Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](O)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.O[N:36]1[C:40]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH:36][CH3:40])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC)c3[nH]2)S1
Temperature: 0 °C
Yield: 87.5 %

Procedure:
To an ice-cooled and stirred mixture of methylamine hydrochloride (48 mg) and triethylamine (0.10 mL) in N,N-dimethylformamide (10 mL) were added (2-{7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (0.16 g), 1-hydroxybenzotriazole (94 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg). After stirring at 4° C. to room temperature for 7 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give a pale yellow oil, which was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio) to give a colorless oil. The oil was crystallized from ethyl acetate-hexane to give the title compound (144 mg, 88%) as colorless needles. MS 474 (MH+). mp 125-126° C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[C:23]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C@H:33]2[CH2:35][O:34]2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:35][C@@H:33]([OH:34])[CH2:32][O:31][C:30]5[CH:36]=[CH:37][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(OC[C@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)(C)c1ccc(OC[C@H](O)CN2CCC3(CC2)CSC2=C(O3)c3cc(Br)ccc3C(=O)C2=O)cc1

Procedure:
Compound 223 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. 400 MHz 1H NMR (DMSO) δ: 7.83 (s, 1H), 7.79 (m, 2H), 7.29 (d, 2H), 6.86 (d, 2H), 4.86 (br s, 1H), 3.99-3.94 (m, 2H), 3.89-3.86 (m, 1H), 3.19 (s, 2H), 2.87-2.72 (m, 2H), 2.56-2.50 (m, 2H), 2.47-2.35 (m, 2H), 2.04-1.96 (m, 2H), 1.87-1.78 (m, 2H), 1.25 (s, 9H); LCMS: 587 [M+H].
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:16]([O:8][C:7]([C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1)=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 387 g of L-pyro-glutamic acid in 300 mL of dimethylformamide is treated with 103.6 g of potassium carbonate at room temperature. Benzyl bromide (35.6 mL) is added and the suspension stirred room temperature for 4 hours. The suspension is filtered and the solid washed with 300 mL of acetone. The filtrate is evaporated at 50° C. to give an oil. The oil is dissolved in 300 mL of ethyl acetate and washed with 300 mL of water. The aqueous phase is re-extracted with 150 mL of ethyl acetate and the organic layers combined, dried and the solvent removed to give (S)-5-oxo-pyrrolidine-2-carboxylic acid benzyl ester as an oil.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([OH:17])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5][N:4]=1)[CH3:2].[H-].[Na+].I[CH3:21]>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:3]1[C:11]2[C:6](=[C:7]([O:17][CH3:21])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1cc(O)c2[nH]nc(CC)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC)c2[nH]nc(CC)c2c1
Reaction time: 1 h
Yield: 100.5 %

Procedure:
A solution of ethyl 3-ethyl-7-hydroxy-1H-indazole-5-carboxylate (2.47 g, 10.5 mmo) in DMF (40 mL) was cooled to 0° C. To this mixture was added 60% NaH (0.42 g, 10.5 mmol) and stirred for 1 hour. To this was added a 0° C. solution of iodomethane (1.50 g, 0.66 mL, 10.5 mmol) in DMF (10 mL). The mixture was kept at 0° C. for several hours before stirring at room temperature overnight. The mixture was diluted with EtOAc, washed with a mixture of saturated aqueous NaHCO3 and saturated aqueous NaCl followed by saturated aqueous NaCl. The organic extract was dried over Na2SO4, filtered and concentrated. Purify by CombiFlash (80 g column, 0-30% EtOAc/hexanes gradient) to provide ethyl 3-ethyl-7-methoxy-1H-indazole-5-carboxylate (2.62 g, 40%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20](I)[CH3:21]>O>[NH2:1][C:2]1[C:3]([C:11]([O:13][CH2:20][CH3:21])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1ccnc(C(=O)O)c1N
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCCc1ccnc(C(=O)OCC)c1N
Reaction time: 0.25 h
Yield: 84 %

