Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.C[O-].[Na+].[CH2:14]([O:16][CH:17]([O:22][CH2:23][CH3:24])[C:18](=[NH:21])OC)[CH3:15]>CO>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:18](=[NH:21])[CH:17]([O:22][CH2:23][CH3:24])[O:16][CH2:14][CH3:15])=[CH:5][CH:4]=1
Reactant: CCOC(OCC)C(=N)OC
Reactant: NCc1ccc(Br)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1ccc(Br)cc1
Yield: 62.3 %

Procedure:
(4-Bromophenyl)methanamine hydrochloride (2.359 g, 10.39 mmol) and sodium methoxide (2.376 mL, 10.39 mmol) were added to a solution of methyl 2,2-diethoxyacetimidate (3.35 g, 20.78 mmol) in methanol (10 ml). The cloudy mixture was heated at 70 C for 1.5 h and the resulting yellow mixture was concentrated. The residue was purified by silica gel with 100% ethyl acetate to give a yellow viscous oil (2.04 g, 62%). 1H NMR (400 MHz, CDCl3) δ ppm 7.47 (2H, d, J=8.56 Hz), 7.23 (2H, d, J=8.06 Hz), 6.76 (1H, br. s.), 5.31 (1H, br. s.), 4.94 (1H, br. s.), 4.45 (2H, br. s.), 3.47-3.77 (4H, m), 1.26 (6H, t, J=7.05 Hz). LCMS: R.T.=2.12; [M+2]+=317.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([NH:11][CH2:12][C@@H:13]([OH:28])[C@@H:14]([NH:24][C:25](=[O:27])[CH3:26])[CH2:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([F:22])[CH:19]=1)[CH2:15][C@H:14]([NH:24][C:25](=[O:27])[CH3:26])[C@H:13]([OH:28])[CH2:12][NH:11][C:8]1([C:4]2[CH:3]=[C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH3:29])[CH:36]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:9]1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(Br)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(-c2cccc(C3(NC[C@@H](O)[C@H](Cc4cc(F)cc(F)c4)NC(C)=O)CC3)c2)c1
Temperature: 90 °C
Yield: 31.4 %

Procedure:
To a solution of N-[(1S,2R)-3-{[1-(3-bromophenyl)cyclopropyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide (0.030 g) in DMF (0.75 mL) was added 3-methoxyphenylboronic acid (0.030 g), Cs2CO3 (0.085 g) and Pd(Ph3P)4. The mixture was heated for 12 h at 90° C. The cooled solution was diluted with EtOAc (15 mL) and washed with brine (10 mL×2). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by column chromatography to give 0.010 g of the title compound. ES+found (M+H+): 481.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](O)=[N:13][CH:12]=[N:11][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C1C=CC=CC=1.P(Br)(Br)[Br:33]>>[Br:33][C:14]1[C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: Oc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Reactant: BrP(Br)Br
Solvent: CN(C)c1ccccc1
Product: Brc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Temperature: 120 °C

Procedure:
A mixture of 68 (8.2 g, 0.028 mol), phosphorous tribromide (80 mL) and N,N-dimethylaniline (5 mL) was heated to 120° C. for 3 h. After cooling, the reaction mixture was carefully poured into ice, extracted with EtOAc, and purified by silica gel column chromatography, providing 69(2.5 g) as a yellow solid. MS: 349.1, 351.1 (M+1). 1HNMR (DMSO-d6) ppm 8.82 (s, 1H), 7.55-7.41 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClC(Cl)=C(Cl)Cl.[N+](C1C=CC=CC=1)([O-])=O>[O:16]=[C:10]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:8][CH3:9])[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)=C(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(Cl)cc1C(=O)CCC(=O)O

