 82%).
Reaction SMILES: [Cl-].[CH3:2][Zn+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([CH3:14])[N:8]=[C:7]([O:15][CH3:16])[N:6]=1>O1CCCC1.O>[CH3:16][O:15][C:7]1[N:8]=[C:9]([CH3:14])[C:10]([N+:11]([O-:13])=[O:12])=[C:5]([CH3:2])[N:6]=1
Reactant: COc1nc(C)c([N+](=O)[O-])c(Cl)n1
Reactant: C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C)c([N+](=O)[O-])c(C)n1
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 93.4 %

Procedure:
Methylzinc chloride (2.0 M solution in tetrahydrofuran, 14.8 mL, 29.6 mmol) was added dropwise to a solution of 4-chloro-2-methoxy-6-methyl-5-nitropyrimidine (4.01 g, 19.7 mmol) and tetrakis(triphenyl phosphine)palladium (1.90 mmol) in tetrahydrofuran (60 mL), and the mixture was stirred at 50° C. for 50 minutes. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a pale yellow solid (3.37 g, 18.4 mmol, 93%).
Reaction SMILES: [H-].[Na+].[CH3:3][SH:4].Br[C:6]1[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:17][CH2:18][CH3:19].Cl>CN(C=O)C>[CH2:18]([O:17][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:14][CH2:15][CH3:16])[C:6]=1[S:4][CH3:3])[CH:10]=[O:11])[CH3:19]
Reactant: CS
Reactant: CCOc1cc(C=O)cc(OCC)c1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(OCC)c1SC
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
To a suspension of sodium hydride (2.62 g, 60.0 mmol, 2.0 equiv; 55% free-flowing powder moistened with oil) in DMF (50 mL) under Ar was added carefully methanethiol (2.88 g, 60.0 mmol, 2.0 equiv). After 15 min, a solution of 4-bromo-3,5-diethoxy-benzaldehyde (8.2 g, 30.0 mmol, 1.0 equiv; prepared according to S. P. Dudek, H. D. Sikes, C. E. D. Chidsey J. Am Chem. Soc. 2001, 123, 8033-8038) in DMF (30 mL) was added, and the reaction mixture stirred overnight. The mixture was acidified to pH 2 by addition of a solution of 1 M HCl and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with heptane/ethyl acetate (1:1) providing 6.9 g (96%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.50 (t, J=7.0 Hz, 6H), 2.50 (s, 3H), 4.18 (q, J=7.0 Hz, 4H), 7.02 (s, 2H), 9.88 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.66, 17.50, 64.88, 105.71, 122.00, 135.90, 159.54, 191.31. MS (ISP): 240.9 [M+H]+.
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21](OS(C(F)(F)F)(=O)=O)[C:20]=1[N+:33]([O-:35])=[O:34].Cl.[CH:37]1([C@H:41]([NH2:43])[CH3:42])[CH2:40][CH2:39][CH2:38]1>>[Cl:8][C:9]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[C:12]([F:18])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:43][C@@H:41]([CH:37]2[CH2:40][CH2:39][CH2:38]2)[CH3:42])[C:20]=1[N+:33]([O-:35])=[O:34]
Reactant: C[C@@H](N)C1CCC1
Reactant: CN(C)c1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-])C1CCC1
Yield: 48.8 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester TFA (1.1 g, 2.49 mmol) and (R)-1-cyclobutyl-ethylamine HCl (225 mg, 1.7 mmol) were treated substantially as described in Part C of Example 19a to produce 326 mg of crude (R)-[4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-ethyl)-amine.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:43]1([CH3:55])[CH:48]=[CH:47][C:46]([S:49]([N:52]=[C:53]=[O:54])(=[O:51])=[O:50])=[CH:45][CH:44]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:53]([NH:52][S:49]([C:46]5[CH:47]=[CH:48][C:43]([CH3:55])=[CH:44][CH:45]=5)(=[O:51])=[O:50])=[O:54])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nn3c(NCCCCNC(=O)NS(=O)(=O)c4ccc(C)cc4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 41.9 %

