Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([S:24][CH2:25][CH2:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1)[C:20]([O:22]C)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>CO.O>[CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([S:24][CH2:25][CH2:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1)[C:20]([OH:22])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccccc1C(SCCc1nnn[nH]1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCc1ccccc1C(SCCc1nnn[nH]1)C(=O)O
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A stirred suspension of methyl 2-(2-dodecylphenyl)-2-[2-(tetrazol-5-yl)ethylthio]acetate (0.57 g, 1.28 mmol) in 10 ml of methanol and 8 ml of water at 70° was treated with 3 ml of 2.5N sodium hydroxide. After 30 minutes at 70°, the mixture was cooled, diluted with 10 ml of water and filtered. The filtrate was acidified, extracted with ethyl acetate, and the extracts were dried and the solvente evaporated. The residue was recrystallized from methanol and gave the desired product 0.415 g (74%). NMR (CDCl3 /Me2CO): 10.23-11.70 (broad, 2H), 7.52-7.62 (m,1H), 7.27 (s,3H), 5.04 (s,1H), 3.0-3.44 (m,4H), 2.63-2.92 (t,2H), 1.12-1.84 (m,20H), 0.62-1.02 (t,3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][SH:38])=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:28][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([S:38][CH2:37][C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)([CH3:15])[CH3:16])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: COc1ccc(CS)cc1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CSC(C)(C)c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)cc1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d), 86 mg, 0.22 mmol) and (4-methoxy-phenyl)-methanethiol (157 μL, 1.13 mmol) in 2 mL of DCM at 0° C. was added 175 μL (2.27 mmol) of TFA. The mixture was allowed to warm to room temperature overnight, at which time it was diluted with DCM (20 mL), washed with water (1×20 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC on silica gel (5% methanol-CHCl3) to afford the title compound (63 mg, 54%). 1H-NMR (CDCl3; 400 MHz): δ 12.78 (br s, 1H), 9.75 (s, 1H), 8.32 (d, 1H, J=8.6 Hz), 7.75 (s, 1H), 7.51 (dd, 1H, J=7.5, 2.1 Hz), 7.41 (d, 1H, J=2.1 Hz), 7.04 (d, 2H, J=8.6 Hz), 6.75 (d, 2H, J=8.6 Hz), 5.80 (m, 1H), 3.75 (s, 3H), 3.41 (s, 2H), 2.31 (m, 2H), 2.13 (m, 2H), 1.72 (s, 6H), 1.61 (t, 2H, J=6.2 Hz), 1.12 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([O:10]CC)=[O:9])=[C:4]([CH3:7])[S:5][CH:6]=1.[OH-].[Na+]>CCO>[Cl:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[C:4]([CH3:7])[S:5][CH:6]=1
Reactant: CCOC(=O)c1c(Cl)csc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1scc(Cl)c1C(=O)O
Temperature: 25 °C

Procedure:
To a mixture of ethyl 4-chloro-2-methylthiophene-3-carboxylate (F-6) (4.98 g, 24.3 mmol, 1.0 eq) in EtOH (50 mL) ar RT, aqueous NaOH solution (20%, 14.6 g, 73.0 mmol, 3.0 eq) is added and the resulting mixture is stirred at reflux for 1 h. The mixture is allowed to cool to RT and concentrated in vacuo. The residue is poured into ice water (30 mL) and neutralized with concentrated HCl to adjust the pH to 1-2 while keeping the temperature below 5° C. The precipitate is collected by filtration, rinsed with H2O (80 mL) and dried in vacuo to afford the product, 4-chloro-2-methylthiophene-3-carboxylic acid (F-7).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1([C:6]([O:8]CC)=O)[CH2:5][CH2:4]1.Br[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[ClH:1].[OH:8][CH2:6][C:3]1([N:2]2[CH2:12][C:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH:16]=[CH:15][C:14]=3[CH2:23]2)[CH2:4][CH2:5]1
Reactant: CCOC(=O)C1(N)CC1
Reactant: BrCc1ccc2ccccc2c1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: OCC1(N2Cc3ccc4ccccc4c3C2)CC1
Yield: 22.1 %

