Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:6]=1[O:7][CH2:8][C:9]#[N:10])(OC)=[O:2].C[O-].[Na+]>C1C=CC=CC=1>[Cl:15][C:12]1[CH:13]=[CH:14][C:5]2[C:1]([OH:2])=[C:8]([C:9]#[N:10])[O:7][C:6]=2[CH:11]=1
Reactant: COC(=O)c1ccc(Cl)cc1OCC#N
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#Cc1oc2cc(Cl)ccc2c1O
Yield: 98.1 %

Procedure:
A mixture of 2-(2-carbomethoxy-5-chlorophenoxy)acetonitrile (22.6 g, 0.1 mol, described in Example 2) and sodium methoxide (0.2 mol, prepared from 4.6 g sodium metal and 50 mL dry methanol) in benzene (400 mL) was stirred and refluxed for 2 hr. After cooling, the precipitate was collected and dissolved in water. The solution was acidified with concentrated hydrochloric acid. The precipitate was extracted into diethyl ether and the solution was dried and evaporated. The solid residue was triturated with petroleum ether and gave 19.0 g of the title compound: mp ca 205° C., and NMR (DMSO-d6) δ7.6 (3H,m), and 11.4 (1H, broad).
Reaction SMILES: C[O-].[Na+].CO.[N+](C1C=CC(S([NH:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1)([O-])=O.Cl>C(COC)OC>[CH:19]([NH2:18])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NC(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 95.6 %

Procedure:
A 28% sodium methoxide/methanol solution (0.34 ml; 1.51 molar equivalents) was added to a solution of N-(4-nitrobenzenesulfonyl)benzhydrylamine (402.0 mg) in dry dimethoxyethane (3 ml) at room temperature in a nitrogen atmosphere, followed by stirring for 7 hours at room temperature and for 40 hours under heating at 46 to 49° C. On the way, dry dimethoxyethane (3 ml) was further added after 7 hours, and a 28% sodium methoxide/methanol solution (0.34 ml; 1.51 molar equivalents) was further added about 18 hours after heating. The reaction mixture was cooled with ice, and 1 N hydrochloric acid (5 ml) was added. The reaction solvents were removed by evaporation under reduced pressure, and water (5 ml), 1 N hydrochloric acid (5 ml) and ether (25 ml) were added to the resulting concentrate, followed by extraction and solution separation. The organic layer was extracted again with water (5 ml). Sodium hydroxide (0.61 g) was added to the resulting aqueous layer, and extraction was conducted three times with ether (20 ml), followed by drying over sodium sulfate, filtration, concentration and drying under vacuum to obtain benzhydrylamine (191.2 mg; yield: 95.6%).
Reaction SMILES: [H-].[Na+].[Cl-].[PH4+].BrC1N=CC=CC=1C=O.C(=O)(O)[O-].[Na+].[Br:19][C:20]1[C:25]([CH:26]=[CH:27][O:28]C)=[CH:24][CH:23]=[CH:22][N:21]=1>CS(C)=O.C(O)=O>[Br:19][C:20]1[C:25]([CH2:26][CH:27]=[O:28])=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: COC=Cc1cccnc1Br
Agent: O=C([O-])O
Agent: O=Cc1cccnc1Br
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O=CO
Product: O=CCc1cccnc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.2 %

