Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.CC(C)([O-])C.[Na+].[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(N2C3C(=CC=CC=3)C=C2P(C(C)(C)C)C(C)(C)C)C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[N:23]([CH3:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNc1ccccc1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Agent: [Pd]
Agent: CC(C)(C)P(c1cc2ccccc2n1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1cnn(C2CCCCO2)c(=O)c1Cl
Temperature: 120 °C
Reaction time: 24 h
Yield: 10.8 %

Procedure:
A mixture of 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (2.0 g, 8.02 mmol) (Intermediate 20), sodium tert-butoxide (0.93 g, 9.67 mmol), tris(dibenzylideneacetone)dipalladium(0) (19 mg, 0.02 mmol) and N-phenyl-2-(di-tert-butylphosphino)indole (27.4 mg, 0.08 mmol) in a glass reaction tube was fitted with a septa and then evacuated via house vacuum followed by a nitrogen flush three times to remove air from the reaction system. The reaction was then treated with anhydrous toluene (8 mL, 1.0M) and N-methylaniline (1.05 mL, 9.69 mmol). The reaction was heated to 120° C. for 4 d. After this time, the reaction was cooled to 25° C. where it stirred for an additional 1 d. After this time, the reaction mixture was then partitioned between water (200 mL) and ethyl acetate (200 mL). The aqueous layer was back extracted with ethyl acetate (100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 115 g, 10-40% ethyl acetate/hexanes gradient) afforded 4-chloro-5-(methyl-phenyl-amino)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (277.2 mg, 11%) as an orange/red oil.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[C:26]2[CH:27]=[CH:28][NH:29][C:30]=2[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH2:13][CH2:14][N:15]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6-trifluoromethyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 1.9 mmol), 1-chloro-3-(1H-indole -4-oxy)propane (0.39 g, 1.9 mmol) and potassium carbonate (0.29 g, 2.1 mmol). The product was isolated as a white foam. Yield 0.53 g (64%). mp 190°-195° C. FDMS m/e=440 (M+ of free base).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].C(=O)([O-])O.[Na+].[CH2:15]([OH:17])[CH3:16]>>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([O:17][CH2:15][CH3:16])[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1nc(Cl)nc(Cl)n1
Temperature: 0 °C

Procedure:
In addition, 92.21 g (0.500 mole) of cyanuric chloride and 50.41 g (0.600 mole) of sodium hydrogen carbonate were added in this order to 800 ml (13.73 moles) of ethanol kept at 5° C. with mechanical stirring and the mixture was reacted at this temperature for 8 hours with stirring. The resulting solution was poured into 650 g of ice-water and the precipitated white substance was immediately collected by filtration with suction. The substance was washed with 200 ml of water (0° C.) two to three times and dried in a vacuum dryer. It was recrystallized from petroleum ether to give b 2,4-dichloro-6-ethoxy-s-triazine as a colorless solid substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(F)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)ccc1CBr

Procedure:
With no precautions to maintain a dry atmosphere, methyl 5-fluoro-2-methylbenzoate (Maybridge, 5 g, 29.7 mmole) was dissolved in CCl4 (50 mL). N-bromosuccinimide (5.82 g, 32.7 mmol) and benzoyl peroxide (0.36 g, 1.48 mmole) were added and the reaction brought to reflux overnight. An additional 0.3 eq of NBS and 0.01 eq of benzoyl peroxide was added and the reaction refluxed for 4 hrs, then cooled, filtered and concentrated. The residue was chromatographed on silica eluting with a gradient of 0-10% EtOAc/Hexanes. The fractions were collected to give the product, which was a mixture of mono and bis-brominated materials, as a clear oil.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O.C(OCC)(=O)C>[CH2:10]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCBr
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCOC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A mixture of (1R*,2R*)-4,4-dimethyl-2-(2-propenyl)=cyclohexanol (150 mg), and sodium hydride (43 mg, 60% dispersion in oil) and n-octyl bromide (180 ml) in dry N,N-dimethylformamide (1 ml) was stirred for 3 hrs at room temperature. The mixture was allowed to cool to 0° C., and the reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by silica gel column chromatography (using n-hexane:ethyl acetate=20:1 as an eluent) gave (1R*,2R*)-4,4-dimethyl-2-(2-propenyl)=cyclohexyl octyl ether (222 mg, 89% yield) as a colorless oil.
Reaction SMILES: [I:1]I.N(OCCCC)=O.[CH3:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:22]=[CH:21][C:19](N)=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=2)[CH:13]=[N:12]1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CS(C)=O.C(#N)C>[I:1][C:19]1[CH:21]=[CH:22][C:16]([C:14]2[CH:13]=[N:12][N:11]([CH3:10])[CH:15]=2)=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24]
Reactant: Cn1cc(-c2ccc(N)c([N+](=O)[O-])c2)cn1
Reactant: II
Agent: CCCCON=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CS(C)=O
Product: Cn1cc(-c2ccc(I)c([N+](=O)[O-])c2)cn1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 94.5 %

