Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]=[C:10]2[CH2:24][CH:13]3[CH2:14][N:15]([C:17](OC(C)(C)C)=[O:18])[CH2:16][CH:12]3[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:26](F)(F)C(O)=O.ClCC(OC(=O)CCl)=O.[Na+].[I-:42]>C(Cl)Cl.CC(C)=O.C(N(CC)CC)C>[I:42][CH2:26][C:17]([N:15]1[CH2:16][CH:12]2[CH2:11][C:10](=[N:9][O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:24][CH:13]2[CH2:14]1)=[O:18]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC2CC(=NOCc3ccccc3)CC2C1
Reactant: [I-]
Agent: O=C(CCl)OC(=O)CCl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CI)N1CC2CC(=NOCc3ccccc3)CC2C1

Procedure:
The title compound of example F is treated with trifluoroacetic acid in methylene chloride at room temperature. The volatiles are removed under reduced pressure to afford a residue which is treated with chloroacetic anhydride and triethylamine. The chloroacetylated material is then reacted with NaI in acetone to give the title compound.
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-:3])=[O:2].C[O:12][CH:13](OC)[CH2:14][CH2:15][CH2:16][CH:17]=O>CCOC(C)=O.CCCCCC>[N+:1]([C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH:17][CH2:16][CH2:15][CH2:14][CH:13]=[O:12])([O-:3])=[O:2]
Reactant: COC(CCCC=O)OC
Reactant: O=[N+]([O-])Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=CCCCC=C(c1ccccc1)[N+](=O)[O-]
Yield: 41.1 %

Procedure:
Prepared according to the general procedure B from 1-(nitromethyl)benzene 112d (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (E/Z=6.7/1) (1.44 g, 41% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][N:11]([CH3:28])[S:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])(=[O:14])=[O:13]>C(Cl)Cl>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][S:12]([N:11]([CH3:28])[CH3:10])(=[O:13])=[O:14])(=[O:23])=[O:24])=[O:27])[N:3]=1
Reactant: CN(C)S(=O)(=O)Oc1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(C)nc(N)n1
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2OS(=O)(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a suspension of 0.37 g (0.003 mole) 2-amino-4,6-dimethylpyrimidine in 5 ml methylene chloride was added 1.2 g (0.004 mole) 2-(dimethylaminosulfonyloxy)-benzenesulfonyl isocyanate. The reaction exothermed (18°-26° C.) and was stirred at room temperature for 3 hours. The resultant white precipitate was filtered to give 0.9 g of a white solid, m.p. 195°-196° C. The infrared spectrum shows absorption bands at 1705, 1380, 1180 cm-1.
Reaction SMILES: Br.C([N:4]([CH2:7]C)[CH2:5][CH3:6])C.[Br:9][C:10]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([OH:21])=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C(Cl)Cl>[CH3:7][NH:4][CH2:5][CH2:6][C:11]1[CH:10]=[CH:18][C:17]([OH:19])=[CH:16][CH:15]=1.[CH3:7][N:4]([CH2:5][CH2:6][C:11]1[CH:10]=[CH:18][C:17]([OH:19])=[CH:16][CH:15]=1)[C:12]([C:11]1[CH:15]=[C:16]([OH:21])[C:17]([O:19][CH3:20])=[CH:18][C:10]=1[Br:9])=[O:13]
Reactant: COc1cc(Br)c(C(=O)Cl)cc1O
Reactant: CCN(CC)CC
Agent: Br
Solvent: ClCCl
Product: CNCCc1ccc(O)cc1
Product: COc1cc(Br)c(C(=O)N(C)CCc2ccc(O)cc2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A separate solution of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine (A12) was prepared by mixing A12.HBr (100 g), triethylamine (360 mL) in methylene chloride (1000 mL). To this A12 solution was added slowly the above mentioned B13-Cl solution with agitation at room temperature. The reaction mixture was stirred for another one hr at room temperature after the addition was completed. The solid precipitate was removed by filtration and the filter cake was washed with methylene chloride. The combined methylene chloride solution was distilled until the pot temperature reached 55° C. To this residue, methanol (198 g) was added. The methanol of the resulted solution was removed by distillation until the pot temperature reached 70° C. The residue was cooled to room temperature and 15% NaOH/MeOH solution (460 mL) was added. The resulting solution was stirred at room temperature for 12 hr. The reaction mixture was acidified with 36% hydrochloric acid until the pH was between 3 and 5. The solution was set for distillation until the pot temperature reached 75° C. To the residue was added methylene chloride (200 mL) and 1N HCl (1500 mL) and stirred at 0° C. for 4 hr. The precipitate was collect by filtration to give 100 g (56% yield) of N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2).
