Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[N-:23]=[C:24]=[O:25].[K+].O>C(O)(=O)C>[CH3:20][NH:19][C:15]1[N:14]=[C:13]([C:12]2[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:24]([NH2:23])=[O:25])=[CH:3][CH:4]=3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(N)=O)cc2)n1

Procedure:
Dissolved 4-(2-(4-aminophenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (75 mg, 0.26 mmol) in acetic acid (1.0 mL), then added potassium isocyanate (0.01 ml, 0.33 mmol), water (0.1 ml), and stirred at RT for 18 hours. Concentrated and purified by reverse phase HPLC (Gilson, acidic mobile phase), extracted into CH2Cl2 washed with NaHCO3 and H2O. Product began to crash out of CH2Cl2 layer, transfered to round bottom flask, concentrated to yield 1-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)urea as off-white solid. MS m/z=337 [M+1]+. Calc'd for C17H16N6O2: 336.35.
Reaction SMILES: [Na].[N:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:3]=[N-:4].[CH3:11][Si:12]([CH3:22])([CH3:21])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[NH4+].[Cl-]>CCO>[N:2]([C:5](=[CH:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([Si:12]([CH3:11])([CH3:22])[CH3:21])[CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:3]=[N-:4]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C[Si](C)(C)c1cccc(C=O)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccc([Si](C)(C)C)c1)N=[N+]=[N-]
Temperature: -10 °C
Reaction time: 4 h
Yield: 26.9 %

Procedure:
To a solution of 2 g (87.5 mmol) of sodium in 30 mL of anhydrous EtOH, maintained under a nitrogen atmosphere and cooled to −10° C., is added, dropwise, a mixture of 31.4 mL (87.5 mmol) of ethyl azidoacetate (at 34% in CH2Cl2) and 3.9 g (21.87 mmol) of 3-trimethylsilylbenzaldehyde prepared according to the procedure described in the preceding step, diluted with 3 mL of EtOH. The reaction mixture is stirred at 0° C. for 4 hours. It is then hydrolysed by adding, with vigorous stirring, 100 mL of aqueous NH4Cl solution (30%). The aqueous phase is extracted with 3×50 mL of EtOAc. The combined organic phases are washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude reaction product is purified by chromatography on a column of silica gel, eluting with an isocratic mixture of heptane and CH2Cl2 (80/20). 1.7 g of the expected ethyl 2-azido-3-(3-trimethylsilylphenyl)propenoate are thus isolated in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]([O:13][CH:14]=[CH:15][C:16]#[N:17])[CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:16]([C:15]([C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[CH:14][O:13][CH2:11][CH3:12])#[N:17]
Reactant: CCOC=CC#N
Reactant: N#Cc1ccc(F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC=C(C#N)c1cc(F)ccc1C#N
Temperature: 100 °C
Reaction time: 24 h
Yield: 81.1 %

