Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: O=C(O)c1ccc(CBr)cc1Br
Reaction time: 1 h
Yield: 51.9 %

Procedure:
2-Bromo-4-methylbenzoic acid (33.5 g, 156 mmol, 1 eq) and N-Bromosuccinimide (40.7 g, 233 mmol, 1.5 eq) were dissolved in refluxing 1,2-dichloroethane (600 ml) and a catalytic amount of AIBN was added. The mixture was left stirring under a lamp and under nitrogen for 1 hour. The solvent was removed and the mixture was partitioned between 600 ml of water and 600 ml EtOAc. The organic layer was washed twice with water (600 ml), washed once with brine (600 ml) and then dried with sodium sulfate. The solvent was removed and the crude mixture was triturated with 10% EtOAc/Hexane for 2 hours and 23.8 g (52%) of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][NH2:23])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:13][C:4]1[CH:3]=[C:2]([NH:23][CH2:22][CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: NCCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)cc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (2.2 g, 10.0 mmol) and 3-fluoro-phenylethylamine (1.5 g, 11.0 mmol) in DMF (20 mL) was added K2CO3 (4.1 g, 30 mmol) at r.t. The reaction mixture was stirred at r.t. overnight. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give ethyl 6-chloro-4-(3-fluorophenethylamino)nicotinate (1.1 mg, 34%). LRMS (M+H+) m/z 323.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[CH2:20][CH2:19][CH2:18][NH:17][C:16]=2[N:15]=1)[CH3:2].C1C=CC(O[C:40](OC2C=CC=CC=2)=[N:41][C:42]#[N:43])=CC=1.O.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[N:7]1[CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][NH:17][C:16]=3[N:15]=2)[C:40]1=[N:41][C:42]#[N:43])[CH3:2]
Reactant: CCOC(=O)C[C@H](NCCNCCCc1ccc2c(n1)NCCC2)c1ccc(OC)nc1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](c1ccc(OC)nc1)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=NC#N
Temperature: 75 °C

Procedure:
A solution of the diamine 1-2 (120 mg, 0.27 mmol), diphenyl cyanocarbonimidate (65 mg, 0.27 mmol) and K2C03 (94 mg, 0.68 mmol) in EtOAc (10 mL) and water (5 mL) was stirred at room temperature for 16 hours then heated to 75° C. for 6 hours. After cooling, the mixture was poured into saturated Na2CO3, extracted with EtOAc and washed successively with water and brine. The EtOAc layer was dried (MgSO4) and concentrated in vacuo to give 1-3 an oil which was used as such in the next step.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([C:9]2[C:10]3[CH:19]=[CH:18][NH:17][C:11]=3[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:8]=1.[NH:27]1[CH:31]=[CH:30][CH:29]=[N:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH3:15][N:13]1[CH:14]=[C:9]([C:7]2[CH:8]=[C:3]([CH2:2][N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)[CH:4]=[CH:5][C:6]=2[O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]2[CH:19]=[CH:18][NH:17][C:11]=2[C:12]1=[O:16]
Reactant: Cn1cc(-c2cc(CO)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Reactant: c1cn[nH]c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(Cn3cccn3)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.2 %

