Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:12])[C:5]([OH:7])=O.[F:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[NH2:28]>C1COCC1>[C:17]([O:16][C:14](=[O:15])[NH:13][CH:11]([C:10]1[CH:9]=[CH:8][C:4]([C:5](=[O:7])[NH:28][C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[F:21])=[CH:3][C:2]=1[Br:1])[CH3:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1Br
Reactant: Nc1ccncc1F
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2F)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid (8352 μmol) in dry THF (20 ml) was added Ghosez reagent (2 eq.). The mixture was stirred at RT for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in dry pyridine (20 ml) and 3-fluoro-pyridin-4-ylamine (1.2 eq) was added. The reaction mixture was stirred at RT for 2.5 hours. The pyridine was removed under reduced pressure. The residue was dissolved in 1N Na2CO3 and extracted with EtOAc. The combined organic layers were washed with 1N NaHCO3, citric acid and water. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCOCC1>[F:34][C:30]1[CH:29]=[C:28]([C:23]2[C:22]([CH2:21][NH:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH3:27])[O:25][N:24]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2cccc(F)c2)c1CNc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 500 μL, 1.0 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (99 mg, 79 μL, 1.0 mmol) in dioxane (4 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinic acid methyl ester (85 mg, 0.25 mmol) in dioxane (3 mL) was added. The resulting mixture was then heated at 85-95° C. for 2 h and then cooled to room temperature and then poured into a sodium potassium tartrate solution and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound (88 mg, 86%) which was obtained as a white solid. MS: m/e=409.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([OH:14])=[CH:9]2)([O-:3])=[O:2].[F:15][CH:16](F)[CH2:17]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.ClCCl>[F:15][CH2:16][CH2:17][O:14][C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2]
Reactant: CS(=O)(=O)OCC(F)F
Reactant: O=[N+]([O-])c1cccc2cc(O)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2cc(OCCF)cnc12
Temperature: 25 °C
Yield: 24.1 %

Procedure:
A solution of 8-nitro-quinolin-3-ol (500 mg, 2.63 mmol), methanesulphonic acid 2,2-difluoro-ethyl ester (463 mg, 2.9 mmol), ad potassium carbonate (810 mg, 5.86 mmol) in dimethylformamide (7 ml) was heated at 100° C. for 16 hours. For the workup, the reaction mixture was cooled to room temperature, then saturated aqueous sodium carbonate solution and dichloromethane were added. The organic layer was separated, dried over sodium sulphate, then evaporated. The crude product was purified by chromatography on silica gel using a gradient of cyclohexane/ethyl acetate=10:1 to 1:1 as the eluent yielding 150 mg (24%) of the 3-(2-fluoro-ethoxy)-8-nitro-quinoline as a yellow solid; (calculated) C11H9FN2O3 [236.2]; (found) [M+H]+=237.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Cl.N#N>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][CH:12]=2)[N:7]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:25]=2[Cl:24])[N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]c2cc(C(F)(F)F)ccc12
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1nn(Cc2ccc(Cl)cc2Cl)c2cc(C(F)(F)F)ccc12

