Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO.O>C(Cl)Cl>[OH:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(Cl)c2oc(Cc3ccc(O)cc3)c(C)c2c1O
Temperature: -78 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (100 mg, 0.29 mmole) in methylene chloride (5 mL) cooled to -78° C., was added dropwise over a period of 5 minutes a 1M solution of boron tribromide (0.3 mL; 0.3 mmole) in methylene chloride. The temperature was allowed to rise to room temperature and the reaction mixture was stirred for 3 hours. It was then cooled to -78° C. and methanol (2 mL) was added rapidly. The resulting solution was poured into water. The phases were separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 15% ethyl acetate in hexane to yield 63 mg gm (66%) of 2-(p-hydroxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran, mp. 142°-143° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.[NH:13]1[C:21]2[C:16](=[C:17]([C:22]3[CH:23]=[C:24]([NH2:37])[C:25]4[C:29]([CH:30]=3)=[N:28][N:27](C3CCCCO3)[CH:26]=4)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO>[NH:13]1[C:21]2[C:16](=[C:17]([C:22]3[CH:30]=[C:29]4[C:25]([CH:26]=[N:27][NH:28]4)=[C:24]([NH:37][C:10]([C:2]4[NH:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[O:12])[CH:23]=3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1H-Benzimidazole-2-carboxylic acid (available from Apollo Scientific, 25 mg, 0.151 mmol), O-(7-Azabenzatriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (63 mg, 0.17 mmol) and 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (50 mg, 0.15 mmol) were dissolved in anhydrous DMF (3 ml) and then treated with DIPEA (0.05 ml, 0.30 mmol). The reactions were then stirred at room temperature for 15 hours. The mixture was treated with methanol (3 ml) and then Macroporous-Tosic Acid (170 mg, 0.75 mmol) then stirred for 15 hours. The mixture was then treated with 0.88 ammonia solution (0.60 ml), stirred for 10 minutes, then filtered and solvent blown off under a stream of nitrogen. The crude residue was purified by Mass Directed Automated Preparative HPLC (Method B) to give after evaporation of solvents the title compound as a yellow solid (27 mg). LCMS (Method B) m/z 393 [MH+], Rt=1.04 min.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:45])[CH:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37]([C:39]4[O:40][CH:41]=[CH:42][C:43]=4[CH3:44])=[O:38])[CH:31]=3)[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:45])[CH:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37]([C:39]4[O:40][CH:41]=[CH:42][C:43]=4[CH3:44])=[O:38])[CH:31]=3)[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCNC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)C(CCC(=O)O)NC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 5-(ethylamino)-4-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoate (34 mg, 0.055 mmol) in 5 ml of methylene chloride was added 2 ml of TFA. The mixture was stirred at room temperature for 1 hour, and evaporated to dryness under reduced pressure. The residue was re-dissolved in 5 ml of methanol and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 5-(ethylamino)-4-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoic acid as white solid. Yield: 26 mg, 84%.
Reaction SMILES: [F:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[S:9][C:8](S(C)=O)=[N:7][C:6]=2[CH:13]=1.[NH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=2[C:30]([F:33])([F:32])[F:31])=[O:22])[CH2:17]1.C([O-])(O)=O.[Na+]>CS(C)=O.O>[F:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[S:9][C:8]([NH:15][C@@H:16]3[CH2:20][CH2:19][N:18]([C:21]([C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=4[C:30]([F:33])([F:31])[F:32])=[O:22])[CH2:17]3)=[N:7][C:6]=2[CH:13]=1
Reactant: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](N)C2)c1
Reactant: CS(=O)c1nc2cc(F)c(F)cc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](Nc3nc4cc(F)c(F)cc4s3)C2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixture of 30 mg (0.129 mmol) rac-5,6-difluoro-2-methanesulfinyl-benzothiazole and 70.3 mg (0.258 mmol) ((R)-3-Amino-pyrrolidin-1-yl)-(5-methyl-2-trifluoromethyl-phenyl)-methanone (intermediate 13) in 540 μL dimethyl sulfoxide was heated in a 100° C. oil-bath for 4 h. The solution was cooled to room temperature, diluted with water and basified with a saturated NaHCO3 solution. The mixture was stirred for 1 h. The solid was filtered, washed with water and dissolved in dichloromethane. The solution was dried over Na2SO4, filtered and concentrated in vacuo. The crude compound was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 27 mg (47.6%) of the title compound as a white solid. MS(m/e): 442.2 (M+H+).