Procedure:
To a white suspension of sodium hydride (1.36 g, 34 mmol) in DMSO (16 mL) at room temperature was added clear solution of (methoxymethyl)triphenyl)phosphonium chloride in DMSO (40 mL). The mixture became a yellow suspension. To the above suspension was added 2-bromonicotinaldehyde (2.48 g, 13.3 mmol) in DMSO (16 mL) dropwise. The mixture was stirred at room temperature for 20 hours then treated with excess sodium bicarbonate (sat), extracted with ether. The combined ether layer was washed with brine, dried over magnesium sulfate and concentrated. Purification by chromatography on silica gel gave E and Z mixture of 2-bromo-3-(2-methoxyvinyl)pyridine (1.88 g, 66%) as yellow oil. A solution of E and Z mixture of 2-bromo-3-(2-methoxyvinyl)pyridine(1.88 g, 8.79 mmol) in formic acid (96%, 10 mL) was stirred at 60° C. for 16 hours and at 80° C. for 3 hours before cooled to room temperature. Most of formic acid was removed. The mixture was diluted with ethyl acetate, washed with sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. Purification by chromatography on silica gel gave 2-(2-bromopyridin-3-yl)acetaldehyde (864 mg, 53% yield) as yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C1COCC1.O.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>[Cl:8][C:6]1[CH:5]=[C:4]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:3]=[CH:2][N:7]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1ccnc(Cl)n1
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: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cc(Cl)ncn2)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 2,4-dichloro-pyrimidine (1 eq) in THF/H2O (4:3) solution, was added 4-chloro phenyl boronic acid (1 eq), Pd(PPh3)4 (0.01 eq) and Na2CO3 (2 eq) under Ar. The reaction mixture was stirred at reflex for overnight. EtOAc (10 mL) was added. The organic phase was separated, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:Hexane:1:3) to give the desired product as a white powder (71% yield. MS: (ESI), M/Z, 225 (M+1). Retention time: 1.07 min (FA-non polar).
Reaction SMILES: C1(C)C=CC=CC=1.S(Cl)(Cl)=O.[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[CH2:23][CH2:24][C:25]1[N:29]([CH2:30][CH2:31][CH3:32])[N:28]=[C:27]([C:33](O)=[O:34])[CH:26]=1.[OH-].[NH4+:37]>ClCCl>[O:22]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](=[O:12])[N:14]1[CH2:23][CH2:24][C:25]1[N:29]([CH2:30][CH2:31][CH3:32])[N:28]=[C:27]([C:33]([NH2:37])=[O:34])[CH:26]=1
Reactant: CCCn1nc(C(=O)O)cc1CCN1C(=O)c2ccccc2C1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCn1nc(C(N)=O)cc1CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Toluene (70 mL) and thionyl chloride (70 mL) were added to 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxylic acid (28.8 g, 87.8 mmol) and the mixture was heated at reflux for 1 hour, cooled to ambient temperature, and concentrated under reduced pressure to yield a yellow solid. The solid was dissolved in dichloromethane (200 mL). The solution was cooled to 0° C., then concentrated ammonium hydroxide (125 mL) was added in one portion. The resulting mixture was stirred for 1 hour at 0° C. The dichloromethane was removed under reduced pressure. A solid was isolated by filtration, washed with water, and dried to afford 28.70 g of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-propyl-1H-pyrazole-3-carboxamide.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N:20]1([CH2:2][C:3]([NH:5][C:6]2[CH:19]=[CH:18][C:9]3[O:10][C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:8]=3[CH:7]=2)=[O:4])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CN1CCOCC1)Nc1ccc2oc3c(c2c1)CCCCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A mixture of 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), morpholine (0.049 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) was stirred overnight at room temperature. The reaction mixture was concentrated and the crude material was purified using reverse-phase HPLC to provide 2-morpholin-4-yl-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.085 g). MS (ESI) m/z 329 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:10][C:9]=2[C:25]([O:27]CC)=O)=[CH:4][CH:3]=1.[CH3:30][NH2:31]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[N:10][C:9]=2[C:25](=[O:27])[NH:31][CH3:30])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc([C@@H]2CCCN2C(=O)OC(C)(C)C)[nH]c1-c1ccc(Br)cc1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1nc([C@@H]2CCCN2C(=O)OC(C)(C)C)[nH]c1-c1ccc(Br)cc1
Temperature: 70 °C

