Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1C)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.[OH:28][CH:29](COC1C=CC(OC)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:55][CH:56](COC1C=CC=C(C(F)(F)F)C=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:28][CH3:29])[CH:23]=[C:22]([O:55][CH3:56])[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C(F)(F)F)c2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cc(OC)cc(OC)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 390 (M+, 0.0), 269 (16), 268 (100), 193 (9), 163 (8), 154 (7), 121 (24), 114 (46), 76 (6), 71 (11), 70 (18).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[CH2:29]([N:31]=[C:32]=S)[CH3:30].C(Cl)CCl>CO.C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][CH:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:32]([NH:31][CH2:29][CH3:30])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: CCN=C=S
Reactant: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Solvent: ClCCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1CC1CCOCC1
Temperature: 50 °C
Yield: 32.5 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (for a preparation see Intermediate 17) (100 mg, 0.261 mmol) was dissolved in methanol and ethyl isothiocyanate (45.6 mg, 0.523 mmol) was added. The mixture was heated at 50° C. for 6 h, cooled and evaporated in vacuo to give a beige solid residue. This was re-dissolved in THF (5 ml) and EDC (100 mg, 0.523 mmol) was added, then the mixture heated at 60° C. overnight. The solvent was evaporated in vacuo and the residue dissolved in DCM (10 ml) and washed with water (10 ml), the organic layer dried and evaporated and the residue dissolved in DCM (2 ml) and loaded onto a 10 g silica column, then eluted with 2M methanolic ammonia/DCM (0-10%) and product-containing fractions evaporated in vacuo to give 7-(3,5-dimethylisoxazol-4-yl)-N-ethyl-8-methoxy-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-c]quinolin-2-amine (37 mg, 0.085 mmol, 32.5% yield) as a colourless glass. LCMS (formate) Rt 0.71 min, MH+ 436
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][OH:7].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>C1COCC1>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH2:6][CH2:5][NH:4][CH3:3])[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c(N)cccc1F
Reactant: CNCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCCOc1cccc(N)c1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Sodium hydride (8.81 g, 220.38 mmol) was added portionwise to 2-(methylamino)ethanol (16.55 g, 220.38 mmol) in THF (500 mL) at 0° C. over a period of 10 minutes under an atmosphere of argon. The resulting solution was stirred at 0° C. for 1 hour and then 2-amino-6-fluorobenzonitrile (20 g, 146.92 mmol) was added in one portion and the mixture heated at 85° C. for 2 hours. The mixture was quenched with water and then evaporated. The residue was dissolved in EtOAc (300 mL), and the mixture washed sequentially with water (2×300 mL), and then with a saturated solution of NaCl (300 mL). The organic layer was dried over MgSO4, and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-10%, of a 7M solution of NH3 in MeOH, in CH2Cl2. Fractions containing product were evaporated to afford 2-amino-6-(2-methylaminoethoxy)benzonitrile (12.08 g, 43% yield); Mass spectrum: m/z (ESI+) (M+H)+=192.43. b) Potassium hydroxide (32 g, 570.35 mmol) was added in one portion to 2-amino-6-(2-methylaminoethoxy)benzonitrile (16 g, 83.67 mmol) in ethanol (160 mL). The resulting mixture was heated at 90° C. for 2 days. The mixture was then diluted with water (1000 mL) and acidified to ˜pH1 with 2M HCl. The mixture was loaded onto an SCX column and the product was eluted first using MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated to afford 2-amino-6-(2-methylaminoethoxy)benzoic acid which was used without further purification. c) HATU (35.0 g, 92.04 mmol) was added in one portion to 2-amino-6-(2-methylaminoethoxy)benzoic acid (17.59 g, 83.67 mmol) and DIPEA (15.92 mL, 92.04 mmol) in DMF (200 mL) and the resulting solution was stirred for 1 hour. The mixture was evaporated and the residue dissolved in EtOAc (500 mL). The mixture was washed sequentially with a saturated solution of Na2CO3 (500 mL), water (500 mL), and finally with a saturated solution of NaCl (500 mL). The organic layer was dried over MgSO4, and then evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% EtOAc in isohexane. Fractions containing product were combined and evaporated to afford 6-amino-4-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (1.635 g, 10% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.09 (s, 3H), 3.44 (t, 2H), 4.20 (t, 2H), 5.74 (br s, 2H), 6.22 (dd, 1H), 6.52 (dd, 1H), 7.08 (appt t, 1H); Mass spectrum: m/z (ESI+) (M+H)+=193.41.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][C:22](=[O:25])[N:21]4[CH2:26][CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:29]=[C:20]34)[CH:16]=[CH:15][N:14]=2)[CH3:11])=[CH:5][CH:4]=1.N12CCCN=C1CCCCC2.C1(P([N:61]=[N+:62]=[N-:63])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:61]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][C:22](=[O:25])[N:21]4[CH2:26][CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:29]=[C:20]34)[CH:16]=[CH:15][N:14]=2)[CH3:11])=[CH:5][CH:4]=1)=[N+:62]=[N-:63]
