Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:20]2[CH:21]=[CH:22][S:23][C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([C:24]#[N:25])=[CH:14][C:13]=2[N:12]=1.O>CN(C=O)C>[O:7]([C:11]1[C:20]2[CH:21]=[CH:22][S:23][C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([C:24]#[N:25])=[CH:14][C:13]=2[N:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc2c(c1)nc(Cl)c1ccsc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)nc(Oc1ccccc1)c1ccsc12

Procedure:
Phenol (2.0 eq, 85 mg) was dissolved in anhydrous DMF. 60% sodium hydride (2.0 eq, 36 mg) was added and the reaction mixture stirred for a few minutes. 4-chlorothieno[3,2-c]quinoline-7-carbonitrile (1.0 eq, 110 mg) was added to the mixture and the whole reaction was stirred at 100° C. for two days. Water was added and the solid was filtered and dried. 4-phenoxythieno[3,2-c]quinoline-7-carbonitrile was isolated as a solid (114 mg). LCMS (ES)>95% pure, m/z 303 [M+1]+.
Reaction SMILES: N1C=CC=CC=1.[S:7]([NH:11][C:12]([NH2:14])=[O:13])([CH3:10])(=[O:9])=[O:8].[C:15](Cl)([Cl:17])=[O:16]>ClCCl>[S:7]([NH:11][C:12]([NH:14][C:15]([Cl:17])=[O:16])=[O:13])([CH3:10])(=[O:9])=[O:8]
Reactant: O=C(Cl)Cl
Reactant: CS(=O)(=O)NC(N)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)NC(=O)Cl

Procedure:
6.1 parts by volume of pyridine were added dropwise, while cooling, to a mixture of 10.5 parts by weight of N-mesylurea, 60 parts by volume of dichloromethane and 15.0 parts by weight of phosgene, while cooling, and after some hours at 0°C the excess of the phosgene was removed, the precipitate present was filtered off and the filtrate was completely concentrated in vacuo. A viscous oil remained, which had an absorption at 1800 cm-1 in the carbonyl region of the IR-spectrum. The substance was used without further purification for the production of the penicillin.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([CH3:32])[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[C:14]1[C:15]([CH3:31])=[N:16][N:17]2[C:22](=O)[C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:20]([CH3:30])[NH:19][C:18]=12.C(=O)(O)[O-].[Na+]>>[Cl:3][C:22]1[N:17]2[N:16]=[C:15]([CH3:31])[C:14]([C:7]3[C:8]([CH3:13])=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=3[CH3:32])=[C:18]2[N:19]=[C:20]([CH3:30])[C:21]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)Cc1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1Cl
Reaction time: 1 h
Yield: 103.2 %

Procedure:
Phosphorus oxychloride (1.7 g) was added to ethyl 2-(3-mesityl-2,5-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)acetate (120 mg) of Reference Example 27 at room temperature, followed by stirring for one hour under heating under reflux. After cooling, the reaction solution was poured onto ice. The reaction mixture was basified with an aqueous saturated solution of sodium bicarbonate, and then extracted twice with ethylacetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (130 mg) as a reddish brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12](=[O:18])[NH:13][C:14](=O)[CH2:15]Cl>CN(P(N(C)C)(N(C)C)=O)C>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:15]=[C:14]([NH:13][C:12]([O:11][CH3:10])=[O:18])[N:1]=2)[CH:4]=1
Reactant: CSc1ccc(N)nc1
Reactant: COC(=O)NC(=O)CCl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)Nc1cn2cc(SC)ccc2n1
Temperature: 100 °C

Procedure:
A suspension of 2-amino-5-(methylthio)pyridine (0.667 mol) and methyl(chloroacetyl)carbamate (0.667 mol) in 325 ml of HMPT is heated at 100° C. for 5 hours. After dilution with 2000 ml of H2O, the product is collected by filtration, successively washed with H2O, MeOH and CH2Cl2, and dried.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[CH:4][N:3]=1.[CH3:20][O-].[Na+].IC>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH3:20])[CH:18]=2)=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Nc1ncc(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: Cn1cc(-c2cnc(N)nc2-c2ccco2)ccc1=O
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
To a suspension of 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (2.2 g, 8.65 mmol) in methanol (44 ml) was added sodium methoxide (940 mg, 17.4 mmol) at room temperature under an atmosphere of nitrogen gas, followed by stirring. After 15 minutes, iodomethane (1.6 ml, 25.7 mmol) was added thereto, followed by stirring as it was for 22 hours. After concentrating the reaction mixture, water was added to the residue. Then, the precipitates were collected by filtration and washed with water, to give the crude crystals of the title compound (1.98 g). The crude crystals were suspended in ethanol, and then the precipitates were collected by filtration and washed with ethanol, to give the title compound (1.54 g, 66%) as a pale yellow solid.
Reaction SMILES: [F:1][CH:2]([F:30])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]([O:27]CC)=[O:26])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.Cl>O1CCCC1.O>[F:30][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Reaction time: 3 h

