Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][N:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18])=O.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:18][C:9]3[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=3[N:7]=2)[CH:19]=[CH:20][N:21]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccnc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2oc(-c3ccnc(Cl)c3)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
To a mixture of 0.77 g of 2-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 20 ml of tetrahydrofuran and 0.80 g of triphenylphosphine, 1.32 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature, and the mixture solution was stirred for 1.5 hours at room temperature and then 1.5 hours at 60° C. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.60 g of 2-(2-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 21”).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1)=[O:4].[CH2:19]([C:21]([O-:23])=[O:22])[CH3:20].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O>[N:24]1([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)=[O:4])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[CH2:19]([C:21]([O-:23])=[O:22])[CH3:20]
Reactant: C1COCCN1
Reactant: O=C(CCl)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: O
Product: O=C(CN1CCOCC1)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 26 %

Procedure:
A solution of 80 mg (0.24 mmol) of 8-(2-chloro-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 420 μL (4.8 mmol) of morpholine is heated at 60° C. for 4 hours. Water is added and the solid is filtered and then purified by chromatography on silica (eluent dichloromethane/methanol 95/5) to give 24 mg (26%) of 8-(2-morpholin-4-yl-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a brown solid.
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4](C(N)CCN)=[N:3][CH:2]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O>>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:1][CH2:6][CH2:5][CH2:4][NH:3][C:2]1[N:3]=[CH:4][C:5]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[S:7][C:6]=2[N:1]=1
Reactant: NCCC(N)c1ncnc2sc3c(c12)CCCC3
Reactant: O=Cc1cccc(F)c1
Product: Fc1cccc(CNCCCNc2ncc3c4c(sc3n2)CCCC4)c1

Procedure:
The title compound was prepared (145 mg, 69%) from 3N-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine-4-yl)-1,3-diaminopropane(150 mg, 0.57 m. mol) and 3-fluorobenzaldehyde (70 mg, 0.57 mmol) by following the general procedure described for Preparation 3. 1H NMR (400 MHz, CDCl3):δ 8.40 (s, 1H), 7.30 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.20 (bs, 1H), 3.80 (s, 2H), 3.70 (m, 2H), 2.80 (m, 6H), 1.80 (m, 6H), 1.70 (bs, 1H). MS (ESI) m/z: Calculated: 370.49; Observed: 371.1 (M++1).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:10]1[C:4]2[C:3]3[C:11](=[O:12])[NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[O:20][C:2]=3[S:6][C:5]=2[CH2:7][CH2:8][CH2:9]1
Reactant: O=C(Nc1ccccc1O)c1c(Br)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1Nc2ccccc2Oc2sc3c(c21)CCCC3
Temperature: 140 °C
Reaction time: 4 h
Yield: 51.4 %

Procedure:
To a solution of 2-bromo-4,5,6,7-tetrahydro-N-(2-hydroxyphenyl)-benzo[b]thiophene-3-carboxamide (5.3 g) in dimethyl sulfoxide (50 ml) was added potassium carbonate (4.2 g) and the mixture was stirred at 140° C. for 4 hours. The completion of the reaction was confirmed by thin layer chromatography. The mixture was cooled to room temperature and the reaction mixture was poured into water (300 ml). After neutraition with hydrochloric acid, the mixture was extracted twice with chloroform and washed with saturated brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one (2.1 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:13])[CH3:12].O>ClCCCl>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:13])[CH3:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 50 °C
Yield: 73 %

