Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[OH:3][CH:4]1[O:23][C@H:22]([CH2:24][OH:25])[C@@H:9]([O:10][C@@H:11]2[O:19][C@H:18]([CH2:20][OH:21])[C@H:16]([OH:17])[C@H:14]([OH:15])[C@H:12]2[OH:13])[C@H:7]([OH:8])[C@H:5]1[OH:6]>>[CH2:20]([OH:21])[C@H:18]1[O:19][C@@H:11]([O:10][C@H:9]2[C@H:7]([OH:8])[C@@:4]([OH:3])([CH2:5][OH:6])[O:23][C@@H:22]2[CH2:24][OH:25])[C@H:12]([OH:13])[C@@H:14]([OH:15])[C@H:16]1[OH:17].[OH2:1]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reactant: [OH-]
Agent: [Na+]
Product: O
Product: OC[C@H]1O[C@@H](O[C@@H]2[C@@H](CO)O[C@](O)(CO)[C@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Temperature: 70 °C

Procedure:
Sodium hydroxide is added to a 10% aqueous solution of commercially available lactose. followed by mixing, and thereafter the mixed solution was heated at 70° C. for 30 minutes and cooled. The cooled solution was purified by an ion-exchange resin, concentrated, cooled and crystallized and the unreacted lactose is removed to give an aqueous solution of lactulose in which the solid content is about 68% (where the solid contains about 79% of lactulose). This aqueous solution is passed through a column filled with a strongly acidic ion-exchange resin and a fraction containing lactulose is collected and concentrated to give an aqueous solution of pure lactulose containing about 68% of solid (where the solid contains about 86% of lactulose). This is the method disclosed in JP 3-169888 A.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:10][CH3:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.[I:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:22]([O-:24])=[O:23])[NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[I:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:22]([O-:24])=[O:23])[N:15]([CH2:2][C:3]2[C:4]([O:10][CH3:11])=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:14]=1
Reactant: COc1nc(C)ccc1CBr
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(C)ccc1Cn1nc(I)c2c([N+](=O)[O-])cccc21
Yield: 101.9 %

Procedure:
A mixture of 3-(bromomethyl)-2-methoxy-6-methylpyridine (500 mg, 2.314 mmol) and 3-iodo-4-nitro-1H-indazole (668.8 mg, 2.314 mmol) (prepared as in Example 1, step E) was dissolved in dry N,N-dimethylformamide (11.6 mL) with stirring under an atmosphere of nitrogen. Potassium carbonate (479.7 mg, 3.471 mmol) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with water (50 mL) and extracted into ethyl acetate. The combined organic extracts were washed with brine and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 3-iodo-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (1.0 g) which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]2=[O:14])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]2=[O:14])=[CH:6][CH:7]=1)=[N+:19]=[N-:20]
Reactant: Nc1ccc(-n2cccnc2=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1ccc(-n2cccnc2=O)cc1

Procedure:
1-(4-Aminophenyl)pyrimidin-2(1H)-one (2.3, 250 mg, 1.3 mmol) was dissolved in 10 mL TFA and stirred in ice bath. To it was added sodium nitrite (95 mg, 1.3 mmol) in small portions. The mixture was stirred in ice bath for 30 min. Sodium azide (260 mg, 4.0 mmol) was dissolved in 2 mL water and chilled in ice bath and added to the reaction mixture. The mixture was stirred for 2 hrs and directly subjected to reverse phase prep HPLC to isolate 1-(4-azidophenyl)pyrimidin-2(1H)-one 2.4. MS found for C10H7N5O (M+H)+ 214.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:32]O>>[CH3:32][O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=2)=[CH:12][CH:13]=1
Reactant: CO
Reactant: Nc1ccc(CCCc2ccc(Nc3ccccc3C(=O)O)cc2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1Nc1ccc(CCCc2ccc(N)cc2)cc1

