Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH3:9][S:10][C:11]1[CH:12]=[CH:13][C:14]2[O:20][CH2:19][CH2:18][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=2[CH:26]=1.[OH2:27]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:9][S:10]([C:11]1[CH:12]=[CH:13][C:14]2[O:20][CH2:19][CH2:18][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=2[CH:26]=1)(=[O:2])=[O:27]
Reactant: O=S(=O)([O-])O[O-]
Reactant: O
Reactant: CCOC(=O)C1=Cc2cc(SC)ccc2OCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(S(C)(=O)=O)ccc2OCC1
Reaction time: 3 h

Procedure:
A solution of potassium peroxymonosulfate (4.1 g) in water (21 ml) was added dropwise to a mixture of ethyl 2,3-dihydro-7-methylthio-1-benzoxepin-4-carboxylate (0.8 g) and tetrabutylammonium hydrogen sulfate (0.2 g) in ethyl acetate (8 ml) and water (4 ml) at ambient temperature and the mixture was stirred at the same temperature for 3 hours. The separated organic layer was washed with 10% aqueous sodium thiosulfate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl 2,3-dihydro-7-methanesulfonyl-1-benzoxepin-4-carboxylate (0.77 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17].[OH-].[NH4+]>C(Cl)Cl.O.C(#N)C>[N+:16]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2ncccc2c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc2ccccc2n1
Temperature: 100 °C
Yield: 90.7 %

Procedure:
Quinoline (Formula (1), 12.9 g, 0.10 mole) was added dropwise over 5 min. with good agitation to a solution of 50 mL of concentrated sulfuric acid in a 250 mL round bottom flask. No attempt was made to control the exotherm and on this scale the final temperature was 77° C. The mixture was heated to 100° C. and 71% nitric acid (13.3 g, d. 1.42, 9.4 mL, 0.15 mole) was added at such a rate to keep the temperature between 100° C. and 110° C. Stirring was continued for an additional 30 minutes or until an HPLC (Zorbax® SB-C18 HPLC column, from Mac-Mod Analytical, Inc. of Chadds Ford, Pa. U.S.A.; dimensions 4½ mm (inside diameter) by 25 cm (length); HPLC conditions: 40:60 acetonitrile:water-0.5% ammonium acetate, 220 nm, flow 0.5 mL/min.) sample showed the reaction was complete. The mixture was cooled slightly and poured onto a mixture of 200 mL methylene chloride and 300 mL (by volume) of ice. The two phase mixture was placed in an ice bath and the temperature was kept below 25° C. while the pH was increased to 10 with concentrated ammonium hydroxide. The mixture was vacuum filtered through paper and transferred to a separatory funnel. The lower organic phase was separated and the aqueous layer was extracted with an additional 100 mL of methylene chloride. The combined organic layers were dried over magnesium sulfate, filtered and evaporated affording 15.8 g (91% yield) of a clear light amber oil which crystallized on standing. HPLC Analysis was conducted for 5-nitroquinoline and 8-nitroquinoline only: 45% 8-nitroquinoline (Formula (3), rt 9.0 min.) and 55% 5-nitroquinoline (Formula (2), rt 12.8 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].Cl[C:14]([O:16][CH:17]([CH2:19][CH3:20])[CH3:18])=[O:15]>O>[C:14](=[O:15])([O:16][CH:17]([CH3:18])[CH2:19][CH3:20])[O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CCC(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)OC(=O)OC(=O)c1cccc(Cl)c1
Yield: 97.4 %