Reaction SMILES: [CH2:1]([O:6][CH:7]=[CH:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:2]([CH2:4][OH:5])[OH:3]>[Pd]>[CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:2]([CH2:4][OH:5])[OH:3]
Reactant: CCCCC=CC=COCC(O)CO
Agent: [Pd]
Product: CCCCCCCCOCC(O)CO
Temperature: 47.5 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
In a 500-mL autoclave were added 100 g of the resulting octadienyl glyceryl ether and 5 g of 5% Pd—C (product of NE Chemcat Corporation). The mixture was stirred at 25 to 70° C. for 6 hours under a hydrogen atmosphere of 1 to 5 MPa. After completion of the reaction, the catalyst was filtered away, whereby 102 g of octyl glyceryl ether was obtained as a colorless transparent oil. GC analysis of the resulting oil showed that the content of monooctyl glyceryl ether was 99%, while that of dioctyl glyceryl ether was 1% or less.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11]C)=[O:10])[C:3]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21](=O)([O-])[O-:22].[K+].[K+].CO.Cl>O>[Br:8][C:6]1[N:5]=[C:4]([C:9]([OH:11])=[O:10])[C:3]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:2]([O:22][CH3:21])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nc(Br)cc(Br)c1OCc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(Br)nc(C(=O)O)c1OCc1ccccc1
Yield: 95.3 %

Procedure:
A vigorously stirred mixture of 15 (25.5 g), potassium carbonate (75 g) and methanol (300 mL) was heated at reflux for 30 hours. The mixture was cooled, poured into water (800 mL), and the pH adjusted to 2 by the addition of conc. HCl. The resulting mixture was extracted with CH2Cl2 (3×150 mL). The organic extracts were combined, dried (MgSO4) and the solvent was evaporated to give a nearly colorless oil (20.5 g) which slowly solidified upon standing. This was recrystallized from methanol (125 mL)/water (40 mL) to give the desired acid 16 (11.6 g), m.p. 134-135° C.
Reaction SMILES: [Na].[CH2:2]([SH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[N:12]=[C:13]2[C:18](=[N:19][C:20]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[N:17]=[C:16]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[N:15]=[C:14]2[N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCOCC1>[CH2:2]([S:9][C:11]1[N:12]=[C:13]2[C:18](=[N:19][C:20]=1[N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)[N:17]=[C:16]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[N:15]=[C:14]2[N:33]1[CH2:34][CH2:35][O:36][CH2:37][CH2:38]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Clc1nc2c(N3CCOCC3)nc(N3CCNCC3)nc2nc1N1CCOCC1
Reactant: SCc1ccccc1
Agent: [Na]
Solvent: C1COCCO1
Product: c1ccc(CSc2nc3c(N4CCOCC4)nc(N4CCNCC4)nc3nc2N2CCOCC2)cc1

Procedure:
A solution of 0.35 g of sodium and 2 ml (about 0.017 mol) of benzylmercaptan in 100 ml of dioxane was added to a solution of 6.3 g (0.015 mol) of 6-chloro-4,7-dimorpholino-2-piperazino-pteridine in 200 ml of dioxane, and the resulting mixture was refluxed for about 2 hours. The solvent was substantially distilled off in vacuo and the residue was taken up in about 200 ml of water. After it had solidified, the reaction product was suction-filtered off, washed with water and dried in vacuo at room temperature.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33](=[O:36])[CH2:34]Br>CC(C)=O>[CH3:31][O:32][C:33](=[O:36])[CH2:34][N:14]1[CH2:15][CH2:16][C:17]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:12][CH2:13]1
Reactant: COC(=O)CBr