Procedure:
To a cold (0° C.) solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (28 mg, 0.05 mmol) in dichloromethane (5 mL) was added triethylamine (0.1 mL) and p-tolylsulfonyl isocyanate (0.012 mL, 0.08 mmol). The resultant solution was stirred at 0° C. for 1 hour and saturated aqueous sodium bicarbonate was added. The organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (5% methanol in dichloromethane) and recrystallization from dichloromethane-ether provided N-{[(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]carbonyl}-4-methylbenzenesulfonamide (14 mg, 35%) as a yellow solid. 1H NMR (CDCl3): δ 8.03 (m, 1 H), 7.84–7.76 (m, 3 H), 7.58 (d, 2 H), 7.36–7.26 (m, 5 H), 7.01 (d, 2 H), 6.66 (m, 1 H), 6.34 (m 1 H), 6.04 (m, 2 H), 4.36 (m, 1 H), 3.91 (s, 3 H), 3.38–3.30 (m, 4 H), 2.36 (s, 3 H), 2.07 (m, 2 H), 1.82–1.54 (m, 10 H); MS m/z 669 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:9]([O:8][C:7](=[O:13])[NH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:2]1)([CH3:10])([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 97.5 %

Procedure:
tert-Butyl(3R)-pyrrolidin-3-ylcarbamate (4.54 g, 24.4 mmol), 4-fluoronitrobenzene (3.78 g, 24 mmol) and potassium carbonate (3.54 g 25.6 mmol) in acetonitrile (70 ml) were heated under reflux for 18 hours. After evaporation under reduced pressure, the mixture was dissolved in DCM (200 ml), and washed with water (100 ml) and saturated sodium chloride solution (25 ml). The solution was dried and filtered. After evaporation under reduced pressure, chromatography on silica gel eluting with DCM gave the title compound (7.19 g, 97%). NMR: 1.39 (s, 9H), 1.87-1.98 (m, 1H), 2.09-2.21 (m, 1H), 3.15-3.23 (m, 1H), 3.32-3.44 (m, 1H), 3.45-3.51 (m, 1H), 3.53-3.61 (m, 1H), 4.09-4.21 (m, 1H), 6.57 (d, 2H), 7.21 (s, 1H), 8.01 (d, 2H); m/z (MH+—C4H8) 252.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([NH:17][CH3:18])=[CH:12][C:11]=2[O:19][CH2:20][CH:21]([F:23])[F:22])=[CH:4][CH:3]=1.[F:25][C:26]1[C:39]([N:40]=[C:41]=S)=[C:38]([F:43])[CH:37]=[CH:36][C:27]=1[CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].CC(C)N=C=NC(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2[C:11]([O:19][CH2:20][CH:21]([F:22])[F:23])=[CH:12][C:13]3[N:17]([CH3:18])[C:41]([NH:40][C:39]4[C:38]([F:43])=[CH:37][CH:36]=[C:27]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]=4[F:25])=[N:16][C:14]=3[CH:15]=2)=[O:24])=[CH:4][CH:3]=1
Reactant: CNc1cc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(F)c(N=C=S)c1F
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(F)ccc(CNC(=O)C(C)(C)C)c2F)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21

Procedure:
The title compound is prepared from N-(4-bromophenyl)-2-(2,2-difluoro-ethoxy)-4-methylamino-5-amino-benzamide and N-(2,4-difluoro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide with DIC in analogy to example 1g.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]([NH:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:29](OC)=O)=[O:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.ClCCl>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[CH:29]=[C:28]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[NH:27][C:25]2=[O:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(NC(=O)NC1CCN(Cc2ccccc2)CC1)c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(F)cc2)cn1C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
Diisobutylaluminum hydride (1 M, 1.18 mL, 1.18 mmol) was added to a solution of methyl ({[(1-benzylpiperidin-4-yl)amino]carbonyl}amino)(4-fluorophenyl)acetate (430 mg, 1.08 mmol) in toluene (5 mL) and dichloromethane (5 mL) at −78° C. and stirred for 30 min and then warmed to 0° C. After 20 min at 0° C., the reaction was quenched with 1 N saturated potassium sodium tartrate solution (20 mL) and the mixture was extracted with ethyl acetate (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude material was treated with 4 N HCl in dioxane (4 mL), and stirred for 5 min. The mixture was concentrated, dissolved in dichloromethane and extracted with saturated sodium bicarbonate (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 0 to 7% {1% ammonium hydroxide/methanol} in methylene chloride gradient elution), gave the title compound (150 mg). MS 400.29 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:51])([CH3:50])[C:29]([F:49])([F:48])[C@:30]([C:33]3[CH:38]=[C:37](B4OCC(C)(C)CO4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br[C:53]1[N:54]=[CH:55][N:56]([C:58]2[CH:63]=[CH:62][C:61]([C:64]([F:67])([F:66])[F:65])=[CH:60][N:59]=2)[CH:57]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:51])([CH3:50])[C:29]([F:48])([F:49])[C@:30]([C:33]3[CH:38]=[C:37]([C:53]4[N:54]=[CH:55][N:56]([C:58]5[CH:63]=[CH:62][C:61]([C:64]([F:67])([F:66])[F:65])=[CH:60][N:59]=5)[CH:57]=4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(B4OCC(C)(C)CO4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: FC(F)(F)c1ccc(-n2cnc(Br)c2)nc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cn(-c5ccc(C(F)(F)F)cn5)cn4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 25.3 %

