Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:12]([CH:15]([CH2:19][C:20]#[CH:21])[C:16](O)=O)[C:13]#[CH:14].CN([C:25]([O:29]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][NH:11][C:25](=[O:29])[CH2:16][CH:15]([CH2:19][C:20]#[CH:21])[CH2:12][C:13]#[CH:14])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: C#CCC(CC#C)C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C#CCC(CC#C)CC(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
N-boc-ethylenediamine (18.3 gm, 0.1143 mol) in 50 ml of CH3CN was added slowly via an addition funnel to a stirred solution containing dipropargylacetic acid (15.56 gm, 0.1143 mol), TBTU (36.74 gm, 0.114 mol) and DIPEA (29.6 gm, 0.229 mol) in 300 ml of CH3CN at 0 C. Precipitation occurred. The ice bath was removed and the product was stirred at ambient temperature overnight (16 hours). The reaction was now totally homogeneous. The solution was concentrated in vacuo and the residue was diluted with 800 ml of water. The resulting solids were filtered, washed copiously with water, and vacuum dried to give 14.3 gm of crude product. Re-crystallization (2×) from DCM, filtration and washing with hexanes affords the product (9.85 gm, 31% yield, 98% purity by HPLC (214 nm)).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.[NH2:22][C:23]1[C:24]([Cl:29])=[N:25][CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:29][C:24]1[C:23]([N:22]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Nc1cccnc1Cl
Reactant: CN(C)CCCNc1ccccc1C(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCCNc1ccccc1C(=Nc1cccnc1Cl)c1ccccc1

Procedure:
To a mixture of 2.82 g (0.01 mole) of [2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone and 1.29 g (0.01 mole) of 3-amino-2-chloropyridine, 6.2 ml (0.048 mole) of triethylamine and 20 ml of methylene chloride stirred in an ice bath under nitrogen atmosphere was added 2.28 g (0.012 mole) of titanium tetrachloride in 10 ml of methylene chloride during a 5 minute period. The mixture was then stirred at room temperature for 2 days during which time mass spec-CI showed little change in relative intensity of M.W. 129 (starting pyridine) and M.W. 393 (title product). Water was added to the reaction mixture and stirring was continued for 1.5 hr. The mixture was filtered to remove solid and the filter cake was rinsed with methylene chloride. Saturated sodium chloride solution was added to facilitate separation of layers. The methylene chloride layer was washed once with more sodium chloride solution. The aqueous layer having a pH of about 6 was basified to about pH 8-9 with potassium carbonate and then extracted twice with methylene chloride. The latter methylene chloride layers were washed with sodium chloride solution. All the methylene chloride extracts were combined, dried and evaporated to give 4.8 g of semi-solid product. TLC of the product showed it contained evey little starting 3-amino-2-chloropyridine. Mass Spec. analysis showed the presence of compounds with molecular weight corresponding to title product (393), 3-amino-2-chloropyridine (129) and triethylamine (102) but no [2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone. 1HNMR spectrum in CDCl3 containing 1% TMS indicated the product was mostly title compound and some triethylamine. No 3-amino-2-chloropyridine was seen. The chemical shifts, multiplicities and assignments are given below. ##STR52##
Reaction SMILES: [O:1]=[C:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][C:10]([CH3:15])([CH2:13]O)[CH2:11][OH:12].B(F)(F)F.CCOCC>C(#N)C>[CH3:8][C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:12][CH2:11][C:10]([CH3:15])([CH3:13])[CH2:9][O:1]1
Reactant: CC(C)(CO)CO
Reactant: CCOC(=O)C(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)C1(C)OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
To a solution of ethyl 2-oxopropanoate (0.581 g, 5 mmol) and 2,2-dimethylpropane-1,3-diol (0.521 g, 5.00 mmol) in acetonitrile (5 mL) cooled to 0° C. was added BF3.OEt2 (0.063 mL, 0.500 mmol), and the mixture was allowed to warm to rt and stirred at rt for 18 h. The reaction mixture was quenched with sat. NaHCO3 (5 mL) and diluted with ether/hexane (1:1, 20 mL). The organic layer was washed with water, brine and dried (MgSO4). The solvent was evaporated to yield ethyl 2,5,5-trimethyl-1,3-dioxane-2-carboxylate as a clear oil (681 mg). 1H NMR (500 MHz, CDCl3) δ ppm 4.31 (2H, q, J=7.07 Hz), 3.48-3.58 (4H, m), 1.55 (3H, s), 1.35 (3H, t, J=7.17 Hz), 1.22 (3H, s), 0.69-0.75 (3H, m). Ethyl 2,5,5-trimethyl-1,3-dioxane-2-carboxylate (90 mg) was saponified (1 N NaOH, MeOH-THF) to afford Cap P-24 (69 mg). 1H NMR (500 MHz, CDCl3) δ ppm 3.53-3.64 (4H, m), 1.63 (3H, s), 1.23 (3H, s), 0.78 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](O)=[O:26])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25]([N:38]2[CH2:39][CH2:40][CH:35]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[O:26])=[CH:12][N:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Product: COc1cc2c(CC(=O)N3CCC(Cc4ccccc4)CC3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC

Procedure:
As described in Example 1, 94 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with 4-benzyl-piperidine to give 132 mg of {-4-[2-(4-benzyl-piperidin-1-yl)-2-oxo-ethyl]-6,7-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C31H39N3O5+H 534.7; found 534.1.
