Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5]([CH2:17][CH3:18])(CC)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[C:13]#[N:14].[F:21][C:22]1[CH:29]=[CH:28]C(C=O)=[CH:24][CH:23]=1.[Na+].[Cl-]>CN(C=O)C.O>[F:21][C:22]1[CH:29]=[CH:28][C:18]([CH:17]=[CH:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]#[N:14])=[CH:24][CH:23]=1
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccc(F)cc1C#N
Reactant: O=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.2 %

Procedure:
Sodium hydride (60% in mineral oil; 1.66 g [0.993 g NaH], 1.4 mmol, 1.10 equiv) was added to a solution of diethyl-2-cyano-4-fluorobenzyl phosphonate (10.2 g-equiv, 37.6 mmol, 1.0 equiv) in DMF (40 mL) over a period of 2 min. The reaction was stirred for 20 min at room temperature. 4-Fluorobenzaldehyde (4.67 g, 38 mmol, 1.0 equiv) was then added over a period of 2 min. After stirring for 18 h, H2O (200 mL) and satd. NaCl (50 mL) were added and the resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with 1N NaOH (1×100 mL) and H2O (2×100 mL), dried (anhyd. Na2SO4), and rotary evaporated (>100° C., heat gun). The crude, dark-red crystalline/oil (7.49 g, 82.7%) was chromatographed twice on silica gel (50×250 mm, dry pack), eluting first with hexane/EtOAc [4:1] and the second chromatography with [30:1] to provide a TLC-pure, yellow compound (2.1 g, 23.2%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16](=[O:42])[C@@H:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([N:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37](O)=[O:38])=[CH:34][CH:35]=3)[C:30]([CH3:40])=[C:29]2[CH3:41])[CH3:27])=[CH:22][CH:21]=1)[CH3:18]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([NH:13][C:37]([C:33]2[CH:32]=[C:31]3[C:36](=[CH:35][CH:34]=2)[N:28]([CH:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][C@@H:17]([CH3:18])[C:16]([O:15][CH3:14])=[O:42])=[CH:21][CH:22]=2)[CH3:27])[C:29]([CH3:41])=[C:30]3[CH3:40])=[O:38])[CH3:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Reactant: COC(=O)[C@H](C)Oc1ccc(C(C)n2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Product: COC(=O)[C@H](C)Oc1ccc(C(C)n2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 5, Example 35, using (S)-1-(4-(tert-butyl)phenyl)ethanamine instead of (S)-1-(3-bromophenyl)ethylamine and 1-(1-(4-(((S)-1-methoxy-1-oxopropan-2-yl)oxy)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of 1-(4-(1-(methoxycarbonyl)cyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid′
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[C:19]([Zn]C#N)#[N:20].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>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.CCOC(C)=O>[C:19]([C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1)#[N:20]
Reactant: N#C[Zn]C#N
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
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: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a 10 ml microwave vial was added methyl 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (500 mg, 1.612 mmol), dicyanozinc (150 mg, 1.277 mmol) and DMF (5 mL). The mixture was degassed and stirred at rt under N2 for 15 min. To the mixture was added palladium tetrakis (118 mg, 0.102 mmol) and the reaction was stirred at 95° C. for 1 h. The reaction was allowed to cool and poured into saturated aqueous Na2CO3 (50 mL) and EtOAc (50 mL) and stirred for 20 min. The mixture was extracted with ether (100 ml) and EtOAc (100 ml) (1:1), followed by filtration and evaporation to yield a residue. The residue was purified by silica gel chromatography (Analogix IF280, 0-8% EtOAc/hexanes, SF25-40 g, 30 minutes) to give methyl 6-cyano-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (130 mg, 0.497 mmol, 38.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (d, J=1.52 Hz, 1 H) 7.82 (s, 1 H) 7.71 (d, J=1.52 Hz, 1 H) 4.85-4.97 (m, 1 H) 3.90 (s, 3 H) 2.29 (s, 3 H) 1.45 (d, J=6.57 Hz, 6 H). MS(ES) [M+H]+ 257.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25]O)=[CH:22][C:21]=3[CH2:27][CH3:28])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:54]1[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25][N:54]4[CH2:57][CH:56]([C:58]([O:60][CH3:61])=[O:59])[CH2:55]4)=[CH:22][C:21]=3[CH2:27][CH3:28])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3)c(Cl)c2)n1
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)c(Cl)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using {5-[5-(3-chloro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-4-ethyl-2-thienyl}methanol (0.17 g, 0.41 mmol) that was obtained in Example 15 (15b), carbon tetrabromide (0.18 g, 0.53 mmol), triphenylphosphine (0.14 g, 0.53 mmol), methyl 3-azetidinecarboxylate hydrochloride (93 mg, 0.62 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.2 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 (1:3) as the eluent to afford the title compound (0.15 g) in a yield of 73% as a pale yellowish oily product.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:3]([OH:5])=[O:4].CI.[C:13](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:3]([O:5][CH3:13])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C(O)c1ccsc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C(O)c1ccsc1
Yield: 65.3 %

