Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.[CH3:6][O:7][Si:8]([O:15][CH3:16])([O:13][CH3:14])[CH2:9][CH2:10][CH2:11][NH2:12]>Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>[CH3:6][O:7][Si:8]([O:13][CH3:14])([O:15][CH3:16])[CH2:9][CH2:10][CH2:11][NH:12][C:3](=[O:5])[CH2:2][Br:1]
Reactant: O=C(O)CBr
Reactant: CO[Si](CCCN)(OC)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CO[Si](CCCNC(=O)CBr)(OC)OC
Reaction time: 2 h

Procedure:
Binder DNA oligonucleotide-derivatized porous silicon films were employed to test the selectivity and limits of detection of a contemplated sensor. For attachment of DNA, a trimethoxy-3-bromoacetamido-propylsilane linker was synthesized by reaction of bromoacetic acid with trimethoxy-(3-aminopropyl)silane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-hydrochloride in methylene chloride as solvent. The linker product was purified by column chromatography on silica gel. The oxidized porous silicon samples were then contacted with a toluene solution of the linker for 2 hours. The resulting linker-bound substrate was thoroughly rinsed with pure toluene and methylene chloride, and dried for about 18 hours under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]#[CH:22]>CC(C)=O.C1(C)C=CC=CC=1>[CH2:22]([O:1][C:2]1[C:10]([CH2:11][CH2:12][CH3:13])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1)[C:21]#[CH:20]
Reactant: C#CCBr
Reactant: CCCc1cc2c(cc1O)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#CCOc1cc2c(cc1CCC)OCO2

Procedure:
Following the same procedure as in Example 3 a) and b), but using 7.2 g (0.04 moles) of 5-hydroxy-6-propyl-benzo[1.3]dioxole, 5.92 g (0.04 moles) of anhydrous potassium carbonate in 40 ml of acetone were reacted with 5.95 g (0.04 moles) of a solution of propargyl bromide in toluene, (80% w/w).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:30])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH3:30]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1
Product: CC(C)(NC(=O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid (Example 125 b) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=428.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5[N:26]=[CH:27][N:28](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[CH:29]=5)[CH:20]=4)=[O:17])=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[CH:29]=[C:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16]([C:13]3[CH:14]=[CH:15][C:10]4[N:9]=[C:8]5[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]5[C:11]=4[CH:12]=3)=[O:17])[CH:24]=[CH:23][CH:22]=2)[N:26]=[CH:27]1
Reactant: O=C(Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1)c1ccc2nc3n(c2c1)CCCNC3=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2c[nH]cn2)c1)c1ccc2nc3n(c2c1)CCCNC3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of 1-oxo-N-[3-(1-trityl-1H-imidazol-4-yl)phenyl]-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxamide (53 mg, 0.08 mmol) in CH2Cl2 (3 mL) is added TFA (0.5 mL) and the solution is stirred for 2 h at room temperature. The solvent is evaporated and the residue treated with 0.1M aqueous NaOH solution. A brown solid is formed which is collected by filtration, washed with CH2Cl2, and dried to afford the title compound (26 mg, 80%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=O)[O:6]C2C=CC=CC=2)[CH2:3][CH2:2]1.CS(C)=O.[C:18]1([C:24]2[NH:40][C:27]3[N:28]=[CH:29][N:30]=[C:31]([O:32][C:33]4[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=4)[C:26]=3[CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH:1]1([NH:4][C:5]([NH:39][C:36]2[CH:37]=[CH:38][C:33]([O:32][C:31]3[C:26]4[CH:25]=[C:24]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[NH:40][C:27]=4[N:28]=[CH:29][N:30]=3)=[CH:34][CH:35]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Nc1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1
Reactant: O=C(NC1CC1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1)NC1CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 11.8 %