Reaction SMILES: C[O-].[Na+].[N:4]([CH2:7][C:8]([O:10][CH2:11]C)=[O:9])=[N+]=[N-].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([O:22][CH3:23])[CH:15]=1>CO>[CH3:11][O:10][C:8]([C:7]1[NH:4][C:20]2[C:17]([CH:18]=1)=[C:16]([O:22][CH3:23])[CH:15]=[C:14]([F:13])[CH:21]=2)=[O:9]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: COc1cc(F)ccc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(OC)cc(F)cc2[nH]1
Temperature: -20 °C
Reaction time: 3.5 h

Procedure:
Sodium methoxide solution (25% by weight in methanol, 22.25 mL) and methanol (52 mL) were added to a flask and cooled to −20° C. using an acetonitrile/dry ice bath. Ethyl 2-azidoacetate (25% by weight in ethanol, 50.3 g) and 4-fluoro-2-methoxybenzaldehyde (5.00 g, dissolved in ethyl 2-azidoacetate solution) were added drop-wise to the stirring sodium methoxide solution at −20° C. The solution was then stirred at −20° C. for 3.5 hours, then at 0° C. for one hour. The solution was poured over ice, vacuum filtered, and washed with water. The filtered solid was taken up in xylenes (100 mL), washed twice with brine, and dried using anhydrous sodium sulfate and filtered. In a separate flask xylenes (50 mL) was brought to reflux. The xylene solution containing the filtered material was added drop-wise to the refluxing xylenes. The solution was then refluxed for five hours, cooled, and placed in a freezer for 16 hours. The precipitate was filtered out. The volume of the filtrate was reduced on vacuum to generate a second crop of precipitate, which was washed with hexanes, then 5% ethyl acetate in hexanes and combined with material from the first filtration.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][C:15]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:31])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:31])=[N:14][C:15]([C:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:27])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1nc2cc(OCc3ccccc3)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccc(OCc3ccccc3)cc2n1
Temperature: 56 °C
Reaction time: 0.03 h
Yield: 72 %

Procedure:
To phosphorous oxychloride (10 mL) cooled to 5° C. was added portionwise 7-(benzyloxy)-2-(4-fluorobenzoyl)quinazolin-4(3H)-one (500 mg, 1.34 mmol) followed by the addition of DMF (4 drops). The mixture was warmed to 56° C. over 10 min and held at this temperature for 2 min, then the heating bath was removed. The mixture was concentrated, and the residue was diluted with EtOAc, then the solution was and washed with cold water, saturated sodium bicarbonate (aq), brine, and dried over sodium sulfate. The solution was concentrated to afford (7-(benzyloxy)-4-chloroquinazolin-2-yl)(4-fluorophenyl)methanone as an off-white solid (380 mg, 72%). 1H NMR (300 MHz, DMSO-d6) δ ppm 5.40 (s, 2H) 7.37-7.45 (m, 5H) 7.52-7.55 (m, 2H) 7.66-7.71 (m, 2H) 8.09-8.14 (m, 2H) 8.31 (d, J=9.04 Hz, 1H). LC-MS (ESI) m/z 393 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1=[O:35].C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:34]1[CH2:33][CH2:32][CH2:31][C:30](=[O:35])[CH:29]=1)=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COC1CCCCC1
Reactant: O=C1CCCCC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c(Cl)c1COC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.53 g (1.53 mmol) of 2-chloro-3-cyclohexanyloxymethyl-4-methylsulfonylbenzoic acid was treated with 2 drops of N,N-dimethylformamide and 0.59 g (4.58 mmol) of oxalyl chloride in 23 ml of methylene chloride and the mixture was refluxed for 2.5 h. It was then stripped off on a rotary evaporator, the residue was taken up in 23 ml of methylene chloride and the mixture was treated at 0° C. with 0.19 g (1.68 mmol) of cyclohexanedione and 0.46 g (4.58 mmol) of triethylamine. It was stirred at room temperature for 4 h. It was then concentrated on a rotary evaporator and purified by chromatography (silica gel, ethyl acetate:hexane=1:1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([OH:15])[CH:7]=1.C[Si](Cl)(C)C.Br[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[SiH3]Cl>O1CCOCC1>[OH:15][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: NCCOc1ccc(C(=O)O)c(O)c1
