Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:19])=[N:4][C:5]2[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1>Cl>[NH2:16][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]2[N:11]=[C:2]([OH:1])[C:3]([OH:19])=[N:4][C:5]=2[CH:6]=1
Reactant: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2ccccc12
Agent: Cl
Product: Nc1cc2nc(O)c(O)nc2c2ccccc12
Temperature: 65 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A solution of stannous chloride dihydrate (3.7 g, 16 mmol) in 10 ml of conc. hydrochloric acid was added dropwise to a stirred suspension of 2,3-dihydroxy-6-nitrobenzo(f)quinoxaline (1.3 g, 5 mmol) in 8 ml of conc. hydrochloric acid. Then the mixture was stirred at 60-70° C. on an oil bath for 2 h. After cooling on ice, the precipitate was collected, dissolved in boiling water (1 1), filtered while hot, and neutralized to pH 6 with solid sodium hydrogen carbonate. The yellow product was isolated and recrystallized from DMF/water, washed with water, ethanol and ether and finally dried at 110 ° C. to give 0.90 g (63%) of pure title compound, m.p. >300° C., IR (KBr): 1690, ? 1640 and 1605 cm-1,1H-NMR (DMSO-d6): 5.8 (broad s, 2H,NH2), 6.63(s,1H, H-5), 7.2-8.7 (m, 4H, ArH), 11.8 (broad s, 2H, 20H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][CH2:13]C)=[CH:5][C:4]=1[N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:17][CH2:16]1)[CH3:2]>CCOC(C)=O.CO.[Pt]>[CH2:1]([C:3]1[C:4]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19][CH2:20]2)=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:8]=1)[NH2:9])[CH3:2]
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(CC)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc(N)c(OC)cc1N1CCN(CCS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[2-Ethyl-5-(ethyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (0.63 g, 1.6 mmol) was taken up in EtOAc (30 mL) and MeOH (5 mL). The catalyst, 5% sulfided platinum on carbon (0.25 g) was added. The reaction was placed under 1 atm of H2 gas and was allowed to stir at rt overnight. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound without further purification (0.55 g, 1.5 mmol, 91%). MS (ESI) m/z=356 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[CH:20][C:21]([C:23]3[S:24][C:25]([N:33]([CH3:43])[CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=3)=[CH:22][C:14]1=2)=[O:12].[OH-].[K+].CO>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[CH:20][C:21]([C:23]3[S:24][C:25]([N:33]([CH3:43])[CH2:34][CH2:35][O:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=3)=[CH:22][C:14]1=2)=[O:12]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCO3)sc1N(C)CCOc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CCOc1ccccc1)c1sc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCO3)nc1C(=O)O
Temperature: 55 °C
Reaction time: 24 h
Yield: 7.5 %

Procedure:
The title compound 2-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylic acid (20) was prepared by the following procedure: To ethyl 2-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylate (20C) (0.210 g, 0.34 mmol) and KOH (0.1 g, 1.8 mmol) was added MeOH (2 mL) and water (5 mL). The reaction mixture was allowed to heat to 55° C. and stirred 24 hours. The reaction was monitored by LCMS. To the reaction mixture was added (0.1 g, 1.8 mmol). The reaction mixture was allowed to heat to 55° C. and stirred for 24 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the crude residue was added EtOAc and water. The layers were separated and extracted with EtOAc and the combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC to provide 0.015 g (8%) of the desired product 2-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl) amino)thiazole-4-carboxylic acid (20): LC/MS (APCI): m/z 588.1 (M+H).