Procedure:
Ethyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (IV-1, 13.3 g) is dissolved in tetrahydrofuran (80 ml). LiOH monohydrate (1.86 g) dissolved in water (20 ml) is then added. After 3 hours, water is added, the pH is adjusted to 2-3 with dilute hydrochloric acid (1M), the mixture is then extracted with ethyl acetate and the combined organic phases are dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. This gives 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (11.7 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[H-].[Na+].[N+]([C:15]1[CH:16]=[C:17]([CH3:22])[N+:18]([O-:21])=[CH:19][CH:20]=1)([O-])=O>CN1CCCC1=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[CH:19][N+:18]([O-:21])=[C:17]([CH3:22])[CH:16]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: Oc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(Br)cc2F)cc[n+]1[O-]
Temperature: 180 °C
Yield: 46.6 %

Procedure:
To a room temperature solution of 4-bromo-2-fluorophenol (3.44 ml, 31.41 mmol) in N-methylpyrrolidone (20 ml) was added sodium hydride (1.34 g, 56 mmol, 60% in mineral oil) portionwise. After stirring for 20 minutes 4-nitro-2-picoline N-oxide (5.6 g, 36.12 mmol) was added The reaction mixture was heated at 180° C. for 60 minutes under microwave irradiation. After cooling to room temperature the mixture was diluted with EtOAc (250 ml) and washed with water (250 ml). The solution was then extracted with additional EtOAc (2×150 ml). The combined organic extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM to DCM/MeOH(NH3) up to 2% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 15 (4.36 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].O[N:12]=[C:13]([NH2:15])[CH3:14]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:4]2[O:5][N:15]=[C:13]([CH3:14])[N:12]=2)=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: CC(N)=NO
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: c1ccncc1
Product: Cc1noc(-c2cccnc2Cl)n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 2-chloro nicotinoyl chloride (1.0 eq.) and N′-hydroxy ethanimidamide (1.1 eq) in pyridine (0.6 M) was stirred at 100° C. for 4 h and then concentrated. The residue was purified by flash chromatography (Hexane:EtOAc, 70:30) to afforded the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[NH2:14].C(O)(=O)C>O1CCOCC1>[Br:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: Cc1cc(N)cc(Br)c1
Reactant: COc1ccnc(Cl)n1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1ccnc(Nc2cc(C)cc(Br)c2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A 10-20 mL microwave vial was charged with 2-chloro-4-methoxypyrimidine (0.835 g, 5.78 mmol), 3-bromo-5-methylaniline (1.075 g, 5.78 mmol), acetic acid (0.347 mL, 6.06 mmol) and dioxane (11.55 mL). The system was purged and flushed with Ar(g) three times before sealing and heating to 120° C. for 3 hours. The mixture was cooled and stirred overnight. The light brown solids were collected by filtration and were dried in a vacuum oven overnight to yield N-(3-bromo-5-methylphenyl)-4-methoxypyrimidin-2-amine (1.7 g, 5.78 mmol, 100% yield) as a tan solid. MS ESI: [M+H]+ m/z 296.0.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1[nH]c(=O)ccc1C#N
Product: Cc1nc(Cl)ccc1C#N

Procedure:
A mixture of 2-Methyl-6-oxo-1,6-dihydro-pyridine-3-carbonitrile (44 g) and POCl3 (250 ml) was refluxed for 3 h. The reaction mixture was dried down in vacuum and ice followed by conc. aqueous ammonia (300 ml) was added. The aqueous layer was extracted with EtOAc. The organic layer was separated, dried and concentrated in vacuum affording the title compound (23.5 g, BP (18 mbar) 119-120° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl[Si](C)(C)[CH3:15]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:12])[C:10]=1[OH:11])[C:5]([O:7][CH3:15])=[O:6]
Reactant: O=C(O)c1cc(O)c(O)c(Cl)c1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1cc(O)c(O)c(Cl)c1
Yield: 81.6 %

