Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.CCOC(C)=O>[O:23]=[C:14]1[N:13]([CH2:24][CH2:25][CH3:26])[C:12]2[N:11]=[C:10]([C:5]34[CH2:8][CH2:9][C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])([CH2:7][CH2:6]3)[CH2:3][CH2:4]4)[NH:18][C:17]=2[C:16](=[O:19])[N:15]1[CH2:20][CH2:21][CH3:22]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(N)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCn1c(=O)c2[nH]c(C34CCC(NS(C)(=O)=O)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
To a solution 100 mg of 8-(4-Amino-bicyclo[2.2.2]oct 1-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione. (Example 20), (0.28 mmol) in 2 ml of pyridine chilled in an ice/water bath was added 22 μL of methanesulfonyl chloride (0.28° mmol), 30% completion after 24 h at 10° C. Two more aliquots (22 μL and 50 μL) of methanesulfonyl chloride were added to drive the reaction to completion. The reaction mixture was concentrated in vacuo to afford a yellow oil which was taken up in EtOAc (10 ml) and washed twice with sat'd NaHCO3 (5 ml), once with 0.5N HCl and once with brine. The organic layer was dried over NaSO4 and conc'd to an oil. Crystallized from acetonitrile to afford 27 mg (22%) as a white solid (MH+=438.08). The following compounds were prepared in an analogous manner:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A151) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:23][N:10]2[CH2:11][CH2:12][C:13]3[C:18]([CH:9]2[CH2:8][C:7]1=O)=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:29]>CO>[CH2:1]([O:3][C:4]([C:6]1[CH2:23][N:10]2[CH2:11][CH2:12][C:13]3[C:18]([CH:9]2[CH2:8][C:7]=1[NH2:29])=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)=[O:5])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C1CN2CCc3cc(OC)c(OC)cc3C2CC1=O
Agent: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)C1=C(N)CC2c3cc(OC)c(OC)cc3CCN2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
A mixture of 9,10-dimethoxy-2-oxo-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (Helv. Chim. Acta 1958, 41, 119; 4.00 g, 12.0 mmol) and ammonium acetate (13.9 g, 180 mmol) in methanol was stirred 5 h at room temperature. After evaporation of the solvent the residue was partitioned between dichloromethane and 1 M aq. sodium hydroxide solution. The organic layer was dried (MgSO4), and triturated with heptane to afford the title compound (3.71 g, 93%). Off-white solid, MS (ISP) 333.2 (M+H)+.
Reaction SMILES: I[CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.O.[NH2:14][NH2:15]>C(O)C>[NH:14]([CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)[NH2:15]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(NN)C1
Temperature: 85 °C
Yield: 94.1 %

Procedure:
Tert-butyl 3-iodoazetidine-1-carboxylate (142 g, 0.5016 mol) and hydrazine hydrate (245.21 mL, 5.02 mol) were mixed in ethanol (284 mL) and the reaction was heated to 85° C. for 48 hours under nitrogen. The reaction was cooled and the ethanol was removed in vacuo. The residue was partitioned between water (200 mL) and dichloromethane (300 mL), the water layer was re-extracted with dichloromethane (2×200 mL), the combined organics were dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a colourless oil, (88.37 g). This compound was used immediately in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][C@@H:7]([NH:32]C(=O)OC(C)(C)C)[C:8]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH:13]([N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:14]3)=[O:9])=[CH:4][CH:3]=1>Cl.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]([C:8]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH:13]([N:18]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:19]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:20])[CH2:14]3)=[O:9])[NH2:32])=[CH:40][CH:41]=1
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@H](N)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
1.42 g of tert-butyl [(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]carbamate are placed in 12 ml of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred at ambient temperature for 3 h. 5 ml of 2N hydrochloric acid in diethyl ether are added and stirring is maintained for 16 h. After evaporation to dryness, the crude obtained is chromatographed on silica gel, elution being carried out with a 95/5/0.5 mixture of dichloromethane, methanol and aqueous ammonia. 1.03 g of N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N′,N′-diethylurea are obtained.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][P:13]([OH:16])(=[O:15])[OH:14])[C:7](=[O:17])[C:6](=[O:18])[NH:5]2.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:28].[K+].N>O>[I:28][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][P:13]([OH:16])(=[O:15])[OH:14])[C:7](=[O:17])[C:6](=[O:18])[NH:5]2
Reactant: [I-]
Reactant: Nc1ccc2c(c1)[nH]c(=O)c(=O)n2CP(=O)(O)O
Agent: N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1[nH]c2cc(I)ccc2n(CP(=O)(O)O)c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 15.8 %

Procedure:
180 mg of 1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)methanephosphonic acid is added dropwise to 10 ml of 25% strength sulfuric acid. After 5 minutes of agitation, a suspension of the salt is formed which is cooled to 0° C. To this is added a solution of 60 mg of sodium nitrite in 2 ml of water. After 15 minutes of stirring at 0° C., the reaction mixture is almost dissolved. To this is added a solution of 180 mg of potassium iodide in 2 ml of water. The ice bath is removed and the mixture heated to 100° C. for 2 hours. The cooled-off reaction mixture is neutralized with concentrated ammonia solution and evaporated to dryness. The residue is extracted by boiling with ethanol and a small amount of water, filtered, and the filtrate is concentrated. After chromatography over silanized silica gel with water:methanol=4:1, 40 mg of 1-(6-Iodo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)methanephosphonic acid is obtained, mp: 295-297° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(OO)(=[O:21])C.Cl>O.[OH-].[Na+]>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[N+:12]([O-:21])[C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(NCc2ccc(F)cc2)cn1
Reactant: CC(=O)OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(NCc2ccc(F)cc2)c[n+]1[O-]
Temperature: 25 °C

Procedure:
5.77 g of 5-(p-fluorobenzylamino)-pyridine-2-carboxylic acid are dissolved in 40 ml of water and 20 ml of 2 N aqueous sodium hydroxide. The solution is stirred at room temperature and 3.6 g of 40% aqueous peracetic acid are added. The solution becomes green and within less than a minute a solid separates. Another 3.6 g of said peracetic acid are added and the mixture is stirred for 4 hours. The pH of the mixture is adjusted to 4 with hydrochloric acid and filtered after cooling. The solid is collected and recrystallized from 90% aqueous acetonitrile, to yield the 5-(p-fluorobenzylamino)-pyridine-2-carboxylic acid N-oxide melting at 206°-209°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH:20]([C:25](=O)[CH2:26][CH2:27][CH3:28])[CH2:21][C:22]([OH:24])=[O:23]>C(O)(C)C>[CH3:19][CH:20]([CH2:25][C:26]1[N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[C:12]2[C:17]([C:27]=1[CH3:28])=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCC(=O)C(C)CC(=O)O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)O
Product: Cc1c(CC(C)CC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the method of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-fluorophenyl)hydrazine hydrochloride and 3-methyl-4-oxoheptanoic acid as the starting materials and isopropanol as the solvent, the title compound was prepared.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:6][CH:7]=1.C1C(=O)N([Br:30])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:30][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)cn1
Temperature: 80 °C
Yield: 65.4 %

