Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@@H:8]([CH3:11])[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[C:14]([F:21])([F:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C1COCC1.[Zn]>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH3:11])[C@@H:9]([OH:10])[C:14]([F:21])([F:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(F)(F)Br
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)[C@H](O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 44 %

Procedure:
tert-Butyl[(1S)-1-methyl-2-oxoethyl]carbamate (7.21 g) and ethyl bromodifluoroacetate (25.1 g) were dissolved in THF (65 mL), and the solution was added dropwise to a suspension of zinc powder (25.1 g) in THF (14 mL) at room temperature over 30 min. The suspension was heated under reflux for 30 min and cooled to 0° C. A 1 mol/L aqueous hydrochloric acid solution (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The extracted organic layer was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10→3/10) to give the title compound as a pale-yellow oil (yield: 5.45 g, 44%).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:35]#[N:36])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:34]=[CH:33][C:23]3[N:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[S:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+].CO>>[C:35]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:34]=[CH:33][C:23]4[N:24]=[C:25]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[S:26][C:22]=4[CH:21]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:37][CH2:38][C:39]([OH:41])=[O:40])=[O:7])[N:9]=1)#[N:36]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4nc(N5CCOCC5)sc4c3)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Oc3ccc4nc(N5CCOCC5)sc4c3)ccc12
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of 1-cyano-4-hydroxy-6-(2-morpholin-4-yl-benzothiazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester (137 mg, 0.27 mmol), glycine (408 mg, 5.43 mmol) and 0.5 M sodium methoxide/methanol (10.3 mL) was refluxed for twenty-six hours before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (40 mL) and extracted with dichloromethane (2×35 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (7.5 mL). The white precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (119 mg): MS: (+) m/z 506.26 (M+1); (−) m/z 504.24 (M−1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]=2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)=[CH:6][CH:5]=1.[C:34](O)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[N:29]1([CH2:28][CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C:11]3[C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[S:14][C:10]=3[C:7]3[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:34]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)=[O:41])=[CH:5][CH:6]=3)=[CH:25][CH:24]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reactant: O=C(O)c1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NCCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 33 %

Procedure:
A solution of 2-[4-(2-aminoethyl)phenyl]-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (111 mg) in dichloromethane (3.0 mL) was treated isonicotinic acid (35 mg) and DCC (50 mg) sequentially and allowed to stir at ambient temperature for 25 h. The reaction mixture was then concentrated and fractionated by column chromatography with Et3N:MeOH:EtOAc (5:10:85) to afford the product (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:20]C(=O)C)[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[OH-].[Na+]>CO.O>[NH2:20][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([S:8][C:9]2[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[C:12](=[O:18])[NH:11][N:10]=2)=[C:6]([Cl:19])[CH:5]=1
Reactant: CC(=O)Nc1cc(Cl)c(Sc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1cc(Sc2c(Cl)cc(N)cc2Cl)n[nH]c1=O
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of N-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-acetamide (84) (4.0 g, 10.7 mmol) in methanol (15 mL) and water (15 mL) was treated with powdered sodium hydroxide (2.14 g, 53.5 mmol). The reaction was then heated to reflux for 18 h. At this time, the reaction was cooled to 25° C., diluted with water (500 mL) and extracted with ethyl acetate (3×300 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried with magnesium sulfate, filtered and concentrated under vacuum to afford 6-(4-amino-2,6-dichloro-phenylsulfanyl)-4-isopropyl-2H-pyridazin-3-one (85) (3.5 g, 99%) as a light tan solid. The material was used without further purification; ES(+)-HRMS m/e calcd for C13H13Cl2N3OS (M+H)+ 330.0229, found 330.0229. Exact Mass=329.0156; Molecular weight=330.24
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1([C:12]2[C:21]3[O:20][CH2:19][CH2:18][O:17][C:16]=3[C:15]([O:22][CH3:23])=[CH:14][CH:13]=2)[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)#[N:4].[OH2:24]>C1COCC1>[C:3]([C:5]1([C:12]2[C:21]3[O:20][CH2:19][CH2:18][O:17][C:16]=3[C:15]([O:22][CH3:23])=[CH:14][CH:13]=2)[CH2:6][CH2:7][C:8](=[CH:15][C:16]([O:17][CH2:18][CH3:19])=[O:24])[CH2:9][CH2:10]1)#[N:4]
Reactant: O
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)c2c1OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCC(C#N)(c2ccc(OC)c3c2OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of triethyl phosphonoacetate (0.72 mL, 3.6 mmol) in THF (9.4 mL) was added 60% sodium hydride (0.15 g, 3.6 mmol) under ice-cooling. The mixture was stirred at room temperature for 15 minutes, Compound 1 (0.94 g, 3.3 mmol) obtained in Example 1 was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, water was added under ice-cooling, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=2/1) to give Compound 10 (1.4 g, 97%) as a white solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(=O)(O)(O)O.C1(N=C=NC2CCCCC2)CCCCC1>CS(C)=O.C(Cl)Cl.O>[CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h
Yield: 68 %

