Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:21]=[C:9]2[NH:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:13](=[O:14])[N:8]2[N:7]=1)=[O:5])C.[OH-].[K+].Cl>C(O)C.O1CCOCC1.C(OCC)(=O)C>[O:14]=[C:13]1[N:8]2[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:21]=[C:9]2[NH:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12]1
Reactant: CCOC(=O)c1cc2[nH]c(-c3ccccc3)cc(=O)n2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1cc2[nH]c(-c3ccccc3)cc(=O)n2n1

Procedure:
To a solution of 50 mg (0.18 mmol) of 7-oxo-5-phenyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester in 4 mL of ethanol (EtOH) was added 26 mg (0.40 mmol) of potassium hydroxide (KOH) and the resulting mixture was heated at reflux for 60 h. The reaction mixture was then acidified with 4 M HCl in dioxane solution, and diluted with ethyl acetate. The organic extract was washed with water and brine, dried over sodium sulfate, and concentrated to give desired 7-oxo-5-phenyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid as indicated by 1H NMR; LC-MS—calcd for C13H9N3O3 [M++H]+: 256.06, found: 256.1. This corresponds to entry 619.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(NB)(C)(C)C.[CH2:11]([N:18]1[CH2:26][CH2:25][CH:24]2[CH:20]([C:21](=O)[C:22]3[CH:29]=[CH:28][S:27][C:23]=32)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].B.Cl.[OH-].[Na+]>C(Cl)Cl>[CH2:11]([N:18]1[CH2:26][CH2:25][CH:24]2[CH:20]([CH2:21][C:22]3[CH:29]=[CH:28][S:27][C:23]=32)[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2ccsc2C2CCN(Cc3ccccc3)CC12
Agent: B
Agent: BNC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: c1ccc(CN2CCC3c4sccc4CC3C2)cc1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A slurry of AlCl3 (2.74 g, 20.76 mmol) in CH2Cl2 (21 ml) was treated with tert-butylaminoborane (3.57 g, 41.52 mmol) at 0° C. and stirred for 30 minutes. Next, a solution of the product from step e) (1.96 g, 6.92 mmol) in CH2Cl2 (15 ml) was added dropwise to the AlCl3/borane solution. After 2 hours at 0° C., the crude reaction mixture was poured into cold 10% HCl, treated with 2 M NaOH to pH 12 and extracted with CH2Cl2 (3×75 ml). The combined organic extracts were washed with brine (75 ml), dried (MgSO4), and the solvent evaporated in vacuo leaving the crude product that was purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (0% to 75% ethyl acetate) to give 1.16 g (62%) of the subtitle compound. MS calculated for C17H19NS+H 270, observed 270.
Reaction SMILES: [ClH:1].[CH2:2]=[CH:3][CH2:4][CH:5]([NH2:9])[C:6]([OH:8])=[O:7].[CH3:10]O>>[ClH:1].[CH3:10][O:7][C:6](=[O:8])[CH:5]([NH2:9])[CH2:4][CH:3]=[CH2:2]
Reactant: CO
Reactant: C=CCC(N)C(=O)O
Agent: Cl
Product: C=CCC(N)C(=O)OC
Reaction time: 8 h
Yield: 100 %

Procedure:
HCl (g) was bubbled through a solution of DL-allylglycine (2.0 g, 17.4 mmol) in methanol (50 mL) at room temperature. The reaction was stirred overnight, concentrated in vacuo, taken up in acetonitrile (50 mL), and re-concentrated to give 2-amino-pent-4-enoic acid methyl ester hydrochloride salt (2.8 g, 100%) as an oil. MS found: (M+CH3CN)+=171.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.CN([CH:17]=[O:18])C.P(Cl)(Cl)(Cl)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][C:6]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)c(C)n1-c1ccccc1
Temperature: 80 °C
Yield: 29.2 %