Reactant: Brc1ncccn1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [SiH3]Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(OCCNc2ncccn2)cc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.5 %

Procedure:
A mixture of compound (14) (20 g), dissopropylethylamine (74 mL), trimethylsilylchloride (21.6 mL) and 2-bromopyrimidine (Lancaster, 13.5 g) were combined in 350 mL 1,4-dioxane at room temperature, then brought to reflux under N2 atmosphere. After 2 days, an additional 12 mL silylchloride was added, and the mixture continued at reflux for an additional 2 days (until TLC showed no starting material remained). The reaction mixture was cooled to ambient temperature, concentrated to dryness in vacuo on a rotary evaporator and the residue suspended in water. The heterogeneous mixture was refluxed briefly, allowed to cool to room temperature, the product collected on a vacuum filter and air dried to give 15.3 g of (16), as a tan powder. NMR (400 MHz, DMSO-d6) d 12 (very broad, 2H) 8.3 (d, J=5 Hz, 2H) 7.7 (d, J=9 Hz, 1H), 7.28 (t, J=6 Hz, 1H), 6.57 (t, J=5 Hz, 1H), 6.49 (m, 2H), 4.13 (t, J=6 Hz, 2H), 3.62 (q, 2H); MS (+ESI) m/z 276 (M+H)+; IR (KBr) n (cm−1) 3275, 3000, 1660, 1625.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[F-].[CH2:14]([N+:18](CCCC)(CCCC)CCCC)CCC.C[Si](C#N)(C)C>CC#N>[C:14]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:18]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#N
Agent: [F-]
Solvent: CC#N
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
To an ice-cold solution of methyl 3-bromomethylbenzoate (9.1 g, 40 mmol) in CH3CN (108 mL) was added tetrabutylammonium fluoride (17.3 mL, 60 mmol) and trimethylsilylcyanide (8.0 mL, 60 mmol), and the reaction mixture was heated at reflux for 20 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, 1:1 EtOAc/hexanes) provided methyl 3-cyanomethylbenzoate as a clear oil (3.0 g, 43%): 1H NMR (300 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.92 (d, J=8 Hz, 1H), 7.64 (d, J=8 Hz, 1H), 7.56 (t, J=8 Hz, 1H), 4.16 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([N:15]1[CH:19]=[C:18]([NH:20][C:21](=[O:27])[CH:22]([NH2:26])[CH2:23][CH2:24][CH3:25])[N:17]=[CH:16]1)([CH3:14])[CH2:3][CH2:4][NH:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7].[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[C:37]([F:39])[CH:38]=1)[CH2:35][C:34](=O)[CH2:33][CH2:32]2>>[CH3:14][C:2]([N:15]1[CH:19]=[C:18]([NH:20][C:21](=[O:27])[C@@H:22]([NH:26][CH:34]2[CH2:33][CH2:32][C:31]3[C:36](=[C:37]([F:39])[CH:38]=[C:29]([F:28])[CH:30]=3)[CH2:35]2)[CH2:23][CH2:24][CH3:25])[N:17]=[CH:16]1)([CH3:1])[CH2:3][CH2:4][NH:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7]
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CCNC(C)c2ccccc2)cn1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CCN[C@H](C)c2ccccc2)cn1

Procedure:
2-Amino-pentanoic acid {1-[1,1-dimethyl-3-(1-phenyl-ethylamino)-propyl]-1H-imidazol-4-yl}-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to afford the title: 538.6 m/z (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([Cl:27])[N:18]=1>CN1C(=O)CCC1.O>[Cl:27][C:19]1[N:18]=[C:17]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(Cl)cc3ccccc23)C1
Temperature: 135 °C
Reaction time: 0.08 h
Yield: 300.3 %

Procedure:
To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.134 g, 6.06 mmol) in NMP (10 mL) at 0° C. was added NaH (60%) (202 mg, 5.05 mmol). The mixture was stirred for 5 minutes and 1,3-dichloroisoquinoline (1.000 g, 5.05 mmol) was added. The reaction mixture was stirred at RT for 5 minutes and then heated at 135° C. for 30 minutes in a microwave reactor. The mixture was diluted with water (400 mL) and extracted with EtOAc (3×125 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with a gradient of 25-50% EtOAc in hexane to give the title compound (5.29 g, 75%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=14.16 Hz, 9H), 2.12-2.34 (m, 2H), 3.42-3.58 (m, 3H), 3.69 (td, J=12.33, 4.64 Hz, 1H), 5.63-5.76 (m, 1H), 7.59 (s, 1H), 7.64 (ddd, J=8.30, 7.08, 1.22 Hz, 1H), 7.81 (td, J=7.57, 1.46 Hz, 1H), 7.87-7.92 (m, 1H), 8.11-8.19 (m, 1H); ESI-MS m/z [M+H-tert-butyl]+ 293.5.