Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])[CH3:12]>C(#N)C.O.C(OCC)(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:18][CH2:19][N:14]([C:11](=[O:13])[CH3:12])[CH2:15][CH2:16]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 87.2 %

Procedure:
A solution of 5.0 g (35.44 mmol) of 1-fluoro-4-nitrobenzene and 4.99 g (38.98 mmol) of N-acetylpiperazine in 50 mL of acetonitrile is heated at 60°C. for 15 hours. The resulting mixture is diluted with water and with ethyl acetate. After separation of the phases by settling and extraction of the aqueous phase with ethyl acetate, the organic phases are combined, dried over Na2SO4, filtered and concentrated under vacuum. 7.7 g of the expected product are obtained in the form of a yellow solid, which is used as obtained in the following step. Yield=88.8%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH2:26]([O:28]C(C1C=CNC=1C)=O)C.COC1C=CC=CC=1CCl>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:28][CH3:26])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Agent: COc1ccccc1CCl
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1OC

Procedure:
Prepared similarly according to a reaction sequence in Example 117 steps (a), (b), (c) and (d) for the synthesis of 2,3-dibromo-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester starting from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester, 2-methoxybenzyl chloride. The title compound, ESI MS (m/z): 483 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][CH2:24][OH:25])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:15][C:14]=3[F:26])=[O:9])=[CH:27][CH:28]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCCO)cc2c1O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCCO)cc2c1O
Yield: 44.9 %

Procedure:
A solution of the title compound of Example 94 (0.180 g), Pd/Ba2SO4 (10%, 75.3 mg), and pyridine (5 mL) in EtOAc (25 mL) is maintained under an atmosphere of H2 (balloon) for 3 hrs, then filtered over celite. The crude product is recrystallized from EtOAc/hexanes to afford 81.6 mg of the desired product as an off-white solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)C=CC=CC=1.[CH:26]1([C:31](=O)[CH2:32][C:33]#[N:34])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([C:31]2[CH:32]=[C:33]([NH2:34])[N:9]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:8]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: N#CCC(=O)C1CCCC1
Reactant: c1ccc(C(=NNc2ccc3ncccc3c2)c2ccccc2)cc1
Product: Nc1cc(C2CCCC2)nn1-c1ccc2ncccc2c1
Yield: 53.3 %

Procedure:
Using a procedure analogous to Example B3, 6-(2-(diphenylmethylene)hydrazinyl)quinoline (5.0 g, 15.5 mmol) and 3-cyclopentyl-3-oxopropanenitrile (3.0 g, 1.1 eq) were combined to yield 3-cyclopentyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine (2.3 g, 53% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.87 (m, 1H), 8.38 (dd, J=1.5, 8.4 Hz, 1H), 8.10 (s, 1H), 8.04-8.02 (m, 2H), 7.55 (dd, J=4.2, 8.1 Hz, 1H), 5.41 (br s, 2H), 5.38 (s, 1H), 2.90 (m, 1H), 1.85-1.96 (m, 2H), 1.53-1.70 (m, 6H); MS (ESI) m/z: 279.3 (M+H+).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[O:6][CH2:5]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC=CC=1.C1(C)C(C)=CC=CC=1>[CH2:17]([O:3][CH:4]1[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[O:6][CH2:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC1COC(c2cccc(F)c2)OC1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: c1ccccc1
Product: Fc1cccc(C2OCC(OCc3ccccc3)CO2)c1
Yield: 71.2 %

Procedure:
A slurry of sodium hydride (3.7 g of 62%, 0.096 mole) in benzene (100 ml) and xylene (100 ml) was stirred at ambient temperature while 5-hydroxy-2-(3-fluorophenyl)-1,3-dioxane (18.9 g, 0.096 mole) was added dropwise during 1 hour. This mixture was stirred 1 additional hour, then to it was added benzyl chloride (12.2 g, 0.096 mole) during 1/2 hour. The mixture was heated under reflux for 18 hours, cooled, filtered and the filtrate washed with water (2 × 200 ml). The washed solution was dried over magnesium sulfate and concentrated to give 19.7 g of oil which was distilled under 2 × 10-4 mm pressure to give three fractions distilling at bath temperature of 98°-119° C (cut 1); 119°-139° C (cut 2); and 139°-143° C (cut 3). Cut 2 (9.1 g) was found by nmr analysis to be a mixture of cis and trans-dioxanes and the corresponding dioxolane. Cut 3 (1.5 g, m.p. 70°-71° C) was found by nmr to be 100% cis-5-benzyloxy-2-(3-fluorophenyl)-1,3-dioxane and this cut was used in further studies.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:26]([O:28]C)=[O:27])[C:10]3[NH:11][C:12]4[CH:13]=[C:14]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:15]=[CH:16][C:17]=4[C:18]=3[N:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+].Cl>C1COCC1>[CH:23]([O:22][C:20]([C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[N:19]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=[C:9]([C:26]([OH:28])=[O:27])[C:10]=3[NH:11][C:12]=2[CH:13]=1)=[O:21])([CH3:25])[CH3:24]
Reactant: COC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(C(=O)OC(C)C)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)OC(=O)c1ccc2c(c1)[nH]c1c(C(=O)O)cc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.9 %