Procedure:
A mixture of 4-chloroanisole (20 g), succinic anhydride (16 g) and AlCl3 (42 g) in 1:1 tetrachloroethylene/nitrobenzene (200 ml) is stirred at -10°-0° C. for a week. The mixture is poured into a conc. HCl/crushed ice bath and the solvent is distilled under vacuo at 40° C. The resulting suspension is made basic with 10% aqueous NaHCO3. The solids are filtered and the filtrate made acidic forming a precipitate which is filtered, washed with water, taken up in ethanol and dried. The solution is filtered and evaporated affording the desired product as a white solid, M.P. 113°-115° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][C:5]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=3)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:4]=2[O:3]1.[OH-].[Na+]>C(O)C>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:7]2[C:5]3[CH2:6][C:2]([CH3:1])([CH3:23])[O:3][C:4]=3[C:10]([O:11][CH3:12])=[CH:9][CH:8]=2)=[CH:18][CH:17]=1)([OH:21])=[O:20]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c3c2CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(C(=O)O)cc2)c2c1OC(C)(C)C2
Yield: 85.9 %

Procedure:
A mixture of Compound 144 (1.0 g) obtained in Example 144, a 4N aqueous solution (8.0 ml) of sodium hydroxide, and ethanol (40 ml) was stirred at room temperature for 4 hours. The solvent was removed and the residue was dissolved in water. Concentrated hydrochloric acid was dropwise added to the solution, and the generated precipitate was collected by filtration, washed with water, and dried to give Compound 145 (0.82 g, 85.9%) as white crystals.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][O:25][CH3:26])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][O:25][CH3:26])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: COCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
tert-Butyl (3R)-6-cyclohexyl-3-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 48) (350 mg, 0.96 mmol) was treated with trifluoroacetic acid (3 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene then dichloromethane to afford the title compound as a colourless oil (250 mg).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:21][C:22]1[C:23]([C:32](OCC)=[O:33])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2>C(O)CCCCCC>[OH:8][C:6]1[C:7]2[C:32](=[O:33])[C:23]3[N:24]=[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:30]4=[CH:31][C:22]=3[NH:21][C:2]=2[CH:3]=[C:4]([OH:9])[CH:5]=1
Reactant: CCOC(=O)c1nc2ccccc2cc1N
Reactant: Oc1cc(O)cc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCCO
Product: O=c1c2nc3ccccc3cc2[nH]c2cc(O)cc(O)c12
Reaction time: 48 h

Procedure:
3.5 g of 1,3,5-trihydroxybenzene and 62.5 mg of paratoluenesulphonic acid are added to a solution of 5 g of ethyl 3-amino-2-quinolinecarboxylate in 50 ml of heptan-1-ol. The mixture is stirred for 48 hours at reflux using a Dean Stark apparatus and then the reaction mixture is concentrated in vacuo. Chromatography on silica gel (cyclohexane/acetone 90/10) allows 5.2 g of the expected product to be isolated.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:10][C:8](=[O:9])[NH:7][C:5]=2[CH:6]=1.[CH3:11][NH2:12]>>[OH:10][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[NH:7][C:8]([NH:12][CH3:11])=[O:9]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: CN
Product: CNC(=O)Nc1ccccc1O

Procedure:
Benzoxazolinone (1 mole) was stirred with 2 moles of methylamine (25% aqueous solution) for 48 hours at 50° C., then some of the water and the excess of methylamine were distilled off at 60° C. under reduced pressure. The desired urea crystallised out on cooling; it had m.pt. 130° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[CH:17][C:18]=3[O:20][CH2:21][CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:29](O)(=[O:32])[CH2:30][OH:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[CH:17][C:18]=2[O:20][CH2:21][CH:22]2[CH2:26][CH2:25][N:24]([C:30](=[O:31])[CH2:29][OH:32])[CH2:23]2)[N:13]=[CH:12][N:11]=1
Reactant: COc1cc(OCC2CCNC2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: O=C(O)CO
Product: COc1cc(OCC2CCN(C(=O)CO)C2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 45 %

