Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][N:7]([S:26]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)(=[O:28])=[O:27])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][C:14]([C:17]1[S:18][CH:19]([CH2:22][C:23]([OH:25])=O)[CH2:20][N:21]=1)=[CH:13]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:5][O:4][N:3]([CH3:2])[C:23](=[O:25])[CH2:22][CH:19]1[S:18][C:17]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH3:6])[S:26]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)(=[O:28])=[O:27])=[N:21][CH2:20]1
Reactant: CNOC
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (0.28 g) in N,N-dimethylformamide (20 mL) was added triethylamine (0.43 mL) under ice-cooling, and the mixture was stirred for 10 min under ice-cooling. (2-{7-[Methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (1.03 g), 1H-1,2,3-benzotriazol-1-ol (0.42 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.59 g) were added to the mixture, and the mixture was stirred from under ice-cooling to room temperature for 24 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=7:3-10:0), and the obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (911 mg, yield: 81%) as pale-yellow crystals. MS: 479 (MH+). melting point 153-154° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][N:11]2[C:12](=[O:14])[N:13]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:35][C:33]1[CH:34]=[C:29]([O:28][C:27]2[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]3[CH:9]=[C:10]4[NH:17][CH2:16][CH2:15][N:11]4[C:12](=[O:14])[N:13]=3)=[CH:4][C:3]=2[C:1]#[N:2])[CH:30]=[N:31][C:32]=1[F:36]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cnc(F)c(F)c3)c(C#N)c1)nc2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCN3)ccc1Oc1cnc(F)c(F)c1

Procedure:
Prepared in a manner similar to that described for E60 using tert-butyl 7-((3-cyano-4-((5,6-difluoropyridin-3-yl)oxy)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (14 mg, 0.028 mmol) in DCM (4 mL) and TFA (0.5 mL, 6.49 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C@@H:19]1[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]1.O>CN(C=O)C.CCCCC>[CH3:24][C:21]1([CH3:25])[O:20][C@H:19]([CH2:18][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:23][O:22]1
Reactant: CC1(C)OC[C@@H](CCl)O1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCC
Solvent: O
Product: CC1(C)OC[C@@H](COc2cccc([N+](=O)[O-])c2)O1
Temperature: 160 °C
Yield: 52.1 %

Procedure:
A mixture of 3-nitrophenol 102 (2.00 g, 14.4 mmol), potassium carbonate (4.96 g, 35.9 mmol) and (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane 103 (2.55 mL, 18.7 mmol) in DMF (20 mL) was heated in a microwave reactor at 160° C. for 4 h. The crude reaction mixture was poured into H2O and extracted with dichloromethane (3×15 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by chromatography using ethyl acetate: pentane to obtain (R)-2,2-dimethyl-4-((3-nitrophenoxy)methyl)-1,3-dioxolane 104 (1.90 g, 52% yield) as an amber-colored oil.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:16][CH2:15]2)[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH3:27].O1CCCC1.[I-].[K+].C(N(CC)CC)C>C(O)CCC>[CH:22]1([C:20]([N:17]2[CH2:18][CH2:19][CH:14]([N:12]([CH3:13])[C:10](=[O:11])[CH2:9][O:8][C:5]3[N:6]=[N:7][C:2]([N:26]([CH3:27])[CH3:25])=[CH:3][CH:4]=3)[CH2:15][CH2:16]2)=[O:21])[CH2:24][CH2:23]1
Reactant: CNC
Reactant: CN(C(=O)COc1ccc(Cl)nn1)C1CCN(C(=O)C2CC2)CC1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCO
Product: CN(C)c1ccc(OCC(=O)N(C)C2CCN(C(=O)C3CC3)CC2)nn1
Temperature: 110 °C
Reaction time: 48 h
Yield: 19 %

