Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCC1C=NC=CC=1.[NH2:9][CH2:10][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=1.[F:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][N:24]2[C:28](=[O:29])[N:27]([C:30]3[S:34][C:33]([C:35](O)=[O:36])=[C:32]([CH3:38])[CH:31]=3)[CH:26]=[N:25]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][N:24]2[C:28](=[O:29])[N:27]([C:30]3[S:34][C:33]([C:35]([NH:9][CH2:10][C:11]4[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=4)=[O:36])=[C:32]([CH3:38])[CH:31]=3)[CH:26]=[N:25]2)=[CH:21][CH:20]=1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cnc(CNC(=O)c2sc(-n3cnn(Cc4ccc(F)cc4)c3=O)cc2C)cn1
Yield: 76 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 3-(aminomethyl)pyridine with 2-(aminomethyl)-5-methylpyrazine to react with 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid, the title compound was obtained as a colorless solid in 76% yield: mp 189-191° C.; 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.40 (s, 1H), 7.72 (s, 1H), 7.41-7.34 (m, 2H), 7.07-6.99 (m, 2H), 6.98 (t, J=4.7 Hz, 1H), 6.92 (s, 1H), 4.96 (s, 2H), 4.71 (d, J=4.7 Hz, 2H), 2.56 (s, 3H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6 (d, JC-F=246.9 Hz), 162.4, 152.7, 150.4, 148.4, 143.4, 142.8, 140.1, 134.8, 132.4, 131.2 (d, JC-F=3.2 Hz), 130.3 (d, JC-F=8.3 Hz), 126.1, 120.5, 115.7 (d, JC-F=21.7 Hz), 49.0, 42.3, 21.2, 16.0; MS (ES+) m/z 439.2 (M+1).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH3:16])[NH:13][C:10]2=[N:11][CH:12]=1.[OH-].[Na+].Cl>C(Cl)Cl>[CH3:16][C:14]1[NH:13][C:10]2=[N:11][CH:12]=[C:7]([OH:6])[CH:8]=[C:9]2[CH:15]=1
Reactant: COc1cnc2[nH]c(C)cc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2cc(O)cnc2[nH]1
Temperature: -30 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A solution of boron tribromide (64 μl, 0.68 mmol) in methylene chloride (200 l) was added to a solution of 5-methoxy-2-methyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.308 mmol) in methylene chloride (4 ml) cooled at −30° C. The mixture was left to warn up to ambient temperature and further stirred for 3 hours. The mixture was poured onto ice. The pH was adjusted to 6.2 with 6N aqueous sodium hydroxide followed by 2 N aqueous hydrogen chloride. The mixture was extracted with ethyl acetate. The organic layer was washed with water, followed by brine and dried (MgSO4), filtered and the filtrate was evaporated. The residue was purified by column chromatography, eluting with with methylene chloride followed by methylene chloride/methanol (98/2 followed by 95/5). The fractions containing the expected product were combined and evaporated to give 2-methyl-1H-pyrrolo[2,3-b]pyridin-5-ol (45 mg, quantitative). 1H NMR Spectrum: (DMSO d6) 2.4 (s, 3H); 5.96 (s, 1H); 7.12 (d, 1H); 7.69 (d, 1H); 8.9 (s, 1H); 11.07 (br s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][C:11](=[O:25])[NH:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].I[CH3:29]>CC(C)=O>[CH3:29][S:3][C:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][C:11](=[O:25])[NH:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)=[NH:2]
Reactant: COC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1
Reactant: CI
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(=N)SC)cc2)cc1
Temperature: 50 °C

Procedure:
Methyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]phenoxyacetate (870 mg) was suspended in acetone (100 ml) and iodomethane (10 ml) was added. The stirred suspension was heated to 50° C. After 24 and 48 hours respectively, two further aliquots of iodomethane (10 ml+10 ml) were added whilst stirring at 50° C. was continued. Removal of the solvents in vacuo yielded methyl 4-[3-(4-(methylthio)carbonimidoylbenzoyl)ureido]phenoxyacetate as an orange-brown solid residue which was not purified further. The residue was suspended in methanol (40 ml) and heated to 45°-50° C. with stirring before a solution of ammonium acetate (1.54 g) in methanol (20 ml) was added. After stirring overnight at 45°-50° C., extra portions of methanol (10 ml) and ammonium acetate (0.77 g) were added and the reaction mixture was heated to 70° C. with stirring. After stirring for a further 24 hours at 70° C., the solvents were removed in vacuo to yield a pale yellow solid which was crystallised, with filtration, from boiling methanol to give the title compound (208 mg) as an off-white solid: NMR Spectrum (DMSO-d6) 1.78 (3H, s), 3.71 (3H, s), 4.77 (2H, s), 6.93 (2H, d), 7.50 (2H, d), 7.91 (2H, d), 8.14 (2H d) 9.00-11.00 (3H br); Mass Spectrum m/Z 371 (M+H)+ ; Elemental Analysis: calculated for C18H18N4O5. 1.0 CH3CO2H. 0.75 H2O: C, 54.1%; H, 5.34%; N, 12.6%; found: C, 54.3%; H, 5.0%; N, 12.3%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>C(O)(=O)C>[OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:12])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2c([nH]1)CCCC2
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(c(O)c1[N+](=O)[O-])CCCC2

