Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:36])([F:35])[O:24][C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+].[OH-].[Na+]>COCCOC.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>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:11]1[N:10]=[N:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:35])[F:36])=[CH:30][CH:29]=3)=[CH:3][CH:4]=2)=[N:13][CH:12]=1
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
Reactant: Fc1cccc(F)c1-c1cnc(-c2ccc(Br)cc2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1cccc(F)c1-c1cnc(-c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)nn1
Temperature: 70 °C

Procedure:
244 mg of 3-(4-bromophenyl)-6-(2,6-difluorophenyl)-[1,2,4]triazine are placed in 1.8 ml of 1,2-dimethoxyethane, and 2.5 mg of bis(triphenylphosphine)palladium(II) dichloride, 159 mg of 4-trifluoromethoxyphenylboric acid and 176 mg of sodium hydrogen carbonate in 1.8 ml of water are added in succession. The reaction mixture is then heated at 70° C. for 5 h. After cooling to room temperature, the suspension is poured into 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is dissolved in a minimum of hot ethyl acetate, filtered clear and crystallised at 0° C. In this way the title compound having a melting point of 199-202° C. is obtained.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])[C:3]([NH:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:22]1([N:25]2[CH2:30][C:29]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[O:28][CH2:27][C:26]2=[O:36])[CH2:24][CH2:23]1>CN(C)C=O.O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH:2]([N:33]2[CH2:34][CH2:35][C:29]3([O:28][CH2:27][C:26](=[O:36])[N:25]([CH:22]4[CH2:23][CH2:24]4)[CH2:30]3)[CH2:31][CH2:32]2)[C:3]([NH:5][CH3:6])=[O:4])=[C:8]([F:14])[CH:9]=1
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Reactant: CNC(=O)C(Br)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A solution of 2-bromo-2-(4-bromo-2-fluorophenyl)-N-methylacetamide (0.579 mmol) in N,N-dimethylformamide (3 mL) was treated with potassium carbonate (1.715 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.632 mmol). The reaction was allowed to stir at room temperature overnight. The reaction solution was then diluted with water (50 mL) and was extracted three times with dichloromethane. The organic layers were combined and were washed with water three times, twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-6% methanol/dichloromethane) afforded the title compound as a yellow oil (185 mg, 63% yield). MS(ES)+ m/e 454.0/455.9 [M+H]+ (bromide isotope pattern).
Reaction SMILES: Cl[C:2]1[N:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([N:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=1)[CH2:7][O:8][CH3:9])=[O:5].C(P(CCCC)CCCC)CCC.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][O:8][CH2:7][N:6]1[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=2[C:2]2[N:26]=[CH:25][CH:24]=[CH:23][C:3]=2[C:4]1=[O:5]
Reactant: CCOC(=O)CCc1ccc(N(COC)C(=O)c2cccnc2Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc2c(c1)c1ncccc1c(=O)n2COC
Yield: 62.4 %

Procedure:
The compound (55 mg, 0.146 mmol) prepared in step 3 was dissolved in N,N-dimethylformamide (3 ml), sequentially added with palladium(II) acetate (9.83 mg, 0.0438 mmol), 1,3-bis(dephenylphosphino)propane (18 mg, 0.0438 mmol), tributylphosphine (0.036 ml, 0.146 mmol), and potassium carbonate (40 mg, 0.292 mmol). The resulting mixture was refluxed for 5 hours. Water was added to the above solution and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was then purified by flash column chromatography (hexane:ethyl acetate=3:1) to obtain title compound (31 mg, yield: 64%, white solid).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].C([O-])([O-])=O.[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[C:1]([O:7][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCC(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 100 %

Procedure:
A solution of 4-pentynoic acid (5.25 g, 53.5 mmol) in DMF (107 mL) was treated with K2CO3 (11.09 g, 80.3 mmol) and benzyl bromide (6.37 mL, 53.5 mmol), stirred for 24 hours, diluted with water (200 mL), and extracted with diethyl ether (3×150 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography to provide the desired product (10.07 g, 100%). MS (ESI(+)) m/e 206 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 7.37 (m, 5H), 5.12 (s, 2H), 2.61 (t, 1H), 2.57 (m, 2H), 2.42 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([C:22]2[N:23]=[CH:24][N:25]3[CH:29]=[CH:28][S:27][C:26]=23)=[O:21])[CH2:3]1.CN(C=O)C.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl.O>[CH3:42][S:43]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]([C:22]2[N:23]=[CH:24][N:25]3[CH:29]=[CH:28][S:27][C:26]=23)=[O:21])[CH2:3]1)(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ncn2ccsc12)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)c2ncn3ccsc23)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
7-[(2S,4R)-4-Hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazole (850 mg) was dissolved in 20 ml of dichloromethane and 7 ml of DMF under ice cooling to prepare a solution. Triethylamine (0.425 ml) and 0.19 ml of methanesulfonyl chloride were added to the solution, and the mixture was stirred for 30 min. Water was added to the reaction solution, and the mixture was extracted with dichloromethane, followed by washing twice with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation to give 734 mg of a crude product of 7-[(2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazole.
Reaction SMILES: [C:1]([C:9]1[NH:13][C:12]([CH2:14][C:15]([O:17]CC)=[O:16])=[C:11](C(O)=O)[C:10]=1[CH3:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1.Cl.C(C1NC(CC(OCC)=O)=CC=1C)(=O)C1C=CC=CC=1.[OH-].[Na+]>[Cr]([O-])([O-])=O.[Cu+2].C(O)C>[C:1]([C:9]1[NH:13][C:12]([CH2:14][C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[CH3:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1[nH]c(C(=O)c2ccccc2)c(C)c1C(=O)O
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Agent: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2)[nH]1
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: Cc1cc(CC(=O)O)[nH]c1C(=O)c1ccccc1
Yield: 50 %

Procedure:
A solution of 4.13 g. (0.0131 mole) of ethyl 5-benzoyl-3-carboxy-4-methyl-pyrrole-2-acetate in 80 ml. of quinoline in the presence of a trace amount of copper chromite is heated at 180-183° C. for 5 hours. The mixture is poured into dilute hydrochloric acid and extracted three times with ether. The ether extracts are combined and washed successively with dilute hydrochloric acid, sodium bicarbonate solution and brine and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo to give about 4 g. of semisolid ethyl 5-benzoyl-4-methylpyrrole-2-acetate which is used in the following hydrolysis procedure without further purification. The entire semisolid is dissolved in 20 ml. of ethanol and 20 ml. of 1N sodium hydroxide solution is added. The mixture is heated under reflux for 30 minutes. The solvent is then evaporated in vacuo, and the residue dissolved in water and washed with ether. The aqueous solution is acidified with dilute hydrochloric acid and the resulting crystalline solid (1.6 g., 50% yield) is collected by filtration and air-dried. The product, 5-benzoyl-4-methylpyrrole-2-acetic acid is recrystallized three times from acetone-water with charcoaling, m.p. 167-168° C.
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:17]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:33][CH:32]=2)=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)Oc1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCC(C)Oc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 79.8 %

Procedure:
Optically active p-(1-methyl-heptyloxy)phenol (50.0 g, 0.22 mol) was dissolved in pyridine (300 ml), followed by dropwise adding to the solution, a solution of p-benzyloxybenzoic acid chloride (50.0 g, 0.20 mol) prepared above in (ii), dissolved in toluene (300 ml), under ice cooling, agitating the mixture for 2 hours while keeping it at about 50°~60° C., allowing it to stand overnight, thereafter adding toluene (1,500 ml) and water (1,000 ml), agitating the mixture, washing the toluene layer with 6N-HCl, then with 2N-NaOH aqueous solution and further with water until the wash water became neutral, distilling off toluene, and recrystallizing the residue from ethanol to obtain optically active p-benzyloxybenzoic acid p-(1-methyl-heptyloxy)phenyl ester (69.0 g).
Reaction SMILES: C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.N1CCC[C@H]1CO.C(N(CC)CC)C.[C:30]([N:37]1[CH2:43][CH2:42][CH2:41][C@H:38]1[CH2:39][OH:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>ClCCl>[C:30]([N:37]1[CH2:43][CH2:42][CH2:41][C@H:38]1[CH:39]=[O:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: OC[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reaction time: 8 h