Procedure:
To a solution of 2-{4-[3-(4-aminophenyl)propyl]phenylamino}benzoic acid (Example 159) (2.34 g, 6.75 mmol) in MeOH (50 mL) was added concentrated H2SO4 (1.0 mL) at room temperature. The mixture was stirred under reflux for 3.0 days. The reaction was quenched with Et3N (10 mL) at 5° C., and the solvent was removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with Et2O (20 mL, 4 times). The combined ether layer was washed with water (10 mL) and brine (10 mL), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and purification by column chromatography afforded crude title compound as a yellow amorphous material (2.59 g). This material was used without further purification.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH:25]([C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[N:37]([CH2:41][CH:42]1[CH2:44][CH2:43]1)[CH2:38][CH2:39][CH3:40])[CH3:26])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22]CC)=[O:21])[CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH:25]([C:27]1[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[CH:29][C:28]=1[N:37]([CH2:41][CH:42]1[CH2:43][CH2:44]1)[CH2:38][CH2:39][CH3:40])[CH3:26])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]2)=[CH:10][N:9]=1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C(C)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCC(C(=O)OCC)CC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C(C)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCC(C(=O)O)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
Ethyl 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{1-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylate (75 mg) is dissolved in ethanol (1 ml), and thereto is added a 2N-aqueous sodium hydroxide solution (148 μl), and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a dilute hydrochloric acid and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→49:1) to give 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{1-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylic acid (54 mg). MS (m/z): 732 [M+H]+
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:15]3[S:14][C:13]([NH2:16])=[N:12][C:11]=3[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)[N:6]=1.[H-].[Na+].[CH2:21](N(CC)CC)C.[N:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCOCC1.O>[CH3:18][O:17][C:10]1[C:11]2[N:12]=[C:13]([NH:16][C:34]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:35])[S:14][C:15]=2[C:7]([C:5]2[N:6]=[C:2]([CH3:21])[S:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCN(CC)CC
Reactant: COc1ccc(-c2csc(N)n2)c2sc(N)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2csc(C)n2)c2sc(NC(=O)N3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.07 g of 7-(2-Amino-thiazol-4-yl)-4-methoxy-benzothiazol-2-yl-amine (0.00025 Mol) were suspended in dioxane (4 ml) and treated with 0.028 g of NaH (60% dispersion in oil) (0.0006 Mol) for 1 h at room temperature. Then 0.11 ml of triethylamine (0.00076 Mol) and 0.07 ml of morpholine-4-carbonylchloride (0.0006 Mol) were added and the reaction mixture was stirred at room temperature for 3 hrs. Then water (15 ml) was added and the reaction mixture was extracted with ethyl acetate (4×, 20 ml each). The combined organic phases were dried over Na2SO4, filtered and evaporated. The residue was subjected to column chromatography (silicagel, ethyl acetate). The title compound was obtained as a light yellow solid (61%); F.p.: 223-226° C. (dec.).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][C:7]=1[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]([C:23]([O:25]CC)=[O:24])=[CH:13]2)=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].O.Cl>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][C:7]=1[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]([C:23]([OH:25])=[O:24])=[CH:13]2)=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(C(=O)c3ccc(OCC(C)C)cc3OCC(C)C)ccc2n1CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)COc1ccc(C(=O)c2ccc3c(c2)cc(C(=O)O)n3CC(C)C)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
In 2 ml of ethanol is dissolved 0.18 g of ethyl 5-(2,4-diisobutoxybenzoyl)-1-isobutyl-1H-indole-2-carboxylate. After adding 0.3 ml of 5 mol/L sodium hydroxide, the mixture thus obtained is stirred at ambient temperature for one hour. Water and chloroform are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1). Thus, 0.15 g of 5-(2,4-diisobutoxybenzoyl)-1-isobutyl-1H-indole-2-carboxylic acid is obtained as a white solid product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([Cl:22])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=[C:12]3[C:11]2=[O:21])=[C:6]([Cl:22])[CH:5]=1
Reactant: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc([N+](=O)[O-])cc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2C(=O)c3ccc(Cl)cc3C2=O)c(Cl)c1

Procedure:
The mixture of 2.3 g of N-(4-nitro-2-chlorophenyl)-4-chlorophthalimide, 220 ml of ethyl acetate and 1 g of Raney nickel is hydrogenated at room temperature and 3.1 atm. pressure until the hydrogen uptake ceases. It is filtered, evaporated and the residue recrystallized from methanol, to yield the N-(4-amino-2-chlorophenyl)-4-chlorophthalimide melting at 198°-201°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].C([Li])CCC.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1COCC1.CCCCCC>[OH:20][CH:13]([CH:3]1[O:4][CH2:5][CH2:6][NH:1][C:2]1=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1COCCN1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=C1NCCOC1C(O)c1ccccc1
Temperature: -62 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
Under an atmosphere of nitrogen and in a anhydrous apparatus a mixture of 2.02 g of morpholin-3-one in 60 ml of anhydrous THF was stirred. Dropwise addition was made at room temperature of 26.7 ml of 15% butyl lithium in hexane over 45 minutes. After 2.5 hours of stirring at room temperature the whole was cooled to -62° C. and a solution of 2.02 ml of freshly distilled benzaldehyde in 10 ml of anhydrous THF was added, over 45 minutes. The mixture was kept at -62° C. for 3 hours, allowed to rise to room temperature and kept at this temperature for a further 16 hours. A little water was added and the whole was evaporated to dryness. The residue was taken up with a dilute solution of NaHCO3, extracted with ethyl acetate and washed with H2O. The solution was dried over Na2SO4, filtered and evaporated to dryness. The solid residue was ground with 40 ml of ethyl ether and filtered, to obtain 2.4 g of 2-(α-hydroxy-benzyl)-morpholin-3-one which was crystallized from ethyl acetate, melting point 130°-140° C. Yield 58.0%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]([NH:11][NH:12][C:13]([C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[C:18](=[O:23])[NH:17][C:16]=1[CH3:24])=[O:14])=O)([CH3:4])([CH3:3])[CH3:2].S(Cl)([C:29]1C=CC(C)=CC=1)(=O)=O.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>O1CCCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[O:14][C:13]([C:15]2[C:16]([CH3:24])=[N:17][C:18]([O:23][CH3:29])=[C:19]([CH2:21][CH3:22])[CH:20]=2)=[N:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1cc(C(=O)NNC(=O)CNC(=O)OC(C)(C)C)c(C)[nH]c1=O
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: CCc1cc(-c2nnc(CNC(=O)OC(C)(C)C)o2)c(C)nc1OC
Temperature: 145 °C
Reaction time: 0.05 h
Yield: 182 %

