Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH3:14])=[C:7]([CH2:9][OH:10])[CH:8]=1.[CH3:29][C:30](OC(C)=O)=[O:31].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:10][CH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[CH2:11][N:12]([CH2:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=1)[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])[CH2:2][NH:1][C:30](=[O:31])[CH3:29]
Reactant: Cc1cccnc1CN(Cc1ccc(CN)cc1CO)[C@@H](C)c1ccccn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccc(CN(Cc2ncccc2C)C(C)c2ccccn2)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To a solution of (S)-(5-aminomethyl-2-{[(3-methyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-methyl}-phenyl)-methanol (0.0914 g, 0.24 mmol) in CH2Cl2 (3 mL) was added Ac2O (0.0228 mL, 0.24 mmol), Et3N (0.05 mL, 0.36 mmol), and KI (0.0033 g, 0.02 mmol), and stirred at room temperature for 18 hours. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-MeOH—NH4OH) provided 0.0750 g (64%) of COMPOUND 401 as a white solid. 1H NMR (CDCl3) δ 1.55 (d, 3H, J=6.6 Hz), 1.71 (s, 2H), 1.99 (s, 3H), 2.05 (s, 3H), 3.63-3.77 (m, 2H), 3.81-3.96 (m, 2H), 4.02-4.09 (m, 1H), 4.20-4.29 (m, 2H), 4.37 (d, 2H, J=5.4 Hz), 5.76 (s, 1H), 6.87 (s, 1H), 7.04-7.23 (m, 3H), 7.33-7.39 (m, 2H), 7.66 (t, 1H, J=7.5 Hz), 8.38 (d, 2H, J=3.9 Hz), 8.57 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 11.93, 18.45, 23.58, 43.70, 52.43, 53.86, 58.92, 63.32, 122.57, 122.67, 124.03, 127.44, 130.86, 132.10, 132.86, 136.70, 137.05, 138.55, 142.57, 146.56, 148.93, 156.59, 161.08, 170.41. ES-MS m/z 441.4 (M+Na). Anal. Calcd. for C25H30N4O2.0.8CH2Cl2.0.8H2O: C, 63.70; H, 6.55; N, 11.52. Found: C, 63.76; H, 6.56; N, 11.60.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=2)[N:13]=[CH:12][CH:11]=1)(=[O:8])[CH2:6][CH3:7].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:5]([NH:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=2)[N:13]=[CH:12][C:11]=1[N+:1]([O-:4])=[O:2])(=[O:8])[CH2:6][CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)Nc1ccnn1-c1ncc(Cl)cc1Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
1.5 ml (0.033 mole) of 98% strength nitric acid are added to 9.0 g (0.032 mole) of 5-propionamido-1-(3,5-dichloro-pyrid-2-yl)-pyrazole and 3.2 ml (0.035 mole) of acetic anhydride in 35 ml of glacial acetic acid at 10° C. and the mixture is stirred at room temperature for 6 hours. For working up, the mixture is concentrated in vacuo, the residue is taken up in 100 ml of methylene chloride and the mixture is neutralized with sodium bicarbonate solution, washed with sodium chloride solution, dried over magnesium sulphate and freed from the solvent in vacuo. 9.3 g (89% of theory) of 5-propionamido-1-(3,5-dichloropyrid-2-yl)-4-nitro-pyrazole of melting point 53° C.-56° C. are obtained.
Reaction SMILES: C(OC([N:8]([C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.Cl.C[OH:32]>>[OH:32][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Br:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Reactant: CO
Agent: Cl
Product: CN[C@H]1CCN(S(=O)(=O)c2cccc3c(O)ncc(Br)c23)C1
Temperature: 60 °C
Reaction time: 30 h

Procedure:
Intermediate 24a (168 mg) obtained in Step A mentioned above was added with 10% hydrogen chloride/methanol (4 ml), and the mixture was stirred at 60° C. for 30 hours. The solvent was evaporated under reduced pressure to obtain the title compound as hydrochloride (123 mg).
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[C:22]([C:23]2[N:24]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([CH2:32]O)=[CH:27][CH:26]=3)=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C1(P([N:55]=[N+:56]=[N-:57])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:55]([CH2:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:23]([C:22]1[C:13]([Cl:12])=[N:14][C:15]3[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:31]2)=[N+:56]=[N-:57]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CO)ccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(CN=[N+]=[N-])ccc21
Temperature: 23 °C
Reaction time: 20 h