Procedure:
7.17 g (0.03 mole) of 1-benzhydryl-3-hydroxyazetidine were dissolved in a mixture of 35 ml of dimethyl sulfoxide and 20 ml of methylene chloride. 1 ml of pyridine, 0.5 ml of phosphoric acid and then 12.5 g (0.06 mole) of 1,3-dicyclohexylcarbodiimide were added, in turn, to the resulting solution. The reaction mixture was then stirred for 2 hours, after which water was added to it. The reaction mixture was then extracted twice, each time with 200 ml of chloroform. The combined extracts were dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The concentrate was subjected to silica gel column chromatography, and 4.84 g (67%) of 1-benzhydryl-3-oxoazetidine were obtained from the fractions eluted with a 9:1 by volume mixture of toluene and ethyl acetate.
Reaction SMILES: [NH2:1][C:2]([C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)=[O:3].CN(C(ON1N=NC2[CH:21]=[CH:22][CH:23]=[N:24][C:19]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:24]1([C:7]([C:4]2([C:2]([NH2:1])=[O:3])[CH2:6][CH2:5]2)=[O:9])[CH2:23][CH2:22][CH2:21][CH2:19]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: NC(=O)C1(C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCNC1
Product: NC(=O)C1(C(=O)N2CCCC2)CC1
Reaction time: 0.5 h

Procedure:
To 1-(aminocarbonyl)-1-cyclopropane carboxylic acid (Aldrich; 25 g, 193.6 mmol) in DCM (625 mL) was added HATU (73.61 g, 193.6 mmol) and the suspension stirred for 30 minutes. Pyrrolidine (Aldrich; 24.25 mL) and Hunig's base (67 mL) was added and the reaction stirred at room temperature over the weekend.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[CH:8]=[C:7]1[C:16]([OH:18])=[O:17].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[CH:8]=[C:7]1[C:16]([O:18][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17]
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2c1cc(C(=O)O)n2Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCc2c1cc(C(=O)OCc1ccccc1)n2Cc1ccc(Cl)c(Cl)c1
Yield: 97.5 %

Procedure:
1-(3,4-Dichlorobenzyl)-4-oxo-4,5,6,7-tetrahydroindole-2-carboxylic acid (1.32 g) and benzyl bromide (0.68 g) was stirred in DMF (10 mL) over potassium carbonate (0.48 g) for 18 hours. The DMF was removed in vacuo and the residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with 2M HCl and dried over MgSO4. The solvents were removed in vacuo to afford the title compound as a pale solid (1.63 g, 97%), NMR d(CDCl3) 2.20 (2H, di), 2.50 (2H, t), 2.70 (2H, t), 5.21 (2H, m), 5.55 (2H, s), 6.80 (1H, d), 7.10 (1H,s), 7.35(6H, s), 7.50(1H, s); M/z(+)430, 428 (M+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:7][CH:6]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([CH:34]=1)[C:31](Cl)=[O:32]>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([CH:34]=1)[C:31]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9][CH:10]=1)=[O:32]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)CCCCCCCCCc1ccc(CCN)cc1
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(CCCCCCCCCC(=O)O)cc1

Procedure:
By the reaction of ethyl 9-[4-(2-aminoethyl)-phenyl]-nonane-carboxylate hydrochloride (m.p. 135°-138° C.) with 5-chloro-2-methoxybenzoyl chloride, there is obtained 9-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-nonane-carboxylic acid; m.p. 97°-100° C., after recrystallization from ethyl acetate.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13].[CH2:14](S([O-])=O)C.[Na+]>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH3:14])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13]
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: CCS(=O)[O-]
Agent: [Na+]
Product: CCS(=O)(=O)c1ccc(CBr)c(Cl)c1