Procedure:
A solution of 4-hydroxy-5,6,7,8-tetrahydrocarbostyril (1.70g; 0.0103 mole) and concentrated nitric acid (2.5 ml; d 1.42), in glacial acetic acid (10 ml) was heated at 100° C till the oxides of nitrogen were evolved and rapidly cooled in ice. Water (40 ml) was added to the red solution to precipitate the yellow - orange 3-nitro derivative. After filtration, thorough washing with water and recrystallisation from acetic acid -- ethanol the product had m.p. 241°(d).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][O:14][C:13]1[CH:12]=[C:11]([CH:19]=[CH:18][C:16]=1[O:17][CH2:2][CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[CH:10]=[O:9]
Reactant: COc1cc(C=O)ccc1O
Reactant: C[Si](C)(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCCC[Si](C)(C)C
Temperature: 50 °C
Yield: 89.1 %

Procedure:
3-Chloropropyltrimethylsilane (33.14 g, 0.22 mol) was added dropwise over the course of 20 minutes into a mixture of vanillin (30.4 g, 0.2 mol) and potassium carbonate (30.4 g, 0.22 mol) in 150 ml of dry dimethylformamide (DMF) heated to 50° C. under nitrogen. The mixture was maintained for 4 hours at 95°-110° C. The reaction mixture was cooled and poured into ice water. The aqueous phase was extracted 3 times with dichloromethane. The organic phases were dried over sodium sulfate and concentrated in vacuo. After distillation in vacuo (0.04 mm Hg), 47.5 g (yield: 89%) of 3-methoxy4-(3-trimethylsilanylpropyloxy)benzaldehyde were obtained in the form of a slightly pink oil distilling at 112°-114° C. and employed as such in the following step (b).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[F:16][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][NH:1][C:17](=[O:19])[CH3:18])[O:7][C:6]2=[O:8])[CH:14]=[CH:13][C:12]=1[I:15]
Reactant: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A suspension of amine 107 (16.0 g, 47.6 mmol) in CH2Cl2 (150 mL) was treated with TEA (9.62 g, 13.2 mL, 95.2 mmol, 2.0 equiv) at 25° C., and the resulting reaction mixture was cooled to 0-5° C. before being treated with acetic anhydride (Ac2O, 7.29 g, 6.75 mL, 71.4 mmol, 1.5 equiv) and 4-N,N-dimethylaminopyridine (DMAP, 58 mg, 0.5 mmol, 0.01 equiv) at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 2 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was quenched with H2O (100 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 108 (17.36 g, 96.5% yield) as a white powder. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 3H, NHCOCH3), 3.25 (t, 2H, J=5.4 Hz), 3.56 (dd, 1H, J=6.4, 9.2 Hz), 3.95 (t, 1H, J=9.1 Hz), 4.58 (m, 1H), 5.16 (t, 1H, J=5.7 Hz, OH), 7.02 (dd, 1H, J=2.4, 8.2 Hz), 7.38 (dd, 1H, J=2.4, 10.8 Hz), 7.66 (t, 1H, J=7.5, 8.4 Hz), 8.08 (t, 1H, J=5.8 Hz, NHCOCH3). C12H12FIN2O3, LCMS (EI) m/e 379 (M++H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:23])[C:11]1[C:16]([O:17]C)=[C:15]([Cl:19])[CH:14]=[C:13]([Cl:20])[C:12]=1[O:21][CH3:22])[CH3:2].C(CC(C)(C)C)(C)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:23])[C:11]1[C:16]([OH:17])=[C:15]([Cl:19])[CH:14]=[C:13]([Cl:20])[C:12]=1[O:21][CH3:22])[CH3:2]
Reactant: CCN1CCCC1CNC(=O)c1c(OC)c(Cl)cc(Cl)c1OC
Solvent: ClC(Cl)Cl
Solvent: CC(C)CC(C)(C)C
Product: CCN1CCCC1CNC(=O)c1c(O)c(Cl)cc(Cl)c1OC
Yield: 37 %