Procedure:
Ethyl 1-aminocyclopropanecarboxylate hydrochloride (16 g) in chloroform (50 ml) was added to 1,2-bis(bromomethyl)naphthalene (40 g) and potassium carbonate (40 g) in chloroform (200 ml) kept at 60°. The reaction mixture was refluxed for a further 6 hr and then filtered; the filtrate was evaporated to dryness and the residue [i.e. crude 2-(1'-carbethoxycyclopropyl)benz[e]isoindoline] was dissolved in THF (150 ml) and added to lithium aluminium hydride (10 g) in THF (100 ml) over 0.5 h. Water was then added and the resultant slurry was filtered and the filtrate was evaporated to dryness; the residue was partitioned between ether and water and the ether layer was extracted with concentrated hydrochloric acid. The acidic extract was evaporated to dryness to give a residue which was recrystallised from iso-propanol/ethyl acetate to give the title compound (5.9 g. m.p.192°).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[OH:11].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[CH3:9][S:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([O:11][C:14](=[O:15])[N:13]([CH3:17])[CH3:12])=[CH:4][C:5]=1[CH3:10]
Reactant: CN(C)C(=O)Cl
Reactant: CSc1cc(C)c(O)cc1C
Solvent: c1ccncc1
Product: CSc1cc(C)c(OC(=O)N(C)C)cc1C
Temperature: 100 °C

Procedure:
A mixture of 25.2 g 2,5-dimethyl-4-(methylthio)phenol and 20.3 ml dimethylcarbamoyl chloride in 70 ml dry pyridine was heated for 24 hours at 100° C. Addition to excess of ice-cold dilute hydrochloric acid gave an oil. The oil product was extracted into ether and washed three times with cold dilute sodium hydroxide and once with water, dried, and the ether removed by evaporation to give 4-dimethylcarbamoyloxy-2,5-dimethylphenyl methyl sulphide, boiling point 146° C. at 0.6 mm to 150° C. to 0.9 mm.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CN(C=O)C>[C:16]1([NH:15][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1ccccc1C(=O)O
Temperature: 0 °C

