Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH3:57])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH2:56]([O:55][CH2:54][CH2:53][O:52][C:48]1[CH:47]=[C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:51]=[CH:50][CH:49]=1)[CH3:57]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCOc1cccc(OB([O-])[O-])c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOCCOc1cccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 3-(2-ethoxyethoxy)phenyl borate (145 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 10 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[3-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 115) (152 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][C:6]2([C:11]3[NH:12][C:13]4[C:18]([C:10]=3[CH2:9][CH2:8][O:7]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:5][CH2:4]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>Cl>[CH3:27][N:2]([CH3:1])[C:3]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:20][CH2:19][CH:6]([C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][OH:7])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC2(CC1)OCCc1c2[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Successive Sn powder (3.00 g, 25.40 mmol) was added to a suspension of N,N-dimethyl-N-{4-phenyl-2′,3′,4′,9′-tetrahydrospiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-yl}-amine (non-polar diastereomer, cf. WO2004043967) (0.72 g, 2.00 mmol) in conc. HCl (60 ml) in the course of 2 h. A clear solutions was formed during the addition, and was stirred at RT for a further 2 h. For working up, the mixture was rendered basic with saturated Na2CO3 solution, and EtOAc (50 ml) was added to the mixture formed. Since the phase separation was incomplete, the constituents insoluble both in H2O and in EtOAc were separated off by means of filtration. The filter cake was washed with EtOAc (5×20 ml) and the aqueous phase was extracted with the particular ethyl acetate fractions (5×). The combined organic extracts were dried over Na2SO4. After filtration of the drying agent, the solvent was removed on a rotary evaporator and the residue (600 mg) was recrystallized from toluene (100 ml). 2-(2-(4-(Dimethylamino)-4-phenylcyclohexyl)-1H-indol-3-yl)ethanol was obtained as a diastereomer mixture (0.22 g, 30%). The solid (0.22 g, 0.60 mmol) was dissolved in boiling EtOH (30 ml), and citric acid (0.13 mg, 0.67 mmol), dissolved in hot EtOH (5 ml), was added. The ethanolic solution was concentrated (to approx. 10 ml) and ether (10 ml) was added. The precipitate formed was separated off by means of a frit and dried. The citrate (Ex. 1) (0.20 g, 60%, m.p.: from 114° C.) was obtained as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[N:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])SC)=[CH:12][CH:11]=1)#[N:9]>O.C(O)C>[C:24]1([S:21]([N:20]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([C:8]#[N:9])=[CH:15][CH:14]=2)[NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:23])=[O:22])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CSC(=NS(=O)(=O)c1ccccc1)Nc1ccc(C#N)cc1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(NC(=NS(=O)(=O)c2ccccc2)NCC(=O)O)cc1
Reaction time: 7 h
Yield: 52 %

Procedure:
A mixture of 0.57 g (7.6 mmoles) of glycine and 0.3 g (7.6 mmoles) of sodium hydroxide in 3 cm3 of water and 2.5 (7.6 mmoles) of N-(4-cyanophenyl)-N'-phenylsulfonyl-S-methylisothiourea in 30 cm3 of 95% ethanol is heated to boiling for 7 hours. After cooling, the precipitate obtained is filtered and dissolved in 20 cm3 of 1N sodium hydroxide solution. The solution obtained is washed with dichloromethane (3×10 cm3) and ethyl acetate (2×10 cm3) and is then acidified to pH 3 with a 6N HCl solution. After cooling, precipitate forms and is filtered, washed with water (2×5 cm3) and dried in vacuo to give 1.4 g (yield 52%) of N-[phenylsulfonylimino(4-cyanophenylamino)methyl]-2-aminoethanoic acid having a melting point of 133° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].N1C=CN=C1>CN(C)C=O>[Si:1]([O:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(CCO)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.1 %