Reaction SMILES: C(Cl)(Cl)Cl.C[OH:6].[C:7]([NH:9][C:10](=[NH:25])[CH2:11][CH2:12][S:13][CH:14]([NH:20][C:21]([NH2:24])=[N:22][CH3:23])[C:15]1[N:16]=[CH:17][S:18][CH:19]=1)#[N:8].Cl>C(O)C>[C:7]([NH:9][C:10](=[NH:25])[CH2:11][CH2:12][S:13][CH:14]([NH:20][C:21]([NH2:24])=[N:22][CH3:23])[C:15]1[N:16]=[CH:17][S:18][CH:19]=1)(=[O:6])[NH2:8]
Reactant: CN=C(N)NC(SCCC(=N)NC#N)c1cscn1
Reactant: CO
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CN=C(N)NC(SCCC(=N)NC(N)=O)c1cscn1

Procedure:
In a mixture of 20 ml of ethanol, 30 ml of chloroform, and 10 ml of methanol was dissolved 1.0 g of N-cyano-3-(2-methylguanidinothiazol-4-ylmethylthio)propionamidine and after cooling the solution to 0°-5° C. and passing therethrough a hydrogen chloride gas for one hour, the solvents were distilled off under reduced pressure. Then, the residue formed was recrystallized from ethanol to provide 1.2 g of N-carbamoyl-3-(2-methylguanidinothiazol-4-ylmethylthio)-propionamidine.di-hydrochloride showing a melting point of 180°-182° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2.[OH-].[Na+].Cl>CO.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOc4ccccc43)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCOc4ccccc43)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-2-phenylquinoxaline-6-carboxylate (166.8 mg, 0.34 mmol, 1.00 equiv, 80%) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (84 mg, 2.10 mmol, 5.00 equiv) in water (1.5 mL) dropwise with stiffing. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the aqueous solution was adjusted to 3-4 with 1N aqueous hydrogen chloride and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (20% CH3CN up to 35% in 8 min, up to 70% in 8 min, up to 100% in 1.5 min); Detector, uv 220&254 nm. This resulted in 40 mg (31%) of 3-(2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-2-phenylquinoxaline-6-carboxylic acid as a orange solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])=[CH:4][CH:3]=1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH3:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reaction time: 2 h

Procedure:
tert-Butyl 4-(5-methylthiophene-2-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 9, step a) (0.32 g) in DCM (3 mL) was treated with trifluoroacetic acid (1.0 g). After 2 h, the reaction mixture was evaporated in vacuo and azeotroped twice with toluene to yield the subtitled compound which was used directly. Yield 0.32 g.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](/[C:18]2[CH:30]=[CH:29][C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][C:20]=3[CH:19]=2)\[CH3:17])=[CH:9][CH:8]=1)[CH3:6])C.CO>[OH-].[Na+].Cl.C(OCC)(=O)C>[CH:19]1[C:20]2[CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]=2[CH:29]=[CH:30][C:18]=1/[C:16](/[CH3:17])=[CH:15]/[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:5]([CH3:6])[C:4]([OH:31])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)c1ccc(OC/C=C(\C)c2ccc3c(c2)Cc2ccccc2-3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C/C(=C\COc1ccc(C(C)C(=O)O)cc1)c1ccc2c(c1)Cc1ccccc1-2
Yield: 73.6 %

Procedure:
(E)-{4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionic acid ethyl ester (example 18) (220 mg, 0.53 mmol) was suspended in 1N NaOH (5.5 ml) and methanol (20 ml) and stirred for 24 h at room temperature. The mixture was diluted with 1N HCl (50 ml) and ethyl acetate (50 mL). The aqueous layer was separated and extracted with ethyl acetate (50 ml) The organic layers were combined, washed with brine, dried (MgSO4) and evaporated. The residue was recrystallised from boiling ethanol (20 ml) to give 150 mg (73%) of the title compound.
