Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:11][NH:12][C:13]([C:15]2[C:16]3[CH:17]=[CH:18][C:19](Cl)=[N:20][C:21]=3[CH:22]=[CH:23][C:24]=2[Cl:25])=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]2[CH2:10][CH2:9]2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:36][N:37]([CH3:43])[C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[OH:1][C:2]1([CH2:11][NH:12][C:13]([C:15]2[C:16]3[CH:17]=[CH:18][C:19]([N:40]4[CH2:41][CH2:42][C@@H:38]([N:37]([CH3:43])[CH3:36])[CH2:39]4)=[N:20][C:21]=3[CH:22]=[CH:23][C:24]=2[Cl:25])=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]2[CH2:10][CH2:9]2)[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(C2CC2)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(C5CC5)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-cyclopropyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.26 (s, 1H), 3.87 (t, 1H), 3.75 (m, 2H), 3.56 (m, 1H), 3.49 (m, 1H), 3.36 (m, 2H), 3.24 (m, 2H), 2.84 (m, 1H), 2.22 (s, 6H), 1.85 (m, 1H), 1.67 (m, 2H), 1.44-1.38 (m, 4H), 1.27 (m, 2H), 0.30 (m, 2H), 0.23 (m, 2H). m/z: 458 [M+H]
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[CH2:21]1[O:23][CH:22]1[CH2:24][OH:25]>CO>[OH:23][CH:22]([CH2:24][OH:25])[CH2:21][O:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2cccc(O)c2)oc2ccccc12
Reactant: OCC1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(-c2cccc(OCC(O)CO)c2)oc2ccccc12
Temperature: 200 °C

Procedure:
The ester which results from the condensation of 2'-hydroxyacetophenone and m-anisic acid is converted to 2-(3-methoxyphenyl)-3-methylbenzofuran by reductive cyclization in dioxane with a titanium tetrachloride/zinc metal catalyst according to the method of Banerji and Nayak, J Chem. Soc., Chem. Comm., (1990), 150. The 2-(3-methoxyphenyl)-3-methylbenzofuran (47.6 gm, 0.198 mol) is treated with several volumes of pyridine hydrochloride at 200° C. for about 6 hours to cleave the methyl ether moiety to the free hydroxyl group. Three volumes of water are added to the cooled reaction mixture and the system is extracted twice with ether. The ether extracts are combined, washed once with water and then dried over sodium sulfate. Removal of solvent by rotary evaporation affords the desired product, 2-(3-hydroxyphenyl)-3-methylbenzofuran. 2-(3-hydroxyphenyl)-3-methyl-benzofuran (22.4 gm 0.1 mol) is dissolved in 100 mL of methanol in a 250 ml round bottom flask under an atmosphere of argon. To this well stirred solution is added sodium methoxide (0.54 gm, 0.01 mol). Glycidol (Aldrich, 8.14 gm, 0.11 mol) is added and the system is gradually heated and held at reflux for 18 hours. The solution is neutralized with methancsulfonic acid. The solvent is removed by rotary evaporation. The resulting product is heated on a Kugelrohr apparatus at 200° C. under a vacuum of 1 mm Hg, to remove any 3-methoxy-1,2-propanediol by-product, affording 2-[3-(2,3-dihydroxypropoxy)phenyl]-3-methylbenzofuran having the structure: ##STR61##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:27]C(=O)OC(C)(C)C)[C:10]([NH:12][C:13]2[N:17]([CH3:18])[N:16]=[C:15]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH3:26])[N:20]=3)[CH:14]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[NH2:27][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:10]([NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH3:26])[N:20]=2)[CH:14]=1)=[O:11]
Reactant: CNc1nccc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NC(=O)OC(C)(C)C)n(C)n2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1nccc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)n(C)n2)n1

