Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18](=[O:19])[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]#[N:34])=[C:23]([F:35])[CH:22]=3)=[C:16]([CH2:36][CH2:37][CH2:38][CH3:39])[N:15]3[N:40]=[CH:41][CH:42]=[C:14]23)[CH2:9][CH2:8]1)C.[CH3:44][Mg]Br.C([O:50][CH2:51][CH3:52])(=O)C>O1CCCC1>[CH2:36]([C:16]1[N:15]2[N:40]=[CH:41][CH:42]=[C:14]2[N:13]([C@H:10]2[CH2:9][CH2:8][C@H:7]([O:6][CH2:5][C:51]([OH:50])([CH3:52])[CH3:44])[CH2:12][CH2:11]2)[C:18](=[O:19])[C:17]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:23]([F:35])[CH:22]=1)[CH2:37][CH2:38][CH3:39]
Reactant: C[Mg]Br
Reactant: CCOC(C)=O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Solvent: C1CCOC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of ethyl[(trans-4-{7-butyl-6-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-5-oxopyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (0.47 g) in tetrahydrofuran (4 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 1.8 mL) at 0° C., and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.32 g, 66%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=O)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.ClC(OCC(C)C)=O.[NH3:47]>C(N(CC)CC)C>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28]([NH2:47])=[O:30])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: N
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1cccc(C[C@@H]2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (0.2 g) in a tetrahydrofuran (10 ml) were added isobutyl chloroformate (0.15 ml.) and triethylamine (0.2 ml) at 0° C. under N2. After being stirred for 30 minutes, NH3 (5 ml, 4M solution in methanol) was added to the mixture. After being stirred for 30 minutes, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and 1N-NaOH and the organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue and 10% Pd/C (0.2 g) in methanol (20 ml) was stirred under H2 for 8 hours. The catalyst was filtered off and filtrate was evaporated in vacuo. The residue was purified by chromatography on silica gel to give and the obtained residue was purified by chromatography on silica gel to give 3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-1-cyclohexyl]methyl}benzamide (0.11 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[OH:18][CH2:19][CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[CH:21][CH2:20][CH2:19][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1OCc1ccccc1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)O
Product: OCCC=Cc1ccccc1OCc1ccccc1
Yield: 89.3 %

Procedure:
2-Benzyloxybenzaldehyde (8 g; 37 mmole), (3-hydroxypropyl)triphenylphosponium bromide (19.5 g; 47 mmole) and potassium carbonate (6.6 g; 48 mmole) were mixed in isopropanol. The reaction mixture was refluxed over night then filtered and the filtrate was evaporated. Chromatography using ethyl acetate:dichloromethane (up to 5%) as eluant gave 8.4 g (87.6%) of 4-(2-benzyloxyphenyl)-3-buten-1-ol. Both cis and trans 4-(2-benzyloxyphenyl)-3-buten-1-ol were formed according to NMR.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:9])(C)(C)C>CC(O)=O.C1(C)C=CC=CC=1>[C:19]1([N:18]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH:8]([NH2:7])[CH3:9])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(N)c1nc2ccccc2n1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
[1-(2-Phenylaminophenylcarbamoyl)ethyl]carbamic acid tertbutyl ester (400 mg, 1.59 mmol) was suspended in AcOH (4 mL) and the resulting mixture was heated at 80° C. for 12 h whereupon the mixture clarified. The cooled solution was diluted with toluene and volatiles removed under reduced pressure. The resulting residue was stirred with TFA (4 mL) for 2 h and the resulting solution was loaded onto an SCX-2 cartridge which was initially washed with MeOH. The product was eluted with 2M NH3/MeOH and further purified by column chromatography (Si—PCC, gradient 0-6% MeOH in DCM) affording 1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine as a white crystalline solid (211 mg, 80%). LCMS: RT 0.27 min [M−NH2]+ 221.1. The enantiomers, (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine and (R)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine can be resolved and separated. Alternatively, (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine can be prepared from enantiopure (S)-2-tertbutoxycarbonylaminopropionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11].C(N(CC)CC)C.CCCCCC>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][CH2:9][OH:12])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Clc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: OCC#Cc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture of 6 g of 1-chloro-4-iodo-benzene, 1.8 ml of propargyl alcohol and 5.2 ml of triethylamine in 30 ml of chloroform is placed under a nitrogen atmosphere. 208 mg of bis(triphenylphosphine)palladium(II) dichloride and 98 mg of copper(I) iodide are added thereto. The reaction mixture is stirred for one hour at 40° C. 300 ml of hot n-hexane are then added. The n-hexane phase is decanted off. The residue is again digested with 200 ml of hot n-hexane, and the n-hexane phase is decanted off. The n-hexane phases are concentrated and the residue is subjected to flash chromatography on silica gel with ethyl acetate/n-hexane (1:4), yielding 3-(4-chloro-phenyl)-2-propyn-1-ol, which can be recrystallised from n-hexane, m.p. 78-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:3]=1[C:4]([NH:6][CH:7]([C:27]#[N:28])[CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])[CH:13]=[CH:12]2)=[O:5].C[Si]([N:38]=[N+:39]=[N-:40])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:3]=1[C:4]([NH:6][CH:7]([C:27]1[NH:40][N:39]=[N:38][N:28]=1)[CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])[CH:13]=[CH:12]2)=[O:5]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(NC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)c1nnn[nH]1)c1c(Cl)cccc1Cl
Yield: 36 %