Procedure:
A mixture of Example 20b (0.04 g, 0.115 mmol), 1H-pyrazole (0.016 g, 0.231 mmol), and triphenylphosphine (0.061 g, 0.231 mmol) in tetrahydrofuran (1 mL) was stirred for 2 minutes. To this solution was added di-t-butyl azodicarboxylate (DTBAD, 0.053 g, 0.231 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (C18, 10-80% acetonitrile/water with 0.1% TFA) to afford 0.006 g of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 3.49 (s, 3H), 5.37 (s, 2H), 5.21 (t, J=5.8 Hz, 1H), 6.17-6.18 (m, 1H), 6.28 (t, J=1.98 Hz, 1H), 6.86 (d, J=7.63 Hz, 2H), 6.97 (d, J=8.24 Hz, 1H), 7.02 (t, J=7.32 Hz, 4H), 7.22-7.29 (m, 5H), 7.39 (d, J=2.14 Hz, 1H), 7.47 (d, J=1.83 Hz, 1H), 7.53-7.46 (m, 3H), 7.86 (d, J=2.44 Hz, 1H), 11.97 (s, 1H). (ESI+) m/z 397.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:4]=[CH:5][N:6]2[CH2:11][CH:10]([OH:12])[CH2:9][CH2:8][C:7]=12.Cl[CH2:14][C:15]([N:17]1[CH2:36][CH2:35][C:20]2[N:21]=[C:22]([NH:25][CH:26]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[N:23]=[CH:24][C:19]=2[CH2:18]1)=[O:16].O>CN(C)C=O>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH:26]1[NH:25][C:22]1[N:23]=[CH:24][C:19]2[CH2:18][N:17]([C:15](=[O:16])[CH2:14][O:12][CH:10]3[CH2:11][N:6]4[CH:5]=[CH:4][N:3]=[C:7]4[CH2:8][CH2:9]3)[CH2:36][CH2:35][C:20]=2[N:21]=1
Reactant: OC1CCc2nccn2C1
Reactant: O=C(CCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COC1CCc2nccn2C1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.8 %

Procedure:
Add sodium hydride (0.054 g; 1.85 equiv; 1.35 mmoles) to a solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ol (0.252 g; 2.0 equiv; 1.46 mmoles) in dimethylformamide (2 mL) and stir at room temperature for 10 minutes. Add this mixture to a 0° C. solution of 2-chloro-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]ethanone (0.25 g; 1.0 equiv; 0.729 mmoles) in dimethylformamide (2 mL). Stir the resulting solution at 0° C. for 1 hour, then add water and load onto a SCX ion exchange column. Elute off the crude product (methanol to 7N ammonia in methanol). Further purify the product by reverse phase chromatography to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yloxy)ethanone (0.035 g; 11%) as a white foam. MS (m/z): 445(M+1).
Reaction SMILES: [I-].[F:2][C:3]1([F:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]3[CH:16]=[C:15]([CH3:17])[S:14]/[C:13]/3=[N:18]\[C:19]([N:21]3[CH:25]=[CH:24][N+](C)=C3)=[O:20])=[CH:11][C:5]=2[O:4]1.[CH:28](N(C(C)C)CC)(C)C.CC(N)C>C(#N)C>[F:2][C:3]1([F:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]3[CH:16]=[C:15]([CH3:17])[S:14]/[C:13]/3=[N:18]\[C:19]([NH:21][CH:25]([CH3:28])[CH3:24])=[O:20])=[CH:11][C:5]=2[O:4]1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Solvent: CC(C)N
Solvent: CC#N
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)O3)/c(=N/C(=O)NC(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 20 mL vial, a solution of (Z)-1-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-methylthiazol-2(3H)-ylidenecarbamoyl)-3-methyl-1H-imidazol-3-ium iodide (Example 40B, 48 mg, 0.09 mmol) dissolved in acetonitrile (0.5 mL) was added followed by the addition of diisopropylethylamine (21 μL, 0.12 mmol) dissolved in acetonitrile (0.5 mL). Then, to the solution was added propan-2-amine (5.9 mg, 0.10 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (acetonitrile/water 0.1% TFA gradient elution method) to supply the titled compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 1.07 (6 H) 2.22 (3 H) 3.65-3.83 (1 H) 6.99 (1 H) 7.32 (1 H) 7.43 (1 H) 7.61 (1 H); MS (ESI) m/z 356 (M+H)+
Reaction SMILES: CO.[CH3:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[N:5]=1.[F:23][C:24]1[C:25]([CH3:32])=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[F:23][C:24]1[CH:29]=[CH:28][C:27]2[NH:30][C:10]([C:9]3[C:4]([CH3:3])=[N:5][C:6]([NH:12][CH2:13][CH2:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:7][CH:8]=3)=[N:31][C:26]=2[C:25]=1[CH3:32]
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Reactant: Cc1c(F)ccc(N)c1N
Agent: O=[Mn]=O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1-c1nc2c(C)c(F)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
[5-(5-Fluoro-4-methyl-1 H-benzoimidazol-2-yl)-pyrimidin-2-yl]-3-(1-methyl-piperidin-4-yl)-propyl]-amine. A mixture of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-methanol (0.14 g, 0.49 mmol) in toluene (3 mL) was added MnO2 (0.22 g, 2.48 mmol). After 30 min at 70° C., the mixture was filtered through diatomaceous earth. The filtrate was concentrated and immediately dissolved in DMF. A portion of this solution (corresponding to 0.05 mg, 0.17 mmol of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde) was then treated with 4-fluoro-3-methyl-benzene-1,2-diamine (1.1 equiv.) and Na2H2S2O5 (1.25 equiv.) at 90° C. for 12 h. The reaction mixture was purified by FCC to afford the title compound. MS: mass calcd. for C22H29FN6, 396.24; m/z found, 397.2 [M+H]+. 1H NMR (CD3OD): 8.62 (s, 1H), 7.55 (dd, J=8.0, 3.9 Hz, 1H), 7.17 (dd, J=10.3, 8.8 Hz, 1H), 3.60 (t, J=6.9 Hz, 2H), 3.10-2.99 (m, 2H), 2.71 (s, 3H), 2.66 (d, J=1.4 Hz, 3H), 2.44 (s, 3H), 2.26-2.17 (m, 2H), 1.98-1.88 (m, 2H), 1.87-1.77 (m, 2H), 1.55-1.36 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10](CC3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Fc1ccc([C@H]2CN(Cc3ccccc3)CCO2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCO[C@@H](c2ccc(F)cc2)C1
Reaction time: 3 h
Yield: 125.9 %

