Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[NH2:13][C:14]1[C:19](Br)=[N:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][N:15]=1>CN(C=O)C>[NH2:13][C:14]1[C:19]([S:1][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[N:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][N:15]=1
Reactant: Sc1nc2ccccc2s1
Reactant: Nc1ncc(-c2ccccc2)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccccc2)nc1Sc1nc2ccccc2s1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 22.3 %

Procedure:
To a solution of 2-mercaptobenzothiazol (0.07 g, 0.4 mmol) in dry DMF (7 mL), sodium hydride (NaH) (9 mg, 0.4 mmol) was added and the resulting mixture was stirred for 15 min. After this time 2-amino-3-bromo-5-phenylpyrazine 17b (0.05 g, 0.2 mmol) was added and the mixture heated at 110° C. for 4 h. The solvent was removed under reduced pressure and the crude was diluted with dichloromethane, washed with water. Then the organic layer was anidrified over Na2SO4, filtered and the solvent removed under reduced pressure to get a crude that was purified by flash chromatography using dichloromethane-EtOAc (9:1 v/v) to get 15 mg of title compound 18p as a pale yellow solid (yield 23%). 1H-NMR (CDCl3): 5.36 (br s, 2H), 7.28-7.47 (m, 6H), 7.59-7.76 (m, 1H), 7.91-7.93 (m, 2H), 8.53 (s, 1H). MS (ESI): m/z 359 (M+Na1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.C(N(CC)C(C)C)(C)C.[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>C(#N)C>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1F
Yield: 52 %

Procedure:
2-Methylimidazole (9.02 g, 0.11 M) and N,N-diisopropylethylamine (32.2 g, 0.25 M) were dissolved in acetonitrile (160 ml), and 3,4-difluoronitrobenzene (15.9 g, 0.1 M) added. The mixture was stirred and heated to reflux under nitrogen for 24 hours. Solvent was evaporated, the residue dissolved in ethyl acetate (300 ml), washed with water (150 ml), brine (150 ml), and dried (magnesium sulfate). The residue was recrystallised from a mixture of ethyl acetate (25 ml) and cyclohexane (150 ml) with the addition of charcoal to give the title compound (11.5 g), mp 106-107°. NMR(DMSO-d6) δ: 2.25 (s, 3H), 7.00 (d, 1H); 7.35 (t, 1H); 7.87 (t, 1H); 8.23 (dd, 1H); 8.43 (dd, 1H). MS (ESP): 222 (MH+) for C10H8FN3O 2
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:31].[Na+].O.O.P([O-])(O)(O)=O.[Na+]>CC#N.O.C(O)(C)(C)C>[C:22]([C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[Cl:1])[NH:8][CH:7]=[C:6]4[C:11]([OH:31])=[O:12])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1)([OH:24])=[O:23]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(C(=O)O)CC4)cc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(C(=O)O)CC4)cc3)cc12
Temperature: 0 °C
Yield: 30.4 %