Procedure:
2-Oxindole (3 g) was suspended in 1,2-dichloroethane and 3.2 mL acetyl chloride were slowly added. The resulting suspension was heated to 50° C. for 5 hours, cooled, and poured into water. The resulting precipitate was collected by vacuum filtration, washed copiously with water and dried under vacuum to give 2.9 g (73% yield) of the title compound as a brown solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14][CH2:13]1.C(OCC)(=O)C>ClCCl>[CH:16]12[O:9][CH:15]1[CH2:14][CH2:13][N:12]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[CH2:18][CH2:17]2
Reactant: O=C(OCc1ccccc1)N1CCC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC2OC2CC1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
18 g m-chloroperbenzoic acid was added to 10 g benzyl 2,3,6,7-tetrahydro-1H-azepine-1-carboxylate in 250 ml dichloromethane at 0° C. in several portions. The mixture was allowed to warm to RT over 2 h. 1 L ethyl acetate was added and the solution was extracted with aqueous sodium bicarbonate, 1N aqueous sodium hydroxide and brine. The organic layer was evaporated and the residue was purified by chromatographie on silica gel (ethyl acetate/hexanes 1:5) to yield 10.4 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=[O:6].[CH2:28]([Mg]Br)[CH3:29]>O1CCCC1.C(OC)(C)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:28][CH3:29])[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCC(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (1.00 g, 2.7 mmol) in tetrahydrofuran (20 ml) at 0° C. was added ethylmagnesium bromide soln in t-butylmethyl ether. (4.0 ml, 4.0 mmol) dropwise over 5 min. The reaction was allowed to stir 20 min at 0° C. The reaction was quenched with NH4Cl aq. sat soln. The solid was removed by filtration. The filtrate was concentrated and purified by silica gel chromatography: ISCO, 120 g column, 20-30% EtOAc/Hex, followed by 40% (3% EtN3 in EtOAc)/Hex to give 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)propan-1-ol. MS (ESI) m/z: Calculated: 404.1; Observed: 405.1 (M++H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:26]1([CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:11]3[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)=[CH:17][CH:18]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(OCCCN2CCCCC2)ccc1CN1CCCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
4-[4-(3-Piperidin-1-yl-propoxy)-benzyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (D3) (2.27 g, 5.27 mmol) was dissolved in dichloromethane (10 ml), treated with trifluoroacetic acid (5 ml) and stirred at room temperature under argon for 2 hours. The solvent was removed in vacuo and the residue dissolved in methanol and passed down an SCX column (10 g) eluting with methanol followed by 0.88 ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo to afford the title compound (1.57 g).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[F:31][C:32]([F:38])([F:37])/[CH:33]=[CH:34]/[C:35]#[N:36].N12CCCN=C1CCCCC2>C(#N)C>[C:35]([CH2:34][CH:33]([N:2]1[CH:6]=[C:5]([C:7]2[CH:30]=[CH:29][C:10]3[N:11]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=4)[CH:12]=[N:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1)[C:32]([F:38])([F:37])[F:31])#[N:36]
Reactant: N#C/C=C/C(F)(F)F
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cn[nH]c4)ccc32)c1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCC(n1cc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cn1)C(F)(F)F
Temperature: 80 °C

Procedure:
To a solution of N-{3-[5-(1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt (20.0 mg, 0.0458 mmol) in acetonitrile (1 mL) was added (2E)-4,4,4-trifluorobut-2-enenitrile (8.3 mg, 0.069 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (14 μL, 0.092 mmol). The solution was stirred and heated at 80° C. for several hours. The reaction solution was concentrated under reduced pressure to dryness. The residue was dissolved in MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=522.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O)(=[O:18])[CH3:17]>>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:16](=[O:18])[CH3:17])=[CH:3][C:4]=2[F:15])=[N:9][CH:10]=1
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: CC(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine and (2-acetylphenyl)boronic acid. MS (ESI): mass calcd. for C18H14FN3O, 307.11; m/z found, 307.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.03 (d, J=1.2, 1H), 7.91 (m, 1H), 7.69 (d, J=7.5, 1H), 7.61 (m, 1H), 7.53 (d, J=7.5, 1H), 7.48 (d, J=8.2, 1H), 7.26 (d, J=12.4, 1H), 7.19 (dd, J=8.0, 1.3, 1H), 6.75 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36]>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)=[O:36])[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: O=C(Cl)c1ccccn1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccccn4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
Triethylamine (0.7 g, 7.4 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and picolinoyl chloride hydrchloride (0.5 g, 2.5 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with H2O (30 mL). The mixture was filtered, and the solid was slurried with hot methanol (15 mL) to give pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.6 g, 78%): mp 254-256° C.; 1H NMR (DMSO-d6) δ 2.01-2.06 (m, 1H), 2.32-2.66 (m, 2H), 2.86-3.01 (m, 1H), 4.43-4.65 (m, 4H, 2CH2), 5.12-5.19 (dd, J=4.7 and 13.0 Hz, 1H, CH), 7.45-7.64 (m, 4H, Ar), 7.97-8.07 (m, 2H, Ar), 8.65 (d, J=4.2 Hz, 1H, Ar), 9.51 (t, J=5.8 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.17, 46.30, 51.57, 121.63, 122.02, 126.60, 128.28, 130.77, 131.58, 134.73, 137.79, 140.08, 148.44, 149.80, 164.16, 168.06, 170.99, 172.82; Anal. calcd. for C20H18N4O4: C, 63.49; H, 4.79; N, 14.81. Found: C, 63.32; H, 4.66; N, 14.80.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br)([O-:16])=[O:15].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][O:11][CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CC(C)(C)OC(=O)NCCO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOCc1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 22.5 %