Procedure:
tert-Butyl (S)-3-(4-fluorophenyl)-1-(1-methyl-3-(2-(methylamino)pyrimidin-4-yl)-1H-pyrazol-5-ylamino)-1-oxopropan-2-ylcarbamate, 9.E (0.12 g, 0.26 mmol) was treated with hydrogen chloride, 4.0 M solution in 1,4-dioxane (9.32 mg, 0.256 mmol) in 1,4-dioxane (3.0 ml) at 50° C. for 1 h. LCMS showed that Boc group was removed from SM. The solvent was removed. The crude 9.F was used for next step without further purification. MS ESI (pos.) m/e: 370.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C([NH+](CC)CC)C.[CH2:13]([CH:20]1[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22][C:21]1=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([C:20]1[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22][C:21]=1[O:28][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NC(=O)C(Cc2ccccc2)C(=O)N1
Agent: CC[NH+](CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1[nH]c(=O)[nH]c(=O)c1Cc1ccccc1
Yield: 36.2 %

Procedure:
A solution of methanesulfonyl chloride (1.4 ml) in DMF (20 ml) was dropped into a stirred suspension of the triethylammonium salt of 5-benzyl-2,4,6-(1H,3H)-pyrimidinetrione (g 5) in DMF (210 ml). After an hour most of the solvent was removed in vacuo. The residual suspension was then poured into a ice-water mixture, and the precipitated white solid was collected by filtration, to yield, after drying, the title product, (4 g, 36.2% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:36])=[C:17]([C@@:19]23[O:27][CH2:26][CH2:25][C@@H:24]2[CH2:23][S:22][C:21]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:20]3)[CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([F:36])=[C:17]([C@@:19]34[O:27][CH2:26][CH2:25][C@@H:24]3[CH2:23][S:22][C:21]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[N:20]4)[CH:18]=2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(N)ccc3F)OCC[C@@H]2CS1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(NC(=O)c4ccc(C#N)cn4)ccc3F)OCC[C@@H]2CS1
Yield: 40 %

Procedure:
A solution of 5-cyanopicolinic acid (6.65 mg, 0.045 mmol), tert-butyl ((4aS,7aS)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (11 mg, 0.030 mmol), HATU (17.07 mg, 0.045 mmol) and Hunig's Base (10.46 μL, 0.060 mmol) in DMF (299 μL) was stirred at rt for 12 h. The crude product was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 95% eater/5% MeCN/10 nM NH4OAc, B: 5% water/95% MeCN/10 mM NH4OAc) over 12 min to give tert-butyl ((4aS,7aS)-7a-(5-(5-cyanopicolinamido)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.012 mmol, 40.3% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.90 (s, 1H), 8.94 (d, J=1.2 Hz, 1H), 8.45 (d, J=8.1 Hz, 1H), 8.24 (dd, J=8.1, 2.0 Hz, 1H), 8.10-7.97 (m, 1H), 7.72 (d, J=4.0 Hz, 1H), 7.16 (dd, J=10.7, 9.0 Hz, 1H), 4.27-4.06 (m, 2H), 3.32 (d, J=12.7 Hz, 1H), 3.04-2.84 (m, 2H), 2.49-2.34 (m, 1H), 2.23 (td, J=13.0, 7.9 Hz, 1H), 1.51 (s, 9H). MS (M+H)+: 498.20.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:17])([C:13]([F:16])([F:15])[F:14])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:51]([C:53]([C:55]1[C:60]([NH:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[CH:59][C:58]([C:69]([F:72])([F:71])[F:70])=[C:57]([O:73][CH3:74])[N:56]=1)=[O:54])[NH2:52]>CN(C=O)C.O>[CH2:1]([O:8][C:9]([CH3:17])([C:13]([F:16])([F:15])[F:14])[C:10]([NH:52][NH:51][C:53]([C:55]1[C:60]([NH:61][C:62](=[O:68])[O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[CH:59][C:58]([C:69]([F:70])([F:71])[F:72])=[C:57]([O:73][CH3:74])[N:56]=1)=[O:54])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(C(=O)NN)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: CC(OCc1ccccc1)(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1nc(C(=O)NNC(=O)C(C)(OCc2ccccc2)C(F)(F)F)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(benzyloxy)-3,3,3-trifluoro-2-methylpropanoic acid (Int. D) (0.709 g, 2.85 mmol) in DMF (15 ml) was added HATU (1.303 g, 3.43 mmol) followed by DIPEA (0.598 ml, 3.43 mmol). After 30 mins, tert-butyl 2-(hydrazinecarbonyl)-6-methoxy-5-(trifluoromethyl)pyridin-3-ylcarbamate (Int. C) (1 g, 2.85 mmol) was added and the reaction mixture was stirred at RT for 3 h. The mixture was poured into water and the product extracted with EtOAc. The organic portion was washed with 1 MHCl, brine, dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with 0% to 50% EtOAc in iso-hexane afforded the title compound:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:20][C:21](=[O:24])[CH:22]=[CH2:23]>C(O)C.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7](=[O:8])[CH2:23][CH2:22][C:21](=[O:24])[CH3:20])=[CH:5][CH:4]=1
Reactant: C=CC(C)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)CCC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Yield: 59.2 %