Procedure:
6-Trifluoromethyl-1H-indazole-3-carboxylic acid methyl ester (2.75 g, 0.0112 mol) was dissolved in acetonitrile (50 mL), and potassium carbonate (10 g, 0.07 mol), 2,4-dichlorobenzyl chloride (2.42 g, 0.01239 mol) and tetrabutylammonium iodide (catalytic) were added. The reaction mixture was heated to reflux and refluxed for 2 h under good stirring. The progress of the reaction was monitored by TLC. After completion of the reaction, potassium carbonate was filtered while hot and then washed with acetone. The combined solvents were distilled off under reduced pressure to afford the crude mixture of N1 and N2 benzylated products. The isomers were separated by column chromatography (silica gel, eluent started with hexane then changed to 8:2 hexane, ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]([CH3:35])([CH2:32][CH2:33][CH3:34])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:31])=[N:15][N:16]2[C:21]([O:22]CC3C=CC=CC=3)=[CH:20][C:19]([CH3:30])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2].C1CCCCC=1>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]([CH3:35])([CH2:32][CH2:33][CH3:34])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:31])=[N:15][N:16]2[C:21]([OH:22])=[CH:20][C:19]([CH3:30])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3ccccc3)cc(C)cc12)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(O)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 207 mg (0.418 mmol) of rac-[1-{[7-benzyloxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carbonyl]amino}methyl}-1-methylbutyl)carbamic acid tert-butyl ester (Example 140A) in 6 ml of absolute ethanol was admixed with 47 mg of palladium on charcoal (loading 10% by weight, activated) and 1.3 ml of cyclohexene. The reaction mixture was heated to reflux under an argon atmosphere for 2.5 hours. The resulting mixture was cooled to room temperature, filtered through a layer of Celite and concentrated under reduced pressure, which gave 206 mg (99% yield, 81% pure) of the target compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:22]3[O:23][C:24]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:25][C:26](=[O:28])[CH:27]=3)[S:11][C:10]=2[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][CH:21]=1)[S:18][C:17]1[C:16]([C:22]3[O:23][C:24]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:25][C:26](=[O:28])[CH:27]=3)=[CH:15][CH:14]=[CH:13][C:12]=1[S:11]2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)Sc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2c(c1)Sc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [6-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-thianthren-2-yl]-carbamic acid tert-butyl ester (11.95 g, 23.4 mmol) in dichloromethane (150 ml) was added trifluoroacetic acid (30 ml) and left under stirring at room temperature overnight. The solvent was dried in vacuo revealing a viscous dark brown liquid. Saturated sodium bicarbonate solution (400 ml) was added to the residue, which was left to stir for 20 minutes. The brown precipitate was filtered, washing with water and left to dry in a vacuum desiccator overnight. The solid was then purified by column chromatography (silica, MeOH/Dichloromethane, 3:97, Rf=0.28). 1HNMR (300 MHz, CDCl3): δH=3.24 (2H, bs); 3.46 (4H, bs); 3.81 (4H, bs); 6.33 (1H, s); 6.58 (1H, m); 6.86 (1H, d); 7.21 (1H, d); 7.30 (1H, t); 7.38 (1H, d); 7.63 (1H, d); m/z (LC-MS, ESP), RT=3.8 min, (M++1)=411
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:15][CH:14]=3)[C:5]=2[C:4](=[O:31])[N:3]=1.[OH-].[Na+:33].[CH2:34]([OH:45])[C@H:35]([C@H:37]([C@@H:39]([C@@H:41]([CH2:43][OH:44])[OH:42])[OH:40])[OH:38])[OH:36]>O>[Na+:33].[Na+:33].[NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@H:20]([C:26]([O-:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[O:18])=[CH:29][CH:30]=3)[C:5]=2[C:4](=[O:31])[N:3]=1.[CH2:43]([OH:44])[C@H:41]([C@H:39]([C@@H:37]([C@@H:35]([CH2:34][OH:45])[OH:36])[OH:38])[OH:40])[OH:42]
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1

Procedure:
5 grams of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (purity 99.6% by HPLC) was dissolved in 1 L of distilled water and 11.698 ml of a 2.0 M solution of sodium hydroxide was added to the solution. Mannitol (10 g) was then added to the solution and dissolved. The solution was then filtered through a bacterial filter and dried in a freeze-drier to afford the title compound as a white solid in mixture with mannitol (15.5 g, purity 99.6% area by HPLC).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>CCCCCC.C(OCC)(=O)C>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]([CH3:29])=[C:2]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH3:30])[CH:37]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: COc1cccc(B(O)O)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)c1
Yield: 64 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (3-methoxyphenyl)boronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 64%. Melting point: 209-210° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[C:5]([O:34][CH3:35])=[CH:4][C:3]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1.[NH2:43][C:44]1[S:45][CH:46]=[N:47][N:48]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:43][C:44]4[S:45][CH:46]=[N:47][N:48]=4)(=[O:21])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[C:5]([O:34][CH3:35])=[CH:4][C:3]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1nncs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3nncs3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
A vial was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.140 g, 0.224 mmol), 2-amino-1,3,4-thiadiazole (0.027 g, 0.268 mmol), and cesium carbonate (0.219 g, 0.671 mmol). The vial was flushed with Ar (g), then acetonitrile (2.2 mL) was added. The reaction was stirred overnight at RT. The mixture was diluted with EtOAc and NH4Cl (sat.). The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g SNAP Ultra column, 0-50% EtOAc/Heptane) to give 125 mgs of 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-6-sulfonamide as an off-white solid. This material was purified by chiral SFC on Chiralpak AS-H column (40% MeOH/60% CO2) to give (P)-1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-6-sulfonamide as peak 1 and (M)-1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-6-sulfonamide as peak 2, both as off-white solids. Data for peak 1: NMR (400 MHz, DMSO-d6) δ=14.36 (br. s., 1H), 8.77 (s, 1H), 8.31 (d, J=2.15 Hz, 1H); 8.24 (d, J=9.59 Hz, 1H), 7.84 (dd, J=2.15, 8.90 Hz, 1H), 7.68 (s, 1H), 7.60 (dt, J=6.36, 8.07 Hz, 1H), 7.41-7.48 (m, 2H), 7.36 (s, 1H), 7.29-7.34 (m, 1H), 6.78-6.85 (m, 2H), 3.74 (s, 3H). m/z (ESI) 544.0 (M+H)+. Data for peak 2: 1H NMR (400 MHz, DMSO-d6) δ=14.36 (br. s., 1H), 8.77 (s, 1H), 8.31 (d, J=2.25 Hz, 1H), 8.24 (d, J=9.49 Hz, 1H); 7.84 (dd, J=2.20, 8.95 Hz, 1H), 7.68 (s, 1H), 7.59 (dt, J=6.36, 8.07 Hz, 1H), 7.41-7.48 (m, 2H), 7.36 (s, 1H), 7.30-7.35 (m, 1H), 6.81 (dd, J=6.80, 9.24 Hz, 2H), 3.74 (s, 3H). m/z (ESI) 544.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9](Cl)=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:7]=[N:6][CH:5]=1.[CH3:16][O-:17].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([O:17][CH3:16])=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:7]=[N:6][CH:5]=1
Reactant: C[O-]
Reactant: COC(=O)c1cncc(C(=O)OC)c1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cncc(C(=O)OC)c1OC
Reaction time: 0.17 h