Procedure:
To a well-stirred reaction vessel equipped with a thermometer and a pH electrode were added 39 g of water and 0.20 g of Arquad CB50 at 5° C. After the addition of 0.05 mole of 3-chlorobenzoic acid the pH was adjusted to 6 using a 10 wt % aqueous NaOH solution. Then, 0.05 mole of sec-butyl chloroformate was dosed within 5 min at 5° C. During this time and a post-reaction time of 165 min at 5° C. the pH was kept at a value between 6 and 9. The reaction mixture was allowed to separate, giving 12.5 g of 3-chlorobenzoyl 1-methyl-1-propyl carbonate having a content of 98% in a yield of 95%.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:21]=[N:22][N:23]([CH3:37])[C:24]=4[NH:25][C:26]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:30])=[O:27])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.C(O)C>[CH3:37][N:23]1[C:24]([NH:25][C:26]([O:28][C@@H:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:30])=[O:27])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]4)=[CH:13][CH:12]=3)=[CH:15][CH:16]=2)[N:21]=[N:22]1
Reactant: COC(=O)C1(c2ccc(-c3ccc(-c4nnn(C)c4NC(=O)O[C@H](C)c4ccccc4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](OC(=O)Nc1c(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)nnn1C)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester (from Example 1, 566 mg, 1.41 mmol), methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate (511 mg, 1.69 mmol), X-Phos (134 mg, 0.28 mmol), palladium acetate (31.7 mg, 0.14 mmol) and potassium phosphate (898 mg, 4.23 mmol) were combined in toluene (12 mL) and degassed water (3 mL) was added. The mixture was degassed and sealed. The mixture was stirred at 95° C. for 3 hrs and cooled to room temperature. The mixture was extracted with ethyl acetate and water. The organic layer was washed with brine and dried. Solvents were evaporated and the residue was purified by flash column chromatography (40 g silica gel, ethyl acetate in hexanes 10% to 70% in 15 minutes) to give 1-{4′-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester as a pale yellow solid (370 mg, 52.8% yield). LC/MS calcd for C29H28N4O4 (m/e) 496.0, obsd 497.0 (M+H); 1H-NMR (400 MHz, CDCl3) δ ppm 1.25 (m, 3H), 1.66 (m, 4H), 3.67 (s, 3H), 3.93 (s, 3H), 5.91 (m, 1H), 6.44 (br, 1H), 7.29-7.40 (m, 5H), 7.44 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.61 (d, J=8.3 Hz, 2H), 7.78 (br d, J=6.6 Hz, 2H). 1-{4′-[1-Methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester (50 mg) was dissolved in 1 mL of THF and 1 mL of ethanol. To this mixture was added 1N sodium hydroxide solution (1 mL). The clear solution was stirred at room temperature for 12 hrs. Solvents were evaporated and the residue was treated with 2N hydrochloric acid (1.4 mL). The solid was filtered and rinsed with water, dried in the air, to give 1-{4′-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (47.5 mg, 97.8% yield). LC/MS calcd for C28H26N4O4 (m/e) 482.0, obsd 483.0 (M+H); 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.24 (m, 3H), 1.49 (m, 2H), 1.59 (m, 2H), 3.86 (s, 3H), 5.80 (m, 1H), 7.28-7.50 (m, 7H), 7.63 (d, J=8.1 Hz, 2H), 7.71 (m, 2H), 7.80 (d, J=7.6 Hz, 2H), 9.95 and 9.62 (br s, 1H), 12.35 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([OH:10])(=[S:9])[CH3:8].CS(O[CH:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1)(=O)=O>CO.CN(C=O)C.O>[C:7]([S:9][CH:20]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19]1)(=[O:10])[CH3:8]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 24.2 %

