Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[C:9]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:26].[Li]CCCC.[Br:32][C:33]1[CH:34]=[C:35]([CH:39]2[CH2:42][C:41](=[O:43])[CH2:40]2)[CH:36]=[CH:37][CH:38]=1>C1COCC1>[Br:32][C:33]1[CH:34]=[C:35]([CH:39]2[CH2:40][C:41]([C:2]3[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]4[C:9]([C:16]5[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=5[Cl:23])=[N:10][O:11][C:12]=4[CH:13]4[CH2:14][CH2:15]4)=[CH:4][C:3]=3[Cl:26])([OH:43])[CH2:42]2)[CH:36]=[CH:37][CH:38]=1
Reactant: O=C1CC(c2cccc(Br)c2)C1
Reactant: Clc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)cc2Cl)CC(c2cccc(Br)c2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a solution of compound 1a (14 g, 29.6 mmol) in dry THF (500 ml) at −78° C. was added dropwise n-BuLi (18.5 mL, 1.6 M in hexane, 29.6 mmol). The mixture was stirred for an additional 1 h at −78° C. and a solution of compound 2a (6.5 g, 28.9 mmol) in dry THF (50 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h and then warmed to rt and quenched with saturated aq. NH4Cl (500 mL). The mixture was extracted with EA (500 mL×2), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by CC (EA/PE=1:5) to give the title compound 2b (6.5 g, 37%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]([O:19][CH3:20])[C:16]([F:21])=[CH:15][C:11]=1[C:12](O)=[O:13].S(Cl)([Cl:24])=O.CCCCCC>C(Cl)Cl.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]([O:19][CH3:20])[C:16]([F:21])=[CH:15][C:11]=1[C:12]([Cl:24])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: COc1nc(Nc2ccc(F)cc2F)c(C(=O)O)cc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1nc(Nc2ccc(F)cc2F)c(C(=O)Cl)cc1F
Yield: 91.7 %

Procedure:
In 150 ml of methylene chloride was suspended 5.00 g of 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinic acid, and 5.98 g of thionyl chloride and 3 drops of N,N-dimethylformamide were added thereto, after which the resulting mixture was subjected to reaction under reflux for 2 hours. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 10 ml of n-hexane, after which crystals were collected by filtration to obtain 4.87 g (yield 91.7%) of 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl chloride having a melting point of 153°-154° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]([Cl:27])[C:14]=1[OH:28].O>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:16]=[C:15]([Cl:27])[C:14]=1[O:28][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: BrCCCBr
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(OCc2ccccc2)cc(Cl)c1OCCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A reaction vessel was charged with 5.10 g of 1,3-dibromopropane, 2.40 g of potassium carbonate and 50 ml of N,N-dimethylformamide, to which a solution of 4.24 g of 2,6-dichloro-4-(benzyloxy)phenol dissolved in 10 ml of N,N-dimethylformamide was slowly added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with 150 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 4.24 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(benzyloxy)benzene (68% yield).
Reaction SMILES: [C:1]([CH:4]([C:11]1[N:19]2[C:14]([C:15](=[O:28])[NH:16][C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[N:18]2)=[C:13]([CH3:29])[N:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2].[BH4-].[Na+]>>[OH:3][CH:1]([CH:4]([C:11]1[N:19]2[C:14]([C:15](=[O:28])[NH:16][C:17]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[N:18]2)=[C:13]([CH3:29])[N:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCCCCC(C(C)=O)c1nc(C)c2c(=O)[nH]c(Cc3ccc(C)cc3)nn12
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCC(c1nc(C)c2c(=O)[nH]c(Cc3ccc(C)cc3)nn12)C(C)O

