Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:3]=1[C:4]([N:6]([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]([C:26]1[CH:38]=[CH:37][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[CH:28][CH:27]=1)#[N:25]>CN(C)C=O>[C:24]([C:26]1[CH:38]=[CH:37][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:17][C:15]2[CH:14]=[CH:13][C:3]([C:4]([N:6]([CH:10]([CH3:11])[CH3:12])[CH:7]([CH3:8])[CH3:9])=[O:5])=[C:2]([OH:1])[CH:16]=2)=[CH:28][CH:27]=1)#[N:25]
Reactant: CC(C)N(C(=O)c1ccc(O)cc1O)C(C)C
Reactant: N#Cc1ccc(OCCCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)C(C)C
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A solution of 2,4-dihydroxy-N,N-bis(1-methylethyl)benzamide (3 g, 12.7 mmol) in 30 mL of N,N-dimethylformamide is treated with cesium carbonate (4.97 g, 15.2 mmol), and 5-(4-cyanophenoxy)pentyl bromide (3.4 g, 1.27 mmol) and stirred at 40° C. for 24 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford a yellow foam. This material is purified by chromatography on silica gel (30 g) with 30-70% ethyl acetate/hexane as the eluent to afford 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide as colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:4]([F:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 4-chloro-2-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenol (130 mg, 0.36 mmol, 1.0 eq) and Cs2CO3 (175 mg, 0.54 mmol, 1.5 eq) in 2-butanone (20 mL) was added ethyl 2-bromoacetate (59.7 mg, 0.36 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 h. Water was then added and the aqueous layer extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (80 mg, 50%).
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[CH:8][O:7][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:12][O:11][C:5]1[C:6]2[O:7][CH:8]=[CH:9][C:10]=2[C:2]([O:1][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1
Reactant: COc1ccc(O)c2ccoc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(OC)c2occc12

Procedure:
A mixture of 4-hydroxy-7-methoxybenzo[b]furan (2.0 g, 12.2 mmol; prepared according to Eur. J. Med. Chem. 1981, 16, 563), ethyl bromoacetate (2.2 g, 13.2 mmol), potassium carbonate (2.0 g, 14.5 mmol) and 2-butanone (50 mL) was refluxed for 10 h, then filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, chloroform) affording ethyl (7-methoxybenzo[b]furan-4-yloxy)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=4)[CH2:29][CH2:30]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
A solution of 4-(4-chlorophenoxy)benzaldehyde (0.119 g, 0.510 mmol) and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.126 g, 0.510 mmol) in 1,2-dichloroethane (5.00 mL) was treated with sodium triacetoxyborohydride (0.424 g, 2.00 mmol) and HOAc (0.0300 mL, 0.500 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with saturated NaHCO3 aqueous solution (10 mL) and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo and purified by preparative TLC plates using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product (53.0 mg, 23.0%): 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.34–7.19 (m, 7H), 6.98–6.87 (m, 5H), 3.50 (s, 2H), 2.98 (d, 2H, J=11.8 Hz), 2.58–2.44 (m, 2H), 2.10–1.98 (m, 2H) 1.83–1.76 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 463.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][S:7][C:8]=1/[CH:9]=[CH:10]\[S:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(O)=[O:2].Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1>>[N:32]1([C:1]([C:4]2[N:5]=[CH:6][S:7][C:8]=2/[CH:9]=[CH:10]\[S:11][C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:2])[CH2:35][CH2:34][CH2:33]1
Reactant: C1CNC1
Reactant: O=C(O)c1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: O=C(c1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CCC1
Yield: 84.5 %

Procedure:
In the same manner as in step c) in Example 3, 594 mg of the title compound was prepared from 644 mg of 4-carboxy-5-((Z)-2-tritylthioethen-1-yl)thiazole and 168 mg of azetidine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc(F)cc1