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)CN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 1 mmol) in acetone (3 mL) was added Na2CO3 (2 mmol) and bromoacetic methyl ester (2 mmol). The mixture was stirred at RT for 1 h. After concentration and purification (SiO2, 2 M NH3 in MeOH/CH2Cl2), the title compound was obtained (60 mg). MS (ESI): exact mass calculated for C23H24ClN3O2, 409.16; found, m/z 410.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.44-7.42 (m, 2H), 7.31-7.29 (m, 2H), 7.25-7.23 (br m, 2H), 7.20-7.18 (br m, 1H), 7.02-6.99 (br m, 2H), 5.26 (s, 2H), 3.64 (s, 2H), 3.41 (s, 2H), 2.81-2.79 (br m, 4H), 2.75-2.73 (br m, 2H), 2.70-2.68 (br m, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C([N:19]1[CH2:26][C:25]2([CH2:27][CH2:28][CH:29]=[CH2:30])[CH:21]([CH2:22][O:23][C:24]2=[O:31])[CH2:20]1)C1C=CC=CC=1>ClCCl>[CH2:5]([O:4][C:2]([N:19]1[CH2:26][C:25]2([CH2:27][CH2:28][CH:29]=[CH2:30])[CH:21]([CH2:22][O:23][C:24]2=[O:31])[CH2:20]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCCC12CN(Cc3ccccc3)CC1COC2=O
Solvent: ClCCl
Product: C=CCCC12CN(C(=O)OCc3ccccc3)CC1COC2=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 89.1 %

Procedure:
Benzyl chloroformate (1.72 mL, 12.0 mmol) was added to a solution of 7-benzyl-1-(3-buten-1-yl)-3-oxa-7-azabicyclo[3.3.0]octan-2-one (1.09 g, 4.02 mmol) in dichloromethane (13.4 mL) in a nitrogen atmosphere, and the mixture was stirred at room temperature for five days. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→84:16→80:20→75:25→66:34→50:50) to give 1.13 g of the title compound.
Reaction SMILES: [Br:1]P(Br)Br.[CH3:5][N:6]([CH3:32])[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[C:20]([CH:22](O)[CH3:23])[CH:21]=1)[O:18][C:17]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:16][C:15]2=[O:31])=[O:11]>C(Cl)Cl>[BrH:1].[Br:1][CH:22]([C:20]1[CH:21]=[C:12]([C:10]([NH:9][CH2:8][CH2:7][N:6]([CH3:32])[CH3:5])=[O:11])[CH:13]=[C:14]2[C:19]=1[O:18][C:17]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:16][C:15]2=[O:31])[CH3:23]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Solvent: ClCCl
Product: Br
Product: CC(Br)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
A solution of tribromophosphine 1M in DCM (0.154 mL, 0.15 mmol) at 25° C., was added dropwise to N-(2-(dimethylamino)ethyl)-8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (60 mg, 0.15 mmol) suspended in DCM (1 mL). This suspension was stirred at 25° C. for 4 days. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to afford 8-(1-bromoethyl)-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (98 mg, >100%) as a white solid, which was used without further purification. Mass Spectrum: M+H+ 454.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:28])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:29])=[CH:10]2)=[C:4]([CH3:30])[CH:3]=1.[CH2:31](O)[CH3:32].Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)(Cl)Cl.O.C(OCC)(=O)C>[CH2:31]([O:26][C:25](=[O:27])[CH2:24][CH:21]1[CH2:20][CH2:19][N:18]([C:17]2[CH:16]=[C:15]([CH3:28])[N:14]=[C:13]3[N:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:30])[CH:10]=[C:11]([CH3:29])[C:12]=23)[CH2:23][CH2:22]1)[CH3:32]
