Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:23])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][CH2:19][CH2:20][OH:21])=[C:13]([CH3:22])[CH:12]=2)=[C:5]2[CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH2:27][C:4]=12)[CH3:2].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:23])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][CH2:19][CH2:20][O:21][S:40]([CH3:39])(=[O:42])=[O:41])=[C:13]([CH3:22])[CH:12]=2)=[C:5]2[CH2:24][CH2:25][C:26]([CH3:28])([CH3:29])[CH2:27][C:4]=12)[CH3:2]
Reactant: CCc1sc(C(=O)CCc2cc(C)c(CCCO)c(C)c2)c2c1CC(C)(C)CC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(C(=O)CCc2cc(C)c(CCCOS(C)(=O)=O)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
A solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-[4-(3-hydroxy-propyl)-3,5-dimethyl-phenyl]-propan-1-one (135 mg, 0.328 mmol, Example 335) in DCM is treated with DIPEA (70 mg, 0.525 mmol) followed by methanesulfonylchloride (45 mg, 0.394 mmol). The mixture is stirred at rt for 1.5 h before it is diluted with DCM and washed with 0.5 M aq. citric acid solution followed by brine. The organic extract is dried over MgSO4, filtered and the solvent of the filtrate is evaporated to give methanesulfonic acid 3-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2,6-dimethyl-phenyl}-propyl ester (165 mg) as a yellow resin; LC-MS: tR=1.20 min, [M+1]+=491.36.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:23]=[C:24]([C:25]3[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=3)[C:18]=2[N:17]=1>>[Br:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:16]3[NH:17][C:18]4[C:24]([C:25]5[CH:26]=[C:27]([F:33])[C:28]([F:32])=[C:29]([F:31])[CH:30]=5)=[CH:23][C:22]([C:34]([F:37])([F:35])[F:36])=[CH:21][C:19]=4[N:20]=3)[C@@H:10]([CH3:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(c2ncccc2Br)CCN1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Product: C[C@H]1CN(c2ncccc2Br)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
The piperazine from step (a) above (51 mg, 0.2 mmol) reacted with 2-chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (53 mg, 0.15 mmol, Example 51b) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 570 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8]Cl.[Br-:11].[Li+].CCCCCCC>O>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][Br:11]
Reactant: [Br-]
Reactant: COC(=O)C=CCCCCl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: O
Product: COC(=O)C=CCCCBr
Reaction time: 6 h
Yield: 83 %

Procedure:
In an atmosphere of nitrogen, 6-chloro-2-hexenoic acid methyl ester (4Cl); 188.8 g {GC purity; 83.6%, pure amount; 157.9 g (0.971 mol)}, lithium bromide (126.5 g, 1.457 mol) and heptane (16 ml) were added to a 500 ml capacity flask, followed by stirring for 6 hours under heptane reflux. After completion of the reaction, heptane was added as an extraction solvent and water was added thereto to separate the organic layer. The solvent was evaporated under a reduced pressure using an evaporator, and then the residue was distilled under a reduced pressure (70 to 80° C./0.1 ton) to obtain 6-bromo-2-hexenoic acid methyl ester (4Br); 203.4 g {GC purity; 82.3%, pure amount (4Br); 167.5 g (0.809 mol, yield 83%/(4Cl)}.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:33][C:34]([CH3:39])([CH3:38])[C:35](=[S:37])[NH2:36].O>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:37][C:35]([C:34]([CH3:39])([CH3:38])[CH3:33])=[N:36][C:9]=2[C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: CC(C)(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (30 g, 85.9 mmol) (Intermediate 20) in DMA (300 mL), NBS (15.3 g, 85.9 mmol) was added. The reaction mixture was stirred at rt for 1 h. Then 2,2-dimethylpropanethioamide (11.0 g, 94.5 mmol) was added at 0° C. The mixture was stirred at rt for 2 h. The mixture was poured into water and extracted with EtOAc (200 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound. (11 g, 35.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (d, J=5.27 Hz, 1H), 8.12-8.19 (m, 1H), 7.12-7.25 (m, 2H), 6.80-6.88 (m, 2H), 5.85-5.98 (m, 1H), 5.20-5.37 (m, 2H), 4.61-4.67 (m, 2H). MS (ES+): 447 [M+H]+.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[N+:15]([C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)([O-:17])=[O:16].O>C(#N)C>[N+:15]([C:18]1[N:19]=[CH:20][N:21]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=[O:8])[CH:22]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: O=C1CCCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCCC1n1cnc([N+](=O)[O-])c1
Yield: 56.2 %

