Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:48])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[N:29][C:30]([O:36]CC4C=CC(OC)=CC=4)=[C:31]([O:33][CH2:34][CH3:35])[CH:32]=3)=[C:23]([F:46])[C:22]=2[F:47])=[CH:14][C:13]=1[C:49]([F:52])([F:51])[F:50])C1C=CC=CC=1>CO.[Pd]>[CH2:34]([O:33][C:31]1[C:30](=[O:36])[NH:29][CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([C:49]([F:52])([F:50])[F:51])[CH:14]=3)=[O:48])=[C:22]([F:47])[C:23]=2[F:46])[CH:32]=1)[CH3:35]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(OCCOCc4ccccc4)c(C(F)(F)F)c3)c(F)c2F)cnc1OCc1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(OCCO)c(C(F)(F)F)c3)c(F)c2F)c[nH]c1=O
Yield: 44214284 %

Procedure:
To a solution of N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,3-difluorophenyl)acetamide (10 mg, 0.014 mmol) in MeOH (3 mL) stirred under N2 at 20° C. was added Pd/C (0.147 mg, 1.384 μmol) in one charge. The solution was stirred under a H2 atmosphere. The reaction mixture was stirred at 10° C. for 12 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield a light yellow solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2,3-difluorophenyl)-N-(4-(2-hydroxy ethoxy)-3-(trifluoromethyl)phenyl)acetamide (3.17 mg, 6.19 mol, 44.7% yield). TLC (DCM/MeOH=5:1, Rf=0.4): 1H NMR (400 MHz, CD3OD) δ 7.88 (d, J=2.4 Hz, 1H), 7.75 (dd, J=2.2, 8.8 Hz, 1H), 7.37-7.12 (m, 5H), 4.20-4.07 (m, 4H), 3.90 (t, J=5.0 Hz, 2H), 3.85 (s, 2H), 1.48 (t, J=7.0 Hz, 3H); ES-LCMS m/z 513.2 (M+H).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.Cl[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][N:10]=1.O>C1COCC1>[Cl:15][C:14]1[C:9]([O:7][CH:3]2[CH2:6][CH2:5][CH2:4]2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Clc1cccnc1Cl
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cccnc1OC1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Sodium hydride dispersion (60%, 1.22 g, 30.5 mmol) was suspended in anhydrous THF (40 mL) under a nitrogen atmosphere. A solution of cyclobutanol (2.0 g, 27.7 mmol) in THF (10 mL) was added dropwise at room temperature then the reaction was stirred 1 hour at room temperature. 2,3-dichloropyridine (5.0 g, 33.8 mmol) was added and the reaction mixture was stirred at 60° C. under nitrogen for 16 hours. Water (50 mL) was added and the reaction mixture was concentrated in vacuo. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 3% EtOAc in heptane to afford the title compound as a clear oil (3.7 g, 72%):
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=4)[C:11]=3[O:22][C:23]3[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:8]=[CH:9][C:2]1=2.C([S-])C.[Na+]>CN(C)C=O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[C:11]([O:22][C:23]4[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:36][CH:37]=4)=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]4)[CH:8]=[CH:9][C:2]1=2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc4sccc4c3)ccc2c1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc4sccc4c3)ccc2c1
Temperature: 150 °C
Yield: 58.8 %

Procedure:
Dissolve the compound of Example 50 (240 mg, 0.48 mmol) in dimethylformamide (DMF, 7 mL), add sodium ethanethiolate (EtSNa, 100 mg, 1.19 mmol). Flush the flask with N2 and then heat the reaction mixture to 150° C. Continue to heat the reaction mixture for 0.5 hours, cool to room temperature. Add water (15 mL), and extract the aqueous layer with CH2Cl2 (3×15 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 0-8% MeOH—NH4OH (10/1, v/v) in CH2Cl2) to give 140 mg of crude 6-benzo[b]thiophen-5-yl-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol. Purify the impure product by preparative HPLC (Gilson) to give 95 mg of the title compound (55%): mass spectrum (ion spray): m/z=496.3 (M+H−TFA).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:22][N:19]([CH2:20][CH2:21]2)[CH2:18][CH:17]=[CH:16]3)=[CH:11][N:10]=1>CN(C)C=O>[N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:22][N:19]([CH2:20][CH2:21]3)[CH2:18][CH:17]=[CH:16]4)=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Brc1ccc(C23C=CCN(CC2)C3)cn1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=CC2(c3ccc(-n4ccnc4)nc3)CCN(C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