Procedure:
Into each of three microwave vials is added {2-[N′-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hydrazino]-2-oxo-ethyl}-carbamic acid tert-butyl ester (190 mg, 0.519 mmol), tosyl chloride (119 mg, 0.624 mmol), and 2-t-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (2.2 mmol/g, 1.18 g, 2.6 mmol) and anhydrous tetrahydrofuran (6 mL). Each vial is flushed with nitrogen, sealed and heated in the CEM Discover microwave at 145° C. holding at that temperature for 3 min, with a maximum pressure of 7.3 bar. LC/MS shows the reaction is complete. The product from all three vials are filtered and washed with THF. The filtrate is evaporated, and the residue is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1). Fractions containing the product are combined again and evaporated to give [5-(5-ethyl-6-methoxy-2-methyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-ylmethyl]-carbamic acid tert-butyl ester (329 mg, 61% yield). MS: m/e 719 (95%) (2M+Na), 249 (100%) (M+H); 1H NMR (CDCl3, δ, ppm): 7.87 (1H, s), 5.15 (1H, br.), 4.61 (2H, br.d), 4.00 (3H, s), 2.79 (3H, s), 2.60 (2H, q), 1.49 (9H, s), 1.21 (3H, t).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7].ClCCl.O.[S:15]1[CH:19]=[CH:18][N:17]2[CH:20]=[N:21][CH:22]=[C:16]12>C(=S)=S>[C:5]([C:22]1[N:21]=[CH:20][N:17]2[CH:18]=[CH:19][S:15][C:16]=12)(=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: c1cn2cncc2s1
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: S=C=S
Product: CC(C)C(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Aluminum chloride (16.2 g) was added to a solution of 15.0 ml of isobutyryl chloride in 100 ml of carbon disulfide. A solution of 40 ml of dichloromethane in 2.50 g of imidazo[5,1-b]thiazole was added dropwise to the mixture. The mixture was stirred at room temperature for 20 hr. Dichloromethane (100 ml) was added to the reaction solution. Water (60 ml) was added dropwise thereto with stirring. The organic layer was then separated. Dichloromethane (200 ml) and 100 g of sodium carbonate were added to the aqueous layer. The mixture was stirred. The insolubles were removed by filtration, and washed with dichloromethane. The filtrate was combined with the organic layer. The combined organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=1:1) to give 2.75 g of 7-isobutyrylimidazo[5,1-b]thiazole.
Reaction SMILES: [Cl:1]C(O)C.C1C[O:8][CH2:7][CH2:6]1.[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18])=[CH:13][CH:12]=1>C(N(CC)CC)C>[Cl:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][C:16]([CH3:21])([CH3:20])[C:17]([O:8][CH2:7][CH2:6][Cl:1])=[O:18])=[CH:13][CH:12]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: CC(O)Cl
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)OCCCl

Procedure:
To a solution of 80.5 g of chloro-ethanol (1 mole) in THF containing 101 g (1 mole) of triethylamine are added, dropwise with stirring, 233 g (1 mole) of p-chlorophenoxy-2-methylpropionic acid chloride. The triethylamine hydrochloride is filtered, and the ester formed is distilled; it is identical to that obtained under 6.1.1.; the synthesis of (VI) is continued as under 6.1.2., and then 6.1.3.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]([O:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=3[CH3:28])=[N:14][C:13](Cl)=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>O>[CH2:1]([N:8]1[C:16]2[C:15]([O:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=3[CH3:28])=[N:14][C:13]([NH:30][C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1nc(Cl)nc2ccn(Cc3ccccc3)c12
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(Cc3ccccc3)c12
Temperature: 90 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
In a sealed tube was added 5-benzyl-2-chloro-4-(2,6-dimethyl-4-nitrophenoxy)-5H-pyrrolo[3,2-d]pyrimidine (598 mg, 1.46 mmol), 4-aminobenzonitrile (691 mg, 5.85 mmol), TFE (9.1 mL) and TFA (1.97 mL, 11.7 mmol). The reaction mixture was stirred at 90° C. for 16 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water and washed with EtOAc. The combined organic layers were washed with NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (3:1-1:1), to give the product (442 mg, 60%).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([O-])=O.O.[NH2:17]N>C(O)C.[Pd].C(OCC)(=O)C>[N:10]1([C:5]2[CH:6]=[CH:7][C:8]([NH2:17])=[CH:9][CH:4]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccccc1N1CCOCC1
Reactant: NN
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCOCC2)cc1
Reaction time: 12 h