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (0.400 mL, 2.69 mmol, 1.10 equiv) was added dropowise over 2 min to a solution of tert-butyl 2-(2-chloro-3-quinolinyl)-5-(hydroxymethyl)-1H-indole-1-carboxylate (7-2, 1.00 g, 2.45 mmol, 1 equiv) and diphenylphosphoryl azide (0.580 mL, 2.69 mmol, 1.10 equiv) in THF (20 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 20 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution and ethyl acetate (2×75 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane, grading to 50% EtOAc in hexane) to afford tert-butyl 5-(azidomethyl)-2-2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (7-3) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.34 (d, 1H, J=8.5 Hz), 8.19 (s, 1H), 8.08 (d, 1H, J=8.3 Hz), 7.88 (d, 1H, J=7.8 Hz), 7.79 (br t, 1H, J=8.1 Hz), 7.62 (br t, 1H, J=8.0 Hz), 7.58 (s, 1H), 7.36 (dd, 1H, J=8.6, 1.5 Hz), 6.68 (s, 1H), 4.46 (s, 2H), 1.27 (s, 9H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][C:17]3[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)Nc1cccc(CC2c3ccccc3CCc3ccccc32)c1
Reaction time: 8 h

Procedure:
Dissolve N-[3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-methanesulfonamide (100 mg, 0.265) in ethanol (25 mL) and add 10% Pd/C (56 mg). Pressurize to 60 psi with H2 and shake overnight at room temperature. Filter reaction through a pad of Celite and concentrate filtrate to 54 mg (54%) of white foam, mp 149.0° C. 1H NMR (CDCl3) δ 2.70 (s, 3H), 2.98 (br q, 2H), 3.28 (d, 2H), 3.40 (br q, 2H), 4.11 (br s, 1H), 6.16 (s, 1H), 6.58 (s, 1H), 6.82-7.20 (m, 11H); MS (S) 395 (M+Na), 376 (M−H). HPLC shows 94% purity.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[C:15]([CH:20](O)[CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].P(Br)(Br)[Br:24].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[Br:24][CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][N:11]2[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH3:21]
Reactant: BrP(Br)Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)O)cccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of 282 (400 mg, 1.27 mmol) in dry DCM (2 mL) and dry Et2O (2 mL) at 0° C. under Argon was added PBr3 (515 mg, 1.91 mmol) and the mixture was stirred at RT overnight. The mixture was poured into cold NaHCO3 (aq.) and extracted with EtOAc. The combined extracts were washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 450 mg (92%) of 4-(1-bromoethyl)-1-tosyl-1H-indole (284) give as a yellow oil, which was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.65 (d, J=2.8 Hz, 1H), 7.35-7.23 (m, 4H), 6.89 (d, J=2.8 Hz, 1H), 5.53-5.50 (m, 1H), 2.36 (s, 3H), 2.13 (d, J=6.8 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[NH:12][C:13]([CH:17]=[O:18])=[C:14]([I:16])[N:15]=1)[CH2:8][CH2:9][CH3:10].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:7]([CH:11]1[N:15]=[C:14]([I:16])[C:13]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:22]=2)([CH:17]=[O:18])[NH:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1nc(I)c(C=O)[nH]1
Reactant: COC(=O)c1ccc(CBr)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1N=C(I)C(C=O)(Cc2ccc(C(=O)OC)c3ccccc23)N1
Temperature: 70 °C
Reaction time: 15 h
Yield: 84.8 %