Procedure:
To a solution of (2S)-2-(4-fluorophenyl)-4-(benzyl)morpholine (1.00 g, 3.67 mmol) in toluene (10 mL) was added a solution of ethyl chloroformate (0.39 mL, 4.04 mmol) in toluene (5 mL) at 89° C. The mixture was stirred for 3 hrs and the solvent was evaporated to give ethyl (S)-2-(4-fluorophenyl)morpholine-4-carboxylate (1.17 g) as a black oil.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[C:15]1([C:21]2[O:25][C:24]([C:26]([N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:1].[ClH:1].[C:15]1([C:21]2[O:25][C:24]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])=[CH:23][CH:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccccc3)o2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(c1ccc(-c2ccccc2)o1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 89 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(5-phenylfuran-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (58.9 mg, 0.102 mmol). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 39.6 mg (89%) of the desired product as a white solid. LC-MS: RT=4.63 min, [M+H]+=364.1.
Reaction SMILES: [ClH:1].[CH:2]1([C:5]#[N:6])[CH2:4][CH2:3]1.[CH2:7]([O:9]CC)[CH3:8]>CCO>[ClH:1].[CH2:7]([O:9][C:5]([CH:2]1[CH2:4][CH2:3]1)=[NH:6])[CH3:8]
Reactant: CCOCC
Reactant: N#CC1CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=N)C1CC1
Temperature: 0 °C
Yield: 59 %

Procedure:
A steady stream of HCl gas was slowly passed through a solution of cyclopropancarbonitril (25 g, 373 mmol) in EtOH (17.2 ml). After 15 h the reaction mixture was cooled to 0° C. and diethylether was added dropwise. The precipitated title compound was filtered and obtained as a colourless crystalline material (32.9 g, 220 mmol, 59%). MS: m/e=112.2 (M−H).
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:30])[C:14]=2[C:18](=[O:29])[NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23][CH2:22]2)[C:9]1=[O:31])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>>[Cl:30][C:13]1[CH:12]=[CH:11][C:10]2[C:9](=[O:31])[N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[CH:17]=[CH:16][C:15]=2[C:14]=1[C:18]([NH:19][CH2:20][CH:21]1[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23][CH2:22]1)=[O:29]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](CO)n1ccc2c(C(=O)NCC3CCC(F)(F)CC3)c(Cl)ccc2c1=O