Reactant: CC(Cc1ccc(CO)cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(Cc1ccc(CN=[N+]=[N-])cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The mixture of 1-{2-[2-(4-hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,6-tetrahydro -pyrimido[1,2-a]pyrimidin-4-one (0.11 g, 0.24 mmol) and 1,8-diaza-bicyclo[5.4.0]undec-7-ene (47 μL, 0.312 mmol) in tetrahydrofuran (5 mL) was brought to 0° C. followed by the addition of diphenylphosphoryl azide (68 μL, 0.312 mmol). The mixture was removed from the ice-bath and stirred at room temperature for 17 h. The mixture was concentrated and chromatographed on silica gel using 0-8% 2M NH3 MeOH/CH2Cl2to afford a white solid. M+1=494.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH3:20]>>[NH2:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cnc2ccc(OCC)cc2c1Cl
Reactant: N
Product: CCOC(=O)c1cnc2ccc(OCC)cc2c1N

Procedure:
Prepared as in Example 1a from ethyl 4-chloro-6-ethoxyquinoline-3-carboxylate (Example 13b) and ammonia as an off white solid (77%). 1H NMR (400 MHz, DMSO-d6) δ 1.31-1.40 (m, 6H), 4.15 (q, J=7.2 Hz, 2H), 4.31 (q, J=6.8 Hz, 2H), 7.34 (q, J=6.4 Hz, 1H), 7.69-7.74 (m, 2H), 8.21 (bs, 2H), 8.77 (s, 1H). MS 261 (MH+).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].Cl[C:8](Cl)([O:10]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[F:25][C:26]([F:47])([F:46])[O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[N:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=3)=[N:35]2)=[CH:30][CH:29]=1.NC1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]([O:6][C:8](=[O:10])[NH:45][C:42]1[CH:43]=[CH:44][C:39]([C:36]2[N:37]=[CH:38][N:34]([C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:46])[F:47])=[CH:33][CH:32]=3)[N:35]=2)=[CH:40][CH:41]=1)([CH3:3])[C:4]#[CH:5]
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: C#CC(C)(C)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CC(C)(C)OC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
2-Methyl-3-butyn-2-ol (48 μL, 0.44 mmol) was added to a solution of triphosgene (42 mg, 0.14 mmol) and pyridine (38 μL, 0.47 mmol) in CH2Cl2 (1.0 mL) at 23° C. Gas evolution was observed during addition of the alcohol, and a precipitate was observed to form. The resulting slurry was stirred at 23° C. for 1 h. Stirring was ceased, the solid was allowed to settle to the bottom of the flask, and the supernatant was added via cannula to a slurry of 4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-phenylamine (100 mg, 0.312 mmol) and pyridine (38 μL, 0.47 mmol) in CH2Cl2 (1.0 mL) at 23° C. A thick precipitate was observed to form. At this point, TLC analysis indicated some starting material remained, so an equivalent amount of triphosgene/pyridine/alcohol was combined as above, and the resulting supernatant was again added to the aniline mixture. After stirring for another 3 h at 23° C., the reaction mixture was diluted with 30% EtOAc/hexanes (10 mL), and a fine white precipitate was filtered on a coarse frit. The clear yellow filtrate was concentrated, and the resulting yellow oil was purified by silica gel chromatography (Biotage 10 g SNAP column, eluted with a 10% to 25% to 50% EtOAc/hexanes gradient) to provide the title compound (55 mg, 41%) as a white solid: mp 164-165° C.; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.13 (d, J=8.7 Hz, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 6.73 (s, 1H), 2.61 (s, 1H), 1.77 (s, 6H); ESIMS m/z 431 (M+H); HRMS-ESI (m/z): [M]+ calcd for C21H17F3N4O3, 430.125. found, 430.126.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][C:14]([NH:16][NH2:17])=[O:15])[CH:8]=2)[NH:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:17][NH:16][C:14](=[O:15])[CH2:13][O:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:11][CH2:10]3)=[S:27])=[CH:21][CH:20]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: NNC(=O)COc1ccc2c(c1)CCC(=O)N2
Solvent: CN(C)C=O
Product: O=C(COc1ccc2c(c1)CCC(=O)N2)NNC(=S)Nc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 0.1 %

Procedure:
To a stirred solution of 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetohydrazide (0.2 g, 0.85 mmol) in dry DMF (5 mL) at room temperature, 1-chloro-4-isothiocyanatobenzene (0.158 mg, 0.93 mmol) was added and the reaction was heated at 60° C. overnight. The reaction was monitored by LCMS. Solvent was removed under vacuum, then water (10 mL) was added to the residue. The solid was filtered and dried to yield crude N-(4-chlorophenyl)-2-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)acetyl)hydrazinecarbothioamide (0.250 mg, 73%). LCMS: RT 1.39 min. LCMS (ES-API), m/z 405.0 (M+H).