Procedure:
100 mg (0.25 mmol) of 7-(1-acetylheptyl)-5-methyl-2-(4-methylbenzyl)-imidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 3) are reacted analogously to Example 8 with 10 mg (0.25 mmol) of sodium borohydride to give 7-[1-(1-hydroxyethyl)heptyl]-5-methyl-2-(4-methylbenzyl)-imidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CC([C@@H]1N=C(C2C=CC=C(C3OC[C@H](C(C)C)N=3)N=2)OC1)C>CC([C@H]1N=C(C2C=CC=C(C3OC[C@@H](C(C)C)N=3)N=2)OC1)C.CC(N(C)C)=O.[Zn].Cl[Ni]Cl.C(COC)OC.IC1C=CC(CCCCCCCCCCCCCCCCCCO)=CC=1>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: ICCCCCCCCCCCOC1CCCCO1
Reactant: CCOC(=O)CCCCCBr
Agent: Cl[Ni]Cl
Agent: CC(C)[C@@H]1COC(c2cccc(C3=N[C@H](C(C)C)CO3)n2)=N1
Agent: CC(C)[C@H]1COC(c2cccc(C3=N[C@@H](C(C)C)CO3)n2)=N1
Solvent: CC(=O)N(C)C
Solvent: COCCOC
Product: CCOC(=O)CCCCCCCCCCCCCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
From (77) and (36). Zinc powder (342 mg, 5.27 mmol) was dried at 70° C. for 30 min in a sealed tube, then DMA (2 ml) and solid 12 (45 mg, 0.18 mmol) were added. After stirring for 10 min, neat ethyl 6-bromohexanoate (0.63 ml, 3.52 mmol) was added and the reaction mixture was stirred in the sealed tube for 10 h at 75° C. In a 10-ml flask, NiCl2-glyme (52 mg, 0.23 mmol) and (R)-(i-Pr)-Pybox (or (S)-(i-Pr)-Pybox) (92 mg, 0.31 mmol) were dissolved in DMA (1.5 ml), cooled to 0° C. and solution of I(CH2)11OTHP 77 (896 mg, 2.34 mmol) in DMA (0.5 ml) was added. Then the solution of organozinc reagent 36 was added. The reaction mixture was stirred at 0° C. for 6 h and at room temperature for 6 h, then quenched by addition of aqueous NH4Cl, extracted with EtOAc, extract was dried over Na2SO4 and evaporated. The crude product was purified as in Method 1 to give compound 78 (888 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH:7]2[OH:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][CH3:15])[CH:5]=[C:6]([CH:7]=[O:12])[C:10]=1[C:9]([O:8][CH2:23][CH3:24])=[O:11]
Reactant: CCCc1cc(Cl)c2c(c1)C(O)OC2=O
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(Cl)c(C(=O)OCC)c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
To a solution of (±)-7-chloro-3-hydroxy-5-propylisobenzofuran-1 (3H)-one (0.66 g, 2.91 mmol) in 10 mL of DMF was added potassium carbonate (0.80 g, 5.82 mmol) followed by iodoethane (0.26 mL, 3.20 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was cooled to 0° C. and carefully acidified with 6N HCl, diluted with water and extracted with EtOAc. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 0.69 g (93%) of the title compound which was used without purification. 1H NMR (CDCl3): δ 9.88 (s, 1H), 7.52 (d, 1H, J=1.4 Hz), 7.40 (d, 1H, J=1.6 Hz), 4.42 (q, 2H, J=7.1 Hz), 2.60 (t, 2H, J=7.7 Hz), 1.64-1.55 (m, 2H), 1.34 (t, 3H, J=7.1 Hz), 0.89 (t, 3H, J=7.1 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[N:7][N:8]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:32]1([C:38](O)=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>CN(C=O)C.C(#N)C>[CH:32]1([C:38]2[N:8]3[C:3]([C:4](=[O:9])[NH:5][CH:6]=[N:7]3)=[CH:2][N:1]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NCc1nnc[nH]c1=O
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1[nH]cnn2c(C3CCCCC3)ncc12
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-aminomethyl-4H-[1,2,4]triazin-5-one (250 mg, 1.98 mmol) in DMF (7.5 mL) was added 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (760 mg, 2.38 mmol), cyclohexanecarboxylic acid (305 mg, 2.38 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.6 mmol). After 1 h acetonitrile (40 mL) was added to the mixture followed by dropwise addition of phosphoryl chloride (0.28 mL, 3.0 mmol) and the reaction mixture stirred at 55° C. for 1 h. The mixture was then concentrated in vacuo chromatographed over silica gel eluting with 3% MeOH in DCM, to afford 7-cyclohexylimidazo[5,1-f][1,2,4]triazin-4(3H)-one. 1H NMR (400 MHz—DMSO-d6) δ 1.24-1.91 (m, 10H), 3.08-3.16 (m, 1H), 7.68 (s, 1H) 7.88 (s, 1H) 11.76 (s, 1H); MS (ES+): m/z: 219.24 (100) [MH+]. HPLC: tR=2.44 min (OpenLynx: polar—5 min).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[C@@H:10]([CH3:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reaction time: 12 h

Procedure:
A mixture of 2.5 g (S)-4-N-Boc-2-methyl-piperazine, 3.5 g N-(Benzyloxycarbonyl-oxy)succinimide and 2.0 g NaHCO3 in 10 ml dioxane/water 1/1 was stirred for 12 h. The mixture was diluted with ethyl acetate, the phases separated and the organic phase washed with water, saturated aqueous NaHCO3, 0.1 M HCl and brine. The crude product obtained after drying over MgSO4 and evaporation of the solvents was used in the subsequent reaction. Yield: 4.3 g.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH2:7]([NH2:9])[CH3:8]>>[CH2:7]([NH:9][CH2:5][CH2:4][C:3]([NH:2][CH3:1])=[O:6])[CH3:8]
Reactant: CCN
Reactant: C=CC(=O)NC
Product: CCNCCC(=O)NC
Yield: 98.7 %