Procedure:
A mixture of di-tert-butyl (5-methylpyridin-2-yl)imidodicarbonate (Compound 309C, 5.66 g, 18.4 mmol), NBS (3.92 g, 22 mmol), and benzoyl peroxide (0.444 g, 1.84 mmol) in CCl4 (30 mL) was heated at 80° C. for 6 h. The mixture was cooled to room temperature, the solids were filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography (EtOAc/heptane: 1:1) to give 4.66 g of di-tert-butyl [5-(bromomethyl)pyridin-2-yl]imidodicarbonate (yield: 65%).
Reaction SMILES: C[C:2]1[C:3]([O:15][CH3:16])([C:12](O)=[O:13])[CH:4](C)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[H-].[CH2:18]([Al+]CC(C)C)C(C)C.CO>C1(C)C=CC=CC=1.CCCCCC>[CH3:18][O:8][C:6](=[O:7])[C:5]1[CH2:4][C:3]([O:15][CH3:16])([CH:2]=[CH:10][CH:9]=1)[CH:12]=[O:13]
Reactant: COC1(C(=O)O)C(C)=CC=C(C(=O)O)C1C
Reactant: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1=CC=CC(C=O)(OC)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a -78° C. to -100° C. solution of 1.0 mole of dimethyl 3-methoxyisophthalic acid in 5 liters of toluene is slowly added 1.0 mole of diisobutyl-aluminum hydride as a 1 M solution in n-hexane (reaction t≤-78° C.). The reaction mixture is stirred for 3 hours following the addition and is then quenched by the addition of 10 moles of anhydrous methanol. The reaction mixture is allowed to warm to room temperature and is stirred until a filterable precipitate forms. The reaction mixture is filtered and the filtrate evaporated. The residue is purified by vacuum distillation to yield 3-methoxyisophthalaldehydic acid methyl ester.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:29]=[CH:28][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:16]=2)=[O:13])=[C:10]([Cl:30])[CH:9]=1)(=[O:7])=[O:6].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:30][C:10]1[CH:9]=[C:8]([S:5]([CH2:4][CH2:3][CH2:2][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)(=[O:7])=[O:6])[CH:29]=[CH:28][C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:16]=1)=[O:13]
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCCBr)cc1Cl
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)CCCN2CCOCC2)cc1Cl

Procedure:
120 mg of 4-(3-bromopropylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was used in Procedure P with morpholine to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-morpholinopropylsulfonyl)benzamide. MS (Q1) 534.0 (M)+.
Reaction SMILES: [C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:12][C:10](=[O:11])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19]>>[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:19][C:13](=[O:14])[C@H:8]([CH2:9][C:10](=[O:11])[OH:12])[NH:7][C:1](=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CC(C)=O

Procedure:
reacting N-acetoacetyl-L-aspartic anhydride with L-phenylalanine methyl ester to form N-acetoacetyl-α-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+:19].[O:20]1CCOCC1>O>[NH2:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:20])=[O:1].[Na+:19]
Reactant: O=C1Cc2cccc(Oc3ccccn3)c2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1Oc1ccccn1

Procedure:
A mixture of 2-oxo-7-(2-pyridyloxy)indoline (2.9 g.), sodium hydroxide (1.3 g.), dioxane (20 ml.) and water (20 ml.) was refluxed under heating for 16 hours with stirring. Dioxane was distilled off from the reaction mixture under reduced pressure, and water was added to the residue. The solution was washed with ethyl acetate and filtered, and the filtrate was cooled. The precipitates were collected by filtration, washed with a small amount of cold water and dried to give needles of the captioned compound (2.85 g.). mp 245° to 248° C.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[N+:29]([O-:30])=[N:28][C:27]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[N:26][C:25]=2[CH:37]=1.FC(F)(F)C(O)=O>C(Cl)Cl.N>[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[N+:29]([O-:30])=[N:28][C:27]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[N+:26]([O-:6])[C:25]=2[CH:37]=1
Reactant: COCCOc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1ccc2c(c1)[n+]([O-])c(NCCN(C)C)n[n+]2[O-]
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 48.1 %