Procedure:
A suspension of 29.53 g (0.214 mol) of powdered potassium carbonate, 60.00 g (0.214 mol) of 2-butyl-4-iodoimidazole-5-carboxaldehyde, and 65.68 g (0.235 mol) of methyl 4-bromomethylnaphthalene-1-carboxylate (E. A. Dixon, A. Fischer, and F. P. Robinson, Can. J. Chem. 59, 2629 (1981)) in 600 ml of dimethylformamide was stirred for 5 hours under argon at 70° C. An additional 6.56 g (0.0235 mol) of the bromomethyl ester was added and the suspension was stirred an additional 15 hours at 70° C. The mixture was poured into water and the solid which separated was collected by filtration, washed with water, and triturated several times with 250 ml of boiling methanol to give 86.8 g (85%) of a solid; mp 177.5°-179° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC1
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(NC2CCC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (2.0 g, 10 mmol) and cyclobutanone (1.4 g, 20 mmol) in dichloroethane (20 mL), acetic acid (3.6 g, 60 mmol) was added and reaction stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (6.3 g, 30 mmol) was added at 0° C. and the reaction stirred for 3 h at room temperature. On completion, the solvent was removed under reduced pressure and the crude material was purified by column chromatography to afford the title compound (1.4 g, 56%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)[N:3]=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:3]=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCCNC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCCN)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of tert-butyl (4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butyl)carbamate (515 mg, 1.316 mmol) in CH2Cl2 (4 mL) was treated with TFA (2 mL, 26.0 mmol) at 0° C. The mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was triturated with ether to yield a white solid, which was collected by filtration to get 4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butan-1-amine, TFA (440 mg, 83% yield). LC-MS (M+H)+=292.4. 1H NMR (500 MHz, methanol-d4) δ 8.99 (s, 1H), 8.11 (d, J=1.5 Hz, 1H), 8.05 (dd, J=2.1, 1.3 Hz, 2H), 4.38 (t, J=6.2 Hz, 2H), 3.07-2.94 (m, 2H), 2.48 (s, 3H), 2.02 (dd, J=8.8, 6.3 Hz, 2H), 1.84 (d, J=7.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[C:10]([C:22]#[N:23])=[CH:11][C:12]2[CH:17]=[C:16]([O:18]C)[C:15]([OH:20])=[C:14]([Cl:21])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[C:10]([C:22]#[N:23])=[CH:11][C:12]2[CH:17]=[C:16]([OH:18])[C:15]([OH:20])=[C:14]([Cl:21])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=C(C#N)C(=O)Nc2cccc(Cl)c2)cc(Cl)c1O
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: N#CC(=Cc1cc(O)c(O)c(Cl)c1)C(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
Demethylation was effected in the same manner as in Example 2 by using N-(3-chlorophenyl)-2-cyano-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propenamide (587 mg, 1.62 mmol) and 1M solution of boron tribromide in methylene chloride. The resulting solid was suspended in ethanol, refluxed for 10 minutes, allowed to cool to room temperature and filtered to give the objective N-(3-chlorophenyl)-2-cyano-3-(3-chloro-4, 5-dihydroxyphenyl)propenamide (250 mg, 44% in yield).
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CCCOC(=O)c1cc(/C=C/COC)nc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCOC(=O)c1cc(CCCOC)nc2ccccc12

Procedure:
To a solution of propyl 2-[(1E)-3-methoxyprop-1-en-1-yl]quinoline-4-carboxylate from the previous step (1 eq.) in toluene (0.06 M) was added at 80° C. benzenesulfonyl hydrazide (3×1 eq.) over 3 h. The reaction mixture was diluted with EtOAc and washed sequentially with water, sat. aq. NaHCO3 and brine. Drying over MgSO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a yellow oil. Purification by way of column chromatography (SiO2, 10:1 (v/v) Hex:EtOAc→1:1 (v/v) Hex:EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: [O:1]=[C:2]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21](=[O:27])[NH:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[O:15])[N:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]=1)=[O:6].CCN(C(C)C)C(C)C.[CH2:49]([N:53]=[C:54]=[O:55])[CH2:50][CH2:51][CH3:52]>ClCCl>[CH2:49]([NH:53][C:54]([N:37]1[CH2:38][CH2:39][N:34]([C:2](=[O:1])[CH2:3][NH:4][C:5]([C:7]2[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21](=[O:27])[NH:22][CH:23]3[CH2:24][CH2:25][CH2:26]3)=[O:15])[N:9]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:8]=2)=[O:6])[CH2:35][CH2:36]1)=[O:55])[CH2:50][CH2:51][CH3:52]
Reactant: CCCCN=C=O
Reactant: O=C(NCC(=O)N1CCNCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCNC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 100 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide in 5 ml dichloromethane were added at 0° C. 56 l DIPEA and 25 l butyl isocyanate. After stirring for 12 h it was concentrated and the residue obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 55 mg MS (ES+): m/e=637.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: COC(=O)c1ccc(O)nc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cccs2)nc1

Procedure:
A solution of 2.0 g of (methyl 6-hydroxypyridine-3-carboxylate, o-triflate) and 5.23 g of 2-(tributylstannyl)thiophene in 50 ml of dry toluene is stirred under nitrogen at reflux for 16 hours in the presence of tetrakis(triphenylphosphine)palladium(O). The reaction mixture is diluted with 50 ml of chloroform and filtered through a pad of diatomaceous earth. The filtrate is evaporated in vacuo to a residue which is extracted and decanted (2×100 ml) with 1:1 ether:petroleum ether. The combined extracts are evaporated in vacuo to give 1.6 g of the desired product as a residue.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[OH-:18].[K+]>O1CCOCC1>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([OH:18])=[N:7][C:6]=1[NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NC1CCOCC1
Reactant: [OH-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(O)nc1NC1CCOCC1
Yield: 98.4 %

Procedure:
6-Chloro-3-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (0.186 g, 0.722 mmol), 1 M aqueous potassium hydroxide solution (8.0 mL, 16.0 mmol) and dioxane (20 mL) were heated to 100° C. for 4 h. After cooling, the pH was adjusted to ˜7 and the mixture was extracted with EtOAc. The EtOAc extract was concentrated under reduced pressure to give the title compound (0.170 g). LCMS m/z=240.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 1.65-1.80 (m, 2H), 2.05-2.15 (m, 2H), 3.60-3.70 (m, 2H), 4.00-4.10 (m, 2H), 4.20-4.30 (m, 1H), 5.92 (d, J=9.8 Hz, 1H), 8.32 (d, J=9.8 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:14].[Na+]>[N+]([O-])([O-])=O.[Ag+]>[C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(-c2ccccc2)o1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1ccc(-c2ccccc2)o1
Temperature: 60 °C