Procedure:
A mixture of Compound 135 (60 mg), 2M dimethylamine/tetrahydrofuran solution (766 μL), potassium iodide (2.82 mg), triethylamine (23.7 μL) and n-butanol (1.0 mL) was stirred at 110° C. for 2 days in a sealed tube. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 to 99:1) to give 12.1 mg (19% yield) of the desired product as a pale yellow amorphous.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:16])[NH:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)[CH3:2].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[C:27]([O:32][C@@H:33]3[O:50][C@H:49]([CH2:51][O:52][C:53](=[O:55])[CH3:54])[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]3[O:35][C:36](=[O:38])[CH3:37])=[N:28][NH:29][C:30]=2[CH3:31])=[CH:21][CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]2[C:27]([O:32][C@@H:33]3[O:50][C@H:49]([CH2:51][O:52][C:53](=[O:55])[CH3:54])[C@@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:39]([O:40][C:41](=[O:43])[CH3:42])[C@H:34]3[O:35][C:36](=[O:38])[CH3:37])=[N:28][NH:29][C:30]=2[CH3:31])=[CH:21][CH:20]=1)[CH3:18].[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:33]3[O:50][C@H:49]([CH2:51][OH:52])[C@@H:44]([OH:45])[C@H:39]([OH:40])[C@H:34]3[OH:35])=[N:12][NH:13][C:14]=2[CH3:15])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(Cc2c(C)[nH][nH]c2=O)cc1
Agent: CCc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Product: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1

Procedure:
4-[(4-Ethylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole was prepared in a similar manner to that described in Reference Example 17 using 4-[(4-ethylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one instead of 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one. Then, the title compound was prepared in a similar manner to that described in Reference Example 37 using 4-[(4-ethylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole instead of 4-[(4-isopropoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:35])([CH3:34])[C@@H:14]([O:26]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].Cl>[Pd].CO>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:35])([CH3:34])[C@@H:14]([OH:26])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)C(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)C(C)C
Reaction time: 8 h
Yield: 85 %

Procedure:
Following the general procedure of hydrogenolysis of benzyl ethers of Description 18, a mixture of (2-methylpropanoyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (29c) (4.0 g, 9.4 mmol), 1.0 g of 10 wt.-% of palladium on activated carbon in 20 mL of methanol (MeOH) and 0.15 mL of one molar (1.0 M) hydrochloric acid (HCl) was stirred overnight under a hydrogen atmosphere. Upon completion of reaction and following aqueous work-up, 3.4 g (85% yield) of the title compound (29) was obtained as a colorless, viscous oil. RT=13.59 min and 18.45 min (by LC/UV). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=0.95-0.99 (2s, 3H), 1.12-1.14 (2s, 3H), 1.17-1.20 (m, 6H), 1.55-1.57 (2d, J=5.6, 5.6 Hz, 3H), 1.99-2.00 (2s, 3H), 2.04-2.12 (m, 2H), 2.53-2.62 (m, 1H), 3.13-3.23 (m, 2H), 3.26-3.29 (br. m, 1H), 3.34-3.45 (m, 2H), 3.91-3.97 (2d, J=9.6, 9.2 Hz, 1H), 4.03-4.06 (m, 1H), 4.14-4.19 (2d, J=9.2, 9.2 Hz, 1H), 5.96-6.01 (br. m, 1H), 6.91-6.97 (m, 1H) ppm. MS (ESI) m/z: 426.04 (M+H)+, 447.99 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1>CC(C)=O>[CH3:10][C:4]1[N:3]=[C:2]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([CH3:11])[CH2:13]2)[N:7]=[C:6]([NH:8][CH3:9])[N:5]=1
Reactant: CNc1nc(C)nc(Cl)n1
Reactant: CC1CCCNC1
Solvent: CC(C)=O
Product: CNc1nc(C)nc(N2CCCC(C)C2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.1 %

Procedure:
A mixture of 4-chloro-2-methyl-6-methylamino-1,3,5-triazine (1.06 g; 6.7 mM; described in J. Pharm. Soc. (Japan) 1975, 95, p.512) and 3-methylpiperidine (1.32 g, 13.3 mM) in acetone (10 ml) was stirred at ambient temperature for 6 hours. The mixture was filtered and the solid was partitioned between 3N aqueous ammonia solution (50 ml) and dichloromethane (50 ml). The organic solution was separated and dried (MgSO4) and the solvent was removed, and the residue was crystallised from elthanol. There was thus obtained 2-methyl-6-methylamino-4-(3-methylpiperidino)-1,3,5-triazine (608 mg, 1.3% yield) m.p. 155°-155.50° C.; microanalysis found: C,59.9; H,8.7; N,31.6%; C11H19N5 requires C,59.7; H,8.6; N,31.7%.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([OH:23])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C1C=CN=CC=1)C.ClCCCl>[CH3:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:21]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:18])([F:19])[F:20])=[O:23])=[CH:26][CH:27]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2cnc3c(C(F)(F)F)cccc3c2-c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 0.1 h
Yield: 55.3 %