Procedure:
The procedure described in Example 1 was repeated using N-(3-chloro-4-fluoro-phenyl)-7-methoxy-5-(pyrrolidin-3-ylmethoxy)quinazolin-4-amine (100 mg) and glycolic acid (21 mg) to give the title product in 45% yield; NMR spectrum (DMSO-d6 at 373 K) 9.69 (s, 1H), 8.52 (s, 1H), 8.21-8.20 (m, 1H), 7.66-7.63 (m, 1H), 7.40 (t, 1H), 6.90 (d, 1H), 6.83 (d, 1H), 4.41-4.39 (m, 2H), 4.20-4.10 (m, 1H), 4.05-4.00 (m, 2H), 3.97 (s, 3H), 3.73 (dd, 1H), 3.61-3.58 (m, 1H), 3.51-3.47 (m, 1H), 3.42 (dd, 1H), 2.26-2.14 (br m, 1H), 2.00-1.87 (br m, 1H); Mass spectrum MH+ 461.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:12]1[CH:17]=[CH:16][N:15]=[N:14][CH:13]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[Br-].Br[C:43]1[CH:44]=[C:45]([NH:51][S:52]([C:55]2[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:56]=2[F:62])(=[O:54])=[O:53])[C:46]([O:49][CH3:50])=[N:47][CH:48]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:62][C:56]1[CH:57]=[C:58]([F:61])[CH:59]=[CH:60][C:55]=1[S:52]([NH:51][C:45]1[C:46]([O:49][CH3:50])=[N:47][CH:48]=[C:43]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[C:5]3[C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)[CH:44]=1)(=[O:54])=[O:53]
Reactant: Brc1ccc2nccc(-c3ccnnc3)c2c1
Reactant: COc1ncc(Br)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ncc(-c2ccc3nccc(-c4ccnnc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A slurry of 6-bromo-4-(4-pyridazinyl)quinoline (4.8 g, 16.78 mmol), bis(pinacolato)diboron (4.69 g, 18.45 mmol), PdCl2(dppf)-CH2Cl2 (530 mg, 0.649 mmol) and potassium acetate (3.29 g, 33.6 mmol) in anhydrous 1,4-dioxane (120 ml) was heated at 100° C. for 3 h. The complete disappearance of the starting bromide was observed by LCMS. The reaction was then treated with N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (6.68 g, 17.61 mmol) and another portion of PdCl2(dppf)-CH2Cl2 (550 mg, 0.673 mmol), then heated at 110° C. for 16 h. The reaction was allowed to cool to room temperature, filtered, and concentrated. Purification of the residue by chromatography (Analogix; 5% MeOH/5% CH2Cl2/90% EtOAC) gave 6.5 g (76%) desired product. MS(ES)+ m/e 505.9 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](=[O:12])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6]1.N1C=CC=CC=1.S(Cl)([Cl:29])=O.C(OCC)(=O)C>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](=[O:12])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([CH2:10][Cl:29])=[CH:6]1
Reactant: CN(CCc1ccccc1)C(=O)Cn1ccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1)C(=O)Cn1ccc(CCl)c1
Reaction time: 18 h

Procedure:
To a solution of N-methyl-N-phenethyl-2-[3-hydroxymethylpyrrol-1-yl]acetamide and pyridine in methylene chloride is added dropwise 2 molar equivalents of thionyl chloride. The resulting mixture is stirred at room tenperature for 18 hours and ethyl acetate is added. The solution is washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue obtained is purified by a silica gel flash column to give N-methyl-N-phenethyl-2-[3-chloromethylpyrrol-l-yl]acetamide which is used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([OH:16])=[O:15])=[CH:8]2)=[O:4]>C1(C)C=CC=CC=1.C(OC(N(C)C)OC(C)(C)C)(C)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][C:5]([CH3:6])([CH3:13])[CH3:3])=[O:15])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2[nH]c(C(=O)OC(C)(C)C)cc2c1