Procedure:
To 5-phenyl-2-furaldehyde (35) (690 mg, 4.01 mmol) was added solid NaOH (176 mg, 4.40 mmol) then 10% NaOH solution (6.2 mL). Silver nitrate (680 mg, 4.00 mmol) was added and the reaction mixture heated to 60° C. for 4.5 hours then cooled to ambient temperature. The reaction mixture was then filtered and washed with water. The filtrate was acidified to pH 2 using 2N HCl and the precipitated product filtered and dried to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].Br.[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]3[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[C:15]4[CH3:20])=[O:8])[CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCCCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)c2nccc(C)c2c1
Yield: 71.1 %

Procedure:
A mixture of 4.3 g (0.012 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide, 4.0 g (0.0128 mole) of 1-(3,4-dichlorophenyl)piperazine, hydrobromide and 2 ml (0.014 mole) of triethylamine in 100 ml of benzene was heated under reflux for 28 hr, allowed to cool, and filtered to remove the precipitated triethylamine hydrobromide. The filtrate was again heated under reflux for 18 hr, allowed to cool, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to dryness in vacuo. Chromatography over 200 g of silica gel with first ethyl acetate and then with 10% methanol in ethyl acetate afforded 4.4 g of the desired product, Rf(silica--10% methanol/ethyl acetate)=0.3. Recrystallization from 2-propanol gave 3.8 g (62%), mp 99°-100°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1.C1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:9][CH2:8][CH:7]([OH:10])[CH2:6][O:5][C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[O:2][CH3:1])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1OCC(O)CO
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1ccccc1OCC(O)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
A solution of 3-(2-methoxy-phenoxy)-propane-1,2-diol (4.7 g) in pyridine, cooled at 5°-10° C., is treated under stirring with a solution of p-toluensulphonylchloride (4.5 g) in benzene (70 ml). The reaction mixture is stirred overnight at room temperature, then it is washed with 2N HCl (3×100 ml) and with water, dried on Na2SO4 and evaporated to dryness in vacuum. The oily residue is purified by column chromatography (silica gel 230-400 mesh hexane/AcOEt=3/1) to yield 5 g of 3-(2-methoxy-phenoxy)-2-hydroxy-1-propyl p-toluensulphonate (oil, NMR (--CDCl3):δ=2,4 3H (s) CH3SO2 ; δ=3,75-4,4 5H (m) OCH3 +OCH2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[Cl:14][C:15]1[NH2+:16][S:17][S:18][C:19]=1Cl>C(Cl)Cl>[Br:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2](/[N:1]=[C:19]2\[C:15]([Cl:14])=[N:16][S:17][S:18]\2)[CH:11]=1
Reactant: ClC1=C(Cl)SS[NH2+]1
Reactant: COC(=O)c1ccc(Br)cc1N
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)cc1/N=c1/ssnc1Cl

Procedure:
A solution of methyl 2-amino-4-bromobenzoate (1.0 g, 4.34 mmol, 1 eq) and 4,5-dichloro-1,2,3-dithiazolium chloride (2.0 g, 9.6 mmol, 2.2 eq) in DCM (20 mL) was stirred at rt under N2 for 5 days. The reaction mixture was quenched with water and filtered. The filtrate was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 365, 367 (MH+).
Reaction SMILES: [S:1]([CH2:5][CH2:6][C:7]#[CH:8])([CH3:4])(=[O:3])=[O:2].I[C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:1]([CH2:5][CH2:6][C:7]#[C:8][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)([CH3:4])(=[O:3])=[O:2]
Reactant: C#CCCS(C)(=O)=O
Reactant: Cc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cccc(C#CCCS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.8 %

Procedure:
A mixture of 1-mesylbut-3-yne (758 mg, 5.10 mmol), 3-iodotoluene (1.31 g, 6.00 mmol), copper (I) iodide (40 mg), PdCl2(PPh3)2 (70 mg) in 12 mL of Et3N is stirred at room temperature under N2 for 20 hr. The mixture is filtered and washed with Et3N (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a pale yellow oil (565 mg, 47%): 1H NMR (CDCl3) 2.31 (s, 3 H), 2.88 (t, J=6.9 Hz, 2 H), 3.07 (s, 3 H), 4.38 (t, J=6.9 Hz, 2 H), 7.20 (m, 4 H).