Procedure:
In a small vial charged with 4-(trifluoromethyl)benzaldehyde (3.00 mL, 21.98 mmol) in Ethanol (Volume: 9.5 mL) was added triethylamine (6.13 mL, 44.0 mmol), but-3-en-2-one (2 mL, 21.98 mmol), and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium bromide (1.109 g, 4.40 mmol). The reaction mixture was heated at 80° C. for 16 h and then concentrated. The residue was treated with 1N HCl and extracted with DCM (3×). The organic layer was dried with MgSO4. The crude product was added to an 80 g ISCO silica gel column and was purified with a gradient of 0% to 40% EtOAc/hexanes. The product was obtained as a colorless crystalline solid (3.18 g, 13.02 mmol, 59.2% yield). 1H NMR (CDCl3/400 MHz) δ (ppm) 8.07 (d, 2H), 7.71 (d, 2H), 3.26 (t, 2H), 2.91 (t, 2H), 2.25 (s, 3H); MS m/z: 245.18 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.Cl[C:21]1[CH:30]=[CH:29][N:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][C:25]([CH2:31][CH2:32][CH3:33])=[N:26]2.C(O)C>>[CH3:17][NH:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[NH:1][C:21]2[C:22]3[C:27](=[N:26][C:25]([CH2:31][CH2:32][CH3:33])=[CH:24][CH:23]=3)[N:28]=[CH:29][CH:30]=2)=[CH:11][CH:12]=1
Reactant: CNC(=O)c1ccc(Sc2ccc(C)cc2N)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(C(=O)NC)cc3)ccnc2n1

Procedure:
The product from Example 85b (0.155 g, 0.57 mmol) was reacted with the product from Example 2g as a 3.15M solution in ethanol (0.18 mL, 0.57 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.180 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.72-1.91 (m, 2H) 2.41 (s, 3H) 2.75 (d, J=4.41 Hz, 3H) 2.97 (t, J=7.35 Hz, 2H) 6.36 (d, J=6.99 Hz, 1H) 7.20 (d, J=8.46 Hz, 2H) 7.33-7.47 (m, 2H) 7.50 (d, 1H) 7.63 (d, J=8.46 Hz, 2H) 7.77 (d, J=8.82 Hz, 1H) 8.30-8.44 (m, J=6.62, 6.62 Hz, 2H) 8.91 (d, J=8.82 Hz, 1H) 10.86-11.09 (s, 1H); MS (ESI+) m/z 443.2 (M+H)+; (ESI−) m/z 441.2 (M−H)−.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=2[N:10]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[N:12]=1)(=O)=O.[NH2:34][C:35]1[CH:36]=[C:37]([CH2:41][OH:42])[CH:38]=[CH:39][CH:40]=1>CS(C)=O>[OH:42][CH2:41][C:37]1[CH:36]=[C:35]([NH:34][C:7]2[C:8]3[CH2:28][N:27]([C:29](=[O:31])[CH3:30])[CH2:26][CH2:25][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[O:24][CH:23]=[N:22][CH:21]=4)=[CH:18][CH:19]=3)[N:12]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: Nc1cccc(CO)c1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(Nc3cccc(CO)c3)c2C1
Reaction time: 8 h
Yield: 22.5 %

