Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:14]([N:19]([CH2:24][CH:25]4[CH2:27][CH2:26]4)[CH2:20][CH:21]4[CH2:23][CH2:22]4)=[C:15]([S:17][CH3:18])[N:16]=3)[CH:11]=[CH:12][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.C(OCC)(=O)C.[CH3:36][N:37](C)C=O>[C-]#N.[Zn+2].[C-]#N>[CH:21]1([CH2:20][N:19]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:14]2[N:10]3[CH:11]=[CH:12][N:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([C:36]#[N:37])=[CH:3][C:4]=4[O:28][CH3:29])[C:9]3=[N:16][C:15]=2[S:17][CH3:18])[CH2:23][CH2:22]1
Reactant: CN(C)C=O
Reactant: COc1cc(Br)ccc1-c1nccn2c(N(CC3CC3)CC3CC3)c(SC)nc12
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C#N)ccc1-c1nccn2c(N(CC3CC3)CC3CC3)c(SC)nc12
Temperature: 95 °C
Reaction time: 4 h

Procedure:
N-[8-(4-Bromo-2-methoxyphenyl)-2-(methylsulfanyl)imidazo[1,2-a]pyrazin-3-yl]-N,N-dicyclopropylmethylamine (53 mg) was dissolved in N,N-dimethylformamide (0.22 mL), then zinc cyanide (23 mg) and tetrakistriphenylphosphine palladium complex (13 mg) were added thereto. After that, the mixture was heated under stirring at 95° C. for 4 hours and cooled to room temperature, and then ethyl acetate was added thereto. The precipitated insoluble matters were filtered off, and then it was extracted with ethyl acetate. The resulting organic layer was washed with water, dried over magnesium sulfate, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (26 mg) as yellow crystals.
Reaction SMILES: N[C@H:2]([C:11](NCC(NCC(N[C@H](C(N[C@H](C(N[C@H](C(O)=O)CO)=O)CO)=O)[C@H](CC)C)=O)=O)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7](O)=C[CH:5]=1.C1[C@H]2[O:47]C(C[C@H]2[C@@H](/C=C/[C@@H](O)COC2C=C(C(F)(F)F)C=CC=2)[C@@H]1O)=O.N[C@H](C(N1CCC[C@H]1C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(O)=O)CCCCN)=O)CC(C)C)=O)C)=O)CC(=O)O)=O)=O)CC1C=CC=CC=1.C(C[C@H](NC([C@@H](N)CCCN=C(N)N)=O)C(N[C@H](C(O)=O)CCC(O)=O)=O)CCN.N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N1CCC[C@H]1C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(O)=O)CCCNC(=N)N)=O)CC1C=CC=CC=1)=O)CO)=O)CC1C=CC=CC=1)=O)CO)=O)=O)CC(=O)N)=O)CC(=O)O)=O)C)=O)CC(=O)N)=O)CCCCN)=O)CC1C=CC=CC=1)=O)CC1C2C(=CC=CC=2)NC=1)=O)CC(=O)O)=O)CC1C=CC=CC=1>>[CH3:7]/[CH:8]=[CH:9]/[CH:4]1[CH2:3][C@H:2]([OH:47])[C@H:11]([OH:12])[CH2:5]1
Reactant: CC[C@H](C)[C@H](NC(=O)CNC(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O
Reactant: O=C1C[C@H]2[C@@H](/C=C/[C@@H](O)COc3cccc(C(F)(F)F)c3)[C@H](O)C[C@H]2O1
Agent: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(=O)O
Agent: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: NCCCC[C@H](NC(=O)[C@@H](N)CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Product: C/C=C/C1C[C@@H](O)[C@@H](O)C1

Procedure:
Tyr-Gly-Gly-Ile-Ser-Ser SEQ ID NO. 8 (6 amino acids) TP-2: Phe-Pro-Asp-Ala-Leu-Lys SEQ ID NO. 9 (6 amino acids) TP-3: Phe-Asp-Trp-Phe-Lys-Asn-Ala-Asp-Asn-Pro-Ser-Phe-Ser-Phe-Arg SEQ ID NO. 10.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Sc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2Cl)CC1
Temperature: 80 °C
Yield: 83.2 %