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>C1COCC1.CN(C=O)C.CCOC(C)=O>[N:1]1([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of benzimidazole (5 mmol, 0.97 g) in THF/DMF (5:1, 20 mL) is treated with sodium hydride (0.5 g), stirred for 10 minutes at room temperature, treated with methyl 4-(bromomethyl)benzoate (1.4 g, 6 mmol) and stirred at room temperature overnight. The reaction mixture is diluted with EtOAc, washed with saturated NaHCO3, dried over MgSO4 and concentrated in vacuo to give methyl 4-[(1H-benzoimidazol-1-yl)methyl]benzoate as a solid residue. The residue is dissolved in MeOH/water (2:1), treated with lithium hydroxide (0.42 g, 10 mmol), stirred at room temperature overnight, evaporated to remove the MeOH. The resultant concentrate is diluted with 1N sodium hydroxide (50 mL), washed with EtOAc, acidified with concentrated HCl and extracted with EtOAc. The extracts were combined, dried over MgSO4 and concentrated to dryness to give the title product in 75% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 8.08 (s, 1H); 7.99 (d, J=8 Hz, 2H); 7.78 (d, J=8 Hz, 1H); 7.24-7.27 (m, 5H); 5.49 (s, 2H). LCMS (ESI+) 253 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][C:25]#[N:26])=[CH:4][CH:3]=1.[CH2:27](I)[CH3:28].CC(C)([O-])C.[K+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH2:27][CH3:28])[C:25]#[N:26])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(CC#N)c23)c(C)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(C#N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of [9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]acetonitrile (176.0 mg, 0.478 mmol) in tetrahydrofuran (4.5 mL) was added ethyl iodide (57.3 μL, 0.717 mmol) and potassium tert-butoxide (75.8 mg, 0.574 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr under nitrogen atmosphere. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-60% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless powder (154.3 mg, 0.390 mmol, 82%).
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:5]([CH:9]=[O:10])=[N:6][NH:7][CH:8]=1.[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl.O>CN(C=O)C.C(OCC)(=O)C>[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16][N:7]1[CH:8]=[CH:4][C:5]([CH:9]=[O:10])=[N:6]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1n[nH]cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc(C=O)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride was added slowly to a clear solution of commercially available 4-bromo-1H-pyrazole-3-carbaldehyde Compound 2a (1 g, 3.56 mmol) in DMF (20 mL). The reaction was stirred at ambient temperature for 20 min; then 2-(trimethylsilyl)ethoxy-methyl chloride (755.7 μL, 4.27 mmol) was added dropwise to the reaction mixture. After the resultant solution was stirred at ambient temperature overnight, water (1 mL) was added to quench the reaction. The reaction mixture was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate, and saturated sodium chloride. The organic solvent was dried over magnesium sulfate. After filtration and evaporation of the solvent in vacuo, the crude product was purified by flash chromatography (10:1 to 4:1 hexane/ethyl acetate) to yield (2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-3-carbaldehyde Compound 3a (620 mg, 57% yield) as white solid. 1H NMR (300 MHz, CDCl3) δ 9.97 (s, 1H), 7.64 (s, 1H), 5.81 (s, 2H), 3.62 (t, 2H), 0.93 (t, 2H), 0 (s, 9H); MS (ESI) m/z: 306.7 (M+H+), 328.7 (M+Na+).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.CN(C=O)C.[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][NH:16][CH2:15]1.CCN(C(C)C)C(C)C>O>[Br:7][C:5]1[N:6]=[C:2]([N:16]2[CH2:15][C@H:14]([CH3:13])[O:19][C@H:18]([CH3:20])[CH2:17]2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2nc(Br)cs2)C[C@H](C)O1