Procedure:
The title compound was prepared from (-)-N-ethyl-2-(3,5-dichloro-2,6-dimethoxybenzamidomethyl)pyrrolidine by dealkylation in the same manner as described in Example 2. Yield 37%. M.p. 48°-49° C. (i-octane). [α]D25 =-64° C. (c=1.26; CHCl3).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH2:18][CH2:19][CH2:20][CH2:21][OH:22].Cl>C1COCC1>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3]
Reactant: NCCCO
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCCO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (2.80 g, 10 mmol) in 100 ml of THF was cooled to ice temperature and stirred in an ice-bath while a solution of 3-amino-1-propanol (99%) (1.67 g, 22 mmol) was added dropwise over a period of 45 minutes. Stirring in the ice-bath was continued for 30 minutes. The reaction mixture then was acidified by addition of 3.0 ml of 1.2N HCl. The THF was evaporated under reduced pressure and the residue taken up in 100 ml of ethyl acetate. After extracting this solution with 4×20 ml of saturated NaCl solution, the ethyl acetate was evaporated and the residue recrystallized from a mixture of ethyl acetate and hexane to give 2.70 g (84.9%) of light yellow crystalline product, m.p., 87°-88.5°.
Reaction SMILES: [CH:1]([O:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:51]1[N:52]=[C:53]([NH:56]C=O)[S:54][CH:55]=1)[C:21]([NH:23][CH:24]1[C:49](=[O:50])[N:26]2[C:27]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:28]([CH:31]=[CH2:32])[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[CH:1]([O:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:51]1[N:52]=[C:53]([NH2:56])[S:54][CH:55]=1)[C:21]([NH:23][CH:24]1[C:49](=[O:50])[N:26]2[C:27]([C:33]([O:35][CH:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:34])=[C:28]([CH:31]=[CH2:32])[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Temperature: 30 °C
Yield: 90.1 %

Procedure:
To a stirred solution of benzhydryl 7-[2-benzhydryloxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (8.14 g) in methanol (50 ml) and tetrahydrofuran (10 ml) was added 35% hydrochloric acid (2.3 ml). After stirring at 30° C. for an hour, the reaction mixture was poured into ice-water and then adjusted to pH 3.5 with a saturated aqueous sodium bicarbonate. The precipitates were collected by filtration and then dried to give benzhydryl 7-[2-benzhydryloxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (7.08 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:39])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[N:10][C:9]=2[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[CH2:35][CH2:34][CH2:33]3)[CH:29]=1)=[O:5])C>O1CCCC1.[OH-].[Na+]>[CH2:35]1[C:36]2[C:32](=[CH:31][C:30]([N:28]3[C:9]4[N:10]=[C:11]([NH:14][C:15]5[CH:16]=[CH:17][C:18]([N:21]6[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]6)=[CH:19][CH:20]=5)[N:12]=[CH:13][C:8]=4[C:7](=[O:39])[C:6]([C:4]([OH:5])=[O:3])=[CH:29]3)=[CH:38][CH:37]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)c(C(=O)O)cn(-c5ccc6c(c5)CCC6)c4n3)cc2)CC1

Procedure:
Hydrolysis of 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester Cpd 1 (Example 1(g), 50 mg) in a mixture of tetrahydrofuran (THF) and 1 N sodium hydroxide solution at an elevated temperature gave 8-indan-5-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid Cpd 6, which was purified using preparative HPLC, resulting in a formic acid salt form (28 mg, yellow solid). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.38 (s, 1H), 8.80 (s, 1H), 8.35 (br, 1H), 7.83 (br, 1H), 7.42 (m, 2H), 7.20 (m, 4H), 6.65 (br, 2H), 3.20 (m, 4H), 3.03 (m, 4H), 2.88(m, 4H), 2.60(m, 4H), 2.50 (s, 3H), 2.20 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H28N6O3: 497.22 (M+H), Found: 497.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]1>CN(C=O)C.CO>[NH2:16][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1=O
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N)cc2F)CC1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
3-Fluoro-4-(4-methyl-3-oxopiperazin-1-yl)nitrobenzene (3.33 g) was dissolved in a mixture of DMF (40 ml) and methanol (10 ml), and the solution flushed with argon. Ammonium formate (4.15 g) was added, and the mixture cooled to 5° C. Palladium (10% on carbon, 104 mg) was added, and the temperature allowed to rise to ambient as the mixture was stirred under argon for 2 hours. Solvents were evaporated to give an air sensitive product, 5-amino-2-(4-methyl-3-oxopiperazin-1-yl)fluorobenzene, which was used as such in the next stage.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].[NH2:16][CH2:17][CH2:18][OH:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[Na+]>ClCCCl.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:16][CH2:17][CH2:18][OH:19])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=Cc1ccc(Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: OCCNCc1ccc(Cl)nc1
Yield: 37 %