Procedure:
Palladium acetate (II) (0.556 g, 2.5 mmol) is added to a degassed solution of 2-bromo-4-fluoro-benzonitrile (10 g, 50 mmol), 3-ethoxyacrylonitrile (10.3 mL, 100 mmol) and triethylamine (14 mL, 100 mmol) in toluene (75 mL). The reaction mixture is stirred in an oil bath at 100° C. for 1 day. The reaction mixture is cooled to RT, filtered through a pad of Celite, and the filter cake is rinsed with EtOAc. After evaporation of the solvent, the residue is purified using a Biotage column eluted with 0-50% EtOAc/hexanes (20 CV) to afford 8.77 g (94%) of 2-(1-cyano-2-ethoxy-vinyl)-4-fluoro-benzonitrile. LC/MS: RT=3.38 min, no ionization.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][CH:8]([O:11][C:12]1[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][NH2:19])=[CH:14][CH:13]=1)[CH2:9][CH3:10].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:7][CH:8]([O:11][C:12]1[CH:21]=[CH:20][C:15]([O:16][CH2:17][CH2:18][NH:19][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:14][CH:13]=1)[CH2:9][CH3:10]
Reactant: CCC(C)Oc1ccc(OCCN)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)Oc1ccc(OCCNC(=O)C2CC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
At 5° C., 3.4 g of cyclopropanecarboxylic chloride was dripped into a solution of 6.5 g of 2-[4-(1-methylprop-1-yloxy)-phenoxy]-ethylamine and 3.5 g of triethylamine in 100 ml of absolute methylene chloride. After the mixture had been stirred for 8 hours it was poured onto 200 g of ice/water and the resultant solution was adjusted to a pH of 2 with 2N aqueous hydrochloric acid. The aqueous phase was then extracted twice, each time with 50 ml of methylene chloride, and the combined organic phases were washed with saturated sodium carbonate solution and water, and dried over sodium sulfate. After removal of the solvent under reduced pressure and recrystallization from cyclohexane, there was obtained 6.4 g of N-{2-[4-(1-methylprop-1-yloxy)-phenoxy]-ethyl}-cyclopropanecarboxamide (compound no. 2); m.p.: 65°-68° C.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].[Br:9][C:10]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[CH:27]([C:32]2[CH:37]=[C:36]([Cl:38])[C:35]([Cl:39])=[C:34]([Cl:40])[CH:33]=2)[C:28]([F:31])([F:30])[F:29])[CH:22]=[CH:21][C:11]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:13].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:9][C:10]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[CH:27]([C:32]2[CH:33]=[C:34]([Cl:40])[C:35]([Cl:39])=[C:36]([Cl:38])[CH:37]=2)[C:28]([F:31])([F:29])[F:30])[CH:22]=[CH:21][C:11]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:4](=[O:5])[CH2:3][C:2]([F:8])([F:7])[F:1])[CH2:17][CH2:16]1)=[O:13]
Reactant: O=C(O)CC(F)(F)F
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCN(C(=O)CC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3,3,3-trifluoropropanoic acid (0.02 g, 0.16 mmol) in CH2Cl2 (10.0 mL), (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), PYBOP (0.09 g, 0.17 mmol), and DIPEA (0.06 g, 0.48 mmol) were added at ambient temperature. The reaction mixture was stirred at ambient temperature for 5 h. The reaction mixture was diluted with CH2Cl2. The combined CH2Cl2 layer was washed with 3N HCl and saturated NaHCO3 solution, the separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% MeOH in CH2Cl2) to afford the title compound as a off white gummy material (0.035 g, 29.%).
Reaction SMILES: [K].[S:2]([CH2:6][NH:7][C:8](=[S:11])SC)([OH:5])(=[O:4])=[O:3].[N-:12]=[N+:13]=[N-:14].[Na+]>O>[S:2]([CH2:6][N:7]1[C:8]([SH:11])=[N:14][N:13]=[N:12]1)([OH:5])(=[O:4])=[O:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCS(=O)(=O)O
Agent: [K]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)Cn1nnnc1S

Procedure:
A mixture of 45.3 g (0.19 mol.) of methyl sulfomethyldithiocarbamate potassium salt and 16.9 g. (0.26 mol.) of sodium azide in 425 ml. of water was heated at 80° for 4.75 hours. The reaction mixture was passed through an Amberlite IR-120H ion exchange resin column and eluted with water until the pH of the eluant became 3.5. The eluant was extracted with ether and the aqueous solution was evaporated to dryness to give 1-sulfomethyltetrazole-5-thiol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:18]([NH:20][C:21]2([C:24]#[N:25])[CH2:23][CH2:22]2)=[O:19])[CH2:15][CH2:16][CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:24]([C:21]1([NH:20][C:18](=[O:19])[C@H:14]([CH2:15][CH2:16][CH3:17])[NH:13][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)=[CH:3][CH:4]=2)[C:9]([F:12])([F:11])[F:10])[CH2:23][CH2:22]1)#[N:25]
Reactant: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Temperature: 82.5 °C

