Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([OH:25])=O)[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1.[CH2:31]([N:33](CC)CC)C.C(Cl)CCl>C(#N)C.Cl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:33][CH3:31])=[O:25])[C:14]3=[O:29])[CH:10]=[N:9]2)=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C(=O)O)c3)C2=O)cn1
Agent: Cl
Solvent: ClCCCl
Solvent: CC#N
Product: CNC(=O)c1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 24.7 %

Procedure:
3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acid (100 mg, 0.24 mmol) (example 10-8), methylamaine hydrochloride (67 mg, 1 mmol), triethylamine (155 mg, 1.5 mmol), and EDC (57 mg, 0.3 mmol) in acetonitrile (3 mL) were irradiated in the microwave reactor at 80° C. for 10 minutes. The reaction was cooled, diluted with aqueous 1N HCl (100 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in MeOH (3 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 25 minute gradient) to afford 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)-N-methylbenzamide (25 mg, 25%) as white solid. MS M+H calculated 423.17; found 423.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][CH2:40][O:41][CH3:42]>CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:31][CH2:39][CH2:40][O:41][CH3:42])=[CH:28][CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(O)ccc34)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
1-(5-tert-Butylisoxazol-3-yl)-3-(3-(7-hydroxyquinazolin-4-yloxy)phenyl)urea (126 mg, 0.3 mmol) was treated with cesium carbonate (117 mg, 0.36 mmol) in anhydrous N,N′-dimethylformamide (3 mL) and stirred at room temperature for 30 minutes. 2-Bromoethylmethyl ether (50 mg, 0.36 mmol) was added and the mixture was stirred at 50° C. overnight. Cesium carbonate was filtered off and the residue purified by preparative HPLC (phenylhexyl reverse phase column) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (21.16 mg, 15%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (bs, 1H), 9.00 (bs, 1H), 8.65 (s, 1H), 8.27 (d, 1H), 7.57 (s, 1H), 7.41-7.38 (m, 3H), 7.28 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 4.34 (bs, 2H), 3.76 (bs, 2H), 3.35 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 478 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].O1CCOCC1>ClCCl.C(OC(C)C)(C)C>[ClH:24].[F:23][C:20]1[CH:21]=[CH:22][C:17]2[O:16][N:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:18]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3ccc(F)cc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: Fc1ccc2onc(N3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (22.7 g, 70.6 mmol) was dissolved in 40 ml dichloromethane and 4N HCl in dioxane (264 ml, 1.06 mol) was added. The white suspension was stirred for 16 hours at room temperature, diluted with diisopropylether and filtered. The crystals were washed with diisopropylether and dried for 1 hour at 50° C. and <20 mbar, to get the desired salt as a white solid (18.2 g, quant.) [MS: m/e=222.3 (M+H+)].
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:10]=[C:6]2[N:5]([CH2:22][CH3:23])[C:4](=[O:24])[CH:3]=1.[N:25](OCCC(C)C)=[O:26].O>CN(C)C=O>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:10]=[C:6]2[N:5]([CH2:22][CH3:23])[C:4](=[O:24])[C:3]=1[N:25]=[O:26]
Reactant: CC(C)CCON=O
Reactant: CCn1c(=O)cc(N)n2nc(COCc3ccc(OC)cc3)nc12
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c(N=O)c(N)n2nc(COCc3ccc(OC)cc3)nc12
Temperature: 25 °C

