Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:32])[N:9]([CH2:30][CH3:31])[CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41](OS(C(F)(F)F)(=O)=O)[CH:40]=1>>[CH3:35][O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:40]=[C:41]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:19])[F:20])=[CH:16][C:11]=2[CH2:10][N:9]([CH2:30][CH3:31])[C:8]([O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:34][CH:33]=2)=[O:32])[CH:42]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:44]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccc(F)cc1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid 4-fluoro-benzyl ester and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.C(O)(=O)C.[CH3:14][C:15]1[CH:16]=[C:17]([NH2:20])[NH:18][N:19]=1>COC(C)(C)C>[CH3:14][C:15]1[CH:16]=[C:17]2[NH:20][C:3]([CH3:5])=[CH:2][C:1](=[O:7])[N:18]2[N:19]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(N)[nH]n1
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: Cc1cc2[nH]c(C)cc(=O)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
Add ethyl acetoacetate (128 g, 0.98 mol) dropwise to an acetic acid solution (500 mL) of 5-methyl-2H-pyrazol-3-ylamine (100 g, 0.95 mol), keeping the temperature at 25-28° C. Heat the mixture at reflux for 10 h and then cool to room temperature. Add the reaction to tert-butyl methyl ether (5 L) cooled to 5° C., keeping the temperature below 10° C. Stir for 1 h at 5° C., and filter. Dry the resulting material in vacuo overnight to provide a white solid (158 g, 96%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=1[Cl:24].[NH+]1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:24][C:14]1[CH:15]=[C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][C:13]=1[NH:12][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: Fc1ccc2sc(Br)nc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1ccc(Nc2nc3cc(F)ccc3s2)c(Cl)c1
Yield: 37.5 %

Procedure:
In xylene (5 ml), 2-bromo-5-fluorobenzothiazole (516 mg, 2.22 mmol), methyl 4-amino-3-chlorophenylacetate (444 mg, 2.22 mmol), and pyridinium•p-toluenesulfonate (PPTS) (168 mg, 0.67 mmol) were heated under reflux for 10 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (7:1, v/v) eluate fractions, methyl (3-chloro-4-(5-fluoro-2-benzothiazolyl)aminophenyl)acetate (292 mg, 37%) was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:1][C@@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.6 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (may be prepared as described in Description 5) (3.39 g, 8.30 mmol) in 1,4-dioxane (20 ml) was added HCl (4M in 1,4-dioxane) (10.37 ml, 41.5 mmol) and the resultant mixture stirred under an atmosphere of Ar for 16 hours. A further 5 ml of 4M HCl in dioxane was added and the mixture stirred at room temperature for 72 hours. The mixture was concentrated to dryness and the residue triturated with diethyl ether and the solid collected by filtration giving the the title compound (2.507 g) as a white powder.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([F:21])[CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>C(OCC)(=O)C.[Pt]>[C:1]12([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:21])[CH:13]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=[N+]([O-])c1ccc(OC23CC4CC(CC(C4)C2)C3)cc1F
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1F
Yield: 135.5 %

Procedure:
13.4 g of 4-(1-adamantyloxy)-2-fluoronitrobenzene (approximately 80% pure; 0.037 mole) in ethyl acetate solution was hydrogenated for 2 hours over platinum (from 1.0 g of PtO2). The catalyst was filtered and the solvent was evaporated to give 13.1 g of white solid, which was purified by two recrystallizations from CH2Cl2 -Skellysolve B, affording a pink solid, m.p. 152.0-154.0. The NMR spectrum of this material was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH:15](Cl)[CH2:16][CH3:17])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:6]=2[CH:26]=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29].[I-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH:15]([N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[CH2:16][CH3:17])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:6]=2[CH:26]=1
Reactant: CCC(Cl)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: CCCNCCC
Agent: [I-]
Agent: [Na+]
Product: CCCN(CCC)C(CC)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In a manner given in Example 1, 8-chloro-1-(α-chloropropyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine was reacted with dipropylamine in the presence of sodium iodide to give 8-chloro-1-[α-(dipropylamino)propyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)=O.C1([CH2:26][CH2:27][C:28]([NH2:30])=[S:29])C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:27]([C:28]1[S:29][C:3]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=2)=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=2)[N:30]=1)[CH3:26]
Reactant: NC(=S)CCc1ccccc1
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(F)c2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(F)c2)s1
Yield: 38.1 %