Procedure:
After adding 30 mg of phenyl cyclopropylcarbamate and 0.5 ml of dimethylsulfoxide to 40 mg of 4-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenylamine, the mixture was stirred at 80° C. for 4 hours. The mixture was returned to room temperature, water was added, liquid separation and extraction were performed with ethyl acetate, and the solid obtained by concentration to dryness was washed with ether to obtain 6 mg of the title compound. p 1H-NMR Spectrum: (DMSO-d6) 0.30–0.40 (2H, m), 0.55–0.65 (2H, m), 2.43–2.57 (1H, m, coverd by DMSO peak), 6.20 (1H, brs), 6.60 (2H, d, J=8.90 Hz), 6.83 (1H, s), 6.87–6.91 (1H, m), 7.10–7.16 (1H, m), 7.30–7.50 (3H, m), 7.90 (2H, d, J=8.1 Hz), 8.26 (1H, d, J=0.4 Hz), 8.92 (1H, brs,), 12.60 (1H, brs)
Reaction SMILES: C([O:9][C:10](=[O:36])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([S:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:16][CH2:17][S:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C1C=CC=CC=1>O1CCOCC1.O>[C:28]([S:27][CH:15]([CH2:16][CH2:17][S:18][C:19](=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:14][CH2:13][CH2:12][CH2:11][C:10]([OH:36])=[O:9])(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(CCCCC(CCSC(=O)c1ccccc1)SC(=O)c1ccccc1)OC(=O)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCC(CCSC(=O)c1ccccc1)SC(=O)c1ccccc1

Procedure:
In overview, 6,8-Bisbenzoylmercaptooctanoic acid was prepared by a three step procedure from commercially available α-lipoic acid. The lipoic acid was first reduced to 6,8-bismercaptooctanoic acid with sodium borohydride in water under slightly alkaline conditions. The product was benzoylated with three equivalents of benzoyl chloride in the presence of triethylamine to scavenge the HCl byproduct to produce 6,8-bisbenzoylmercaptooctanoic benzoic anhydride. The anhydride was selectively hydrolyzed with dioxane/water to produce 6,8-bisbenzoylmercaptooctanoic acid without any undesired hydrolysis of the benzoylthio ester groups. The product was purified by column chromatography on Silica Gel. The purified acid was dissolved in methanol and converted to the sodium salt by the slow addition of an aqueous solution containing one mole equivalent of sodium bicarbonate.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+].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>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[N:16][CH:17]=2)[S:6][C:5]=1[CH3:7]
Reactant: Cc1sc(Br)cc1C1OCCO1
Reactant: COc1ccc(B(O)O)cn1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc(C3OCCO3)c(C)s2)cn1

Procedure:
A mixture of 2-(5-bromo-2-methylthiophen-3-yl)-1,3-dioxolane (1.7 g), 2-methoxy-5-pyridineboronic acid (1.3 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give 5-[4-(1,3-dioxolan-2-yl)-5-methylthiophen-2-yl]-2-methoxypyridine as an oil. The obtained 5-[4-(1,3-dioxolan-2-yl)-5-methylthiophen-2-yl]-2-methoxypyridine was dissolved in tetrahydrofuran (10 mL), 1N hydrochloric acid (10 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (1.2 g, 75%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][OH:18])=[O:14].ClC(Cl)(Cl)C(=N)O[CH2:34][CH:35]=[CH2:36]>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][O:18][CH2:36][CH:35]=[CH2:34])=[O:14]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CO)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCOC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1- oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluoromethanesuihfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:27][NH:28][O:29][CH3:30].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.Cl>[CH3:30][O:29][N:28]([CH3:27])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (15.8 g, 38 mmol), N,O-dimethyl hydroxylamine hydrochloride (11.1 g, 114 mmol), DIEA (41 mL, 228 mmol), and BOP (69 g, 156 mmol), were suspended in 80 mL DMF and stirred at room temperature over night. The reaction mixture was diluted with 1 (M) HCl (100 mL), extracted with EtOAc, and the organic portions were washed with 1 (M) aqueous HCl, NaHCO3 and brine. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide: MS m/z: (M+H) 458.0.
Reaction SMILES: [CH2:1]([C:3]1([C:8]([OH:10])=[O:9])[NH:7][CH2:6][CH2:5][S:4]1)[CH3:2].O.[C:12](=O)(O)[O-].[Na+]>Cl.CO>[CH3:12][O:9][C:8]([C:3]1([CH2:1][CH3:2])[NH:7][CH2:6][CH2:5][S:4]1)=[O:10]
Reactant: O=C([O-])O
Reactant: CCC1(C(=O)O)NCCS1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC1(C(=O)OC)NCCS1
Yield: 18.4 %

