Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:13][CH3:14])[CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23].O>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:13][CH3:14])[CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]1
Reactant: CCI
Reactant: COC1(c2cccc(F)c2F)CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCN1CC(OC)(c2cccc(F)c2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A mixture of 3-(2,3-difluorophenyl)-3-methoxyazetidine (0.75 g, 4.05 mmol), potassium carbonate (0.99 g, 8.1 mmol) and iodoethane (0.388 ml, 4.05 mmol) in acetonitrile (25 ml) was stirred at ambient temperature for 1 h. Water (50 mL) and ethyl acetate (50 mL) was added, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (ethyl acetate/methanol 1:1) to give the title compound (0.58 g, 63%). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 147-148° C. MS m/z (relative intensity, 70 eV) 227 (M+, 4), 170 (66), 169 (bp), 140 (63), 127 (39).
Reaction SMILES: [NH2:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:31]=[CH:32][C:33]=2[F:34])[CH2:24][CH2:23]1>>[NH2:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[CH:31]=[CH:32][C:33]=2[F:34])[CH2:24][CH2:23]1)=[O:5]
Reactant: NCCCN1CCC(c2cc(NC(=O)C3CC3)ccc2F)CC1
Reactant: NC(C(=O)O)(c1ccccc1)c1ccccc1
Product: NC(C(=O)NCCCN1CCC(c2cc(NC(=O)C3CC3)ccc2F)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 174 was prepared from amino(diphenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}cyclopropanecarboxamide according to the procedures described in Scheme 12; ESMS m/e: 529.4 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:11][CH:12]([CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[C:20]([O:27][CH2:28][CH2:29][O:30][CH3:31])[CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[CH:13]([CH3:15])[CH3:14]>ClCCl>[CH:9]([CH:10]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:11][CH:12]([CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[C:20]([O:27][CH2:28][CH2:29][O:30][CH3:31])[CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[CH:13]([CH3:15])[CH3:14])=[O:8]
Reactant: COCCOc1cccc2ccc(CC(CC(CO)NC(=O)OC(C)(C)C)C(C)C)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOc1cccc2ccc(CC(CC(C=O)NC(=O)OC(C)(C)C)C(C)C)cc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.04 ml of triethylamine and then a solution of 1.31 g of sulphur trioxide-pyridine complex are added at 0° C. to the solution of 0.86 g of tert-butyl {1-hydroxymethyl-3-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-4-methylpentyl}carbamate in 8 ml of dichloromethane. After 45 minutes, the reaction mixture is admixed cautiously with ice-water. The resulting mixture is poured onto 1N HCl/ice and extracted with ethyl acetate (3×). The combined organic phases are washed successively with water (2×) and brine, clarified by filtration through Hyflo®, dried over sodium sulphate and concentrated by evaporation. In this way, the crude title compound is obtained.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:12]1[C:17]([CH2:18][NH:19][C:20]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[C:26]=3[Cl:33])[N:23]=[N:22][N:21]=2)=[CH:16][CH:15]=[CH:14][N:13]=1>>[Cl:33][C:26]1[C:27]([Cl:32])=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[C:20]([NH:19][CH2:18][C:17]2[C:12]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:21][N:22]=[N:23]1
Reactant: Fc1ccc(-n2nnnc2NCc2cccnc2Cl)c(Cl)c1Cl
Reactant: OB(O)c1cccnc1F
Product: Fc1ccc(-n2nnnc2NCc2cccnc2-c2cccnc2F)c(Cl)c1Cl

Procedure:
The title compound was prepared from 2-fluoropyridine-3-boronic acid and the product of Example 285B using General Procedure 6. MS (ESI+) m/z 434.2 (M+H)+; Rt=1.87 min. 1H-NMR (400 MHz, DMSO-d6) δ 5.56 (s, 2H), 7.46 (m, 2H), 7.55 (m, 2H), 7.73 (dd, J=1.5 Hz, J=7.9 Hz, 1H), 7.98 (ddd, J=2.0 Hz, J=7.4 Hz, J=9.6 Hz, 1H), 8.31 (d, J=4.8 Hz, 1H), 8.68 (dd, J=1.6 Hz, J=4.7 Hz, 1H), 8.99 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[C:8]([CH3:15])[CH:7]=1.[CH2:17](O)[CH2:18][OH:19].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]2[O:19][CH2:18][CH2:17][O:14]2)=[C:8]([CH3:15])[CH:7]=1
Reactant: OCCO