Procedure:
3-Amino-4-n-propylpyridine-2-carboxylic acid (Preparation 4; 0.36 g, 0.002 mol) was added to a stirred mixture of cesium carbonate (0.325 g, 0.001 mol) in water (20 ml), then this mixture was evaporated under vacuum and the residue azeotroped with dimethylformamide (2×20 ml). The resulting cesium salt was suspended in dimethylformamide (3 ml) and the stirred suspension then treated dropwise with ethyl iodide (0.17 ml, 0.0021 mol). After a further 0.25 hour, the solvent was evaporated under vacuum and the residue partitioned between water (20 ml) and ethyl acetate (20 ml). The organic phase was washed with water (10 ml), dried (MgSO4) and evaporated under vacuum, then the residue crystallized from acetone:hexane to give the title compound as an off-white solid (0.35 g, 84%), m.p. 93-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([O:17][CH:18](C)C)=O)[N:9]=2)[CH:5]=[C:4]([O:21][CH:22]([CH3:24])[CH3:23])[N:3]=1.ClC1C=C(C2N=C[N:34](/C=C\C(OC(C)C)=O)[N:33]=2)C=C(OC)N=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]3[O:17][CH:18]=[N:33][N:34]=3)[N:9]=2)[CH:5]=[C:4]([O:21][CH:22]([CH3:24])[CH3:23])[N:3]=1
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(Cl)nc(OC(C)C)c2)n1
Reactant: COc1cc(-c2ncn(/C=C\C(=O)OC(C)C)n2)cc(Cl)n1
Product: CC(C)Oc1cc(-c2ncn(/C=C\c3nnco3)n2)cc(Cl)n1

Procedure:
(Z)-isopropyl 3-(3-(2-chloro-6-isopropoxypyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylate, was synthesized by analogy to the synthesis of (Z)-isopropyl 3-(3-(2-chloro-6-methoxypyridin-4-yl)-1H-1,2,4-triazol-1-yl)acrylate in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:27]1[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:27]4[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28]4)[CH:22]=[CH:23][CH:24]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: O=C(O)C1CCNC1
Reactant: CCc1c(C=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(CN2CCC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
To a solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylbenzaldehyde (100 mg, 0.258 mmol) (D11) in Ethanol (10 mL) stirred at room temperature was added 3-pyrrolidinecarboxylic acid (119 mg, 1.034 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (110 mg, 0.522 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water, and EtOH was evaporated in vacuo. The mixture was extracted by EA/THF for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated, and dissolved in THF. The residue was purified by Mass Directed AutoPrep to afford 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-pyrrolidinecarboxylic acid (E44) (58 mg) as a TFA salt (off-white solid).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][O:22][C:23](=[O:27])[CH2:24][NH:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([N:25]([CH3:26])[CH2:24][C:23]([O:22][CH3:21])=[O:27])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNCC(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
N-(tert-Butoxycarbonyl)-phenylalanine (4.85 g, 15 mmol) was condensed with N-methylglycine methyl ester hydrochloride in DMF in the presence of triethylamine, HOBt and WSC.
Reaction SMILES: 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.[NH2:34][C@@H:35]([CH2:60][OH:61])[C:36]([NH:38][C@@H:39]([C@H:50]([OH:59])[C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1)[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])=[O:37].[O:62]1[CH2:67][CH2:66][N:65]([CH2:68][C:69](O)=[O:70])[CH2:64][CH2:63]1>CN(C=O)C>[OH:59][C@H:50]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1)[C@H:39]([NH:38][C:36](=[O:37])[C@@H:35]([NH:34][C:69](=[O:70])[CH2:68][N:65]1[CH2:66][CH2:67][O:62][CH2:63][CH2:64]1)[CH2:60][OH:61])[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@@H](N)CO)C(=O)OCc2ccccc2)cc1
Reactant: O=C(O)CN1CCOCC1
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
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
Sequentially HATU (509 mg, 1.34 mmol) and DIEA (0.78 mL, 4.5 mmol) were added to a 0° C. solution of (2S,3R)-benzyl 2-((S)-2-amino-3-hydroxypropanamido)-3-hydroxy-3-(4-methoxyphenyl)propanoate (HCl salt, 474 mg, 1.12 mmol) and 2-morpholinoacetic acid (162 mg, 1.12 mmol) in DMF (8 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was washed with EtOAc to afford (2S,3R)-benzyl 3-hydroxy-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-methoxyphenyl)propanoate (349 mg, 67% yield) as a colorless solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([O:9][C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@@H:13]1[C:18](O)=[O:19])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@@H:13]1[C:18](=[O:19])[NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Reactant: NC1CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)NC1CC1

Procedure:
Cyclopropylamine was coupled with (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (8 g), EDC, HOBt, TEA in DMF to give 5 g of (2R,4R)-2-cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a white semi-solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C)C(=O)C>[Cl:11][C:8]1[C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:10][CH:9]=1
Reactant: O=C(O)c1cc(Cl)ncc1Cl
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc(N2CCOCC2)ncc1Cl
Yield: 34 %