Procedure:
A solution of 2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide (11 g, 29 mmol) and thiopropionamide (2.7 g, 30 mmol) in N,N-dimethylformamide (30 mL) was stirred for 14 hours at room temperature. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extracted with ethyl acetate. The extracts were washed with water, dried, then, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) to obtain a title compound (3.3 g, yield 38%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][C:20](=[O:28])[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([OH:18])[CH2:13]1)[CH:6]=[CH:5]2.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:1][C:2]1[C:3]([NH:19][C:20](=[O:28])[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCC[C@@H](O)C3)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reaction time: 24 h

Procedure:
To a stirred solution of N-[6-chloro-2-[(3R)-3-hydroxy-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 37) (0.715 g) in dichloromethane (10 mL) was added triethylamine (0.99 mL) followed by methanesulfonyl chloride (0.275 mL). The reaction was stirred under nitrogen for 24 hours followed by the removal of volatiles under vacuum. The resulting mixture was taken up in methanol (20 mL) and placed down a Varian® SCX cartridge, washed with methanol (50 mL) and eluted with ammonia in methanol (0.7M, 50 mL). The solvent was removed to afford the sub-titled compound (0.64 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C@H:18]([CH3:32])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[N:28][C:29]=3[CH3:30])=[O:23])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH2:34][C:35]1[CH:39]=[CH:38][S:37][CH:36]=1>>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([N:11]([CH2:34][C:35]2[CH:39]=[CH:38][S:37][CH:36]=2)[CH:12]2[CH2:13][CH2:14][N:15]([C@H:18]([CH3:32])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[N:28][C:29]=3[CH3:30])=[O:23])[CH2:16][CH2:17]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccsc1
Reactant: CC(=O)Nc1ccc(NC2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cn1
Product: CC(=O)Nc1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cn1
Yield: 20.6 %

Procedure:
Using general procedure H, 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(6-acetylamino-pyridin-3-ylamino)-piperidin-1-yl]-butyl}-amide (see EXAMPLE 246) (343 mg, 0.780 mmol) and 3-(bromomethyl)thiophene (207 mg) gave COMPOUND 328 as a yellow foam (86 mg, 21%). 1H NMR (CDCl3) δ 0.94-1.22 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.55 (m, 1H), 1.75 (m, 3H), 2.10 (s, 3H), 2.19 (m, 1H), 2.51 (s, 6H), 2.55 (m, 1H), 2.73-2.89 (m, 3H), 3.32 (m, 1H), 3.48 (m, 1H), 3.84 (s, 2H), 3.87 (m, 1H), 7.49 (m, 3H), 7.27 (m, 1H), 7.65 (d, 1H, J=3.0 Hz), 7.93 (d, 1H, J=9.3 Hz), 8.06 (s, 1H), 8.63 (m, 1H), 8.83 (s, 1H). 13C NMR (CDCl3) δ 13.82, 22.33, 24.81, 29.56, 30.68, 31.10, 40.51, 53.91, 45.47, 52.40, 56.77, 60.75, 114.94, 121.30, 123.84, 126.63, 126.71, 131.23, 133.74, 140.77, 142.05, 143.02, 158.01, 163.43, 166.72, 168.47. ES-MS m/z 536 (M+H). Anal. Calcd. for C28H37N7SO2.1.1CH2Cl2: C, 55.56; H, 6.28; N, 15.58; S, 5.10. Found: C, 55.76; H, 6.30; N, 15.63; S, 5.27.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([C:14]([O:17]C(=O)C)([CH3:16])[CH3:15])=[O:13])[NH:7][C:6](=[O:21])[CH2:5]2.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12](=[O:13])[C:14]([OH:17])([CH3:16])[CH3:15])[NH:7][C:6](=[O:21])[CH2:5]2
Reactant: CC(=O)OC(C)(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Yield: 51.7 %