Procedure:
Potassium carbonate (4.42 g, 31.96 mmol) was suspended in dry MeOH (20 mL) and thioacetic acid (2.28 g, 29.96 mmol) was added. The mixture was stirred vigorously for 10 mins, concentrated and diluted in dry DMF (30 mL). tert-Butyl 3-[(methylsulfonyl)oxy]pyrrolidine-1-carboxylate (2.65 g, 9.99 mmol) dissolved in dry DMF (20 mL) was added and the reaction mixture was heated to 60° C. for 3.5 h. The reaction mixture was diluted with water (350 mL) and extracted with EtOAc (2×150 mL) The organic phases were dried with MgSO4, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system (25+M column, isocratic run heptane/EtOAc (60:40)) affording the title compound (0.592 g, 24.2%) (the product is a mixture of cis and trans isomers). 1H NMR (500 MHz, CDCl3): δ 1.41 (d, 18H), 1.66 (d, 1H), 1.74-1.86 (m, 2H), 2.20-2.26 (m, 2H), 2.29 (s, 3H), 3.10-3.26 (m, 2H), 3.30-3.43 (m, 4H), 3.46-3.54 (m, 1H), 3.66-3.74 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 28.68, 30.82, 31.25, 32.34, 36.16, 41.09, 44.88, 51.60, 55.37, 79.67, 154.43; Mass Spectrum: M+H+ 241.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O.[CH2:28](O)[CH2:29][OH:30]>S(=O)(=O)(O)O>[OH:30][CH2:29][CH2:28][O:19][C:18](=[O:20])[C@H:17]([CH3:21])[N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: OCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C[C@@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 56 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.00995 mole) and concentrated sulfuric acid (4 drops) in ethylene glycol (50 ml) was refluxed under nitrogen for three hours, and then poured into a saturated sodium bicarbonate solution (200 ml). Water (50 ml) was added and the product was extracted into two portions of ethyl acetate. The combined organic layers were washed twice with water and once with a saturated sodium chloride solution, dried over magnesium sulfate, treated with charcoal and filtered. Evaporation of the solvents under reduced pressure gave 1.9 g (56% yield) of solid which was dissolved in hot isopropyl ether (with a little isopropyl alcohol added). The solution was stirred and cooled to room temperature to precipitate a solid. The mixture was cooled in the freezer, the solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at room temperature overnight to give 1.44 g of title compound, mp 112°-113.5° C.
Reaction SMILES: O.[Cl:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)(C(F)(F)F)=O>[Cl:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Nc1ccc(C2CCC3(CC2)OCCO3)cc1Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CCC(c2ccc(NC(=O)OCc3ccccc3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Water (1 mL) was added in one portion to a stirred solution of benzyl [2-chloro-4-(1,4-dioxaspiro[4.5]dec-8-yl)phenyl]carbamate (2.60 g, 6.47 mmol) in TFA (20 mL) and the reaction mixture was stirred at room temperature for 2 h. The mixture was cooled to 10° C. and a 2N aqueous solution of sodium hydroxide was added until the pH of the mixture was 10. Ethyl acetate (50 mL) was added and the layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to leave the title compound (2.3 g, 99%) as a solid; 1H NMR δ 1.82-1.99 (2H, m), 2.17-2.28 (2H, m), 2.45-2.57 (4H, m), 2.94-3.07 (1H, m), 5.24 (2H, s), 7.17 (1H, dd), 7.25 (1H, d), 7.32-7.5 (5H, m), 8.13 (1H, d); MS m/e (M−H)− 356.
Reaction SMILES: [N+]([O-])(O)=O.[CH2:5]([O:7][C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH:16]=[N:17]N)[CH:10]=1)[CH3:6].[N+:20]([O-])(O)=O.C(OC(=O)[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([NH:35][CH:36]=NN)[CH:29]=1)C>>[CH2:5]([O:7][C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[N:20]=[C:32]([C:33]3[CH:36]=[N:35][CH:30]=[CH:29][CH:28]=3)[CH:31]=[CH:34][N:17]=2)[CH:10]=1)[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(C)c(NC=NN)c1
Reactant: CCOC(=O)c1cccc(NC=NN)c1
Product: CCOC(=O)c1cccc(Nc2nccc(-c3cccnc3)n2)c1

Procedure:
Utilising the procedure described in example 1b but employing 3-[(aminoiminomethyl)amino]-benzoic acid ethyl ester mononitrate in lieu of 3-[(aminoiminomethyl)amino]-4-methyl-benzoic acid ethyl ester mononitrate, afforded the title compound as a crystalline solid, m.p. 197–199° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH3:4].CN1CCOCC1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:1][CH2:2][C@@H:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH3:4])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@H](COS(C)(=O)=O)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 20 h
Yield: 90.7 %