Procedure:
To a solution of 6.3 g (27.5 mmol) of methyl-4-chloro-5-methoxycarbonyl-nicotinate in 100 ml of THF is added 6.48 ml (35 mmol) of a 5.4 m solution of sodium methoxide in methanol. The mixture is stirred for 10 minutes and evaporated. 100 ml of a 0.25M aqueous HCl is added to the residue. The solution is made basic with K2CO3 and extracted with ethyl acetate. The organic phase is dried and evaporated to give an oil which crystallised on cooling. There is obtained 6,2 g (quantitative yield) of a solid (M+1=226).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Ca+2].[I:18]Cl>CO.O>[I:18][C:3]1[CH:4]=[C:5]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(-n2cncn2)cc1
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CO
Product: Nc1ccc(-n2cncn2)cc1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-1,2,4-triazole (1.0 g, 6.25 mmol) in MeOH (10 mL) and water (10 mL) was added CaCO3 (1.2 g, 12.0 mmol), followed by a solution of iodine monochloride (1.2 g, 7.38 mmol) in MeOH (10 mL). The reaction mixture was stirred at r.t. for 1.5 h, and then partitioned between EtOAc (100 mL) and aqueous sat. Na2S2O3 (100 mL). The organic fraction was separated, washed with aqueous sat. Na2S2O3 (100 mL), then water (100 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-100% EtOAc/hexanes) gave the title compound (1.2 g, 67%). LCMS (ES+) 286.9 (M+H)+, RT 2.78 minutes (Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[Br:11]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([Br:11])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Clc1ccc2c(c1)CCO2
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1cc(Br)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 91.5 %