Procedure:
Reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (intermediate B10.1) (300 mg, 380 μmol) with 2-(4-bromo-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine (111 mg, 380 μmol) yielded the [bis-(4-methoxy-phenyl)-phenyl-methyl]-((R)-6,6-difluoro-5-{2-fluoro-5-[1-(5-trifluoromethyl-pyridin-2-yl)-1H-imidazol-4-yl]-phenyl}-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-amine (77 mg, 25% yield) as a yellow foam. MS (ISP): m/z=800.3 [M+H]+.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[Br:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[Br:17])[CH:12]=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6]
Reactant: O=Cc1ccc(Br)c(Br)c1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2ccc(Br)c(Br)c2)S1

Procedure:
A mixture of thiazolidine-2,4-dione (90%, 65 mg, 0.5 mmol), 3,4-dibromobenzaldehyde (132 mg, 0.5 mmol), and piperidine (247 μL, 2.5 mmol) was shaken in acetic acid (2 mL) at 110° C. for 16 hours. After cooling, the mixture was concentrated to dryness in vacuo. The resulting crude product was shaken with water, centrifuged, and the supernatant was discarded. Subsequently the residue was shaken with ethanol, centrifuged, the supernatant was discarded and the residue was further evaporated to dryness to afford the title compound.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[NH2:30][C:31]1[C:40]2[N:41]=[C:42]([CH2:49][O:50][CH2:51][CH3:52])[N:43]([CH2:44][C:45]([CH3:48])([OH:47])[CH3:46])[C:39]=2[C:38]2[CH:37]=[CH:36][C:35](Br)=[CH:34][C:33]=2[N:32]=1.[C:54]([O:58][CH3:59])(=[O:57])[CH:55]=[CH2:56]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:30][C:31]1[C:40]2[N:41]=[C:42]([CH2:49][O:50][CH2:51][CH3:52])[N:43]([CH2:44][C:45]([OH:47])([CH3:48])[CH3:46])[C:39]=2[C:38]2[CH:37]=[CH:36][C:35](/[CH:56]=[CH:55]/[C:54]([O:58][CH3:59])=[O:57])=[CH:34][C:33]=2[N:32]=1
Reactant: C=CC(=O)OC
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3cc(/C=C/C(=O)OC)ccc3c2n1CC(C)(C)O
Temperature: 120 °C

Procedure:
A thick walled glass reaction vessel was charged with anhydrous DMF (2 mL), palladium (II) Acetate (0.01 equivalents (eq)), tri-o-tolylphosphine (0.02 eq) and triethylamine (3 eq). To this orange solution was added a solution of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol in 50 mL anhydrous DMF followed by the addition of methyl acrylate (1.0 eq). The reaction mixture was purged with nitrogen, sealed and heated at 120° C. overnight, and slowly cooled to room temperature. The reaction mixture was concentrated to dryness and then slurried in water (50 mL). Saturated potassium carbonate solution (25 mL) was added. The mixture was extracted with dichloromethane (4×50 mL). The combined extracts were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-25% CMA in chloroform) to provide Methyl(2E)-3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate as a white solid.
Reaction SMILES: OO.[CH3:3][C:4]1([CH3:23])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[CH:11]=2)[C:6](=[O:22])[CH2:5]1.C([O-])([O-])=[O:25].[K+].[K+].CS(C)=O>O>[CH3:3][C:4]1([CH3:23])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]([NH2:19])=[O:25])=[CH:16][N:15]=3)[CH:11]=2)[C:6](=[O:22])[CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CC(=O)c2ccc(Oc3ccc(C#N)cn3)cc21
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2ccc(Oc3ccc(C(N)=O)cn3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 188.3 %