Procedure:
To a well stirred solution of 2,5-dimethyl-1-phenyl-1H-pyrrole (7.65 g, 44.7 mmol) and DMF (3.6 g, 49.2 mmol) in 70 mL of dry toluene, phosphorus oxychloride (6.9 g, 44.7 mmol) was added in small portions. The mixture was heated to 80° C. for 3 hrs. The solution was allowed to cool to room temperature, then 100 mL of saturated aqueous Na2CO3 was added. The aqueous layer was extracted with EtOAc (100 mL×3). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure, the residue was purified by column chromatography (hexane:EtOAc=10:1) to give 2.6 g of 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carbaldehyde (29%). MS [M++1]=200, LC-MS: tR=1.96 mm.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=2)[N:4]([CH3:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.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>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH2:11])=[N:8][CH:9]=3)[N:4]([CH3:12])[N:3]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: Cn1nc(Br)c2cnc(N)nc21
Reactant: COc1ccc(B(O)O)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nn(C)c3nc(N)ncc23)cc1F
Temperature: 70 °C

Procedure:
3-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 3) (1.2 g, 5.2 mmol) is dissolved in THF (40 ml), under an inert atmosphere of argon. To this is added Pd(PPh3)2Cl2 (0.224 g, 0.32 mmol), [3-fluoro-4-methoxyphenyl]boronic acid (0.98 g, 5.8 mmol) and a solution of Na2CO3 (1.5 g, 14 mmol) dissolved in distilled water (4 ml). The reaction mixture is heated to reflux at 70° C. for 24 hours. After cooling to room temperature the reaction mixture is pre-absorbed onto silica and purification by flash chromatography on silica eluting with iso-hexanes:EtOAc (2:1) affords the title compound as a solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[N:14][OH:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[C:7]=2F)[CH2:3][CH2:2]1.N12CCCN=C1CCCCC2>O1CCCC1>[CH:1]1([NH:4][C:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([I:12])[C:7]=3[O:15][N:14]=2)[CH2:3][CH2:2]1
Reactant: ON=C(NC1CC1)c1cccc(I)c1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Ic1cccc2c(NC3CC3)noc12
Temperature: 150 °C
Yield: 66.2 %

Procedure:
A mixture of N-cyclopropyl-2-fluoro-N′-hydroxy-3-iodobenzimidamide (preparation 22f, 2.15 g, 8.1 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.30 mL, 8.7 mmol) in tetrahydrofuran (13 mL) was heated at 150° C. for 150 minutes in Biotage Initiator Microwave Synthesizer. Then, the mixture was cooled to ambient temperature and evaporated. The residue was partitioned between water and ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated. The crude residue was purified by flash chromatography (3:1 hexanes/ethyl acetate) to give the title compound (1.61 g, 68%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2.[OH:16][CH2:17][CH2:18]CCCC12CC(=O)CC1CCC2.O>C(O)(=O)C>[C:17]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2)(=[O:16])[CH3:18]
Reactant: O=C1CC2CCCC2(CCCCCO)C1
Reactant: O=C1CC2CCC(CCCCCO)C2C1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCCCCCC1CCC2CC(=O)CC12
Temperature: 75 °C