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CCc1cc(C)c(C2OCCO2)c(C)c1

Procedure:
To a stirred solution of 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester, (2.2 g, 10 mmol) and ethane-1,2-diol (1.86 g, 30 mmol) in toluene (50 mL) was added p-TsOH.H2O (38 mg, 0.2 mmol) and the solution was refluxed using a Dean-Stark apparatus overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (5:1) as eluent to give 3-(4-[1,3]dioxolan-2-yl-3,5-dimethylphenyl)-propionic acid methyl ester as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:37](Cl)=[O:38]>N1C=CC=CC=1>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][C:42]([O:43][CH3:44])=[C:34]([O:33][CH3:32])[CH:35]=4)=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(=O)c4ccc(OC)c(OC)c4)cc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(4-amino-benzyl)-3-butyl-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione (prepared as described in example 72) in pyridine (1 mL) was added 3,4-dimethoxy-benzoyl chloride (Aldrich) (13 mg, 0.06 mmol). The reaction was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC to afford the product. LCMS, m/z(M+H)=586.33.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=[N:9][OH:10])[NH2:8])([O-:3])=[O:2].[CH3:14][C:15]([CH3:24])([CH3:23])[C:16](=[O:22])[CH2:17][C:18](OC)=O>C1(C)C=CC=CC=1>[CH3:14][C:15]([CH3:24])([CH3:23])[C:16](=[O:22])[CH2:17][C:18]1[O:10][N:9]=[C:7]([C:6]2[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:8]=1
Reactant: COC(=O)CC(=O)C(C)(C)C
Reactant: NC(=NO)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Cc1nc(-c2cccc([N+](=O)[O-])c2)no1
Yield: 89.6 %

Procedure:
In a 250 ml flask, place 16 g (0.088 m) of 3-nitrobenzamidoxime (9a), 21.3 g (0.135 m) of methyl 4,4-dimethyl-3-oxovalerate (10a; R1=t-butyl), and 120 ml of toluene. Heat and stir the reaction mixture under reflux with a Dean-Stark trap for 23 hrs. Distill off toluene under a reduced pressure at 50-60° C. to thick oil. Add 60 ml of heptane to the oil with stirring, cool and stir at 0-5° C. for 30 min. Collect solid, wash with heptane, and dry in air to give 22.9 g (90%) of 5-(3,3-dimethyl-2-oxobutyl)-3-(3-nitrophenyl)-1,2,4-oxadiazole [Formula I: R1=t-butyl and R2=3-nitrophenyl].
Reaction SMILES: [C:1](=[O:67])([O:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][O:60][P:61]([OH:64])([OH:63])=[O:62])=[CH:54][C:53]=1[O:65][CH3:66])[O:2][C@H:3]([C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=1)[C@@H:4]([N:6](C(OC(C)(C)C)=O)[CH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([F:27])=[CH:20][C:19]=1[O:28][CH3:29])[CH3:5].[ClH:68]>>[Cl-:68].[F:50][C:47]([F:48])([F:49])[C:39]1[CH:38]=[C:37]([C@@H:3]([O:2][C:1]([O:51][C:52]2[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][O:60][P:61]([OH:64])([OH:63])=[O:62])=[CH:54][C:53]=2[O:65][CH3:66])=[O:67])[C@@H:4]([NH2+:6][CH2:7][C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:23]=[C:22]([CH:24]([CH3:25])[CH3:26])[C:21]([F:27])=[CH:20][C:19]=2[O:28][CH3:29])[CH3:5])[CH:42]=[C:41]([C:43]([F:44])([F:46])[F:45])[CH:40]=1
Reactant: Cl
Reactant: COc1cc(CCOP(=O)(O)O)ccc1OC(=O)O[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H](C)N(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)c(F)cc1OC)C(=O)OC(C)(C)C
Product: COc1cc(CCOP(=O)(O)O)ccc1OC(=O)O[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H](C)[NH2+]Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)c(F)cc1OC
Product: [Cl-]

Procedure:
A solution of (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propyl 2-methoxy-4-[2-(phosphonooxy)ethyl]phenyl carbonate (72.9 mg, 0.074 mmol) in HCl saturated EtOAc (2 mL) was stirred at 25° C. for 5 h. The reaction mixture was concentrated in vacuo to afford (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-[({2-methoxy-4-[2-(phosphonooxy)ethyl]phenoxy}carbonyl)oxy]propan-2-aminium chloride, as a colorless oil/glass. LCMS calc.=886.2; found=886.0 (M+H)+.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][O:17][CH2:18][O:19][N:20]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:23]=2[CH:22]=[CH:21]1.CN(C)[CH:35]=[O:36]>O1CCCC1>[CH:35]([C:21]1[N:20]([O:19][CH2:18][O:17][CH3:16])[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:23]=2[CH:22]=1)=[O:36]