Procedure:
To a solution of (S)—N-(1-hydroxypropan-2-yl)-2-nitrobenzenesulfonamide (6.20 kg, 23.8 mol) in methylene chloride (32 L) was added 4-methylmorpholine (3.13 kg, 30.9 mol) at an internal temperature of 10° C. or below. The resulting reaction mixture was cooled to 0° C., and added a solution of methanesulfonyl chloride (3.27 kg, 28.5 mol) in methylene chloride (2 L) at an internal temperature of −5° C. to 0° C. Subsequently, the reaction mixture was stirred at room temperature for 20 hours. After confirming the disappearance of the starting materials by TLC, purified water was added to the reaction mixture. The resulting organic layer was partitioned, washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure to give the target product as a yellow solid (7.30 kg, yield 90.70).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3([C:23]([O:25]CC4C=CC=CC=4)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(O)(=O)C>C(O)C.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(NC2CCN(CCC3(C(=O)OCc4ccccc4)CCCCC3)CC2)nc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(NC2CCN(CCC3(C(=O)O)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
To a solution of benzyl 1-[2-[4-(5-methylpiridin-2-yl-amino)piperidin-1-yl]ethyl]cyclohexanecarboxylate (160 mg, 0.37 mmol) in ethanol (16 mL) was added 10% palladium carbon (80 mg) at room temperature. The mixture was stirred at room temperature under hydrogen atmosphere for 24 hours. Acetic acid was added to the mixture, and it was filtered with Celite and concentrated under reduced pressure. Methanol and diethyl ether were added to the residue, and the solution was stirred under ice cooling for 1 hour. The crystals were recovered by filtration to give the title compound (100 mg).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][N:5]([CH2:31][C:32]([O:34]C)=[O:33])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=1.[OH-].[Na+]>CO>[C:3]([CH2:4][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=1)[CH2:31][C:32]([OH:34])=[O:33])([OH:36])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cccc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 17 h
Yield: 0.1 %

Procedure:
A solution of 0.56 g (1.11 mol) of N-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)phenyl]glycine methyl ester and 4.4 ml (4.4 mmol) of 1N NaOH in 50 ml of methanol was stirred at reflux under argon atmosphere for 75 minutes. After standing at room temperature for 17 hours the precipitate was removed by filtration. The solid was suspended in 100 ml of 1N HCl and extracted with ethyl acetate. The dried extract was concentrated at reduced pressure and the resultant solid was recrystallized from methanol-water to give 0.31 g (60% yield, mp 135°-138°) of N-(carboxymethyl)-N-[3-(octadecyloxy)phenyl]glycine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[C:21]([CH2:26][NH2:27])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C([BH3-])#N.[Na+]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[C:21]([CH2:26][NH:27][CH2:33][C:32]4[CH:35]=[CH:36][C:29]([Cl:28])=[CH:30][CH:31]=4)[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:4]([O-:5])=[O:3]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2cccc3c(CN)cccc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2cccc3c(CNCc4ccc(Cl)cc4)cccc23)CC1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25° C. solution of 4-(5-aminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester 55 (62 mg, 0.159 mmol) in MeOH (4 mL) was added 4-chloro-benzaldehyde (45 mg, 0.318 mmol) and sodium cyanoborohydride (50 mg, 0.795 mmol). After stirring for 2 h at 25° C., the solution was concentrated in vacuo and the resultant crude material was purified by reverse phase HPLC to provide the title compound (H-45) as its formate salt. 1H NMR (300 MHz, MeOD) δ 8.78 (d, 1H), 8.38 (s, 1H), 8.33 (m, 2H), 7.70 (m, 3H), 7.45 (m, 4H), 4.57 (s, 2H), 4.20 (s, 2H), 4.05 (q, 2H), 3.75 (d, 2H), 3.20 (m, 1H), 2.75 (m, 2H), 1.50 (m, 2H), 1.25 (m, 2H), 1.17 (t, 3H); LC/MS m/z 516 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[NH2:5].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([I:29])[CH:27]=2)[N:22]=[CH:21][N:20]=1>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([I:29])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: Nc1ccc(OCc2ccccc2F)c(Cl)c1
Reactant: Clc1ncnc2ccc(I)cc12
Solvent: CC(C)O
Product: Cl
Product: Fc1ccccc1COc1ccc(Nc2ncnc3ccc(I)cc23)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 197.4 %