Procedure:
A mixture of 20 grams (0.142 mole) of (6-chloro-3-pyridyl)formaldehyde and 31.3 grams (0.284 mole) of magnesium sulfate in 800 mL of 1,2-dichloroethane was stirred and 13.0 grams (0.213 mole) of 2-aminoethan-1-ol was added. Upon completion of addition, the reaction mixture was stirred for six hours, and 45.1 grams (0.213 mole) of sodium triacetoxyborohydride was added. Following the addition, the reaction mixture was stirred for about 72 hours, and then it was diluted with 250 mL of an aqueous solution comprised of 125 mL of an aqueous solution saturated with sodium chloride and 125 mL of water. The organic layer was separated and the aqueous layer was washed with ten 100 mL portions of 25% isopropanol in methylene chloride. The combined washes were dried with sodium sulfate and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel. Elution was accomplished using mixtures of 5% methanol and 20% methanol in methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 9.8 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([NH:18][NH2:19])=[O:17]>C1(C)C=CC(C)=CC=1>[Br:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([N:18]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)[NH2:19])=[O:17]
Reactant: Clc1nccc2ccccc12
Reactant: NNC(=O)c1cccc(Br)c1
Solvent: Cc1ccc(C)cc1
Product: NN(C(=O)c1cccc(Br)c1)c1nccc2ccccc12
Temperature: 150 °C
Yield: 90.6 %

Procedure:
To a 200-mL three-neck flask were added 3.3 g (20 mmol) of 1-chloroisoquinoline, 4.3 g (20 mmol) of 3-bromobenzoylhydrazine, and 80 mL of para-xylene. This mixture was refluxed at 150° C. for 14 hours under a nitrogen stream. After a predetermined time elapsed, this mixture was cooled to room temperature, and the precipitated solid was collected by suction filtration. The obtained solid was washed with toluene, a saturated aqueous solution of sodium hydrogen carbonate, and water. This solid was dried, so that the substance which was the object of the synthesis was obtained as 6.2 g of a pale yellow powder in 90% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[N+:25]([O-])=O>CCO>[CH2:16]([CH:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:23]=[CH:24][C:2]([NH2:1])=[C:3]([NH2:25])[CH:4]=2)[CH2:11][CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(OCCCN2CCC(Cc3ccccc3)CC2)cc1[N+](=O)[O-]
Solvent: CCO
Product: Nc1ccc(OCCCN2CCC(Cc3ccccc3)CC2)cc1N
Yield: 67.6 %

Procedure:
From a mixture of 1-[3-(4-Amino-3-nitrophenoxy)propyl]-4-benzylpiperidine (226 mg, 0.61 mmol) and stannous dihydrate (690 mg, 3.06 mmol) in EtOH (25 mL) was obtained 140 mg (67.6%) of 4-benzyl-1-[(3,4-diamino-phenoxy)propyl]piperidine as a yellowish viscous oil. 1H NMR (CDCl3): 1.24-1.37 (m, 2H), 1.46-1.58 (m, 1H), 1.58-1.70 (m, 2H), 1.81-1.97 (m, 4H), 2.458 (t, 2H, J=7.5), 2.536 (d, 2H, J=7), 2.90-2.93 (m, 2H), 3.063 (bs, 2H, NH2), 3.503 (bs, 2H, NH2), 3.904 (t, 2H, J=6.5), 6.250 (dd, 1H, J=8; 2.5), 6.319 (d, 1H, J=2.5), 6.619 (d, 1H, J=8), 7.13-7.30 (m, 5H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C@H:8]([CH2:24][O:25][Si](C(C)(C)C)(C)C)[C@H:7]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH2:6]1)(=[O:3])[CH3:2]>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:4][C@H:5]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])[C@H:8]([CH2:24][OH:25])[C@H:7]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@@H](OC2CCCCO2)[C@@H](CO[Si](C)(C)C(C)(C)C)C1CCCCCCCCC(=O)OC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1C[C@@H](OC2CCCCO2)[C@@H](CO)C1CCCCCCCCC(=O)OC(C)C
Reaction time: 8 h