Procedure:
3.7 g of the precursor (7-amino-4-ethyl-2-[(4-methoxybenzyloxy)methyl]-s-triazolo[1,5-a]pyrimidin-5-one) are dissolved in 17 ml of dimethylformamide, and 2.69 ml of isoamyl nitrite are added whilst cooling with ice. Afterwards it is stirred at ambient temperature. After the reaction is complete (about 3 hours) 34 ml of water are added at 5-10° C. The solid obtained is separated off, washed with water and diethyl ether and recrystallised from 80 ml of ethanol. 2.0 g of 7-amino-4-ethyl-2-[(4-methoxybenzyloxy)methyl]-6-nitroso-s-triazolo[1,5-a]pyrimidin-5-one are left.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].Br[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.F[B:15]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=1[CH3:33])[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24]>CCCCCC.C1COCC1>[C:1]1([CH3:4])[CH:3]=[C:30]([CH3:29])[CH:25]=[C:26]([CH3:27])[C:2]=1[B:15]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24])[C:7]1[CH:12]=[CH:11][C:10]([B:15]([C:25]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=2[CH3:33])[C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])=[CH:9][CH:8]=1
Reactant: Brc1ccc(Br)cc1
Reactant: [Li]C(C)(C)C
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(B(c2ccc(B(c3c(C)cc(C)cc3C)c3c(C)cc(C)cc3C)cc2)c2c(C)cc(C)cc2C)c(C)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
25.9 ml (44 mmol) of a 1.7 M solution of tert-butyllithium in n-hexane was added dropwise to a well-stirred solution of 2.36 g (10 mmol) of 1,4-dibromobenzene in 200 ml of absolute THF which had been cooled to −78° C. over a period of 20 minutes at such a rate that the temperature of the reaction mixture did not exceed −65° C. The solution was stirred for another 1 hour at −78° C. and a solution of 6.44 g (24 mmol) of fluorodimesitylborane in 50 ml of absolute THF was then added dropwise over a period of 20 minutes at such a rate that the temperature of the reaction mixture did not exceed −65° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:18])[C:4]([NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)([CH3:6])[CH3:5].[C-:19]#[N:20].[Na+].O.C(Cl)Cl>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[C:19]([CH2:2][C:3](=[O:18])[C:4]([NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)([CH3:6])[CH3:5])#[N:20]
Reactant: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CCl
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CC#N
Yield: 43 %

Procedure:
N-(3'-chloro-1',1'-dimethylacetonyl)-3,5-dichlorobenzamide (30 gm, 0.0972 m), sodium cyanide (15 gm, 0,306 m) and 18-crown-6 (1 gm) were dissolved in 300 ml of acetonitrile in a round bottom flask under a nitrogen atmosphere. The mixture was heated to reflux for about 4 hours. The contents of the flask were then cooled and transferred to a separatory funnel along with 100 ml of water and 500 ml of methylene chloride and mixed well. The aqueous layer was discarded and the organic layer was washed sequentially with water and brine, dried and the solvents stripped off to yield 12.5 gm of the product after recrystallization from methylene chloride and hexane.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[C:10](Br)=[CH:9][C:8]=1[CH3:15].CN([CH:19]=[O:20])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCCC.C1(C)C=CC=CC=1.C1COCC1>[Br:6][C:7]1[C:8]([CH3:15])=[CH:9][C:10]([CH:19]=[O:20])=[C:11]([F:13])[CH:12]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)c(F)cc1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
n-BuLi (5.0 ml, 8.0 mmol, 1.6 M in hexane) was added dropwise to a solution of n-Bu2Mg (8.0 ml, 8.0 mmol, 1.0 M in heptane) at room temperature for 10 minutes. The mixture was stirred at room temperature for 15 minutes and then cooled to −10±2° C. A solution of 2,5-dibromo-4-fluorotoluene (5.466 g, 19.59 mmol) in toluene (30 ml)-THF (6 ml) was added dropwise to this mixed reaction solution over 30 minutes, and the mixture was then stirred at 0° C. for one hour. The reaction mixture was added dropwise to a solution cooled to −10° C. of DMF (2.1 ml, 27 mmol) in toluene (7.6 ml) over 15 minutes. Further, this mixture was stirred at −10 to −5° C. for 30 minutes, and then quenched with an aqueous citric acid solution (2.3 M, 16 ml, 37 mmol) and extracted with Et2O. The organic layer was washed with water, and then dried over MgSO4 and concentrated under reduced pressure to give 4-bromo-2-fluoro-5-methyl-benzaldehyde (3.74 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:2].Cl[S:13]([OH:16])(=O)=[O:14].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:9]([S:13]([N:33]2[CH2:34][CH2:35][N:30]([CH2:28][CH3:29])[CH2:31][CH2:32]2)(=[O:16])=[O:14])=[CH:8][C:5]=1[C:6]#[N:7])[CH3:2]
Reactant: CCOc1ccccc1C#N
Reactant: CCN1CCNCC1
Reactant: O=S(=O)(O)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(S(=O)(=O)N2CCN(CC)CC2)cc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.8 %