Procedure:
A solution of 31.4 g (144 mmol) di-tert-butyl dicarbonate in dichloromethane was added to a solution of 14.6 g (144 mmol) L-prolinol and 22.1 ml (159 mmol) triethyl amine in dichloromethane at 0° C. The reaction was left overnight at rt. The dichloromethane phase was washed with 30% citric acid aq, saturated NaCl aq and saturated NaHCO3 aq. The organic phase was dried with Na2SO4 and evaporated. Yield 27.71 g (138 mmol, 96%). 27.71 g (138 mmol) BOC-L-prolinol was oxidized to the corresponding aldehyde according to procedure G. Yield of crude product 22.63 g. The product was purified with a silica column using 20% ethyl acetate in petroleum ether as eluent. Yield 18.4 g (92 mmol, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:29][CH:28]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C3CCCCO3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[ClH:41].O1CCOCC1>C(O)C>[ClH:41].[OH:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:12]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[CH:29][CH:28]=2)[S:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:10])=[O:11])=[CH:19][CH:18]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)cc2)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(O)cc2)c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C

Procedure:
4-Methoxy-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-N-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide (1.58 g, 2.79 mmol) was suspended in 3:1 ethanol:1N HCl (30 mL) and the solution was stirred at room temperature for 24 hr. The reaction mixture was quenched with sodium bicarbonate solution and the aqueous solution was washed with methylene chloride. The organic layer was dried (sodium sulfate), filtered, and concentrated to a white solid. The crude material was purified via Biotage® (A Dynax Corp., Charlottesville, Va.) chromatography using 10% methanol/methylene chloride as the eluant. The purified material was suspended in methanol (15 mL) and 4.0M HCl in dioxane (1.5 equiv.) was added. The mixture was stirred at room temperature and was concentrated to dryness to yield the title compound as the HCl salt. MS 483.1 (M+1)+
Reaction SMILES: [C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([CH:8]=[CH:9]3)=[CH:6][C:4]([NH:5]1)=[CH:3][CH:2]=2.[CH:25]([Sn](CCCC)(CCCC)CCCC)=[CH2:26]>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>[CH:25]([C:3]1[CH:2]=[C:1]2[CH:24]=[C:22]3[N:23]=[C:19]([CH:18]=[C:16]4[NH:17][C:13](=[CH:12][C:10]5[CH:9]=[CH:8][C:7](=[CH:6][C:4]=1[NH:5]2)[N:11]=5)[CH:14]=[CH:15]4)[CH:20]=[CH:21]3)=[CH2:26]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1cc2cc3nc(cc4ccc(cc5nc(cc1[nH]2)C=C5)[nH]4)C=C3
Yield: 77 %

Procedure:
One porphyrin that was not available via this route was the vinyl-porphyrin Zn10, owing to the lack of access to 5-vinyldipyrromethane (vide supra). The synthesis of Zn10 was achieved following the route outlined in Scheme 6. Diacyldipyrromethane 3248 was reduced with NaBH4 and the resulting 32-diol was condensed with dipyrromethane (36)41,49 in CH2Cl2 containing Yb(OTf)3 at room temperature. Subsequent oxidation with DDQ afforded free base porphyrin 37 in 33% yield. Porphyrin 37 was iodinated at the meso-position using I2 and (CF3CO2)2IC6H5 in CHCl3/pyridine50 to furnish free base porphyrin 8 in 82% yield. Zinc insertion afforded Zn8 in 75% yield. Porphyrin Zn8 was then subjected to a Stille cross-coupling reaction51 with (vinyl)tributyltin and Pd(PPh3)4 to afford vinylporphyrin Zn10 in 77% yield.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N:6]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([N+:20]([O-])=O)[CH:13]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[OH-].[Na+]>Cl>[NH2:20][C:14]1[CH:13]=[C:12]([N:6]2[CH2:7][CH2:8][O:9][CH2:10][CH2:11]2)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a cooled mixture of tin(II) chloride dihydrate 12.8 g (56.7 mmol) in conc. HCl mL with ice bath was added 4-(morpholin-4-yl)-2-nitrobenzonitrile 4.20 g (16.09 mmol) and stirred at room temperature for 2 hours. The reaction mixture was poured into diluted NaOH solution and extracted into ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4 and the solvent was evaporated. The crude product was washed with diethyl ether to give the title compound 3.13 g as off-white solid. Yield 95.0%.
Reaction SMILES: O.Cl.[C:3]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][C:23]([O:32][CH2:33][CH2:34][OH:35])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:51](Cl)(=[O:53])[CH3:52].Cl>C(Cl)Cl>[ClH:42].[C:51]([O:35][CH2:34][CH2:33][O:32][C:23]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][C:13]2([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=3)[CH2:14][CH2:15][CH2:16][N:11]([C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:12]2)[CH2:21][CH2:22]1)(=[O:53])[CH3:52]
Reactant: O=C(c1ccccc1)N1CCCC(CCCN2CCC(OCCO)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCCOC1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Reaction time: 3 h

Procedure:
A solution of 0.6 g of the compound obtained in EXAMPLE 17 and 0.5 ml of triethylamine in 25 ml of DCM is cooled to 0-5° C., 0.085 ml of acetyl chloride is added and the mixture is stirred for 3 hours, the temperature being allowed to rise to RT. It is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM and then a DCM/MeOH mixture (98/2; v/v) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 1.2 g of the expected product, m.p.=105-107° C.
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19]Br)=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:23]>>[C:1]([C:9]1[C:18]([CH2:19][OH:23])=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: O
Product: O=C(c1ccccc1)c1c(CO)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Yield: 59 %

Procedure:
A stirred slurry of 10.0 g (0.028 mol.) of 2-benzoyl-3-bromomethylquinoxaline 1,4-dioxide in 1,000 ml. of water was heated under reflux for 18 hours. The hot reaction mixture was filtered, and the filtrate was allowed to cool to 25° C. The solid which precipitated was collected by filtration to provide a first crop of crude product. The aqueous filtrate was extracted with dichloromethane, which was then dried and evaporated in vacuo, to provide a second crop of crude product. The combined crude product was 7.0 g. (85% yield). It was recrystallized from ethanol to give 4.9 g. (59% yield) of 2-benzoyl-3-hydroxymethylquinoxaline 1,4-dioxide having m.p 178°-179° C.
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]([CH:30]=[O:31])[CH2:26][CH2:27][CH2:28][CH3:29])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C>C1COCC1>[C:18]([O:22][C:23](=[O:32])[NH:24][CH:25]([CH:30]([OH:31])[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH2:9][CH2:10][CH2:11][S:12]1)[CH2:26][CH2:27][CH2:28][CH3:29])([CH3:19])([CH3:20])[CH3:21]
Reactant: CCCCC(C=O)NC(=O)OC(C)(C)C
Reactant: c1ccc(C2SCCCS2)cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC(NC(=O)OC(C)(C)C)C(O)C1(c2ccccc2)SCCCS1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 295 %

