Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:11]([SH:14])[NH:12][N:13]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29]Br>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:11]3[S:14][CH2:28][CH2:29][N:12]3[N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
5-(3-Methoxy-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (630 mg, 2.22 mmol) was dissolved in dry DMF (22 mL) under nitrogen atmosphere. Solid potassium carbonate (1.5 g, 11.1 mmol, 5 eq) was added followed by 1,2-dibromoethane (0.192 mL, 2.22 mmol, 1 eq) and the suspension was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure, diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated to dryness to give 420 mg (61% over two steps) of crude 6-(3-methoxy-phenyl)-7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazole which was used without further purification in the following step.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:28][C:21]3=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:28][C:21]3=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2cc(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)[nH]c2n1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2cc(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)[nH]c2n1
Temperature: 50 °C
Yield: 8.1 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-6-methoxy-1H-pyrrolo[2,3-b]pyridine (0.22 g, 0.56 mmol) and 10% palladium on activated carbon (0.2 g) in methanol (150 mL) was heated at 50° C. under hydrogen (50 psi) for 12 h. After cooling to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo to give a residue which was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-6-methoxy-1H-pyrrolo[2,3-b]pyridine (18 mg, 8.2%) as a white solid: LC/MS m/e calcd for C22H26N2O3S [M+H]+ 399.53, observed 399.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.16 (m, 2H), 1.48 (m, 2H), 1.56-1.85 (m, 5H, H), 2.04 (m, 1H), 2.17 (m, 1H), 3.05 (s, 3H), 3.90 (s, 3H), 4.14 (t, J=7.7 Hz, 1H), 6.29 (s, 1H), 6.55 (d, J=8.5 Hz, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.73 (d, J=8.5 Hz, 1H), 7.86 (d, J=8.1 Hz, 2H), 8.31 (s, 1H).
Reaction SMILES: [C:1]([C:3]([C:14](=[O:30])[N:15]([CH2:26][CH2:27]CC)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[CH:4][NH:5][C:6](=[NH:13])[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])#[N:2].[C:31](O)(=O)C(O)=O>C(O)(=O)C>[CH2:26]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=1)[C:14]([C:3]1[C:1]([NH2:2])=[N:13][C:6]([N:7]2[CH2:11][CH:10]([CH3:31])[NH:9][C:8]2=[O:12])=[N:5][CH:4]=1)=[O:30])[CH3:27]
Reactant: CCCCN(C(=O)C(C#N)=CNC(=N)N1CCNC1=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: CCN(C(=O)c1cnc(N2CC(C)NC2=O)nc1N)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 173.2 %