Procedure:
To a solution of N-Boc-ethanolamine (477 mg) in tetrahydrofuran (10 mL), sodium hydride (118 mg, 60 wt %) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour under a nitrogen atmosphere. To the reaction mixture, 2-nitrobenzyl bromide (500 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour, and then further stirred at room temperature for 4 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 80 to 70% hexane in ethyl acetate) to obtain oily tert-butyl (2-((2-nitrobenzyl)oxy)ethyl)carbamate (C11, 154 mg).
Reaction SMILES: [C@@H:1]12[CH2:7][C:6](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:5]1[CH2:4][CH2:3][CH2:2]2.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+:35]([CH3:38])([O-:37])=[O:36].Cl>CCCCCCC>[N+:35]([CH2:38][C@:6]1([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][C@@H:1]2[C@H:5]1[CH2:4][CH2:3][CH2:2]2)([O-:37])=[O:36]
Reactant: CCOC(=O)C=C1C[C@H]2CCC[C@@H]12
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: CCCCCCC
Product: CCOC(=O)C[C@@]1(C[N+](=O)[O-])C[C@H]2CCC[C@H]21
Reaction time: 17 h
Yield: 87.6 %

Procedure:
The n-heptane solution (12.5 L) of the acrylic ester of Example 6 (0.921 Kg; 5.11 mol) was concentrated by distillation at atmospheric pressure to 36% of its original volume. The n-heptane was then replaced with tetrahydrofuran by atmospheric azeotropic distillation at constant volume. The reaction mixture was cooled to 20–25° C., then tetrabutylammonium fluoride trihydrate (2.10 Kg; 6.64 mol) and nitromethane (0.499 Kg, 8.18 mol) were added. The resulting brown solution was stirred at 20–25° C. for 17 hours. To the reaction mixture a 2M aqueous solution of hydrochloric acid (4.5 L) was added, causing the reaction temperature to rise by 8° C. n-Heptane (4.5 L) was added and the phases were separated. The organic layer was then washed with demineralised water (4.5 L) to give the title product (1.08 Kg) in 88% yield as an organic solution which is used directly in the next step.
Reaction SMILES: [C:1]([C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[C:1]([C:9]1[N+:14]([O-:24])=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(C(=O)c2ccccc2)n1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C(=O)c2ccccc2)[n+]1[O-]
Reaction time: 8 h