0.64 g (9.42 mmol) of imidazole dissolved in 3 ml of dimethylformamide is introduced into a 10 ml three-necked round-bottomed flask. 0.415 g (10.4 mmol) of sodium hydride as a 60% dispersion in oil is then added and the mixture is stirred at room temperature for 1 hour. The mixture is then added to a solution of 5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]oct-3-ene (WO 03/057 697) (0.5 g, 1.89 mmol) in dimethylformamide and the reaction medium is heated at 85° C. for 15 hours and then at 110° C. for 24 hours and the solvent is evaporated off under reduced pressure. The residue is taken up in 10 ml of chloroform and 10 ml of saturated aqueous sodium carbonate solution. The aqueous phase is extracted again with 10 ml of chloroform and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 95/5/0.5 proportions. 0.235 g of 5-[2-(−1H-imidazol-1-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene is obtained and is dissolved in 3 ml of isopropyl alcohol to add 0.327 ml of a 5.7N solution of hydrobromic acid in acetic acid. The crystals formed are collected by filtration and dried under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Yield: 39.4 %

Procedure:
A mixture of 10.0 g (0.06 mol) of 3,5-dihydroxybenzoic acid methyl ester, 12.3 ml (0.06 mol) of 1-bromodecane and 8.2 g (0.06 mol) of potassium carbonate in 200 ml of acetone and 20 ml of DMF was stirred at reflux under argon for 24 hours. After the usual workup, purification by HPLC using 15% ethyl acetate-hexane gave 7.3 g (34% yield, mp 92°-94°) of 3-(decyloxy)-5-hydroxybenzoic acid methyl ester. The nmr spectra was consistent with the structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2([C:36]#[N:37])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[C:16]4[CH:35]=[CH:34][CH:33]=[CH:32][C:17]=4[C:18]4[CH2:19][N:20]([C@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]5[OH:31])[C:21](=[O:24])[C:22]=4[CH:23]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH3:38]B(O)O.C(=O)([O-])[O-].[K+].[K+].ClCCl>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].O1CCOCC1.O>[OH:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@@H:25]1[N:20]1[CH2:19][C:18]2[C:17]3[CH:32]=[CH:33][CH:34]=[CH:35][C:16]=3[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:38])[N:7]=4)([C:36]#[N:37])[CH2:9][CH2:10]3)=[CH:23][C:22]=2[C:21]1=[O:24]
Reactant: N#CC1(c2cccc(Cl)n2)CCN(Cc2cc3c(c4ccccc24)CN([C@H]2CCCC[C@@H]2O)C3=O)CC1
Reactant: CB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cccc(C2(C#N)CCN(Cc3cc4c(c5ccccc35)CN([C@H]3CCCC[C@@H]3O)C4=O)CC2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-(6-chloropyridin-2-yl)-1-({2-[(1S,2S)-2-hydroxycyclohexyl]-3-oxo-2,3-dihydro-1H-benzo[e]isoindol-5-yl}methyl)piperidine-4-carbonitrile (0.050 g, 0.097 mmol) in 1 mL mixture of 1,4-dioxane:water (10:1) under an atmosphere of nitrogen was added methylboronic acid (7.0 mg, 0.12 mmol), potassium carbonate (0.040 g, 0.29 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (1.4 mg, 0.0019 mmol). The mixture was irradiated in a microwave reactor at 125° C. for 1 hr, cooled to ambient temperature and extracted 2× with dichloromethane. The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the titled compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 495.2765 for [M+H]+[calc'd for C31H35N4O2, [M+H]+=495.2755]: 1H NMR (400 MHz, CDCl3) δ 8.35-8.33 (m, 1H), 7.88-7.85 (m, 1H), 7.76 (s, 1H), 7.66-7.54 (m, 3H), 7.34-7.32 (m, 1H), 7.07-7.04 (m, 1H), 4.84-4.68 (m, 2H), 4.20-4.14 (m, 1H), 3.98-3.79 (m, 2H), 3.77-3.74 (m, 1H), 3.02-2.96 (m, 1H), 2.63-2.55 (m, 1H), 2.52 (s, 3H), 2.36-2.21 (m, 2H), 2.06-1.97 (m, 2H), 1.90-1.82 (m, 1H), 1.70-1.25 (m, 6H), 0.97-0.83 (m, 3H) ppm.