Procedure:
A mixture of 4.084 g (10 mmol) of a compound II (R1 =CH3 ; R2, R3, R5, R6 =H; R4 =C2H5), 360 mg (4 mmol) of anhydrous oxalic acid and 9 ml of glacial acetic acid was stirred at 60° for 3 hours and then worked up as described in Example 5. 2.83 g (69.3% yield) of pure 4-amino-2-(4-methyl-2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-ethyl-N-(3-trifluoromethylphenyl)amide were obtained (by crystallization from ether) after drying, melting point 208°-209°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]2=[O:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:23][S:24]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:7]2=[O:22])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(CN)cc2C1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(CNS(C)(=O)=O)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 2-(5-(aminomethyl)-1,3-dioxoisoindolin-2-yl)acetate hydrochloride (0.409 g, 1.252 mmol) in dry pyridine (10 ml) cooled to 0° C., methanesulfonyl chloride (0.117 ml, 1.502 mmol) was added. The reaction was warmed to room temperature and stirred overnight. Additional methanesulfonyl chloride (0.148 ml, 1.878 mmol) was added over 24 hours cooling at 0° C. and stirring at room temperature. The solvent was removed under vacuum and the residue was portioned between ethyl acetate and 1N HCl. The organic phase was washed with brine and dried over sodium sulfate. The solvent was evaporated to dryness affording tert-butyl 2-(5-(methylsulfonamidomethyl)-1,3-dioxoisoindolin-2-yl)acetate (0.461 g, 1.251 mmol, MS/ESI+ 390.9 [MNa]+). This crude was used in the following steps without purification.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:7](=[N:14]\[O:15][CH2:16][C:17]2[N:22]=[C:21]([N:23]3C(=O)C4C(=CC=CC=4)C3=O)[CH:20]=[CH:19][CH:18]=2)/[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][S:5][N:6]=1.O.NN>C1COCC1>[CH3:1][C:2]1[C:3](/[C:7](=[N:14]\[O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:4][S:5][N:6]=1
Reactant: Cc1nsnc1/C(=N\OCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: Cc1nsnc1/C(=N\OCc1cccc(N)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To a stirred solution of 2-{6-[({[(Z)-(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylene]amino}-oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (49 g, 91 mmol) in dry THF (800 mL) was added hydrazine hydrate (22.2 mL, 457 mmol). The reaction mixture was stirred at room temperature for 14 h, then insolubles were removed by filtration and washed with THF. The filtrates were combined and concentrated in vacuo. Purification of the residual oil on silica gel afforded 6-[({[(Z)-(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylene]amino}oxy)-methyl]pyridin-2-amine as a yellow oil [22.2 g, yield 75%; HPLC/MS: m/z=326 (M+H); log P(HCOOH)=1.54].
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:32]=[CH:31][C:17]2[C:18]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)=[N:19][O:20][C:16]=2[CH:15]=1.[Cl-].[NH4+]>BrC(Br)C.CCOCC.O1CCCC1>[F:13][C:14]1[CH:32]=[CH:31][C:17]2[C:18]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][C:27]([OH:30])([C:3]4[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=4)[CH2:28][CH2:29]3)=[N:19][O:20][C:16]=2[CH:15]=1
Reactant: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccc(C(F)(F)F)cc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a suspension of 1.2 g of magnesium shavings and a few drops of dibromoethane in 30 ml of ether was added a solution of 10.3 g of 4-bromobenzotrifluoride in 20 ml of ether at such a rate so as to maintain reflux of the mixture. After the addition was complete, the mixture was diluted with 35 ml of tetrahydrofuran, and a solution of 6.3 g of 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-piperidone in 50 ml of tetrahydrofuran was slowly added. After one hr, the mixture was diluted with ether, poured into 400 ml of saturated ammonium chloride solution and extracted with ether. The organic extracts were washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate, filtered and concentrated. Trituration with hexane/ether gave 7 g (73%) of product, mp 150°-152° C. Recrystallization from ether gave the analytical sample, mp 152°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH:10][S:11](O)(=[O:13])=[O:12].O=S(=O)=O>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([S:11]([OH:13])(=[O:12])=[O:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=Cc1cc(S(=O)(=O)O)ccc1Cl
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
2-chlorobenzaldehyde 500 g (3.35 moles) was added to 23% oleum 1050 g (1.35 moles), and the contents were cooled to 0 to 5° C. The reaction mixture was stirred for 2.5 hours between 0-15° C. To this stirred solution, 660 g of 65% oleum (2.41 moles) was added over a period of 2.5 hours, maintaining the temperature below 15° C. The reaction mass was stirred and allowed to come to a temperature of 25-30° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[C:6]([CH3:24])=[C:7]([CH3:23])[C:8](OS(C(F)(F)F)(=O)=O)=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].[CH2:34](C([Sn])=C(CCCC)CCCC)[CH2:35]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.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:1][C:2]1[CH:28]=[C:27]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[CH:26]=[CH:25][C:3]=1[CH2:4][C:5]1[C:6]([CH3:24])=[C:7]([CH3:23])[C:8]([CH:34]=[CH2:35])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2F)c(C)c(C)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2F)c(C)c1C
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 106.8 %

Procedure:
To a solution of methyl 5-(2-fluoro-4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (0.50 g) in DMF (10.0 mL) were added tributylvinyltin (0.50 g), trans-dichlorobis(triphenylphosphine)palladium(II) (0.04 g) and lithium chloride (0.32 g), and the mixture was stirred at 90° C. for 1.5 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.40 g).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]=[C:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH2:22][CH2:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[N:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>CO.[Pd]>[C:7]1([CH:6]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([CH2:22][CH2:23][CH2:24][C:25]4[CH:34]=[CH:33][C:32]5[CH2:31][CH2:30][CH2:29][NH:28][C:27]=5[N:26]=4)=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:5][C:4]([OH:35])=[O:3])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Agent: [Pd]
Solvent: CO
Product: O=C(O)CC(c1ccccc1)n1ccc2cc(CCCc3ccc4c(n3)NCCC4)ccc21
Yield: 9.4 %