Reaction SMILES: C[O-].[Na+].C(O)C.Cl.[N:8]1[CH:13]=[CH:12][C:11]([CH2:14]Cl)=[CH:10][CH:9]=1.[SH:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20]>CO>[OH:21][CH:18]([CH2:19][OH:20])[CH2:17][S:16][CH2:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1
Reactant: OCC(O)CS
Reactant: ClCc1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: OCC(O)CSCc1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium methoxide (3.24 g., 60 mmoles) was dissolved in 36 ml. of absolute ethanol under a nitrogen atmosphere and the stirred solution cooled in an ice bath. With continued cooling, finely divided 4-picolyl chloride hydrochloride (5.07 g., 30 mmoles), slurried in approximately 35 ml. of absolute ethanol, was added over 15 minutes, followed by a solution to 3-mercapto-1,2-propanediol (3.24 g., 30 mmoles) in 6 ml. of absolute alcohol added dropwise over approximately 5 minutes. The reaction mixture was left to warm to room temperature and stirred overnight (16 hours). The reaction mixture was clarified by filtration through diatomaceous earth; the insolubles and the diatomaceous earth were extracted with ethanol, the original filtrate combined with the extract, and the whole concentrated to an oil (5.83 g.). Vacuum distillation, which appeared to produce considerable degradation, gave approximately 2.0 ml. of reasonably pure product (b.p. 230° C./0.3 mm.). The distillate was taken up in cold methanol, a solid impurity removed by filtration, and purified 4-(2,3-dihydroxy-1-propylthiomethyl)pyridine recovered by evaporating the filtrate to an oil (2.15 g.; ir (film): 2.97, 3.46, 3.50, 6.21, 7.05, 9.40 and 12.25μ).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:5]3[C:4]1=[O:15].[CH3:16]I.O>CN(C)C=O>[CH3:16][N:3]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:5]3[C:4]1=[O:15]
Reactant: CI
Reactant: O=c1[nH]c2cccc3c2n1CCC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)n2c3c(cccc31)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (2.36 g) was added to a solution of 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (10 g) obtained in Reference Example 131 in dimethylformamide (100 ml), the mixture was stirred at room temperature for 1 hour, methyl iodide (3.68 ml) was added, and the mixture was stirred at room temperature for 18 hours. Water (200 g) was poured into the reaction mixture, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a pale yellow solid (9.7 g). Further recrystallization from water-ethyl acetate afforded the title compound as colorless crystals (9.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([CH:51]2[CH2:53][CH2:52]2)=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:37]([NH:45][C:46]1[S:47][C:48]([CH:51]2[CH2:53][CH2:52]2)=[N:49][N:50]=1)=[O:43]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: Nc1nnc(C2CC2)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C5CC5)s4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.3 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-cyclopropyl-1,3,4-thiadiazole (55 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 32 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][O:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19][CH:18]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>CC#N>[CH3:36][O:35][C:31](=[O:34])[CH:32]=[CH:33][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][CH2:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:22][CH:21]=1
Reactant: O=S(=O)(Oc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1)C(F)(F)F
Reactant: C=CC(=O)OC
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1

Procedure:
Prepared from the Heck coupling of 3b and methyl acrylate by the general method described for example 2b. Yield (94%); APcI m/z: 410 (M+H+CH3CN+, 100%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[CH2:14][CH2:15][CH2:16][C:17](OC)=[O:18].[NH4+].[Cl-]>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[CH2:14][CH2:15][CH2:16][C:17]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18]
Reactant: COC(=O)CCCC(=O)c1ccccc1Br
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [NH4+]