Procedure:
2,5-Dichloroisonicotinic acid, prepared by the method of E. Marzi, A. Bigi, M. Schlosser, Eur. J. Org. Chem. 2001, 1371-1376, (1.6 g, 0.0083 mol) and morpholine (10.9 g, 0.125 mol) in 4 mL of N,N-dimethylacetamide were heated at 80° C. for 4 days. The volatiles were removed under vacuum and the resulting yellow solid partitioned between water and Et2O. The aqueous layer was acidified to pH=1.5 using an aqueous solution of HCl and extracted once with Et2O (25 mL) and three times with CH2Cl2 (25 mL). The organic extracts were combined and the solvents removed under vacuum. The resulting yellow solid was crystallized from MeOH to afford the title compound 1.07 g (yield: 34%). 1H NMR (300 MHz, d6-DMSO): δ 3.45 (t, 4H, J=4.8 Hz), 3.67 (t, 4H, J=4.8 Hz), 7.06 (s, 1H), 8.21 (s, 1H), 13.79 (s (broad), 1H). 13C HMR (100 MHz, d6-DMSO): δ 45.6, 66.4, 107.3, 116.1, 141.3, 148.3, 158.5, 166.8. M+1=243.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19](O)=[O:20])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:22]([O:26][C:27](=[O:35])[CH2:28][CH:29]([NH2:34])[CH:30]([OH:33])[CH2:31][F:32])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:22]([O:26][C:27](=[O:35])[CH2:28][CH:29]([NH:34][C:19]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:13]1[C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1)=[O:12])=[O:20])[CH:30]([OH:33])[CH2:31][F:32])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)c1nccc2ccccc12
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)c1nccc2ccccc12)C(O)CF
Temperature: 0 °C
Yield: 91.6 %

Procedure:
A stirred mixture of (S)-1-(isoquinoline-1-carbonyl)-2-piperidinecarboxylic acid (278 mg, 0.98 mmol), 3-amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (213 mg, 1.03 mmol), HOBt (145 mg, 1.07 mmol), DMAP (137 mg, 1.12 mmol) and anhydrous THF (25 ml) was cooled to 0° C. then EDC (206 mg, 1.07 mmol) was added. The mixture was allowed to warm to room temperature during 16 hrs then concentrated under reduced pressure. The residue was purified by flash chromatography (5% methanol in DCM) to afford the title compound as a white foam (425 mg, 92%): 1H NMR (400 MHz, CDCl3) δ 1.20-3.30 (17H, m), 3.95-4.18 (2H, m), 4.29-4.64 (4H, m), 4.86-5.01 (1H, m), 7.65-8.00 (4H, m), 8.10-9.00 (3H, m); 19F (376 MHz, CDCl3) δ −229.39, −229.41, −229.57, −229.60, −229.64, −229.69, −230.41, −231.08.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O.C[O-].[Na+]>CCO>[CH3:15][C:13]1[N:10]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]=[C:11]([OH:16])[CH:12]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(O)nc(-c2ccccc2)n1

Procedure:
Benzamidine hydrochloride (1.56 g), ethyl acetoacetate (1.26 ml) and sodium methoxide (30% in MeOH, 3.7 ml) were dissolved in EtOH (10 ml) and the resulting mixture was refluxed overnight. It was cooled down and the white suspension was filtered off. The solid was washed with water and high-vacuum dried. 1.83 g of a white solid were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[CH:3]1.C(Cl)Cl.ClN1C(=[O:28])CCC1=O>C(OCC)C.C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][C:3]1=[O:28]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1ccc2cccc(C(=O)c3ccccc3)c21
Solvent: CCOCC
Solvent: ClCCl
Product: CN1C(=O)Cc2cccc(C(=O)c3ccccc3)c21
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6.17 g. (26.25 mmoles) of 1-methyl-7-benzoylindole in 62 ml. of methylene chloride was added 3.58 g. (26.25 mmoles) of 98% N-chlorosuccinimide and the mixture allowed to stir for 90 minutes. An additional 720 mg. of N-chlorosuccinimide was added and stirring continued for 2 hours. The reaction mixture was concentrated in vacuo and 52 ml. of acetic acid added. The mixture was heated to 80° C. and 27 ml. of 85% phosphoric acid was added. The temperature was raised to reflux for 90 minutes and the reaction was cooled and poured into 200 ml. of ice and water. The precipitate was filtered, dissolved in methylene chloride and the solution dried with magnesium sulfate. Removal of the solvent gave a residue which was dissolved in 5% diethyl ether-methylene chloride and filtered through silica gel. The fractions were collected, combined and concentrated to give 4.0 g. of the product as a viscous oil.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](Br)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][N:26]([CH3:38])[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28]>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.CN(C=O)C>[CH2:1]([O:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:33]3[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:27]([N:26]([CH3:38])[CH3:25])=[O:28])[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Reactant: Brc1cnc2ccn(OCc3ccccc3)c2c1
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: CN(C)C=O
Product: CN(C)C(=O)c1cccc(-c2cnc3ccn(OCc4ccccc4)c3c2)c1