Procedure:
A mixture of N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide (6.46 g, 15.44 mmol), 4-methanesulfonylphenyl-boronic acid (3.40 g, 16.98 mmol), and 2M K2CO3 (19.3 mL) was dissolved in DMF (75 mL) in a thick-walled flask. The reaction mixture was degassed, and [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II), dichloromethane complex (0.678 g, 0.926 mmol) was added. The flask was sealed, heated at 80-85° C. for 3 hours, cooled, and diluted with ethyl acetate (300 mL). The solution was washed with 1:1 water/brine (200 mL), brine (200 mL), filtered through a three-layered plug of silica (bottom) DARCO, and MgSO4 (top), concentrated in vacuo, and purified on a plug of silica gel (50-70% ethyl acetate/hexane elution). The product was then further purified by recrystallization from ethyl acetate/hexanes to yield the title compound.
Reaction SMILES: O.O.O.O.O.[OH-].C[N+](C)(C)C.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].[CH3:28]I>C(#N)C>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: CI
Reactant: COCCCCCCCCCCCC(=O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COCCCCCCCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
Tetramethylammonium hydroxide pentahydrate (1.7 g, 9.4 mmol) was added to a solution of the title product of Example 1 (2.0 g, 8.7 mmol) in 45 mL of anhydrous acetonitrile. After stirring for 4 hours at room temperature, methyl iodide (0.6 mL, 9.6 mmol) was added and the resulting milky solution stirred at room temperature. The solvent was removed by rotary evaporator and partioned between diethyl ether and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (2.1 g) as a pale yellow liquid. The structure was supported by NMR, infrared spectroscopy, elemental analysis and mass spectroscopy.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[C:9]1[CH3:29])(C)(C)C.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:20]1[C:21](=[O:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]=2[CH3:29])=[N:19]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1c(-c2n[nH]c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Product: Cc1c(-c2nn(Cc3ccccc3)c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
The sub-title compound was prepared from the product of step c) and benzyl bromide using the procedure described in example 14. 1H NMR (DMSO-d6) δ 13.20 (bs, 1H), 8.37-8.34 (m, 1H), 7.88-7.80 (m, 2H), 7.52 (d, J=9.3 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.36-7.09 (m, 7H), 5.39 (d, J=15 Hz, 1H), 5.35 (d, J=15 Hz, 1H), 5.08 (s, 2H), 2.18 (s, 3H); MS: ESI (negative): 456,458 (M−H).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].FC(F)(F)S(O[CH2:18][C:19]([F:22])([F:21])[F:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:20][C:19]([F:22])([F:21])[CH2:18][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1OCC(F)(F)F
Reaction time: 72 h

Procedure:
A mixture of methyl salicylate (6.4 ml., 7.6 g., 0.05 mole), 2,2,2-trifluoroethyl trifluoromethanesulfonate (13.9 g., 0.06 mole), anhydrous potassium carbonate (13.8 g., 0.1 mole) and acetone (150 ml.) is heated under reflux with efficient stirring for three days. The product is filtered and the filtrate is concentrated to a small volume. It is diluted with cold water and the resulting precipitate is collected and washed successively with cold dilute sodium hydroxide solution and water. The desired material is recrystallized then from aqueous ethanol to afford white solid, m.p. 61-62.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][CH2:25][OH:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:27]([C:29]1([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:27][C:29]2([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][CH2:31]2)[CH2:24][CH2:25][OH:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNCCO)ccc1Cl
Reactant: CC(C)(C)OC(=O)NC1(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CN(CCO)Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Yield: 83.4 %

Procedure:
2-Chloro-5-[[(2-hydroxyethyl)amino]methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.250 g, Example 71c), (1-formylcyclopropyl)-carbamic acid, 1,1-dimethylethyl ester (0.260 g), sodium triacetoxyborohydride (0.600 g) and dichloromethane (50 ml) were stirred together under nitrogen for 24 h. The mixture was poured into saturated aqueous sodium hydrogencarbonate solution, extracted into dichloromethane, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on silica gel (ethyl acetate), to afford the subtitled compound (0.302 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](O)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1>C(Cl)(Cl)Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:11]=1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Product: c1cncc(-c2nc3ccccc3s2)c1