Reactant: COCOn1ccc2c(C(=O)OC)cccc21
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOn1c(C=O)cc2c(C(=O)OC)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (1.97 g) in tetrahydrofuran (24.0 ml) was added dropwise n-butyllithium (6.8 ml, 1.64M solution in n-hexane) at −40° C. and the mixture was stirred at 0° C. for 30 minutes. A solution of methyl 1-methoxymethoxyindole-4-carboxylate (1.64 g) in tetrahydrofuran (12.0 ml) was added to the above solution at −60° C. and the solution was stirred at the same temperature for 30 minutes. A solution of N,N-dimethylformamide (662 mg) in tetrahydrofuran (9.0 ml) was added to the reaction mixture at −60° C. and the solution was stirred at the same temperature for 2 hours. The temperature was raised to −30° C. and the reaction was quenched with saturated ammonium chloride aqueous solution. The aqueous solution was extracted with ethyl acetate (80 ml) and the organic layer was washed with brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1) to give methyl 2-formyl-1-methoxymethoxyindole-4-carboxylate (1.15 g).
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.C1C(=O)N(I)C(=O)C1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[N:6]1[C:5]2[CH:9]=[CH:10][CH:2]=[CH:3][C:4]=2[NH:8][CH:7]=1
Reactant: Cc1ccc2[nH]cnc2c1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 5-methyl-1H-benzoimidazole (132 mg, 1.0 mmol) and NIS (248 mg, 1.10 mmol) in 1 mL of TFA was reflux for 1 hr and then cooled to RT. Treated with 30 mL of EtOAc, the mixture was neutralized with sat. NaHCO3 solution. The organic layer was washed with H2O (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5% MeOH/CH2Cl2) gave 78 (30%) of product as a white solid: 1H-NMR (CDCl3; 400 MHz) δ 8.07 (d, 1H), 7.57 (br s, 1H), 7.22 (d, 1H, J=8.4 Hz), 2.59 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C8H7IN2, 259.0 (M+H), found 259.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17](Cl)[C:12]=3[S:11][C:10]=2[CH3:20])=[C:4]([CH3:21])[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17]([N:22]4[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24][CH2:23]4)[C:12]=3[S:11][C:10]=2[CH3:20])=[C:4]([CH3:21])[CH:3]=1
Reactant: OCC1CCNCC1
Reactant: Cc1nc(Cl)c2sc(C)c(-c3c(C)cc(Br)cc3C)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc(N2CCC(CO)CC2)c2sc(C)c(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
A mixture of 7-(4-bromo-2,6-dimethyl-phenyl)-4-chloro-2,6-dimethyl-thieno[3,2-d]pyrimidine (500 mg), piperidin-4-ylmethanol (226 mg), N,N-diisopropylethylamine (253 mg) in ethanol (1.5 mL) was heated at reflux for 1 day. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate, and then extracted with EtOAc. The organic layer washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/EtOAc=3:1) to obtain {1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,6-dimethyl-thieno[3,2-d]pyrimidin-4-yl]-piperidin-4-yl}-methanol as a white solid (568 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[CH:5][N:4]=1.[C:12]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([SH:22])[NH:21][C:17]=2[CH:16]=1)(=[O:14])[CH3:13].[OH-].[Na+]>C(O)C.C(Cl)Cl.[Cl-].[Na+].O>[C:12]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[NH:19][C:20]([S:22][CH2:2][C:3]3[C:8]4[O:9][CH2:10][O:11][C:7]=4[CH:6]=[CH:5][N:4]=3)=[N:21][C:17]=2[CH:16]=1)(=[O:14])[CH3:13]
Reactant: ClCc1nccc2c1OCO2
Reactant: CC(=O)c1cc2[nH]c(S)nc2cc1C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc2nc(SCc3nccc4c3OCO4)[nH]c2cc1C

Procedure:
2-Chloromethyl-3,4-methylenedioxypyridine (90 mg, 0.52 mmol) and 5-acetyl-6-methyl-2-mercaptobenzimidazole (214 mg, 1.04 mmol) were dissolved in ethanol (15 ml). The pH value of the solution was adjusted to 9 (0.2M NaOH) whereupon the solution was refluxed for 10 min. After concentration of the reaction mixture at reduced pressure the residue was taken up in methylene chloride (10 ml) and brine (2 ml). The phases were separated and the organic phase was dried over sodium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on silica (ethyl acetate). Yield: 140 mg (79%) of the title compound. Mp: 141°-143° C. (uncorr.)