Procedure:
To 2,6-dichloro-N-{1-cyano-2-[2-(2,6-dichlorophenyl)-6-quinolinyl]ethyl}benzamide 58 (0.358 g) in toluene (5 ml) are added trimethylsilyl azide (184 μl) and dibutyltin oxide (17 mg). The solution is heated at reflux overnight, then evaporated under vacuum. The resulting residue is purified twice over silica gel using one time CH2Cl2/CH3OH 85/15 as eluent and the second time CH2Cl2/(CH3OH-10% NH4OH) 85/15 to give 2,6-dichloro-N-[2-[2-(2,6-dichlorophenyl)-6-quinolinyl]-1-(1H-tetraazol-5-yl)ethyl]benzamide 126.
Reaction SMILES: [OH-].[Li+].C(O/[C:6](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:34])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])[N:20]=2)=[CH:15][CH:14]=1)/[C:7]([O:9]CC)=[O:8])C.[C:35](O)(=[O:37])[CH3:36].O>O1CCCC1.C(OCC)(=O)C>[CH3:36][CH2:35][O:37]/[C:12](/[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:34])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])[N:20]=2)=[CH:15][CH:14]=1)=[CH:6]\[C:7]([OH:9])=[O:8]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)n1
Reactant: CC(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C(=C/C(=O)O)OCC)cc2)n1
Temperature: 68 °C
Reaction time: 18 h

Procedure:
0.68 mL (0.68 mmol) of aqueous 1 M lithium hydroxide solution is added to a solution of 0.20 g (0.45 mmol) of ethyl (Z)-2-ethoxy-3-{4-[6-(1-methyl-3-pentylureido)pyrid-2-yl]phenyl}acrylate in 6 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 18 hours. After cooling, the reaction is worked up by addition of 0.68 mL (0.68 mmol) of aqueous 1 M acetic acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. After filtration, the solvents are evaporated off.
Reaction SMILES: [S:1](/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7])[C:2]#[N:3].C1CCN2C(=NCCC2)CC1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(#N)C>[S:1](/[CH:4]=[CH:5]\[C:6]([O:8][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])[C:2]#[N:3]
Reactant: N#CS/C=C\C(=O)O
Reactant: BrCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CC#N
Product: N#CS/C=C\C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
To a stirred suspension of compound 2 (3.0 g., 0.023 mole) in dry acetonitrile (40 ml), a solution of DBU (3.54 g., 0.023 mole) in 10 ml of dry acetonitrile was added dropwise, keeping the temperature of the mixture below 25° C. To the resulting solution was added dropwise a solution of benzyl bromide (4.0 g., 0.023 mole) in 15 ml of dry acetonitrile at room temperature. After stirring for 5 hours, the mixture was poured into water, and extracted with ether. The ether extract was washed with water, dried (MgSO4) and concentrated to give an oil which solidified upon standing, 4.3 g. The solid recrystallized from ethanol/hexane mixture as plate-like crystals: mp 48.5°-50.5° C.; IR (KBr) 1695, 2180 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1.[CH2:22]([O:24][C:25](=[O:44])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([NH2:39])=[CH:37][C:36]([C:40]([CH3:43])([CH3:42])[CH3:41])=[N:35]2)[CH:29]=1)[CH3:23]>CN(C=O)C>[CH2:22]([O:24][C:25](=[O:44])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([NH:39][C:15]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:16])=[CH:37][C:36]([C:40]([CH3:43])([CH3:42])[CH3:41])=[N:35]2)[CH:29]=1)[CH3:23]
Reactant: COc1ccc(N)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A mixture of 4-methoxy-phenylamine (123 mg, 1.0 mmol) and CDI (165 mg, 1.0 mmol) in DMF (2 mL) was stirred at RT for 30 min, and was then added a solution of Example Z (315 mg, 1.0 mmol) in DMF (2 mL). The resulting mixture was stirred at RT overnight then quenched with of water (50 mL). The reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic extracts were washed with brine, dried (NaSO4), filtered, concentrated under reduced presume to yield a residue which was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[3-(4-methoxy-phenyl)-ureido]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester (210 mg, 45%). 1H-NMR (CD3OD): 7.46 (t, J=7.6 Hz, 1H), 7.38 (s, 1H), 7.34 (d, J=7.6 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 6.38 (s, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.75 (s, 3H), 3.00 (t, J=7.6 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 1.33 (s, 9H), 1.20 (t, J=7.6 Hz, 3H); MS (ESI) m/z: 465 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=O.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([O-])=[O:14].C(O)C.N1CCCCC1>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[C:12]([C:11]([O:17][CH2:18][CH3:19])=[O:16])[C:13](=[O:14])[O:10]2
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=Cc1c(O)cccc1Cl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc2c(Cl)cccc2oc1=O
Yield: 57.8 %