Procedure:
Using the procedure of Example 75, a mixture of 11.2 g (0.1 mole) of 4-flurophenol and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 50 ml of toluene gave, after recrystallization from benzene, 15.0 g (79%) of the title compound as a white solid, mp 82.5°-85.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[K+].[K+].[C:17]([O:20][CH2:21][CH2:22]Br)(=[O:19])[CH3:18]>CC(C)=O.C(OCC)C>[C:17]([O:20][CH2:21][CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10])(=[O:19])[CH3:18]
Reactant: Cc1cc(C=O)ccc1O
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(=O)OCCOc1ccc(C=O)cc1C
Yield: 97.5 %

Procedure:
A mixture of 4-hydroxy-3-methyl-benzaldehyde (7.0 g, 51.4 mmol), K2CO3 (21.32 g, 154.2 mmol) and 2-bromoethyl acetate (25.8 g, 154.2 mmol) in acetone (250 mL) is refluxed for 18 h before it is diluted with diethyl ether (300 mL) and washed with water (3×250 mL). The washings are extracted with diethyl ether (200 mL). The combined organic extracts are dried over MgSO4 and concentrated. The remaining residue is purified by column chromatography on silica gel eluting with heptane/EA 1:1 to afford the title compound (11.14 g) as colourless solid. 1H NMR (CDCl3): δ 9.85 (s, 1H), 7.72-7.67 (m, 2H), 6.92-6.88 (m, 1H), 4.51-4.46 (m, 2H), 4.29-4.25 (m, 2H), 2.27 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[O:15]1[CH2:18][C:17](=[O:19])[CH2:16]1>C1COCC1.C(OCC)(=O)C>[Cl:9][C:3]1[CH:4]=[C:5]([Cl:8])[N:6]=[CH:7][C:2]=1[C:17]1([OH:19])[CH2:18][O:15][CH2:16]1
Reactant: Clc1cc(Cl)c(Br)cn1
Reactant: O=C1COC1
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(c2cnc(Cl)cc2Cl)COC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyridine (CAN 849937-96-8, 15 g, 66.1 mmol) in dry THF (300 ml) cooled down to −15° C. under an argon atmosphere was added isopropyl magnesium chloride, lithium chloride complex (53.4 ml, 69.4 mmol) and the mixture was stirred at −15° C. for 1 hour. Then oxetan-3-one (5.24 g, 72.7 mmol) was added neat to the reaction mixture cooled at −15° C., reaction mixture was stirred and let to warm up to room temperature overnight. Reaction was quenched by addition of water and stirred for 5 minutes. Reaction was diluted with ethyl acetate and was transferred into a separatory funnel. The organic phase was extracted with a saturated aqueous solution of ammonium chloride and the organic phase was collected. The aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (10.5 mg, 72%). MS (ESI, m/z): 220.4 (M+H+)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][N:14]=[C:13]([NH2:16])[CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.N1([C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])C2C=CC=CC=2N=N1>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][N:14]=[C:13]([NH:16][C:36](=[O:37])[O:38][CH2:39][CH:40]=[CH2:41])[CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1cc(-c2ccc3cnccc3c2)on1
Reactant: C=CCOC(=O)n1nnc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)Nc1cc(-c2ccc3cnccc3c2)on1
Reaction time: 0.33 h
Yield: 53.2 %

