Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](F)=[CH:14][C:13]=1[Cl:19])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:19][C:13]1[CH:14]=[C:15]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]=[CH:17][C:12]=1[C:10](=[O:11])[CH3:9]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-chlorophenol (186 g), 2-chloro-4-fluoroacetophenone (250 g) and potassium carbonate (238 g) in DMF (960 mL) was heated to reflux for 48 h. After cooling to room temperature, the reaction mixture was partitioned between MTBE and water and the aqueous phase was extracted twice with MTBE. The combined organic phases were consecutively washed with 10% LiCl solution, dil. NaOH solution and water and dried. The solvent was evaporated under reduced pressure and the crude material was crystallized from diisopropyl ether.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21](C=O)C.[CH2:25]([N:27]([CH2:50][CH3:51])[CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[C:34]([Cl:40])[CH:35]=[C:36](I)[CH:37]=2)[C:32]([OH:48])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:47])[C:31]1=[O:49])[CH3:26].C1(C)C=CC=CC=1>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2]>[CH2:25]([N:27]([CH2:50][CH3:51])[CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[C:34]([Cl:40])[CH:35]=[C:36]([C:20]#[N:21])[CH:37]=2)[C:32]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:47])([OH:48])[C:31]1=[O:49])[CH3:26]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Cl)cc(I)cc21
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Cl)cc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To Pd2(dba)3CHCl3 (5.69 mg, 5 mol %) and triphenyIphosphine (5.76 mg, 20 mol %) under a nitrogen atmosphere was added anhydrous DMF (0.5 mL). The mixture was stirred at room temperature for 30 minutes to give orange/yellow mixture. To this was then added 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-chloro-6-iodooxindole (57.0 mg, 1.1×10−4 mol) followed by Zn(CN)2 (17.2 mg, 0.8 eq., 60%). The resulting suspension was heated to 60° C. (bath temperature) and stirred at that temperature for 3 hours. The mixture was allowed to cool and diluted with EtOAc:toluene (10 mL, 1:1). The mixture was washed with H2O (2×10 mL) and dried (anhydrous MgSO4). After filtration the solvent was removed in vacuo to give the crude title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)=[C:19]([O:38][CH3:39])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1/C=C\CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1/C=C\CCC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A solution of tert-butyl 4-((Z)-4-{(Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}but-3-enyl)piperidine-1-carboxylate (0.0293 g, 0.0553 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[(Z)-4-(piperidin-4-yl)but-1-enyl]benzofuran-3(2H)-one (0.0173 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[C:24]([C:26]1([CH3:40])[CH2:31][CH2:30][C:29]2[C:32]([CH3:39])=[C:33]([OH:38])[C:34]([CH3:37])=[C:35]([CH3:36])[C:28]=2[O:27]1)#[CH:25].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][C:26]3([CH3:40])[CH2:31][CH2:30][C:29]4[C:32]([CH3:39])=[C:33]([OH:38])[C:34]([CH3:37])=[C:35]([CH3:36])[C:28]=4[O:27]3)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Solvent: CCO
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc3c(c1)C(c1ccccc1F)=NCc1nnc(C)n1-3)O2

Procedure:
The title compound was prepared by coupling 6-(2-fluoro-phenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with rac-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol [ref. H. Mayer et al., Helv. Chim. Acta, 67, 650 (1963)]under the conditions described in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The clean fractions containing product were combined and evaporated. The residue was crystallized from ethanol/ethyl acetate to give colorless crystals of rac-2-{[6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepin-8-yl]ethynyl}-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with m.p. 265°-267°.