Procedure:
2-phenyl-1,3-dithiane (Aldrich) (3.79 g; 19.3 mmol) was mixed with dry distilled THF (20 mL) under a nitrogen atmosphere. The solution was cooled to −60° C. and n-butyl lithium (1.6M in pentane, 1.56 mmol, 9.74 mL) was added slowly by syringe. The reaction mixture was warmed to −20° C. and held at that temperature for 30 minutes, and then held at −10° C. for 15 minutes. The yellow solution was cooled to −78° C. and (1-Formyl-pentyl)-carbamic acid tert-butyl ester (1.6 g, 1.4 mmol, in 5 ml THF) was added rapidly (over 20 seconds) and 60 seconds later a mixture of 2 mL acetic acid and 5 mL THF was added rapidly. After warming to 23° C. the solution was concentrated at reduced pressure. Excess 2-phenyl-1,3-dithiane was removed by its crystallization away from the desired product using a minimum of ethyl acetate in hexane. The mother liquors were concentrated and chromatographed using a hexane-ethyl acetate gradient to afford 1.7 g of {1-[Hydroxy-(2-phenyl-[1,3]dithian-2-yl)-methyl]-pentyl}-carbamic acid tert-butyl ester. (56% yield).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]([OH:48])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[CH2:17][CH2:18][C@@H:19]([S:39][CH2:40][C:41]1([CH2:44][C:45]([OH:47])=[O:46])[CH2:43][CH2:42]1)[C:20]1[CH:21]=[CH:22][CH:23]=[C:24](/[CH:26]=[CH:27]/[C:28]2[CH:29]=[CH:30][C:31]3[CH:32]=[CH:33][C:34]([Cl:38])=[CH:35][C:36]=3[N:37]=2)[CH:25]=1)[CH3:10].[OH-].[Na+:50].CCCCCCC>CO>[CH3:10][C:9]([OH:48])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[CH2:17][CH2:18][C@@H:19]([S:39][CH2:40][C:41]1([CH2:44][C:45]([O-:47])=[O:46])[CH2:42][CH2:43]1)[C:20]1[CH:21]=[CH:22][CH:23]=[C:24](/[CH:26]=[CH:27]/[C:28]2[CH:29]=[CH:30][C:31]3[CH:32]=[CH:33][C:34]([Cl:38])=[CH:35][C:36]=3[N:37]=2)[CH:25]=1)[CH3:8].[Na+:50]
Reactant: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)O)CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: CO
Product: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)[O-])CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
1.15 L of toluene were added to 115.2 g of Montelukast acid (e.e.: 99.9%). The mixture was cooled between 2 and 10° C. and 313.3 ml of 0.5M NaOH solution in methanol were added over 15 minutes. Then, the mixture was warmed to room temperature and stirred for 30 minutes. After this period of time, 1.5 L of the solvent were distilled off under reduced pressure at 30° C. Then, 2.4 L of toluene were charged to the crude and the distillation was resumed to obtain a final volume of 300 ml. The solution of crude obtained was added over 1 hour to 1 L of heptane under stirring at room temperature. 18 hours after the addition, an off white solid was filtered off under a nitrogen atmosphere and washed with 500 ml of heptane. The wet product was dried under vacuum at 75° C. for 3 days to yield 120 g of Montelukast sodium. Yield: 100%. e.e.: 99.9%.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[NH:14][C:10]=3[CH:9]=2)[C:5]2[CH:18]=[C:19]([C:22]([OH:24])=O)[CH:20]=[CH:21][C:4]=2[O:3]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:54][N:55]([CH3:59])[CH2:56][CH2:57][NH2:58]>CN(C=O)C.O>[CH3:54][N:55]([CH3:59])[CH2:56][CH2:57][NH:58][C:22]([C:19]1[CH:20]=[CH:21][C:4]2[O:3][C:2](=[O:1])[N:6]([CH2:7][C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[NH:14][C:10]=4[CH:9]=3)[C:5]=2[CH:18]=1)=[O:24]
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc2oc(=O)n(Cc3ccc4[nH]c(=O)[nH]c4c3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1ccc2oc(=O)n(Cc3ccc4[nH]c(=O)[nH]c4c3)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
330 mg (0.76 mmol) of 2-oxo-3-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl-methyl)-2,3-dihydrobenzoxazole-5-carboxylic acid are dissolved in 3 ml of DMF, and 294 mg (1.52 mmol) of EDCl, 106 mg (0.76 mmol) of HOBt and 157 μl (1.52 mmol) of N-methylmorpholine are added. 81 mg (0.91 mmol) of 2-dimethylaminoethylamine are subsequently added, and the reaction solution is stirred at room temperature for 3 days. The reaction mixture is subsequently added to water and extracted with dichloromethane. The organic phase is dried over sodium sulfate, evaporated to dryness and purified by column chromatography on silica gel. The product is purified again by preparative HPLC; 100 mg of “A35” trifluoromethylacetate; ESI 397 (M+H), HPLC: Rt=3.89 min (method A).