Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:8]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl-].[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][CH:44]=[S:45])=[CH:39][CH:38]=1)(=[O:36])=[O:35].CO>ClCCl>[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[NH:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:8]4[O:15][C:14]5[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=5[C:9]=4[N:10]=[CH:11][N:12]=3)[CH2:2][CH2:3]2)=[S:45])=[CH:39][CH:38]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Nc1ncccn1)c1ccc(NC=S)cc1
Reactant: c1ccc2c(c1)oc1c(N3CCNCC3)ncnc12
Agent: [Cl-]
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ncccn1)c1ccc(NC(=S)N2CCN(c3ncnc4c3oc3ccccc34)CC2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-piperazinobenzofurano[3,2-d]pyrimidine (200 mg, 0.79 mmol) and pyridine (0.5 mL, 7.9 mmol) in dichloromethane (20 mL) was added a solution of product 1d in dichloromethane (20 mL) and this was stirred overnight. Methanol was added to quench excess thiophosgene; and the residue after removal of solvent was purified by silica gel column chromatography eluting with 5% methanol/dichloromethane and further recrystallized from dichloromethane/hexane to give 150 mg (37%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:20]([O:21][C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][N:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:14][C:15]1[C:20]([O:21][C:22]2[N:27]=[CH:26][C:25]([NH:28][C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=4)[NH:8][CH:7]=3)=[O:13])=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Cc1ccc2c(C(=O)O)c[nH]c2c1
Reactant: Nc1ccc(Oc2cccnc2Cl)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(C(=O)Nc3ccc(Oc4cccnc4Cl)nc3)c[nH]c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
The 6-methyl-1H-indole-3-carboxylic acid (50 mg, 0.28 mmol) in Example 16 and the 6-(2-chloropyridine-3-yloxy)-pyridine-3-amine (60 mg, 0.28 mmol) in Example 22 were dissolved in DMF (5 ml), HBTU (100 mg, 0.28 mmol) and triethylamine (0.11 ml, 0.84 mmol) were added to the solution, and the mixture was stirred at 80° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a white solid (18 ml, 34%) by chromatography (methanol:dichloroinethane=1:30).
Reaction SMILES: CO[C:3](=[O:22])[C:4]([OH:21])=[CH:5][C:6](=[O:20])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]#[N:19])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:31][N:32](C)[C:33](C1CN(C)C(=O)C=1O)=O>>[C:18]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[F:17])[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:31][N:32]([CH3:33])[C:3](=[O:22])[C:4]=1[OH:21])=[O:20])#[N:19]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)c(C#N)c1)OC
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(F)c(C#N)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 69 %

Procedure:
3-[(3-Cyano-4-fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 61-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (69% yield); mp 175° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.78 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.85 (2H, s, NCH2), 7.19–7.24 (1H, m, aromatic), 7.59–7.62 (2H, m, aromatics).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][NH:3]1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(#N)C.C(OCC)(=O)C>[CH:15]1([NH:18][C:12]([CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[NH:3][CH2:4]2)=[O:14])[CH2:17][CH2:16]1
Reactant: O=C(O)c1c[nH]c(=O)c2ccccc12
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1NCC(C(=O)NC2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.50 g (12.30 mmol) of methyl 1-oxo-1,2-dihydroisoquinoline-4-carboxylate and 1.30 g of 10% strength palladium on carbon were suspended in an autoclave, and the mixture was hydrogenated at 70° C. and 20 bar of hydrogen for 4 h. The autoclave was vented, after which the catalyst was filtered off and the solvent was removed under reduced pressure, and the crude product was purified by chromatography (ethyl acetate: n-heptane 2:1). This gave 2.28 g (88%) of the desired methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate. 1H-NMR (400 MHz, CDCl3 δ, ppm) 8.10 (d, 1H), 7.52 (t, 1H), 7.44 (t, 1H), 7.31 (d, 1H), 6.17 (br. s, 1H), 3.98 (dt, 1H), 3.88 (m, 1H), 3.29 (dd, 1H), 3.71 (s, 3H). 