Procedure:
In a glass flask provided with a condenser, thermometer, mechanical stirrer and nitrogen inlet, —under nitrogen flow—15.0 g of 3-chloro-4-[(2-fluorobenzyl)oxy]aniline of formula (IV), 17.49 g of 4-chloro-6-iodoquinazoline of formula (VIII) (available in the market), 300 mL of Isopropanol were introduced. The reaction mixture was stirred at 70° C. for 2 hrs. Upon completing the reaction cooling was carried out at ambient temperature. The formed yellow solid was filtered washing the solid with 20 mL of cold Isopropanol. 31.9 g of product equivalent to a 98.7% molar yield were obtained. 1H-NMR spectrum according to FIG. 5.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])(=[O:7])=[O:6].[OH-:26].[K+]>O1CCOCC1.O>[F:16][C:11]1[C:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[C:9]([NH:8][S:5]([CH2:4][CH2:3][CH2:2][OH:26])(=[O:7])=[O:6])[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: O=S(=O)(CCCCl)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(CCCO)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
To a solution of 3-chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-propane-1-sulfonamide (69.4 mg, 0.138 mmol) in a mixture of 8 ml 1,4-dioxane and 2 ml H2O was added KOH powder (0.674 g, 12.0 mmol) and the mixture was heated to the reflux temperature for 3 days. It was extracted using EtOAc/brine, the organic fraction was dried with Na2SO4 and the volatiles were removed. The residue was purified using flash-column chromatography (Si, DCM/MeOH 5:1, Rf=0.3). Yield: 41 mg (62%). 1H-NMR (500 MHz, MeOH [d4]): δ=7.38-7.21 (d, 1H), 7.23-7.21 (d, 1H), 7.06-7.00 (q, 1H), 6.52-6.50 (m, 1H), 6.17-6.13 (t, 1H), 3.30-3.27 (t, 2H), 2.86-2.83 (t, 2H), 2.05-2.00 (m, 2H); m/z=485 [M−1]−.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]([C:16](=[O:18])[CH3:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[O:18][C:16]([CH3:17])=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1C
Yield: 70.7 %

Procedure:
2.98 g of ethyl 3-(4-chlorobenzoylamino)-3-acetylpropionate, 15 ml of dimethylformamide and 1.8 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 1.98 g of ethyl 2-[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]acetate are thereby obtained. Yield: 70.9%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(O)C.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[N:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)Nc1cncc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
A mixture of N-(6-chloro-pyrazin-2-yl)-acetamide I-5a (58.6 mg, 0.34 mmol) and piperazine-1-carboxylic acid tert-butyl ester (636 mg, 3.42 mmol) in ethanol (2 mL) was stirred at reflux for 24 h. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with 0.1M HCl (3×35 mL), brine, dried (Na2SO4), filtered, and evaporated to dryness. The crude residue was purified by preparative TLC using ethyl acetate as the eluant to afford the title compound I-5b (36.9 mg).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)#[CH:2].Br[C:12]1[S:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O.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.C(OCC)(=O)C>[N+:17]([C:14]1[S:13][C:12]([C:2]#[C:1][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)=[CH:16][CH:15]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(Br)s1
Reactant: C#Cc1ccc(C#N)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(C#Cc2ccc([N+](=O)[O-])s2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-ethynylbenzonitrile (0.5 g), 2-bromo-5-nitrothiophene (0.9 g) and bis(triphenylphosphine)palladium dichloride (83 mg) in anhydrous dimethylformamide (4 ml) was added triethylamine (2.2 ml). The reaction mixture was stirred at room temperature for 3 days then ethyl acetate (200 ml) and saturated sodium chloride (200 ml) were added. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude solid was triturated with 1:1 dichloromethane/hexane followed by diethyl ether to give 4-[(5-nitro-2-thienyl)ethynyl]benzonitrile as a yellow solid.