Reaction SMILES: O1[CH:5]2[C:6]3[C:7]4[C:12]([C:13]5[C:18]([C:19]=3[CH:2]1[CH:3]=[CH:4]2)=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:11][CH:10]=[CH:9][CH:8]=4.I[C:21]1[CH:35]=[CH:34][C:24]([CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.IC1C=C(C=CC=1)CP(=O)(OCC)OCC.C(N(CC)CC)C>[Zn].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:5]1[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:2]=[CH:3][C:4]=1[C:21]1[CH:35]=[CH:34][C:24]([CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1
Reactant: C1=CC2OC1c1c2c2ccccc2c2ccccc12
Reactant: CCOP(=O)(Cc1ccc(I)cc1)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOP(=O)(Cc1cccc(I)c1)OCC
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(Cc1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1)OCC
Temperature: 110 °C
Yield: 70 %

Procedure:
Compound A (760 mg, 3.11 mmol), zinc (1.85 g, 28.2 mmol), and PdCl2(PPh3)2 (198 mg, 0.28 mmol) were charged in a two-necked bottle. The bottle was then vacuumed and purged with nitrogen, and dried toluene (30 mL), diethyl 4-iodobenzylphosphonate (0.65 mL, 2.82 mmol) or diethyl 3-iodobenzylphosphonate, and triethyl amine (3.91 mL, 28.2 mmol) were added to the bottle. The mixture in the bottle was heated to 110° C. for reaction for 48 hours, and the resulting was filtered to remove metal. The filtrate was condensed to remove the solvent, and then purified by column chromatography (ethyl acetate/hexanes=½) to obtain E (0.90 g, yield=70%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25]([OH:27])=[O:26]>CC(O)C.CCN(C(C)C)C(C)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=2[C:25]([OH:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1cccc(F)c1C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A slurry of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (50 g, 146 mmol) and 2-amino-6-fluorobenzoic acid (27.2 g, 175 mmol) (for instance from Acros Organics, Belgium) in iPrOH (1200 mL) and 30 mL of DIEA was heated to reflux. After 1 h, the solution turned a clear brown color, at which time about 450 mL of solvent were removed via distillation. The remaining mixture was treated with DIEA (90 mL) and heated to reflux for 16 hours. The reaction mixture was then further concentrated by distilling more solvent off (400 mL over 4 hours), then continued heating at reflux overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to obtain a thick oil which was diluted with EtOAc (1.3 L), then sequentially washed with a 1N HCl solution (2×500 mL), and a saturated NaHCO3 solution (500 mL). Further dilution of the separated organic layer with a saturated NaCl solution (500 mL) led to the formation of a thick precipitate. The entire mixture was filtered and the solid was washed with Et2O. The solid was dried overnight in a vacuum oven at 60° C. to obtain 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzoic acid as a yellow solid (61.63 g, 92%). 1H NMR (400 MHz, DMSO-d5) δ ppm 2.37 (s, 3H), 6.67 (d, J=3.85 Hz, 1H), 6.71-6.81 (m, 1H), 7.31 (td, J=8.33, 6.04 Hz, 1H), 7.48 (d, J=8.24 Hz, 2H), 7.74 (d, J=4.03 Hz, 1H), 7.98 (d, J=8.42 Hz, 2H), 8.36 (d, J=8.24 Hz, 1H); ESIMS (M+H)+=461.06.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:13]=1.[C:37]([N:44]1[CH2:49][CH2:48][CH:47](O)[CH2:46][CH2:45]1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:40]([O:39][C:37]([N:44]1[CH2:49][CH2:48][CH:47]([O:36][C:33]2[CH:34]=[CH:35][C:30]([C:27]3[CH:28]=[CH:29][C:24]([CH2:23][C:11]4[N:12]([C:14]5[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=5)[CH:13]=[C:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])[N:10]=4)=[CH:25][CH:26]=3)=[CH:31][CH:32]=2)[CH2:46][CH2:45]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(O)cc3)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc([N+](=O)[O-])cc4)cc3)cc2)CC1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichlorophenyl)-1H-imidazole (3.27 g, 8.6 mmol) was treated as described in general procedure B using 4-fluoronitrobenzene to provide 2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazole, which was treated with 4-hydroxyphenyl boronic acid according to general procedure G to provide 4′-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-biphenyl-4-ol (996 mg, 22% for two steps). To a solution of the phenol in THF (0.5 M) was added N-boc-4-hydroxypiperidine (2 eq) and triphenylphosphine (2 eq) under nitrogen, then while sonicating this mixture diisopropyl azodicarboxylate (2 eq) was added. After sonicating 1 hour the reaction mixture was evaporated in vacuo and the reside was purified by silica gel column chromatography to afford 4-{4′-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H -imidazol-2-ylmethyl]-biphenyl-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [BrH:1].[NH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5](Cl)[N:4]=1>C(O)(=O)C>[NH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([Br:1])[N:4]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Br