Procedure:
(R)-2-(6-Chloro-5-((4,4-difluorocyclohexyl)methylcarbamoyl)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (140 mg, 0.00029 mol) and potassium carbonate (140 mg, 0.0010 mol) were stirred in methanol (6 mL, 0.1 mol) at room temperature for 1 hour, concentrated, purified by reverse phase preparative HPLC to afford the desired product as a white solid. (77 mg, 63%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[N:14]=[CH:15][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(OCCCOCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: c1ccc(COCCCOc2ncc(C3CCNCC3OCc3ccc4ccccc4c3)cn2)cc1

Procedure:
In an analogous manner to that described in Example 125 (h), from tert-butyl (3RS,4RS)-4-[2-(3-benzyloxy-propoxy)-pyrimidin-5-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained 2-(3-benzyloxy-propoxy)-5-[(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-pyrimidine in the form of a yellowish gum; MS: 485 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.[CH:10]([O:12][CH2:13][CH3:14])=[CH2:11].C(=O)(O)[O-].[Na+]>Cl>[CH3:9][CH:4]1[C:5](=[O:8])[C:6]([O:7][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])=[C:2]([CH3:1])[O:3]1
Reactant: C=COCC
Reactant: CC1=C(O)C(=O)C(C)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(C)OC1=C(C)OC(C)C1=O
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
To a heterogenous solution of 2,5-dimethyl-4-hydroxy-3-(2H)-furanone (133.0 g, 1.0 mole) and ethyl vinyl ether (144.0 g, 2.0 moles) at 10° C., under N2, is added dropwise, concentrated hydrochloric acid (1.0 g). The temperature rises to 11° C. and the solution becomes homogeneous. It is stirred for 1.5 hours, and then the coolant is removed. Stirring is continued at room temperature for an additional six hours, after which the reaction is quenched by the addition of solid sodium bicarbonate (10 g, 0.12 mole). The reaction mixture is washed with 100 ml water and a second time with 100 ml of 5% NaHCO3. The product is dried over Na2SO4 and distilled to give a 78.9% yield (161.8 g) of 2,5-dimethyl-4-[(1'-ethoxy)ethoxy]-3(2H)-furanone, b.p. 91° C. (0.05 torr), IR (neat, film) 1200, 1625, 1700, 2030, 2978 cm-1 ; 1H NMR (CDCl3) δ1.20 (t, J=8 Hz, 3), 1.32 (d, J=5 Hz, 3), 1.42 (d, J=7 Hz, 3), 2.2 (S, 3), 3.72 (m, 2), 4.48 (q, J=7 Hz, 1), 5.32 (q, J=5 Hz, 1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=2)=[C:7]([OH:9])[CH:8]=1)[CH3:2].C(N(CC)CC)C.[C:25](O)(=[O:27])[CH3:26]>CN(C)C=O>[C:25]([O:9][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=1)(=[O:27])[CH3:26]
Reactant: CCc1ccc(Oc2cccc(F)n2)c(O)c1
Reactant: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2cccc(F)n2)c(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
To a solution of 5-Ethyl-2-(6-fluoro-pyridin-2-yloxy)-phenol (20 mg; 0.09 mmol), under argon, in dimethylformamide (2 mL), cooled to 0° C., was added triethylamine (36 μL; 0.26 mmol) and acetic acid (10 μL; 0.18 mmol). The reaction mixture was allowed to stir overnight, with gradual warming to room temperature. The reaction was concentrated, diluted with saturated NaHCO3 (5 mL) and extracted with ethyl acetate (3*3 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, the title compound (8 mg; 34%) was obtained as clear oil, after purification on neutral alumina gel (cyclohexane/ethyl acetate: 9/1).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[S:1]1[C:5]2[CH2:6][N:7]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)Cc1ccsc1CN2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3sccc3Cc3ccccc32)cn1