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[OH:17][C:18]1[N:23]=[N:22][C:21]([C:24](O)=O)=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.O>CO>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:24]([C:21]3[N:22]=[N:23][C:18]([OH:17])=[CH:19][CH:20]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:6])[CH2:15][CH3:16]
Reactant: O=C(O)c1ccc(O)nn1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(O)nn3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1,3-dipropyl-5,6-diaminouracil (2.2 mmol) in methanol was added an equimolar amount of 6-hydroxy-pyridazine-3-carboxylic acid, followed by a slight excess of DCl ((N-(3-(dimethylamino)propyl)-N′ethylcarbodiimide hydrochloride). The mixture was stirred at room temperature for 4-5 hours until complete by TLC. Water was then added and the precipitate removed by filtration. The solid was dissolved in 10% aqueous NaOH (20 mL), then heated at 70° C. for 30 minutes. After cooling to room temperature, the reaction mixture was acidified to pH=5 with 10% hydrochloric acid and the precipitated product collected by filtration.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=2[CH:10]=1.[CH2:23]([N:25](CC)[CH2:26][CH3:27])[CH3:24].N1CCCC1>CN(C)C=O>[N:25]1([CH2:7][CH2:8][C:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH2:26][CH2:27][CH2:24][CH2:23]1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCO)=C2
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(=O)Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
Methanesulfonyl chloride (0.131 ml, 1.69 mmol) was added to a dimethylformamide solution (7 ml) of N-[6-(2-hydroxyethyl)-7,8-dihydro-2-naphthalenyl]acetamide (355 mg, 1.53 mmol) obtained in Reference Example 102 and triethylamine (0.235 ml, 1.69 mmol) under ice-cooling, which was stirred for 30 minutes. Pyrrolidine (0.384 ml, 4.60 mmol) was added to the reaction mixture, which was stirred at 60° C. for 4 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, and extraction was conducted using 1N hydrochloric acid. Potassium carbonate was added to the extract to make it alkaline, and extraction was conducted using ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resulting residue was purified by alumina column chromatography (development solvent; ethyl acetate), to give the titled compound (294 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:12]=1[NH2:13].C(N(C(C)C)CC)(C)C>C(O)C>[C:18]([C:15]1[CH:16]=[CH:17][C:11]([CH3:10])=[C:12]([NH:13][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1ccc(C(C)(C)C)cc1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(C)(C)C)cc1Nc1nc(Cl)ncc1F
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A solution of 2,4-dichloro-5-fluoropyrimidine (307 mg, 1.84 mmol), 2-methyl-5-t-butylaniline (300 mg, 1.84 mmol) and diisopropylethylamine (2 mL) in ethanol (2 mL) was heated at 80° C. for 16 h in an oil bath. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/hexane to afford the product (369 mg, 68%) as a solid.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3].[I-].[K+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1>>[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Reactant: ClCc1ccncn1
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccncn1
Yield: 77.1 %

Procedure:
Using an analogous procedure to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (560 mg) was reacted in the presence of catalytic potassium iodide with 4-(chloromethyl)pyrimidine (375 mg) to give 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(pyrimidin-4-ylmethoxy)quinazoline (496 mg, 74%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:15].Cl>[Cu]Cl.C(OCC)(=O)C>[NH2:15][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: N
Agent: Cl[Cu]
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1nc(C(F)(F)F)ccc1C(=O)O
Temperature: 100 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