Procedure:
Hydrogen peroxide (70%, 0.44 mL, ca. 8.7 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (1.23 mL, 8.7 mmol) in DCM (20 mL) at 5° C. The mixture was stirred at 5° C. for 5 min, warmed to 20° C., stirred for 10 min, and cooled to 5° C. The mixture was added to a stirred solution of 1-oxide 13 (268 mg, 0.9 mmol) and trifluoroacetic acid (0.34 mL, 4.4 mmol) in DCM (20 mL) at 5° C. and the mixture stirred at 20° C. for 6 h. The solution was carefully diluted with dil. aq. NH3 solution (2.0 mL) and the mixture extracted with CHCl3 (5×50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 14 (140 mg, 50%) as a red solid, mp (MeOH/DCM) 146-149° C.; 1H NMR δ 8.21 (d, J=9.6 Hz, 1 H, H-8), 7.52 (d, J=2.6 Hz, 1 H, H-5), 7.48 (br s, 1 H, NH), 7.10 (dd, J=9.6, 2.6 Hz, 1 H, H-7), 4.31-4.36 (m, 2 H, CH2O), 3.81-3.84 (m, 2 H, CH2O), 3.61-3.65 (m, 2 H, CH2N), 3.47 (s, 3 H, OCH3), 2.62 (br t, J=6.0 Hz, 2 H, CH2N), 2.31 [s, 6 H, (CH3)2]; 13C NMR δ 165.2, 150.2, 140.2, 125.7, 123.5, 120.5, 95.6, 70.3, 68.8, 59.2, 57.5, 45.0 (2), 38.9. Anal. Calcd for C14H21N5O4¼CH2Cl2: C, 50.1; H, 6.2; N, 20.2. Found: C, 50.1; H, 6.1; N, 20.6%.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:18][CH2:19][CH3:20])[C:7]2[O:12][C:11]([C:13](N)=[O:14])=[CH:10][C:9](=[O:16])[C:8]=2[CH:17]=1)[CH2:2][CH3:3].Br.C(=O)(O)[O-:23].[Na+].C(=O)(O)[O-]>C(O)(=O)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH2:18][CH2:19][CH3:20])[C:7]2[O:12][C:11]([C:13]([OH:23])=[O:14])=[CH:10][C:9](=[O:16])[C:8]=2[CH:17]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(CCC)c2oc(C(N)=O)cc(=O)c2c1
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1cc(CCC)c2oc(C(=O)O)cc(=O)c2c1

Procedure:
A mixture of 1.0 parts of 6,8-dipropyl-4-oxo-4H-1-benzopyran-2-carboxamide, 20 parts of glacial acetic acid, and 20 parts of a solution of hydrogen bromide (45% weight/volume) in glacial acetic acid was heated at reflux for 3 hours, then the organic layer with saturated sodium bicarbonate solution, followed by acidification of the bicarbonate layer, afforded 0.16 parts of 6,8-dipropyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, melting point 183°-184° C (decomposition). The melting point, IR spectrum and thin layer chromotographic properties of this material were identical with those of the compound prepared in Example 8.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>[Zn+2].[Br-].[Br-].CC(O)(C)C.ClCCCl>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)[N:7]=1
Reactant: CNC(=O)c1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Br-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: CNC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (8.63 mmol) in 1:1 t-BuOH/DCE (10 mL) was cooled to 5° C., treated with solid ZnBr2 (22.5 mmol), and stirred at 5° C. for 30 minutes. The resultant solution was maintained at 5° C. and treated first with solid 4-amino-N-methyl-benzamide (7.5 mmol) followed by TEA (16.5 mmol). The resultant white mixture was allowed to warm 25° C., and it was mixed at 25° C. for 20 hours. The mixture was adsorbed onto silica gel, and the fraction eluting 0-10% methanol/DCM was collected and concentrated. The resultant residue was triturated with water and filtered to provide B20. Yield: 3.0 mmol, 40%. LCMS 2.3 min, MZ+=331.1 1H NMR (500 MHz, d6-DMSO) δ ppm 10.89 (s, 1H), 8.87 (s, 1H), 8.34 (d, J=4.67 Hz, 1H), 7.73-7.89 (m, 3H), 2.78 (d, J=4.67 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:4]2[C:13]3[CH:12]=[C:11]([Cl:14])[CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:15]=1.[C:23]([Cu])#[N:24]>[C-]#N.C([N+](CC)(CC)CC)C.O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]2[N:7]=[CH:6][C:5]3[N:15]=[C:2]([C:23]#[N:24])[N:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Cl:22])[C:4]=3[C:13]=2[CH:12]=1
Reactant: Clc1ccc2ncc3nc(Br)n(-c4ccccc4Cl)c3c2c1
Reactant: N#C[Cu]
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: N#Cc1nc2cnc3ccc(Cl)cc3c2n1-c1ccccc1Cl
Temperature: 140 °C