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]([OH:32])[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC(O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
23.8 ml of diisopropylamine were initially charged under argon in 250 ml of THF and cooled to 0° C., and 70 ml of n-butyllithium solution (2.5 M in toluene) were added. The mixture was stirred at 0° C. for 30 minutes, then cooled to −75° C., 16.2 ml of ethyl acetate were added slowly and the mixture was stirred for 30 minutes. Then, at −75° C., 30 g of p-benzyloxybenzaldehyde, dissolved in 250 ml of THF, were added dropwise (internal temp. max. −68° C.; 1 h). The mixture was stirred for a further 20 minutes and then the reaction mixture was quenched with 200 ml of sat. NH4Cl solution and 20 ml of 1 N HCl (internal temp. max. −50° C.). The mixture was allowed to thaw to room temperature, the phases were separated and the organic phase was washed three times with 100 ml each time of sat. NH4Cl solution and once with 100 ml of sat. NaCl solution. The solvent was removed under reduced pressure. The residue was extracted by stirring with n-heptane/2% THF and the precipitated solid was filtered off with suction and dried under reduced pressure at 40° C. This gave 41 g of ethyl 3-(4-benzyloxyphenyl)-3-hydroxypropionate as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[CH:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]2[C:28]3[C:23](=[CH:24][C:25](B4OC(C)(C)C(C)(C)O4)=[CH:26][CH:27]=3)[C:22]([CH3:39])([CH3:38])[NH:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]2[C:28]3[C:23](=[CH:24][C:25]([C:2]4[CH:3]=[CH:4][C:5]5[N:6]([N:8]=[CH:9][N:10]=5)[CH:7]=4)=[CH:26][CH:27]=3)[C:22]([CH3:39])([CH3:38])[NH:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CC1(C)NCC(c2ccc(Cl)c(Cl)c2)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Brc1ccc2ncnn2c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)NCC(c2ccc(Cl)c(Cl)c2)c2ccc(-c3ccc4ncnn4c3)cc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
6-Bromo-[1,2,4]triazolo[1,5-a]pyridine (600 mg, 3.03 mmol) was added to a mixture of the boronate ester from step E (873 mg, 1.68 mmol), cesium carbonate (1.97 g, 6.06 mmol) in DMF (60 mL) and water (12 mL). The reaction mixture was deoxygenated with argon. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (82 mg, 0.10 mmol) was added and the reaction mixture was stirred at 90° C. for 1 hour, cooled, diluted with water, and extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (0 to 100% 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide solution in dichloromethane) gave the desired 4-(3,4-dichlorophenyl)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline (431 mg, 50% over 2 steps): 1H NMR (CDCl3, 500 MHz) 1H NMR (CDCl3, 500 MHz) δ 8.79 (s, 1H), 8.38 (s, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.77 (dd, J=8.0, 1.5 Hz, 1H), 7.48 (s, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.0, 1.5 Hz, 1H)), 7.21 (d, J=1.5 Hz, 1H), 6.99-6.92 (m, 2H), 4.08 (t, J=5.5 Hz, 1H), 3.45 (dd, J=13.5, 5.5 Hz, 1H), 3.10 (dd, J=13.5, 5.5 Hz, 1H), 1.68 (s, 3H), 1.60 (s, 1H), 1.57 (s, 3H); ESI MS m/z 423 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13]([C:15]1[N:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:14].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:21]([C:18]3[CH:19]=[N:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)(=[O:22])=[O:23])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1cc(F)cc2cccnc12
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)Nc2cc(F)cc3cccnc23)cn1
Yield: 26.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-ylamine (Intermediate 48) (125 mg, 0.77 mmol), 6-cyano-pyridine-3-sulfonyl chloride (Intermediate 19) (187 mg, 0.92 mmol), pyridine (121 mg, 1.54 mmol), DMAP (cat.) and DCM (10 ml) gave the title compound (67 mg, 26%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:22][OH:23])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 100 %

Procedure:
To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanone, prepared as described in Procedure 4, (860 mg, 3.0 mmol) in pyridine (6 mL) was added hydroxylamine hydrochloride (830 mg, 12.0 mmol) and the reaction mixture was heated at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (50 mL), washed with 1 N HCl (2×20 mL), water (20 mL) and sat. NaCl (20 mL), then dried over MgSO4, filtered and concentrated under reduced pressure to yield (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanone oxime (912 mg, 100% yield) as a white solid. TLC (30% EtOAc/hexane) shows two spots, the cis and trans isomers of (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanone oxime, that were not separated. LCMS: RT=1.59 min [M+H] 302.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])([CH3:16])[CH3:15])=[CH:9][CH:8]=[C:7]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:6]=2.NC1C=NC2C(C=1NCCCCNC(=O)OC(C)(C)C)=CC=[C:36]([O:54][CH2:55][C:56]1C=CC=CC=1)[CH:35]=2.C(OCC(Cl)=O)C.COCCC(Cl)=O>ClCCl>[CH2:23]([O:22][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][C:14]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])([CH3:16])[CH3:15])[C:35]([CH2:36][O:54][CH2:55][CH3:56])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(CNc1c(N)cnc2cc(OCc3ccccc3)ccc12)NS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Agent: CCOCC(=O)Cl
Agent: COCCC(=O)Cl
Solvent: ClCCl
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O

Procedure:
A modification of the general method described in Part C of Example 50 was followed using N-[2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]methanesulfonamide (12.6 g, 30.4 mmol) in lieu of tert-butyl {4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate and ethoxyacetyl chloride (3.33 mL, 30.4 mmol) in lieu of methoxypropionyl chloride. The crude product was dissolved in dichloromethane (300 mL), and the resulting solution was washed with water (2×100 mL) and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a brown oil. The oil was purified by column chromatography on silica gel (eluting with 97.5:2.5 chloroform:methanol) to provide 12.4 g of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a beige foam.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10](=[O:21])[C@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CC(O)C.[Al](OC(C)C)(OC(C)C)OC(C)C>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[C:7]([C@@H:10]([OH:21])[C@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH3:12])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)c1ccc2c(c1)OCC2
Agent: CC(C)O[Al](OC(C)C)OC(C)C
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: C[C@@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccc2c(c1)OCC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