Procedure:
1-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]cyclopropanecarboxylic acid (253 mg, 0.577 mmol) was dissolved in MeCN (6 mL) and warm t-butanol (6 mL). 2-methyl-2-butene (4 mL) was added and the mixture was cooled to 0° C. Sodium chlorite (780 mg, 11.6 mmol) and sodium dihydrogen phosphate dihydrate (1800 mg, 11.54 mmol) were dissolved in water (4 mL). The aqueous solution was added to the organic solution dropwise via addition funnel and the ice bath was removed and the mixture was allowed to warm to room temperature overnight. The reaction was concentrated to remove the organics and extracted with ethyl acetate (20 mL×3). The combined organics were washed with brine (20 mL), dried and concentrated and then purified by reverse phase HPLC to give the title compound (62.4 mg, 30.5% yield) as a white solid. MS (AP+) 377.9 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 8.00 (s, 1H), 7.57 (s, 1H), 7.40 (m, 4H), 1.61 (m, 2H), 1.27 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([NH:19][CH3:20])=[CH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[NH:11][CH:10]=1)=[O:8])C.[OH-].[Na+].Cl>O1CCOCC1>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:7](=[O:8])[CH:6]=[C:5]([NH:19][CH3:20])[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C(=CC(=O)c1c[nH]c2ccc(Cl)cc12)NC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CNC(=CC(=O)c1c[nH]c2ccc(Cl)cc12)C(=O)O
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 0.22 g of the ester described in above (1) in dioxane (2.2 ml) was added 1 N NaOH (0.9 ml). After stirring for 2 hours, the mixture was treated with 1 N hydrochloric acid (0.9 ml), and concentrated under reduced pressure. The residue was diluted with water. The obtained crystal was collected by filtration, and washed with water and 95% EtOH to give 0.15 g of the titled compound. Yield: 80%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=2[Cl:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)[CH2:28][CH2:29][CH2:30][N:31]=[C:32]=NCC.ClCCl.N1CCCC1>O>[Cl:24][C:16]1[CH:17]=[C:18]([C:19]([N:31]2[CH2:32][CH2:28][CH2:29][CH2:30]2)=[O:21])[CH:22]=[CH:23][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)O)cc2Cl)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCNC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)N3CCCC3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
A 100 mL round-bottom flask was charged with 4-([4-[(tert-butoxy)carbonyl]piperazin-1-yl]methyl)-3-chlorobenzoic acid (600 mg, 1.69 mmol, 1.00 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (487 mg, 2.54 mmol, 1.50 equiv), 1-Hydroxybenzotrizole (342 mg, 2.53 mmol, 1.50 equiv), dichloromethane (15 mL). The resulting solution was stirred for 30 min at room temperature and pyrrolidine (240 mg, 3.37 mmol, 2.00 equiv) was added. The resulting solution was stirred for 3 h at room temperature and diluted with H2O (10 mL). The resulting solution was extracted with dichloromethane (3×15 mL) and the organic layers were combined, washed with brine (1×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (80/20) to provide 430 mg (62% yield) of tert-butyl 4-([2-chloro-4-[(pyrrolidin-1-yl)carbonyl]phenyl]methyl)piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 408 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.C(N1C=CC(N)=N1)[CH2:43][CH:44]([CH3:46])[CH3:45]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:43][CH:44]([CH3:46])[CH3:45])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC(C)CCn1ccc(N)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 192 mg, 0.58 mmol) was dissolved in methylene chloride and a 2.0 M solution of oxalyl chloride in methylene chloride (211 mg, 0.64 mmol) was added. The reaction stirred at 25° C. for 1 h. The reaction was chilled to 0° C. under nitrogen and 2,6-lutidine (155 μL, 1.34 mmol) was added dropwise. The reaction became golden brown, the ice bath was removed and the reaction continued to stir at 25° C. for 30 min. 1-Iso-pentyl-1H-pyrazol-3-ylamine (89 mg, 0.58 mmol) was dissolved in methylene chloride and added dropwise to the reaction. The solution continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride, washed with water and saturated aqueous brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-iso-pentyl-1H-pyrazol-3-yl)-propionamide (153 mg, 57%) as a white foam: ESI-LRMS m/e calcd for C23H32ClN3O3S [M+] 465.2, found 466.2 [M+H+]; 1H NMR (400 MHz, CDCl3) δppm 0.93 (t, J=6.6 Hz, 6H, 2×CH3), 1.05-1.20 (m, 2H, CH2), 1.42-1.96 (m, 11H, CH and 5×CH2), 2.14-2.34 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.52 (t, J=7.6 Hz, 1H, CH), 3.96-4.02 (m, 2H, NCH2), 6.63 (d, J=2.3 Hz, 1H, Ar), 7.25 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.82 (s, 1H, NH), 8.08 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:20][C:21](=[O:23])[CH3:22])[CH:12]=[C:13]([N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)[CH:14]=2)=[C:4]([N+:24]([O-])=O)[CH:3]=1.[Cl-].[Ca+2].[Cl-]>C(O)C.[Fe]>[NH2:24][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[CH:10]=[C:11]([NH:20][C:21](=[O:23])[CH3:22])[CH:12]=[C:13]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:14]=1
Reactant: CC(=O)Nc1cc(Nc2ccc(Br)cc2[N+](=O)[O-])cc(-n2cncn2)c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CC(=O)Nc1cc(Nc2ccc(Br)cc2N)cc(-n2cncn2)c1
Temperature: 100 °C

