Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:3]=1.[CH3:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)[N:3]=[C:2]([C:34]3[N:33]([CH3:32])[CH:37]=[CH:36][N:35]=3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(Cl)n2)cc1Cl
Reactant: Cn1ccnc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cn1ccnc1-c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Temperature: 150 °C

Procedure:
To a mixture of 2-chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (200 mg, 0.43 mmol), 1-methyl-1H-imidazole (42 mg, 0.51 mmol), CuI (161 mg, 0.86 mmol), MgO (21 mg, 051 mmol), and PPh3 (22 mg, 0.086 mmol) in dioxane add Pd(OAc)2 (5 mg, mg, 0.021 mmol). Purge the reaction mixture for 10 minutes with dry N2. Heat the mixture at 150° C. for 24 hours, cool to room temperature, and partition between water and EtOAc. Dry the solution (Na2SO4), concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with DCM:MeOH:NH4OH (95:5:1) to afford 4-(3-chloro-4-fluoro-phenyl)-2-(1-methyl-1H-imidazol-2-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine. 1H NMR (2HCl salt, 300 MHz, DMSO-d6): δ3.35 (m, 4H); 4.01 (m, 4H); 4.31 (s, 3H, NCH3); 7.23 (m, 1H, Ar—H); 7.63 (m, 2H); 7.89 (s, 1H); 7.97 (s, 1H); 8.11 (m, 1H); 8.43 (m, 1H); 8.54 (m, 1H); 8.66 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:18][C:19]1[N:20]=[CH:21][N:22](S(C2C=CC(C)=CC=2)(=O)=O)[CH:23]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:35].O1CCOCC1>>[ClH:35].[NH2:7][C@@H:8]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)=[O:10]
Reactant: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N3CCC(O)CC3)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-{2-(4-Hydroxy-piperidin-1-yl)-2-oxo-1-[1-(toluene-4-sulfonyl)-1H-imidazol-4-ylmethyl]-ethyl}-carbamic acid tert-butyl ester (512 mg, 1.0 mmol) was dissolved in 4 M HCl-dioxane (3 mL) at 0° C. The mixture was stirred at 25° C. for 1.5 hours, concentrated and the residue triturated with ether. Yield, 422 mg, 105%; TSPMS 283 (MH+, 100%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1>C(O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(COC2CCCCO2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.8 %

Procedure:
To a solution of 4-(2-tetrahydropyranyloxymethyl)nitrobenzene (59.7 g, 0.256 mol) in ethanol (EtOH) (300 ml) was added under nitrogen atmosphere at room temperature 10% Pd/C (5.97 g), and catalytic hydrogenation was carried out. The mixture was stirred at room temperature for 24 hours. After the reaction completed, the catalyst was filtered off, and the organic layer was concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 4-(2-tetrahydropyranyloxymethyl)-aniline (39.7 g, 76%) as syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[C:26]([CH3:36])=[N:27][N:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH:29]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[C:26]([CH3:36])=[N:27][N:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH:29]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn(-c4ccccn4)nc3C)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3cn(-c4ccccn4)nc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (680 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid (620 mg, yield: 97%). This was recrystallized from acetone-hexane. Melting point: 126–127° C.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([CH:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22].[BH4-].[Na+]>CO>[CH2:21]([CH:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH:26][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:22]
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: CCC(CC)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)CCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(OC)c1
Reaction time: 8 h
Yield: 31.7 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719 Part A) (0.700 g, 2.56 mmol), 3-ethylpentylamine (Example 733, Part B) (0.310 g, 2.69 mmol) and 3 Å molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, then add EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate. Dissolve the product in ether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and then concentrate to about a quarter of the volume. Filter the precipitate to give the title compound (0.302 g, 31.7%): TOF MS ES+ 373.2 (M+H)+, HRMS calcd for C20H29N4O3 373.2240 (M+H)+, found 373.2247, time 0.39 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 0-20% over 5 min, 20-95% over 18], tR=12.0 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:39]=[C:40]([NH2:44])[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:39]=[C:40]([NH:44][C:25]([C:24]3[CH:23]=[N:22][N:15]4[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]([C:4]5[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=5)=[N:13][C:14]=34)=[O:26])[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1
Reactant: CN1CCN(S(=O)(=O)c2cccc(N)c2)CC1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCN(C)CC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 3-(4-methyl-piperazine-1-sulfonyl)-phenylamine [CAS 436095-35-1] according to general procedure II. Yellow solid. MS (ISP) 627.4 [(M+H)+]; mp 199° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[Cl:25][C:26]1[CH:27]=[C:28]([CH2:33]/[C:34](=[N:37]/[H])/[NH:35]O)[CH:29]=[CH:30][C:31]=1[Cl:32].[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:35]=[C:34]([CH2:33][C:28]3[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=3)[N:37]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: [H]/N=C(/Cc1ccc(Cl)c(Cl)c1)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(Cc3ccc(Cl)c(Cl)c3)no2)c(=O)c2[nH]c(Cl)nc21
Yield: 47.7 %