Procedure:
Acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester 9a (2.035 g, 6.9 mmol) was dissolved in 20 ml of methanol under stirring, added with sodium hydroxide solution (20 ml, 0.7 mol/L) (20 ml) to the solution and stirred for 4 hours at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was neutralized with hydrochloride acid (1 mol/L) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and dried to obtain N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide 9b (900 mg, yield 59.2%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[C:19](Cl)=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=1[NH2:29]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[C:19]([NH:29][C:28]3[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:27]=3[CH3:26])=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncc(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(Cl)n1
Reactant: COc1ccc(N)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Nc2nc(C)ncc2S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a solution of 5-(4-benzyloxy-benzenesulfonyl)-4-chloro-2-methyl-pyrimidine (38 mg, 0.106 mmol) and 2-methyl-4-methoxy aniline (31 mg, 0.23 mmol) in toluene (1 mL) was added p-toluenesulfonic acid monohydrate (1.6 mg, 0.0081 mmol). The resulting mixture was heated at reflux under N2 for 1 h and then cooled to room temperature. The mixture was quenched by addition of water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified using preparative TLC on silica (1:1 hexanes/EtOAc) to provide the desired product (46 mg, 95%) as a pale yellow solid: mp 110–114° C.; 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.61 (s, 1H), 7.86 (d, J=9.1 Hz, 2H), 7.49 (d, J=8.6 Hz, 1H), 7.38–7.33 (m, 4H), 7.07–7.04 (m, 2H), 6.79–6.75 (m, 2H), 5.12 (s, 2H), 3.81 (s, 3H), 2.46 (s, 3H), 2.17 (s, 3H); ESI MS m/z 476 [(M+H)+, calcd for C26H26N3O4S, 476.2].
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:4].Cl.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH3:25])[C:19]([CH2:18][CH2:17][CH2:16][C:15]#[C:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[C:6]([NH:5][CH:3]([CH3:4])[CH2:2][OH:1])=[O:7])=[O:21]
Reactant: CNC
Reactant: CC(CO)NC(=O)c1cccc(C#CCCCC(=O)O)c1
Agent: Cl
Product: CC(CO)NC(=O)c1cccc(C#CCCCC(=O)N(C)C)c1
Yield: 96 %

Procedure:
6-[3-(2-Hydroxy-1-methyl-ethylcarbamoyl)phenyl]-hex-5-ynoic acid (4) (0.109 g, 0.377 mmol) was reacted using method C with dimethylamine hydrochloride to obtain 8 (0.115 g, 0.363 mmol; 96% yield).
Reaction SMILES: [Cl:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]1[NH:8][C:9]([CH3:26])=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:12]=1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][CH2:26][C:9]1[NH:8][C:7]([C:3]2[N:4]=[CH:5][S:6][C:2]=2[Cl:1])=[N:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C1=C(C)NC(c2ncsc2Cl)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2ncsc2Cl)=NC1c1ccc(Cl)cc1Cl
Yield: 48.3 %

Procedure:
Ethyl 2-(5-chlorothiazol-4-yl)-4-(2,4-dichlorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (5.77 g, 13.4 mmol) (The compound was synthesized according to the procedure as described in CN200610098646.3) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.3 g, 48%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.[BrH:14].C(O)(=O)C.O>C(O)(=O)C>[Br:14][C:11]1[S:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:12]=1
Reactant: Br
Reactant: N#CSCC(=O)c1cccc(F)c1
Solvent: O
Solvent: CC(=O)O
Product: Fc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 2-(3-fluorophenyl)-2-oxoethyl thiocyanate (1.76 g, 9.02 mmol) in acetic acid (15 ml) was added a 25% hydrogen bromide/acetic acid solution (15 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1) to give the desired product (2.31 g, 99.0%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=O)=[C:10]([O:22][CH3:23])[CH:9]=2)=[CH:4][C:3]=1[C:24]1[N:25]=[N:26][N:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=1.B(F)(F)F.CCOCC.[BH4-].[Na+]>C1COCC1>[CH:29]([N:27]1[CH:28]=[C:24]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)=[C:10]([O:22][CH3:23])[CH:9]=3)[CH:4]=2)[N:25]=[N:26]1)([CH3:31])[CH3:30]
Reactant: COc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)N1CCOCC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1CN1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution of [4-[6-amino-5-(1-isopropyltriazol-4-yl)-3-pyridyl]-2-methoxy-phenyl]-morpholino-methanone (200 mg, 0.473 mmol) in THF (10.0 mL) was added BF3.Et2O (0.3 mL, 2.36 mmol) at 0° C. and stirred for 30 min. After 30 min, NaBH4 (89 mg, 2.36 mmol) was added at 0° C. and stirred at room temperature for 18 h. After cooling to 0° C., quenched with MeOH (2 mL) and heated to reflux for 6 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (30 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 100% EtOAc to afford 100 mg (yield: 51.81%) of the title compound as white solid.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19].[Na].[CH2:21]([OH:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:21]([O:29][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Reactant: CCCCCCCCO
Agent: [Na]
Product: CCCCCCCCOc1c(C#N)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-5-cyano-2-trifluoromethylbenzimidazole is reacted with the sodium derivative of 1-octanol to obtain 4-octyloxy-7-nitro--cyano-2-trifluoromethylbenzimidazole, m.w., 384.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Br)[CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:10])[CH:4]([NH:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[C:13]([CH3:19])[CH:14]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(Br)C(=O)OC
Reactant: Cc1cc(N)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(Nc1ccc(F)c(C)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 88 h
Yield: 44.8 %