2.28 g (11.11 mmol) of methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate were dissolved in 20 ml of tetrahydrofuran, and 20 ml of 1 N aqueous sodium hydroxide solution were added. The solution was stirred at room temperature for 8 h, the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and 1 N hydrochloric acid. The phases were separated, the organic phase was dried over magnesium sulphate and the solvent was removed under reduced pressure. In this manner, 2.12 g (94% of theory) of the desired 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid were obtained. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 12.65 (br. s, 1H), 7.94 (d, 1H), 7.83 (d, 1H), 7.51 (t, 1H), 7.41-7.35 (m, 2H), 3.89 (t, 1H), 3.68-3.54 (m, 2H). 0.200 g (1.046 mmol) of 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid were dissolved in 10 ml of acetonitrile, and 0.109 ml (1.569 mmol) of cyclopropylamine, 0.170 g (1.255 mmol) of 1-hydroxy-1H-benzotriazole and 0.221 g (1.151 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. The solution was stirred at room temperature for 8 h, diluted with ethyl acetate and the organic phase was extracted initially with saturated sodium bicarbonate solution and then with 1 N hydrochloric acid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16](Cl)=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>CO.CCOCC>[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([N:6]2[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]2)=[O:17])=[CH:12][CH:11]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)COc2ccc(Cl)cc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
To a solution of (cis)-2,6-dimethylpiperazine (0.115 g, 1.1 mmol) in methanol (35 mL) was added 4-chlorophenoxyacetyl chloride (0.205 g, 1.0 mmol, in solution of 6 mL of anhydrous ether). The resulting mixture was stirred at ambient temperature for 10 minutes and then triethylamine (0.10 mL, 0.72 mmol) was added. After 30 minutes, the mixture was concentrated in vacuo to afford an oily residue. This was taken up in ether and washed with saturated aqueous NaHCO3 solution, then brine. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to afford an oil. Purification by flash column chromatography afforded 0.202 g (80% yield) of (cis)-1-((4-chlorophenoxy)methyl)carbonyl-3,5-dimethylpiperazine, a compound of formula (K), as a clear, colorless oil; NMR (CDCl3) 7.3 (d, 2), 6.9 (d, 2), 4.7 (d,1), 4.6 (d,1), 4.4 (d,1), 3.8 (d,1), 2.7 (m, 3), 2.2 (t, 1), 1.1 (m, 6) ppm.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([O:10][C:11]([CH2:13][O:14][N:15]=[C:16]([C:20]1[N:21]=[CH:22][S:23][CH:24]=1)[C:17]([OH:19])=O)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH3:25][N+:26]([CH3:29])=[CH:27][Cl:28].[Cl-].C[Si](CC(N)=O)(C)C.[NH2:39][CH:40]1[C:65](=[O:66])[N:42]2[C:43]([C:49]([O:51][CH:52]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[O:50])=[C:44]([CH2:47][Cl:48])[CH2:45][S:46][C@H:41]12>C(OCC)(=O)C.O.CN(C)C=O>[CH3:25][N+:26]([CH3:29])=[CH:27][Cl:28].[Cl-:3].[C:6]([O:10][C:11]([CH2:13][O:14][N:15]=[C:16]([C:20]1[N:21]=[CH:22][S:23][CH:24]=1)[C:17]([NH:39][CH:40]1[C:65](=[O:66])[N:42]2[C:43]([C:49]([O:51][CH:52]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:50])=[C:44]([CH2:47][Cl:48])[CH2:45][S:46][C@H:41]12)=[O:19])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1cscn1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1cscn1
Reaction time: 0.33 h

Procedure:
Vilsmeier reagent was prepared from phosphorus oxychloride (14.4 g) and N,N-dimethylformamide (6.9 g) in ethyl acetate (27.6 ml) in a usual manner. 2-t-Butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetic acid (syn isomer) (22.8 g) was added to the stirred suspension of Vilsmeier reagent in ethyl acetate (200 ml) under ice-cooling and the mixture was stirred for 20 minutes at the same temperature to produce an activated acid solution. Trimethylsilylacetamide (56.9 g) was added to a stirred suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (30 g) in ethyl acetate (300 ml) and the resultant mixture was stirred for 30 minutes at ambient temperature. To the solution was added the activated acid solution obtained above at -10° C. and the mixture was stirred for 30 minutes at the same temperature. Water was added to the reaction mixture, and the separated organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, successively. The ethyl acetate layer was dried over magnesium sulfate and evaporated to give benzhydryl 7-[2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (37.3 g).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[NH:38]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][N:38]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:3](=[O:5])[C:2](=[O:1])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH:7]=1)[CH3:44]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: O=C(O)C(=O)c1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)C(=O)c1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