Procedure:
To a stirred solution of 2-chlorobenzenethiol (2.5 g, 0.017 mole) in DMF (20 mL) was added cesium carbonate (6.77 g, 0.0208 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (4.8 g, 0.0173 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 4.64 g (82%) of 4-(2-chloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 328.11 (M+1)+, 95.12%. A solution of 4-(2-chloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (4 g, 0.0122 mole) in dioxane.HCl (7 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 3.75 g (99%) of 4-(2-chloro-phenylsulfanyl)-piperidine hydrochloride. LCMS: 228.05 (M+1)+, 92.02%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:12]([OH:14])=[O:13]>C(OC(=O)C)(=O)C>[C:5]([NH:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:12](=[O:13])[CH3:3])=[C:3]2[C:12]([O:13][C:5](=[O:7])[C:4]=12)=[O:14])(=[O:7])[CH3:4]
Reactant: Nc1ccc(N)c(C(=O)O)c1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(NC(C)=O)c2c1C(=O)OC2=O
Reaction time: 0.5 h

Procedure:
3,6-diaminophthalic acid (0.21 g, 1.07 mmol) was dissolved in acetic anhydride (10 mL) at about 100° C., and stirred at this temperature for about 0.5 hour. After the reaction was cooled the product was filtered and washed with ether. A yellow precipitate was obtained (0.243 g, 86%). 1H NMR (300 MHz, DMSO) δ 9.85 (s, 2.0H, CONHAr), 8.29 (s, 2.1H, ArH), 2.17 (br s, 6.2H, COCH3).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14](=O)[NH:13][N:12]=3)[CH:9]=2)[N:4]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:3]=1.CN.[CH:29]([N:32](C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN([PH+](N(C)C)N(C)C)C>CN(C=O)C.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:32][CH3:29])=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4n[nH]c(=O)o4)ccc32)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)[PH+](N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNc1nnc(-c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (585 mg, 1.216 mmol), methylamine (1.82 mL of 2 M in THF, 3.65 mmol) and diisopropylethylamine (0.42 mL, 2.43 mmol) in DMF (1.5 mL) was added 1H-benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (V) (591 mg, 1.33 mmol). The reaction was stirred at RT for 18 h, then diluted with H2O (5 mL) and extracted with EtOAc (2×15 mL). The combined organic solution was washed with brine, dried over MgSO4, and concentrated. The residue was suspended in 5 mL of EtOAc, and filtered to 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-methyl-1,3,4-oxadiazol-2-amine (507 mg, 84%) as an off white crystalline solid. MS (ESI, pos. ion) m/z: 495.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (1H, s), 8.13 (1H, d, J=8.8 Hz), 7.98 (2H, d, J=8.4 Hz), 7.91 (1H, m), 7.71 (1H, m), 7.70 (1H, m), 7.44 (2H, d, J=8.0 Hz), 2.88 (3H, d, J=4.9 Hz), 2.35 (3H, s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.I[C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C@@:26]([CH3:41])([S:37]([CH3:40])(=[O:39])=[O:38])[C:27]([NH:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)=[O:28])[C:20](=[O:42])[CH:19]=1.O>O1CCOCC1.[Pd]>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C@@:26]([CH3:41])([S:37]([CH3:40])(=[O:39])=[O:38])[C:27]([NH:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)=[O:28])[C:20](=[O:42])[CH:19]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccc(F)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C