Procedure:
To a solution of the compound of Example 155(c) N-(3-(4-bromo-2-nitro-phenylamino)-5-(1H-1,2,4-triazol-1-yl)phenyl)acetamide (5.2 g, 12.5 mmol) in ethanol (100 ml) were added calcium chloride (2.78 g, 25 mmol, 2 eq.) and iron powder (1.3 g, 25 mmol, 2 eq.) and the mixture was heated at 100° C. for 4 h and filtered. The filtrate was diluted with water and extracted as in Example 1(d). The solvent was distilled off and the crude residue was directly used for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(NCc2cccnc2)c1
Reactant: CCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
Into a 0° C. solution of N-(3-methoxycarbonylphenyl) pyrid-3-ylmethylamine (204 g, 0.842 mole, 1 eq) in dichloroethane (3610 mL) and pyridine (1775 mL) was added ethanesulfonyl chloride (114 mL, 1.2 mole, 1.43 eq). The reaction was allowed to warm to room temperature overnight. The dark red reaction was stirred with potassium carbonate (204 g) for 30 minutes and then filtered and concentrated to dryness. The residue was purified by Biotage, eluting with 3:1 to 2:1 DCM/EtOAc mixture to give the title compound as a white solid (137.0 g, 49% yield).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])[CH2:10][CH2:9]2)C=CC=CC=1.C>C(O)(=O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C(C1CCN(Cc2ccccc2)CC1)N1CCc2ccccc2C1
Solvent: CC(=O)O
Product: O=C(C1CCNCC1)N1CCc2ccccc2C1

Procedure:
115 g (0.34 mmol) of 2-[(1-phenylmethyl-4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline are dissolved 1n 1 1 of acetic acid, 4 g of palladinized charcoal (10% palladium) are added and the mixture is subjected to a hydrogenation at 75° C. under 0.35 MPa.
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[CH2:24]([O:15][C:14](=[O:16])[CH:13]=[CH:12][C:11]1[CH:17]=[CH:18][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH3:25]
Reactant: O=C(O)C=Cc1ccc(Oc2ccccc2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccc(Oc2ccccc2)cc1
Yield: 98 %

Procedure:
4-Phenoxycinnamic acid (4.0 g), conc. sulfuric acid (0.4 ml) and ethanol (40 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(b) to obtain the title compound (4.4 g, 98%) as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH:8]1[CH:12]([C:13]([NH2:15])=O)[CH2:11][N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1.ClCCl.O>O1CCCC1>[OH:7][CH:8]1[CH:12]([CH2:13][NH2:15])[CH2:11][N:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1
Reactant: NC(=O)C1CN(Cc2ccccc2)CC1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: NCC1CN(Cc2ccccc2)CC1O
Yield: 90.7 %

Procedure:
In a dry flask was place 1.34 g (35.0 mmol) of lithium aluminum hydride in 20 ml dry tetrahydrofuran cooled to -5° C. To this suspension was added dropwise 2.58 g (11.7 mmol) of 3-hydroxy-4-aminocarbonyl-1-phenylmethyl pyrrolidine. After completion of addition the suspension was warmed 2 hours under relux, cooled. It was successively added 35 ml dichloromethane, 50 ml tetrahydrofuran and 2.3 ml water. The suspension was passed through a celite pad. The solvent removed to give 2.19 g (90.8%) of title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:16][CH2:15][N:14]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:49]([O:51][C:52](=[O:55])[CH2:53]Br)[CH3:50]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:22][CH2:21][N:20]([CH2:53][C:52]([O:51][CH2:49][CH3:50])=[O:55])[CH2:19][CH2:18][N:17]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:16][CH2:15][N:14]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(OCc1ccccc1)N1CCNCCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CN1CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1