Procedure:
A mixture of (RS) 2-hydroxy-2-(thien-3-yl)acetic acid (prepared as described in Akiv. Kemi., 58, 519, 1957) (6.32 g), methyl iodide (17 g) and potassium carbonate (6 g) in acetone was refluxed for 2 hours, evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic extracts, after drying over magnesium sulphate, were evaported to leave the title compound as a yellow oil (4.49 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH3:19]C#N.[OH-:22].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[O:22])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: CC#N
Reactant: [OH-]
Reactant: COc1ccc(-c2cc3cc[nH]c3cc2Cl)cc1
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Temperature: 100 °C

Procedure:
6-Chloro-5-(4-methoxy-phenyl)-1H-indole (25.0 g, 97 mmol), (chloromethylene)dimethyliminium chloride (18.8 g, 147 mmol) and MeCN (100 mL) were stirred at room temperature for 20 minutes. To the resulting bright yellow slurry was added 1N NaOH (400 mL, 400 mmol) and water (400 mL). The reaction mixture was heated to 100° C. for 45 minutes, then cooled to 0° C. The slurry was filtered, and the collected solid was washed with water and air dried to afford the title compound as a yellow solid. MS (ES+) 286.5 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.74 (br. s., 1H), 8.29 (s, 1H), 7.87 (d, J=2.93 Hz, 1H), 7.58 (s, 1H), 7.42 (d, J=8.54 Hz, 2H), 6.98 (d, J=8.54 Hz, 2H), 3.88 (s, 3H)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([NH:22][C:23](=[O:37])[C@@H:24]2[CH2:28][C@H:27]([OH:29])[CH2:26][N:25]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:13]=1>CN(C)C1C=CN=CC=1.ClCCl>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([NH:22][C:23](=[O:37])[C@@H:24]2[CH2:28][C@H:27]([O:29][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:26][N:25]2[C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)Nc1cnc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)Nc3cnc4ccccc4c3)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.3 %

Procedure:
4-Dimethylaminopyridine (395 mg) and p-toluenesulfonyl chloride (468 mg) were added to a solution of N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline 3-quinolylamide (B, 572 mg) in dichloromethane (10 mL) at 0° C. After stirring at room temperature for 2.5 hr, additional 4-dimethylaminopyridine (399 mg) and p-toluenesulfonyl chloride (465 mg) were added. Additional 4-dimethylaminopyridine (400 mg) and p-toluenesulfonyl chloride (467 mg) were added again after 2 hr. The resulting solution was stirred at room temperature for 14 hr, and the solvent was evaporated in vacuo. The residue was diluted with ethyl acetate, and washed with 0.5 M citric acid, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform:methanol=50:1, v/v) to afford the title compound (805 mg) as a pale yellow sticky oil: 1H NMR (400 MHz, CD3OD) δ 1.3-1.5 (m, 9H), 2.23 (m, 3H), 2.3-2.7 (m, 2H), 3.4-3.8 (m, 2H), 4.5 (m, 1H), 5.25 (m, 1H), 7.20 (m, 2H), 7.7-7.9 (m, 5H), 8.00 (d, 1H), 8.58 (br s, 1H), and 8.85 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(OCC)(=O)C.[OH-].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1
Reactant: O=C(NCCc1ccccc1F)c1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Fc1cccc2c1CCN=C2c1ccc(C(F)(F)F)cc1
Temperature: 125 °C