Procedure:
Commercially available 2-ethoxybenzonitrile (25 g, 0.17 Mol) was added dropwise to an ice cooled mixture of chlorosulfonic acid (50.8 mL, 0.765 Mol) and thionyl chloride (12.4 mL, 0.17 Mol) so as to keep the temperature below 10° C. The reaction was then stirred at ambient temperature for 18 h before being poured onto ice/water. This mixture was stirred 1 hr before the precipitated material was filtered off. The resultant solid was dissolved in acetone (300 mL) and triethylamine (25 mL, 0.179 Mol) was added followed by a slow addition of N-ethylpiperazine (25 mL, 0.198 Mol). After being left at ambient temperature for 65 h the mixture was evaporated and the residue stirred with water (1 L) for 2 h. The solids were filtered off, washed with water and dried before being chromatographed over silica gel using ethyl acetate methanol mixtures. Combination and evaporation of like fractions yielded 9.8 g, 17.8% of the title compound. Melting point═86–88° C. M/Z=324 (M+H). 300 MHz Proton NMR (CDCl3); 1.06 (t, 3H), 1.55 (t, 3H), 2.43 (q, 2H), 2.54 (m, 4H), 3.06 (m, 4H), 4.25 (q, 2H), 7.08 (d, 1H), 7.90 (dd, 1H), 7.97 (d,1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]2[N:7]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:6]=[C:5]3[C:20]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=4[S:22][C:3]=1[C:4]=23.Br.[Br:30][CH2:31][CH2:32][NH2:33]>CCO>[BrH:30].[CH2:16]([N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][N:7]1[C:8]2[C:9]([O:11][CH3:12])=[CH:10][C:2]([NH:1][CH2:31][CH2:32][NH2:33])=[C:3]3[S:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:20]=4[C:5]([C:4]=23)=[N:6]1)[CH3:17]
Reactant: CCN(CC)CCn1nc2c3c(c(N)cc(OC)c31)Sc1ccc(OC)cc1-2
Reactant: NCCBr
Agent: Br
Solvent: CCO
Product: CCN(CC)CCn1nc2c3c(c(NCCN)cc(OC)c31)Sc1ccc(OC)cc1-2
Yield: 36.3 %

Procedure:
Reaction of a solution of 3.6 g (0.0095 mol) of 5-amino-N,N-diethyl-3,9-dimethoxy-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine and 5.8 g (0.0283 mol) of 2-bromoethylamine, hydrobromide, in 30 ml of EtOH as described in Example 38 gave 1.8 g of product.
Reaction SMILES: [N:1]([CH:4]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][CH2:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[C:10](=[O:23])[CH2:9][CH2:8]1)=[N+:2]=[N-:3].CO.O.[OH-].[K+].Cl>CCOCC>[N:1]([CH:4]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:5][CH2:6][C@@H:7]1[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:10](=[O:23])[CH2:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)N=[N+]=[N-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O)N=[N+]=[N-]