Procedure:
To 13 g 1H-Indole-2,5-dicarboxylic acid 5-methyl ester in 300 ml toluene, 59 ml Di-tert-butoxymethyl-dimethyl-amine were added dropwise at 80° C. Then, the reaction mixture was heated under reflux for additional 6 h. After removal of the solvents under reduced pressure the residue was dissolved in 300 ml DCM and washed with sat. aqueous NaHCO3 solution (2×100 ml). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a n-heptane/ethyl acetate gradient. The fractions containing the product were collected and concentrated under reduced pressure. Yield: 8.3 g. MS (ES+): m/e=276.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:58]=[CH:57][C:6]([CH2:7][N:8]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([NH:40]C(=O)OC(C)(C)C)=[N:38][CH:39]=4)=[N:18][CH:19]=[C:20]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]4)[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:56][O:55][C:52]1[CH:51]=[CH:50][C:49]([CH2:48][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:58][CH:57]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=4)=[N:18][CH:19]=[C:20]([CH2:22][N:23]4[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH2:28]4)[CH:21]=3)[N:10]=2)=[CH:54][CH:53]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(N)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
tert-Butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)pyridin-2-ylcarbamate (0.306 g, 0.377 mmol) was dissolved into DCM (5 mL total) in two 20 mL scintillation vials. TFA (2.5 mL total) was added and the solutions were stirred at rt for 3 h. The reaction mixtures were combined and poured into 20 mL of saturated aqueous sodium bicarbonate. The aqueous phase was extracted with 25% iPrOH in CHCl3+1% NH4OH (2×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (25 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-20%) to give N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)pyridine-2,5-diamine (0.221 g, 82% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.44 (br. s., 1H); 8.69 (br. s., 1H); 8.15-8.21 (m, 1H); 8.12 (br. s., 1H); 7.69-7.79 (m, 1H); 7.21 (d, J=8.61 Hz, 4H); 6.85 (dd, J=15.75, 8.51 Hz, 4H); 6.49 (d, J=8.80 Hz, 1H); 4.83 (d, J=15.85 Hz, 4H); 4.27 (br. s., 2H); 3.75-3.85 (m, 6H); 3.48 (br. s., 2H); 3.18 (br. s., 4H); 2.68-2.76 (m, 3H); 2.49-2.61 (m, 7H). m/z (ESI, +ve ion) 711.0 (M+H)+.
Reaction SMILES: [H-].[Na+].Cl.[OH:4][C@H:5]([CH3:9])[C:6](=[NH:8])[NH2:7].[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[C:19]([C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)=[O:34])[C:20]([C:22]1[CH:23]=[CH:24][C:25]([F:32])=[C:26]([S:28](Cl)(=[O:30])=[O:29])[CH:27]=1)=[O:21]>C1COCC1>[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[C:19]([C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)=[O:34])[C:20]([C:22]1[CH:23]=[CH:24][C:25]([F:32])=[C:26]([S:28]([NH:8][C:6](=[NH:7])[C@H:5]([OH:4])[CH3:9])(=[O:29])=[O:30])[CH:27]=1)=[O:21]
Reactant: O=C(C(C(=O)c1ccc(F)c(S(=O)(=O)Cl)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Reactant: C[C@@H](O)C(=N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)C(=N)NS(=O)(=O)c1cc(C(=O)C(C(=O)c2cccc(F)c2)=C2Nc3ccccc3N2)ccc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
At room temperature, sodium hydride (579 mg) was added to a THF (70 mL) suspension of (2R)-2-hydroxypropanimidamide hydrochloride (1.65 g), followed by heating up to 60° C. and stirring for 30 minutes. The reaction mixture was cooled to room temperature, and a THF (35 mL) solution of 5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorobenzenesulfonyl chloride (2.10 g) was added, followed by stirring for 20 minutes. Then, this was subjected to liquid-liquid separation with water and ethyl acetate added thereto, the organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to obtain (2R)-N-({5-[2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-(3-fluorophenyl)-3-oxopropanoyl]-2-fluorophenyl}sulfonyl)-2-hydroxypropanimidamide (1.95 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH3:7][C@@H:8]([C@@H:15]1[C@@:19]2([CH3:37])[CH2:20][CH2:21][CH:22]3[C@@:27]4([CH3:36])[CH2:28][CH2:29][CH:30]([O:32][C:33](Cl)=[O:34])[CH2:31][C:26]4=[CH:25][CH2:24][CH:23]3[CH:18]2[CH2:17][CH2:16]1)[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:33]([O:32][C@H:30]1[CH2:29][CH2:28][C@@:27]2([CH3:36])[C:26](=[CH:25][CH2:24][C@@H:23]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:37])[C@H:18]3[CH2:17][CH2:16][C@@H:15]2[C@H:8]([CH3:7])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:31]1)=[O:34]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: NCC(O)CO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCC(O)CO)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