Procedure:
Tert-butyldimethylsilyl chloride (22.5 g) was added to a mixture of 3-hydroxypropiophenone (18.7 g), imidazole (21.3 g) and dimethylformamide (100 ml) and the solution was stirred at ambient temperature for 6 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with an aqueous sodium chloride solution, dried (Na2SO4) and evaporated. Petrol (b.p. 60°-80° C., 250 ml) was added to the residue, the resulting mixture was filtered and the filtrate was evaporated to give 3-(tert-butyldimethylsilyloxy)propiophenone as a pale yellow oil (31 g) which was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])OCC1CO1>C(O)(C)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:41][CH:31]([OH:30])[CH2:32][C:33]3[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:31]([O:30][CH3:29])[CH:32]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Reactant: COc1cc(OCC2CO2)cc(OC)c1OC
Solvent: CC(C)O
Product: COc1cc(CC(O)CN2CCC(C(=O)NC(CCCc3ccccc3)CCCc3ccccc3)CC2)cc(OC)c1OC
Temperature: 70 °C
Yield: 121 %

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (150.7 mg; 0.4 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (+/−)-2-(3,4,5-Trimethoxy-phenoxymethyl)-oxirane (95.2 mg; 0.4 mmol) is added, then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (10%→100% acetone in hexanes) affording the desired product (145.9 mg) as an oil. ESMS:MH+ 619.4 (base).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[N:18]2[CH:19]=[CH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)=[CH:22][C:17]2=[N:16][CH:15]=1)=[O:13].[CH3:29][C:30]1([CH3:38])[CH2:34][CH2:33][CH2:32][N:31]1[CH2:35][CH2:36][NH2:37].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O.CO.CCOC(C)=O>[CH3:29][C:30]1([CH3:38])[CH2:34][CH2:33][CH2:32][N:31]1[CH2:35][CH2:36][NH:37][C:6]([C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[CH:4]=1)=[O:7]
Reactant: CC1(C)CCCN1CCN
Reactant: Cn1cc(-c2ccn3c(C(=O)Nc4cc(C(=O)O)ccc4F)cnc3c2)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCCN5CCCC5(C)C)ccc4F)cnc3c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-fluoro-3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamido)benzoic acid (step 1) (6.31 g, 16.63 mmol), 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.84 g, 19.96 mmol) and triethylamine (6.96 ml, 49.9 mmol) in DMF (36.9 ml) and EtOAc (2 ml) was treated dropwise with ®T3P (propylphosphonic anhydride) (50% w/w in EtOAc) (15.88 g, 24.95 mmol). The resulting mixture was stirred at RT for 16 hrs and diluted with 10% MeOH/EtOAc (62.7 ml). The mixture was washed with 0.5 M LiCl, H2O and sat. NaHCO3. The aqueous layer was back-extracted with 10% MeOH EtOAc (62.7 ml) (3×100 ml). The combined organic extracts was dried MgSO4, filtered and concentrated in vacuo. The resulting solid was triturated with EtOAc and dried at 45° C. to afford the title compound;
Reaction SMILES: C([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:8]=1)(C)(C)C.Br.SCC(O)=O>C(O)(=O)C>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([OH:30])=[O:5])[CH:14]=2)[NH:19][CH:20]=1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Agent: Br
Agent: O=C(O)CS
Solvent: CC(=O)O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cccc(C(=O)O)c3)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.4 %