Reaction SMILES: [CH3:1][CH:2]([C:15](=O)[CH2:16][CH2:17][CH3:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=O.[NH2:20][C:21]([NH2:23])=[O:22].Cl>C(O)C>[CH3:1][C:2]1[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=2)=[N:20][C:21](=[O:22])[NH:23][C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)C(C)C(=O)c1cccc(C(F)(F)F)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCCc1[nH]c(=O)nc(-c2cccc(C(F)(F)F)c2)c1C
Yield: 57.7 %

Procedure:
A stirred mixture of 2-methyl-1-(3-trifluoromethylphenyl)-hexane-1,3-dione (102 mg), urea (45 mg), HCl (0.10 mL, 5M) and ethanol (4 mL) was heated at reflux for 16 h. Further urea (30 mg) and HCl (0.10 mL, 5M) were added and heating continued at reflux for 24 h. The mixture was allowed to cool and the solvent was evaporated at reduced pressure. The residue was dissolved in a mixture of ethyl acetate (10 mL) and water (10 mL), the organic layer was separated and further washed with a solution of saturated sodium carbonate (10 mL) followed by water (10 mL). The ethyl acetate extract was then dried over sodium sulphate and evaporated at reduced pressure to afford 5-methyl-6-propyl-4-(3-trifluoromethylphenyl)-1H-pyrimidin-2-one as a yellow oil (64 mg).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)=[O:30]>C(O)(C)C>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)=[O:30])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(O)cc1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
2.52 g (10 mmol) of 1-diphenylmethylpiperazine and 1.11 g (11 mmol) of triethylamine were dissolved in 30 ml of isopropanol, followed by addition of a solution obtained by dissolving 2.15 g (10 mmol) of α-bromo-p-hydroxyacetophenone in 20 ml of isopropanol. The mixture was allowed to stand overnight at room temperature. Precipitated crystals were collected by filtration. The crystals were successively washed with isopropanol, water and isopropanol and then dried to give 3.27 g of crude crystals of 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanone (yield: 84.6%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][NH:3]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](C)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of (2R,5S)-2,5-dimethylpiperazine (commercially available) (3.495 g, 30 mmol) in dichloromethane (25 mL) at 0° C. was added triethylamine (3.76 mL, 27 mmol) followed by dropwise benzyl chloroformate (4.0 mL, 27 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was then evaporated to dryness. The residue was taken up in aqueous 1N HCl solution and washed with EtOAc. The organic layer was extracted with 1N HCl solution twice and the combined aqueous layers were basicified with 6N NaOH to ˜pH 11. The resulting basic aqueous solution was extracted with EtOAc three times. The combined organic layers were washed with brine, dried (MgSO4) and evaporated to yield phenylmethyl trans-2,5-dimethyl-1-piperazinecarboxylate (enantiomeric mixture) (1.35 g, 18%). LCMS: (M+H)+: 249.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:28]([F:31])([F:30])[F:29])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH2:24][C:25]([OH:27])=O)[N:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([C:28]([F:29])([F:31])[F:30])/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19](=[O:23])[N:18]([CH2:24][C:25]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:27])[N:17]=[CH:16]3)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C(O)Cn1ncc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc2c1=O
Reactant: NCC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1ncc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc2c1=O)NCC(F)(F)F
Reaction time: 18 h
Yield: 63.8 %

Procedure:
To a stirred solution of (E)-2-(6-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1-oxophthalazin-2(1H)-yl)acetic acid (0.15 g, 0.31 mmol) in CH2Cl2 (20.0 ml) was added 2,2,2,-trifluoroethanamine (0.03 g, 0.31 mmol), PyBOP (0.17 g, 0.34 mmol) and DIPEA (0.15 ml, 0.93 mmol) at ambient temperature, and the reaction was stirred for 18 h. The reaction mixture was diluted with CH2Cl2 and washed with 3N HCl (2×20 mL), NaHCO3 (2×20 mL) and brine solution (2×). The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 20-25% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.11 g): mp 172-175° C.; 1H NMR (400 MHz, CDCl3) δ 8.83 (t, J=6.6 Hz, 1H), 8.42 (t, J=14.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (t, J=6.3 Hz, 1H), 7.98-7.86 (m, 2H), 7.16-7.07 (m, 1H), 7.01-6.93 (m, 1H), 4.96-4.81 (m, 3H), 4.00-3.88 (m, 2H); ESIMS m/z 554.0 ([M−H]−).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[Cl:31][C:32]1[CH:33]=C(CCN)[CH:35]=[CH:36][CH:37]=1>>[Cl:31][C:32]1[CH:33]=[C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCc1cccc(Cl)c1