Procedure:
A suspension of 880 mg. of ethyl 15-azido-9-oxoprostanoate (Example 110) in 15 ml. of methanol-water (1:1) containing 360 mg. of potassium hydroxide is stirred at ambient temperature for 18 hours. The resulting solution is acidified with dilute hydrochloric acid and the oily layer is taken up in ether. The ether is washed with saturated sodi sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 797 mg. (98%) of an oil; λmax. 3.0-3.5 broad (acid group), 4.88 (azido group), 5.78 and 5.90 (carbonyl groups).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=O.[Cl:16][CH:17]([Cl:21])[C:18](Cl)=[O:19]>O>[C:1]1([CH:7]2[N:11]([C:18](=[O:19])[CH:17]([Cl:21])[Cl:16])[CH2:10][CH2:9][S:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2NCCS2)cc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(C(Cl)Cl)N1CCSC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Five (5) grams of 2-phenyl thiazolidine was dissolved in 50 ml. of acetone, 3.1 g. of thiethylamine was added and the mixture stirred in a room temperature water bath, while 4.4 g. of dichloroacetyl chloride was added dropwise. The mixture was allowed to stand for about 30 minutes and then poured into water, extracted with methylene chloride, separated, dried over magnesium sulfate, and the solvent stripped under vacuum. There was obtained a yield of 7.3 g. of an oil, the title compound, ND30 =1.5836.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[O:16]=[C:17]1[C:22]2=[CH:23][NH:24][C:25]([CH:26]=O)=[C:21]2[CH2:20][CH2:19][NH:18]1.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:26][C:25]1[NH:24][CH:23]=[C:22]2[C:21]=1[CH2:20][CH2:19][NH:18][C:17]2=[O:16])=[O:4]
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: CN(C)C(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)C(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide (40.8 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 eq.) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: O.[NH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[OH:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)C>[OH:13][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:3]2[NH:2][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c(O)cccc12
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1cccc2c(O)cccc12
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Into a 500 ml round bottom flask (fitted with a magnetic stirrer), a 50:50 mixture of water:ethanol was combined with 5-amino-1-naphthol (20 g, 125 mmole) until the solid was completely dissolved. The solution was warmed to boiling and to it was added acetic anhydride (14 g) and the resulting solution was stirred for 1 hour. Upon cooling, crystals of N-(5-hydroxy1-napthyl)acetamide (21 g, 84% yield) formed.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:21]Br>C(Cl)(Cl)(Cl)Cl>[Br:21][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2
Reactant: BrBr
Reactant: CC(=O)Oc1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc2ncc(Br)cc2c1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
To a mixture of acetic acid quinolin-6-yl ester (120 g, 0.642 mol) and pyridine (114 mL, 1.41 mol) in 6 L of CCl4 was added Br2 (66 mL, 1.28 mol) dropwise. The mixture was heated to reflux for 2 hours before being cooled to room temperature. The liquid in the flask was decanted and washed with saturated aqueous NaHCO3 and water. The dark solid on the bottom of the flask was partitioned between aqueous NaHCO3 and dichloromethane. The combined organic layers were washed with water again and dried before being evaporated to dryness in vacuo. The crude product was purified through flash column chromatography eluting with Petroleum Ether/ethyl acetate (10/1˜1/1) to provide 108 g of acetic acid 3-bromo-quinolin-6-yl ester as a yellow solid (63% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C([C:9](CC)(CC)[C:10]([O-:13])([O-])[O-])C.[NH:18]1[CH2:23][CH2:22]O[CH2:20][CH2:19]1>C(#N)C>[CH3:20][C:19]([N:18]1[CH2:9][CH2:10][O:13][CH2:22][CH2:23]1)=[C:3]([C:1]#[N:2])[C:4]([NH2:6])=[O:5]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: C1COCCN1
Reactant: N#CCC(N)=O
Solvent: CC#N
Product: CC(=C(C#N)C(N)=O)N1CCOCC1
Temperature: 25 °C
Yield: 53 %

Procedure:
A stirred mixture of cyanoacetamide (84 g.), triethylorthoacetate (178 g.) and morpholine (108 g.) was heated under reflux for 3 hours. The initial reflux temperature was 104° C. and the final reflux temperature was 89° C. At the end of the reflux period acetonitrile (50 ml.) was added, the mixture was cooled at 25° C., the crystalline precipitate was collected, and washed with 2 × 100 ml. of cold ethanol. Weight = 104.7 g. Yield = 53%. A sample was recrystallized from ethanol as white needles m.p. 173°-174.5° C.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][NH:8][S:9]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)(=[O:11])=[O:10])(=[O:6])[O:4][CH3:5].[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][P:3]([CH2:7][N:8]([S:9]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)(=[O:10])=[O:11])[CH3:21])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CNS(=O)(=O)c1cc2ccccc2s1)OC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COP(=O)(CN(C)S(=O)(=O)c1cc2ccccc2s1)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
A reaction mixture consisting of 290 mg (0.83 mmol) of [(2-benzothiophenesulfonylamino)-methyl]-phosphonic acid dimethyl ester, 380 mg (1.16 mmol) of anhydrous cesium carbonate, 0.11 mL (1.16 mmol) of methyl iodide and 5 mL of anhydrous DMF stirred for 16 hours at room temperature. After the reaction was complete, DMF was evaporated in vacuum, and the residue was suspended in 15 mL of water and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, filtered and evaporated, providing an oily residue which was chromatographed on a silica gel column, eluent EtOAc/hexane (7:3), then dichloromethane/MeOH (20:1), to yield the title compound as a yellowish oil (190 mg, 63%): 1H NMR: (300 MHz, CDCl3) δH 3.00 (s, CH3), 3.48 (d, J=11.5 Hz, 2 H), 3.83 (d, J=10.9 Hz, 6 H, 2CH3), 7.45-7.50 (m, 2 H, Ar—H), 7.83-7.89 (m, 3 H, Ar—H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[K+].[CH2:11](Br)[CH2:12][OH:13].N1C=CC=NC=1>C(O)C>[OH:13][CH2:12][CH2:11][N:4]1[CH:3]=[C:2]([F:1])[CH:7]=[N:6][C:5]1=[O:8]
Reactant: O=c1ncc(F)c[nH]1
Reactant: OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: c1cncnc1
Product: O=c1ncc(F)cn1CCO
Yield: 50 %