Procedure:
A solution of 3-chloro-4,5-dihydroxybenzoic acid (2) (3.16 g, 16.76 mmol) and chlorotrimethylsilane (6.36 mL, 50.3 mmol) in MeOH (50 mL) was stirred at 50° C., under nitrogen overnight. The solvent was removed in vacuo and the residue was partitioned between brine (75 mL) and EtOAc (75 mL). The organic layer was washed with brine (75 mL), dried over MgSO4 and filtered. The solvent was removed in vacuo to give methyl 3-chloro-4,5-dihydroxybenzoate (3) (3.26 g, 13.68 mmol, 82% yield): m/z 201 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 10.17 (2H, br s), 7.38 (1H, d), 7.35 (1H, d), 3.78 (3H, s).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N:7]1[C:16]1[N:17]=[C:18](N)[CH:19]=[C:20]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[C:21]=12.N([O-])=[O:37].[Na+].N>O>[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][N:7]1[C:16]1[N:17]=[C:18]([OH:37])[CH:19]=[C:20]2[C:24]([CH3:25])=[C:23]([CH3:26])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[C:21]=12
Reactant: O=N[O-]
Reactant: Cc1c(C)n(Cc2cccc(F)c2)c2c(N3CCc4ccccc4C3)nc(N)cc12
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1c(C)n(Cc2cccc(F)c2)c2c(N3CCc4ccccc4C3)nc(O)cc12
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
The compound prepared in Example 847 was treated with a saturated sodium bicarbonate solution to obtain 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-amine. Concentrated sulfuric acid (1 ml) and water (5 ml) were added to 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-amine (50 mg, 0.13 mmol) and then sodium nitrite (43.1 mg, 0.63 mmol) was added thereto. The reaction mixture was stirred for 5 minutes at 100° C. under heating and then excess ammonia solution was added thereto. The reaction mixture was stirred for 2 minutes under heating at the same temperature and then filtered to discard insoluble matertals. A potassium hydroxide solution was added to the reaction mixture, which was then filtered to discard insoluble matertals. The reaction mixture was extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give 28.4 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]3[C:21]([NH2:26])=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].O>C1COCC1>[CH:1]1([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[NH:26][C:27]3=[O:28])[CH2:17][CH2:18]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: Nc1ccccc1NC1CCN(C2CC3CCCc4cccc2c43)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2n1C1CCN(C2CC3CCCc4cccc2c43)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
N-[1-(1,2,2a,3,4,5-Hexahydroacenaphthylen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (1.15 g) was dissolved in THF (70 ml), 1,1′-carbonyldiimidazole (0.591 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.76 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH:11]=[C:10]([CH2:13]O)[C:9]3[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[BrH:20]>>[Br:20][CH2:13][C:10]1[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[O:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:12]=2[CH:11]=1
Reactant: OCC1=Cc2c(Cl)cccc2Oc2ccccc21
Reactant: Br
Solvent: O
Product: Clc1cccc2c1C=C(CBr)c1ccccc1O2
Yield: 38.7 %

Procedure:
4.58 g (17.70 mmol) of (1-chlorodibenz[b,f]oxepin-10-yl)-methanol are heated under reflux in 50 ml of 48% hydrobromic acid for 2 hours. The mixture is cooled, water is added and the mixture is extracted 3× with ethyl acetate. The organic phases are washed with brine, dried over sodium sulfate and concentrated. 5.57 g of crude product are obtained which becomes solid on being left to stand (3 days). Recrystallisation from tert-butyl methyl ether/hexane yields 2.205 g (6.86 mmol)=38.7% of 10-bromomethyl-1-chloro-dibenz[b,f]oxepine in the form of light-beige crystals; TLC (silica gel; ethyl acetate; UV): Rf =0.73; 1H-NMR (CDCl3, 200 MHz): 4.60 (s, 2H); 7.15-7.58 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[C:31](=[O:32])[C:30]([CH3:34])([CH3:33])[NH:29][C:28]1=[O:35]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[C:30]([CH3:34])([CH3:33])[C:31](=[O:32])[N:27]([CH3:26])[C:28]4=[O:35])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CN1C(=O)NC(C)(C)C1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4(C)C)cc3F)CC2)c(C)c1
Yield: 4.3 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (163 mg) described in Preparation Example 211 and 3,5,5-trimethylimidazolidine-2,4-dione (63 mg) described in Preparation Example 218 and by the reaction and treatment in the same manner as in Example 536, the title compound (8 mg) was obtained.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]([CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:20]1>N1C=CC=CC=1.CN(C)C=O>[CH2:30]([N:29]([CH2:28][CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]([C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH2:20]1)[CH2:32][CH3:33])[CH3:31]
Reactant: CCN(CC)CC1CNc2ccccc21
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCN(CC)CC1CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c2ccccc21
Yield: 44.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 150 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 238 mg of (2,3-dihydro-1H-indol-3-ylmethyl)diethylamine and 140 mg of N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride in a mixture of 0.1 ml of pyridine and 3 ml of N,N-dimethylformamide. 108 mg of 2-(2-{3-[(diethylamino)methyl]-2,3-dihydro-1H-indol-1-yl}-2-oxoethyl)-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a cream solid, the characteristics of which are the following:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:7][O:8][C:9]=1[CH3:10])=[O:4].CCN=C=NCCCN(C)C.[NH2:29][C:30]1[CH:31]=[C:32]([CH2:36][C:37]([NH:39][C:40]2[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=2)=[O:38])[CH:33]=[CH:34][CH:35]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:47][O:46][C:44]1[CH:45]=[C:40]([NH:39][C:37](=[O:38])[CH2:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([NH:29][C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[F:17])=[N:7][O:8][C:9]=3[CH3:10])=[O:4])[CH:31]=2)[CH:41]=[C:42]([O:50][CH3:51])[C:43]=1[O:48][CH3:49]
Reactant: COc1cc(NC(=O)Cc2cccc(N)c2)cc(OC)c1OC
Reactant: COC(=O)c1c(-c2ccccc2F)noc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)Cc2cccc(NC(=O)c3c(-c4ccccc4F)noc3C)c2)cc(OC)c1OC
Reaction time: 6 h
Yield: 61.3 %