Procedure:
o-Aminothiophenol 36.9 g (0.30 mole) and nicotinic acid 55.5 g (0.45 mole) are dissolved in 600 cc of chloroform and 360 g of polyphosphoric acid ethyl ester (PPE). The resulting solution is heated at reflux for 1 hour. It is then concentrated to dryness. The residue is poured onto 1500 cc of ice-water, and the resulting mixture is brought to pH 10 with 50% NaOH solution. The aqueous mixture is extracted with CHCl3, and the extracts dried (MgSO4), filtered, and concentrated in vacuo. The residue is recrystallized from acetonitrile to yield the title A compound (42.8 g, 68%, of theory).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[C:24]([CH3:32])([CH3:31])[C:23]2=[O:33])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C.CO>[CH3:31][C:24]1([CH3:32])[C:25]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:17][CH:18]=2)[C:23]1=[O:33]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CC1(C)C(=O)N(c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(Oc2ccc(N3C(=O)C(C)(C)c4cccnc43)cc2)nc2cccnc21
Temperature: 180 °C
Yield: 73.1 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) was added to a solution of 1-(4-hydroxyphenyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (119 mg) and NaH (20.45 mg) in DMF (2 mL) at 100° C. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 3,3-dimethyl-1-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (120 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[C:13]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:18]=[CH:17][C:16]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[Cl:1])=[CH:15][CH:14]=1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Product: O=Cc1c(Cl)n(-c2ccc(-c3ccccc3)cc2)c2ccccc12
Yield: 52 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-biphenylboronic acid as described in Step 1 of Example 29 to afford 1-biphenyl-4-yl-2-chloro-1H-indole-3-carboxaldehyde (52% yield) as a yellow solid. ESI/MS 332 (M+H), RT=4.14 min; NMR 10.15 (1H, s); 8.23 (1H, d, J=9 Hz); 7.99 (2H, d, J=9 Hz); 7.82 (2H, d, J=9 Hz); 7.69 (7H, m); 7.54 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:22]=1[N+:29]([O-:31])=[O:30]>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:22]=1[N+:29]([O-:31])=[O:30]
Reactant: Nc1ccc(I)cc1F
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of 2-fluoro-4-iodoaniline (1.0 g, 4.21 mmol) in THF (20 mL) was dropwise added LHMDS solution (5.1 mL, 5.1 mmol, in 1 M THF) at −78° C. After stirring at −78° C. for 30 min, a solution of 2,4,6-trifluoronitrobenzene (0.747 g, 4.21 mmol) in THF (5 mL) was added dropwise into the reaction mixture, which was slowly warmed to room temperature and stirred for 16 h. After completion (as indicated by TLC), the reaction mixture was quenched with water and extracted with ether. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was triturated with hexane to yield 2-fluoro-N-(3,5-difluoro-2-nitrophenyl)-4-iodobenzenamine (1.1 g). 1H-NMR (400 MHz, CDCl3): δ 6.42-6.47 (2H, m), 7.08 (1H, t, J=8.0 Hz), 7.52-7.58 (2H, m), 8.60 (1H, s).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:34])[CH:40]=3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCC(N2CCCCC2)CC1
Yield: 77 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light red solid (77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:35])[C:10]=2[C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl.[OH-].[Na+]>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:35])[C:10]=2[C:36]2[CH:37]=[N:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)cc3C2=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cn1
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(3-(3-(3,5-difluorophenyl)-2-(6-methoxypyridin-3-yl)-1-oxo-1H-inden-6-yloxy)propyl)piperazine-1-carboxylate (115 mg, 0.2 mmol) obtained in Step 1 in CH2Cl2 was added trifluoroacetic acid (20 eq, 3.0 mmol). After being stirred for 1.5 h, the mixture was diluted with CH2Cl2 and basicified to pH 9 with a 3N NaOH solution. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.[BH4-].[Na+]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([OH:14])[CH:11]([CH3:12])[CH3:13])=[C:7]([CH3:15])[C:6]=2[CH:16]=1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(Br)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(O)C(C)C)oc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
1-(5-Bromo-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (6.2 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (100 mL) and methanol (10 mL), and sodium borohydride (90%, 1.8 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (10 mL) and 1N hydrochloric acid (50 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 1-(5-bromo-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-ol (6.1 g, quantitative) as a pale-yellow oil. The obtained oil was dissolved in tetrahydrofuran (50 mL), and thionyl chloride (2.3 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min then ice-cooled, and saturated aqueous sodium hydrogen carbonate solution (30 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (100 mL), sodium iodide (3.9 g), sodium carbonate (2.7 g) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (4.4 g) synthesized in Example 2(2) were added to the solution, and the mixture was stirred at 70° C. for 4 hr. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (1.12 g, 12%) as a yellow oil.