Procedure:
In an alternative way, the title compound is prepared from 2-bromo-8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-c]quinoline (50 mg, 0.13 mmol; Example 82), CuCN (68 mg, 0.76 mmol; Fluka, Buchs, Switzerland), tris(dibenzylideneacetone)dipalladium chloroform adduct (Pd2(dba)3.CHCl3; 20 mg, 0.02 mmol; Aldrich), 1,1′-bis(diphenylphosphino)ferrocene (DPPF; 45 mg, 0.08 mmol; Aldrich), and tetraethylammonium cyanide (40 mg, 0.25 mmol; Fluka, Buchs, Switzerland) in 5 ml 1,4-dioxane by heating the reaction mixture for 5 h at 140° C. in a sealed tube.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]3[O:15]C[O:13][C:10]=3[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[N:4]1)[CH3:2].B(Br)(Br)Br.[CH3:24]O>ClCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:15])=[C:10]([OH:13])[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([O:19][CH3:24])=[O:18])=[N:4]1)[CH3:2]
Reactant: CO
Reactant: CCn1nc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCn1nc(C(=O)OC)c(=O)c2cc(O)c(O)cc21
Temperature: -30 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a suspension of 1-ethyl-4-oxo-1,4-dihydro-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid (12.6 g, 48.1 mmol) in dichloromethane (DCM) (50 mL) stirred under nitrogen at −30° C. was added dropwise a solution of boron tribromide (168 mL, 168 mmol) in dichloromethane (140 mL). The white suspension turned yellowish. The mixture was kept at −30° C. for 1 h and then allowed to warm up to room temperature, and stirred for 40 h. The reaction mixture was again cooled to −30° C., methanol (100 mL) was added, and the resulting mixture was stirred at room temperature over the weekend. The organic solvents were partially removed to afford a light yellow suspension. The solid was collected by filtration and washed with dichloromethane (20 mL). The filtrate was concentrated again to provide more yellow solids that was collected and washed by dichloromethane (20 mL). The solids were combined to afford methyl 1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydrocinnoline-3-carboxylate (11 g, 35.8 mmol, 74.5% yield). LCMS: (M+H)+: 265.0
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]([NH:17][NH2:18])=O)[CH2:14][CH2:13]1.O.C([O-])(O)=O.[Na+]>O=P(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[C:3]([C:4]2[O:6][C:15]([CH:12]3[CH2:14][CH2:13]3)=[N:17][N:18]=2)[C:2]([NH2:1])=[N:10][CH:9]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: NNC(=O)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Nc1ncc(Br)cc1-c1nnc(C2CC2)o1
Temperature: 0 °C
Yield: 95.4 %

Procedure:
A solution of 2-amino-5-bromo-nicotinic acid (300 mg, 1.38 mmol) and cyclopropanecarboxylic acid hydrazide (300 mg, 3.0 mmol) in POCl3 (30.0 mL) was stirred for 18 h at 65° C. The reaction mixture was distilled under reduced pressure to obtain a residue, which was cooled to 0° C. by adding iced water and neutralizing with saturated NaHCO3 solution (100 mL). The aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was separated, dried over anhydrous Na2SO4 and evaporated to afford 370 mg of crude 5-bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine. Crude compound was purified by column chromatography using silica gel (100-200 mesh). The column was eluted with 15% EtOAc in petroleum ether to afford the title compound as a pale yellow solid used without further purification.