Procedure:
Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (71 mg, 0.2 mmol), (1Z)-2-(3,4-dichlorophenyl)-N-hydroxyethanimidamide (48 mg, 0.22 mmol) and 21% by wt. ethanolic sodium ethoxide (0.111 ml, 0.3 mmol) were heated together in EtOH (1 ml) in the microwave reactor at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl, the organic phase separated and evaporated, and the crude product was purified by MDAP to give the title compound as a solid (48.8 mg).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]([C:14]2[O:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[N:15]=2)=[C:12]([Cl:22])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO>[Cl:3][C:4]1[C:13]([C:14]2[O:18][N:17]=[C:16]([CH:19]([CH3:20])[CH3:21])[N:15]=2)=[C:12]([Cl:22])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(Cl)c(-c2nc(C(C)C)no2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1noc(-c2c(Cl)ccc(C(=O)O)c2Cl)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.7 %

Procedure:
2.06 g (51.5 mmol) of sodium hydroxide in 150 ml of methanol were added dropwise to 13.50 g (42.9 mmol) of methyl 2,4-dichloro-3-(3-i-propyl-1,2,4-oxadiazol-5-yl)benzoate in 330 ml of methanol. The mixture was stirred at room temperature for 12 hours and a further 0.52 g (12.9 mmol) of sodium hydroxide were added. The mixture was subsequently stirred at room temperature for a further 48 hours and the solvent was then removed. The residue was taken up in 200 ml of 5% strength potassium carbonate solution and washed once with ethyl acetate and twice with methylene chloride. The aqueous phase that remained was then acidified (pH=2) using hydrochloric acid and extracted repeatedly with methylene chloride. The combined organic phases were dried and concentrated. 7.20 g (56% of theory) of 2,4-dichloro-3-(3-i-propyl-1,2,4-oxadiazol-5-yl)benzoic acid were obtained.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:16]=[CH:15]1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:3]1([C:16]2[C:17]3[C:22](=[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:20]=[CH:19][CH:18]=3)[NH:14][CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(O)CCc2cc(F)ccc21
Reactant: CS(=O)(=O)Nc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(c2c[nH]c3c(NS(C)(=O)=O)cccc23)CCc2cc(F)ccc21
Yield: 84.3 %

Procedure:
Combine 1-ethyl-5-fluoro-indan-1-ol (502 mg, 2.79 mmol, 1.30 equivalents), N-(1H-Indol-7-yl)-methanesulfonamide (450 mg, 2.14 mmol, 1.00 equivalents), and trifluoroacetic acid (0.25 ml, 3.21 mmol, 1.50 equivalents) in dichloromethane (5 ml) and stir at room temperature under nitrogen overnight. Load the solution on silica and purify eluting with 0 to 100% ethyl acetate/hexanes over 25 minutes to obtain the title compound (672 mg, 84%). LC-MS m/z 373.0 (M++1). The racemic mixture is separated on a Chiralcel OJ 8×33 cm column eluting with methanol with 0.2% dimethylethylamine (flow: 375 ml/min, UV detection at 230 nm) to provide the individual enantiomers, Examples 1A and 1B, in 96.3% ee and 97.4% ee, respectively.
Reaction SMILES: CO[C:3]1[C:8](OC)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][N:18]([CH3:20])[CH3:19].Cl.Br>>[C:11]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][N:18]([CH3:19])[CH3:20]
Reactant: COc1cccc(-c2ccccc2CN(C)C)c1OC
Agent: Br
Agent: Cl
Product: CN(C)Cc1ccccc1-c1ccccc1