Procedure:
The titled compound is prepared analogously to 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene by replacing sodium methanesulfinate with sodium ethanesulfinate.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH2:25][CH2:26][CH3:27]>O>[CH2:24]([N:11]1[CH2:12][CH2:13][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])([OH:14])[CH2:10]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCBr
Reactant: OC1(c2cccc(F)c2F)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCN1CCC(O)(c2cccc(F)c2F)C1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
In a sealed tube a mixture of enantiomer E2 of 3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.5 g, 2.5 mmol), acetonitrile (20 mL), potassium carbonate (0.69 g, 5 mmol) and n-butylbromide (0.25 mL, 2.6 mmol) was stirred at ambient temperature for 30 min after which an additional amount of n-butylbromide (0.12 mL, 1.25 mmol) was added and the mixture was stirred for 1 h. Water was added and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:1) gave the title compound (0.35 g). [α]D=−26° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 155.3° C.; MS m/z (relative intensity, 70 eV) 255 (M+, 8), 182 (30), 98 (25), 57 (16), 212 (bp).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Reaction time: 144 h
Yield: 107.8 %

Procedure:
2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (1.246 g) was dissolved in methanol (20 ml)-tetrahydrofuran (10 ml), and then 10% palladium carbon (1.0 g) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring for 6 days. After replacing with nitrogen inside the system, the catalyst was filtered and washed with ethanol. The filtrate was concentrated under a reduced pressure to provide the titled compound (1.182 g, quantitative) as brown crystals.
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[OH:15])[C:9]([OH:11])=[O:10].[C:16](Cl)(=[O:18])[CH3:17]>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.ClCCl>[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[C:9]([OH:11])=[O:10]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc(O)c(F)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=[N+]([O-])O
Product: CC(=O)Oc1ccc(C(=O)O)cc1F
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a solution of 2′-hydroxy-5′-bromoacetophonone (10 g, 46.5 mmol) in carbon tetrachloride (60 mL) at reflux was added 70% nitric acid (5.2 mL, 79.6 mmol). The reaction mixture was stirred at reflux for 40 min. and then cooled to rt. The resulting solid was filtered off and washed with water and hexanes to provide 2′-hydroxy-3′-nitro-5′-bromoacetophonone (10.19 g, 84%). To a solution of 3-fluoro-4-hydroxybenzoic acid (3.0 g, 19.2 mmol) in pyridine (20 mL) and dichloromethane (50 mL) was added acetyl chloride (1.8 mL, 25 mmol) and the reaction mixture was stirred at rt for 1 h. The reaction mixture was washed with HCl (1 N, 2×100 mL), and concentrated to afford 3-fluoro-4-acetoxybenzoic acid (3.18 g, 83%). To a solution of 3-fluoro-4-acetoxybenzoic acid (3.18 g, 16.1 mmol) in dichloromethane (100 mL) was added oxalyl chloride (2.1 mL, 24.0 mmol) and DMF (0.2 mL) sequentially. The resulting mixture was stirred at rt for 1 h and then concentrated to afford the corresponding acid chloride. A mixture of the acid chloride, 2′-hydroxy-3′-nitro-5′-bromoacetophonone (4.17 g, 16.1 mmol) and triethylamine (8.9 mL, 64.2 mmol) in dichloromethane (100 mL) was stirred at rt for 1 h and then concentrated. The residue was re-dissolved in THF (100 mL) and mixed with potassium tert-butoxide (4.0 g, 35.3 mmol). The reaction was stirred at rt for 16 h and then quenched by adding water (100 mL). The mixture was extracted with dichloromethane (3×100 mL) and concentration to afford the crude diketone as a yellow solid. This solid was re-dissolved in AcOH (100 mL) and HCl (conc., 5 mL) and the mixture was stirred at reflux for 20 h. The reaction was quenched with water (100 mL), extracted with dichloromethane (3×100 mL) and concentrated. A solution of the resulting residue in MeOH (50 mL) and water (50 mL) was mixed with potassium carbonate (2 g) and stirred at rt for 2 h. MeOH was removed and the aqueous layer was acidified with HCl (1 N) to pH=5. The solid was filtered off and washed with water, acetone, and dichloromethane sequentially to provide a solid of the flavone analog (1.85 g, 30% five steps combined). To a solution of the flavone analog (1.85 g, 4.87 mmol) in pyridine (50 mL) and dichloromethane (100 mL) at rt was added acetyl chloride (1.1 mL, 14.6 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was washed with HCl (1 N, 2×100 mL), and concentrated to afford a solid residue, which was purified by column chromatography (hexane:EtOAc 2:1). The resulting solid was re-crystallized from EtOAc and hexanes to afford 4-(6-bromo-8-nitro-4-oxo-4H-chromen-2-yl)-2-fluorophenyl acetate (1.1 g, 54%) as a light yellow solid. MS (ES) m/z: 423.78, 421.77; Mp. 236.2-238.5° C.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1.[C:15]1([C:21]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:22]2[CH:26]=[C:25]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[N:24]=[CH:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:28]([C:27]([C:2]1[C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1)([C:25]1[N:24]=[CH:23][N:22]([C:21]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:26]=1)[OH:32])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC1(C)OCc2cc(Cl)cc(Br)c2O1
Product: CCCCC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cc(Cl)cc2c1OC(C)(C)OC2
Yield: 54.6 %