Procedure:
A solution of 2-(N-Bromoacetylamino)benzoic acid from Example 79 (5.0 g, 19.37 mmol), aniline (4.51 g, 4.41 mL, 48.4 mmol) and anhyd DMF (50 mL) was heated in an oil bath at 85° C. for 4.5 h. The reaction mixture was cooled and poured into ice-water (500 mL). A solution of 50 KOH (100 mL) was added to dissolve the milky white suspension and the resulting homogenous solution was extracted with CH2Cl2 (200 mL, 2×100 mL). The combined CH2Cl2 extract was set aside and the aqueous layer was acidified to pH=3 (pH meter) with 5% HBr. The resulting precipitate was washed with 5% HBr solution and water, and then dried in a vacuum oven at 50° C. for 2 days, yielding 4.74 g (90.6%) of a white powder, mp 192.4-192.8° C. (sealed tube); 1H NMR (DMSO-d6) δ 13.41 (bs, 1H), 12.01 (s, 1H), 8.72 (d, J=8.4, 1H), 7.93 (dd, J=7.6, J=1.6, 1H), 7.59 (dt, J=8.8, J=1.6, 1H), 7.15-7.05 (m, 3H), 6.63-6.45 (m, 4H); 3.83 (s, 2H); 13C NMR (DMSO-d6) δ 170.85, 169.01, 148.11, 140.56, 134.13, 131.10, 128.94, 122.63, 119.38, 117.10, 115.96, 112.40, 48.93; MS (EI, m/z) 270.1 (M+)
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].B(F)(F)F.[CH3:20]COCC>CO>[CH2:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([CH2:9][CH2:10][C:11]([O:13][CH3:20])=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ccc(CCC(=O)O)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: C=CCNc1ccc(CCC(=O)OC)cc1
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 4-(allylamino)hydrocinnamic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice-cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzeneethanol to yield methyl 4-(allylamino)hydrocinnamate.
Reaction SMILES: [C:1]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)([O:3][CH3:4])=[O:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Cl:15][S:16]([C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][C:1]([O:3][CH3:4])=[O:2])[NH:7][C:8]=2[CH:14]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Product: COC(=O)Nc1nc2ccc(S(=O)(=O)Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 2-carbomethoxyamino-benzimidazole (5.0 g, 0.026 mole) in chlorosulfonic acid (35.00 mL) was stirred at 0° C. for 30 minutes and at room temperature for 3 hours. The resulting dark colored reaction mixture was poured into an ice-water mixture (200 mL), and stirred at room temperature for 30 minutes. The resulting precipitate was filtered and washed with cold water (500 mL). The solid was dried overnight under high vacuum in a desiccator over NaOH pellets to give 5-chlorosulfonyl-2-carbomethoxyamino-benzimidazole (5.9 g, 78%) as a grey powder. 1H NMR (DMSO-d6) d: 3.89 (s, 3H), 7.55 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.88 (s, 1H). (German Patent DE 3826036)
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH:11]1[N:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:24])[CH2:13]C1>>[CH3:11][N:15]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([CH2:13][N:1]1[CH2:9][CH2:8][N:7]([CH2:13][C:14](=[O:24])[N:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:11])[CH2:6][CH2:5][N:4]([CH2:13][C:14](=[O:24])[N:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:11])[CH2:3][CH2:2]1)=[O:24]
Reactant: O=C1CCC(Br)N1OCc1ccccc1
Reactant: C1CNCCNCCN1
Product: CN(OCc1ccccc1)C(=O)CN1CCN(CC(=O)N(C)OCc2ccccc2)CCN(CC(=O)N(C)OCc2ccccc2)CC1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), 5-bromo-1-benzyloxy-2-pyrrolidone (1.2.6.11) and base. 1.3.5.15 N,N′,N″-Tris(1-oxy-2-pyrrolidone-5-yl)-1,4,7-triazacyclononane.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8](B(O)O)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].Cl[C:16]1[C:25]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=2)[N:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:16]3[C:25]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=4)[N:17]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2cc(B(O)O)ccc21
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1ncc2cc(-c3nc4ccc(C(=O)OC)cc4nc3N(C)C(C)C)ccc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
To a solution of 1-ethyl-1H-indazol-5-ylboronic acid (196 mg, 1.03 mmol) in dioxane (6 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 120 mg, 0.41 mmol), K3PO4 (259 mg, 1.23 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) and water (5 drops) with stirring for 4 h at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 1% to 5% ethyl acetate in petroleum ether to afford methyl 2-(1-ethyl-1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (80 mg, 49%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.[CH2:19]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCCC1>CO>[CH2:19]([N:26]1[CH2:31][CH2:30][C:29]2([O:1][C:2]3[C:3](=[N:4][N:5]([CH2:7][C:8]4[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=4)[CH:6]=3)[C:16](=[O:18])[CH2:17]2)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(Cn2cc(O)c(C(C)=O)n2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc(Cn2cc3c(n2)C(=O)CC2(CCN(Cc4ccccc4)CC2)O3)cc1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
Suspended 1-(4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)ethanone (350 mg, 1.42 mmol) in 10 mL methanol and added N-benzyl-4-piperidone (0.25 mL, 1.42 mmol) and pyrrolidine (0.036 mL, 0.3 eq). The mixture was then heated at reflux for 18 h. The reaction was then cooled to room temperature and methanol was removed under reduced pressure. The resultant orange oil was partitioned between 50 mL ethyl acetate and 50 mL water. The aqueous phase was extracted with an additional 50 mL ethyl acetate. The organic layers were combined and dried over sodium sulfate, filtered and concentrated. The resultant oil was flash chromatographed (50-100% ethyl acetate/heptane gradient, 25 g silica) to yield 428 mg (72%) of 1-benzyl-2′-(4-methoxybenzyl)-2′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.25-7.37 (m, 6H), 6.95 (s, 1H), 6.81-6.92 (m, 2H), 5.20 (s, 2H), 3.79 (s, 3H), 3.49 (s, 2H), 2.63 (s, 2H), 2.57 (d, J=11.3 Hz, 2H), 2.25-2.44 (m, 2H), 2.02 (d, J=12.5 Hz, 2H), 1.62-1.77 (m, 2H); m/z (M+1)=418.5.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31]Cl)[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:31][CH2:30][CH2:29][N:28]([CH2:33][CH3:34])[CH2:26][CH3:27])=[CH:19][CH:18]=2)=[O:7])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc(Cl)cc1)c1c(-c2ccc(O)cc2)oc2ccccc12
Reactant: CCN(CC)CCCCl
Product: CCN(CC)CCCOc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(Cl)cc2)cc1