Procedure:
To a stirred solution of (33) (1.84 g, 11.93 mmol) in acetic acid (10 ml) at 0° C., was slowly added a solution of bromine (1.24 ml, 24 mmol) in acetic acid (5 ml). The reaction mixture was stirred at room temperature for 4.5 h. A 10% sodium thiosulphate solution (70 ml) was added and the mixture stirred for 10 min. The bulk of the solvent was evaporated in vacuo. The resulting oil was dissolved in ether (50 ml), washed with water (20 ml), saturated NaHCO2 (2×15 ml), brine (1×15 ml), dried Na2SO4 and evaporated in vacuo to give 2.55 g (92%) of (34) as a oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH:31]2[CH2:33][CH2:32]2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1C(=O)NN=C2COc3cc(C4CC4)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A degassed mixture of 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (Example #75, Step A, 0.06 g, 0.127 mmol), cyclopropylboronic acid (0.021 g, 0.250 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloride dichloromethane complex (0.020 g, 0.025 mmol) and K2CO3 (0.035 g, 0.250 mmol) in dioxane (1 mL) and water (0.2 mL) was heated to reflux for 8 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give 4-(7-cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.024 g, 44%) as a pale-white solid. LC/MS (Table 1, Method 2) Rt=1.223 min.; MS m/z: 441 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]3[CH:23]4[CH2:24][C:19]5([C:26]([O:28][CH3:29])=[O:27])[CH2:20][CH:21]([CH2:25][CH:17]3[CH2:18]5)[CH2:22]4)=[O:14])[CH2:9]2)=[N:6][CH:7]=1.I[C:31]1[CH:36]=[CH:35][N:34]([CH3:37])[C:33](=[O:38])[CH:32]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.CC([O-])=O.[K+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:37][N:34]1[CH:35]=[CH:36][C:31]([C:2]2[CH:3]=[N:4][C:5]([CH:8]3[CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]4[CH:23]5[CH2:24][C:19]6([C:26]([O:28][CH3:29])=[O:27])[CH2:20][CH:21]([CH2:25][CH:17]4[CH2:18]6)[CH2:22]5)=[O:14])[CH2:9]3)=[N:6][CH:7]=2)=[CH:32][C:33]1=[O:38]
Reactant: Cn1ccc(I)cc1=O
Reactant: COC(=O)C12CC3CC(C1)C(OC(=O)N1CCC(c4ncc(Br)cn4)C1)C(C3)C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C12CC3CC(C1)C(OC(=O)N1CCC(c4ncc(-c5ccn(C)c(=O)c5)cn4)C1)C(C3)C2
Yield: 146.2 %

Procedure:
To a solution of 1-(methoxycarbonyl)adamantan-4-yl 3-(5-bromopyrimidin-2-yl)pyrrolidine-1-carboxylate (24 mg, 0.05 mmol), 4-iodo-1-methylpyridin-2(1H)-one (25 mg, 0.1 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (38.1 mg, 0.15 mmol), KOAc (49 mg, 0.5 mmol) and Pd(dppf)Cl2 (1 mg, 0.001 mmol) in DMSO (5 mL) under nitrogen was heated to 100 C for 2 h. The reaction mixture was treated with water and extracted with EtOAc (10 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford an oil which was purified by preparative TLC to afford 1-(methoxycarbonyl)adamantan-4-yl 3-(5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2-yl)pyrrolidine-1-carboxylate (36 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C>CO>[C:7]([CH:6]1[NH:5][CH:4]=[N:3][C:2]1=[N:1][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:8]
Reactant: N#Cc1[nH]cnc1N
Reactant: O=Cc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: N#CC1NC=NC1=NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a stirred solution of 4-amino-1H-imidazol-5-carbonitrile (1.1 g, 0.01 mole) in 25 ml of methanol was added 1.1 grams of benzaldehyde. The reaction mixture was then stirred at ambient temperature for 16 hours, heated on a steam bath for 20 minutes, cooled to ambient temperature, then stirred with 25 ml of diethyl ether. The mixture was filtered and the filtrate concentrated under reduced pressure to a residual solid. The solid was recrystallized from toluene-butanol to give 5-cyano-4-phenylmethylimino-1H-imidazole (0.92 g; mp, 200°-202°).
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][N:11]=2)C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[NH:9]([C:10]1[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][N:11]=1)[NH2:8]
Reactant: CN(C)c1ccnc(NN=C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C)c1ccnc(NN)c1
Temperature: 110 °C
Yield: 86.4 %

Procedure:
A mixture of 4.5 g (14.22 mmol) of 2-[2-(diphenylmethylidene)hydrazino]-N,N-dimethylpyridin-4-amine in 300 mL of toluene and 80 mL of aqueous 37% hydrochloric acid is heated for 4 hours at 110° C. After cooling to room temperature, the reaction medium is extracted with toluene (3×300 mL). The aqueous phase is diluted with 200 mL of water, neutralized at 0° C. by adding 12N sodium hydroxide solution, and then extracted with DCM (3×150 mL). The organic phases are combined, washed with brine (300 mL) and then dried over Na2SO4, filtered and concentrated under reduced pressure. 1.87 g of 2-hydrazino-N,N-dimethylpyridin-4-amine are obtained in the form of a brown solid, which is used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:19]3[CH2:26][CH:27]([NH2:29])[CH3:28])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[CH2:20][N:19]3[CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](C)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12

Procedure:
The desired compound was prepared according to the previous example from 4-(2-Amino-propyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8yl)-amide (3 CF3COOH salt) and acetic anhydride.