Temperature: 70 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A 1 L flask equipped with a mechanical stirrer and a thermometer was charged with 2,4-dibromothiazole (60 g, 0.247 mol) and DMF (480 mL). After dissolution, cis-2,6-dimethylmorpholine (33.65 mL, 0.272 mol) and DIPEA (61.23 mL, 0.37 mol) were added under a stream of nitrogen. The reaction mixture was heated to 70° C. under nitrogen and stirred overnight. The reaction mixture was cooled to 10° C. in an ice/water bath. Then water (1 L) was added dropwise in a temperature range of 10-20° C. A slightly exothermic reaction was observed, with formation of an off-white precipitate. After the addition, the reaction mixture was stirred for 30 min. The precipitate was then filtered and washed with water (50 ml). The collected solid was dried in a vacuum oven at 50° C., yielding 52.8 g (77%) of Intermediate 1 as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][CH:22]=[N:23]3)=[C:18](OS(C(F)(F)F)(=O)=O)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.N[C:35]1[CH:36]=[CH:37][C:38](=[O:41])[NH:39][CH:40]=1.[CH:42]([NH:45]C(C)C)(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][CH:22]=[N:23]3)=[C:18]([NH:45][CH2:42][C:35]3[CH:36]=[CH:37][C:38](=[O:41])[NH:39][CH:40]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: Nc1ccc(=O)[nH]c1
Reactant: CC(C)NC(C)C
Reactant: COc1cc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)ccc1OC1CCOCC1
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2cc3ncccc3c(NCc3ccc(=O)[nH]c3)n2)ccc1OC1CCOCC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
200 mg Trifluoro-methanesulfonic acid 7-[3-methoxy-4-(tetrahydro-pyran-4-yloxy)-phenyl]-[1,6]naphthyridine-5-yl ester (6.6) was placed in 3 mL dimethylacetamide at ambient temperature before 51 mg 5-amino-1H-pyridine-2-one (2.31) and 109 mg N,N-diisopropylamine was added. The reaction was heated to 70° C. overnight in a sealed tube and then cooled to ambient temperature. After this time, additional 5-amino-1H-pyridin-2-one was added and the reaction was heated to 100° C. for 6 h, cooled to ambient temperature overnight. The reaction was then heated again at 100° C. for 24 h and then additional N,N-diisopropylamine was added and heating continued for 24 h. The reaction mixture was then cooled to ambient temperature and partitioned between water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted with additional ethyl acetate (×3) and the combined organic fractions were dried, filtered and the solvent was concentrated from the filtrate under reduced pressure. Purification by silica gel chromatography (ethyl acetate/methanol: 95:5) and then by preparative HPLC provided the title compound.
Reaction SMILES: CO.[CH2:3]([NH2:6])[CH2:4][CH3:5].C[Si](C)(C)[C:9]#[C:10][C:11]1[C:17]([Si](C)(C)C)=[C:16]([OH:22])[C:15]([CH3:23])=[C:14]([CH3:24])[C:12]=1[OH:13].[C:27](OCC)(=O)[CH3:28]>>[CH2:3]([N:6]1[C:10]([CH3:9])=[C:11]2[C:17]([C:16](=[O:22])[C:15]([CH3:23])=[C:14]([CH3:24])[C:12]2=[O:13])=[C:27]1[CH3:28])[CH2:4][CH3:5]
Reactant: CCCN
Reactant: Cc1c(C)c(O)c([Si](C)(C)C)c(C#C[Si](C)(C)C)c1O
Reactant: CCOC(C)=O
Solvent: CO
Product: CCCn1c(C)c2c(c1C)C(=O)C(C)=C(C)C2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
Following procedure A MeOH (0.8 mL) and propylamine (0.02 mL) were added to 2 (46.2 mg, 0.14 mmol) and stirred at room temperature for 2 days. Column chromatography with 3% ethyl acetate in petroleum ether gave pure yellow product in 97% yield (33.3 mg). Melting point 165°-167° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][CH:3]=1.[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O.[CH3:16][C:17]1(C)OC(=O)CC(=O)[O:18]1>CCO>[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]1[CH2:16][C:17](=[O:18])[NH:1][C:2]2=[N:6][NH:5][CH:4]=[C:3]12
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccccc1Cl
Reactant: Nc1ccn[nH]1
Solvent: CCO
Product: O=C1CC(c2ccccc2Cl)c2c[nH]nc2N1
Temperature: 65 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To a stirring solution of 5-aminopyrazole (2.0 g, 20.1 mmol) in EtOH (40 mL) was added 2-chlorobenzaldehyde (2.8 mL, 20.1 mmol), followed by Meldrum's Acid (2.9 g, 20.1 mmol). The reaction was heated to 65° C. After 16 hr, the reaction was cooled to room temperature, filtered, washed with EtOH, and dried under reduced pressure to give the title compound (3.9 g, 78% yield) as a colorless solid. LRMS m/z (APCI+) 248 (M+1).