2-Chloro-6-trifluoromethylnicotinic acid (3000 mg, 13.30 mmol) was added under argon to 24% aqueous ammonia solution (5 ml), and copper(I) chloride (1580 mg, 15.96 mmol) was added. The resulting reaction mixture was stirred at a temperature of 100° C. and at an elevated pressure of approx. 5 bar in a pressure vessel for 15 h. After cooling to room temperature and lowering the pressure to standard pressure, ethyl acetate and dilute hydrochloric acid (2N) were added to the reaction mixture. The aqueous phase was extracted repeatedly with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification (ethyl acetatein-heptane gradient) of the crude product gave 2-amino-6-trifluoromethylnicotinic acid (1640 mg, 58% of theory) as a colorless solid. 2-Amino-6-trifluoromethylnicotinic acid (500 mg, 2.43 mmol) was dissolved in abs. tetrahydrofuran (8 ml), and triethylamine (369 mg, 3.64 mmol) was added. Thereafter, the reaction solution was cooled under argon to 0° C., and cyclobutanecarbonyl chloride (316 mg, 2.69 mmol) was slowly added dropwise. The resulting reaction mixture was stirred at room temperature for a further 7 h, then dist. water and dichloromethane were added. The aqueous phase was extracted repeatedly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Preparative HPLC purification (acetonitrile/water/trifluoroacetic acid gradient) of the crude product gave 2-[(cyclobutylcarbonyl)amino]-6-(trifluoro-methyl)nicotinamide (197 mg, 28% of theory) as a colorless solid. 2-[(Cyclobutyl-carbonyl)amino]-6-(trifluoromethyl)nicatinamide (197 mg, 0.68 mmol) was dissolved in acetic anhydride (5 ml) and stirred under reflux conditions under argon for 5 h. After cooling to room temperature, concentrated ammonia solution was added (10 ml) and the reaction mixture was stirred at room temperature for a further 6 h. The precipitated solid was filtered off with suction and dried. Preparative HPLC purification of the crude product gave 2-cyclobutyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4(3H)-one (55 mg, 30% of theory) as a yellowish solid. 1H NMR (400 MHz, CDCl3 δ, ppm) 8.79 (d, 1H), 7.78 (d, 1H), 7.28 (br. s, 1H, NH), 3.62 (quint, 1H), 2.64 (m, 2H), 2.48 (m, 2H), 2.18 (m, 1H), 2.02 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9](OCCC2C=CC=CC=2)[CH2:8][CH2:7]1)=[O:5])C.[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1.CO>[OH-].[Na+]>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:6]2([C:4]([OH:3])=[O:5])[CH2:7][CH2:8][N:9]([CH2:32][CH2:36][O:35][C:34]3[CH:33]=[CH:8][CH:7]=[CH:6][CH:4]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(OCCc2ccccc2)CC1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCOc3ccccc3)CC2)cc1

Procedure:
4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine-4-carboxylic acid ethyl ester (5.0 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (63%); off white powder; mp 235° C.; MS: 420.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Br)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-Butyl 1-(4-bromophenyl)piperidin-4-ylcarbamate (365 mg) is dissolved in dichloromethane (10 mL), treated with trifluoroacetic acid (780 μL) and stirred for 6 hours at room temperature. Then the mixture is partitioned between dichloromethane and saturated aqueous K2CO3 solution and stirred vigorously for 30 minutes. The phases are separated and the organic phase is washed with saturated aqueous K2CO3 solution. The organic phase is dried (MgSO4) and concentrated to give the title compound. LC (method 2): tR=0.93 min; Mass spectrum (ESI+): m/z=255 [M+H]+.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1([C:39]([O:41]C)=[O:40])[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[C:25]([CH:26]4[CH2:28][CH2:27]4)=[CH:24][N:23](S(C4C=CC(C)=CC=4)(=O)=O)[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.CCOC(C)=O>[C:3]([O:7][C:8]([NH:10][C:11]1([C:39]([OH:41])=[O:40])[CH2:12][CH2:13][N:14]([C:17]2[C:18]3[C:25]([CH:26]4[CH2:27][CH2:28]4)=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3c2c(C2CC2)cn3S(=O)(=O)c2ccc(C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]cc(C4CC4)c23)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 68.2 %

Procedure:
2M sodium hydroxide solution (5.00 mL) was added to methyl 4-(tert-butoxycarbonylamino)-1-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (Intermediate 63) (780 mg, 1.37 mmol) in THF (10 mL) at 20° C. The resulting solution was stirred at 40° C. for 24 hours. The reaction mixture was diluted with EtOAc (50 mL) and the aqueous layer was collected and acidified to pH4 with 2M HCl solution. The aqueous layer was extracted with DCM (2×50 mL) and the organic layers combined and washed with saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product 4-(tert-butoxycarbonylamino)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (375 mg, 68.2%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][Si](C)(C)C)=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][Cl:16]>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:14][CH2:15][Cl:16])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Sc1ccc(Cl)cc1
Reactant: ClCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: ClCCSc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
A mixture consisting of 12.21 g (56.5 mmoles) of 4-chlorophenylthio(trimethyl)silane, 20 ml of hexamethylphosphoric triamide and 18.7 ml (226 mmoles) of 1-bromo-2-chloroethane was heated at 60° C. and it was established that the conversion was complete after 10 minutes. After treating the reaction mixture as described in Example 3, there were obtained 10.03 g (85.7% yield) of 2-chloroethyl 4-chlorophenyl sulfide boiling at 105°-109° C./1.0 mm Hg and melting at 28°-29° C. The residue of the distillation contained 1,2-bis(4-chlorophenylthio)ethane as a by-product which after crystallization from methanol melted at 87°-88° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[N:13]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH:17]=[CH:16][N:15]=[CH:14]1>O1CCOCC1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:21][CH2:20][CH2:19][CH2:18][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCCn1ccnc1
Solvent: C1COCCO1
Product: Nc1ccccc1C(=O)NCCCn1ccnc1
Reaction time: 0.67 h

Procedure:
Isatoic anhydride (22.0 g) was added in portions to a stirred solution of 3-imidazol-1-ylpropylamine (17.2 g) in dioxan (100 ml) over a period of 15 minutes. Stirring was continued for 40 minutes before the solution was evaporated in vacuo to give 2-amino-N-(3-imidazol-1-ylpropyl)benzamide as a buff coloured solid, used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:12][CH2:13][P:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])[O:15][CH:16]([CH3:18])[CH3:17]>>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N:12][CH2:13][P:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])[O:15][CH:16]([CH3:18])[CH3:17])([O-:3])=[O:2]
Reactant: CC(C)OP(=O)(CN)c1ccccc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Product: CC(C)OP(=O)(CN=Cc1ccccc1[N+](=O)[O-])c1ccccc1
Yield: 100 %

Procedure:
Starting from 0.1 mol o-nitrobenzaldehyde and 0.1 mol isopropyl aminomethyl-phenylphosphinate, 0.1 mol (100%) of the desired imine is obtained (by following the procedure described in Example 1) in the form of a yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:12]2[CH2:13][CH2:14][O:15][C:11]=2[C:10]([C:16]([OH:18])=[O:17])=[CH:9][C:8]=1[Cl:19].[CH3:20]O.N>CO>[NH2:6][C:7]1[C:12]2[CH2:13][CH2:14][O:15][C:11]=2[C:10]([C:16]([O:18][CH3:20])=[O:17])=[CH:9][C:8]=1[Cl:19]
Reactant: CO
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCO2
Agent: N
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)c(N)c2c1OCC2
Yield: 81 %

Procedure:
Sulfuric acid (18 ml) was added dropwise to cooled methanol (90 ml). 4-Amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (20 g) was added to the mixture which was subsequently stirred and refluxed for 3 hours. The reaction mixture was cooled and alkalized with CH3OH/NH3. The solvent was evaporated and the residue stirred in water. The precipitate was filtered off and washed with water and DIPE. The remaining solid was dried, yielding 17.2 g (81%) of methyl 4-amino-5-chloro-2,3-di-hydro-7-benzofurancarboxylate (intermediate 1; mp. 135.4° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([I:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([I:15])=[C:13]([O:16][C:19](=[O:21])[CH3:20])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(O)c1I