Procedure:
4-Phenyl-8-trifluoromethyl-quinoline-3-carboxylic acid (0.110 g, 0.347 mmol), whose preparation is described in Scheme 2, p-toluidine (0.074 mL, 0.693 mmol), EDCI-HCl (0.110 g, 0.520 mmol), and DMAP (0.084 g, 0.520 mmol). are dissolved in 1,2-dichloroethane (3 mL) in a 5 mL microwave tube. After stirring in the microwave reactor for 6 min at 70° C. the cooled solution is poured into 2 N aq HCl and extracted with methylene chloride, washed with water, brine, and dried with magnesium sulfate. The combined extracts are concentrated and the residue is chromatographed in 1:9 ethyl acetate:hexanes to afford the title amide as a white solid (0.078 g, 56%). mp 203-205° C.; MS (ES) m/z 405.2; HRMS: calcd for C24H17N2F3O+H, 407.13712; found (ESI, [M+H]+), 407.1376.
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.[C:11]([CH:15]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]3[N:32]=[C:31]2[CH2:41][CH3:42])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:13][CH3:14])=[O:12].[CH:43](Br)([CH2:45][CH3:46])[CH3:44]>>[C:11]([CH:15]([N:22]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]3[N:32]=[C:31]2[CH2:41][CH3:42])=[CH:25][CH:24]=1)[CH:43]([CH2:45][CH3:46])[CH3:44])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([O:13][CH3:14])=[O:12]
Reactant: CCC(C)Br
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC(C(=O)OC)c2ccccc2)cc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N(C(C)CC)C(C(=O)OC)c2ccccc2)cc1

Procedure:
Using the general procedure for the alkylation of secondary amines with LiN(TMS)2 described in Step A of Example 29, 3-[4-(N-(1-carbomethoxy -1-phenylmethyl)amino)phenylmethyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]-pyridine (Step A, Example 28) was alkylated with sec-butyl bromide. Standard workup and purification by flash chromatography afforded the title compound.
Reaction SMILES: [CH2:1]([C@:8]1([OH:15])[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([C@:8]1([OH:15])[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:25][CH:26]=2)[CH2:10][C@@H:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CNCC[C@@]1(O)Cc1ccccc1
Reactant: ClCCOc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H]1CN(CCOc2ccc(OCc3ccccc3)cc2)CC[C@@]1(O)Cc1ccccc1
Temperature: 90 °C
Yield: 104.8 %

Procedure:
To a solution of 5.0 g (24 mmol) (3S,4S)-4-benzyl-3,4-dihydroxy-piperidine in 150 ml DMF were added 7.4 g (24 mmol) 1-benzyloxy-4-(2-chloro-ethoxy)-benzene and 5.0 g (36 mmol) K2CO3 and the reaction mixture was heated to 90° C. for 72 hours. After the addition of water the aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with water, dried over MgSO4 and the solvent was removed under reduced pressure to give 10.9 g (quant., ˜95% purity) (3S,4S)-4-benzyl-1-[2-(4-benzyloxy-phenoxy)-ethyl]-piperidine-3,4-diol as a solid.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[CH3:9][O:10][C:11](=[O:35])[C@H:12]([CH2:33]O)[NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N+:1]([C:4]1[N:5]([CH2:33][C@@H:12]([C:11]([O:10][CH3:9])=[O:35])[NH:13][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cn1ccnc1[N+](=O)[O-])NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.8 %

Procedure:
Di-isopropylazodicarboxylate (1.3 mL, 6.6 mmol) was added dropwise to a solution of 2-nitroimidazole (1.0 g, 9 mmol), N-trityl-L-serine methyl ester (2.0 g, 6 mmol) and triphenylphosphine (1.73 g, 6.6 mmol) in THF (100 mL). The reaction was stirred at ambient temperature for approximately 5 hours The volatiles were removed by evaporation under reduced pressure and the residue purified by column chromatography (EtOAc:isohexane 1:19) to afford the title compound (1.2 g, 44%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:26])[C@@H:5]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[CH2:23])[C:17]=2[F:24])=[CH:12][C:11]1=[O:25])[CH2:6][CH:7]([CH3:9])[CH3:8])C.O.[OH-].[Li+]>O1CCCC1>[F:24][C:17]1[C:18]([CH:22]=[CH2:23])=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:13]1[CH2:14][N:10]([C@@H:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:26])=[O:3])[C:11](=[O:25])[CH:12]=1
Reactant: C=Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)OCC)C2)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Temperature: 20 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
To a solution containing (S)-2-[4-(2-fluoro-3-vinyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (0.400 g, 0.001 mol) in tetrahydrofuran (6 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 3 mL, 0.002 mol). The mixture was stirred at 20° C. for 2 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(2-fluoro-3-vinyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.35 g, 95%) as a white solid.
Reaction SMILES: Br.[CH:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[CH:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([NH:19][S:26]([C:23]4[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=4)(=[O:28])=[O:27])[S:17][CH:18]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccc(C3CCCCC3)cc2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(C4CCCCC4)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
A mixture of 0.5 g of 4-(4-cyclohexyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.31 g of p-toluenesulfonyl chloride was stirred for 3 hours with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated in amorphous form upon neutralization with concentrated hydrochloric acid. After chromatography on 70 g of Kieselgel 60 with ethyl acetate/hexane (1:2) the product-containing fractions were concentrated. Recrystallization from 50% ethanol yielded 0.22 g of N-[4-(4-cyclohexyl-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide as colorless crystals.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[NH2:20]OS(O)(=O)=O.O>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([NH2:20])[CH:13]=[CH:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NOS(=O)(=O)O
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nn1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 1 h
Yield: 133.1 %

