Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=S)[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1>CC(C)=O.[Ni]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=S)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ni]
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A suspension of Raney® 2800 nickel (3 big spatula, pre-washed with H2O, MeOH and acetone) in acetone (50 mL) was stirred at refluxing for 1 h. Triacetate 77 (0.93 g, 2.03 mmol) was subsequently added into the above suspension at reflux. The mixture was stirred for 5 min, cooled to room temperature over 30 min. The reaction was quenched by bubbling H2S (g) into the mixture for 2 h. The resulting mixture was filtered through a short pad of Celite® and washed with EtOH. The filtrate was concentrated and purified by flash column chromatography (silica, MeOH/CHCl3=1-2%) to afford 0.52 g (60%) of 78 as a white solid: mp 121-123° C.; 1H (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 6.93 (s, 2H), 6.03 (d, J=3.6 Hz, 1H), 5.93 (dd, J=6.4, 3.6 Hz, 1H), 5.58 (t, J=6.0 Hz, 1H), 4.38 (dd, J=11.6, 3.6 Hz, 1H), 4.26 (m, 1H), 4.11 (q, J=6.0 Hz, 1H), 2.08 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H); MS (+)-ES [M+H]+ m/z 427.2. Elemental Analysis calc'd for C16H18N4O8S.0.5 CH3OH.0.25 H2O: C, 44.34; H, 4.62; N, 12.54; S 7.17. Found: C, 44.54; H, 4.88; N, 12.16; S, 7.17.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH:17]3[CH2:19][CH2:18]3)[N:11]=2)=[O:9])=[N:3]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:14][CH:13]=[C:12]([CH:17]3[CH2:19][CH2:18]3)[N:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2nc(C3CC3)ccc2N)n1
Reactant: Brc1cncnc1
Product: Cn1ccc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-cyclopropyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide and 5-bromopyrimidine in accordance with the general method of example 4 using to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=336.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:16]1(C)C=CC=CC=1>>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: Cc1ccccc1
Reactant: Cc1ccc(C(=O)O)c(F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-fluoro-4-methylbenzoic acid from Example D1 (6.04 g, 39.18 mmol) in toluene (80 ml) was added thionyl chloride (6.5 ml, 89.11 mmol). The mixture was heated at reflux for 2.5 h, cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (50 ml) and methanol (50 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a tan solid; yield 5.07 g (77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)=[CH:4][CH:3]=1.[Br:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([CH:37]=O)=[O:36])=[CH:31][CH:30]=1.FC(F)(F)C(O)=O>>[Br:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([CH:37]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:36])=[CH:31][CH:30]=1
Reactant: Fc1ccc(NCCc2cccc(OCc3ccccc3)c2)cc1
Reactant: O=CC(=O)c1ccc(OCCBr)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(OCCBr)cc1)C1c2ccc(OCc3ccccc3)cc2CCN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
To a solution of (4-fluorophenyl){2-[3-(phenylmethoxy)phenyl]ethyl}amine (0.643 g, 2.0 mmol) and [4-(2-bromoethoxy)phenyl]glyoxal (0.617 g, 2.4 mmol) was added trifluoroacetic acid (0.342 g, 3.0 mmol). The reaction stirred at room temperature for 4 hours. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography (SiO2, 20% ethyl acetate/hexane) to provide the title compound (0.879 g, 78% yield): 1H NMR (CDCl3) 8.00 (d, 2H), 7.40 (m, 4H), 7.18 (m, 1H), 7.07 (d, 1H), 6.79-6.92 (m, 8H), 5.85 (s, 1H), 5.02 (s, 2H), 4.33 (t, 2H), 3.71 (m, 1H), 3.64 (t, 2H), 3.47 (m, 1H), 3.07 (m, 1H), 2.87 (m, 1H); ES-MS (m/z) 560 [M+H]+.