Procedure:
84.0 ml (0.736 mol) of 2-chlorocyclohexanone and 92.54 g (0.670 mol) of potassium carbonate were added to a suspension of 75.16 g (0.885 mol) of 4-nitroimidazole in 1 l of acetonitrile. The obtained mixture was heated under reflux for 18 hours and cooled by allowing to stand, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The obtained organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was triturated with ethyl acetate to give 86.46 g of the title compound as a light-brown powder (yield: 62%).
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].[C:20]([NH:23][CH2:24][C:25](O)=[O:26])(=[O:22])[CH3:21].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:20]([NH:23][CH2:24][C:25]([NH:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17])=[O:26])(=[O:22])[CH3:21]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Reactant: CC(=O)NCC(=O)O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCC(=O)NC[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-C-(Aminomethyl)thymidine (4) (0.025 g, 0.1 mmol), N-acetylglycine (0.023 g, 0.2 mmol) and TSTU (0.09 g, 0.3 mmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL) at ambient temperature. Diisopropylethylamine (0.065 g, 0.5 mmol, 0.087 mL) was then added and the reaction mixture stirred for 18 hours at ambient temperature. The solvent was then removed under vacuum and the residue re-dissolved in 9:1 dichloromethane:methanol and eluted through a flash silica gel column with 9:1 dichloromethane:methanol. The title compound (19) was obtained as an amorphous solid on removal of solvent from the appropriate fractions (0.023 g). δH(300 MHz, CD3OD) 7.78(1H, s, H-6), 6.26(1H, dd, H-1′), 4.48(1H, dd, H-3′), 3.83(2H, s, glycyl CH2), 3.60(2H, 2d, H-5′), 3.58(1H, d, 4′-C—CH2), 3.42(1H, d, 4′-C—CH2), 2.33(2H, m, H-2′), 2.00(3H, s, CH3CO), 1.86(3H, s, 5-CH3); ES +ve m/z 393(M+Na)+.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[CH3:4].[CH2:5]([NH2:9])[CH2:6][CH2:7][CH3:8]>C1(C)C=CC=CC=1>[CH2:1]([N:9]1[CH2:8][CH:7]=[CH:6][CH2:5]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: C/C=C\C
Solvent: Cc1ccccc1
Product: CCCCN1CC=CC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a solution of 60.0 g of the cis-2-butene derivative solution prepared in Example 1 and 250 g of toluene in a round flask reactor, 117.0 g (1.6 mol) of butylamine was added dropwise with stirring for 30 min. at about 5° C. using an ice-bath. After 2 hours of stirring, the crystallized solid was removed by filtration; 42.0 g of 35% HCl (aq) was added to the filtrate, and then excess benzylamine hydrochloride was removed by filtration or extraction. After the solvent was evaporated under reduced pressure, 46.1 g of 1-butyl-3-pyrroline (yield 92.0%) was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[ClH:24]>CO.CCOCC>[ClH:24].[ClH:24].[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=c1[nH]c2ncccc2n1C1CCNCC1
Reaction time: 2 h

Procedure:
2-Oxo-1-(1-tert-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine (1.03 g, 3.23 mmol) was dissolved in methanol (25 mL) and a solution of 2 N hydrochloric acid in ether (8 mL) was added at room temperature. After 2 h, the volatiles were removed in vacuo, to give the title compound (0.92 g). MS 219 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.01 (dd, J=6, 1 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.28 (dd, J=8, 6 Hz, 1H), 4.60 (m, 1H), 3.59 (d, J=12 Hz, 2H), 3.21 (t, J=12 Hz, 2H), 2.70 (dq, J=13, 4 Hz, 2H), 2.12 (d, J=13 Hz, 2H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>CN(C)C=O>[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=2)=[CH:7][CH:6]=1
Reactant: CNCCc1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CNCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 85 °C
Yield: 22.7 %