Solvent: CC(=O)O
Product: Nc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A 30% solution of hydrogen bromide in acetic acid (10 ml) was added to 2-amino-6-chloro-3-nitropyridine (1.0 g) at room temperature and the mixture was heated at 100° C. After 24 hr, a 30% solution of hydrogen bromide in acetic acid (5 ml) was added. After 48 hr, the reaction mixture was cooled and concentrated. The residue was neutralized with 28% aqueous ammonia and extracted three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was crystallized from isopropyl ether to give the objective compound (1.14 g) as yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1)[NH2:23]
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc(C(=O)Nc2ccc(C(F)(F)F)cc2)cn1
Yield: 64 %

Procedure:
6-Chloro-N-[4-(trifluoromethyl)phenyl]nicotinamide (0.49 g) and hydrazine monohydrate (4 mL) were suspended in ethanol (8 mL), and the suspension was heated to reflux for 15 hours. The reaction solution was concentrated under reduced pressure, and the obtained solid was then collected by filtration and washed with ethyl acetate. The solid was dried under reduced pressure to obtain the title compound (0.31 g) as a white solid (yield: 64%).
Reaction SMILES: FC(F)(F)COP([CH2:13][C:14]([O:16][CH3:17])=[O:15])(OCC(F)(F)F)=O.C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:48][C:49]1[CH:50]=[C:51]([C:59]2[O:63][N:62]=[C:61]([C:64]3[CH:65]=[CH:66][CH:67]=[C:68]4[C:72]=3[N:71]([CH3:73])[CH:70]=[C:69]4[CH:74]=O)[N:60]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH:56]([CH3:58])[CH3:57]>C1COCC1>[Cl:48][C:49]1[CH:50]=[C:51]([C:59]2[O:63][N:62]=[C:61]([C:64]3[CH:65]=[CH:66][CH:67]=[C:68]4[C:72]=3[N:71]([CH3:73])[CH:70]=[C:69]4/[CH:74]=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])[N:60]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH:56]([CH3:57])[CH3:58]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl {bis[(2,2,2-trifluoroethyl)oxy]phosphoryl}acetate (0.16 mL), 18-crown-6 (1.0 g) in THF (5 mL) stirred under nitrogen at −70° C. was added NaHMDS (1.0 mol/L in THF, 0.8 mL) during 1 min. The reaction mixture was stirred at −70° C. for 10 mins. 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (200 mg) was added and the mixture was stirred at this temperature for 1.5 h and then left to warm to room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with water (25 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with brine, dried over sodium sulphate and evaporated to afford the crude product, which was purified by column chromatography (10% ethyl acetate in hexane) to afford methyl (2Z)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-propenoate (D63) (120 mg). MS (ES): C24H22ClN3O4 requires 451; found 452.2 (M+H+).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@@H:37]([CH:42]([CH3:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@@H:37]([CH:42]([CH3:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(C)C
Agent: Cl
Product: COC(=O)[C@@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(2-chloro-5-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17].[C:22]([Si:26]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]I)=[CH:35][CH:34]=1)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[Si:26]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH:14]([CH2:15][CH:16]=[CH2:17])[C:13]([O:19][CH2:20][CH3:21])=[O:18])=[CH:35][CH:34]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: C=CCCC(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(CI)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCC(Cc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (1.1 eq.) in THF (0.12 M) was added, at −78° C., n-butyllithium (1.6 M hexane solution, 1.1 eq.) over a period of 5 min. The resulting mixture was stirred at −78° C. for 15 min and then warmed at RT for 10 min. With the reaction mixture re-cooled to −78° C., ethyl pent-4-enoate (1.1 eq.) was added dropwise as a 1.6 M THF solution. The resulting solution was stirred for 30 min at −78° C. Finally, tert-butyl{2-[4-(iodomethyl)phenoxy]ethoxy}dimethylsilane (1 eq.) was added dropwise as a 1.5 M THF solution. The reaction mixture was allowed to warm slowly to RT over 12 h. After the reaction was carefully quenched with the addition of a sat. aq. NH4Cl solution, the reaction mixture was extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 10:1 (v/v) Hex:ether) afforded the title compound as a colorless oil.