Procedure:
15 g (0.0958 mole) of 2-chloro-6-hydroxy-benzaldehyde, 16.7 g (0.105 mole) ethyl malonate, 40 mL ethanol, 0.6 mL piperidine and 0.1 mL acetic acid are refluxed for 5 hours. After cooling the resultant product is dried. After drying, 14 g of ethyl 5-chlorocoumarin-3-carboxylate are obtained. (Yield=58%). Melting pointG =142°-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[C:10]([C:14]1[O:18][N:17]=[C:16]([NH:19][C:20]([CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[O:21])[CH:15]=1)([CH3:13])([CH3:12])[CH3:11].Cl.C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:10]([C:14]1[O:18][N:17]=[C:16]([NH:19][C:20]([CH:22]2[CH2:27][CH2:26][CH2:25][N:24]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:23]2)=[O:21])[CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1cc(NC(=O)C2CCCNC2)no1
Reactant: ClCc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)C2CCCN(Cc3ccc(Cl)cc3)C2)no1

Procedure:
To a solution of 4-chlorobenzyl chloride (134 mg; 0.832 mmol) in DMF (3 mL) is added piperidine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (238.86 mg; 0.83 mmol) and N,N-diisopropylethylamine (0.331 mL; 1.9 mmol). The reaction mixture is left stirring at room temperature for 18 hours in the presence of catalytic amount of 4-dimethylaminopyridine (1 mg). The mixture is diluted with ethyl acetate and washed with water 3 times then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica using methanol/methylene chloride provides the title compound, m/z 376/378 [M+H+].
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C(Cl)[Cl:30]>>[ClH:30].[ClH:30].[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc2ncccc2o1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: c1cnc2cc([C@H]3CCCN3)oc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 614 mg (2.13 mmol) sample of 2-(1-BOC-2-(R)-pyrrolidinyl)furo[3,2-b]pyridine, from step 3b above, was dissolved in 3 mL of CH2Cl2, and the solution was cooled to 0° C. To this solution was added 3 mL of TFA, and the reaction mixture was stirred at 0° C. for 2 hours. The reaction was quenched with saturated aqueous K2CO3 solution, and the mixture was extracted with CH2Cl2. The organic extract was dried over MgSO4, and the solvent was removed. The residue was purified by chromatography on silica gel and treated with HCl in Et2O as described in Example 1e above to obtain the title compound: 1H NMR (D2O, 300 MHz) δ 2.17-2.69 (m, 4H), 3.52-3.59 (m, 2H), 5.14 (t, 1H, J=5.5 Hz), 7.42 (t, 1H, J=1 Hz), 7.80 (dd, 1H, J=5.6, 8.5 Hz), 8.5 (dt, 1H, J=1, 8.5 Hz), 8.70 (dd, 1H, J=1, 5.5 Hz); MS m/z: 189 (M+H)+, 206 (M+NH4)+ ; Anal. Calcd for C11H12N2O.2.0 HCl.0.5 H2O: C, 48.90; H, 5.60; N, 10.90. Found: C, 48.75; H, 5.74; N, 10.11.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:17](=[O:18])[C:16]([O:19][CH3:20])=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)[C:14]2=[O:21])=[C:9]1[C:31]([O:33]C)=[O:32])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:17](=[O:18])[C:16]([O:19][CH3:20])=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)[C:14]2=[O:21])=[C:9]1[C:31]([OH:33])=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1c2c(c(OC)c(=O)n1CC(=O)OC(C)(C)C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c2c(c(C(=O)O)n(CC(=O)OC(C)(C)C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.49 g, 0.96 mmol) and lithium hydroxide monohydrate (0.12 g, 2.9 mmol) in a mixture of tetrahydrofuran (3 mL) and water (2 mL) was stirred at room temperature for one hour. The reaction mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and dilute hydrochloric acid. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound. This was used in the following step without further purification. ES MS M+1=495
Reaction SMILES: [CH3:1][NH:2][C:3]1C2C(=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[C:6]([Br:19])=[CH:5][CH:4]=1.C(O[C:24](=[O:26])[CH3:25])(=O)C.OS(O)(=O)=O.[OH-].[Na+].[CH3:34][CH2:35][O:36]C(C)=O>O>[C:35]([N:2]([CH3:1])[C:3]1[C:25]2[C:24](=[O:26])[C:10]3[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:18])[C:7]=2[C:6]([Br:19])=[CH:5][CH:4]=1)(=[O:36])[CH3:34]
Reactant: CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N(C)c1ccc(Br)c2c1C(=O)c1ccccc1C2=O