Procedure:
10.0 g of the 2-ethyl-thiazolidine-2-carboxylic acid thus obtained was dissolved in 200 ml of 20% hydrogen chloride-methanol solution. After being refluxed for 30 minutes, the reaction mixture was concentrated under reduced pressure to afford a residue, to which was added water, and was then neutralized with an aqueous saturated solution of sodium bicarbonate. Upon extracting with ethyl acetate, the extract was chromatographed on a column of silica gel to give 2.0 g (yield 18.4%) of 2-ethyl-thiazolidine-2-carboxylic acid methyl ester with a reflex index of nD26 1.501.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:22][C:23]3[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(Oc3ccc(Cl)cc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from 4-chloro-phenol and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-Chloro-phenoxy)-5-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 382(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][Mg]Br>C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](=[O:5])[CH3:15]
Reactant: Cc1ccc(C(F)(F)F)cc1C(=O)Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(F)(F)F)ccc1C

Procedure:
The title compound was synthesized from 2-methyl-5-(trifluoromethyl)-benzoyl chloride via the reaction of the corresponding Weinreb amide with methyl magnesium bromide in THF.
Reaction SMILES: CS(O[CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)[CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1)(=O)=O.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>C(#N)C>[N:22]1([CH2:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:8][CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: CS(=O)(=O)OCC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: Clc1ccc(C(CC2OCCO2)Cn2ccnc2)cc1Cl
Yield: 77.7 %

Procedure:
1-Methanesulphonyloxy-2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propane (15.5 g) (see Preparation 16) and imidazole (9 g) were dissolved in anhydrous acetonitrile (100 ml) and the mixture heated at reflux for 90 hours. The solvent was removed under reduced pressure, the residue dissolved in dichloromethane (100 ml) and the solvent again removed under reduced pressure. The residue was dissolved in dichloromethane (300 ml) and washed with sufficient aqueous sodium carbonate solution to ensure that the aqueous phase reached pH14. The two phases were separated and the aqueous phase extracted with dichloromethane (100 ml). The organic phases were then combined and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel, eluting with a solvent gradient of 99:1 changing to 95:5, by volume, dichloromethane:methanol to give 1-(imidazol-1-yl)-2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propane (11.1 g) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:21]([NH:20][CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=1)=[O:22])[CH:8]=[CH:7][CH:6]=2
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2c(N)cccc2cn1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc2cn1

Procedure:
Prepared from 3-methylisoquinolin-5-amine (Description 45) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 360 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)([C:14]([O:16]CC2C=CC=CC=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc(CC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
To a solution of 4-(4-methoxycarbonyl-benzyl)-piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (10.65 mmol; 4.98 g) in tetrahydrofuran (20 mL) and ethanol (40 mL) was added 10% palladium on carbon (3 g), and the resulting mixture was hydrogenated under 50 psi of hydrogen pressure for 5 hours at room temperature. The catalyst was removed via filtration, and the filtrate was evaporated to yield 4-(4-methoxycarbonyl-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. 1H-NMR (CDCl3): 7.95 (2H, d), 7.19 (2H, d), 3.90 (3H, s), 2.92 (4H, m), 2.05 (2H, s), 1.40-1.70 (4H, m), 1.45 (9H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:1]1[C:12](=[O:13])[C:11]2[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]1=[O:14]
Reactant: NCc1ccccn1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1Cc1ccccn1
Yield: 86.2 %