Procedure:
The starting material 2-(5-hydroxypent-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-hydroxypentyl)-2(1H)-pentalenone} (0.8 g, 3.8 mmoles) is diluted with glacial acetic acid (7 ml). The reaction is stirred and heated in a 75° C. oil bath for 24 hours, after which time water (20 ml) is added and the reaction partitioned between ether. The ether layer is separated and the aqueous phase extracted again with ether (2×50 ml). The extracts and the organic phase are combined and neutralized with saturated sodium bicarbonate. The organic phase is dried over anhydrous magnesium sulfate and the remained solvent removed under vacuum leaving a pale yellow oil. The product is kugelrohred under reduced pressure leaving a clear, colorless oil (0.5 g, 2.0 mmoles).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([S:28]([NH:31][NH2:32])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[O:21]=[C:19]([NH:32][NH:31][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:29])=[O:30])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: NNS(=O)(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)NNS(=O)(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.7 mmol), benzenesulfono hydrazide (179.8 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=2:1) and dried so that ivory (E)-tert-butyl 3-(3-oxo-3-(2-(phenylsulfonyl)hydrazinyl)prop-1-enyl)-1H-indole-1carboxylate was obtained (56.2 mg, 16.7%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@H:7]([O:16][C:17](=[O:19])[CH3:18])[C@@H:8]([O:12][C:13](=[O:15])[CH3:14])[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Cl:32][CH2:33][CH2:34][NH:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1>C(Cl)Cl.N1C=CC=CC=1>[C:17]([O:16][C@H:7]([C@@H:8]([O:12][C:13](=[O:15])[CH3:14])[C:9]([N:35]([CH2:34][CH2:33][Cl:32])[C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:38][CH:37]=1)=[O:11])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H](C(=O)O)[C@@H](OC(C)=O)C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1ccc(NCCCl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C(=O)OC(C)(C)C)[C@@H](OC(C)=O)C(=O)N(CCCl)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.8 %

Procedure:
To a solution of (R,R)-2,3-bis(acetyloxy)-butanedioic acid mono tert-butyl ester (3.25 g: Tetrahedron, 45, 3071-3080, 1989) in CH2Cl2 (65 mL), were added oxalyl chloride (1.06 mL) and DMF (50 microL) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes then pyridine (3.82 mL) was added into the mixture at the same temperature. The reaction mixture was stirred at the same temperature for 5 minutes. To the mixture, was added a solution of compound 54-2 (2.5 g) in CH2Cl2 (12.5 mL) at 0° C. The mixture was stirred for 1 hour at the same temperature. Then the mixture was concentrated in vacuo and the resulting residue was suspended in water. The mixture was extracted with EtOAc and the organic layer was washed with 1N HCl aq., sat. NaHCO3 aq., brine, and it was dried with anhyd. Na2SO4. The solvent was removed under reduced pressure to obtain compound 54-3 (5.7 g) as brown oil.
Reaction SMILES: O1[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH:23]C(C(O)CCCCCCCCO)CCCCCCCC(O)=O.OCCCCCCCCCCCCCCCCCCCCCC(O)=O.OCCCCCCCCC=CCCCCCCCC(O)=O.C(O)(=O)CCCCCCCCCCCCCCCCCCCCC(O)=O>>[C:10]([OH:12])(=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:22])=[O:23]
Reactant: O=C(O)CCCCCCCC1OC1CCCCCCCCO
Reactant: O=C(O)CCCCCCCC(O)C(O)CCCCCCCCO
Agent: O=C(O)CCCCCCCC=CCCCCCCCCO
Agent: O=C(O)CCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: O=C(O)CCCCCCCCCCCCCCCCCCCCCO
Product: O=C(O)CCCCCCCC=CCCCCCCCC(=O)O

Procedure:
The process of claim 1 wherein the hydrolysis is carried out at a pH of about 6.5 to about 7.5 and a mixture of9,16-dihydroxyhexadecanoic acid; 9,10-epoxy-18-hydroxyoctadecanoic acid; 9,10,18-trihydroxyoctadecanoic acid (phloionolic acid); 20-hydroxyeicasanoic acid; 22-hydroxydocosanoic acid; 18-hydroxyoctadec-9-enoic acid; docosandioic acid; and octadec-9-enedioic acid is obtained in a ratio of about 1.0-3.0:0-1.0:45.0-75.0:1.0-6.0:10.0-18.0:1.0-5.0:4.0-16.0:1.0-6.0.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.FC1C(O)=C(F)C(F)=C(F)C=1F.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.Cl.[NH2:62][CH2:63][CH2:64][C:65]1[N:69]=[CH:68][NH:67][CH:66]=1>C(OCC)(=O)C.CN(C)C=O>[NH:67]1[CH:66]=[C:65]([CH2:64][CH2:63][NH:62][C:26](=[O:27])[C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH3:29])[N:69]=[CH:68]1
Reactant: NCCc1c[nH]cn1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1c[nH]cn1
Reaction time: 2 h
Yield: 47.3 %