Procedure:
6-Acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (35 mg, 0.07 mmol, Example 26a) in DMSO (1 mL) was dispensed in a library plate. (3-aminophenyl)methanol (8.62 mg, 0.07 mmol) was added to the funnel and the plate was left to shake overnight at 80° C. before it was filtered and purified by preparative HPLC to give 1-(4-(3-(hydroxymethyl)phenylamino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (7.2 mg, 22%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]([C:14]1[N:18]2[CH:19]=[CH:20][C:21]3[C:26]([C:17]2=[C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:15]=1/[CH:33]=[CH:34]/[C:35](OCC)=[O:36])=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.O1CCCC1>[CH:11]([C:14]1[N:18]2[CH:19]=[CH:20][C:21]3[C:26]([C:17]2=[C:16]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:15]=1[CH2:33]/[CH:34]=[CH:35]/[OH:36])=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH3:13])[CH3:12]
Reactant: CCOC(=O)/C=C/c1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1c(C/C=C/O)c(-c2ccccc2)c2c3ccccc3ccn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diisobutyl aluminium hydride in toluene (1.5M; 16.8 ml) was added dropwise to a stirred solution of ethyl (E)-3-(3-isopropyl-1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)propenoate (2.4 g) in dry tetrahydrofuran (50 ml) at 0° C. under an atmosphere of argon. The mixture was stirred at 0° C. for 30 minutes and then the reaction mixture was quenched by the dropwise addition of saturated aqueous sodium sulphate solution (50 ml) at 0° C. The resulting gel was then allowed to warm to 20° C. and it was then treated with sufficient aqueous hydrochloric acid (2N) to dissolve the gel. The organic phase was separated and the aqueous phase was extracted with diethyl ether (50 ml). The organic solutions were combined, washed with brine, dried over magnesium sulphate and evaporated, to give (E)-3-(3-isopropyl1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)propen-1-ol in the form of an orange oil (2.14 g).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[S:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[CH2:13][CH2:12]1.C([C:24]([O:26][CH3:27])=[O:25])#N.[NH4+].[Cl-]>C1COCC1>[CH3:27][O:26][C:24]([CH:13]1[C:14](=[O:21])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:11][CH2:12]1)=[O:25]
Reactant: O=C1CCSc2ccccc21
Reactant: COC(=O)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1CSc2ccccc2C1=O
Temperature: -78 °C
Reaction time: 1.33 h
Yield: 47.9 %

Procedure:
LHMDS (1.12 g, 6.7 mmol) dissolved in anhydrous THF (7 ml) was cooled to −78° C. under N2. Thiochroman-4-one (1.00 g, 6.1 mmol) in anhydrous THF (20 ml) was added dropwise under 20 minutes. After an additional 60 minutes methyl cyanoformate (0.62 g, 7.3 mmol) in anhydrous THF (1.5 ml) was added dropwise under 5 minutes and the suspension was then stirred at −78° C. for 80 minutes. The suspension was poured onto 10% NH4Cl and extracted with ether. The organic phase was washed with water, dried (Na2SO4), filtered and the solvent evaporated. The crude product was purified by chromatography on silica gel (heptane-ethyl acetate 10:1) to yield 4-oxo-thiochroman-3-carboxylic acid methyl ester (0.65 g): 1H NMR (400 MHz, CDCl3; enol tautomer) δ 12.64 (1H, s), 7.83 (1H, d), 7.25-7.29 (2H, m), 7.16-7.20 (1H, m), 3.84 (3H, s), 3.71 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Si]([O:48][CH2:49][C:50]1[S:54][C:53]([C:55](=[N:57]O)[NH2:56])=[C:52]([CH2:59][CH3:60])[CH:51]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:57]=[C:55]([C:53]3[S:54][C:50]([CH2:49][OH:48])=[CH:51][C:52]=3[CH2:59][CH3:60])[N:56]=2)[CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO
Reactant: O=C(O)c1ccc(Oc2cccc(F)c2)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3cccc(F)c3)c(Cl)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 5 (5a) using 3-chloro-4-(3-fluorophenoxy)benzoic acid (0.14 g, 0.53 mmol) that was obtained in Example 16 (16a), 1-hydroxybenzotriazole (0.086 g, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.56 mmol), 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N′-hydroxythiophene-2-carboximidamide (0.16 g, 0.51 mmol) that was obtained in Example 10 (10d), and 1.0M solution of tetrabutylammoniumfluoride in tetrahydrofuran (1.0 mL, 1.0 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:8 to 5:5) as the eluent to afford the title compound (0.17 g) in a yield of 89% as a pale yellowish crystalline solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[CH2:10]([O:17][C:18]([NH:20][C@H:21]([C:32](O)=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:32](=[O:33])[C@H:21]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:20][C:18]([O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1