Procedure:
(S)-ethyl 5-(4-bromophenyl)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole-4-carboxylate (1 g, 2.1 mmol) was dissolved in 2M methylamine in MeOH (35 mL) and heated in a pressure vessel at 70° C. for 48 h. The reaction mixture was concentrated and the residue applied to a Biotage 25 m silica gel cartridge and eluted by 10-100% gradient, ethyl acetate/Hex to give 556 mg (57%). 1H NMR (300 MHz, DMSO-d6) δ 12.5 (br.s, 1H), 7.86-7.82 (m, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 4.83-4.70 (m, 1H), 3.69-3.52 (br.s, 1H), 3.42-3.32 (m, 1H), 2.71 (d, 4.8 Hz, 3H), 2.30-1.78 (m, 4H), 1.19-1.14 (m, 9H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([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>O1CCCC1>[C:19]1([C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:4][CH2:3][CH2:1][OH:2])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethanolamine (5 g, 82 mmol) and triethylamine (11.4 ml, 8.28 g, 82 mmol) were dissolved in dry tetrahydrofuran (50 ml). Chlorotrimethylsilane (10.4 ml, 8.90 g, 82 mmol) was added over five minutes and the mixture was stirred for 30 minutes. The white solid was removed by filtration and washed with dry tetrahydrofuran. The combined filtrate and washings were stirred and triethylamine (11.4 ml, 8.28 g, 82 mmol) was added followed by chlorotriphenylmethane (22.8 g, 82 mmol). The mixture was stirred at ambient temperature for two hours, when it was filtered and the filtrate cooled to 0° C. for 30 minutes. Following a further filtration the liquors were stirred with methanol (60 ml) for fifteen minutes. The solvent was removed under vacuum and the residue crystallised from hot ethyl acetate. The resulting white solid was dried under vacuum at room temperature for 16 hours before triturating successively with diethyl ether (twice) and acetone (twice). The residue was heated with boiling acetone (700 ml) for ten minutes before the solid was collected by filtration, washed with cold acetone and dried under vacuum for four hours to give N-(triphenylmethyl)ethanolamine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([N:13]([CH2:28][CH3:29])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=O)=[CH:20]2)[CH3:12].N1CCCCC1>C(O)C>[CH2:28]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH:26]=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])=[CH:20]2)[CH3:29]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCN(CC)CCOc1ccc2[nH]c(C=O)cc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccccc43)cc2c1
Temperature: 100 °C
Yield: 66.6 %

Procedure:
A mixture of oxindole (26 mg, 0.2 mmol), 5-(2-diethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 50 mg (67%) of the title compound.
Reaction SMILES: C1(COC([NH:11][CH2:12][CH2:13][C:14]2[C:23]3[C:18](=[C:19]([CH2:24][CH2:25][NH:26]C(OCC4C=CC=CC=4)=O)[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=O)C=CC=CC=1>[Pd]>[NH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[C:19]2[CH2:24][CH2:25][NH2:26]
Reactant: O=C(NCCc1cccc2c(CCNC(=O)OCc3ccccc3)cccc12)OCc1ccccc1
Agent: [Pd]
Product: NCCc1cccc2c(CCN)cccc12
Yield: 45.2 %