Procedure:
To a solution of 3-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid tert-butyl ester (1.97 g, 4.92 mmol) in acetic acid (4 mL) was added dropwise a premixed solution of hydrogen bromide (33% wt in acetic acid) (889 uL, 4.92 mmol) and mercaptoacetic acid (444 uL, 6.39 mmol). The sides of the flask were rinsed with additional acetic acid (3 mL) and the reaction solution was stirred at ambient temperature for 10 minutes whereupon the product began to precipitate out of solution. The reaction was stirred for an additional hour at ambient temperature. The precipitate was filtered and rinsed well with acetic acid and diethyl ether, affording the title compound as a bright yellow solid (448 mg, 67% yield). 1H NMR (500 MHz, d6-DMSO) δ 12.03 (br s, 1H), 8.58 (s, 1H), 8.21 (d, 2H), 7.99 (d, 1H), 7.94 (d, 1H), 7.76 (d, 1H), 7.61 (m, 2H), 7.31 (t, 1H), 7.14 (d, 1H), 7.06 (t, 1H), 3.83 (s, 3H). MS: m/e 345.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=2[F:30])[N:23]=[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:21]=1[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=3[F:30])[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:21]=2[CH3:38])[C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1ccc(-c2ncc(Br)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ncc(Br)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-2-(4-methoxyphenyl)pyridin-3-amine (0.14 g, 0.52 mmol) in dry DMF (5.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (0.043 g, 1.07 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.18 g, 0.62 mmol) was added in portions. Upon complete addition, the mixture was warmed to 60° C. After 18 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the black residue was purified on silica gel (50-100% EtOAc in hexanes) to afford a mostly N-(5-bromo-2-(4-methoxyphenyl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=533.0 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[C:13]([F:14])([F:15])[F:16]
Reactant: COC(=O)c1ccc(SC)c(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(CO)cc1C(F)(F)F
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
To a solution of methyl 4-(methylthio)-3-(trifluoromethyl)benzoate (10.0 g, 40.0 mmol) in tetrahydrofuran (100 mL) was added lithium aluminum hydride (1.52 g, 40.0 mmol) at 0° C. by small portions, and the resulting mixture was stirred for 15 min. Sodium sulfate decahydrate (12.9 g, 40.0 mmol) was added to the reaction mixture by small portions, and the obtained mixture was further stirred at room temperature for 1 hr. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1), and crystallized from hexane/ethyl acetate to give the title compound (8.46 g, yield 95%) as colorless crystals.
Reaction SMILES: CC(C)(CC(=O)N1CCCN(C2C=CC(NC(C3N=C(C4C=CC=CC=4)OC=3C(F)(F)F)=O)=CC=2)CC1)C(O)=O.C1(C(O)=O)CCCC1.Cl.[N:50]1([C:57]2[N:62]=[CH:61][C:60]([NH:63][C:64]([C:66]3[N:67]=[C:68]([C:75]4[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=4)[O:69][C:70]=3[C:71]([F:74])([F:73])[F:72])=[O:65])=[CH:59][CH:58]=2)[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.[C:81]1(=[O:91])[C:85]2([CH2:89][CH2:88][CH2:87][CH2:86]2)[CH2:84][C:83](=[O:90])[O:82]1>>[O:90]=[C:83]([N:53]1[CH2:54][CH2:55][CH2:56][N:50]([C:57]2[CH:58]=[CH:59][C:60]([NH:63][C:64]([C:66]3[N:67]=[C:68]([C:75]4[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=4)[O:69][C:70]=3[C:71]([F:72])([F:74])[F:73])=[O:65])=[CH:61][N:62]=2)[CH2:51][CH2:52]1)[CH2:84][C:85]1([C:81]([OH:91])=[O:82])[CH2:89][CH2:88][CH2:87][CH2:86]1
Reactant: O=C1CC2(CCCC2)C(=O)O1
Reactant: O=C(Nc1ccc(N2CCCNCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CC(C)(CC(=O)N1CCCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1)C(=O)O
Agent: Cl
Agent: O=C(O)C1CCCC1
Product: O=C(Nc1ccc(N2CCCN(C(=O)CC3(C(=O)O)CCCC3)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to that used for the preparation of 2,2-dimethyl-4-oxo-4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepan-1-yl)-butyric acid, 1-[2-Oxo-2-(4-{5-(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-[1,4]diazepan-1-yl)-ethyl]-cyclopentanecarboxylic acid was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-[1,4]diazepan-1-yl-pyridin-3-yl)-amide hydrochloride and 2-oxa-spiro[4.4]nonane-1,3-dione. LCMS for C29H30F3N5O5 calcd. (m/e) 585, observed 586 (M+H).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[OH:7][C:2]([CH3:6])([CH3:1])[CH2:3][CH2:4][O:5][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CC(C)(O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10.0 ml (93.7 mmol) of 3-methylbutane-1,3-diol and 7.60 ml (94.9 mmol) pyridine are dissolved in 100 ml DCM. The mixture is cooled in an ice bath. 15.0 g (78.7 mmol) of 4-methylbenzenesulfonyl chloride are added portionwise. The reaction mixture is stirred at r.t. for 16 h. The reaction mixture is poured into 100 ml of 1N aq. HCl and stirred for 10 min. Then the layers are separated. The aq. layer is extracted with DCM. The combined organic layers are washed with brine and dried. The solvent is evaporated and the residue is chromatographed on silica gel (PE/EtOAc) to give the title compound. Yield: 15.3 g; Mass spectrum (ESI+): m/z=276 [M+NH4]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].CC1C=C([OH:18])C=C(C)C=1.CC1C=CC(C)=C(O)C=1O>>[CH3:1][C:2]1[CH:7]=[C:6]([OH:18])[C:5]([CH3:8])=[CH:4][C:3]=1[OH:9]
Reactant: Cc1ccc(C)c(O)c1
Reactant: Cc1cc(C)cc(O)c1
Agent: Cc1ccc(C)c(O)c1O
Product: Cc1cc(O)c(C)cc1O