Procedure:
To a stirred solution of Intermediate 4 (3.2 g) in ethanol (60 ml) were added hydrazine hydrate (3.71 ml) and palladium on charcoal (5%, 0.1 g). The reaction was stirred for 12 h, before being diluted with ethyl acetate (60 ml). The reaction was extracted with aqueous citric acid (5%, 4×15 ml), and the combined aqueous extracts neutralised with sodium bicarbonate. The aqueous was extracted with ethyl acetate (3 ×15 ml), and the combined organic extracts washed with brine (50 ml), dried over magnesium sulphate (2 g) and the solvent removed in vacuo to yield the title compound as a light brown oil (1.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([CH:9]=1)[C:7]#[N:8].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>>[NH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:9]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)Nc1ccc(Cl)cc1C#N
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2cc(Cl)ccc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 5-chloro-2-(ethoxycarbonylamino)benzonitrile (K. O. Geolotte et al, J. Heterocyclic Chem., 1990, 27, 1549) and 2-bromoacetophenone.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][O:21][C:22]1[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1.[CH:33]1([C:36]2[O:40][N:39]=[C:38]([C:41](O)=[O:42])[CH:37]=2)[CH2:35][CH2:34]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[CH:33]1([C:36]2[O:40][N:39]=[C:38]([C:41]([N:15]3[CH2:19][CH2:18][CH2:17][C@@H:16]3[CH2:20][O:21][C:22]3[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=3)=[O:42])[CH:37]=2)[CH2:35][CH2:34]1
Reactant: O=C(O)c1cc(C2CC2)on1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)c1cc(C2CC2)on1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifluoroacetic acid) salt (EXAMPLE 34 Step 1) and 5-cyclopropylisoxazole-3-carboxylic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)m ethoxy)picolinic acid.
Reaction SMILES: C[CH:2]([S:4][CH2:5][C:6]([OH:8])=O)[CH3:3].[CH3:9]N1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:24][CH2:25][CH2:26][C@H:27]([OH:44])[C@@H:28]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1.C(OCC)(=O)C>[CH2:2]([S:4][CH2:5][C:6]([NH:24][CH2:25][CH2:26][C@H:27]([OH:44])[C@@H:28]([NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:8])[CH2:3][CH3:9]
Reactant: CC(C)SCC(=O)O
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCN
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCSCC(=O)NCC[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
To (2-propylmercapto)acetic acid (44.3 mg, 0.33 mmol) in the THF (3 mL) at 0°(b) was added N-methylmorpholine (37 microliters, 0.34 mmol) followed by isobutylchloroformate (43 microliters, 0.33 mmol). The mixture was stirred at 0° C. for 15 minutes and (3S,4S)-1-amino-3-hydroxy-4-t-butyloxycarbonylamino-5-cyclohexylpentane (51.0 mg, 0.17 mmol) was added followed by stirring at 0° C. for 15 minutes and at 25° C. for 2 hours. The mixture was poured into ethyl acetate, washed with 0.5 M H3PO4, 2 M Na2SO4 and evaporated to afford 36 mg (50%) of the desired compound. Mass spectrum: (M+1)+ =417.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([OH:14])=[O:13].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27]3[O:13][C:12](=[O:14])[C:3]4[C:4]5[C:9](=[N:8][CH:7]=[CH:6][CH:5]=5)[CH:10]=[CH:11][C:2]=4[N:1]=3)=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Nc1ccc2ncccc2c1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3ncccc3c12
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a suspension of 240 mg (1.28 mmol) of 6-amino-quinoline-5-carboxylic acid in 9.60 mL of anhydrous tetrahydrofuran at 10° C., is added 372 mg (1.28 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 5134 (6.38 mmol) of pyridine. Then the suspension is cooled to 0° C. and 398 μL (5.10 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 48 hours. Then the solvent is evaporated and the residue is precipitated with a minimum of ethyl acetate and washed with ethyl acetate. After filtration, water is added to the filtrate and the new suspension formed is filtrated again. After drying on high vacuum pump 303 mg (54%) of solid are obtained; LC/MS:444/446 (M+H)+.