Procedure:
To a solution of 5-(isoquinolin-6-yl)isoxazol-3-amine (0.10 g, 0.47 mmol) in 4 mL of DMF at 0° C. was added LiHMDS (0.57 mL, 1.0 M in THF). The mixture was stirred for 20 minutes. Allyl 1H-benzo[d][1,2,3]triazole-1-carboxylate (0.14 g, 0.71 mmol) (prepared as described by Katritzky, A. et al. J. Phys. Org. Chem. 1993, 6(10), 567-73 which is hereby incorporated by reference for all purposes as if specifically set forth herein) was added to the mixture. The mixture was stirred for 20 minutes. The reaction was quenched with 5 mL of aqueous NH4Cl. The mixture was extracted three times with 10 mL of EtOAc, and the combined organic extracts were washed with 20 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (20% to 50% EtOAc/hexanes) afforded allyl 5-(isoquinolin-6-yl)isoxazol-3-ylcarbamate (0.075 g, 0.25 mmol, 54% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 9.39 (s, 1H), 8.59 (d, J=5.7 Hz, 1H), 8.57 (s, 1H), 8.27 (d, J=8.6 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.45 (s, 1H), 6.03-5.95 (m, 1H), 5.39 (dd, J=1.4 Hz, 17.1 Hz, 1H), 5.27 (d, J=10.5 Hz, 1H), 4.68 (d, J=5.5 Hz, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][F:26])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:36]=[C:35]([C:37]#[C:38][CH2:39][CH2:40][O:41][CH3:42])[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]=1[NH2:43].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:27][C:28]1[CH:36]=[C:35]([C:37]#[C:38][CH2:39][CH2:40][O:41][CH3:42])[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]=1[NH:43][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][F:26])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(CCF)CC1
Reactant: COCCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(CCF)CC4)c(OC)cc23)c2c1OCO2
Yield: 59.9 %

Procedure:
This was prepared by the method described in example 4 using 4-chloro-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline (200 mg, 0.52 mmol), 5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-amine (146 mg, 0.57 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 1.10 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (187 mg, 60%) as colourless solid, NMR Spectrum:(CDCl3) 2.10 (quintet, 2H), 2.57 (m, 8H), 2.67 & 2.72 (dt, 2H), 2.74 (t, 2H), 3.41 (s, 3H), 3.60 (t, 2H), 3.98 (s, 3H), 4.23 (t, 2H), 4.51 & 4.63 (dt, 2H), 6.06 (s, 2H), 6.85 (s, 1H), 7.04 (s, 1H), 7.08 (s, 1H), 7.28 (s, 1H), 8.61 (s, 1H); Mass Spectrum: M+H+ 600/602
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:21])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:30]([C:34]1[CH:38]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:36][N:35]=1)([CH3:33])([CH3:32])[CH3:31].B(O)O>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([N:36]4[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:38][C:34]([C:30]([CH3:31])([CH3:33])[CH3:32])=[N:35]4)=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2c(=O)ccc3cc(B(O)O)ccc32)cc1
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2c(ccc(=O)n2Cc2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
1-(4-Methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-ylboronic acid (1.8 g, 5.8 mmol) was dissolved in CH2Cl2 (120 mL) and pyridine (10 mL) with molecular sieves (activated, 4 A) and the solution was kept overnight at RT. Commercially available ethyl 3-t-butyl-1H-pyrazole-5-carboxylate (1.2 g, 5.8 mmol), Cu(OAc)2 (1.1 g, 5.8 mmol) and molecular sieves (4 Å activated, powder) were added to the boronic acid solution and the reaction mixture was stirred open to the air at RT for 3 days. The reaction mixture was filtered through a pad of Celite®, and the filtrate was evaporated under reduced pressureand purified by silica gel column chromatography to yield ethyl 1-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-yl)-3-t-butyl-1H-pyrazole-5-carboxylate (2.5 g, 94% yield). LC-MS (EI) m/z: 460.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[ClH:10]>C(Cl)Cl>[C:2]([Cl:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:1])[CH3:3]
Reactant: Cl
Reactant: C=C(C)c1ccccc1
Solvent: ClCCl
Product: CC(C)(Cl)c1ccccc1