Procedure:
A solution of 7-isopropyl 4-methyl 2-phenyl-5H-pyrido[3,2-b]indole-4,7-dicarboxylate (380 mg, 0.978 mmol) in a mixture of THF (5.6 mL), MeOH (1.9 mL) and 1 N aqueous sodium hydroxide solution (2.0 mL, 2.0 mmol) was stirred at 25° C. for 15 min. The reaction was treated with 1 N aqueous HCl (0.52 mL) and the organic solvents were removed. The residue was diluted with water and acidified to about pH 3.0 with 1 N aqueous HCl to give an yellow gel-like precipitate. This was chilled in an ice bath and the precipitate was collected by filtration, washed with water and dried to leave impure 7-(isopropoxycarbonyl)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylic acid (395 mg). MS (ESI) m/z 375.09 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.88 (1H, s), 8.35-8.50 (3H, m), 8.25 (2H, d, J=7.94 Hz), 7.83-7.96 (1H, m), 7.56 (2H, t, J=7.78 Hz), 7.46 (1H, t, J=7.17 Hz), 5.22 (1H, quin, J=6.26 Hz), 1.40 (6H, d, J=6.10 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:29]=[CH:28][C:15]2[CH2:16][CH:17]([CH2:22][C:23]([O:25]CC)=[O:24])[C:18](=[O:21])[NH:19][CH2:20][C:14]=2[CH:13]=1.O.[OH-].[Li+].C1COCC1.O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:29]=[CH:28][C:15]2[CH2:16][CH:17]([CH2:22][C:23]([OH:25])=[O:24])[C:18](=[O:21])[NH:19][CH2:20][C:14]=2[CH:13]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CNC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CNC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.1 %

Procedure:
A mixture of ethyl (±)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.7 g, 2 mmol), lithium hydroxide monohydrate (0.12 g, 3 mmol), 5 mL THF (5 mL), H2O (5 mL), and MeOH (2 mL) was stirred at room temperature for 18 hr, then was then concentrated. The residue was partitioned between ethyl acetate and water, and the layers were separated. The aqueous phase was cautiously brought to pH 4 with 3 N HCl and allowed to stand. The resulting crystals were collected by filtration and dried to give the title compound (0.4 g, 65%) as a tan solid: MS m/e 370.4 (M+H)+. Anal. Calcd for C20H23N3O4.0.25 H2O: C, 64.25; H, 6.34; N, 11.24. Found: C, 64.02; H, 6.37; N, 11.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:17]([F:24])=[N:18][CH:19]=[C:20]([CH3:23])[C:21]=1[I:22])[OH:15]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:17]([F:24])=[N:18][CH:19]=[C:20]([CH3:23])[C:21]=1[I:22])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(F)ncc(C)c2I)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(F)ncc(C)c2I)c(OC)c1OC
Temperature: 25 °C
Yield: 64.8 %