Procedure:
N-methylacrylamide (ABCR: 851 mg, 10.00 mmol) and ethylamine (2 M in methanol, 10 mL, 20.00 mmol) were combined in a microwave reaction vessel, which was sealed and irradiated at 140° C. for 30 mins. The reaction mixture was allowed to cool and then loaded directly onto a 50 g SCX-2 cartridge, washing with methanol (100 mL) and eluting the desired product with 7 N methanolic ammonia (100 mL). Concentration under reduced pressure of product containing fractions gave the title compound as a clear oil (1.285 g; 99%)
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:19])[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:13]1([CH3:19])[NH:14][CH2:15][CH2:16][N:17]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)[CH2:18]1
Reactant: CC1(C)CNCCN1
Reactant: CCOC(=O)c1ccc(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N2CCNC(C)(C)C2)s1
Temperature: 110 °C
Reaction time: 23 h
Yield: 36.1 %

Procedure:
Palladium(II) acetate (0.112 g, 0.50 mmol) was added to ethyl 5-bromothiophene-2-carboxylate (1.175 g, 5 mmol), 2,2-dimethyl-piperazine (0.571 g, 5.00 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.311 g, 0.50 mmol) and cesium carbonate (2.281 g, 7.00 mmol) in toluene (50.0 ml) at 20° C. under nitrogen. The resulting suspension was stirred at 110° C. for 23 h. The crude product was purified by ion exchange chromatography, using a SCX2 column. The crude material was dissolved in methanol and then applied to the column. The desired product was eluted from the column using 2M NH3 in methanol and pure fractions were evaporated to dryness to afford the crude product as a brown solid. This material was further purified by silica column chromatography, eluting with a gradient of 0 to 4% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 5-(3,3-dimethylpiperazin-1-yl)thiophene-2-carboxylate (0.484 g, 36.1%) as a brown gum.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([N:15]1[C@@H:20]2[C@H:21]([C:23]([OH:25])=[O:24])[CH2:22][C@@:16]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:17]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[CH2:18][CH2:19]2)C1C=CC=CC=1>[Pd].C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:41][C:38]([F:39])([F:40])[C:30]1[CH:29]=[C:28]([CH2:27][O:26][C@@H:17]2[CH2:18][CH2:19][C@@H:20]3[NH:15][C@@:16]2([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:22][C@H:21]3[C:23]([OH:25])=[O:24])[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:31]=1
Reactant: O=C(O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: O=C(O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 110.7 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate (Example 53; 2.7 g, 4 mmol), 10% palladium on charcoal (500 mg) and ethanol (30 ml) was stirred under hydrogen atmosphere (1 atm) at +40° C. for 20 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (2.6 g) as a white solid.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[N:15]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)=[C:20]([O:36][CH3:37])[CH:19]=2)[CH3:17])[C:9]2=[N:10][CH:11]=[C:12]([I:14])[CH:13]=[C:8]2[N:7]=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O>[I:14][C:12]1[CH:13]=[C:8]2[N:7]=[C:6]([NH2:5])[N:15]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:27]=[N:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=4)=[C:20]([O:36][CH3:37])[CH:19]=3)[CH3:17])[C:9]2=[N:10][CH:11]=1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1C(C)c1ccc(OCc2ccc(C(F)(F)F)nc2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(C)n2c(N)nc3cc(I)cnc32)ccc1OCc1ccc(C(F)(F)F)nc1
Temperature: 160 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a stirred solution of ethyl(6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (1.53 g, 2.39 mmol), in ethanol (10 mL)/water (4 mL) was added potassium phosphate tribasic (2.07 g, 9.54 mmol). The mixture was irradiated in a microwave reactor at 150° C. After 1 h, the mixture was subjected to an additional round of microwave heating (160° C., 30 min). After a total of 90 min, the mixture was diluted with water (100 mL) and extracted with dichloromethane (2×50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 1.31 g (97%) of 6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine as an orange foamy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[C:34]([CH3:35])[C:26]=4[CH3:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: Cc1cccc(C(=O)Cl)c1C
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c1C
Yield: 13.4 %