Procedure:
183 g of α-methyl styrene, dissolved in 600 ml of methylene chloride, were reacted with hydrogen chloride at a temperature of from -12 to -10° C. to yield α-cumyl chloride. The resulting solution was added dropwise at a temperature of -10° C. to a mixture of 3 g of anhydrous aluminum trichloride, 12 g of anhydrous iron trichloride, 0.5 g of phosphorus pentoxide and 1800 ml of methylene chloride in the course of 60 minutes, and the mixture was then stirred at -10° C. for a further 4 hours. To terminate the reaction, the reaction mixture was poured into 6 liters of water at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])=[N:10]2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10]2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1ccn(-c2ccc(OC)cc2)n1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccn(-c2ccc(OC)cc2)n1
Yield: 88.7 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-[E-2-(methoxycarbonyl) ethenyl]-1H-pyrazole-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl) carboxyamide (35 mg, 0.065 mmol) in 20 mL of absolute ethanol at ambient temperature was added 10% palladium on carbon catalyst (3.5 mg). This mixture was stirred under 1 atm of hydrogen gas for 3 h and then was filtered through a pad of celite and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 15 mg (42%) of the title compound as a white powder. LRMS (ES+): 534.9 (M+H)+.
Reaction SMILES: NCC(N1C2C(=CC(/C=C/[CH:16](C3C=C(Cl)C(F)=C(Cl)C=3)[C:17]([F:20])([F:19])[F:18])=CC=2)C=C1)=O.[Cl:30][C:31]1[CH:32]=[C:33]([CH:39]([C:62]([F:65])([F:64])[F:63])/[CH:40]=[CH:41]/[C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[N:47]([C:51](=[O:61])[CH2:52][NH:53][C:54](=[O:60])OC(C)(C)C)[CH:46]=[CH:45]3)[CH:34]=[C:35]([Cl:38])[C:36]=1[F:37].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:39]([C:62]([F:65])([F:63])[F:64])/[CH:40]=[CH:41]/[C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[N:47]([C:51](=[O:61])[CH2:52][NH:53][C:54](=[O:60])[CH2:16][C:17]([F:20])([F:19])[F:18])[CH:46]=[CH:45]3)[CH:34]=[C:35]([Cl:38])[C:36]=1[F:37]
Reactant: NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC(F)(F)F)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(E)-2-Amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)ethanone (BI23): To a stirred solution of (E)-tert-butyl 2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)-2-oxoethylcarbamate (0.05 g, 0.09 mmol) in CH2Cl2 (5.0 mL) was added TFA (0.01 mL) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound which was used in the next step without further purification (50 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=[O:13])[CH:5]=[C:6]([F:8])[CH:7]=1.S(=O)(=O)(O)O.[CH3:23]O>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([O:14][CH3:23])=[O:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CO
Reactant: O=C(O)c1cccc(-c2cc(F)cc(F)c2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(-c2cc(F)cc(F)c2)c1
Temperature: 25 °C