Procedure:
To 5-phenylmethoxyindole (50 g) in 300 ml of dimethylformamide at ice bath temperature was added milled potassium hydroxide (62.72 g). Then hydroxylamine-O-sulfonic acid (32.93 g) was added portionwise, keeping the internal temperature below 20° C. After the addition was complete, the mixture was stirred for one hour, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4). After filtration, the solvent was evaporated to yield an oil (71 g), which was eluted with dichloromethane on silica gel columns via HPLC. The desired fractions were concentrated to yield a solid (21.15 g). Of this material, 3.0 g was triturated with ether to yield a solid, 2.4 g, m.p. 126°-128° C.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C(O[Na])(C)(C)C.[C:37]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:40]([O:39][C:37]([N:44]1[CH2:49][CH2:48][N:47]([C:2]2[CH:30]=[CH:29][C:5]3[S:6][C:7]([S:10]([N:13]4[CH2:18][CH2:17][N:16]([C:19]5[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][N:20]=5)[CH2:15][CH2:14]4)(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=3[CH:3]=2)[CH2:46][CH2:45]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(S(=O)(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)sc2ccc(Cl)cc12
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1c(S(=O)(=O)N2CCN(c3ncccc3C(F)(F)F)CC2)sc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc12
Yield: 68.2 %

Procedure:
1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-4-(3-trifluoromethyl-pyridin-2-yl)-piperazine (142.5 mg, 0.3 mmol), Pd2(dba)3 (13.7 mg, 0.015 mmol), t-BuONa (82.7 mg, 0.84 mmol) and the ligand (9 mg, 0.03 mmol) were mixed in a sealed tube which was flushed with N2. To this was added tolene (2 mL) and then 1-BOC-piperazine (67.1 mg, 0.36 mmol). The resultant mixture was heated at 80° C. for 3 hours. The solvent was removed under vacuum and the crude product was purified with flash column chromatography to yield 4-{3-methyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-benzo[b]thiophen-5-yl}-piperazine-1-carboxylic acid tert-butyl ester 68% yield (128 mg) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][N:3]=1.C1(C)C=CC=CC=1.CCO.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[CH3:26].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.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([F:19])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: Clc1cc(Br)ccn1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a vial was added 2-chloro-4-bromopyridine (96 mg, 0.5 mmol), Pd(PPh3)4 (30 mg), and toluene/EtOH (4:1, 3 mL). After stirring at room temperature for 5 min, 3-fluoro-4-methylphenylboronic acid (115 mg, 0.75 mmol) and 2 M aqueous K2CO3 (1 mL) were added, and the resulting mixture was heated at 90° C. for 16 h. The resulting mixture was poured into water and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield 2-chloro-4-(3-fluoro-4-methyl-phenyl)-pyridine as a solid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[F:19][C:20]1[CH:26]=[CH:25][C:23](N)=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:22][CH:21]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(F)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(F)cc4)c3c2s1
Yield: 92 %

Procedure:
Prepared from VII and 4-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 92%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3049, 2840, 2226, 1722, 1643, 1610, 1581, 1557, 1502, 1377, 1355, 1305, 1269, 1227, 1208, 1166, 1130, 1090, 981, 846, 829, 818; 19F NMR (282 MHz, DMSO-d6) δ −120.31; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.16 (s, 1H), 7.76 (d, 1H, J=9.0 Hz), 7.26-7.08 (m, 4H); HRMS calcd for C16H9N5SF (M+H+): 322.0563, found 322.0551.