3-Amino-1,2-propanediol (2.0 g, 22.0 mmoles) is coevaporated twice with dry pyridine (50 mL each) then dissolved in dry pyridine (147 mL). The solution is stirred in an ice bath, and a solution of cholesteryl chloroformate (10.4 g, 23.1 mmoles) in toluene (50 mL) is added dropwise over 30 minutes. After addition, the ice bath is removed and the reaction mixture is stirred at ambient temperature for 16 hours. The solution is then evaporated, and the residue is coevaporated twice with toluene (50 mL each). The crude product is purified on silica gel (300 mL bed volume) eluting with hexanes:acetone (90:10 [v/v], 1000 mL; then 85:15 [v/v], 1000 mL; then 70:30 [v/v], 1000 mL; then 65:35 [v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to syrup which is dried well in vacuo. The yield is 5.7 g (51%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:19]4[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]4)[CH:15]=3)[N:10]=[CH:9]2)[CH:7]=1.[Cl:28][C:29]1[CH:34]=[C:33]([C:35](Cl)=[O:36])[CH:32]=[CH:31][N:30]=1>>[Cl:28][C:29]1[CH:34]=[C:33]([C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([N:8]3[C:17](=[O:18])[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([N:19]5[CH2:25][CH2:24][CH2:23][N:22]([CH3:26])[CH2:21][CH2:20]5)[CH:15]=4)[N:10]=[CH:9]3)[CH:7]=2)=[O:36])[CH:32]=[CH:31][N:30]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Cc1ccc(N)cc1-n1cnc2ccc(N3CCCN(C)CC3)cc2c1=O
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-n1cnc2ccc(N3CCCN(C)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described in Example 5, 3-(5-amino-2-methylphenyl)-6-(4-methylhomopiperazin-1-yl)-3,4-dihydroquinazolin-4-one was reacted with 2-chloropyridine-4-carbonyl chloride to give the title compound; NMR Spectrum: (DMSOd6) 1.84–1.96 (m, 2H), 2.06 (s, 3H), 2.29 (s, 3H), 2.42–2.49 (m, 2H), 2.62–2.68 (m, 2H), 3.53 (t, 2H), 3.58–3.64 (m, 2H), 7.22 (d, 1H), 7.34 (m, 1H), 7.44 (m, 1H), 7.58 (d, 1H), 7.73–7.78 (m, 2H), 7.82–7.86 (m, 1H), 7.96–7.98 (m, 2H), 8.50–8.62 (m, 1H), 10.68 (s, 1H); Mass Spectrum: M+H+ 503 & 505.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:8].C(N(C(C)C)CC)(C)C>CN(C=O)C>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:1]2[CH2:5][C:4](=[O:6])[NH:3][CH2:2]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=C1CNCN1
Reactant: O=[N+]([O-])c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2)CN1
Temperature: 25 °C

Procedure:
A solution of 4-imidazolidinone (9.5 g, 110.5 mmol), 4-nitrobenzene (1 eq) and diisopropyl ethylamine (28.6 mL, 165 mmol) in dry DMF (80 mL) was heated to 60° C. overnight under argon. The reaction mixture was allowed to cool to room temperature and ice pieces were added. The solid formed was filtered and washed with water. The solid was air dried to yield the nitro compound as yellow crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][CH2:49][C:50](O)=[O:51])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C1C=CN=CC=1.C(#N)C>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:14]=1)[C:50](=[O:51])[CH2:49][NH:48][C:46]([O:45][CH2:44][CH:42]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:43]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:47])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amine (3.40 g), N-(9-fluorenylmethoxycarbonyl)glycine (2.34 g), diisopropylethylamine (1.03 g) and 4-(dimethylamino)pyridine (961 mg) were dissolved in acetonitrile (40 mL), and to the solution HBTU (3.13 g) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to obtain the title compound.