To 1.12 g (2.6 mmol) of alpha-oxo-4-[(12-phenoxydodecyl)oxy]benzeneacetic acid in 50 ml of methylene chloride containing 2 drops of anhydrous DMF stirred and cooled in an ice bath was added 1.1 ml (13 mmol) of oxalyl chloride. The cooling bath was removed and stirring was continued at room temperature for 1.5 hours. The solvent was removed at reduced pressure and the resultant solid acid chloride was dissolved in 50 ml of methylene chloride and added dropwise to a stirred, ice bath cooled solution of 0.7 ml (5.25 mmol) of diethyl iminodiacetate and 0.7 ml (5.25 mmol) of triethylamine in 15 ml of methylene chloride. The reaction mixture was stirred at room temperature for 16 hours and then was concentrated at reduced pressure. The resultant crude product was triturated with methanol and filtered to give 1.32 g (84% yield, mp 55°-56°) of N-(2-ethoxy-2-oxoethyl)-N-[1,2-dioxo-2-[4-[(12-phenoxydodecyl)oxy] phenyl]ethyl]glycine ethyl ester. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([Li])CCC.CCCCCC.CI.P([O-])(O)(O)=O.[K+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH3:23])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Reactant: [Li]CCCC
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.30 g) was dissolved in tetrahydrofuran (10 ml), and a solution of n-butyllithium/n-hexane (1.56M, 1.4 ml) was added dropwise thereto at -70° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture for 10 minutes. Then, methyl iodide (0.09 ml) was added dropwise to the reaction mixture, and the resulting mixture was stirred for 10 minutes. After the temperature of the reaction mixture was raised to 0° C., the reaction mixture was poured into ice-cold water, and an aqueous potassium dihydrogenphosphate solution was added to the mixture to adjust the pH to a value of 6. Then, the mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous NaCl solution, followed by drying over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the title compound (0.29 g, 94%) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[S:6][CH:7]=1.Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>[Pd]>[F:20][C:2]([F:19])([F:1])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: Cc1ccc(N)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Agent: [Pd]
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, was prepared in accordance with the general method of example 4, step 2 using 4-Trifluoromethyl-thiazol-2-ylamine instead of 2-Chloro-4-aminopyridine to yield [6-Methyl-2-(4-trifluoromethyl-thiazol-2-ylcarbamoyl)-pyridin-3-yl]-carbamic acid tert-butyl ester as an off-white solid. MS (ISP): m/e=403.0 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide as an off-white solid, MS (ISP): m/e=303.0 (M+H+). Palladium catalysed arylation with 3-Bromopyridine as described in example 4 step 4 yielded the final product as a yellow solid, MS (ISP): m/e=380.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1.[CH3:21][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:12])[CH3:21])[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1
Reactant: C[Mg]Br
Reactant: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(C=O)c2n1
Solvent: C1CCOC1
Product: CC(O)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carbaldehyde (0.88 g, 2.83 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to −78° C. and treated with methylmagnesium bromide (3.0 M in diethyl ether, 0.9 mL, 2.83 mmol) over several minutes. After 1 h, cooling was removed and stirring continued for 1 h at room temperature. The reaction was cooled to 0° C., treated with saturated ammonium chloride and diluted with ethyl acetate. The layers were separated. The organic layer was washed with water (2×), brine (2×), dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel (30% ethyl acetate/hexanes) afforded 540 mg (58%) as a light brown oil. 1H-NMR (CDCl3, 300 MHz) δ 8.00 (s, 1H), 8.21 (s, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.13 (m, 1H), 5.65 (s, 2H), 5.28 (q, J=6.2 Hz, 1H), 3.57-3.62 (m, 2H), 1.64 (d, J=6.2 Hz, 3H), 0.86-0.92 (m, 2H), 0.07 (s, 9H). Mass spec.: 327.04 (MH)+.