Reaction SMILES: [BrH:1].N[C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOCC>[Br:1][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(Br)cc1
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
A solution of 48% aqueous HBr (2.31 ml, 20 mmol) dissolved in DMSO (25 ml) was added dropwise to a solution of 4-aminobenzophenone (0.986 g, 5 mmol) in a mixture of 25 ml of DMSO and KNO2 (0.851 g, 10 mmol) at 35° C. with agitation. The added mixture was stirred at 35° C. for 10 minutes, and then transferred to a solution containing K2CO3 (5 g) in 100 ml ice-water. The reaction mixture was then taken up in ether, and then the ethereal extracts were washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave the crude 4-bromobenzophenone. The crude product was further purified by column chromatography to obtain 4-bromobenzophenone. The yield determined by gas chromatography was 72% (based on decane as an internal standard).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:22][C:19]([F:20])([F:21])[CH2:18][N:13]1[C:12]([C:36]2[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(CC(F)(F)F)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)Cn1nc2c(c1-c1ccc(C(F)(F)F)cc1)CCNCC2
Yield: 57.2 %

Procedure:
The title compound (128 mg) was prepared as in Example 177, Steps C and D, using 288 mg of 2-(2,2,2-trifluoro-ethyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 187, Step A) and 468 mg of 4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated for C16H15F6N3, 363.12; found, m/z 364.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.93-7.83 (m, 2H), 7.62-7.54 (m, 2H), 4.75 (q, J=8.6 Hz, 2H), 3.47-3.39 (m, 2H), 3.38-3.27 (m, 2H), 3.24-3.15 (m, 2H), 2.87-2.76 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]=[CH:28][N:27]=1)=[O:24].[CH3:38][NH2:39].C1COCC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:39][CH3:38])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]=[CH:28][N:27]=1)=[O:24]
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(-c5ccccc5)ncn4)c3)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(-c5ccccc5)ncn4)c3)c(=O)n(C)c2n1
Yield: 54 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(6-phenylpyrimidin-4-yl)urea (265 mg, 0.516 mmol) and 2.00 N methylamine in THF (3.87 mL, 7.73 mmol) were combined to afford 1-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(6-phenylpyrimidin-4-yl)urea (139 mg, 54% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.89 (m, 3H), 3.54-3.62 (m, 3H), 7.29-7.35 (m, 2H), 7.53-7.55 (m, 3H), 7.70-7.82 (m, 1H), 7.91 (s, 1H), 8.03-8.06 (m, 2H), 8.13 (s, 1H), 8.44-8.46 (s, 1H), 8.60-8.75 (m, 1H), 8.98 (s, 1H), 10.1 (br. s, 1H), 10.2 (s, 1H); MS (ESI) m/z: 497.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2C=O)CC1
Temperature: 150 °C
Yield: 44 %

Procedure:
A mixture of 5-chloro-2-fluoro-benzaldehyde (10 g, 63 mmol), Piperazine-1-carboxylic acid tert-butyl ester (12 g, 63 mmol), K2CO3 (17 g, 123 mmol) in DMF (60 mL) was heated at 150° C. for 2 h. After cooled to room temperature, the mixture was poured into water (300 mL) and partitioned between diethyl ether and water. The combined organic phases were washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a yellow solid (9 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=O)[CH2:11][C:12](=[O:30])[C:13](=[N:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:14](=[O:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>C(#N)C>[C:14]([C:13]1[C:12](=[O:30])[CH:11]=[C:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:17]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)C(=NNc1ccccc1OC(C)(C)C)C(=O)CC(=O)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)c1nn(-c2ccccc2OC(C)(C)C)c(COCc2ccccc2)cc1=O
Yield: 65.9 %

Procedure:
A solution of 1-(benzyloxy)-5-[(2-tert-butoxyphenyl)hydrazono]heptane-2,4,6-trione (5.58 g) and triethylamine (9.61 g) in acetonitrile (55 mL) was heated under reflux for 1 hr. After cooling, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.52 g).