(R)-t-butyl 1-(2,3-dihydrobenzofuran-6-yl)-1-oxopropan-2-ylcarbamate (306d, 2.21 g, 7.59 mmol) was dissolved in propan-2-ol (6.35 mL, 83.4 mmol) and toluene (10 mL). Al(OiPr)3 (0.310 g, 1.52 mmol) was added, and the reaction vessel was capped and flushed with argon. The mixture was stirred at 50° C. overnight. Then another portion of Al(OiPr)3 (330 mg) was added, and stirring was continued for 5 h. The mixture was cooled to r.t., and partitioned between aq. HCl (1N, 25 ml) and ethyl acetate (80 ml). The organic layer was separated and dried. The solvent was removed in vacuo and purified by flash chromatography on silica gel with n-heptane/ethyl acetate (6:4) to give 1.58 g (71%) of subtitle compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-].[CH2:10]([N:17]1[CH2:23][CH2:22][CH2:21][O:20][CH:19]([CH2:24]Cl)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(O)CCC.C(Cl)Cl>[CH2:10]([N:17]1[CH2:23][CH2:22][CH2:21][O:20][CH:19]([CH2:24][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClCC1CN(Cc2ccccc2)CCCO1
Reactant: Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Solvent: ClCCl
Product: c1ccc(CN2CCCOC(CNc3ccccc3)C2)cc1
Temperature: 110 °C

Procedure:
Aniline (2.59 mL, 28.4 mmol) and NaI (4.06 g, 27.1 mmol) were added to a solution of 4-benzyl-2-chloromethyl-1,4-oxazepane (79) (6.49 g, 27.1 mmol) in n-butanol (68 mL, 0.4 M), and the reaction was heated to 110° C. until the reaction was judged complete by TLC (4 h). The reaction was cooled to room temperature, and water and CH2Cl2 were added. The organic layer was removed, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to achieve (4-benzyl-1,4-oxazepan-2-ylmethyl)-phenyl amine 80, which was used without purification in the next reaction. 1H NMR (partial, CDCl3) 4.08-3.86 (3H, m), 3.80 (1H, d, J=13.3 Hz), 3.73 (1H, d, J=13.3 Hz), 3.22-3.05 (2H, m), 2.95-2.70 (3H, m), 2.64 (1H, dd, J=13.6, 7.6 Hz), 2.1-1.9 (2H, m) ppm. 13C NMR (CDCl3) 148.33, 139.38, 129.28, 129.11, 128.46, 127.23, 117.44, 113.13, 76.70, 67.49, 62.92, 59.35, 54.76, 46.93, 30.75 ppm. LRMS: 296.68.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[C:15]([C:17]([N:19]3[CH2:23][CH2:22][C@@H:21]([O:24][CH3:25])[CH2:20]3)=[O:18])[S:16][C:9]=12.[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([OH:36])=[CH:31][CH:30]=2>CN(C=O)C>[CH3:25][O:24][C@@H:21]1[CH2:22][CH2:23][N:19]([C:17]([C:15]2[S:16][C:9]3[C:10](=[N:11][CH:12]=[CH:13][C:8]=3[O:36][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:26])=[CH:35]4)[CH:14]=2)=[O:18])[CH2:20]1
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5[nH]c(C)cc5c4)c3s2)C1
Temperature: 90 °C
Yield: 84 %

Procedure:
Cs2CO3 (0.495 g, 1.52 mmol) was added to a solution of (3R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-pyrrolidin-1-yl)-methanone (0.228 g, 0.76 mmol) and 2-methyl-1H-indol-5-ol (0.223 9, 1.52 mmol) in DMF (5 mL), and the resulting solution was heated to 90° C. After 20 h the reaction was quenched with water, EtOAc was added, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4 then concentrated. The resulting material was purified on silica gel by flash column chromatography, eluting with CH2Cl2/MeOH (98/2) to afford the title compound as a white solid (0.26 g, 84%). MS: 408.8 (MH+); HPLC Rf: 5.394 min.; HPLC purity: 97%.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[N:11][CH:12]=1)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH:10]=[N:11][CH:12]=1)#[CH:5]
Reactant: CC(C)(C)OC(=O)Nc1cncc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cncc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
Into a reaction flask were added tert-butyl {5-[(trimethylsilyl)ethynyl]pyridin-3-yl}carbamate (2.0 g, 6.9 mmol), methanol (25 mL), and a solution of potassium carbonate (7.1 g, 52 mmol) in water (25 mL). The reaction mixture was stirred at rt overnight. The solvent was removed under vacuum and the residue was diluted with EtOAc and water. After separation, the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product as a white powder (1.0 g, 67%). LCMS for C12H15N2O2 (M+H)+: m/z=219.0.