Procedure:
3-[5-(3-[1,8]Naphthyridin-2-yl-propyl)-indol-1-yl]-3-phenyl-acrylic acid ethyl ester (30.0 mg, 0.484 mmol) in methanol (2 mL) was stirred under hydrogen in the presence of 10% palladium on carbon (15.0 mg) at room temperature for 3 days. Then, the reaction mixture was filtered through celite and purified via column chromatography on silica gel (methylene chloride/methanol) (95/5) to give the title product as yellow oil (20.0 mg, 66% yield). 1H NMR (CDCl3) δ 8.2 (d, 1H), 8.0 (m, 1H), 7.45 (m, 2H), 7.27 (m, 2H), 6.9–7.2 (m, 4H), 6.5 (1H), 6.3 (1H), 6.20 (m, 1H), 6.10 (m, 1H), 4.15 (m, 2H), 3.4 (m, 2H), 3.3 (m, 4H), 2.6 (m, 4H), 2.1 (m, 2H), 1.89 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C30H34N3O2 468.27 (M+H); found 468.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[OH:16][C:17]1[C:26]([CH3:27])=[CH:25][C:20]([C:21]([NH:23]O)=[NH:22])=[CH:19][C:18]=1[CH2:28][CH2:29][CH3:30]>>[CH2:4]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:14][N:23]=[C:21]([C:20]3[CH:19]=[C:18]([CH2:28][CH2:29][CH3:30])[C:17]([OH:16])=[C:26]([CH3:27])[CH:25]=3)[N:22]=2)=[CH:9][C:8]=1[CH3:15])[CH2:1][CH3:2])[CH3:5]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: CCCc1cc(C(=N)NO)cc(C)c1O
Product: CCCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1O
Yield: 42.8 %

Procedure:
The title compound (20 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and 4,N-dihydroxy-3-propyl-5-methyl-benzamidine (24 mg, 117 μmol) according to Method A; LC-MS: tR=0.64 min; [M+1]+=400.22; 1H NMR (D6-DMSO): δ0.94 (t, J=7.3 Hz, 3H), 1.03 (t, J=7.0 Hz, 6H), 1.53-1.64 (m, 2H), 2.22 (s, 3H), 2.26 (s, 2H), 2.57 (q, J=7.0 Hz, 4H), 2.61-2.66 (m, 2H), 3.73 (s, 2H), 7.59-7.62 (m, 1H), 7.62-7.65 (m, 1H), 7.78 (s, 1H), 8.88 (s br, 1H).
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[C:18]([C:41]([F:44])([F:43])[F:42])=[N:19][N:20]([C:22]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:52]1([C:58](Cl)=[O:59])[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.C(OCC)(=O)C>ClCCl.O>[O:55]1[CH2:56][CH2:57][N:52]([C:58]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]5[C:18]([C:41]([F:43])([F:42])[F:44])=[N:19][N:20]([C:22]([C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=6)([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH:21]=5)[CH:15]=4)[N:10]=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)=[O:59])[CH2:53][CH2:54]1
Reactant: FC(F)(F)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCNCC3)c2c1
Reactant: O=C(Cl)N1CCOCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N1CCOCC1)N1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
While a solution of 118 mg 4-piperazin-1-yl-6-[3-(trifluoromethyl)-1-trityl-1H-4-pyrazolyl]quinoline obtained in Example 188 and 61 mg triethylamine in dichloromethane was stirred under ice-cooling in a stream of nitrogen, 35 μL 4-morpholine carbonyl chloride was added thereto, and the mixture was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 125 mg of the title compound as a colorless amorphous.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:16])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][C:6]([Cl:16])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C)c1OCC(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1OCC(=O)Cl
Temperature: 65 °C
Reaction time: 7 h

Procedure:
2,6-dimethylphenoxyacetylchloride is prepared in a separate vessel as follows: 2,6-dimethylphenoxyacetic acid, 5.4060 grams (29.99 mmol) is charged to a 50 mL round bottom flask equipped with a teflon-coated magnetic stir bar. Toluene, 15 mL is added stirring is initiated and thionyl chloride, 9.0 mL (123.3 mmol) is added followed by one drop of N,N-dimethylformamide at ambient temperature. After seven hours, the reaction mixture is heated to 65° C. for thirty minutes and allowed to cool to ambient temperature. The solution is concentrated at 60° C. and ca. 60 mm Hg pressure to remove all volatiles. The residue is diluted with toluene, 25 mL and reconcentrated. This is repeated a second time to give a final residue.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)(O)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.ClCCCl>C(O)CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1(c2cccc(F)c2)CCC(C2CCC3(CC2)OCCO3)CC1
Solvent: OCCO
Solvent: ClCCCl
Product: Fc1cccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)c1
Yield: 75.3 %