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:5]=1[O:6][C:7]([O:9]C1C=CC=CC=1C(O)=O)=O)([CH3:3])[CH3:2].Cl.C([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])(C)(C)C.C(N([CH:43]([CH3:45])[CH3:44])CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[O:6][C:7]([C:44]1[CH:43]=[CH:45][CH:2]=[CH:1][C:4]=1[C:5]([NH:35][CH2:34][CH2:33][C:32]([OH:31])=[O:36])=[O:6])=[O:9])([CH3:24])[CH3:25]
Reactant: CC(C)c1cccc(C(C)C)c1OC(=O)Oc1ccccc1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1OC(=O)c1ccccc1C(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 8 %

Procedure:
To a solution of crude compound (106) (0.4 g, 1.1 mmol) from above and beta-alanine tert-butyl ester hydrochloride (0.2 g, 1.1 mmol) in DMF (5 mL) was added diisopropylethylamine (0.41 mL, 2.3 mmol) followed by O-(benotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.44 g, 1.1 mmol). The resulting reaction mixture was stirred at room temperature for 14 h, diluted with ethyl acetate (50 mL), washed with 10% aqueous citric acid solution (30 mL), followed by saturated aqueous NaHCO3 solution (30 mL) and brine (2×20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The crude residue was then dissolved in anhydrous dichloromethane (5 mL) and cooled to 0° C. before a solution of hydrochloric acid (1 mL, 4 N in dioxane) was added. The reaction was stirred for 2 h at 0° C. and the solvent was removed in vacuo. The crude residue was purified by preparative LC/MS to afford 50 mg (8% yield over three steps) of the title compound (103). 1H NMR (400 MHz, CDCl3): δ 6 7.85 (dd, J=7.6, 1.6 Hz, 1H), 7.51-7.48 (m, 1H), 7.34-7.13 (m, 5H), 3.72 (q, J=6.0 Hz, 2H), 3.13-3.10 (m, 2H), 2.67 (t, J=6.4 Hz, 2H), 1.25 (d, J=6.8 Hz, 12H). MS (ESI) m/z 414.3 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]([OH:11])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:26][C:27]1[CH:28]=[C:29]([C:33]2[CH:34]=[C:35]([NH:39][C:40]3[C:45]([N+:46]([O-:48])=[O:47])=[CH:44][CH:43]=[CH:42][N:41]=3)[CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]([NH:26][C:27]1[CH:28]=[C:29]([C:33]2[CH:34]=[C:35]([NH:39][C:40]3[C:45]([N+:46]([O-:48])=[O:47])=[CH:44][CH:43]=[CH:42][N:41]=3)[CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:31][CH:32]=1)=[O:11]
Reactant: Nc1cccc(-c2cccc(Nc3ncccc3[N+](=O)[O-])c2)c1
Reactant: O=C(O)C=Cc1ccccn1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccn1)Nc1cccc(-c2cccc(Nc3ncccc3[N+](=O)[O-])c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To an ice cooled suspension of 3-(2-pyridyl)acrylic acid (1.07 g) in dry methylene chloride (80 ml) was added triethylamine (1.46 g) and pivaloyl chloride (0.87 g) and the mixture was stirred for 2 hours. After the clear reaction mixture was obtained, 2-[3-(3-aminophenyl)phenylamino]-3-nitropyridine (2.0 g) was added thereto and stirred under reflux overnight. The reaction was chromatographed on silica gel (chloroform-methanol 50:1 as an eluent) to give 2-[3-[3-[(E)-3-(2-pyridyl)acryloylamino]phenyl]phenylamino]-3-nitropyridine as an orange crystal (2.85 g).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].Br[CH:14](Br)[C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1>C(O)C.C(OCC)C>[CH2:21]1[C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][C:3]1([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccccc1C(Br)Br
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)C1(C(=O)O)Cc2ccccc2C1

Procedure:
Sodium (3.7 g) was dissolved in 80 ml of ethyl alcohol, followed by the addition of 150 ml of diethyl ether. Diethyl malonate (12.5 ml) was added followed by 20 g of α, α-dibromo-o-xylene in 150 ml of diethyl ether with overhead stirring. The reaction was heated to reflux for 5 hours. The reaction was cooled, filtered, and the solvent was removed under vacuum. The residue was treated with a potassium hydroxide solution (20 g in 125 ml of water) and heated to reflux for 15 hours. The reaction was then cooled and rinsed with 200 ml of diethyl ether. The aqueous phase was acidified with 30% hydrochloric acid. The precipitate was collected and dried under vacuum over Drieruite for 5 hours to yield 8.86 g of indan-2,2-dicarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([O:22]C)[CH:16]=[C:15]([O:24]C)[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33].Cl.N1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[C:17]([OH:22])[CH:16]=[C:15]([OH:24])[C:14]=2[C@@H:26]1[CH2:30][CH2:29][N:28]([CH3:31])[C@H:27]1[CH2:32][OH:33]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccc([N+](=O)[O-])cc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: CO
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccc([N+](=O)[O-])cc4Cl)oc23)[C@@H]1CO

Procedure:
A mixture of (−)-trans-2-(2-chloro-4-nitrophenyl)-8-(2-hydroxymethyl-1-methyl pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one (0.4 g, 0.8 mmol), pyridine hydrochloride (0.48 g, 4.1 mmol) and a catalytic amount of quinoline was heated at 180° C. for a period of 2 hrs. The reaction mixture was cooled and diluted with methanol (50 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.1% ammonia and 3% methanol in chloroform as eluent to yield the title compound as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[I-].[Na+].O>CN(C)C=O>[CH2:18]([NH:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1ccc2cc(OCCCCCl)ccc2[nH]1
Reactant: NCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2cc(OCCCCNCc3ccccc3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A suspension of 30 g of 6-(4-chlorobutoxy)carbostyril, 103 ml of benzylamine and 33 g of sodium iodide in 300 ml of dimethylformamide was stirred at 80° C. for 8 hours. The reaction mixture was allowed to cool and then poured into water. The resulting precipitate was collected by filtration. The precipitate was washed with water and diethyl ether in this order to obtain 29.1 g of 6-(4-benzylaminobutoxy)carbostyril.
Reaction SMILES: [C:1]([C@@:4]1([OH:23])[C@@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[O:7][C@@H:6]([N:14]2[CH:21]=[C:20]([Br:22])[C:18](=O)[NH:17][C:15]2=[O:16])[CH2:5]1)(=[O:3])[CH3:2].[CH2:24](N(CC)CC)C.C1(C)C=C(C)C=C(C)C=1S(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1.[NH2:55][C:56]1[C:57]([OH:66])=[CH:58][C:59]2[C:64]([CH:65]=1)=[CH:63]C=CC=2>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:22][C:20]1[C:18]([NH:55][C:56]2[CH:65]=[C:64]([CH3:63])[CH:59]=[C:58]([CH3:24])[C:57]=2[OH:66])=[N:17][C:15](=[O:16])[N:14]([CH:21]=1)[C@@H:6]1[O:7][C@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[C@@:4]([C:1](=[O:3])[CH3:2])([OH:23])[CH2:5]1
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)C[C@@]1(O)C(C)=O
Reactant: Nc1cc2ccccc2cc1O
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)C(O)[C@H]1O[C@@H](n2cc(Br)c(Nc3cc(C)cc(C)c3O)nc2=O)C[C@@]1(O)C(C)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3',5'-diacetyl-5-bromo-2'-deoxyuridine (4.0 g; 10 mmol), methylene chloride (50 ml), triethylamine (4.0 g; 40 mmol) and DMAP (0.1 g) was added 2-mesitylsulfonyl chloride (4.4 g; 20 mmol). After stirring at room temperature for 6 h. DBU (3.0 g; 20 mmol) and 3-amino-2-naphthol (6.4 g; 40 mmol) were added and the solution was stirred for 4 h. at room temperature. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate aq. solution, but the title compound was precipitated from solution. The precipitates were filtered off and washed thoroughly with ethyl acetate, then methylene chloride, and dried. A small quantity of title compound also was obtained from the filtrate.