Product: O=C(NCCc1cccc(Cl)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(3-chlorophenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 396 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (1H, br. s.) 10.29 (1H, s) 8.19 (1H, t, J=5.71 Hz) 8.03 (1H, d, J=5.47 Hz) 7.78 (1H, d, J=5.42 Hz) 7.47 (1H, d, J=5.37 Hz) 7.32 (2H, td, J=3.77, 1.93 Hz) 7.27 (1H, d, J=7.27 Hz) 7.22 (1H, t, J=1.83 Hz) 7.17 (1H, t, J=1.56 Hz) 6.81 (1H, d, J=5.52 Hz) 6.45 (1H, dd, J=3.49, 1.68 Hz) 3.43-3.51 (2H, m) 2.84 (2H, t, J=7.32 Hz)
Reaction SMILES: CC(C)N=C=NC(C)C.O[CH2:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14].[CH3:20][CH2:21][N:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:25]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:45][CH2:44][N:43]([C:46]4[CH:51]=[CH:50][C:49]([NH:52][S:53]([C:56]5[CH:61]=[CH:60][C:59]([NH:62][C@@H:63]([CH2:73][S:74][C:75]6[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=6)[CH2:64][CH2:65][N:66]6[CH2:71][CH2:70][CH:69]([OH:72])[CH2:68][CH2:67]6)=[C:58]([S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH:57]=5)(=[O:55])=[O:54])=[CH:48][CH:47]=4)[CH2:42][CH2:41]3)[CH:35]=2)[C:24]([C:88]([OH:90])=[O:89])=[C:23]1[CH3:91]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]2[N:22]([CH2:21][CH3:20])[C:23]([CH3:91])=[C:24]([C:88]([O:90][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:89])[C:25]=2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:41][CH2:42][N:43]([C:46]4[CH:47]=[CH:48][C:49]([NH:52][S:53]([C:56]5[CH:61]=[CH:60][C:59]([NH:62][C@H:63]([CH2:64][CH2:65][N:66]6[CH2:67][CH2:68][CH:69]([OH:72])[CH2:70][CH2:71]6)[CH2:73][S:74][C:75]6[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=6)=[C:58]([S:81]([C:84]([F:85])([F:86])[F:87])(=[O:82])=[O:83])[CH:57]=5)(=[O:55])=[O:54])=[CH:50][CH:51]=4)[CH2:44][CH2:45]3)[CH:35]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CCO
Reactant: CCn1c(C)c(C(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCn1c(C)c(C(=O)OCCC(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 957 (100 mg, 0.09 mmol), DIC (18 mg, 0.14 mmol) and DMAP (20 mg, 0.14 mmol) in DCM (2 mL) was added tert-butyl 3-hydroxypropanoate (41 mg, 0.28 mmol). The solution was stirred for 6 hours at room temperature until no BM-957 was observed by TLC. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 solution (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give crude product which was used for next step without purification. The resulting residue was dissolved in DCM (5 mL) and followed by adding TFA (2.5 mL). The solution was stirred at room temperature for 3 h until no starting material was observed by TLC. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to give the pure product 5 (salt with TFA, 75 mg, yield 70% over two steps). The gradient ran from 60% of solvent A and 40% of solvent B to 20% of solvent A and 80% of solvent B in 40 min. MS (ESI): m/z 1238.17 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH:19]=[CH:20][CH2:21]Cl)=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].O>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:21][CH:20]=[CH:19][C:18]2[CH:23]=[CH:24][C:15]([O:14][CH2:13][O:12][CH3:11])=[C:16]([N+:25]([O-:27])=[O:26])[CH:17]=2)=[CH:6][CH:5]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COCOc1ccc(C=CCCl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(C=CCSc2ccc(Cl)cc2)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
Under a current of argon, a solution having 251 mg of sodium hydride suspended in 10 ml of tetrahydrofuran and 906 mg of p-chlorothiophenol added thereto as kept cooled with ice were stirred for 30 minutes and the produced mixture and a solution of 1.62 g of 4-methoxymethoxy-3-nitrocinnamyl chloride in 5 ml tetrahydrofuran added thereto were stirred at normal room temperature for 14 hours. The resultant reaction mixture was combined with water and extracted from ethyl acetate. The consequently separated organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The residue from drying was concentrated under a vacuum. The concentrate was subjected to silica gel column chromatography. From the hexane-ethyl acetate (5:1 V/V) eluate, 1.77 g of 5-[3-(4-chlorophenylthio)-1-propenyl]-2-methoxymethoxy nitrobenzene was obtained in the form of a colorless oily substance. The yield was 77%.