Procedure:
Combine 4-(2-methylamino-ethyl)-phenol (1.0 g, 6.6 mmol), 6-chloronicotinamide (1.0 g, 6.6 mmol), and cesium carbonate (4.3 g, 13.2 mmol) in N,N-dimethylformamide (30 mL), stir and heat at 85° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator to yield the crude product (1.3 g). The crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform then ethanol to yield 6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide (0.4 g, 1.5 mmol): 1H NMR (DMSO-d6, 300.00 MHz): 8.58 (d, 1H); 8.22 (dd, 1H); 7.26-7.23 (m, 2H); 7.05-7.02 (m, 3H); 3.32 (br, 2H); 2.69 (m, 5H); 2.29 (m, 4H) m/z=271.87 (M+1); HPLC=99% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[I:14]Cl>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:10]([F:11])([F:12])[F:13])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[I:14]
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Reactant: ClI
Solvent: ClCCl
Product: N#Cc1cc(I)c(N)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 18.1 %

Procedure:
4-Amino-3-trifluoromethylbenzonitrile (100 mg, 0.54 mmol) and ICl (1.1 eq, 0.58 mmol, 96.00 mg) were added methylene chloride. The mixture was stirred for 12 hr. The reaction mixture was purified according to step 2 of Example 8 to give a title compound (30.5 mg, 18.10%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[N:4][C:5]([S:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>CN(C)C=O>[CH3:21][S:22]([O:14][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[C:5]([S:9][CH2:10][CH:11]([CH3:12])[CH3:13])[N:4]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CSc1nc(O)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CSc1nc(OS(C)(=O)=O)c(Cl)cc1Cl
Temperature: 50 °C
Yield: 73.8 %

Procedure:
6.0 g of 3,5-dichloro-6-isobutylthio-2-pyridinol and 3.0 g of anhydrous sodium carbonate were suspended in 25 ml of N,N-dimethylformamide, followed by stirring. 3.3 g of methanesulfonyl chloride was added dropwise to the suspension at 10° C. The obtained mixture was allowed to stand to lower the temperature to room temperature, heated to 50° C. and stirred for 2.5 hours. The reaction mixture was poured into 200 ml of chilled water and extracted with ether twice. The ether layer was washed with 5% aqueous caustic soda and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography (with n-hexane and toluene) to obtain 5.8 g of objective 3,5-dichloro-6-isobutylthio-2-pyridyl methanesulfonate as a colorless oil (yield: 73.8%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([F:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Si](C=[N+]=[N-])(C)C>CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:19])=[O:16])=[CH:13][C:12]([F:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(F)ncc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To 44 g of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid in 100 mL of methanol and 300 mL of chloroform at 0° C. was added 200 mL of 2 M (trimethylsilyl)diazomethane in hexanes. After allowing the reaction to warm to ambient temperature and stirring for 2 hours, the solvents were removed and the crude product purified by passing through a plug of silica gel with chloroform The product was then recrystallized from hexanes to give 32.6 g (73%) of 5-tert-butoxycarbonylamino-2-fluoro-isonicotinic acid, methyl ester: melting point 104 105° C. (decomposed); mass spectrum (m/e): M+H 270.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][C:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)([CH3:17])[CH3:16].[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH:40]=O)=[N:32]1.N1CCCCC1>CO>[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](/[CH:40]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][C:15]([N:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]4)([CH3:17])[CH3:16])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:32]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1C#CC(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
A solution of tert-butyl 4-[4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)-2-methylbut-3-yn-2-yl]piperazine-1-carboxylate (0.113 g, 0.273 mmol) in methanol (1 mL) was added with 1H-indazole-3-carboxaldehyde (0.0399 g, 0.273 mmol) and piperidine (0.0186 g, 0.218 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}-2-methylbut-3-yn-2-yl)piperazine-1-carboxylate (0.136 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][NH:12][C:11](=[O:17])[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH:18]1([C:21]2[N:22]=[C:23]3[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]3[C:32]=2[CH3:33])[CH2:20][CH2:19]1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:16][C:15]3[CH:14]=[CH:13][N:12]([C:26]4[CH:27]=[CH:28][C:23]5[N:24]([C:32]([CH3:33])=[C:21]([CH:18]6[CH2:20][CH2:19]6)[N:22]=5)[CH:25]=4)[C:11](=[O:17])[C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(C2CC2)nc2ccc(B(O)O)cn12
Reactant: O=c1[nH]ccc2oc(-c3ccc(Cl)cc3)cc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc4oc(-c5ccc(Cl)cc5)cc4c3=O)cn12
Temperature: 50 °C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
A mixture of 2-(4-chlorophenyl)furo[3,2-c]pyridin-4(5H)-one (100 mg), (2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)boronic acid (106 mg), copper(II) acetate (4.99 mg), pyridine (0.066 mL), MS-4A (48.9 mg) and DMF (5.0 mL) was stirred at room temperature for 4 hr and at 50° C. overnight. After filtration of the obtained mixture through Celite, the filtrate was poured into 1 N hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained solid was washed with ethanol to give the title compound (10.0 mg) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17]S(C)(=O)=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:22][C:23]([F:41])([F:40])[C:24]1[CH:25]=[C:26]([CH2:34][S:35]([NH:38][CH3:39])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:41][C:23]([F:22])([F:40])[C:24]1[CH:25]=[C:26]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:34][S:35]([N:38]([CH2:17][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1)[CH3:39])(=[O:36])=[O:37]
Reactant: COC(=O)c1cc(CS(C)(=O)=O)nn1-c1ncccc1Cl
Reactant: CNS(=O)(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(CN(C)S(=O)(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nn1-c1ncccc1Cl
Temperature: 50 °C
Reaction time: 12 h