Procedure:
Scheme IVa, step B: (Phenylmethoxy)-N-[2-(5-{2-[(phenylmethoxy)carbonylamino]ethyl}naphthyl)ethyl]carboxamide (0.6 g, 1.24 mmol) and 10% palladium on carbon (0.5 g, 83 mole %) were combined and hydrogenation was carried out in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, 2-[5-(2-aminoethyl)naphthyl]ethylamine, (0.12 g, 44%) as a colorless oil. Electron spray M.S. 215 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23]C)=[O:22])[O:5][C:6]=1[CH:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17].Cl>CCO.[OH-].[Na+]>[CH3:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([OH:23])=[O:22])[O:5][C:6]=1[CH:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17]
Reactant: COC(=O)c1cccc(-c2cc(C)c(C=C3C(=O)Nc4ccccc43)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2cccc(C(=O)O)c2)oc1C=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A solution of methyl 3-(4-methyl-5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoate (125 mg, 0.35 mmol) in EtOH (5.0 mL) and NaOH (3N, 3.0 mL) was heated at 80° C. for 30 min. The reaction mixture was cooled to rt and pH was adjusted (pH=4) with HCl (6N). The resulting precipitate was collected by filtration to give the desired 3-(4-methyl-5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzoic acid (95 mg). LCMS (ES): m/z 346 [M+1]+.
Reaction SMILES: C([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[C:13](Br)[CH:12]=[CH:11][CH:10]=1)(OC(C)(C)C)=O.[OH-].[K+].[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1>CCOC(C)=O.[Cu]>[N:25]1([C:13]2[N:14]=[C:9]([NH2:8])[CH:10]=[CH:11][CH:12]=2)[CH:29]=[CH:28][CH:27]=[N:26]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cccc(Br)n1
Reactant: c1cn[nH]c1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1cccc(-n2cccn2)n1
Temperature: 160 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
6-(Di-Boc-amino)-2-bromopyridine (1.0 g, 2.68 mmol, ChronTech), copper (341 mg, 5.36 mmol), potassium hydroxide (301 mg, 5.36 mmol), and 1H-pyrazole (1.82 g, 26.8 mmol, Eq: 10) were combined and stirred at 160° C. for 18 h. The reaction mixture was cooled, diluted with EtOAc (50 mL) and the solids removed by filtration. The dark blue filtrate was washed with saturated aqueous NaHCO3 and brine then concentrated onto silica gel and purified by chromatography (40 g RediSep column, 20 to 100% ethyl acetate in hexanes, 20 min) to give 6-(1H-pyrazol-1-yl)pyridin-2-amine (365 mg, 2.28 mmol, 85%) as a white solid. MS (EI/CI) m/z: 161.2 [M+H].
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[NH:29]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]1>>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:29]4[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OC1CCNCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCC(O)CC4)cn3)nc2n1C1CCCC1

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.2 g, 0.529 mmol) and piperidin-4-ol (56 mg, 0.556 mmol) gave 7-cyclopentyl-2-[5-(4-hydroxy-piperidin-1-ylmethyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide is obtained as a white solid (25 mg, 10%) [following purification by preparative LCMS and further purification by SiO2 chromatography, eluting with 0-7% (2N NH3 in MeOH/EtOAc). MS(ESI) m/z 464.3 (M+H)+ (method B).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])C(=O)C2=CC=CC=C12.O.NN.Cl>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCCCCCCCCCCCCCCCCCC(=O)O
Yield: 77.5 %

Procedure:
A mixture of methyl 22-phthalimidodocosanoate (1.5 g, 3.0 mmoles), 40 ml of ethanol and 80% hydrazine hydrate was refluxed for 10 hours. To the reaction mixture was added 11.3 ml of 6N aqueous hydrochloric acid solution, and further refluxed for 1 hour. After removal by filtration of the insoluble matter that formed, the reaction mixture was concentrated under reduced pressure. To the residue were added 30 ml of ethanol and 15 ml of 1N aqueous sodium hydroxide solution, and the resulting mixture was refluxed for 19 hours. After neutralization of the reaction mixture with 6N aqueous hydrochloric acid solution, the precipitates that formed were collected by filtration and recrystallized from ethanol-acetic acid-water to give 22-aminodocosanoic acid (827 mg, 77%) having the following properties.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[CH:10]=1.CCN(C(C)C)C(C)C.C(Cl)(Cl)(Cl)Cl.[P:40]([O-:57])([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CC#N.CN(C1C=CN=CC=1)C>[P:40]([O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C@@H:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][N:12]2[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH:20]=1)([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:57]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1cccc(O)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1cccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S)-4-(2,5-difluorophenyl)-2-(3-hydroxyphenyl)-N,N-dimethyl-2,5-dihydro-1H-pyrrole-1-carboxamide (4-2, 97 mg, 0.28 mmol) in anhydrous CH3CN (1.0 mL) at 0° C. was treated sequentially with iPr2NEt (0.10 mL, 0.6 mmol), CCl4 (0.14 mL, 1.5 mmol), DMAP (catalytic) and lastly dibenzyl phosphite (0.09 mL, 0.40 mmol) and the resulting off-yellow solution was stirred 2 h at 25° C. Upon completion, the reaction was concentrated and directly subjected to flash column chromatography (SiO2, 0-100% EtOAc/hexanes gradient) to provide dibenzyl 3-{(2S)-4-(2,5-difluorophenyl)-1-[(dimethylamino)carbonyl]-2,5-dihydro-1H-pyrrol-2-yl}phenyl phosphate (8-1) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 11H), 7.15 (m, 2H), 7.05 (m, 2H), 6.96 (m, 2H), 6.32 (br s, 1H), 6.10 (m, 1H), 5.12 (d, J=1.8 Hz, 2H), 5.09 (d, J=1.8 Hz, 2H), 4.78 (ddd, J=13.7, 5.8, 1.8 Hz, 1H), 4.47 (d, J=13.7 Hz, 1H), 2.85 (s, 6H). LRMS m/z (M+H) 605.6 found, 605.6 required.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH:12]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:13][C:14](O)=[O:15]>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14](=[O:15])[CH2:13][NH:12][C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:6][CH:5]=1)=[O:11]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: COC(=O)c1ccc(OC(=O)CNC(=O)OCc2ccccc2)cc1
Yield: 70 %