Reaction SMILES: NC1N(C2C=CC(F)=CC=2)C(C2C=NC=CC=2)=CC=1C([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]2[CH2:21][O:20]C(C)(C)[O:18]2)[CH:10]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:48][OH:49]>O>[OH:18][C@@H:17]([CH2:21][OH:20])[CH2:16][O:15][C:11]1[CH:10]=[CH:9][CH:14]=[CH:13][C:12]=1[CH:48]=[O:49]
Reactant: CO
Reactant: CC1(C)OC[C@H](COc2cccc(C(=O)c3cc(-c4cccnc4)n(-c4ccc(F)cc4)c3N)c2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=Cc1ccccc1OC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.7 g (1.44 mmol) of [2-amino-1-(4-fluorophenyl)-5-pyridin-3-yl-1H-pyrrol-3-yl]-[3-(2,2-dimethyl-[1,3]dioxolan-4(S)-ylmethoxy)-phenyl]-methanone and 0.35 g of p-toluenesulfonic acid in 20 mL of methyl alcohol and 5 mL of water was heated to 50°. After 18 h, the reaction mixture was cooled to room temperature and the solvent was concentrated under reduced pressure. The residue was partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The product was purified by flash chromatography (gradient elution: 100% ethyl acetate-10% methyl alcohol/ethyl acetate/0.4% ammonium hydroxide). The purified product was converted to a HCl salt by treatment of an ethyl acetate solution with HCl/ether. The salt was isolated by filtration and dried to give 0.4 g (56%) of 2-amino-1-(4-fluorophenyl)-5-pyridin-3-yl-1H-pyrrol-3-yl]-3-{[2(S), 3dihydroxypropoxy]phenyl}-methanone (MH+=448).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCCCCc1ccco1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCc1ccco1

Procedure:
19 g of 8-(2-furyl)-octanoic acid were refluxed for 4 hours with 100 ml of methanol and 1.5 ml of sulphuric acid. The mixture was then evaporated to one third of its original volume. 100 g. of ice-water were then added, whereupon the mixture was extracted with ether.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C@H:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](=O)(O)[O-].[Na+].IC>CN(C=O)C>[CH3:23][O:20][C:19](=[O:21])[C@H:18]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH3:22]
Reactant: O=C([O-])O
Reactant: C[C@H](C(=O)O)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
A suspension of (R)-2-(5-benzyloxy-indol-1-yl)-propionic acid (Example 4, 18.0 g, 0.061 mol), sodium bicarbonate (15.36 g, 0.183 mol), and iodomethane (11.40 mL, 0.183 mol) in DMF (164 mL) was stirred at rt for 20 h. The reaction was monitored by reverse phase HPLC. Upon completion, the reaction was quenched by pouring into ice/water (300 mL) followed by extracting with ethyl acetate (2×150 mL). The combined organic layer was washed with water (2×150 mL) and brine (150 mL) and was dried over anhydrous sodium sulfate. Filtration and concentration to dryness gave a crude oil which was purified by silica gel chromatography using 10-35% ethyl acetate/hexanes to give 16.38 g (87%) of (R)-2-(5-benzyloxy-indol-1-yl)-propionic acid methyl ester as an oil. 1H NMR (DMSO-d6) δ 7.45 (d, 2H), 7.38 (m, 3H), 7.30 (m, 2H), 7.13 (s, 1H), 6.82 (d, 1H), 6.38 (s, 1H), 5.41 (q, 1H), 5.08 (s, 2H), 3.60 (s, 3H), 1.70 (d, 3H); LC/MS (+esi) m/z 310.2 (M+H)+, RT 3.47 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:20]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Si:20]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:11]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22]
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCO
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
In toluene (30 ml) was dissolved the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (0.94 g, 3.1 mmol) obtained in Example 5, followed by the addition of 5-(t-butyldimethylsilyloxy)-1-pentanol (1.1 ml, 4.6 mmol) and cyanomethylenetri-n-butylphosphorane (1.0 g, 4.1 mmol). The resulting mixture was heated under reflux for 14 hours under an argon atmosphere. The reaction mixture was allowed to cool down and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=15:1), whereby the title compound (1.4 g, 87%) was obtained as a colorless oil.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]2[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=2[N:30]=1)=[O:21])=[O:7])(C)(C)C.[ClH:32].[F:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](C(O)=O)=[CH:37]2>O1CCOCC1>[ClH:32].[F:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38]([C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@H:10]1[NH:19][C:20]([C:22]1[S:23][C:24]3[CH2:25][N:26]([CH3:31])[CH2:27][CH2:28][C:29]=3[N:30]=1)=[O:21])=[O:7])=[CH:37]2
Reactant: COC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CC[C@H](NC(=O)c2cc3cc(F)ccc3[nH]2)[C@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1

Procedure:
(1S,2R,4R)—N1-tert-Butoxycarbonyl-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a 4N dioxane solution of hydrochloric acid and then condensed with 5-fluoroindole-2-carboxylic acid in a similar manner to Example 118 to obtain the title compound.