Procedure:
By following in the same manner as in Example 53, except that 100 g. (819 m. moles) of 2,5-dimethylphenol were used instead of 3,5-dimethylphenol, 1.45 g. (10.5 m. moles) of 3,6-dimethylcatechol and 1.85 g. (13.4 m. moles) of 2,5-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 46.9 percent.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([Mg:16][Cl:17])C=CC=CC=1.C1OC1>ClC1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][O:9][Mg:16][Cl:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccccc1
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CO1
Solvent: Clc1ccccc1
Product: Cl[Mg]OCCc1ccccc1

Procedure:
2-phenylethanol is also prepared by the Grignard synthesis, starting from chlorobenzene, which is converted to phenyl-magnesium chloride, which then reacts with ethylene oxide to give phenylethoxy magnesium chloride. Phenylethoxy magnesium chloride thus obtained is decomposed with sulphuric acid to give 2-PEA. The main drawbacks of this process are (i) generation of potentially dangerous and air and moister sensitive phenyl-magnesium chloride (ii) requirement of sulphuric acid for the decomposition of Grignard complex and subsequent extraction of the desired product, (iii) produces large amounts of hazardous effluent and poor quality of the 2-phenylethanol which has low acceptability in perfumery industry [E. T. Theimer in Fragrance Chemistry, Academic Press, New York, (1982) p. 271].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].C(N(CC)CC)C.[Br:21][C:22]([CH3:27])([CH3:26])[C:23](Br)=[O:24]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][C:23](=[O:24])[C:22]([Br:21])([CH3:27])[CH3:26])([O-:3])=[O:2]
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 91.2 %

Procedure:
2,4-Dinitrophenol (9.6 gm, 52 mmol) in 80 ml anhydrous tetrahydrofuran was placed under a nitrogen atmosphere and cooled in an icebath. To this was added triethylamine (5.80 g, 57 mmol) followed by the dropwise addition of bromoisobutyryl bromide (15.6 g, 67 mmol) in 20 ml anhydrous tetrahydrofuran over 5 min. After stirring for 4 h, the solids were filtered off and the solution concentrated, and then recrystallized from 100 ml methanol to give 15.8 g yellow solid, >99% pure by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[C:12]([O:16][C:17]([NH:19][C:20]1[C:21]([NH:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][CH2:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:30][N:29]=2)=[O:27])=[CH:22][S:23][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[C:12]([O:16][C:17]([NH:19][C:20]1[C:21]([NH:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:35]([CH2:36][CH2:37][CH2:38][N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[O:11])=[CH:30][N:29]=2)=[O:27])=[CH:22][S:23][CH:24]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1cscc1NC(=O)c1ccc(CNCCCN2CCOCC2)cn1
Reactant: O=C=Nc1ccc(F)c(F)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cscc1NC(=O)c1ccc(CN(CCCN2CCOCC2)C(=O)Nc2ccc(F)c(F)c2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
3,4-Difluorophenyl isocyanate (15 μL, 0.13 mmol) was added to a solution of N-(4-t-butoxycarbonylaminothiophen-3-yl)-5-[3-(morpholin-4-yl)propylaminomethyl]pyridine-2-carboxylic acid amide (Reference Compound No. 5-12, 43 mg, 0.091 mmol) in dichloromethane (2.0 mL), and then the reaction mixture was stirred at room temperature for 1.5 hours. The reaction solution was purified by silica gel column chromatography (chloroform-methanol) to give 53 mg of the title reference compound as a colorless solid. (Yield 92%)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH3:21])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:22]([O:24]C)=[O:23])[CH:12]=3)[N:7]=2)=[CH:2]1.[OH-].[Na+]>CO.O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH3:21])=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:22]([OH:24])=[O:23])[CH:12]=3)[N:7]=2)=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccoc3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccoc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of methyl 2-(furan-3-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (111 mg, 0.33 mmol) in methanol (20 mL) and water (1.0 mL) was added sodium hydroxide (52.9 mg, 1.32 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL), adjusted pH to 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(furan-3-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylic acid as a light yellow solid (72 mg, 68%).