Procedure:
A 250 ml flask equipped with a mechanical stirred was charged with 30 g (95 mmole) of 1-methylamino-4-bromoanthraquinone (purchased from Sandoz), 19.5 g (191 mmole) of acetic anhydride, and 0.23 g of 96% H2SO4. The sludgelike mixture was heated and stirred at 110° for 30 minutes. The reaction mixture was cooled to 0° and 50 ml of H2O was added. After stirring 1/2 hour, 55 ml of 30% NaOH was added and the entire mixture was then transferred to a pressure reactor for the following reaction. A TLC (EtOAc) showed only a single product in the reaction.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12]C(O)=O)(=O)[CH3:2].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][CH:12]=[C:1]([CH3:2])[C:4]=2[CH:9]=1
Reactant: CC(=O)c1cc(Br)ccc1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1coc2ccc(Br)cc12
Temperature: 140 °C
Reaction time: 3.5 h

Procedure:
A solution of [(2-acetyl-4-bromophenyl)oxy]acetic acid (1.648 mmol) in acetic acid (2.075 mL) was treated with sodium acetate (9.89 mmol) and acetic anhydride (21.42 mmol). The reaction solution was heated with stirring to 140° C. for 3.5 h. Analysis by LCMS showed a major product that did not ionize, and consumption of starting material. The mixture was diluted with water and ethyl acetate and was washed with 1N aq NaOH until the aqueous phase was basic (pH˜12). The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to an oil in vacuo. No further purification was carried out. 1H NMR (400 MHz, chloroform-d) δ ppm 7.67 (d, J=1.77 Hz, 1H) 7.38-7.45 (m, 2H) 7.32-7.38 (m, 1H) 2.24 (d, J=1.26 Hz, 3H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:29]2[N:30]=[C:31]([O:38][C@@H:39]([C@H:41]3[CH2:45][NH:44][C:43](=[O:46])[CH2:42]3)[CH3:40])[C:32]3[N:33]([N:35]=[CH:36][CH:37]=3)[CH:34]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>ClCCl>[C:1]([N:26]1[CH2:25][CH2:24][N:23]([C:22]2[CH:21]=[CH:20][C:19]([C:29]3[N:30]=[C:31]([O:38][C@@H:39]([C@H:41]4[CH2:45][NH:44][C:43](=[O:46])[CH2:42]4)[CH3:40])[C:32]4[N:33]([N:35]=[CH:36][CH:37]=4)[CH:34]=3)=[CH:18][C:17]=2[O:16][CH3:15])[CH2:28][CH2:27]1)(=[O:3])[CH3:2]
Reactant: COc1cc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cn3nccc3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(C)=O)CC1
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Acetic anhydride (5 μL, 0.05 mmol) was added to a solution of (R)-4-((R)-1-(6-(3-methoxy-4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.48 (22.4 mg, 0.04 mmol) and triethylamine (0.05 ml, 0.33 mmol) in dichloromethane (1.8 mL) at room temperature. After two hours, reaction mixture was loaded directly onto silica and purified (0-8% methanol/dichloromethane) to yield (R)-4-((R)-1-((6-(4-(4-acetylpiperazin-1-yl)-3-methoxyphenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.49 (15.9 mg).
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:17])[NH:8]C(OC(C)(C)C)=O.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)=[O:17])[NH2:8].[F:31][C:32]([F:37])([F:36])[C:33]([O-:35])=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1ccc(O)cc1
Reactant: O=C(O)C(F)(F)F
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(O)cc1
Product: O=C([O-])C(F)(F)F
Yield: 70 %

Procedure:
Prepared analogously to Example 5e) from (R)-N5 -[amino(nitroimino)methyl]-N2 -(tert.-butoxycarbonyl)-N-[(4-hydroxyphenyl)methyl]-ornithinamide and trifluoroacetic acid in a yield of 70% of theory. Colourless amorphous substance Rf 0.3 (test conditions as in Example 9a).