Reaction SMILES: C(C1N=C(N2CCOCC2)[C:8]2N=N[N:11]([CH2:14][C:15]3[CH:20]=CC=C[C:16]=3Cl)[C:9]=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].CC1(C)CCNC1>>[C:28]([C:32]1[N:33]=[C:34]([N:11]2[CH2:9][CH2:8][C:15]([CH3:16])([CH3:20])[CH2:14]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC1(C)CCNC1
Product: CC1(C)CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-dimethylpyrrolidine. MS(m/e): 399.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([OH:18])=O)=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[K].C(N(C(C)C)C(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:39]([C:41]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][CH3:49])[C:42]=1[NH2:43])[CH3:40]>CN(C)C=O.O>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH:43][C:42]4[C:44]([CH2:48][CH3:49])=[CH:45][CH:46]=[CH:47][C:41]=4[CH2:39][CH3:40])=[O:18])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1
Reactant: Cn1nc(C(=O)O)c2c1-c1nc(N)ncc1CC2
Reactant: CCc1cccc(CC)c1N
Agent: On1nnc2ccccc21
Agent: [K]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A suspension of potassium 8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid (180 mg, 0.73 mmol) in anhydrous dimethylformamide (5.0 mL) was treated with N-ethyl-N,N-diisopropylamine (0.258 mL, 1.47 mmol) and N-ethyl-N′,N′-diisopropyl carbodiimide hydrochloride (EDCI) (280 mg, 1.47 mmol) and 1-hydroxybenzotriazole (200 mg, 1.47 mmol). The mixture was then treated with 2,6-diethylaniline (0.170 mL, 1.1 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (190 mg, 70% yield).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[CH:21]1([Mg]Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH:21]1([C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(C2CCCCC2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
34 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of tetrahydrofuran, followed by adding 1 mg of [1,3-bis (diphenylphosphino)propane]nickel(II) chloride. Under stirring in nitrogen atmosphere, 0.1 ml of cyclohexyl magnesium chloride (2.0M ether solution) was added dropwise thereinto. The mixture was stirred at room temperature in nitrogen atmosphere for 1 hour, followed by heating under reflux for 72 hours. After cooling to room temperature, water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (chloroform/methanol system), to give 5 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([F:24])([F:23])[F:22])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6]([O:27][CH3:28])[C:3]=1[C:4]#[N:5].O.[NH2:30][NH2:31]>C(O)C>[CH3:26][NH:25][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:30][NH:31]3)=[C:6]([O:27][CH3:28])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]([F:22])([F:24])[F:23])[N:13]=1
Reactant: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CNc1nc(-c2cc(OC)c3c(N)n[nH]c3c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Temperature: 100 °C
Yield: 54.9 %

Procedure:
2-Fluoro-4-{2-(methylamino)-6-[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]-4-pyrimidinyl}-6-(methyloxy)benzonitrile (131 mg, 0.331 mmol) was dissolved in ethanol (3 mL) in a 5 mL sealable vial. Hydrazine monohydrate (0.487 mL, 9.94 mmol) was added, the vial was capped, and the reaction was heated at 100° C. overnight. The reaction was concentrated, dissolved in 2 mL of DMSO and purified in HPLC (HPLC condition: open-access Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 mL/min, 18% CH3CN/H2O, 0.1% TFA to 43% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the CH3CN. To the water left behind was added saturated NaHCO3, then extracted with EtOAc (3×15 mL). The organic was washed with brine, dried over MgSO4, filtered, concentrated, and transferred to a haystack vial. Water (1 mL) was added, and the resulting mixture was freeze dried to afford the title compound (74 mg) as a light yellow solid. LC-MS (ES) m/z=408 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.95-2.03 (m, 2H), 2.05 (bs, 2H), 2.77 (d, J=3.3 Hz, 3H) 3.47 (d, J=8.8 Hz, 1H) 3.62 (d, J=4.6 Hz, 1H), 3.87 (s, 3H), 4.98 (bs, 2H), 5.08 (bs, 1H), 6.39 (bs, 1H), 6.64 (bs, 1H), 6.88 (bs, 1H), 7.43 (bs, 1H), 11.50 (bs, 1H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.C(N(CC)CC)C.[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1>CN(C)C=O>[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]1[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3ccccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A suspension of 0.80 g (0.0041 2 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 17 ml of dimethylformamide was treated with 1.7 ml (0.0123 mol) of triethylamine and 0.67 g (5.3 mol) of 1,2,3,4-tetrahydroisoquinoline and the mixture was stirred at room temperature under argon for 3 hours. The mixture was completely freed from the solvents and the residue was chromatographed over silica gel with dichloromethane/methanol 9:1 as the eluent and recrystallized from ethyl acetate/diethyl ether. 0.72 g (69%) of 5-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine was obtained as beige crystals; m.p. 150°-153°.