Reactant: Cc1cc(N2CCC(CC(=O)O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CC1CCN(c2cc(C)nc3c2c(C)cn3-c2c(C)cc(Br)cc2C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of {1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetic acid (100 mg) in CHCl3 (4 mL) in an ice cooling bath was added ethanol (20 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61 mg), and dimethylaminopyridine (26 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ethyl acetate and water, and separated. The organic phase was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=4/1) to obtain {1-[1-(4-bromo-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-4-yl}acetic acid ethyl ester (99 mg). {1-[1-(4-Bromo-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-4-yl}acetic acid ethyl ester was dissolved in ethanol (2 mL) and 4 M HCl in ethyl acetate solution (60 μL) was added into the solution with cooling in an ice bath. After stirring at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropylether (1 mL). The crystal was collected by filtration to obtain the title compound. (95 mg)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:8]O>[Ti].O>[C:1]1([C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:8])[OH:7].[C:1]1([CH:6]=[CH:5][C:4]([OH:8])=[CH:3][CH:2]=1)[OH:7].[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Agent: [Ti]
Solvent: O
Solvent: Oc1ccccc1
Product: Oc1ccc(O)cc1
Product: Oc1ccccc1O
Temperature: 98 °C

Procedure:
A 10-liter reactor equipped with a condenser and a stirrer is charged with 4,890 g of phenol, 920 g of demineralized water and 50 g of titanium silicalite. The mixture is heated to 98° C. As the system reaches its thermal equilibrium, there are added, by means of a metering pump, 576 g of 60% H2O2. On completion of the reaction there are obtained 603 g of pyrocatechol+Hydroquinone corresponding to 5.486 mols of phenol with a yield relative to H2O2 of 54% and a selectivity in hydroquinone of 55%, the tar content being less than 20% and the selectivity towards phenol being 75%-80%.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([N:13]1[CH2:12][CH2:11][N:10]([C:16]2[CH:17]=[CH:18][C:19]([C:22](=[O:24])[CH3:23])=[CH:20][CH:21]=2)[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Benzoyl chloride (0.341 ml, 2.94 mmol) was added dropwise to a stirred mixture of 1-(4-piperazin-1-yl-phenyl)-ethanone (500 mg, 2.45 mmol) and TEA (0.681 ml, 4.9 mmol) in DCM (25 ml). The resulting solution was stirred overnight at room temperature, then diluted with DCM and washed with water, with NaHCO3 (5% in H2O) and finally with citric acid (20% in H2O). The organic phase was dried over Na2SO4 and evaporated in vacuo. The resulting solid was triturated with di-isopropylether and filtered to give 687 mg of 1-[4-(4-benzoyl-piperazin-1-yl)-phenyl]-ethanone.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[N:4]=[C:5]3[CH:10]=[N:9][CH:8]=[CH:7][N:6]3[C:2]=2[C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(-c2nc3cnccn3c2Br)cc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2nc3cnccn3c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 27.8 %

Procedure:
To a 25 mL round bottom flask charged with 3-bromo-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (Preparation #5, 0.090 g, 0.31 mmol), 4-pyridineboronic acid (0.045 g, 0.37 mmol), Pd(PPh3)4 (0.018 g, 0.015 mmol) and Cs2CO3 (0.250 g, 0.77 mmol) was added DME (10 mL) followed by water (1 mL). The reaction was allowed to stir at ambient temperature for about 3 minutes followed by submersion into an oil bath which was at about 90° C. After about 16 h, the reaction was concentrated in-vacuo and then purified by RP-HPLC (Table 1, Method d). The pure fractions were combined, concentrated, and lyophilized for about 12 h to give the title compound as a white solid (0.025 g, 23%): LC/MS (Table 1, Method b) Rt=1.54 min; MS m/z: 291.2 (M+H)+.