Procedure:
5-Fluoropyrimid-2-one (0.008 mol) was dissolved in a solution of potassium hydroxide (0.008 mol) in absolute ethanol (100 ml) at 80° C. and ethylene bromohydrin (0.008 mol) added gradually with stirring. The alkylation was incomplete when the pH had become neutral. The reaction was further monitored by chromatography and equivalent amounts of potassium hydroxide and ethylene bromohydrin added until all the pyrimidine had been alkylated. The reaction mixture was then filtered and the filtrate evaporated to dryness before the residue was triturated with ether and extracted with warm acetone. Evaporation of the acetone solution left the title compound in 50% yield, m.p. 134°-136° C. after recrystallisation from ethanol; Found: C, 45.83; H, 4.42; Calc. for C6H7FN2O2 : C, 45.58; H, 4.46.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:26]2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: Clc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4cccc(Cl)c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 33.7 %

Procedure:
141 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 115 mg of 4-chloroisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 70 mg of the target compound.
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9]O[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]1(=O)CCC1.[CH:17]1([N:20]2CCNCC2)[CH2:19][CH2:18]1>>[CH:17]1([N:20]2[CH2:4][CH2:5][N:1]([C:6]3([C:10]#[N:11])[CH2:9][CH2:12][CH2:7]3)[CH2:2][CH2:3]2)[CH2:19][CH2:18]1
Reactant: O=C1CCC1
Reactant: C1CN(C2CC2)CCN1
Reactant: N#CC1(N2CCCC2)COC1
Product: N#CC1(N2CCN(C3CC3)CC2)CCC1

Procedure:
The title compound, colourless oil, MS: m/e=179.1 [(M−CN)+], was prepared in accordance with the general method of intermediate A from cyclobutanone and 1-cyclopropyl-piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[I-].[Li+].[NH:12]([C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:21][N:22]=[C:23]2[Cl:26])=[CH:18][CH:17]=1)[C:13]([CH3:15])=[O:14]>C(O)CCC>[ClH:26].[NH:12]([C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH2:27][C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[N:21][N:22]=[C:23]2[NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1)[C:13]([CH3:15])=[O:14]
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Cl)c2c1
Agent: [I-]
Agent: [Li+]
Solvent: CCCCO
Product: COc1ccc(Nc2nnc(Cc3ccncc3)c3ccc(NC(C)=O)cc23)cc1
Product: Cl
Reaction time: 20 h

Procedure:
Under exclusion of air, 354 mg (2.88 mmol) 4-methoxyaniline and 13 mg lithium iodide are added to 300 mg (0.96 mmol) 7-acetamino-1-chloro-4-(4-pyridylmethyl)phthalazine in 3.9 ml 1-butanol and heated to boiling for 20 h. After cooling, the dark suspension is filtered off, washed with 1-butanol and ethanol, and dried to obtain title compound: m.p.: 160-163° C.; HPLC: tRet(Grad5-40)=9.5; FAB MS (M+H)+=400.