Procedure:
When 3-p-chlorobenzoyl-2-p-hydroxyphenylbenzofuran was reacted with 3-diethylaminopropyl chloride by the procedure of Example 1, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15](O)[CH2:16][N+:17]([O-:19])=[O:18])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]\[N+:17]([O-:19])=[O:18])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COc1cc(C(O)C[N+](=O)[O-])ccc1-c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(/C=C\[N+](=O)[O-])ccc1-c1ccccn1

Procedure:
A solution of 1-(3-methoxy4-pyridin-2-ylphenyl)-2-nitroethanol (290 mg, 1.06 mmol) in anhydrous dichloromethane (5 mL) was treated with triethylamine (0.24 mL, 1.69 mmol), followed by methanesulfonyl chloride (0.10 mL, 1.27 mmol), 1 hr later, the mixture was partitioned between sat. NaHCO3 (10 mL) and dichloromethane (20 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to afford a yellow solid.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:9][C:8]([CH2:32][C:33]#[N:34])([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH2:1]([S:3]([N:6]1[CH2:9][C:8]([CH2:32][C:33]#[N:34])([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Reaction time: 1.5 h
Yield: 47 %

Procedure:
To a solution of 1-(ethylsulfonyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-ylacetonitrile (0.111 g, 0.22 mmol) in methylene chloride (3 mL) was added trifluoroacetic acid (2 mL) and the solution was stirred for 1.5 hours. The solvents were removed in vacuo and the residue was dissolved in methanol (3 mL) and ethylenediamine (0.1 mL) was added. After stirring for 3 hours, the volume was reduced in vacuo and the product was purified by preparative-HPLC/MS, (SunFire C18 column, eluting with a gradient of MeCN/H2O containing 0.1% TFA) to afford the product as the trifluoroacetic acid salt (50 mg, 47%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[S:13])[NH:11][NH2:12])[CH2:3][CH2:2]1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=O)[CH3:15].C(O)C>C(O)(=O)C>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][NH:9][C:10](=[S:13])[NH:11][N:12]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH3:15])[CH2:5][CH2:6]1
Reactant: NNC(=S)NCCN1CCOCC1
Reactant: CC(=O)c1ccccn1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NNC(=S)NCCN1CCOCC1)c1ccccn1
Reaction time: 8 h