Procedure:
To a solution of 4-methoxycarbonyl-5-methyl-3-(2-fluorophenyl)isoxazole (1.00 g, 4.52 mmol) in CH2Cl2 (30 ml) was added EDCI (1.51 g, 9.04 mmol), DMAP (0.11 g, 0.90 mmol), and 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (1.70 g, 5.42 mmol). The reaction was allowed to stir for 6 h then applied to a silica gal column eluting first CH2Cl2 with followed by 10% acetone in CH2Cl2 to give the title compound (1.44 g, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34](OCC1C=CC=CC=1)=[O:35].CC(C)([O-])C.[K+]>C1COCC1>[CH2:27]([O:26][C:24]([C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[C:13](=[CH:12][C:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[CH:23][CH:22]=3)[CH:14]([CH:34]=[O:35])[C:15]=2[CH:16]=1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=COCc1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc2c(c1)Cc1cc(C(=O)OCc3ccccc3)ccc1-2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=CC1c2cc(C(=O)OCc3ccccc3)ccc2-c2ccc(C(=O)OCc3ccccc3)cc21
Reaction time: 3 h

Procedure:
In a dry argon-purged flask, 2,7-fluorenedicarboxylic acid dibenzyl ester (3.0 g, 0.0065 mol) was dissolved in anh. THF (60 mL) at room temperature. Benzyl formate (4.2 mL, 0.035 mol, stored over anhydrous K2CO3) was added followed by addition of potassium tert-butoxide 95% (2.7 g, 0.023 mol). The reaction was stirred for three hours then the reaction was quenched with the addition of water and acidified with HCl to pH 2. The organic solvent was partially evaporated at reduced pressure. The product was twice extracted with ethyl acetate (600 mL then 200 mL). The combined organic layers were washed three times with brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was washed with hexanes and methanol (1.9 g, 60%). 1H-NMR (d6-DMSO): δ (ppm) 11.9 (s, ˜1H, formyl); 8.8 (s, 1H, Ar); 8.5 (s, 1H, Ar); 8.4 (s, 1H, Ar); 8.2 (m, 2H, Ar); 7.9 (m, 2H, Ar); 7.5-7.4 (m, 10H, Bz); 5.4 (s, 4H, Ar).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[C:15]([F:23])=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].C(N(CC)CC)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl>[Br:13][C:14]1[C:15]([F:23])=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([N:33]([O:34][CH3:35])[CH3:32])=[O:18]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
Carbonyldiimidazole (7.76 g) was added portionwise to commercially available 3-bromo-2-fluorobenzoic acid [161957-56-8] (9.53 g) in dichloromethane (100 mL) over 30 min. The mixture was then heated at reflux for 30 min (until gas evolution ceased). The reaction was then cooled to room temperature and triethylamine (6.37 mL) followed by N,O-dimethylhydroxylamine hydrochloride (4.7 g) were added. The reaction was left to stir at room temperature for 16 h before being washed with 10% citric acid (2×100 mL) and sat. NaHCO3 (2×100 mL), and then dried over sodium sulfate. The solvent was removed by evaporation to yield the product as a brown oil (10.89 g, 95%). NMR (CDCl3): 3.20-3.80 (6H, m, ArCONCH3OCH3), 7.10 (1H, t, Ar), 7.35 (1H, td, Ar), 7.60 (1H, dt, Ar).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccsc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 3-thiopheneboronic acid according to the general procedure B. Obtained as a yellow solid (326 mg).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.[CH:30](=[O:32])[CH3:31]>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([CH:30]([OH:32])[CH3:31])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C(C)O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, acetaldehyde was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 7.06(s,2H), 4.84(m,1H), 6.08(s,1H), 3.73(d,1H), 3.35(m,1H), 2.14(s,3H), 2.12(s,3H), 2.11 (s,6H), 1.4-1.7(m,4H), 1.51 (d,3H), 0.96(t,6H) ppm.