Procedure:
To a solution of 2-bromo-hexanoic acid methyl ester (0.500 g, 2.404 mmol) and 4-fluoro-3-methylaniline (0.301 g, 2.404 mmol) in 15 mL of DMF, was added K2CO3 (1.661 g, 12.020 mmol). After stirring at room temperature under N2 for 88 h, the reaction mixture was diluted with 60 mL of water and extracted with dichloromethane (60 mL×3). The organic extracts were combined dried over anhydrous Na2SO4 and the solvent removed under reduced pressure. Flash chromatography (silica gel) eluting with 0-20% ethyl acetate/hexanes afforded the title compound as brown oil (0.273 g, 45% yield). LC-MS: tR=9.9 min; m/z 254 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:9][C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[N:16]=2)=[C:12]([O:24][CH3:25])[CH:11]=1>CN(C=O)C>[F:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]2[CH:22]=[CH:23][C:10]([CH2:9][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:11][C:12]=2[O:24][CH3:25])[N:16]=1
Reactant: COc1cc(CCl)ccc1Oc1cccc(F)n1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cn2ccnc2)ccc1Oc1cccc(F)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of imidazole (18 mg; 0.27 mmol) and NaH (12 mg; 0.30 mmol) in DMF (1 mL), under argon, was added a solution of 2-[4-(chloromethyl)-2-methoxyphenoxy]-6-fluoropyridine (65 mg; 0.24 mmol) in DMF (1 mL). The reaction mixture was allowed to stir overnight, to 40° C. After concentration, the reaction was hydrolysed with saturated NH4Cl (1 mL), extracted with AcOEt (2*1 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, the title compound (68 mg; 93%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17].P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:15]=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reaction time: 6 h
Yield: 56.8 %

Procedure:
To 30 ml of toluene were added 5-chlorosalicylic acid (862 mg, 5 mmol), 3,5-bis(trifluoromethyl)aniline (1.37 g, 6 mmol), and phosphoroustrichloride (755 mg, 5.5 mmol) in the presence of argon gas, followed by stirring for 6 hours through heat-reflux. Sodium hydrogen carbonate was added to the mixture to adjust pH to 7, followed by concentration under reduced pressure. The mixture was dissolved in 60 ml of ethylacetate, which was washed with water (40 ml×2). The organic layer was concentrated under reduced pressure, followed by column chromatography to give 1.09 g of the target compound (yield: 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([CH3:23])[CH:3]=1.[Cl:24][CH2:25][CH2:26][N:27]=[C:28]=[O:29]>C1COCC1>[Cl:24][CH2:25][CH2:26][NH:27][C:28]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([CH3:23])[CH:3]=1)=[O:29]
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(N)cc2C)n1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)NCCCl)cc2C)n1

Procedure:
To a slurry of 4-(2-(4-amino-2-methylphenoxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.500 g, 1.63 mmol) in THF (3.3 mL) under nitrogen was added 1-chloro-2-isocyanatoethane (0.157 mL, 1.79 mmol). The reaction became clear and brown, and then a precipitate formed. Additional THF (4 mL) was added to promote stirring, and the reaction was allowed to stir for 16 h. The mixture was filtered, the solid was rinsed with diethyl ether, and dried in vacuo to give 1-(2-chloroethyl)-3-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)urea as a tan solid. MS m/z=413 [M+1]+. Calc'd for C20H21ClN6O2: 412.14.