Procedure:
p-Hydroxybenzoic methyl ester and Z-Gly.OH were treated in the same manner as in Example 78 to obtain N-benzyloxycarbonyl glycine p-methoxycarbonylphenyl ester (hereinafter represented by ##STR11## COOCH3 ") in a yield of 70%.
Reaction SMILES: [NH2:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:11]([NH:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(NC(=O)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A solution of 2-amino-3-methylbutanoic acid (500 mg, 4.27 mmol) in 2N NaOH (2.35 ml, 4.69 mmol) was stirred at RT for 30 minutes, then the reaction mixture was cooled at 0° C., and benzoyl chloride (471 μl, 4.05 mmol) and 2N NaOH (2.35 ml, 4.69 mmol) were simultaneously added dropwise from two different syringes. The reaction was stirred at RT for 3 hours. Water was added, the aqueous phase was washed with Et2O, then acidified with 1M HCl and back-extracted with Et2O, dried over Na2SO4 and evaporated. The residue was triturated with i-Pr2O to obtain 2-benzamido-3-methylbutanoic acid (780 mg, 83% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.C1C(=O)N([I:27])C(=O)C1>CS(C)=O>[Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[C:10]3[I:27])[C:6]=2[CH:18]=1
Reactant: O=C1CCC(=O)N1I
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Solvent: CS(C)=O
Product: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (150 g, 459.95 mmol, 1.00 equiv) in DMSO (1500 mL), and NIS (206.1 g, 916.08 mmol, 2.00 equiv). The resulting solution was stirred overnight at 80° C., cooled to room temperature, quenched by the addition of 6 L of water, and diluted with 600 mL of saturated aqueous Na2SO3 and 600 mL saturated aqueous Na2CO3. The solids were collected by filtration and washed with 5×300 mL of water. The crude product was purified by Flash-Prep-HPLC to afford 98 g (47%) of 9-Bromo-8-fluoro-3-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a light brown solid. LC-MS: 452 [M+H]+: 1H-NMR (DMSO, 300 MHz, ppm): δ 8.80 (d, J=8.1 Hz, 1H), 7.76 (s, 1H), 7.20 (s, 1H), 7.14 (d, J=9.6 Hz, 1H), 4.57-4.54 (m, 2H), 4.39-4.36 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].[CH3:13][C:14]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1>[C:14]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[F:12])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:13])[CH3:15]
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2F)CC1
Temperature: 80 °C

Procedure:
A mixture of 20 mmol 1-bromo-2-fluoro-4-trifluoromethyl-benzene, 24.7 mmol n-Boc-piperazine, 0.1 mmol Tris(dibenzylideneacetone)dipalladium chloroform complex, 28.8 mmol sodium-t-butoxide and 0.4 mmol 2-(dicyclohexylphosphino)biphenyl in 50 ml toluene was heated for 16 h at 80° C. After cooling to RT the mixture was treated with 15 g Isolute HM-N and all volatiles were removed under vacuum. The residue was purified on silica eluting with a gradient of heptane/EtOAc to yield after evaporation the title compound.