Procedure:
(2′,3′-dimethoxybiphenyl-2-ylmethyl)dimethylamine, and the corresponding hydrochloride and the corresponding hydrobromide;
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CN1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.N1C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1cccc(O)c1
Reactant: Brc1ccccn1
Agent: [Cu]I
Agent: Cn1ccnc1
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Product: Oc1cccc(Oc2ccccn2)c1
Temperature: 140 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
Under a nitrogen atmosphere, a pressure vessel was charged with a magnetic stir bar, resorcinol (110 mmol), 2-bromopyridine (100 mmol), 1-methylimidazole (5 mmol), and potassium carbonate (200 mmol). Pyridine (80 mL) was added and bubbled with nitrogen for 20 minutes before copper(I) iodide (10 mmol) was added and bubbled 10 minutes further. The vessel was sealed and heated to 140° C. while stirring. After 2 days, the solution was allowed to cool. The solids were filtered off and rinsed with a 50:50 mixture of toluene and methanol. The filtrate was reduced by rotary evaporation and 150 ml of water containing 10 mL glacial acetic acid was added and shaken vigorously. The water was decanted off and 50 mL of DCM was added, forming an off white precipitate which was collected by vacuum filtration and dried with ether, resulting in the pure product 3-(pyridin-2-yloxy)phenol with a 55% yield. 1H NMR (CDCl3): 5.98 (s, 1H), 6.59 (s, 1H), 6.62-6.69 (m, 2H), 6.94 (d, 1H), f 7.02 (dd, 1H), 7.23 (vt, 1H), 7.70 (dd, 1H), 8.23 (b, 1H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:14][CH3:15])[N:3]=1.[F-:16].[Cs+]>CS(C)=O>[F:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:14][CH3:15])[N:3]=1
Reactant: [F-]
Reactant: COc1ccc2c(Cl)nc(OC)cc2c1
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1ccc2c(F)nc(OC)cc2c1
Temperature: 140 °C

Procedure:
To a solution of 1-chloro-3,6-dimethoxyisoquinoline (300 mg, 1.341 mmol) in DMSO (5 mL) was added CsF (408 mg, 2.68 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with Ethylacteate and washed with water, and brine. The organic phase was collected, dried over MgSO4, and concentrated under vacuum to give the crude product 1-fluoro-3,6-dimethoxyisoquinoline (250 mg, 90% yield) as a reddish brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.93 (d, J=9.0 Hz, 1H), 7.03 (dd, J=9.3, 2.3 Hz, 1H), 6.95 (t, J=1.9 Hz, 1H), 6.75 (s, 1H), 4.01-3.96 (m, 3H), 3.96-3.90 (m, 3H). MS: MS m/z 208.07(M++1).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:18])[O:16][O:17][C@@:10]42[C@H:5]([C@H:6]([CH3:30])[C@H:7]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=2)[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:30])[C@@H:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: C[C@@H]1[C@H](OCc2ccc(C(=O)O)cc2)O[C@@H]2O[C@@]3(C)CC[C@@H]4[C@@H](C)CC[C@@H]1[C@]24OO3
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: C[C@H]1[C@@H](OCc2ccc(C(=O)O)cc2)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Yield: 119.5 %

Procedure:
8 arm PEG (20 Kda) (2.0 g, ˜0.10 mmol) was dissolved in CHCl3 (300 ml) and the solvent was removed in vacuo. The gum was dissolved in CH2Cl2 (˜30 ml) under an argon atmosphere and to the solution was added artelinic acid (0.85 g, 2.00 mmol), 1-hydroxybenzotriazole (0.085 g, 0.63 mmol) and 4-(dimethylamino)pyridine (cat.). The mixture was allowed to reflux overnight under an argon atmosphere. The cloudy mixture was concentrated to dryness and to the residue was added CH2Cl2 (˜5 ml). To the slightly turbid solution was added EtOH (˜100 ml) and a white solid was obtained upon cooling in an ice bath for ˜3 h. Repeating the purification afforded pure 8 arm PEG (20 Kda) artelinate (1.00 g) as a water-soluble white solid. 1H NMR (CDCl3, 300 MHz) indicated a near quantitative conversion. HPLC (C-4 reversed-phase) indicated a mixture of products arising from different degrees of substitution. Partial 1H NMR data (CDCl3, 300 MHz): δ 0.94 (s, 24H, C9—CH3), 0.95 (s, 24H, C6—CH3), 1.44 (s, 24H, C3—CH3), 2.68 (m, 8H, H-9), 3.63 (bs, 1818H, PEG backbone), 4.45 (t, 16H, J 4.4 Hz, PEG—OCH2CH2O—COAr), 4.56 (d, 8H, J 13.1 Hz, OCHAHB—Ar), 4.91-4.96 (m, 16H, H-10 overlapped with OCHAHB—Ar), 5.44 (s, 7.5H, H-12), 7.37 (d, 8H, J 7.8 Hz, Ar), 8.01 (d, 8H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([NH:20][CH3:21])[C:17]([N+:22]([O-])=O)=[CH:16][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][CH3:15])=[O:13])[CH:7]=1>CO.[Pd]>[NH2:22][C:17]1[CH:16]=[C:4]([C:3]([O:2][CH3:1])=[CH:19][C:18]=1[NH:20][CH3:21])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][CH3:15])=[O:13])[CH:7]=1
Reactant: CNC(=O)c1cc(Oc2cc([N+](=O)[O-])c(NC)cc2OC)ccn1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(Oc2cc(N)c(NC)cc2OC)ccn1