Procedure:
Pd EnCat™ (200 mg, 0.06 mmol) was added to a mixture of potassium carbonate (250 mg, 1.81 mmol), (4-fluorophenyl)boronic acid (84 mg, 0.602 mmol), and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be produced as in Preparation 2 B, (300 mg, 0.602 mmol) in dioxane:water (5.5 mL, 10:1 mixture) in a 25 mL round bottom flask. The flask was heated overnight at 80° C. The reaction was cooled to ambient temperature and filtered through celite and washed with ethyl acetate (20 mL). The crude material was concentrated, and purified by chromatography on silica gel (gradient: 100:0 dichloromethane:methanol to 95:5 dichloromethane:methanol) to provide title compound as a viscous, foamy oil. Yield: 257 mg, 91.5%. MS (APCI) m/z 467.6 (M+H) 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54-1.65 (m, 3H) 1.68 (d, J=2.34 Hz, 3H) 1.71-1.99 (m, 3H) 2.32-2.44 (m, 1H) 2.44-2.57 (m, 1H) 3.18 (d, J=2.93 Hz, 3H) 3.54-3.66 (m, 1H) 3.97-4.10 (m, 1H) 4.11-4.25 (m, 1H) 4.25-4.38 (m, 1H) 5.16 (d, J=15.81 Hz, 1H) 6.48 (dd, J=6.93, 1.27 Hz, 1H) 6.76 (s, 1H) 7.12 (t, J=8.59 Hz, 2H) 7.39 (d, J=7.02 Hz, 1H) 7.47-7.57 (m, 2H) 12.15 (d, J=7.42 Hz, 1H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:60]1[S:61][CH:62]=[C:63]([C:65]#[N:66])[N:64]=1>C(O)(C)(C)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:60]2[S:61][CH:62]=[C:63]([C:65]#[N:66])[N:64]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: N#Cc1csc(Br)n1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2nc(C#N)cs2)C1
Temperature: 25 °C

Procedure:
To a 500 mL round bottom flask were added (R)-piperidin-3-yl-carbamic acid tert-butyl ester (10.3 g, 51.6 mmol), cesium carbonate (33.6 g, 103 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (BrettPhos, CAS number 1070663-78-3) (369 mg, 688 μmol) and 2-bromothiazole-4-carbonitrile (6.5 g, 34.4 mmol) followed by tert-butanol (225 mL). The mixture was degassed under vacuum (˜50 mmHg) while sonicating and the flask then charged with argon. Degassing repeated twice. Tris-(dibenzylideneacetone)dipalladium(0) (CAS number 51364-51-3) (315 mg, 344 μmol) was added and the flask evacuated and recharged with argon. Repeated twice. The reaction flask was transferred to an aluminum block heating mantle and heated to reflux under argon for 5 hours. The reaction mixture was cooled to ambient temperature and poured into water (1 L), extracted with ethyl acetate (3×200 mL), the combined organic extracts washed with brine (2×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography using a 330 g silica column gradient eluted from 10% up to 40% ethyl acetate in hexanes at a flow rate of 100 mL/min Product containing fractions were combined and concentrated in vacuo to give of [(R)-1-(4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester as an off white solid (8.75 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12]
Reactant: NCCc1ccccc1F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1ccccc1F