Procedure:
5.00 g (14.4 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-[(methylsulphonyl)methyl]-1H-pyrazole-5-carboxylate were dissolved in 50 ml of acetonitrile, and 4.64 g (14.4 mmol) of 1-[3,5-bis(trifluoromethyl)phenyl]-N-methylmethanesulphonamide were added a little at a time at room temperature. Then 2.40 g (17.35 mmol) of potassium carbonate were added to the reaction solution, and the mixture was stirred at 50° C. for 12 hours. After cooling to room temperature, the reaction solution was freed from the solvent under reduced pressure. 250 ml of water were added to the residue, and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic phases were dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by chromatography. (logP: 3.83; MH+: 571; 1H-NMR (400 MHz, DMSO, δ, ppm): 2.79 (s, 3H), 3.74 (s, 3H), 4.43 (s, 2H), 4.80 (s, 2H), 7.06 (s, 1H), 7.70 (dd, 1H), 8.12 (s, 2H), 8.15 (s, 1H), 8.26 (d, 1H), 8.57 (d, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][N:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:11]2.CN(C)[CH:24]=[O:25].Cl>CCCCCC.CCOCC>[C:16]1([N:10]2[CH2:9][C:8]3[C:7]([CH:24]=[O:25])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc2c1CN(c1ccccc1)C2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cccc2c1CN(c1ccccc1)C2
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
2.3 ml (3.7 mmol) of a 1.6 molar solution of butyllithium in hexane are added to 14 ml of dry ether in a dry apparatus under argon. A solution of 930 mg (3.4 mmol) of 4-bromo-2-phenylisoindoline in 10 ml of dry ether is then added dropwise at -70° C. The mixture is stirred at -70° C. for 30 minutes, and 0.3 ml of dry dimethylformamide in 0.5 ml of ether is added. The mixture is stirred at 70° C. for 3 hours and heated to -5° C., and 13.6 ml of 1N hydrochloric acid are added dropwise. 50 ml of ether are added and the mixture is separated. The aqueous phase is extracted by shaking with ether and the combined ether phases are washed once with water, dried and concentrated. 600 mg of yellowish crystals of melting point 120°-122° C. are obtained.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1O.CCN(C(C)C)C(C)C>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[O:5][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Oc1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCOc2ccc(F)cc2F)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), 2,4-difluorophenol (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(2,4-difluorophenoxy)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=397.1). 1H NMR (DM50-d6, 400 MHz) δ 4.41 (m, 2H), 4.53 (m, 2H), 6.63 (m, 1H), 6.72 (m, 1H), 6.99 (m, 1H), 7.23 (m, 4H), 7.55 (br s, 2H, NH2), 7.92 (s, 1H). Anal. calculated for (C19H14F2N6O2+0.5H2O): C, 56.30; H, 3.73; F, 9.37; N, 20.73; 0, 9.87. Found C, 56.36; H, 3.59; N, 18.51.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](OC(OCC)OCC)C.C1CCN2C(=NCCC2)CC1>ClCCCl>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][C:25]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[N:1]=[CH:34]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Reactant: CCOC(OCC)OCC
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-n2cnc3cc(Oc4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1

Procedure:
2-Amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide [Example C1] (50 mg, 0.11 mmol) was dissolved in 1,2-dichloroethane (5 ml) and treated with triethylorthoformate [Aldrich] (2 ml) then heated to reflux for 12 h. The mixture was cooled and DBU (0.1 ml) introduced. The solvent was evaporated then the residue purified by flash chromatography on silica gel (eluting with ammonia-methanol-dichloromethane) to obtain the title compound;