Procedure:
This compound is prepared like the preceding compound by reacting the organomagnesium compound of 8-bromo-6-chloro-2,2-dimethyl-4H-1,3-benzodioxin with 1-(1-triphenylmethyl-1H-imidazol-4-yl)-1-pentanone. Yield: 54.6% of theory; M.P.: 124° C. (recrystallized from petroleum ether).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:20]([CH3:24])[C:21](=[O:23])[CH3:22].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[Br:11][C:9]1[C:8](=[O:12])[N:7]([CH:20]([C:21](=[O:23])[CH3:22])[CH3:24])[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=1
Reactant: COC(=O)c1c[nH]c(=O)c(Br)c1
Reactant: CC(=O)C(C)Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)c(=O)n(C(C)C(C)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl-5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (10.0 g, 43.1 mmol) and cesium carbonate (16.9 g, 51.7 mmol) in N,N-dimethylformamide (144 mL) was added 3-bromo-2-butanone (7.8 g, 51.7 mmol). The reaction mixture was stirred at ambient temperature. After 20 min, saturated aqueous sodium bicarbonate and water were added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→50% dichloromethane/ethyl acetate) gave the title compound. MS 302.1 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[CH2:30]([N:32]([CH2:43][CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:31]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:40][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH2:34][CH2:33][N:32]([CH2:43][CH3:44])[CH2:30][CH3:31])=[CH:42][CH:41]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1ccc(Cl)cc1Cl)C2
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(c2ccccc2)C(=O)N(c2ccc(Cl)cc2Cl)C3)cc1
Temperature: 180 °C
Yield: 8 %

Procedure:
A mixture of 300 mg (0.65 mmol) of 3-(2,4-dichlorophenyl)-3,4-dihydro-7-methanesulfonyl-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one and 400 mg (1.9 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 30 minutes. The mixture was cooled and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to afford 30 mg (8%) of 3-(2,4-dichlorophenyl)-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 106-108° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:8].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([O:27][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)=[CH:4][C:5]([F:18])=[C:6]([CH:17]=1)[C:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[O:8]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4-methylphenyl 5-chloro-2,4-difluorobenzoate (Preparation 10, 39.0 g, 137.97 mmol) and 4-chloro-3-(trifluoromethyl)phenol (27.12 g, 137.97 mmol) in DMSO (197 mL) was added potassium carbonate (47.67 g, 344.92 mmol) portion wise maintaining the internal at 15-25° C. with a cold water jacket. The reaction mixture was stirred at room temperature for 2 hours, cold water charged and the resulting slurry stirred for 20 minutes. The mixture was filtered, washed with water and dried to give the title compound as a pale yellow solid (56.4 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH2:11])[CH2:8][CH2:7][C:5]=2[N:6]=1.[CH:12](=O)[CH2:13][CH2:14][CH3:15].[BH4-].[Na+].[ClH:19]>CN(C)C=O.O>[ClH:19].[ClH:19].[NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Nc1nc2c(s1)CC(N)CC2
Reactant: CCCC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC1CCc2nc(N)sc2C1
Temperature: 50 °C

Procedure:
To a solution of 3.4 g (0.02 Mol) of 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole in 34 ml of dimethylformamide are added 1.8 g (0.022 Mol) of n- butanal and the mixture is heated to 50° C. for 1 hour. After cooling, the reaction solution is mixed with 0.8 g (0.02 Mol) of sodium borohydride and heated to 50° C. for 30 minutes. The solvent is largely eliminated in vacuo. Whilst cooling with ice, the residue is mixed with 20 ml of water and 2N hydrochloric acid until a pH of 1 is obtained. The aqueous solution is extracted with ethylacetate and the organic phase discarded. The aqueous phase is mixed with potassium carbonate until an alkaline reaction is obtained and then extracted with ethyl acetate. The organic phase is dried and concentrated. The compound crystallizes out when ethereal hydrochloric acid is added.