Procedure:
A solution of {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. In methanol was hydrogenated with 10% Pd/C. The catalyst was filtered off and the solvent was concentrated to yield {4-[3-amino-6-methoxy-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide. MS:MH+: 302.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[C:22]([NH:29][C@H:30]([C:34](O)=[O:35])[CH:31]([CH3:33])[CH3:32])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:22]([NH:29][C@H:30]([C:34]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)[CH2:6][CH2:7]1)=[O:35])[CH:31]([CH3:32])[CH3:33])([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23]
Reactant: COc1cc2ncnc(N3CCC(N)CC3)c2cc1OC
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: COc1cc2ncnc(N3CCC(NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
4-Amino-1-(6,7-dimethoxyquinazolin-4-yl)piperidine (0.9 g) was added to a mixture of Boc-L-valine (1.3 g), N,N'-dicyclohexylcarbodiimide (0.7 g) and acetonitrile (30 ml) while cooling with ice. The mixture was further stirred at room temperature for 30 minutes. Insoluble substances were removed from the reaction solution by filtration. The filtrate was concentrated and partitioned between ethyl acetate and a saturated aqueous solution of NaHCO3. The organic layer was dried over anhydrous magnesium sulfate and concentrated. By purification using a 40 g silica gel column, 4(Boc-L-valyl)amino-1-(6,7-dimethoxyquinazolin-4-yl)piperidine (1 g, 74%) was obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].B1(C=C)OB([CH:33]=[CH2:34])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH:33]=[CH2:34])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: C=Cc1nc(C(=O)OCCCC)c(O)c2ccc(Oc3ccccc3)cc12
Reaction time: 3 h

Procedure:
A mixture of 1-Bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (416 mg, 1 mmol, see example D-28a), Pd(PPh3)4 (118 mg, 0.1 mmol), 2,4,6-Trivinylcyclotriboroxane-pyridine complex (241 mg, 1 mmol), K2CO3 (414 mg, 3 mmol), and 1,4-dioxane (8 ml) was refluxed with stirring under N2 protection for 3 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (5 ml) and the mixture was extracted with EtOAc (20 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes EtOAc=98 2 as the eluent gave the title compound as a yellowish solid (65 mg); MS-(+)-ion M+1=364.1.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH2:16]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCn1c2ccccc2c2ccccc21
Temperature: 95 °C
Reaction time: 0.42 h
Yield: 95 %

Procedure:
Carbazole (23.66 g, 0.16 mol), potassium hydroxide (14.45 g. 0.226 mol), water (30 g) and line (100 g) were added into a 500 ml four neck flask equipped with Dean-stark apparatus, and refluxed. Water (about 30 g) was separated, and the reaction mixture was cooled to 90 to 100° C. Hexyl bromide (33 g, 0.2 mol) was added dropwise thereto over about 25 minutes, and then reflux was carried out for 1 hour. 9-hexylcarbazole was obtained in a 95% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:17]=O)[CH:14]=[N:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:19].[O:20]([NH2:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>>[ClH:19].[CH3:21][O:20][N:22]=[CH:17][C:13]1[CH:14]=[N:15][CH:16]=[C:11]([C:10]#[C:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH:12]=1
Reactant: O=Cc1cncc(C#Cc2ccc(F)c(F)c2)c1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CON=Cc1cncc(C#Cc2ccc(F)c(F)c2)c1
Yield: 80 %

Procedure:
Prepare in a similar manner as described in EXAMPLE 6 using 5-(3,4-difluorophenylethynyl)-pyridine-3-carbaldehyde, (prepared essentially as described in EXAMPLE 101), (0.28 g, 1.15 mmol), methoxylamine hydrochloride (0.77 g, 9.21 mmol) and potassium carbonate (0.80 g, 5.76 mmol) to give the title compound (0.28 g, 80%).
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=3)=[CH:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(C(=O)O)c3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(C(=O)O)c3)cc2)cc1)C(=O)O
Yield: 75.9 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(3′-carboxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (273 mg), which is the product of Example 40, was reacted with aqueous sodium hydroxide solution (1N, 1.10 ml) and the reaction mixture was treated to give the title compound (196 mg) as colorless crystals.