Procedure:
2-Aminomethylpyridine (4.0 g, 37 mmol) and phthalic anhydride (5.5 g, 37 mmol) were dissolved in toluene (100 ml), and triethylamine (3.7 g, 36 mmol) was added thereto. The mixture was refluxed for 3 hrs. The solvent was evaporated, and the residue was recrystallized from hexane-ethanol to give the titled compound (7.6 g, 86%).
Reaction SMILES: C([NH:4][C:5]1[N:10]=[C:9]2[NH:11][CH:12]=[C:13]([CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([NH2:18])=[O:17])[C:8]2=[CH:7][CH:6]=1)(=O)C.O.[Na]>CO>[NH2:4][C:5]1[N:10]=[C:9]2[NH:11][CH:12]=[C:13]([CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:16]([NH2:18])=[O:17])[C:8]2=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc2c(C=C(C(N)=O)c3ccccc3)c[nH]c2n1
Agent: [Na]
Solvent: CO
Solvent: O
Product: NC(=O)C(=Cc1c[nH]c2nc(N)ccc12)c1ccccc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
1 g (3.13 mmol) of 3-(6-acetylamino-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenyl-2-propenamide was dissolved in 20 ml of methanol and 3.13 ml of sodium hydrate 1 M were added. The solution is maintained at room temperature for 5 hours and then concentrated under vacuum. The residue was redissolved with dichloromethane and washed with water. The organic layer was finally dried over sodium sulfate and evaporated to give 696 mg (80% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.O.C(OO)(=[O:24])C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:24])[CH:5]=[N:4][C:3]=1[O:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Oc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: CC(=O)OO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Oc1ncc(O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
To a solution of 3-chloro-2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 5, 297.6 g, 897.9 mmol) in acetic acid:water (2.2 L:1.0 L) at 0° C. was added peracetic acid (191 mL; 1.077 mol) and the reaction was allowed to warm gradually to room temperature. After 4 hours the reaction was complete and was quenched with 0.5 M aqueous solution of sodium thiosulfate (225 mL). The resulting dark solution was evaporated to dryness and the residue was passed through a plug of silica eluting with heptanes:ethyl acetate 1:0 to 10:1 to afford a pale yellow viscous oil which contained 8% of the 4-isomer. Further silica gel column chromatography was performed eluting with EtOAc:heptane 1:4 to afford a pale yellow solid which was triturated with heptanes and dried under suction to afford the title compound as a white solid (110 g, 65% over two steps).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].[CH:23]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:23]([N:36]1[CH2:41][CH2:40][N:39]([C:20](=[O:21])[CH2:19][N:3]2[CH2:4][CH2:5][C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:2]2=[O:1])[CH2:38][C:37]1=[O:42])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: O=C1CNCCN1C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.18 g, 0.6 mmol) and the product from Example 28A (0.18 g, 0.6 mmol) in methylene chloride (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.23 g, 0.6 mmol) and diisopropylethylamine (0.5 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with methylene chloride, and then washed with 1 N HCl, water, 1 N NaOH, and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.28 (m, 20H), 6.91 (s, 1H), 4.26 (d, J=21.70 Hz, 2H), 4.18 (d, J=12.88 Hz, 2H), 3.69 (m, 2H), 3.35 (m, 2H), 3.13 (m, 1H), 3.07 (m, 1H), 2.71 (m, 2H), 2.69 (s, 1H); MS (ESI+) m/z 544 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:17])[C:6]([CH3:16])=[C:7]([O:11]CC(C)=C)[CH:8]=2)[N:3]1[CH:18]=[O:19]>C(N(CC)C1C=CC=CC=1)C.C(OCC)C>[OH:11][C:7]1[C:8]([CH2:6][C:5]([CH3:17])=[CH2:4])=[C:9]2[C:4](=[C:5]([CH3:17])[C:6]=1[CH3:16])[N:3]([CH:18]=[O:19])[CH:2]([CH3:1])[CH2:10]2
Reactant: C=C(C)COc1cc2c(c(C)c1C)N(C=O)C(C)C2
Solvent: CCOCC
Solvent: CCN(CC)c1ccccc1
Product: C=C(C)Cc1c(O)c(C)c(C)c2c1CC(C)N2C=O
Yield: 137.5 %

Procedure:
A solution of 2,3-dihydro-2,6,7-trimethyl-5-[(2-methyl-2-propenyl)oxy]-1H-indole-1-carbaldehyde (0.59 g, 2.3 mmol) in N,N-diethylaniline (3 mL) was stirred at 200° C. for 4.5 hours under the nitrogen atmosphere. The reaction mixture was dissolved in diethyl ether, washed with 1N hydrochloric acid, water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to obtain 0.41 g of the title compound.