Procedure:
A suspension of N-(2-fluorophenethyl)-4-(trifluoromethyl)benzamide (2.0 g, 6.5 mmol) and phosphoric pentoxide (2.7 g, 19.1 mmol) in anhydrous toluene (40 mL) was heated at 125° C. for 4 h. At this stage more phosphoric pentoxide (2.7 g, 19.1 mmol) was added and continued stirring the reaction at 125° C. for additional 16 h. The reaction was cooled to RT, added ethyl acetate (100 mL), and the resulting slurry was slowly poured into ice-water (100 mL). Then more ethyl acetate (75 mL) was added and the resulting suspension was treated with KOH (3.0 N) until pH˜11.0 was achieved. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to provide 5-fluoro-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline as a yellow oil. MS (ESI pos. ion) m/z: 294 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2([OH:54])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[CH:44][CH:43]=1>>[Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30]([N:51]3[CH2:50][CH2:49][C:48]([C:45]4[CH:46]=[CH:47][C:42]([Cl:41])=[CH:43][CH:44]=4)([OH:54])[CH2:53][CH2:52]3)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)N4CCC(O)(c5ccc(Cl)cc5)CC4)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 61.7 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7, 0.081 g, 0.135 mmol) was reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 0.035, 0.166 mmol) to form [2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidin-3-yl]-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-methanone (0.066 g, 62%). m/z=791 (M+1); HRMS: calcd for C40H54Cl2FN4O5S. Calc [M+H+] 791.3171. found 791.3169.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Br[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=1>>[C:15]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=3)[CH2:2][CH2:3]2)=[CH:18][CH:17]=1)#[N:16]
Reactant: N#Cc1ccc(OCCCBr)cc1F
Reactant: N#Cc1ccc(OCCCC2CCNCC2)cc1
Product: N#Cc1ccc(OCCCC2CCN(CCCOc3ccc(C#N)c(F)c3)CC2)cc1
Yield: 48.3 %

Procedure:
As described in Production Example 7, 0.12 g of 4-[3-(4-piperidinyl)propoxy]benzonitrile and 0.15 g of 4-(3-bromopropoxy)-2-fluorobenzonitrile were used to provide 0.10 g of 4-(3-{4-[3-(4-cyanophenoxy)propyl]-1-piperidinyl}propoxy)-2-fluorobenzonitrile as white solid form.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:15][C:16](=[O:29])[CH2:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][CH:24]2[O:26][CH2:25]2)=[CH:20][CH:19]=1>CO>[NH2:15][C:16](=[O:29])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH:24]([OH:26])[CH2:25][NH:14][CH2:13][CH2:12][CH2:11][CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:27][CH:28]=1
Reactant: NC(=O)Cc1ccc(OCC2CO2)cc1
Reactant: NCCCCn1cnc2ccccc21
Solvent: CO
Product: NC(=O)Cc1ccc(OCC(O)CNCCCCn2cnc3ccccc32)cc1

Procedure:
A mixture of 2.84 grams of 1H-benzimidazole-1-butanamine and 3.11 grams of 1-[4-(2-amino-2-oxoethyl)phenoxy]-2,3-epoxypropane in 50 ml of 90% methanol was heated at reflux for 22 hours. The solvent was evaporated and the residue was triturated with ether to give an off-white solid. This was chromatographed on a silica gel column using methanol. The fractions containing the desired product were determined by thin-layer chromatography and combined. The solvent was then evaporated to give N-{3-[4-(2-amino-2-oxoethyl)phenoxy]-2-hydroxypropyl}-1H-benzimidazole-1-butanamine as an off-white solid melting at about 119°-123° C. This compound has the following structural formula: ##STR13##
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCCC1.O.[Cl-].[Zn+2].[Cl-]>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH:1][C:2]2[C:15]3[C:10]([N:9]=[C:8]4[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]4)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: Cc1c2ccccc2nc2ccccc12
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C=Cc2c3ccccc3nc3ccccc23)cc1
Temperature: 130 °C
Yield: 35 %

Procedure:
A mixture of 9-methylacridine (4.83 g, 25.0 mmol), 4-nitrobenzaldehyde (4.23 g, 31.25 mmol) and zinc chloride (5.06 g, 31.25 mmol) is heated at 130° C. for 3 hours with an oil bath. The solid recovered is heated in a solution of sodium metabisulfite in order to eliminate the excess aldehyde and the hot mixture is filtered. Precipitates obtained are dissolved in a minimum amount of tetrahydrofuran and water is added to the solution so as to obtain the product in the form of precipitates. These precipitates are recovered by filtration and dried. The product can be recrystallized from ethanol. The yield is 35%.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])(OCC)(SCC)=[S:11]>Cl.C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH2:9])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP([O-])(=S)SCC
Reactant: N#CCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=S)Cc1ccccc1
Yield: 55 %

Procedure:
A solution of phenylacetonitrile (10.0 g, 85.4 mmol) and diethyl dithiophosphate (17.5 g, 93.9 mmol) in 4N-HCl/ethyl acetate (400 mL) was stirred at room temperature for 16 hours. This reaction mixture was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol to provide 7.1 g of the title compound. Yield 55%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:31][O:30][C:29](=[O:32])[N:28]1[CH3:33].[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][CH:27]3[CH2:31][O:30][C:29](=[O:32])[N:28]3[CH3:33])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CN1C(=O)OCC1CCCCl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C(O)C(=O)O
Product: CN1C(=O)OCC1CCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Following the procedure of Example 1, α,α-bis(p-fluorophenyl)-4-piperidinemethanol and 4-[(3-chloro)propyl]-3-methyl-2-oxazolidinone are reacted and the product thereof is reacted with oxalic acid to give the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=2)=[CH:15][C:14]=1[C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[CH:32][CH:31]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:39]([N:36]([CH2:37][CH3:38])[C:33]1[CH:34]=[CH:35][C:30]([C:14]2[CH:15]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:24]=3)[CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:31][CH:32]=1)[CH3:40]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc(N(CC)CC)cc3)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCO)c(-c3ccc(N(CC)CC)cc3)c2)cc1
Yield: 73.9 %