Reaction SMILES: [CH:1]([CH2:3][C:4]([OH:6])=[O:5])=[CH2:2].[CH3:7][C:8]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:28]=[CH:27][C:23]([CH:24]=[N:25][OH:26])=[CH:22][CH:21]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1>C1COCC1>[CH3:7][C:8]1[CH:17]=[C:16]([CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]3[CH2:2][CH:1]([CH2:3][C:4]([OH:6])=[O:5])[O:26][N:25]=3)=[CH:27][CH:28]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: C=CCC(=O)O
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(C3=NOC(CC(=O)O)C3)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A solution of Clorox® was added dropwise (1 mL) to a solution of vinyl acetic acid (0.071 g, 0.8 mmol) and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime (0.12 g, 0.40 mmol) in THF (4 mL) under nitrogen atmosphere at room temperature. The reaction was stirred overnight, partitioned between ethyl acetate and water saturated KH2PO4 solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give {3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-acetic acid (0.15 g, 100%) as a crude solid. MS found: (M+H)+=377.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28]O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCCCc2ccccc2)cc1
Yield: 62.6 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (249 mg, 0.991 mmol) prepared in Example 1 (1a) and 4-phenylbutan-1-ol (200 μL, 1.30 mmol) to give 203 mg of the title compound (white powder, yield: 63%).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>CO>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:23][CH:22]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccccc2)cc1
Solvent: CO
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccccc2)cc1

Procedure:
Methyl α-bromo-α-[p-(phenoxy)phenyl]acetate (6.42 g) is reacted with 3.21 g of 4-chlorophenol in methanol as in Example 16 to afford a white solid, which is recrystallized from hexane to yield the product, mp 99°-102° C.
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]([F:47])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][NH:11][C:12]1[C:13]([F:40])=[C:14]([CH2:19][C:20]([NH:22][CH2:23][C:24]2[C:25]([CH3:39])=[N:26][C:27]([NH:31]C(OC(C)(C)C)=O)=[CH:28][C:29]=2[CH3:30])=[O:21])[C:15]([Cl:18])=[CH:16][CH:17]=1>>[ClH:18].[NH2:31][C:27]1[N:26]=[C:25]([CH3:39])[C:24]([CH2:23][NH:22][C:20](=[O:21])[CH2:19][C:14]2[C:15]([Cl:18])=[CH:16][CH:17]=[C:12]([NH:11][CH2:10][C:9]([F:8])([F:47])[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:13]=2[F:40])=[C:29]([CH3:30])[CH:28]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(N)nc(C)c1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 153.4 %

Procedure:
A solution of HCl in 1,4-dioxane (4.0 M, 0.5 mL, 2 mmol) was added to 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}-N-({6-[(tert-butoxy) carbonylamino]-2,4-dimethyl(3-pyridyl)}methyl) acetamide (18.5 mg, 32 μmol), as prepared in the preceding step. After stirring at ambient temperature for 3 hours, solid precipitated. A solution of MeOH (0.1 mL) in DCM (1 mL) was added to dissolve the solid. After stirring for another 2 hours the reaction was concentrated to give a brown solid, that was washed with ether and DCM and dried in vacuo to produce the title compound (12.6 mg, 77% yield) as a pale brown solid. 1H-NMR (400 MHz, CD3OD) δ 8.40 (bs, 1H), 7.53-7.51 (m, 2H), 7.47-7.40 (m, 3H), 6.93 (dd, J=8.8, 1.3 Hz, 1H), 6.68 (s, 1H), 6.64 (t, J=9.1 Hz, 1H), 4.31 (d, J=4.6 Hz, 2H), 3.81 (t, J=13.8 Hz, 2H), 3.67 (d, J=1.2 Hz, 2H), 2.54 (s, 3H), 2.42 (s, 3H). Mass spectrum (LCMS, ESI) calc'd for C24H25ClF3N4O (M+H): 477.2. Found: 477.5.