Procedure:
Add 30% aqueous H2O2 (3.15 ml) to a suspension of 6-(3,3-Dimethyl-1-oxo-indan-5-yloxy)-nicotinonitrile (877 mg, 3.15 mmol), K2CO3 (218 mg, 1.57 mmol) and DMSO (10 ml) stirring under nitrogen at ambient temperature. After four hours, dilute the reaction mixture with water (100 ml) and extract with EtOAc (2×). Wash the extract with water and brine, dry (MgSO4) and concentrate on rotary evaporator to yield 876 mg of the title compound as an off-white solid. Mass spectrum (ion spray): m/z=297 (M+1); 1HNMR (CDCl3): 8.62 (s, 1H), 8.24 (d, 1H), 7.75 (d, 1H), 7.24 (s, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 5.91 (broad, 2H), 2.63 (s, 2H), 1.43 (s, 6H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[N:5]1)(=[O:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][Br:14])=[N:5]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)n1nc(C)c2ccccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)n1nc(CBr)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 320 g (1.84 mol) of 1-acetyl-3-methylindazole, 327 g (1.84 mol) of N-bromosuccinimide and 3 liters of carbon tetrachloride solution containing 0.2 g of benzoyl peroxide was refluxed over a 2-hour period as the mixture was irradiated with light. After cooling to room temperature, 0.2 g of benzoyl peroxide was further added, and the reaction mixture was refluxed for additional three hours. After conclusion of the refluxing step, the reaction mixture was cooled to 20° C. to precipitate succinimide. The precipitate of succinimide was filtered out, and the filtrate was concentrated under reduced pressure. To the residue was added 1.2 liters of n-hexane to precipitate crystals. The crystals was filtered off, and washed with n-hexane. Thus, 275 g of crude bromomethyl body was obtained. It was found from measurements of thin-layer chromatograph and NMR spectrum that the crude bromomethyl body was contaminated by about 17% of dibromomethyl body.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=2)[CH2:11][C@H:10]([NH2:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51](Cl)(=[O:53])=[O:52])([O-:44])=[O:43]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([NH:35][S:51]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N+:42]([O-:44])=[O:43])(=[O:52])=[O:53])[CH2:11][C@@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=2)[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NS(=O)(=O)c3ccccc3[N+](=O)[O-])CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (3S*,5R*)-3-Amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.83 mmol) in CH2Cl2 (1 mL) are added pyridine (1 mL) and o-nitrobenzenesulfonyl chloride (274 mg, 1.2 mmol) at 0° C., then the mixture is stirred at room temperature. After 20 h, the reaction mixture is quenched by H2O (30 mL) and extracted with EtOAc (100 mL). The organic layer is successively washed with 5% aqueous KHSO4, H2O, and brine, then dried over Na2SO4 and concentrated in reduced pressure. The residue is purified by silica gel column chromatography to afford the title compound as brown amorphous material. MS: 670 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 4.14 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]=[CH:10]N(C)C)=[C:4]([N+:14]([O-])=O)[CH:3]=1>[Pd].CO>[F:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[F:1])[NH:14][CH:10]=[CH:9]2
Reactant: CN(C)C=Cc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Fc1cc2cc[nH]c2cc1F
Reaction time: 2 h
Yield: 27.2 %

Procedure:
A suspension of [2-(4,5-difluoro-2-nitro-phenyl)-vinyl]-dimethyl-amine (7.0 g, 30.7 mmol) and 10% palladium on charcoal (1.4 g) in methyl alcohol was hydrogenated in a Parr apparatus at 50 psi for 2 h and then filtered through Celite. The filtrate was concentrated in vacuo and the crude product purified by silica gel column chromatography (hexanes/ethyl acetate, 8:2) to afford 5,6-difluoroindole (1.28 g, 28%) as a yellow solid. 1H-NMR δ (400 MHz, CDCl3) 8.10 (1H, br s), 7.36 (1H, dd, J=10.7, 7.8 Hz), 7.22 (1H, t, J=2.8 Hz), 7.17 (1H, dd, J=7.4, 3.1 Hz), 6.50 (1H, m).