Procedure:
17.3 g (0.18 mol) of manganese dioxide was added to a solution having 4.35 g (9.70 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(2-fluoro-4-iodo-5-methyl-3-pyridyl)methanol obtained in Step (b) dissolved in 130 ml of toluene, followed by reflux with heating for 2 hours. After cooling to room temperature, manganese dioxide was removed by filtration on the pad of celite, and toluene was distilled off under reduced pressure, followed by purification by silica gel chromatography to obtain 2.80 g (yield: 65%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-fluoro-4-iodo-5-methylpyridine (Compound No. 18, melting point 140 to 141° C.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH:14]([CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:34])[NH:22][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([CH:14]([CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:15]([NH:17][CH:18]([C:20]1[C:21](=[O:34])[NH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[N:24][N:25]=1)[CH3:19])=[O:16])(=[O:11])[CH3:13]
Reactant: Cc1ccc(Cc2nnc(C(C)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)C(CCCc1ccccc1)C(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
270 mg (2.14 mmol) of oxalyl chloride in 10 ml of dichloromethane are treated dropwise at −70° C. with 360 mg (4.64 mmol) of dimethyl sulphoxide. The mixture is stirred at −70° C. for 30 min, then 800 mg (1.78 mmol) of 2-(1-hydroxyethyl)-N-{1-[3-(4-methylbenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenylpentanamide are added. After a further 30 min, during which the temperature in the batch rises to about −60° C., 900 mg (8.92 mmol) of triethylamine are added and the cooling bath is then removed. If the batch temperature has warmed almost to room temperature, 10 ml of water are added and, after stirring briefly, the phases are separated. The dried organic phase is chromatographed in dichloromethane/methanol 50/1.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6](F)[NH:5][C:4]=2[CH:3]=1.Cl.[CH3:15][C:16]1([NH2:20])[CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:20][C:16]3([CH3:15])[CH2:19][CH2:18][CH2:17]3)[NH:5][C:4]=2[CH:3]=1
Reactant: CC1(N)CCC1
Reactant: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(NC2=NS(=O)(=O)c3sc(Cl)cc3N2)CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
A mixture of 6-chloro-3-fluoro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.3 g, 5.3 mmol), 1-methylcyclobutylamine hydrochloride (1.0 g, 8.1 mmol) and triethylamine (2.5 ml, 18.1 mmol) in ethanol (10 ml) was stirred for 16 h at 50° C. and then for 5 h at 70° C. in a sealed flask. The cooled mixture was concentrated in vacuo and the residue was triturated with water (25 ml) followed by adjustment to pH <2 with 1M hydrochloric acid. The crude product was isolated by filtration, recrystallised from acetic acid and finally purified by chromatography (C18; 20-60% acetonitrile+0.01% TFA) to give 363 mg (22%) of the title compound; mp 294-296° C.; 1H-NMR (DMSO-d6): δ1.48 (s, 3H), 1.75-1.88 (m, 2H), 1.94-2.05 (m, 2H), 2.18-2.31 (m, 2H), 7.08 (s, 1H) 7.33 (br s, 1H), 10.67 (br s, 1H); LC-MS: m/e 306/308 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[N:14]([CH3:21])[C:13]=2[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:25]1(C)C=CC=C[CH:26]=1.C(I)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]([CH2:25][CH3:26])[C:17](=[O:19])[CH2:16][C:15](=[O:20])[N:14]([CH3:21])[C:13]=2[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: CN1C(=O)CC(=O)Nc2ccc(OCc3ccccc3)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCI
Solvent: O
Product: CCN1C(=O)CC(=O)N(C)c2cc(OCc3ccccc3)ccc21
Temperature: 45 °C
Reaction time: 4 h

Procedure:
8-benzyloxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (33.4 g, 113 mmol), tetrabutyl ammonium bromide (7.28 g, 22.6 mmol) and an aqueous solution of 25% sodium hydroxide (20.8 g, 130 mmol) were added to the mixture of toluene (167 mL) and water (150 mL). Ethyl iodide (10.4 mL, 130 mmol) was added thereto, and the reaction was performed at 80° C. for 4 hours. The reaction solution was cooled, and ethyl acetate (334 mL) extraction was performed. The resulting organic layer was washed with water, and the solvent was distilled off under reduced pressure. Ethyl acetate (70 mL) was added to the resulting residue, and the mixture was heated and dissolved. Thereafter, hexane (35 mL) was added thereto, and heating was performed again. The mixture was stirred at 40-50° C. for 30 minutes, and stirred under ice cooling for 1 hour to collect precipitated crystals by filtration. The resulting crystals were washed with ethyl acetate-hexane (1:1; 50 mL), and dried at 60° C., thereby obtaining 39.6 g of a light-yellow, powdery target compound (containing ammonium salt).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=1.[NH2:15][CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][CH2:16][NH:15][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH:8]=3)=[O:14])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Reactant: O=C(O)C1=NN=C(c2ccccn2)C1
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(-c4ccccn4)n[nH]3)n2)cc1Cl
Yield: 22.7 %

Procedure:
The title compound was prepared using the method of Example 53 but starting from 5-pyridin-2-yl-4H-pyrazole-3-carboxylic acid (38 mg; 0.20 mmol) and 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (50 mg; 0.20 mmol). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% MeOH/DCM) to obtain 19 mg (23%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.70-3.74 (m, 2H), 4.38 (t, 2H), 6.96 (d, 1H), 7.23-7.40 (m, 2H), 7.82-8.02 (m, 5H), 8.09 (s, 1H), 8.48, (broad s, 1H), 8.62 (d, 1H), 13.89 (broad s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9]C=O)=[C:4]([Cl:12])[N:3]=1.O.P(=O)(O)(O)O>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: O
Product: Nc1nc(Cl)c(N)c(Cl)n1