Procedure:
As described for Example 1, 9,10-dihydro-4-H-thieno[2,3-c][1]benzazepine in dichloromethane, in the presence of triethylamine is reacted with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a non-crystalline yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][C:27]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][C:27]=1[O:35][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1cc2cc[nH]c2cc1F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3F)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 95 °C
Yield: 47.7 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (282 mg, 0.662 mmol), 6-fluoro-5-hydroxyindole (120 mg, 0.794 mmol), (prepared as described for the starting material in Example 242), in DMF (3 ml) containing potassium carbonate (137 mg, 0.994 mmol) was heated at 95° C. for 3 hours. After cooling, the residue was poured in water (12 ml) and the pH was adjusted to 8. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by preparative column chromatography on C18 silica eluting with 60% methanol in aqueous ammonium carbonate (2 g ammonium carbonate/liter saturated with CO2). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether and the solid was filtered, dried under vacuum to give 4-(6-fluoroindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (147 mg, 48%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:33][C:34]1[C:39]([C:40]#[N:41])=[C:38](Cl)[N:37]=[CH:36][N:35]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[NH2:33][C:34]1[C:39]([C:40]#[N:41])=[C:38]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[NH:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:37]=[CH:36][N:35]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nn2ccc(Sc3ccccc3NCCN(C)C)c2c(=O)n1-c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nn2ccc(Sc3ccccc3NCCN(C)C)c2c(=O)n1-c1ccccc1
Yield: 2.9 %

Procedure:
(S)-2-(1-Aminoethyl)-5-((2-((2-(dimethylamino)ethyl)amino)phenyl)thio)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (267 mg, 0.54 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (123 mg, 0.81 mmol) and DIEA (280 μl, 1.61 mmol) in 10 ml of tert-BuOH were stirred overnight at 80° C. After evaporation of the solvent under reduced pressure, the residue was purified using SP1® Purification System (0% to 20%, DCM-MeOH) to obtain 9 mg of the title compound as a solid. Purity 99%.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:28]
Reactant: NCCCSc1ccncc1
Reactant: Cc1ccsc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)NCCCSc1ccncc1
Yield: 84.5 %

Procedure:
In 100 ml of benzene was suspended 3.00 g (21.1 mmol) of 3-methyl-2-thiophenecarboxylic acid, oxalyl chloride [7.36 ml (84.4 mmol)] was added and the mixture was refluxed for 2 hours. After cooling, the solvent was distilled off to obtain 3.40 g of 3-methylthenoyl chloride (yield: quant.). To a solution of 1.50 g (6.23 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.61 ml (18.7 mmol) of triethylamine in 60 ml of methylene chloride, 1.20 ml (7.48 mmol) of the 3-methylthenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 1.54 g of the desired compound (yield: 84.5%, pale yellow powder).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([CH:28]=[CH:29][C:30]#[N:31])[C:16]=3[N:15]=2)[C:5]1=[O:32])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][CH:26]=[C:27]([CH2:28][CH2:29][C:30]#[N:31])[C:16]=3[N:15]=2)[C:5]1=[O:32])([CH3:2])[CH3:3]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(C=CC#N)cccc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2c(CCC#N)cccc21
Yield: 73.6 %

Procedure:
A mixture of 3-[2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-4-yl]-acrylonitrile (100 mg, 0.234 mmol) and 10% Pd-C (10 mg) in THF (2 mL) and methanol (25 mL) was rocked in a Parr shaker under a hydrogen atmosphere (50 psi) for 15 hrs. The catalyst was removed by filtration and the filtrate purified by flash chromatography (eluent hexane:ethyl acetate 1:1) to afford 3-[2-(3-Isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-4-yl]-propionitrile (74 mg, 74%) as a white solid: