Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](=[O:15])([O-])[O-].[K+].[K+]>CC(C)=O>[NH:2]1[CH2:3][CH2:9][C@H:10]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:12]1=[O:15]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)/C(=N\O[C@H]1CCNC1=O)C(C)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 135.5 %

Procedure:
3.2 g of ethyl 2-hydroxyimino-3-oxo-n-butyrate are dissolved in 25 ml of acetone, and 4.2 g of potassium carbonate and 7.6 g of (R)-3-(p-tosyloxy)-2-pyrrolidone are added thereto. After the mixture is stirred at room temperature for 15 hours, the mixture is concentrated under reduced pressure to dryness. 50 ml of ice-water are added to the residue, and the mixture is extracted with ethyl acetate. The extract is dried and concentrated under reduced pressure to dryness. 3.3 g of ethyl (Z)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]-3-oxo-n-butyrate are obtained.
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[CH:37][N:38]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])O1>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH:36]=[CH:37][N:38]4[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Product: CC(C)(C)OC(=O)n1ccc2c(-c3cnc(NCCN4C(=O)NC(=O)C4(C)C)nc3-c3ccc(Cl)s3)cccc21

Procedure:
The title compounds were prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrim-idin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and tert-butyl 4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate in a manner analogous to Example 269, then purified and separated by C-8 prep HPLC to give tert-butyl 4-{4-(5-chlorothiophen-2-yl)-2-[2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)ethylamino]pyrimidin-5-yl}-1H-indole-1-carboxylate: MS (M+H)+ 581; and 1-{2-[4-(5-chlorothiophen-2-yl)-5-(1H-indol-4-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione: MS (M+H)+ 481.
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[C:12](OC)=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:19])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:22][CH:23]=1
Reactant: COc1c(N)ccc2c1CCC(NCC(F)F)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 60.7 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide to yield N-((1R,2R)-2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (382.94 mg, 60.7% yield) as a white foam. 1H-NMR (CDCl3) δ 7.92 (m, 2H), 7.29 (m, 1H), 6.88 (d, J=8.17 Hz, 1H), 5.83 (m, 1H), 5.42 (m, 1H), 3.90 (m, 1H), 3.72 (s, 3H), 3.25 (m, 2H), 3.00 (t, J=15.0 Hz, 2H), 2.78 (m, 5H), 2.63 (m, 1H), 2.51 (m, 1H), 2.22 (m, 2H), 1.85 (m, 2H), 1.37 (m, 6H). LC/MS=573 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.[NH2:14][C@H:15]([C:19]([NH:21][C@H:22]([CH:35]=[O:36])[CH2:23][C:24](=[N:30][NH:31][C:32]([NH2:34])=[O:33])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20])[CH:16]([CH3:18])[CH3:17].C(Cl)Cl.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([CH:35]=[O:36])[CH2:23][C:24](=[N:30][NH:31][C:32]([NH2:34])=[O:33])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)[C@H](N)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1C)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
1-Methylindole-2-carboxylic acid (88 mg, 0.5 mmol) and (3S)-3-(Valinyl)amino-4-oxobutanoic acid, t-butyl ester semicarbazone (163 mg, 0.5 mmol) were dissolved in DMF (1 mL) and methylene chloride (2 mL) then both DMAP (61 mg, 0.50 mmol) and EDAC (134 mg, 0.7 mmol) were added to the solution under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and an additional 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution. The ethyl acetate solution was washed successively with 5% KHSO4 solution, saturated sodium bicarbonate solution and brine solutions, dried over sodium sulfate, and concentrated to give a yellow foam. Trituration of the foam with ether afforded the title product as a slightly yellow powder (203 mg, 86%). TLC (methanol/methylene chloride:5/95, silica gel): Rf=0.17.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[N:20]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][C:27]2[CH:28]=[C:29]([C:30]3[NH:1][C:2]4=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]5[C@@H:15]6[CH2:16][C@@H:12]([CH:13]=[CH:14]6)[C@@H:11]5[C:17]([NH2:19])=[O:18])=[C:7]4[N:8]=3)[CH:32]=[CH:33][CH:34]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccc(CN2CCOCC2)c1
Product: NC(=O)[C@@H]1[C@H](Nc2ccnc3[nH]c(-c4cccc(CN5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 33.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 3-morpholin-4-ylmethyl-benzaldehyde (43.5 mg, 0.212 mmol) were reacted to produce 29 mg (34%) of the title compound. mp: 240-244° C., 1H NMR (300 MHz, DMSO-d6) 13.09 (s, 1H), 8.10 (s, 1H), 8.02 (d, J=8 Hz, 1H), 7.91 (d, J=8 Hz, 1H), 7.67 (s, 1H), 7.47 (t, J=8 Hz, 1H), 7.39 (m, 1H), 7.17 (s, 1H), 6.91 (m, 1H), 6.41 (d, J=8 Hz, 1H), 6.34 (s, 1H), 3.88 (br s, 1H), 3.60 (br s, 4H), 3.54 (s, 2H), 2.88 (s, 1H), 2.77 (s, 1H), 2.61 (d, J=8 Hz, 1H), 2.40 (s, 4H), 2.24 (d, J=8 Hz, 1H), 1.43 (d, J=8 Hz, 1H). MS: 445 (M+H), HPLC: 1.54 min (G method).
Reaction SMILES: [NH2:1][OH:2].[C:3](Cl)(=[O:7])[C:4]([CH3:6])=[CH2:5].Cl.NO.Cl>N1C=CC=CC=1>[C:3]([NH:1][O:2][C:3](=[O:7])[C:4]([CH3:6])=[CH2:5])(=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: C=C(C)C(=O)Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: C=C(C)C(=O)NOC(=O)C(=C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,O-dimethacryloylhydroxylamine was prepared by the reaction of hydroxylamine with methacryloyl chloride in pyridine medium. Hydroxylamine hydrochloride (10 g; 0.144 mol) was dissolved in 50 ml pyridine (0.632 mol) and 25.4 g (0.243 mol) methacryloyl chloride was dropwise added. Temperature of the reaction mixture was kept below 45° C. After completed addition of methacryloyl chloride, the mixture was stirred at ambient temperature for 2 hours. Then, the mixture was diluted with 100 ml dropwise added in order to transfer pyridine to its hydrochloride. The organic layer was separated, washed four-times with 100 ml water, and then dried over MgSO4. Chloroform was evaporated in vacuum and the oily residue was dried in vacuum of an oil pump. The product crystallized during drying, the crystals were filtered and twice recrystallized from the mixture diethyl ether - light petroleum. The yield was 7.0 g (34%) N,O-dimethacryloylhydroxylamine, m.p. 55° C., elemental analysis; calculated C- 56.70, H - 6.55, N - 8.28%; found C - 56.74, H - 6.22, N - 8.34%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][CH:25]=1>>[CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=4)=[CH:28][CH:29]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: NCCCOc1ccc(C2=NNC(=O)CC2)cc1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Product: O=C1CCC(c2ccc(OCCCNCC(O)COc3ccc(CCOCC4CC4)cc3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclopropylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Mg].[CH2:2]([Br:4])[CH3:3].[Cl:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:7]=1[NH2:8].[C:14]([O:18][C:19]([NH:21][C:22]1[S:23][C:24]([C:27](OCC)=[O:28])=[CH:25][N:26]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>O1CCCC1.II.C(OCC)(=O)C>[CH2:2]([Br:4])[CH3:3].[Cl:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:7]=1[NH:8][C:27]([C:24]1[S:23][C:22]([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[N:26][CH:25]=1)=[O:28]
Reactant: Cc1cccc(Cl)c1N
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCBr
Product: Cc1cccc(Cl)c1NC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Reaction time: 0.08 h

Procedure:
Magnesium turnings (3.87 g) were charged into a round bottom flask. Tetrahydrofuran (15 mL) was added to the flask. Iodine (30 mg) was added. A solution of ethyl bromide (16 g in 60 mL tetrahydrofuran) was prepared and 10 mL of this solution was slowly charged to the round bottom flask. The reaction mixture was stirred at 20° C. to 25° C. for 5 minutes and the remaining amount of ethyl bromide was added slowly over 30 minutes. The reaction mixture was heated to gentle reflux for 30 minutes and was cooled to −5° C. to −10° C. 2-Chloro-6-methylaniline (22.86 g) was added drop-wise at −5° C. to −10° C. and the temperature of the reaction mixture was slowly raised to 15° C. to 20° C. Ethyl 2-[(tert-butoxycarbonyl)amino]-1,3-thiazole-5-carboxylate (10 g) dissolved in tetrahydrofuran (60 mL) was slowly added to the reaction mixture over 30 minutes. The reaction mixture was stirred for 3 hours. The reaction mixture was poured slowly into 25% ammonium chloride solution (100 mL) with stirring. Ethyl acetate (100 mL) was added and stirred for 30 minutes, filtered, suck dried, and dried under vacuum at 40° C. to 45° C. to obtain the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[NH:6][C@H:5]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:41])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][C:30]=1[O:39][CH3:40].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:41])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:6]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]2[CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[O:37])=[CH:31][C:30]=1[O:39][CH3:40]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-methyl-2-(S)-pirrolidinylmethoxy]benzoate (141 mg, 0.57 mmol), 4-[N′-(2-methylphenyl)ureido]-3-methoxyphenylacetic acid (178 mg, 0.57 mmol) and N,N-dimethylaminopyridine (69.0 mg, 0.57 mmol) in DMF (10 ml) was added EDC.HCl (120 mg, 0.62 mmol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with EtOAc as eluent to give methyl 4-[1-[4-[N′-(2-methylphenyl)ureido]-3-methoxyphenyl acetyl]-5-(R)-methyl-2-(S)-pyrrolidinylmethoxy]benzoate (297 mg, 96%) as a colorless amorphous solid. 1H-NMR (CDCl3) δ 1.24–1.34 (m, 3 H), 1.93–2.18 (series of m, 4 H), 2.28 (s, 3 H), 3.65 (s, 3 H), 3.88 (s, 3 H), 3.62–3.87 (m, 3 H), 4.11–4.38 (series of m, 3 H), 6.42–8.06 (series of m, 13 H); MS (ESI) m/z, 546 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)c2ccccc2c1=O
Yield: 66.6 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 03.00 g (13.8 mmol) of 4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester, 0.66 g (16.6 mmol) of 60% sodium hydride, 2.60 g (16.6 mmol) of 4-methoxybenzyl chloride in 30 mL DMF to give 3.10 g of the product as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.CS[C:17](=[N:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[NH:18][C:19]#[N:20].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:17]([NH:18][C:19]#[N:20])=[N:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:10]=1
Reactant: CSC(=Nc1ccncc1)NC#N
Reactant: NCCCCCCOc1cccnc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: N#CNC(=Nc1ccncc1)NCCCCCCOc1cccnc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 3-[6-amino-1-hexyl-oxy]-pyridine (150 mg), S-methyl-N-cyano-N′-4-pyridyl-isothiourea (123 mg), triethylamine (0.18 ml), 4-(N,N-dimethylamino)-pyridine (3.5 mg) and pyridine (5 ml) was stirred overnight at 60° C. After cooling to room temperature the pyridine was removed by evaporation twice with toluene in vacuo and the residue was distributed between water and ethyl acetate. The organic phase was dried and evaporated to yield a crude product which was purified by chromatography on silica gel with ethyl acetate/methanol/aqueous ammonia (40:10:2.5) as eluent. The pure fractions were pooled and evaporated to give the title compound which crystallised from ethyl acetate.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[C:9]([P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[C:10]=1[P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])CCC.I[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1.[F-].[K+]>C1COCC1.[Cu]Cl>[CH2:14]([O:13][P:11]([C:10]1[C:9]([P:19]([O:21][CH2:22][CH3:23])([O:24][CH2:25][CH3:26])=[O:20])=[CH:8][S:7][C:6]=1[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)([O:16][CH2:17][CH3:18])=[O:12])[CH3:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1scc(P(=O)(OCC)OCC)c1P(=O)(OCC)OCC
Reactant: Ic1cccs1
Agent: Cl[Cu]
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1csc(-c2cccs2)c1P(=O)(OCC)OCC
Yield: 88 %

Procedure:
In THF, 0.600 g (0.930 mmols) of 2-tributylstannyl-3,4-bis(diethoxyphosphoryl)thiophene and 0.1013 g (1.023 mmols) of commercially available copper(I) chloride were dissolved, to which 0.2344 g (1.116 mmols) of 2-iodothiophene was added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 4 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 2 hours. Subsequently, the resulting solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (ethyl acetate:methanol=15:1) to obtain the specified substance at a yield of 0.3595 g (yield: 88%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([N:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:26]N1C(=O)CCC1=O.O>ClCCl>[Br:26][C:10]1[N:9]=[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: CC(=O)N1CCC(N2CCN(c3ncc4c(C)nccn34)CC2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(N2CCN(c3nc(Br)c4c(C)nccn34)CC2)CC1
Yield: 74.5 %

Procedure:
To 1-(4-(4-(8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)piperidin-1-yl)ethanone (0.102 mmol, 35 mg) in dichloromethane (1 ml) at room temperature was added N-bromosuccinimide (0.102 mmol, 18.19 mg). After stirring at room temperature for 5 minutes water was added and the mixture extracted three times with dichloromethane. The combined organic extracts were dried over a phase separation filter and concentrated in vacuo to give 1-(4-(4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)piperazin-1-yl)piperidin-1-yl)ethanone (32 mg).
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[CH3:14][N:15]([CH2:17][CH:18]1[CH2:24][CH2:23][CH:22]2[CH:20]([CH2:21]2)[C:19]1=[O:25])[CH3:16]>C1COCC1>[CH3:16][N:15]([CH2:17][CH:18]1[CH2:24][CH2:23][CH:22]2[CH:20]([CH2:21]2)[C:19]1([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[OH:25])[CH3:14]
Reactant: CN(C)CC1CCC2CC2C1=O
Reactant: Oc1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN(C)CC1CCC2CC2C1(O)c1cccc(O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
Add a solution of t-BuLi (5.8 mL, 8.68 mmol) via syringe to a solution of 3-bromo-phenol (752 mg, 4.34 mmol) in THF (60 mL) at −78° C. under N2. After being stirred at −78° C. for 1 hour, add a solution of 3-dimethylaminomethyl-bicyclo[4.1.0]heptan-2-one (300 mg, 2.17 mmol) in THF (2 mL) to the reaction mixture and stir the reaction mixture at −78° C. for additional 2 hours. Quench the reaction mixture with saturated NH4Cl solution (30 mL). Extract the aqueous resultant mixture with EtOAc (60 mL×3). The combined organic layers are washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by Preparative HPLC to give 3-dimethylaminomethyl-2-(3-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol as white solid (73 mg, yield: 12.9%). MS (m/z): 262 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](OC)=[O:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[N:29][CH:30]=[N:31][CH:32]=2)=[N:23][C:22]=1[NH:33][C:34]1[CH:35]=[C:36]([NH2:41])[CH:37]=[CH:38][C:39]=1[CH3:40].C[Al](C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[N:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[N:29][CH:30]=[N:31][CH:32]=2)=[N:23][C:22]=1[NH:33][C:34]1[CH:35]=[C:36]([NH:41][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[CH:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[CH2:9][CH2:10]3)=[O:18])[CH:37]=[CH:38][C:39]=1[CH3:40]
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncnc2)n1
Reactant: COC(=O)c1ccc2c(c1)CCC2N1CCN(C)CC1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCN(C)CC2)cc1Nc1nccc(-c2cncnc2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
Methyl 1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-5-carboxylate (823 g, 3 mmol) and N(3)-4,5′-bipyrimidin-2-yl-4-methyl benzene-1,3-diamine (973 g, 3.5 mmol) were suspended in 15 mL of toluene, and then a 2 M trimethylaluminium solution (3 mL, 6 mmol) was added. The mixture was stirred overnight at 50° C. and another 2 M trimethylaluminium solution (2 mL, 4 mmol) was added. The solution was stirred overnight at 60° C. and then cooled in an ice bath. Saturated aqueous solution of potassium sodium tartrate was added with stirring. The solution obtained was extracted with methylene chloride (3×100 mL). The pooled extracts were washed with sodium bicarbonate (100 mL) and with brine (2×100 mL), dried over magnesium sulfate, concentrated, and purified by silica gel column chromatography using 50% ethyl acetate/methylene chloride/5-10% triethylamine as eluent to obtain 702 mg of the title compound (45% yield). MS (M+1)=527.27. 1HNMR (DMSO-d6, ppm): δ 10.10 (s, 1H); 9.46 (s, 2H); 9.28 (s, 1H); 9.08 (s, 1H); 8.50 (d, J=5.7 Hz, 1H); 8.04 (s, 1H); 7.74 (s, 1H); 7.70 (d, J=9.0 Hz, 1H); 7.46 (d, J=5.7 Hz, 1H); 7.42 (d, J=9.0 Hz, 1H); 7.32 (d, J=9.0 Hz, 1H); 7.15 (d, J=9.0 Hz, 1H); 4.25 (t, J=5.7 Hz, 1H); 2.2-2.9 (m, 10H); 2.15 (s, 3H); 2.07 (s, 3H); 2.0 (m, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[C:17](Cl)(=[O:28])[O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][C:17]([NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:28])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a solution of methyl 2-aminoacetate hydrochloride (0.137 g, 1.09 mmol) and DIPEA (0.52 mL, 2.98 mmol) in DCM (5 mL) at 0° C. was added a solution of 4-nitrophenyl carbonochloridate (0.20 g, 0.992 mmol) in DCM (2 mL) dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. After this time, the reaction was quenched with water, and the organic layer was separated. The aqueous phase was extracted with DCM, and the combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (0.213 g, 84% yield) as a white solid. LCMS, [M+Na]+=277.1. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=9.1 Hz, 2H), 7.32 (d, J=9.1 Hz, 2H), 5.62 (br. s, 1H), 4.07 (d, J=5.5 Hz, 2H), 3.80 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=1
Reactant: CC(C)(C)Nc1nc(Cl)cc(Cl)n1
Reactant: C1CCNC1
Product: CC(C)(C)Nc1nc(Cl)cc(N2CCCC2)n1
Yield: 93 %

Procedure:
4,6-Dichloro-2-(1,1-dimethylethylamino)pyrimidine is reacted with pyrrolidine as described in Example 28 to give the title compound in a yield of 93%, m p.: 153°-157° C.