Procedure:
A solution of 1-(benzyloxy)-6-bromo-1H-pyrrolo[3,2-b]pyridine (60 mg, 0.21 mmol, 1.0 eq), Pd(PPh3)4 (13 mg), 2.0 M K2CO3 (1.0 ml), DMF (1.2 ml), and [3-(dimethylcarbamoyl)phenyl]boronic acid (1.5 eq, 0.315 mmol) were reacted in microwave (110° C.) for 20 minutes. The upper layer was removed with a pipette and filtered, and purified with preparation HPLC to give the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1.[CH2:19]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[CH2:19]([N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[C:2]1[N:7]=[C:6]([N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:20][CH2:21][CH3:22])[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)nc(Cl)n1
Reactant: CCCCNCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCN(CCCC)c1nc(N(CCCC)CCCC)nc(N2C(C)(C)CCCC2(C)C)n1
Reaction time: 2 h

Procedure:
57.8 g of 2,4-dichloro-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine are suspended in 200 ml of xylene at room temperature. 25.8 g of dibutylamine are added dropwise to this during the course of 15 minutes, the temperature climbing to 40°. A solution of 8.87 g of sodium hydroxide in 40 ml of water is added to the reaction mixture in about 15 minutes and it is subsequently stirred at 60° for 2 hours. The aqueous phase is then separated off and 28.4 g of dibutylamine and a solution of 9.6 g of sodium hydroxide in 20 ml of water is added to the clear organic phase. The mixture is then heated in a water separator until an internal temperature of about 135° is reached and is then stirred for 12 hours at this temperature. The contents of the flask are cooled to 90°, a solution of 3 g of sodium hydroxide in 100 ml of water is added and the mixture is vigorously stirred at 90° for 30 minutes. The aqueous phase is then separated off, the xylene solution is washed five times, each with 100 ml of water, and evaporated in vacuo. The yellowish, oily residue is distilled in a high vacuum. 2,4-Bis-dibutylamino-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine is obtained as a colorless oil having a boiling point of 173° at 6.5 Pa.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([OH:33])[CH2:29][C:30](=[O:32])[CH3:31])[CH:23]=1)=[O:21])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:12].[BH4-].[Na+]>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=[O:12])[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([OH:33])[CH2:29][CH:30]([OH:32])[CH3:31])[CH:23]=1)=[O:21]
Reactant: CC(=O)CC(O)c1cccc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CC(O)c1cccc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)c1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
At −10° C., 10 ml of ethanol solution containing 184 mg of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-(1-hydroxy-3-oxobutyl)phenyl]propane-1,3-dione was mixed with sodium borohydride and stirred for 30 minutes. This was appropriate amounts of saturated ammonium chloride aqueous solution and purified water, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. After concentration, the thus formed residue was purified by a silica gel column chromatography to obtain 110 mg (60%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,3-dihydroxybutyl)phenyl]-3-(3-fluorophenyl)propane-1,3-dione (Example 6-1) from a hexane-ethyl:acetate (1:1-1:3) eluate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]([C:15](=[O:21])[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[C:11]([O:22][CH2:23][CH:24]=[CH2:25])[C:6]=1[NH:7][C:8](=[O:10])[CH3:9])[CH:2]=[CH2:3].C(O)C.[BH4-].[Na+].[OH-].[Na+]>O>[CH2:1]([O:4][C:5]1[CH:14]=[C:13]([CH:15]([OH:21])[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[C:11]([O:22][CH2:23][CH:24]=[CH2:25])[C:6]=1[NH:7][C:8](=[O:10])[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C(=O)CS(C)(=O)=O)cc(OCC=C)c1NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1cc(C(O)CS(C)(=O)=O)cc(OCC=C)c1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1.7 g. of 2',6'-bis(allyloxy)-4'-[(methylsulfonyl)-acetyl]acetanilide in 20 ml. of ethanol and 20 ml. of water was treated with a solution of 0.40 g. of sodium borohydride in 5 ml. of water. There was also added 0.1 g. of sodium hydroxide. The mixture was stirred for 3 hours at room temperature and evaporated to dryness. The residue was taken up in water, removed by filtration under vacuum, dried and recrystallized from ethyl acetate/petroleum ether, whereby there was obtained 2',6'-bis(allyloxy)-4'-[1-hydroxy-2-(methylsulfonyl)-ethyl]-acetanilide having a melting point of 162° C.