Procedure:
To the solution of the compound (13-3) (4.05 g) in THF(8 ml), tetrabutylammonium fluoride (1M, THF solution, 8.51 ml) was added at room temperature and the mixture was left overnight. The crude product obtained by the conventional treatment was purified by silica gel chromatography (n-hexane/ethyl acetate=6/4) to give the titled compound (13-4).
Reaction SMILES: C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([C:44]([OH:46])=O)[CH:41]=[C:40]([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)[N:39]=2)=[CH:34][CH:33]=1.Cl.[NH:55]1[C:59]([C:60]2[CH:61]=[C:62]3[C:72](=[CH:73][CH:74]=2)[O:71][C:65]2([CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)[CH2:64][C:63]3=[O:75])=[N:58][N:57]=[N:56]1>CN(C)C=O>[F:53][C:50]1[CH:49]=[CH:48][C:47]([C:40]2[CH:41]=[C:42]([C:44]([N:68]3[CH2:69][CH2:70][C:65]4([CH2:64][C:63](=[O:75])[C:62]5[C:72](=[CH:73][CH:74]=[C:60]([C:59]6[NH:58][N:57]=[N:56][N:55]=6)[CH:61]=5)[O:71]4)[CH2:66][CH2:67]3)=[O:46])[CH:43]=[C:38]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=3)[N:39]=2)=[CH:52][CH:51]=1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)nc(-c2ccc(F)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC2(CCN(C(=O)c3cc(-c4ccc(F)cc4)nc(-c4ccc(F)cc4)c3)CC2)Oc2ccc(-c3nnn[nH]3)cc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Triethylamine (71.0 μl, 0.51 mol), 1-hydroxybenzotriazole hydrate (35 mg, 0.26 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (49.0 mg, 0.26 mol) were added to an N,N-dimethylformamide solution (0.5 mL) of 2,6-bis(4-fluorophenyl)pyridine-4-carboxylic acid (53.0 mg, 0.17 mmol) and 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (82.0 mg, 0.26 mol), and stirred at 60° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, and the resulting residue was purified through high-performance preparative liquid chromatography (0.1% TFA, water/acetonitrile) to obtain the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.42 (1H, d, J=2.0 Hz), 8.31 (4H, dd, J=8.7, 5.7 Hz), 8.25 (1H, dd, J=8.7, 2.3 Hz), 7.94 (2H, s), 7.39-7.33 (5H, m), 4.35-4.32 (1H, m), 3.46-3.32 (3H, m), 2.99 (2H, s), 2.13-2.10 (1H, m), 1.91-1.87 (3H, m). MS [M+H]+=579.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:11]([Cl:13])=[CH:10][CH:9]=[C:8]3[C:14](=[O:22])[CH:15]([NH:17][C:18](=[O:21])[CH2:19][Cl:20])[CH2:16][C:6]([C:7]=23)=[CH:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([N:4]1[C:12]2[C:11]([Cl:13])=[CH:10][CH:9]=[C:8]3[C@@H:14]([OH:22])[C@H:15]([NH:17][C:18](=[O:21])[CH2:19][Cl:20])[CH2:16][C:6]([C:7]=23)=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1cc2c3c(ccc(Cl)c31)C(=O)C(NC(=O)CCl)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)n1cc2c3c(ccc(Cl)c31)[C@@H](O)[C@H](NC(=O)CCl)C2
Temperature: 0 °C

Procedure:
An ice cold, solution of 1-acetyl-4-chloroacetamido-8-chloro-3,4-dihydrobenz[cd]indol-5-(1H)-one in ethanol is reduced with excess sodium borohydride to the subject alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13]C(=O)C>CCO.[OH-].[K+]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH2:13]
Reactant: COc1cc(OC)c(Cl)c(NC(C)=O)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(Cl)c(N)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A solution of N-(2,6-dichloro-3,5-dimethoxy-phenyl)-acetamide (3.6 g, 13.7 mmol) in EtOH (130 mL) and KOH (2M, 75 mL) was heated to reflux for 24 hours. The reaction was cooled to 0° C. and stirred for 1 hour at this temperature. The precipitate was filtered and dried to obtain the title compound (2.3 g, yield: 76%). 1H-NMR (400 MHz, CDCl3) δ 3.90 (s, 6H), 4.57 (bs, 2H), 6.05 (s, 1H).