Procedure:
A mixture of 174.3 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(3-fluorophenyl)cyclohexanol, 1000 ml of 1,2-dichloroethane, 25 ml of ethylene glycol and 25 g of Amberlyst 15 was boiled under reflux for 22 hrs., the condensate being dried over a dropping funnel filled with 175 g of neutral aluminiumoxide. Then, the reaction mixture was cooled, filtered, washed with water and the organic phase was dried over sodium sulphate. Subsequent chromatography on 1000 g of silica gel with hexane/ethyl acetate (90:1) gave 124.2 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(3-fluorophenyl)-cyclohexene as colorless crystals. M.p. of a sample recrystallized from methylene chloride/hexane: 133.7°-135.3° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[N:24]=[C:23]2[S:25][C:26]([NH2:28])=[N:27][C:22]2=[CH:21][CH:20]=1>S(Cl)(Cl)=O.C1COCC1.N1C=CC=CC=1>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:28][C:26]2[S:25][C:23]3[C:22]([N:27]=2)=[CH:21][CH:20]=[C:19]([O:18][CH3:17])[N:24]=3)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccccc1
Reactant: COc1ccc2nc(N)sc2n1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc2nc(NC(=O)[C@H](CC3CCCC3)c3ccccc3)sc2n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The title D compound, (R)-3-cyclopentyl-2-phenyl-propionic acid (1.66 g, 7.605 mmol) is dissolved in thionyl chloride (15 mL) and heated at 50° C. for 1.5 h. The reaction is then cooled to RT and concentrated to afford a yellow oil. This is dissolved in anhydrous THF (10 mL) and added dropwise to a solution of the title E compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (1.38 g, 7.605 mmol) in anhydrous pyridine (10 mL) at 0° C. The reaction is allowed to stir and warm to RT. After 2 h, the reaction is concentrated to remove the THF and most of the pyridine. The resulting brown oil is dissolved in ethyl acetate (250 mL)/1 N HCl (250 mL) and extracted further with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product as a brown oil. This is chromatographed over silica eluting with 5→60% ethyl acetate in hexanes to afford (R)-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-phenyl-propionamide as a yellow foam: 1H NMR (400 MHz, DMSO-D6) 1.1 (m, 2 H) 1.4 (dd, J=7.2, 4.7 Hz, 2 H) 1.6 (m, 3 H) 1.7 (m, 3 H) 2.1 (m, 1 H) 3.9 (m, 4 H) 6.9 (d, J=8.8 Hz, 1 H) 7.3 (m, 1 H) 7.4 (m, 4 H) 8.0 (d, J=8.6 Hz, 1 H) 12.5 (s, 1 H); LC/MS 382.1 (M+1), 380.2 (M−1).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][CH2:20][C:21](O)=[O:22])[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O.CO>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCC(=O)O)ccc21
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCO)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
3-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)propionic acid (1.0 g) was dissolved in THF(20 ml) and was cooled to 0° C. in ice water bath. Triethylamine(0.525 ml) and ethyl chloroformate(0.325 ml) were added to this solution and stirred for 30 minutes at same temperature. Sodium borohydride(0.36 g) was added to the mixture under cooling in ice methanol bath. Methanol(0.64 ml) was added dropwise to the mixture and stirred for 1 hour at same temperature. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with magnesium sulfate, and was condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1→0:1). The purified product was condensed to dryness under reduced pressure to give the title compound(0.71 g) as a colorless oil.
Reaction SMILES: II.Br[CH:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]([O:7][CH2:8][C:9](=[O:11])[CH3:10])=[O:6].Cl>O1CCCC1.[Zn]>[OH:11][C:9]1([CH3:10])[CH2:8][O:7][C:5](=[O:6])[CH:4]1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(Br)C(=O)OCC(C)=O
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCCCC1C(=O)OCC1(C)O
Yield: 136.8 %

Procedure:
Powdered zinc (39.61 g, 606 mmol) is suspended in 500 ml of tetrahydrofuran. Then, 1.92 g (15 mmol) of iodine are added and 80.34 g (303 mmol) of acetylmethyl 2-bromoheptanoate in 100 ml of tetrahydrofuran are added dropwise at 67° C. within 1 hour. The grey-green suspension is stirred at reflux temperature for a further 1 hour. The cooled reaction mixture is poured onto 500 ml of 1N HCl and ice and stirred for 10 minutes. It is then extracted in a separating funnel with 3×500 ml of ethyl acetate. The organic phases are dried with MgSO4, concentrated on a rotary evaporator and dried in high vacuum. There are obtained 77.21 g of 4-hydroxy-4-methyl-3-pentyl-tetrahydrofuran-2-one.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1>[Ni].CN(C=O)C>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(NC2Cc3ccccc3C2)nc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1ccc(NC2Cc3ccccc3C2)nc1

Procedure:
A mixture of N-(2,3-dihydro-1H-inden-2-yl)-5-nitropyridin-2-amine (5.5 g) and Raney Nickel (50 mg) was stirred in DMF (30 ml) under hydrogen overnight. The reaction mixture was filtered through celite and the solvent removed in vacuo, giving as a residue crude N2-(2,3-dihydro-1H-inden-2-yl)pyridine-2,5-diamine, which was on-reacted without further characterization other than ascertaining that the compound was one spot by tlc with the expected molecular weight (M+1) of 226.