Product: O=C(CCCC(=O)N1CCCC1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 1 ml of pyrrolidine is added with stirring 0.100 g (0.35 mmol) of the product of Example 3, and 5 mg of NH4Cl. The combined reagents were stirred in a sealed tube for 16 hours at room temperature. After this time, an additional 1 ml of pyrrolidine and 5 mg of NH4Cl was added and the reaction mixture was stirred an additional 16 hours. The solvent was removed under reduced pressure and the residue was flash chromatographed. Elution with diethyl ether produced 0.13 g of the titled product, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[NH:14][CH:13]=[C:12]([C:15]2[CH:38]=[CH:37][C:18]3[N:19]([C:22]4[CH:23]=[C:24]([NH2:36])[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=5[F:35])[CH:27]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:39]([N:45]=[C:46]=[O:47])[C:40]1[O:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:38]=[CH:37][C:18]3[N:19]([C:22]4[CH:23]=[C:24]([NH:36][C:46]([NH:45][CH2:39][C:40]5[O:44][CH:43]=[CH:42][CH:41]=5)=[O:47])[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=5[F:35])[CH:27]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccco1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(C4=CNC(OCc5ccccc5)C=C4)ccc32)c1
Solvent: ClCCl
Product: O=C(NCc1ccco1)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4ccc(OCc5ccccc5)nc4)ccc32)c1
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 5-(5-(6-(benzyloxy)-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (75 mg, 0.148 mmol) in DCM was added furfuryl isocyanate (19 mg, 0.163 mmol, 1.1 eq.). The mixture was stirred overnight and quenched and extracted as in Example 2(b). The solvent was distilled off to afford the crude residue which was recrystallized in ether to afford the title compound in 86% yield (80 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[H-].[Na+].[Cl:33][C:34]1[N:39]=[C:38](Cl)[CH:37]=[CH:36][N:35]=1.C(OCC)(=O)C>O1CCCC1>[Cl:33][C:34]1[N:39]=[C:38]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[N:6][N:5]3[CH:30]=2)[CH:37]=[CH:36][N:35]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Oc2ccc3nc(Nc4ccnc(Cl)n4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.5 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (103 mg, 0.25 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (60% in oil, 80 mg, 2.0 mmol), and the mixture was stirred at room temperature for 10 min. 2,4-Dichloropyrimidine (149 mg, 1.00 mmol) was added to the reaction mixture, and the mixture was heated to 60° C. After 1 hr, the reaction mixture was cooled to room temperature and ethyl acetate was added thereto. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/19→ethyl acetate alone) and the obtained solid was washed with ethyl acetate/hexane (=1/2) to give the title compound (27 mg, 21%) as a light blue solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][S:30][CH2:31][C@@H:3]12.Cl.[CH2:33]([N:35]=C=NCCCN(C)C)[CH3:34].O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N)C.CN1CCOCC1>CN(C=O)C>[CH2:33]([NH:35][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][S:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1)[CH3:34]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
(R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.114 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (32.7 mg, 0.171 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (26.1 mg, 0.171 mmol), and DMF (Volume: 0.5 mL) were stirred together to give a yellow solution. Ethanamine hydrochloride (9.28 mg, 0.114 mmol) and 4-methylmorpholine (0.065 mL, 0.593 mmol) were added. The reaction was stirred at room temperature for 4 hours. The crude reaction was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (12.0 mg, 22.6%) as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 7.79 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.53 (s, 1H), 6.85-7.00 (m, 3H), 5.96 (br. s., 1H), 5.06 (d, J=13.4 Hz, 1H), 4.43 (dd, J=10.5, 3.4 Hz, 1H), 3.39-3.54 (m, 4H), 3.30 (br. s., 4H), 3.15 (td, J=12.9, 2.3 Hz, 1H), 3.00 (br. s., 1H), 2.87 (d, J=10.4 Hz, 2H), 2.60 (br. s., 4H), 2.42 (d, J=1.5 Hz, 1H), 1.25 (t, J=7.2 Hz, 3H). [M+H] calc'd for C24H30N6O2S, 467. found, 467. MP: 288.9° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:3]=12.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[N:10]=[C:9]2[CH2:11][CH2:12][CH3:13])=[CH:29][CH:28]=1)([OH:20])=[O:18]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc2nccc(C)c2[nH]1
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
7-Methyl-2-propylimidazo[4,5-b]pyridine (described in Example 9) was alkylated with 2-t-butoxycarbonyl-4'-bromomethylbiphenyl and the resulting protected derivative was deprotected according to the procedure described in Step 2 of Example 3. NMR (CDCl3): δ 0.93 (t, J=7.5 Hz, 3H), 1.69 (q, 2H), 2.63 (s, 3H), 2.78 (t, J=7.5 Hz, 2H), 5.49 (s, 3H), 7.04-7.5(m, 8H), 7.8 (d, J=2.4 Hz, 1H), 8.14 (d, J=5 Hz, 1H). FAB-MS: m/e 386 (M+H).