Reaction SMILES: C(O[C:4](=O)[O:5][C:6]1[C:15]2[C:16](=[O:29])[N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:18](=[O:19])[C:14]=2[C:13]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)C.O.C(=O)([O-])[O-].[K+].[K+].IC>O1CCCC1.C(OCC)(=O)C>[CH:31]([O:30][C:13]1[C:14]2[C:18](=[O:19])[N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:16](=[O:29])[C:15]=2[C:6]([O:5][CH3:4])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)Oc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(CCc1ccc(F)cc1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(CCc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To carbonic acid 9-benzhydryloxy-7-[2-(4-fluoro-phenyl)-ethyl]-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester ethyl ester 311 (140 mg, 0.24 mmol) dissolved in tetrahydrofuran (0.50 ml) and water (0.25 ml) was added potassium carbonate (345.4 mg, 2.5 mmol) and N,N-dimethyl-aminopyridine (DMAP, 29.3 mg, 3.8 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo and diluted with ethyl acetate. It was then washed twice with 5% citric Acid (aqueous), twice with water, once with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was dissolved in dimethylformamide (3.0 ml). To this solution was added potassium carbonate (179 mg, 1.3 mmol) and iodomethane (319 mg, 2.6 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate. It was then washed twice with 5% citric Acid, twice with water, once with brine, and concentrated in vacuo to afford 9-benzhydryloxy-7-[2-(4-fluoro-phenyl)-ethyl]-5-methoxy-pyrrolo[3,4-g]quinoline-6,8-dione 312 (130 mg, 0.24 mmol, 100%). 1H NMR (CDCl3) δ 9.16 (dd, 1H), 8.58 (dd, 1H), 7.82 (s, 1H), 7.74 (m, 1H), 7.55 (m, 4H), 7.20 (m, 8H), 7.0 (t, 2H), 4.04 (s, 3H), 3.87 (t, 2H), 2.91 (t, 2H). MS: 555.2 (M+23).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9].[C:21]([N:29]=[C:30]=[O:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:19]([C:3]1[C:4]([O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH3:13])=[CH:16][CH:17]=[CH:18][C:2]=1[NH:1][C:30]([NH:29][C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31])#[N:20]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CCCNC(=O)C(C)(C)COc1cccc(N)c1C#N
Product: CCCNC(=O)C(C)(C)COc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Yield: 85 %

Procedure:
Prepared as in Example 146a from 3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propyl-propanamide (Example 215b, Method A) and benzoyl isocyanate in 85% yield as a white solid. MS 423 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[C:33]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC4CCCC4)C3)sc12
Yield: 75 %

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), cyclopentanone (33.5 μL, 0.038 mmol) and sodium (triacetoxy)borohydride (175 mg, 0.83 mmol), to obtain 25.6 mg of the title compound as a white solid (75%).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:7][C:8]([CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH2:20][C@H:21]3[CH2:23][C@@H:22]3[C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=3)[N:16]=[C:15]([CH3:31])[N:14]=2)=[N:9][N:10]=1)=[O:5].C[Mg+].[Br-].[C:36](=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[CH3:31][C:15]1[N:14]=[C:13]([NH:12][CH2:11][C:8]2[S:7][C:6]([C:4](=[O:5])[CH3:36])=[N:10][N:9]=2)[CH:18]=[C:17]([O:19][CH2:20][C@H:21]2[CH2:23][C@@H:22]2[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=2)[N:16]=1
Reactant: CON(C)C(=O)c1nnc(CNc2cc(OC[C@H]3C[C@@H]3c3ccc(C)cn3)nc(C)n2)s1
Reactant: O=C([O-])O
Agent: C[Mg+]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)c1nnc(CNc2cc(OC[C@H]3C[C@@H]3c3ccc(C)cn3)nc(C)n2)s1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To the solution of N-methoxy-N-methyl-5-((2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidin-4-ylamino)methyl)-1,3,4-thiadiazole-2-carboxamide (17-1) (355 mg, 0.78 mmol) in THF (2 mL) was added CH3MgBr (1.3 mL, 3.90 mmol) in toluene dropwise at 0° C. The mixture was stirred for 30 min. Then the solution was adjusted to pH=9-10 with saturated sodium bicarbonate and extracted with ethyl acetate (20 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate and purified by Prep TLC (PE/EA=1:1). The product was obtained as a white solid (248 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.03 (d, J=7.9 Hz, 1H), 5.59 (s, 1H), 5.42 (s, 1H), 4.99 (d, J=6.3 Hz, 2H), 4.28 (m, 2H), 2.79 (s, 3H), 2.44 (s, 3H), 2.28 (s, 3H), 2.07 (m, 1H), 1.89-1.81 (m, 1H), 1.32-1.27 (m, 1H), 1.04-1.02 (m, 1H); LRMS (ES) calculated M+H for C20H23N6O2S: 411.5. Found:411.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)=[CH:3][CH:2]=1.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][S:23][CH2:24][CH2:25][NH2:26]>>[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][S:23][CH2:24][CH2:25][NH:26][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:13][N:12]=1
Reactant: NCCSCc1nccs1
Reactant: CSc1ncc(Cc2ccncc2)c(=O)[nH]1
Product: O=c1[nH]c(NCCSCc2nccs2)ncc1Cc1ccncc1

Procedure:
An intimate mixture of 5-(4-pyridylmethyl)-2-methylthio-4-pyrimidone (1.55 g) and 2-(2-thiazolylmethylthio)ethylamine (1.16 g) was heated at 135°-140° with frequent stirring. After cooling, the reaction mixture was triturated under water to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(4-pyridylmethyl)-4-pyrimidone. This product was acidified with dilute ethanolic hydrogen chloride, evaporated to dryness and the residue recrystallised from methanol to give the title compound m.p. 190°-195°.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:23][C@H:24]1[O:29][C@@H:28]([CH3:30])[CH2:27][NH:26][CH2:25]1>C1COCC1>[CH3:30][C@H:28]1[O:29][C@@H:24]([CH3:23])[CH2:25][N:26]([C:2]2[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:27]1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(C(=O)O)ccc(F)c2F)C[C@H](C)O1
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2,3,4-trifluorobenzoic acid (25.0 g, 142 mmol) in THF (250 mL), was added lithium bis(trimethylsilyl)amide (1M in THF, 156 mL, 156 mmol) at −78° C. under nitrogen atmosphere and the solution stirred for 45 min. To this was added a premixed solution of cis-2,6-dimethylmorpholine (17.4 mL, 142 mmol) and lithium bis(trimethylsilyl)amide (1M in THF, 156 mL, 156 mmol) (which was stirred for 45 minutes at −78° C., before the addition was made) and stirring continued for 1 h at −78° C. It was brought to room temperature and stirring continued for additional 12 hours. Solvents were evaporated and the residue dissolved in ethyl acetate, which was washed with 1N HCl, water and brine. The organic layer was dried and concentrated to give the title compound as semi-solid. Yield: 27.5 g, (72%).
Reaction SMILES: [N:1]([CH2:4][CH:5]([F:22])[CH2:6][N:7]1[C:19]2[CH:18]=[CH:17][C:16]([Br:20])=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([Br:21])[CH:12]=2)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Br:21][C:11]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:6][CH:5]([F:22])[CH2:4][NH2:1])[C:19]3[C:14]([C:13]=2[CH:12]=1)=[CH:15][C:16]([Br:20])=[CH:17][CH:18]=3
Reactant: [N-]=[N+]=NCC(F)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCC(F)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
9-(3-azido-2-fluoropropyl)-3,6-dibromo-9H-carbazole (60 mg, 0.14 mmol) and triphenylphosphine (44 mg, 0.168 mmol) were combined in 0.5 mL of THF and stirred overnight at 60° C. Upon completion 1 ml of H2O was added and the mixture was stirred for 1 hour. The mixture was extracted with EtOAc. The organic layer was washed with H2O, brine, and dried over Na2SO4 and concentrated to a white foam. This material was used in the next step without further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[NH:14][CH:13]=[CH:12]3)[CH2:4][CH2:3]1.[Cl:20]N1C(=O)CCC1=O.[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:20][C:10]1[C:9]([O:8][CH:5]2[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]2)=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][NH:14][C:15]2=[O:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1[nH]ccc2cc(OC3CCNCC3)ccc12
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]ccc2c(Cl)c(OC3CCNCC3)ccc12
Temperature: 50 °C

Procedure:
60 mg (0.21 mmol) 6-(piperidin-4-yloxy)-2H-isoquinolin-1-one-hydrochloride (12) were dissolved in 5 mL of concentrated sulphuric acid. At 0° C. 28.6 mg (0.21 mmol) of N-chloro succinimide were added and the mixture was stirred at 50° C. After 2 h the solution was poured on ice and the pH was brought to about 12 by adding solid NaOH. The aqueous solution was extracted twice with dichloromethane. The organic layers were dried with MgSO4 and evaporated. The crude product was purified by preparative HPLC. The obtained trifluoroacetate was dissolved in 2 N HCl and the solvent was removed i. vac. Dissolving the residue in water, followed by lyophilization gave the desired product as HCl-salt. Rt=0.86 min (Method A). Detected mass: 279.1/281.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19][CH3:20])=[N:15][CH:16]=2)[NH:11][C:10]1=[O:21].[H-].[Na+].Br[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19][CH3:20])=[N:15][CH:16]=2)[N:11]([CH:25]([CH3:27])[CH3:26])[C:10]1=[O:21]
Reactant: CC(C)Br
Reactant: CSc1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)N(C(C)C)C(=O)N(c1c(Cl)cccc1Cl)C2
Temperature: 90 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
A solution, cooled in ice, of 100 mg (0.27 mmol) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 6 ml of dimethylformamide was treated with 13 mg (0.33 mmol) of sodium hydride (60% w/w). After 30 minutes the mixture was treated with 0.03 ml (0.3 mmol) of 2-bromopropane and then heated to 90° C. for 2 hours, cooled and left to stand for 3 days. The mixture was evaporated and the residue was treated with 30 ml of dichloromethane and 30 ml of water. The phases were separated and the organic phase was washed with 30 ml of water, dried over magnesium sulfate, filtered and evaporated to give 60 mg (54%) of 3-(2,6-dichlorophenyl)-1-isopropyl-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid. [Mass spectrum (ESI) MH+ =383].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:38][O:39][C:40]([C:42]1[C:50]2[N:49]=[C:48]([NH2:51])[NH:47][C:46]=2[CH:45]=[C:44]([CH2:52][CH2:53][CH3:54])[CH:43]=1)=[O:41]>>[CH3:38][O:39][C:40]([C:42]1[C:50]2[N:49]=[C:48]([NH:51][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[NH:47][C:46]=2[CH:45]=[C:44]([CH2:52][CH2:53][CH3:54])[CH:43]=1)=[O:41]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: CCCc1cc(C(=O)OC)c2nc(N)[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCCc1cc(C(=O)OC)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Yield: 75 %

Procedure:
0.4 g (75%) of 2-[(isoquinoline-3-carbonyl)-amino]-6-propyl-1H-benzoimidazole-4-carboxylic acid methyl ester was synthesized from 0.25 g (1.4 mmol) of isoquinoline-3-carboxylic acid, 0.6 g (1.6 mmol) of HBTU, and 0.3 g (1.3 mmol) of the above synthesized 2-Amino-6-propyl-1H-benzoimidazole-4-carboxylic acid methyl ester as described in general procedure A. LCMS: 389 (M+1)+.