Procedure:
L-Serine methyl ester hydrochloride, 5 g., is dissolved in 75 ml. of dimethylformamide and the solution cooled in an ice bath. Triethylamine, 4.9 ml., is added then 11.9 g. of Nα -benzyloxycarbonyl-L-tryptophan, 5.25 g. of 1-hydroxybenztriazole and finally 8.0 g. of dicyclohexylcarbodiimide. The reaction is stirred with ice bath cooling overnight, allowing the temperature to rise to room temperature, then an additional twenty-four hours at room temperature. The mixture is filtered and the solid washed with dimethylformamide. The filtrate is evaporated under reduced pressure and the residue dissolved in ethyl acetate and washed with dilute hydrochloric acid, saturated salt solution, three times with 5% sodium bicarbonate solution, saturated salt solution, and finally with water. The ethyl acetate solution is then dried over magnesium sulfate and evaporated. The residue is crystallized from 250 ml. of benzene and then from ethyl acetate and petroleum ether; 12.5 g.; m.p. 133°-135° C.; [α]D23 -12.4° (c 2, methanol); ultraviolet in methanol λmax 290 E11 115; λmax 281 E11 131; λmax 274 E11 122.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20](O)=[O:21])[CH:18]=3)[N:6](COCC[Si](C)(C)C)[C:5]=2[C:4](=[O:31])[N:3]1[CH2:32][CH2:33][CH3:34].S(Cl)([Cl:37])=O>>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]([Cl:37])=[O:21])[CH:18]=3)[NH:6][C:5]=2[C:4](=[O:31])[N:3]1[CH2:32][CH2:33][CH3:34]
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC(=O)O)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Reactant: O=S(Cl)Cl
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC(=O)Cl)c3)nc2n(CCC)c1=O

Procedure:
{4-[2,6-Dioxo-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-pyrazol-1-yl}-acetic acid (350 mg, 0.71 mmol) was taken with thionyl chloride (25 ml) and refluxed for 3 hrs. The volatiles were evaporated to obtain [4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-pyrazol-1-yl]-acetyl chloride (400 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].CI.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:9][CH3:12])[C:2]=1[F:1]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(F)c1F
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2,3-difluorophenol 21a (2.08 g, 14.5 mmol, purchased from Beijing yu xiang hui da chemical Co., Ltd) in acetone (50 mL) were added methyl iodide (1.24 mL, 19.98 mmol) and potassium carbonate (3.18 g, 23.06 mmol) in turn at room temperature. The mixture was stirred at room temperature for 16 hours and then filtered. To the filtrate was added ethyl acetate (40 mL). The resulting mixture was washed with water (40 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 21b as yellow oil (2.09 g, 100%). This material was not further purified. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.01 (m, 1H), 6.83-6.71 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:29]=[CH:28][C:9]([O:10][CH2:11][CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH3:22])=[C:14]2[N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH3:22])=[C:14]2[N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:28][CH:29]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(OCCn2c(-n3ccnc3)c(C)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-n2ccnc2)n(CCOc2ccc(C(=O)O)cc2)c2ccccc12

Procedure:
A solution of 1-[2-(p-ethoxycarbonylphenoxy)-ethyl]-2-(1-imidazolyl)-3-methylindole (1.66 g) and 3N sodium hydroxide (20 ml) in absolute ethanol (20 ml) is stirred and refluxed for 2 hours. The solution is cooled and acidified to pH 3 with 3N hydrochlorid acid. The precipitate which forms (m.p.>300°) is collected. This solid is dissolved in a saturated sodium bicarbonate solution and the carboxylic acid is reprecipitated by acidifying the solution to pH 5 with 3N hydrochloric acid. The white solid is collected to give 1-[2-(p-carboxyphenoxy)-ethyl]-2-(1-imidazolyl)-3-methylindole; NMR (DMSO): δ2.17 (s, 3H), 4.30 (m, 4H).