Procedure:
A mixture of 6.00 g (0.0294 mole) of 4-(2-morpholinoethyl)thiosemicarbazide, 3.91 g (0.0323 mole) of 2-acetylpyridine, 20 mL of 95% ethanol, and 0.4 mL of glacial acetic acid was heated under reflux for 1.25 hours. The mixture then stood overnight at room temperature. Colourless crystals were collected and recrystallised from 40 mL of 95% ethanol; yield 7.81 g (86%) of pale yellow crystals of 2-acetylpyridine 4-(2-morpholinoethyl)thioseicarbazone, mp 167.5°-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]I)=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][O:30][CH3:29])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CC(=O)Nc1cccc(-n2nc(CI)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
According to Scheme 7 Step 7: To a cooled solution of 14(A) (220 mg, 0.43 mmol) in DMF (2 mL) under nitrogen atmosphere was added dropwise at 0° C. sodium methoxide 2M (in methanol, 215 μL, 0.43 mmol). The mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with with water (100 mL) and the aqueous layer was extracted twice with DCM (100 mL). The organic layers were combined and successively dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 25 g C18) using water/CH3CN 6/4 as eluant to afford N-(3-(4-(4-chlorobenzyl)-6-(methoxymethyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 14(B) (16 mg, 9%) as a yellow solid.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=3[CH3:25])=[C:9]([C:14]#[N:15])[CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:26]([O-])=O)=[N+]=[N-].[H][H]>[Pd].C(O)C.O1CCCC1>[NH2:26][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[NH2:1])[N:11]=[CH:10][C:9]([C:14]#[N:15])=[C:8]2[NH:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[CH3:25]
Reactant: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N=[N+]=[N-])c([N+](=O)[O-])cc23)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N)c(N)cc23)c1
Yield: 72.4 %

Procedure:
A mixture of 0.65 g (1.73 mmol ) of 7-azido-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile and 0.12 g of 10% palladium on carbon in a 1:1 mixture of ethanol/tetrahydrofuran is shaken on Parr apparatus with hydrogen gas at 40 psi for 2 hours. The mixture is filtered through a pad of diatomaceous earth, washed with methanol and tetrahydrofuran, then dried to provide a dark solid. The crude product is purified by silica gel chromatography, utilizing a gradient of methylene chloride/methanol (95:5 to 88:12) to yield 0.4 g of 6,7-diamino-4-(5-methoxy-2-methylanilino)-3-quinolinecarbonitrile as a dark solid, mp 245° C. (dec).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)(C)(C)C.[ClH:16].[CH3:17][O:18][NH2:19].Cl>CO.O1CCOCC1>[ClH:16].[CH3:17][O:18]/[N:19]=[C:9]1/[C@@H:8]([NH2:7])[CH2:13][CH2:12][CH2:11][CH2:10]/1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCC1=O
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CO/N=C1\CCCC[C@@H]1N
Yield: 127 %

Procedure:
To a solution of 2.13 g ((S)-2-oxo-cyclohexyl)-carbamic acid tert-butyl ester in 10 ml methanol was added 0.46 g O-methylhydroxylamine hydrochloride and the mixture was heated to reflux for 18 h. To the resulting yellow solution was added 2.0 ml of a 4M solution of hydrochloric acid in dioxane and the mixture was refluxed for 30 min. The reaction mixture was evaporated and dried under high vacuum. The semisolid residue was triturated under acetonitrile. The solid was collected by filtration and dried to constant weight under high vacuum to yield 1.25 g of the title compound as white crystals. MS (EI): 142 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:17]=[O:18])[CH:13]=2)[N:8]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][OH:18])[CH:13]=2)[N:8]=1
Reactant: COc1ccccc1CNc1ccc2cc(C=O)ccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1CNc1ccc2cc(CO)ccc2n1

Procedure:
2-(2-Methoxy-benzylamino)-quinoline-6-carbaldehyde (663 mg, 2.27 mmol) was dissolved in 25 mL methanol and sodium borohydride (343 mg, 9.03 mmol) was added. The reaction mixture was refluxed for 3 h. The solvent was evaporated off. The residue was taken up in 100 mL water and extracted three times with ethyl acetate (100 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The crude product was recrystallized from dichloromethane. [2-(2-Methoxy-benzylamino)-quinolin-6-yl]-methanol was obtained as a white solid (369 mg, 59%), MS: m/e=295.3 (M+H+).