Procedure:
To a solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0.401 g, 1.01 mmol) in dry ethyl acetate (6 mL) and N,N-dimethylformamide (4 mL) under nitrogen atmosphere was added pentafluorophenol (0.189 g, 1.03 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.200 g, 1.04 mmol). This mixture was stirred 2 hours, then triethylamine (0.36 mL, 2.6 mmol) and histamine dihydrochloride (0.240 g, 1.30 mmol) were added. After stirring an additional 40 hours, the resulting mixture was diluted with ethyl acetate (20 mL), and washed with water. The organic phase was dried over MgSO4, concentrated, purified by flash chromatography (SiO2, 4×20 cm, 230-400 mesh, 10% methanol/dichloromethane eluant), and dried for 48 hours under vacuum at 70° C. to provide 0.234 g (47%) of product; 1H NMR (CDCl3) δ1.40-1.60 (2H, m), 1.57 (3H, s), 1.65-2.00 (13H, m), 2.65-2.75 (2H, m), 3.25-3.45 (4H, m), 4.82 (1H, br s), 5.42 (1H, br s), 6.67 (1H, s), 6.81 (1H, br s), 6.91 (1H, br s),7.00-7.20 (2H, m), 7.34 (1H, d, J 7 Hz), 7.46 (1H, s), 7.55 (1H, d, J 7 Hz), 8.67 (1H, br s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([NH:7][C:8]2[C:9](=[O:16])[N:10]([CH3:15])[CH:11]=[C:12](Br)[CH:13]=2)[N:2]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:24][CH:25]=[CH:26][C:27]=1[C:12]1[CH:13]=[C:8]([NH:7][C:3]2[N:2]=[N:1][CH:6]=[CH:5][N:4]=2)[C:9](=[O:16])[N:10]([CH3:15])[CH:11]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2nccnn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3nccnn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 172a (200 mg, 0.71 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (272 mg, 0.71 mmol), Pd(dppf)Cl2 (58 mg, 0.071 mmol), sodium acetate (193 mg, 1.42 mmol), K3PO4 (321 mg, 1.42 mmol), water (0.5 mL) and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was stirred at 100° C. for 3 h. After this time the reaction was filtered and the filtrate was evaporated in vacuo. The resulting residue was recrystallized from ethyl acetate to afford 172b as yellow solid (380 mg, 99%). MS-ESI: [M+H]+ 541.2
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc(O)cc1
Solvent: CCOCC
Product: O=C(Nc1ccc(O)cc1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 4-aminophenol (Aldrich) according to the method described in Example 1c. Melting Point: 167-169° C. (diethylether).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Br[C:8]1[CH:16]=[CH:15][C:14]2[C:10](=[CH:11][N:12]([CH2:17][CH3:18])[N:13]=2)[C:9]=1[C:19](OC)=[O:20].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:17]([N:12]1[CH:11]=[C:10]2[C:14]([CH:15]=[CH:16][CH:8]=[C:9]2[CH2:19][OH:20])=[N:13]1)[CH3:18]
Reactant: CCn1cc2c(C(=O)OC)c(Br)ccc2n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc2c(CO)cccc2n1
Temperature: 25 °C
Reaction time: 50 h
Yield: 90.2 %

Procedure:
To a suspension of lithium aluminum hydride (1.09 g, 28.7 mmol) in tetrahydrofuran (60 mL) was added a solution of methyl 5-bromo-2-ethyl-2H-indazole-4-carboxylate (2.03 g, 7.17 mmol) in tetrahydrofuran (15 mL) under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature for 50 hr. Sodium sulfate decahydrate (10 g) was added under ice-cooling, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate/hexane=25/75→60/40) to give the title compound (1.14 g, yield 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]([NH:20]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)([CH3:19])[CH2:9][O:10][C@@:11]([C:17]#[N:18])([CH3:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=1.C(N[C@H](C(O)=O)CS)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]2([CH3:19])[CH2:9][O:10][C@@:11]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:17]([NH2:18])=[N:20]2)[CH:7]=1
Reactant: C[C@](C#N)(OC[C@](C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F)C(F)(F)F
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@@]1(c2cc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Temperature: 80 °C