Procedure:
To a mixture of 3-(3,5-difluorophenyl)benzoic acid (2.3 g) in anhydrous methanol (46 ml) was added concentrated sulfuric acid (2.3 ml). The mixture was heated under reflux for four hours. After cooling to ambient temperature, the mixture was concentrated. Ethyl acetate (200 ml) and water (100 ml) were added and the layers were separated. The organic layer was successively washed with 20% aqueous potassium carbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with hexane-ethyl acetate (10:1) as an eluent. The fractions containing the object product were collected and evaporated in vacuo to give methyl 3-(3,5-difluorophenyl)benzoate.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([N:18]3[CH2:24][C:23]4([CH3:26])[CH2:25][CH:19]3[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22]4)=[O:17])=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)C.[OH-].[Na+].Cl>C(O)C>[CH3:26][C:23]12[CH2:25][CH:19]([N:18]([C:16]([C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][CH2:5][C:4]([OH:29])=[O:3])[CH:8]=[CH:9]4)=[O:17])[CH2:24]1)[CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22]2
Reactant: CCOC(=O)CCn1ccc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc3c(ccn3CCC(=O)O)c2)C1
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of 3-[5-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-indol-1-yl]-propionic acid ethyl ester (80 mg, 0.2 mmol) in ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the resulting solution stirred for 2 h. The solution was acidified with 1N hydrochloric acid solution before the organic volatiles were removed in vacuo, and the aqueous residues were extracted with DCM (3×5 mL). The combined organic phases were dried (MgSO4), filtered, and evaporated in vacuo. The resulting solid was purified by preparative HPLC, dried in vacuo at 50° C. affording 55 mg (74%) of the title compound as a solid. MS-ESI m/z 369; 1H NMR (400 MHz, DMSO-d6) δ 0.94 (d, 3H), 1.04 (d, 3H), 1.13-1.17 (m, 4H), 1.28-1.38 (m, 2H), 1.43-1.45 (m, 1H), 1.60-1.63 (m, 1H), 1.75-1.79 (m, 1H), 2.24-2.32 and 3.25-3.26 (m, 1H), 2.74 (t, 2H), 3.27-3.35 (m) and 3.62-3.65 (m), 1H), 4.08-4.10 and 4.62-4.63 (m, 1H), 4.39 (t, 2H), 6.47-6.48 (m, 1H), 7.17-7.23 (m, 3H), 7.70 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[C:6]([Sn](CCCC)(CCCC)CCCC)[N:7]=1.Cl[C:22]1[S:23][CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28]>>[CH3:1][O:2][C:3]1[S:4][CH:5]=[C:6]([C:22]2[S:23][CH:24]=[CH:25][C:26]=2[N+:27]([O-:29])=[O:28])[N:7]=1
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc(OC)n1
Product: COc1nc(-c2sccc2[N+](=O)[O-])cs1

Procedure:
2-Methoxy-4-(3-nitrothiophen-2-yl)thiazole was prepared from 2-methoxy-4-(tributylstannyl)thiazole (1.0 g, 2.47 mmol) and 2-chloro-3-nitrothiophene (0.404 g, 2.47 mmol) according to protocol E. Retention time (min)=2.516, method [1], MS (ESI) 242.9 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11](=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C1COCC1>[C:21]([Si:24]([CH3:26])([CH3:25])[N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11](=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([CH3:23])([CH3:22])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCN(CC)C(=O)Oc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1ccc2c(ccn2[Si](C)(C)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diethyl-carbamic acid 1H-indol-5-yl ester (5.72 g, 24.6 mmol) is dissolved in THF (200 mL) and cooled to 0° C. The flask is purged with nitrogen and then 60% NaH (1.1 g, 27.5 mmol) is added and the mixture stirred in an ice bath for 30 minutes. At that point TBDMSCl (0.210 g, 1.39 mmol) is added and the reaction is allowed to stir overnight (14 hours). The reaction is quenched with a saturated solution of ammonium chloride and the mixture is diluted with ethyl acetate and water. The organic layer is removed, dried (sodium sulfate) and concentrated to obtain the title compound as an oil that is used without further purification. MS (ESI) m/z 347.21 (M+1).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[N:8]=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:15]=3[CH:16]=2)[S:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(OCC)(=O)C>[C:22]([N:5]([CH2:6][C:7]1[N:8]=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:15]=3[CH:16]=2)[S:10][CH:11]=1)[C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NCc1csc(-c2cc3cc(O)ccc3o2)n1
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1csc(-c2cc3cc(O)ccc3o2)n1)C(C)(C)C
Yield: 99.6 %

Procedure:
A mixture of 4-(tert-butylaminomethyl)-2-(5-hydroxybenzofuran-2-yl)thiazole (0.82 g) and acetic anhydride (0.75 g) in ethyl acetate (10 ml) was stirred under reflux for 4 hours. After being cooled, the resulting mixture was concentrated under reduced pressure. A solution of the resulting mixture in methanol (3 ml) and conc. ammonia water (1 ml) was stirred for 2 hours at ambient temperature, poured into brine, extracted with ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure to give 4-(N-acetyl-tert-butylaminomethyl)-2-(5-hydroxybenzofuran-2-yl)thiazole (0.93 g).