Procedure:
The 6-benzoyl-2-methylpyridine (3.9 g, 21 mmol), in 20 ml CHCl3, is added over 1 hour to 4.2 g (21 mmol) m-chloroperbenzoic acid (in 50 ml CHCl3). The temperature is kept below 25° as the mixture is stirred overnight. The reaction is diluted with CHCl3, washed with sat. NaHSO3, water, 20% NaHCO3 (2×) and then water, dried, stripped and finally titrated with hexane/ethyl acetate to give 6-benzoyl-2-methylpyridine N-oxide.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[CH2:12]([N:19]=[N+:20]=[N-:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[ClH:1].[CH2:12]([N:19]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3ccccc3)nn2)c[nH]1
Yield: 45.8 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.073 g, 0.423 mmol) was reacted with benzyl azide (0.068 g, 0.509 mmol) following the general procedure for click reactions outlined above to produce 4-[2-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-ethyl]-1H-imidazol-2-ylamine hydrochloride (0.059 g, 46%) as a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.83 (d, 1H), δ 7.37-7.24 (m, 5H), δ 6.44 (d, 1H), δ 5.54 (d, 2H), δ 2.96 (m, 2H), δ 2.83 (m, 2H) ppm; 13C (75 MHz, CD3OD) δ 163.7, 147.3, 146.4, 135.7, 128.8, 128.4, 127.9, 127.8, 126.5, 122.6, 109.1, 53.7, 24.1, 23.9 ppm; HRMS (ESI) calcd for C14H16N6 (M+) 269.1515. found 269.1513.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.[CH3:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.Cl[Si](C)(C)C.O>CN(C=O)C>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])=[CH:20][CH:19]=4)=[C:3](/[CH:1]=[CH:31]/[C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: Cc1ccc2ccccc2n1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of compound 5f (0.68 g, 1.7 mmol) and 2-methylquinoline (0.26 mL, 2.0 mmol) in DMF (5 mL) was added chlorotrimethylsilane (0.64 mL, 5.0 mmol) dropwise. The resulting mixture was stirred at 90° C. for 2 h. The reaction mixture was cooled, and water (20 mL) was added. The precipitated solid was collected by filtration, washed with MeOH (2×5 mL), and dried under high vacuum. Compound 5g was obtained as an orange solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C32H31 N5O3: 534.2 (M+H). found: 534.4.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C:13]2[O:41][C:16]3=[C:17]([NH2:40])[N:18]=[CH:19][C:20]([C:21]4[CH:22]=[N:23][N:24]([CH:26]5[CH2:31][CH2:30][CH:29]([O:32][Si](C(C)(C)C)(C)C)[CH2:28][CH2:27]5)[CH:25]=4)=[C:15]3[CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[NH2:40][C:17]1[N:18]=[CH:19][C:20]([C:21]2[CH:22]=[N:23][N:24]([C@H:26]3[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]3)[CH:25]=2)=[C:15]2[CH:14]=[C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:43])([F:1])[F:42])[CH:4]=3)[O:41][C:16]=12
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(-c3cnc(N)c4oc(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cc34)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[3,5-bis(trifluoromethyl)phenyl]-4-[1-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-7-amine (104 mg) in THF (2 mL) was treated with tetra-n-butylammonium fluoride (2.7 M in water, 0.20 mL, 0.56 mmol) and stirred at RT overnight. The solution was diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc and the combined organic fractions were dried over sodium sulfate and concentrated. Purification of the residue by ISCO chromatography (0 to 5% 7 N NH3/MeOH:EtOAc) afforded 33 mg (35%) of the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 1.48-1.60 (m, 2H) 2.01 (qd, J=12.7, 3.2 Hz, 2H) 2.10-2.26 (m, 4H) 3.73 (tt, J=10.9, 4.1 Hz, 1H) 4.26 (tt, J=11.9, 3.9 Hz, 1H) 7.88 (s, 1H) 7.91-7.94 (m, 2H) 8.00-8.03 (m, 1H) 8.12-8.15 (m, 1H) 8.67 (s, 2H); MS (ESI): 510.34 [M+H]+; HPLC tR=1.16 min (TOF: polar—3 min).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22](=[O:25])CC.BrCCO>O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:21][CH2:22][OH:25])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: OCCBr
Agent: [K+]
Solvent: O
Product: OCCOc1ccc(Oc2ccccc2)cc1
Temperature: 90 °C
Yield: 62 %

Procedure:
To a solution of 4-Phenoxyphenol (3 g, 16.1 mmol), Potassium carbonate (11.1 g, 80.6 mmol), and 2-Butanone (37.5 mL) was added 2-Bromoethanol (3.14 mL, 44.3 mmol). The resulting mixture was stirred and refluxed at 90° C. overnight under nitrogen. The mixture was poured into 30 mL water solution and extracted with ethyl acetate (EtOAc) (3×10 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (2.3 g, 62%): 1H NMR (400 MHz, CDCL3).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][C:13]1[N:18]=[C:17]2[S:19][C:20]3[CH2:21][N:22]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:24][C:25]=3[C:16]2=[C:15]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[C:14]=1[Cl:43].C(N(CC)CC)C>ClCCl>[CH2:26]([N:22]1[CH2:23][CH2:24][C:25]2[C:16]3[C:17]([S:19][C:20]=2[CH2:21]1)=[N:18][C:13]([CH2:12][NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[C:14]([Cl:43])[C:15]=3[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2c(Cl)c(CNS(=O)(=O)c3ccccc3)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Benzenesulfonyl chloride (0.156 g) was added to a mixture of the compound (0.35 g) obtained in Example 18B, triethylamine (0.096 g) and dichloromethane (8 ml) under ice-cooling, the mixture was stirred for 1 hour, the reaction mixture was washed successively with water, an aqueous saturated solution of sodium bicarbonate and water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to yield 7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-2-phenylsulfonylaminomethyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine (0.25 g, 55%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 153 to 154° C.