Procedure:
As described for Example 9, 0.628 g (2 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.506 g (3.0 mmol) of 2,3-dimethylbenzoyl chloride in dichloromethane. The product is recrystallized from hexane-dichloromethane to give 0.12 g of crystals, m.p. 138°-142° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH2:12][CH2:11][CH2:10][NH:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:12][CH2:11][CH2:10][N:9]1[S:36]([CH3:35])(=[O:38])=[O:37])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1NCCCC(N2C(=O)c3ccccc3C2=O)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCCN1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
To a solution of [6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-7-oxo-[1,2]diazepan-1-yl]-acetic acid tert-butyl ester (21) (155 mg, 0.42 mmol), triethylamine (0.5 mL) and 4-N,N-dimethylaminopyridine (DMAP) (101 mg, 0.50 mmol) in dichloromethane was added dropwise methanesulfonyl chloride (95 mg, 0.83 mmol). The mixture was stirred at 0° C. for 5 min then at room temperature for 16 hours. The mixture was quenched with water, extracted with dichloromethane. The organic solution was washed with water then brine, dried over anhydrous Na2SO4, filtered and purified by flash chromatography using dichloromethane/ethyl acetate (99/1 to 95/5) to afford 154 mg (82% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.47 (s, 9H), 2.05-2.21 (m, 2H), 2.83-2.87 (m, 1H), 3.27 (s, 3H), 3.53-3.58 (m, 1H), 4.07-4.11 (d, 1H), 4.29-4.33 (m, 1H), 4.50-4.53 (d, 1H), 5.42-5.44 (m, 1H), 7.70-7.85 (m, 4H). Analytical HPLC: 12.27 min. LC-MS (ES+): m/e=452 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1cc(Br)c2[nH]c(=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Br)c2[nH]c(=O)[nH]c2c1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
Methyl 7-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (238 mg, 0.878 mmol) and 2 N aqueous sodium hydroxide (1.50 mL, 3.0 mmol) were combined in methanol (5 mL) and heated to 50° C. for 90 minutes. The reaction solution was concentrated to remove the methanol. To the reaction residue was added ethyl acetate (5 mL). The resultant solution was acidified with 1N aqueous hydrochloric acid (1.5 mL) to give a final pH of 4. A precipitate formed which was filtered and dried under vacuum to give the title compound (226 mg, 100%) as a solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (d, J=1.37 Hz, 1 H) 7.65 (d, J=1.37 Hz, 1 H).
Reaction SMILES: C([NH:3]CC)C.C(OC([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](CCOS(C)(=O)=O)[CH:23]=2)[NH:18][C:17]=1C(F)(F)F)=O)C1C=CC=CC=1>>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:17]1[NH2:3]
Reactant: CCNCC
Reactant: CS(=O)(=O)OCCc1ccc2[nH]c(C(F)(F)F)c(C(=O)OCc3ccccc3)c2c1
Product: Nc1cc2ccccc2[nH]1
Yield: 20 %

Procedure:
Diethylamine (0.48 mL, 4.63 mmol, 3 eq) was added into the crude 5-(2-Methanesulfonyloxy-ethyl)-2-trifluoromethyl-1H-indole-3-carboxylic acid benzyl ester in dioxanes (20 mL) solution. The reaction mixture was heated to reflux overnight. After the solvent was removed, the residue was purified by gravity chromatography (SiO2, ethyl acetate-methanol-NH4OH) to yield the desire indole amine as pale yellow gel (20.0% yield). Elemental Analysis: C23H25F3N2O2.HCl: Calcd: C: 60.73; H: 5.76; N: 6.16. Found: C: 60.40; H: 5.83; N: 6.06. ESI-MS: m/z 419.73 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29](Cl)=[O:30]>ClCCl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[N:10]=1)=[O:30]
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine (520 mg, 2.29 mmol, 1.00 equiv) in dichloromethane (5 mL), pyridine (540 mg, 6.84 mmol, 3.00 equiv), and 5-chloro-2-nitrobenzoyl chloride (500 mg, 2.27 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was washed with 2×50 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1). This resulted in 800 mg (85%) of product as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:19]=[O:20].[C:21]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[CH:4][C:3]=2[CH:19]=[O:20])=[CH:29][CH:30]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1F
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)c1ccc(Oc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2C=O)cc1
Temperature: 160 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
A mixture of 4-fluoro-4′-(trifluoromethoxy)biphenyl-3-carbaldehyde (750 mg, 2.639 mmol), 4-(tert-butyl)phenol (436 mg, 2.903 mmol), potassium carbonate (547 mg, 3.958 mmol) and dimethylacetamide (4 ml) was stirred at 160° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=15:1) to give the title compound (598 mg, 54.7%) as a pale yellow solid.