Procedure:
In close analogy to the procedure described above, 2-(2-fluoro-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)=[N:9][NH:10][CH:11]=2)=[CH:3][CH:2]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C>N1C=CC=CC=1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]([C:12]3[CH:13]=[C:14]([NH:18][C:28]([NH:27][C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:26][CH:25]=4)=[O:29])[CH:15]=[CH:16][CH:17]=3)=[N:9][NH:10][CH:11]=2)=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To 3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (700 mg, 3 mmol) in anhydrous pyridine (15 mL) at 0° C. 4-trifluoromethylphenylisocyanate (420 μL, 3 mmol) was added. The reaction was stirred for 2 hours at 0° C. under nitrogen atmosphere to give a mixture of monourea and bis-urea as regioisomeric mixture. Solvent was removed under reduced pressure. The residue was dissolved in methanol (15 mL) and triethylamine (1 mL, 7.8 mmol) was added and the reaction was stirred at room temperature overnight. After this time only the monourea could be detected by HPLC/MS. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL) and washed successively with water (3×50 mL). The crude was purified by silica gel column chromatography (DCM/methanol 9:1) to give the desired product as a white solid (75%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:36])[C:18]([N:20]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:21][CH2:22][S:23][CH2:24][C:25]#[C:26][C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:37][CH3:38].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:36])[C:18]([N:20]([C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:21][CH2:22][S:23][CH2:24][C:25]#[C:26][C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCSCC#Cc1cccs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCSCC#Cc1cccs1)C(C)(C)C)CC2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 505 mg of 9h in 6 ml of dioxane and a solution of 180 mg of KOH in 1 ml of water were mixed and stirred for 3 h at 50° C. The reaction mixture was cooled and diluted with 20 ml of water and acidified to pH 3 by addition of 0.5 N HCl and extracted with ethyl acetate. The extract was once washed with water, dried and concentrated, to provide 480 mg of crude and unstable 91, which was used without further purification directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])[CH:23]=[CH:24][C:25]=1[F:26]>>[F:26][C:25]1[CH:24]=[CH:23][C:22]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])=[CH:21][C:20]=1[C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: O=C(O)C=Cc1ccc(F)c(Br)c1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Product: Cc1cc2c(cc1-c1cc(C=CC(=O)O)ccc1F)C(C)(C)CCC2(C)C
Yield: 63.3 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 2.0 g (8.12 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid (prepared in Example 5(a) of the patent WO-97/33881) and 1.54 g (6.25 mmol) of 3-(3-bromo-4-fluorophenyl)acrylic acid, 1.45 g (63%) of the expected compound was obtained in the form of a beige powder having a melting point of 181°-183° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[NH:7][CH:8]1[C:26](=[O:27])[N:25]2[CH:21]([CH2:22][CH:23]([O:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][N:30]=3)[CH2:24]2)[C:20](=[O:39])[NH:19][C:18]2([C:40]([NH:42][S:43]([CH:46]3[CH2:48][CH2:47]3)(=[O:45])=[O:44])=[O:41])[CH:16]([CH2:17]2)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N(C([O-])=O)=NC([O-])=O.[K+].[K+].C(O)(=O)C>CO>[C:1]([O:5][C:6](=[O:49])[NH:7][CH:8]1[C:26](=[O:27])[N:25]2[CH:21]([CH2:22][CH:23]([O:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][N:30]=3)[CH2:24]2)[C:20](=[O:39])[NH:19][C:18]2([C:40]([NH:42][S:43]([CH:46]3[CH2:48][CH2:47]3)(=[O:44])=[O:45])=[O:41])[CH:16]([CH2:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCCCCCCC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.3 %

Procedure:
To a mixture of 140 mg (0.2 mmol) of [4-cyclopropanesulfonylaminocarbonyl-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester in 3 mL of methanol was added 656 mg (4 mmol)of dipotassium azodicarboxylate. Glacial acetic acid (480 mg, 8 mmol)in 2 mL of methanol was added slowly by a syringe pump over 5 h. The mixture was stirred at rt. After 5 h, another 656 mg (4 mmol) of dipotassium azodicarboxylate and 480 mg (8 mmol) of glacial acetic acid was added over the course of 5 h and the stirring was continued overnight. This cycle was repeated twice. LC-MS showed about 40% starting material still was remaining. The solvent was then removed on a rotary evaporator. Water was added to the residue and the mixture was extracted three times with ethyl acetate. It was then dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was dissolved in methanol and purified by preparative HPLC (YMC XTERRA, S5, 30×50 mm, gradient: 72% B to 78% B, 15 min, hold 2 min, flow rate 40 ml/min) to isolate the product as a white powder (80 mg, 57%). LC-MS (Method A, retention time: 3.59 min), MS m/z 698 (M++1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C1(C)C=CC=CC=1.[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([CH2:28][C:29]([CH3:31])=[CH2:30])[C:21]=1[OH:32].O>C(OCC)(=O)C>[CH3:30][C:29]1([CH2:31][OH:9])[CH2:28][C:22]2[C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]([CH3:19])[C:21]=2[O:32]1
Reactant: C=C(C)Cc1c(C)cc(C)c(C)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2c(c1C)OC(C)(CO)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.7 %