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1cc2ccc(F)cc2c(OC(C)=O)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a stirred solution of (6-fluoro-4-hydroxy-3-iodo-naphthalen-2-yl)-acetic acid methyl ester (500 mg, 1.4 mmol) and 4-dimethylaminopyridine (34 mg, 0.28 mmol) in pyridine (3 mL) was added acetic anhydride (160 μL, 1.7 mmol). After being stirred at room temperature overnight, the resulting mixture was diluted with 10% hydrochloric acid (20 mL), and extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine (30 mL×2), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (elution with 20% ethyl acetate in petroleum ether) to afford (4-acetoxy-6-fluoro-3-iodo-naphthalen-2-yl)acetic acid methyl ester (300 mg, 53%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([C:12](=[O:23])[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]2)[NH:8][C:7]=1[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]1[CH:38]=[C:37]([C:39]2[S:40][C:41]([Cl:44])=[CH:42][CH:43]=2)[O:36][N:35]=1.C(O)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([C:12](=[O:23])[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH:20]([CH3:21])[CH3:22])[CH2:18][CH2:19]2)[N:8]([CH2:33][C:34]2[CH:38]=[C:37]([C:39]3[S:40][C:41]([Cl:44])=[CH:42][CH:43]=3)[O:36][N:35]=2)[C:7]=1[CH3:24]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)CCc1c(C)[nH]c(C(=O)NC2CCN(C(C)C)CC2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)CCc1c(C)c(C(=O)NC2CCN(C(C)C)CC2)n(Cc2cc(-c3ccc(Cl)s3)on2)c1C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
55 mg (0.16 mmol) of 3-[5-(1-isopropyl-piperidin-4-ylcarbamoyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid methyl ester were dissolved in DMF (5 mL). Subsequently 103 mg (2 equiv.) of Cs2CO3 and 65.8 mg (1.5 equiv.) of 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole were added and the resulting mixture was stirred for 4 h at 800 C. Because of low conversion 206 mg (4 equiv.) of Cs2CO3 were added stirring was continued for 7 h at 80° C. The reaction mixture was acidified by the addition of acetic acid and concentrated. The residue was purified by preparative HPLC(CH3CN/H2O gradient+0.05% formic acid) to give 3-[1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-(1-isopropyl-piperidin-4-ylcarbamoyl)-2,4-dimethyl-1H-pyrrol-3-yl]-propionic acid methyl ester (34 mg) as a colorless amorphous material. MS (ESI+): m/e=548 [M+H]+, chloro pattern.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:20]([F:21])=[C:19]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:23])[C:8]=1[F:24].Cl[CH2:26][C:27]([Cl:29])=[CH2:28].[Cl-].[NH4+]>O1CCCC1.O>[Cl:29][C:27](=[CH2:26])[CH2:28][C:7]1[C:20]([F:21])=[C:19]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:23])[C:8]=1[F:24]
Reactant: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1Br
Reactant: C=C(Cl)CCl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(Cl)Cc1c(F)c(F)c(COC2CCCCO2)c(F)c1F
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (2.5M in hexane, 2.3 cm3) was added portionwise to a solution of 2-[4-bromo-2,3,5,6-tetrafluorobenzyloxy]tetrahydropyran (1.7 g) in dry tetrahydrofuran (10 cm3) under an atmosphere of dry nitrogen, whilst the reaction temperature was maintained between -30° C. and -20° C. After 15 minutes, copper (I) bromide-dimethyl sulphide complex (1.2 g) was added in one portion and the reaction temperature was maintained at -10° C. for 1 hour, after which time 1,2-dichloroprop-2-ene (1 cm3) was added, the reaction temperature then being allowed to warm to ±15° C. After 3 hours, water followed by saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted into diethyl ether. The organic layer was then washed with water and brine, dried, and the solvent evaporated under reduced pressure. The residue was then subjected to medium pressure column chromatography on a silica gel column using a Gilson apparatus, eluting with petroleum ether (boiling range 30°-40° C.) containing diethyl ether (10% by volume) to give 2-[4-(2-chloroprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyloxy]tetrahydropyran (1.5 g).