Procedure:
68.2 g (118.6 mmol) of 1,4,7-tris-(benzyloxycarbonyl)-1,4,7,10-tetrazacyclododecane (Delaney et al., J Chem. Soc. Perkin Trans. 1991, 3329) is dissolved in 700 ml of acetonitrile and mixed with 75.4 g (545.5 mmol) of sodium carbonate. Then, 39.6 g (355.5 mmol) of bromoacetic acid ethyl ester is added while being stirred vigorously, and it is heated for 20 hours to 40° C. Insoluble components are filtered out, evaporated to the dry state and chromatographed on silica gel (mobile solvent: ethyl acetate/hexane 20:1). The fractions that contain the product are combined and concentrated by evaporation.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:24]3[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccc(Cl)c(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(OC)ccc3Cl)CC2)c(OC)nc1C
Yield: 70 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin3-yl)carbamate and 1-(2-chloro-5-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[N:22]=[C:16]2[C:17](Cl)=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1)(=[O:12])=[O:11].[CH3:23][O-:24].[Na+].CS(C)=O.C[O-].[K+]>CO.ClCCl.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[N:22]=[C:16]2[C:17]([O:24][CH3:23])=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Nc1c(F)cccc1F)c1nc2c(Cl)cccn2n1
Reactant: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cccn2nc(S(=O)(=O)Nc3c(F)cccc3F)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2,6-Difluorophenyl)-8-chloro[1,2,4]triazolo[1,5-a]pyridine-2-sulfonamide (0.8 g, 0.0023 mol) and 25 percent sodium methoxide in methanol (1.6 mL, 0.37 g, 0.007 mol) were combined with 20 mL of dimethyl sulfoxide and the resulting solution was stirred at ambient temperature overnight. Another 1.6 mL of 25 percent sodium methoxide in methanol was added and the reaction mixture was stirred another 3 days. The mixture was then acidified with acetic acid and diluted with dichloromethane. The resulting solution was washed well with water and concentrated by evaporation under reduced pressure. The residue, which appeared to contain considerable starting material, was dissolved in 20 mL of dimethyl sulfoxide and potassium methoxide (0.4 g, 0.0057 mol) was added with stirring at ambient temperature. After about 3 hours the mixture was acidified with acetic acid and diluted with dichloromethane. The resulting solution was washed well with water and concentrated by evaporation under reduced pressure. The residue was mixed with hexane and the solids present were collected by filtration, washed with ether and with dichloromethane and dried to obtain 0.30 g (38 percent of theory) of the title compound as a white powder melting at 254°-255° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[C:4]([F:12])[CH:3]=1.[CH:13]([Mg]Br)=[CH2:14].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([CH3:11])=[C:6]2[C:7]=1[NH:8][CH:14]=[CH:13]2
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(F)cc(Cl)c2[nH]ccc12
Temperature: -50 °C

Procedure:
Under an atmosphere of argon, 4-chloro-2-fluoro-5-nitrotoluene (1.9 g) was dissolved with anhydrous tetrahydrofuran (100 mL), and the reaction mixture was stirred at −50° C. Vinylmagnesium bromide (1.0 M solution in tetrahydrofuran, 40 mL) was dropped to the reaction mixture. The reaction mixture was raised slowly to −20° C. for 40 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and a saturated salt solution. The obtained extract was concentrated under reduced pressure after drying with sodium sulfate. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=95:5→91:9) to give the title compound (1.09 g) having the following physical data.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]([CH3:20])[CH:18]=[C:17]([CH3:21])[CH:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=3)[O:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+]>CO.ClCCl>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[CH:19]([CH3:20])[CH:18]=[C:17]([CH3:21])[CH:16]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=3)[O:15]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: CCOc1ccc(C2ON(S(=O)(=O)c3ccc(NC(C)=O)cc3)C(C)C=C2C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccc(C2ON(S(=O)(=O)c3ccc(N)cc3)C(C)C=C2C)cc1