Procedure:
70% m-chloroperbenzoic acid (1.95 g, 7.89 mmol) was added to a solution of toluene (18 mL) containing 2,3,5-trimethyl-6-(2-methylprop-2-en-1-yl)phenol (1.00 g, 5.26 mmol) synthesized in Reference Example 2, and the mixture was stirred at room temperature for 15 hours. The resulting mixture was poured into water, and extraction was performed using ethyl acetate. The extract was washed with 5% sodium sulfite aqueous solution, saturated sodium bicarbonate water and saturated saline, and dried using anhydrous magnesium sulfate. After that, concentration was performed under reduced pressure, and the residue was dissolved in toluene (10 mL). To this solution, trifluoroacetic acid (0.2 mL) was added, and the mixture was stirred at room temperature for 1 hour. After that, the reaction solution was poured into saturated sodium bicarbonate water, and extraction was performed using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-85/15) to give 420 mg of the title compound (yield: 39%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:12]3[C:21]([OH:22])=[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=[N:19]4)=[C:14]([N:23]4[CH2:28][CH2:27]S[CH2:25][CH2:24]4)[N:13]=3)=[N:10][N:11]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.O[O:36][S:37]([O-:39])=O.[K+]>CO>[O:36]=[S:37]1(=[O:39])[CH2:27][CH2:28][N:23]([C:14]2[N:13]=[C:12]([C:9]3[NH:8][C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:30][CH:29]=4)=[N:11][N:10]=3)[C:21]([OH:22])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[N:19]3)[CH2:24][CH2:25]1
Reactant: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(N2CCSCC2)c2cccnc12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=S1(=O)CCN(c2nc(-c3nnc(Cc4ccc(F)cc4)[nH]3)c(O)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25.9 %

Procedure:
A 100 mL flask was charged with 7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-5-thiomorpholin-4-yl-1,6-naphthyridin-8-ol (26 mg, 0.062 mmol). Methanol (15 mL) and chloroform (˜3 mL to dissolve insoluble solids) were added, followed by a freshly prepared 0.16 M solution of Oxone (0.75 mL, 0.12 mmol) in methanol. The solution was stirred for 14 hours at room temperature. The reaction mixture was concentrated in vacuo, diluted with dichloromethane and extracted twice. The combined organics were concentrated in vacuo and purified by preparative HPLC. Thus, 5-(1,1-dioxidothiomorpholin-4-yl)-7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol (7.3 mg, 26%) was prepared as a tan solid. 1H NMR (CD3OD/CDCl3): δ 8.99 (dd, J=4.4, 1.6 Hz, 1 H), 8.31 (dd, J=8.4, 1.6 Hz, 1 H), 7.52 (dd, J=8.4, 4.4 Hz, 1 H), 7.24 (m, 2 H), 6.91 (m, 2 H), 4.08 (s, 2 H), 3.85 (m, 4 H), 3.25 (m, 4 H); MS m/z 455 (M+1).
Reaction SMILES: [CH3:1][N:2]([C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)[C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][N:2]([C@H:15]1[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:16]1)[C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: CN(C(=O)C12CC3CC(CC(C3)C1)C2)[C@H]1CCNC1
Reactant: BrCCc1ccccc1
Product: CN(C(=O)C12CC3CC(CC(C3)C1)C2)[C@H]1CCN(CCc2ccccc2)C1

Procedure:
(S)-N-Methyl-N-(pyrrolidin-3-yl)-1-adamantanecarboxamide and (2-bromoethyl)benzene were reacted under the same conditions as in Example 1 to give (S)-N-methyl-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([OH:31])=O)=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.[C:51]([O:55][C:56]([N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)=[O:57])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C.O>[C:51]([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]([C:29](=[O:31])[CH2:28][C:27](=[O:32])[NH:26][C:23]2[CH:22]=[CH:21][C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:25][CH:24]=2)[CH2:60][CH2:59]1)=[O:57])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
HOBt (570 mg, 4.2 mmol) and DIPEA (541 mg, 4.2 mmol) were added to a stirred solution of N-biphenyl-4-yl-malonamic acid (1 g, 3.5 mmol) in DMF (10 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (810 mg, 4.2 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (720 mg, 3.86 mmol) were added. The resulting reaction mixture was stirred at room temperature overnight. Water was then added and the resulting precipitate was filtered and dried to afford 1.4 g (93%) of 4-[2-(biphenyl-4-ylcarbamoyl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester. 1H NMR: (CDCl3): δ 8.6 (s, 1H), 7.9 (m, 2H), 7.7 (m, 2H), 7.65 (m, 1H), 7.5 (m, 3H), 7.4 (s, 1H), 4.1 (m, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.1 (m, 2H).