Procedure:
To a solution of N—[(R)-1-(5-bromo-2-fluoro-phenyl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-2-nitro-benzenesulfonamide (6.54 g, 11.8 mmol) and N-acetyl-cysteine (2.4 g, 26.0 mmol) in MeOH (80 ml) was added K2CO3 (3.62 g, 26.0 mmol) and the reaction mixture was heated at 80° C. for 16 h. After removal of the solvent the residue was dissolved in water and extracted with EtOAc. Combined extracts were washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated to provide the title compound after chromatographic purification over silica gel (hexane-EtOAc 10:1 to 1:2 containing 0.03% NEt3) as a yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.58; HPLC RtH5=0.843 min; ESIMS: 369, 371 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 7.66 (dd, 1H), 7.35 (m, 1H), 6.91 (dd, 1H), 3.97 (m, 2H), 1.53 (s, 3H), 1.49 (s, 3H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.CCCCCC.[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[Cl:29].[N:30]([Si](C)(C)C)=[C:31]=[O:32].C(O)(=O)C>C(OCC)C.O>[Cl:22][C:23]1[C:24]([C:31]([NH2:30])=[O:32])=[N:25][CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: Clc1ccncc1Cl
Reactant: C[Si](C)(C)N=C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOCC
Product: NC(=O)c1nccc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (31.1 g, 0.22 mol) in diethyl ether (400 mL) at 0° C. was added n-BuLi in hexane (1.6 M, 138.0 mL, 0.22 mol) via syringe over 15 min. The resulting solution was stirred at 0° C. for 0.5 h and at −78° C. for 0.5 h. To this mixture was then slowly added a solution of 3,4-dichloropyridine (29.6 g, 0.20 mol) in diethyl ether (20 mL) via syringe over 15 min. The resulting mixture was stirred at −78° C. for 2 h before the addition of isocyanatotrimethylsilane (85% pure, 40.0 mL, 0.30 mol). The source for isocyanatotrimethylsilane is TCI. After the addition, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature over 1 h. The reaction mixture was quenched with acetic acid (40 g, 0.67 mol) and 200 mL of water. The mixture was allowed to stir overnight and the white solid that formed was collected through filtration and washed with water. The filtrate was extracted with ethyl acetate (3×300 mL). The solid that was collected previously was dissolved in the combined organic layers, and the resulting solution was washed with brine (2×200 mL), dried over MgSO4 and concentrated in vacuo. The residue was suspended in 200 mL of diethyl ether and sonicated. The remaining solid was collected through filtration and washed with minimum amount of diethyl ether to provide 3,4-dichloropicolinamide (14.8 g, 39%).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH2:4][CH:5]([CH:7](NC([C@H]1O[C@@H]1C(O)=O)=O)[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14]N)=O)[CH3:6].C[N:26]([CH3:28])C>O>[CH2:13]1[C:12]2[C:11](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:10]([CH2:8][CH2:7][C:5]2[CH:4]=[CH:3][N:26]=[CH:28][CH:6]=2)[CH2:14]1
Reactant: CCC(C)C(NC(=O)[C@H]1O[C@@H]1C(=O)O)C(=O)NCCCCN
Reactant: CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)CCN2CCc1ccncc1
Reaction time: 0.5 h

Procedure:
Another core-shell polymer, according to the present invention, was prepared by combining 200 g of SP-1 with 533 g of demineralized water and adjusting the pH to 10 with sodium hydroxide. The mixture was combined with 267 g of CPI-2 and stirred for 30 minutes. 59.1 g of trimethylamine (25% aq.) were added and allowed to stir for one hour. After one hour, the pH was raised to 12 and the mixture was vacuum distilled for 3 hours to remove residual trimethylamine.