Procedure:
In a manner similar to that of Example 2b, by reacting 730 mg of ethyl 4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate (1.3 mmol) in 25 mL of tetrahydrofuran with 1.6 mL of 1M tetrabutylammonium fluoride. 430 mg of ethyl 4″-diethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=74%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[O:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2ncco2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2ncco2)cc1
Yield: 89.2 %

Procedure:
A solution of 2-(4-nitro-phenyl)-oxazole (400 mg, 2.1 mmol) in methanol (10 ml) was hydrogenated over 10% Pd/C at 30 psi until no further gas uptake was observed. The reaction mixture was then filtered over celite and concentrated to give a residue which was purified by column chromatography using ethyl acetate/pet ether (3:7) to yield 4-oxazol-2-yl-phenylamine (300 mg, 89%).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:17]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C>[OH-].[Li+].C1COCC1.O>[CH:19]([O:18][C:16]1[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=1)[C:4]([OH:22])=[O:3])([CH3:21])[CH3:20]
Reactant: CCCN(C)C(=O)c1cc(OC(C)C)cc(C(=O)OCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(C)C(=O)c1cc(OC(C)C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
Dissolve crude 5-isopropoxy-N-methyl-N-propyl-isophthalamic acid ethyl ester (12.7 mmol) in 1 N lithium hydroxide (50 mL) and THF (50 mL). Stir at room temperature for 4 h. Dilute with water (100 mL). Wash with diethyl ether (3×30 mL), and acidify the aqueous layer with 5 N HCl to about pH=1. Extract with ethyl acetate to give the title compound (3.1 g, 87% over 2 steps).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[Br:14])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pt]=O>[Br:14][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])[NH2:11]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cc1Br
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(N)cc1Br
Reaction time: 1 h
Yield: 61.5 %

Procedure:
Platinum oxide (50 mg) was added to a solution of 2-isopropoxy-5-nitrobromobenzene (1.7 g, 6.5 mmol) in ethyl acetate (50 ml) and the mixture was stirred under hydrogen (50 psi) for 1 hour. The mixture was filtered, further platinum oxide (50 mg) was added and the mixture was stirred under hydrogen (50 psi) for 1 hour. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with hexane/EtOAc (80:20), to give the title compound (0.92 g, 62%); δH (360MHz, CDCl3) 1.32 (3H, d, J 5.6Hz, OCH(CH3)2), 4.33 (1H, m, OCH(CH3)2), 6.57 (1H, dd, J 8.7, 2.8Hz, 6-H), 6.78 (1H, d, J 8.7Hz, 5-H), 6.91 (1H, d, J 2.8 Hz, 2-H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][C:17]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)=[CH:16][CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([NH2:43])([CH3:42])([CH3:41])[CH3:40]>CO>[C:39]([NH:43][CH2:26][CH:25]([OH:27])[CH2:24][O:23][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12]([C:11]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=1)=[CH:21][C:20]2=[O:22])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)N
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2ccc(OCC3CO3)cc12
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc2oc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)cc(=O)c2c1

Procedure:
3′,4′-Dibenzyloxy-6-(2,3-epoxy-propoxy)-flavone, 30 (1.5 g, 3 mmol) and tert-butyl amine (0.96 mL, 9 mmol) in dry methanol (125 mL) were reacted in a similar manner to that described under 34 to afford 39. Yield 1.5 g (89%); mp 156-157° C.; MS (FAB) 580 (M++1); IR (KBr) 3404, 1621; 1H NMR (200 MHz, CDCl3) δ 7.51-7.26 (m, 15H), 6.97 (d, J=8.9 Hz, 1H), 6.62 (s, 1H), 5.22 (s, 2H), 5.20 (s, 2H), 4.26-4.22 (m, 1H), 4.14-4.10 (m, 2H), 3.07-2.86 (m, 2H), 1.29 (s, 9H). Analysis Calcd for C36H37NO6: C, 74.59; H, 6.43; N, 2.42. Found: C, 74.61; H, 6.62; N, 2.36.