Procedure:
A stirred mixture of 2-(4-acetamidobenzenesulphonyl)-3, 6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl) -2H-1,2-oxazine (0.153 g) and powdered potassium hydroxide (40mg) in methanol (5 ml) was-heated under reflux for 24 h. The cooled mixture was diluted with dichloromethane and the solution washed with water. The dichloromethane solution was separated, dried over magnesium sulphate, filtered and evaporated to dryness. The residual oil was purified by chromatography on silica using ethyl acetate:n-hexane 3:2 as eluant to give 2-(4-aminobenzenesulphonyl)-3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H-1,2-oxazine as a colourless foam. 1H NMR (CDCl3) δ 1.44(9H, m), 4.02(2H, q), 4.13(2H, br s), 4.44 (1H, m), 5.02(1H, br s), 5.70(1H, m), 6.61(2H, d), 6.83(2H, d), 7.13(2H, d), 7.65(2H, d).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH2:4][CH2:3]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl-].[NH4+]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[CH2:9]2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCN(C2CCCNC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(C2CCCN(c3ccc([N+](=O)[O-])cc3)C2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
1-Methyl-4-piperidin-3-yl-piperazine (1.46 g, 7.96 mmol), 4-Fluoronitrobenzene (1.0 g, 7.2 mmol) and Potassium carbonate (2.50 g, 18.1 mmol) were dissolved in N,N-Dimethylformamide (50 mL, 600 mmol). The reaction mixture was then heated at 100° C. and was allowed to stir overnight. The reaction mixture was poured over saturated ammonium chloride and organics were extracted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was then purified by Isco flash column chromatography (hexanes/ethyl acetate eluent). Combined fractions were reduced and dried under vacuum to afford 1.40 g of 1-Methyl-4-[1-(4-nitro-phenyl)-piperidin-3-yl]-piperazine.
Reaction SMILES: [CH:1]1([C:7]([NH:9][NH2:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)(=O)[CH3:12]>C(O)C>[N:17]1[CH:18]=[CH:19][C:14]([C:11](=[N:10][NH:9][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[CH3:12])=[CH:15][CH:16]=1
Reactant: CC(=O)c1ccncc1
Reactant: NNC(=O)C1CCCCC1
Solvent: CCO
Product: CC(=NNC(=O)C1CCCCC1)c1ccncc1
Yield: 73.1 %

Procedure:
A solution of 4.26 gm (0.03 mole) of cyclohexanecarboxylic acid hydrazide, 3.63 gm (0.03 mole) of 4-acetylpyridine and 100 ml of ethanol is refluxed 7 hr. The solvent is evaporated in vacuo to give a white solid. The product is crystallized from ethyl acetate to yield 5.38 gm (73%) of the title compound having a melting point of 195.3° C.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7](OCC)=[O:8])=[CH:5][C:4]=1[F:14])#[N:2].[Li+].[BH4-]>C1COCC1>[F:14][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[C:1]#[N:2])[CH2:7][OH:8]
Reactant: CCOC(=O)c1ccc(C#N)c(F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)cc1F
Reaction time: 1 h

Procedure:
40 g of ethyl 4-cyano-3-fluorobenzoate in 40 ml of THF are added dropwise to a solution of 8 g of LiBH4 in 120 ml of THF. In the course of this, the reaction mixture comes to the boil. After one hour it is acidified with 2NHCl and worked up in a customary manner. 3-Fluoro-4-cyanobenzyl alcohol, m.p. 70°-72° C., is obtained.