Procedure:
A mixture of 2-amino-4,6-dichloro-5-[(dimethylamino)methylene]amino}pyrimidine (Example 2, 500 mg, 2.14 mmol), pH 3.2 aqueous potassium phosphate buffer (1.5 M, 6 mL, prepared as described in Example 3), water (1 mL), and ethanol (5 mL) was refluxed gently for 28 hours. During the reflux period, pH was maintained at ca. 3 by addition of 85% phosphoric acid. Volatiles were evaporated in vacuo and the residual solids partitioned between water (30 mL, adjusted to pH 8 with dilute ammonium hydroxide) and chloroform (75 mL. The chloroform layer was dried (sodium sulfate) and the chloroform evaporated to leave off-white solid (0.30 g). Crystallization of this solid from ethanol:water/4:1 gave the title compound (IV) as light pink needles (332 mg, 61%); darkens and shrinks to black solid above 185° C., does not become fluid below 300° C.; 1H-NMR (DMSO-d6) and mass spectra identical to those described in Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[N:20][C:21]([Cl:27])=[CH:22][CH:23]=2)[N:18]=1.C(O)C>O>[Cl:27][C:21]1[N:20]=[C:19]2[C:24]([CH:25]=[CH:26][C:17]([NH:16][C:6](=[O:8])[C:5]3[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:18]2)=[CH:23][CH:22]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc(OC)c1OC
Temperature: 4 °C
Yield: 44.3 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 3,4,5-trimethoxybenzoic acid (17 g), N,N'-carbonyldiimidazole (13 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product obtained by precipitation in water (10.3 g; m.p. 90° C.) is dissolved in boiling ethanol (500 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with ethanol (20 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3,4,5-trimethoxybenzamide (8.2 g), m.p. 210° C., is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>O>[OH:1][C:2]1[C:3]([N+:20]([O-:22])=[O:21])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(O)c(C(=O)OC)s1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1sc(C(=O)OC)c([N+](=O)[O-])c1O
Reaction time: 1 h
Yield: 19.9 %

Procedure:
Methyl 4-hydroxy-5-(methoxycarbonyl)thiophene-2-carboxylate (5 g, 23.14 mmol) was added slowly for 15 min at 0 to −5° C. to concentrated sulfuric acid (25 mL). Then concentrated nitric acid (3.2 mL, 70%, 34.7 mmol) was added to the above reaction mixture for 10 min and stirred at the same temperature for 1 h. The mixture was poured into ice cooled water and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as a yellow color semi-solid (1.2 g, 20%).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:16]([CH3:18])[CH3:17])([CH2:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[O:5][C:4](=[O:19])[CH:3]=1.[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33][C:3]1[C:4](=[O:19])[O:5][C:6]([CH:16]([CH3:17])[CH3:18])([CH2:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][C:2]=1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)C1(CCc2cccnc2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccnc3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 4-hydroxy-6-isopropyl-6-(2-pyridin-3-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-16; 0.92 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 1.01 mmol), potassium carbonate (3.67 mmol) in DMF (5 mL). The product was triturated from Et2O, mp 122-125° C. MS (APCI): 470 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>CN(C=O)C>[CH3:26][O:27][C:28]1[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1ncccc1B(O)O
Solvent: CN(C)C=O
Product: COc1ncccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-methoxy-3-pyridinyl boronic acid (CAS RN 163105-90-6) and using DMF as reaction solvent. Colorless solid (23%). MS (ESI): m/z=455.8 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[NH2:18])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)([O-:14])=[O:13]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3,5-dinitroaniline to yield 2-[(3,5-dinitrophenyl)amino]phenylacetic acid.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH:10]1([CH2:16]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Br:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: BrCC1CCCCC1
Reactant: O=C(O)c1ccc(Br)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(OCC1CCCCC1)c1ccc(Br)o1
Reaction time: 8 h

Procedure:
A mixture of 5-bromofuran-2-carboxylic acid (2.64 g, 13.8 mmol), (cyclohexylmethyl)bromide (2.62 g, 14.8 mmol), K2CO3 (2.30 g, 16.64 mmol) in anhydrous NMP was stirred under Ar at +70° C. for 8 hrs after which additional (cyclohexylmethyl)bromide (1.55 g, 8.75 mmol) was added. Stirring continued overnight then the reaction mixture was concentrated under reduced pressure. The residue was partitioned between aqueous NaHCO3 (10%) and hexanes, and then aqueous layer was extracted with hexanes. Combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure to give cyclohexylmethyl 5-bromofuran-2-carboxylate as a light yellow oil. Yield (2.22 g, 56%); 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J=3.9 Hz, 1H), 6.44 (d, J=3.4 Hz, 1H), 4.10 (d, J=6.4 Hz, 2H), 1.64-1.84 (m, 6H), 1.12-1.34 (m, 3H), 0.95-1.09 (m, 2H).