Procedure:
Iodine (3.5 g, 14 mmol), acetonitrile (40 ml), and test-butyl nitrite (0.82 mL, 6.9 mmol) were combined under N2 in a 3-neck round bottom flask fitted with reflux condenser and an addition funnel. The mixture was stirred at rt. To the addition funnel was added a solution of 4-(1-methyl-1H-pyrazol-4-yl)-2-nitroaniline (1.0 g, 4.6 mmol) dissolved in DCM (20 mL) and DMSO (2 mL). This solution was added dropwise to flask at rt. The reaction was placed in a 60° C. oil bath and after 5-10 minutes bubbles began appearing. The reaction was stirred for an additional 2 h at 60° C. and then the heat was turned off and the reaction stirred at rt overnight. Aqueous sodium sulfite solution was added and the mixture was extracted with EtOAc (3×). Combined organic layers were dried over anhydrous MgSO4, filtered, concentrated onto silica gel and purified by flash chromatography using 20-60% EtOAc/hexanes. 1.43 g (95%) of 4-(4-iodo-3-nitrophenyl)-1-methyl-1H-pyrazole was isolated as a yellow solid. MS (ESI): 330, 331 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][OH:18])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].O1CCOCC1>>[ClH:19].[OH:18][CH2:17][CH2:16][CH2:15][C:11]1([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCCO)CC1
Agent: Cl
Solvent: C1COCCO1
Product: OCCCC1(O)CCNCC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperidin-4-ol and 4M HCl-dioxane solution was stirred at ambient temperature for 3.5 hours to yield 4-(3-hydroxypropyl)piperidin-4-ol hydrochloride.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[Cl:20][CH2:21][C:22]([N:5]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9])[C:1]([CH3:4])([CH3:2])[CH3:3])=[O:23]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)Nc1ccccc1C(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)N(C(=O)CCl)c1ccccc1C(=O)c1ccccc1

Procedure:
A mixture of 2-(tert-butylamino)benzophenone (7.5 g) and chloroacetyl chloride (20 ml) in anhydrous toluene (250 ml) was refluxed for 2 hours under nitrogen. Solvents were removed under vacuum and the remaining residue was dissolved in ethyl acetate (250 ml), washed with 5% sodium bicarbonate solution, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel, toluene-ethyl acetate, 99:1 to 95:5) gave the title compound (7 g) as a solid; δH (360 MHz, CDCl3) 7.87-7.84 (2H, m), 7.68-7.46 (6H, m), 7.36 (1H, d, J=7.7 Hz), 4.05 (1H, d, J=13.2 Hz), 3.72 (1H, d, J=13.2 Hz), 1.27 (9H, s); m/z (CI) 329 (M-).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH:19](I)([CH3:21])[CH3:20].O>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][CH:19]([CH3:21])[CH3:20])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 20 °C
Yield: 57.9 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-nitrophenol (19.1 g) in acetonitrile (100 ml), there was added anhydrous potassium carbonate (8 g). After stirring at room temperature (ca. 20° C.) for several minutes, isopropyl iodide (25 g) was added thereto, and the resultant mixture was heated under reflux for 3 hours. After allowed to cool to room temperature (ca. 20° C.), water was added thereto, and the reaction mixture was extracted with ether. The ether extract was washed with a 5% aqueous sodium hydroxide solution and water in order, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give 13.5 g of 4-chloro-2-fluoro-5-isopropoxynitrobenzene. M.P., 61.3°-62.4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[C:15]2[O:16][CH2:17][CH:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[CH:6]=[CH:7][CH:8]=1.C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][CH:12]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1COC(c2c(-c3ccccc3)cnnc2-c2cccc(OC)c2)=N1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Br
Product: COC(=O)c1coc(-c2c(-c3ccccc3)cnnc2-c2cccc(OC)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a solution of methyl 2-(3-(3-methoxyphenyl)-5-phenylpyridazin-4-yl)-4,5-dihydrooxazole-4-carboxylate (compound 25) (60 mg, 0.16 mmol) in DCM (3 mL), DBU (76 mg, 0.5 mmol), bromotrichloromethane (83 mg, 0.41 mmol) was added at 0° C., stirred for 3 h and then warmed to rt. Reaction was quenched by addition of sat. sodium bicarbonate solution, extracted with DCM (2×25 mL), washed with brine (1×5 mL) and dried over anhydrous Na2SO4. Evaporation of solvent under reduced pressure gave the crude product that was purified by column chromatography (100-200 mesh silica gel, 35% EtOAc-Hexane) to furnish methyl 2-(3-(3-methoxyphenyl)-5-phenylpyridazin-4-yl)oxazole-4-carboxylate (compound 26) (35 mg, 59%) as an off white solid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[C:23]4[CH3:30])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.C([O-])=O.[NH4+]>CN(C=O)C.[Pd]>[CH3:29][C:24]1[NH:25][C:26]2[C:22]([C:23]=1[CH3:30])=[CH:21][C:20]([O:19][C:13]1[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:31][CH3:32])[CH:11]=3)[N:16]=[CH:15][N:14]=1)=[CH:28][CH:27]=2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.8 %

Procedure:
A solution of 7-benzyloxy-4-(2,3-dimethylindol-5-yloxy)-6-methoxyquinazoline (2 g, 4.7 mmol) in DMF (120 ml) containing ammonium formate (11 gr, 174 mmol) and 10% palladium on charcoal (200 mg) was stirred for 2.5 hours at ambient temperature. The mixture was filtered, and the filtrate was evaporated under vacuum. The residue was triturated with ether and the solid was filtered, washed with water followed by ether and dried under vacuum at 50° C. to give 4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (1.1 g, 69%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[CH:20]=[CH:19][N:18]([CH:21]5[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[N:17]=4)=[N:14][N:13](C4CCCCO4)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.Cl>O1CCOCC1>[NH:24]1[CH2:23][CH2:22][CH:21]([N:18]2[CH:19]=[CH:20][C:16]([C:15]3[C:9]4[C:10](=[CH:11][N:12]=[C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH:8]=4)[NH:13][N:14]=3)=[N:17]2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cncc(-c2cc3c(-c4ccn(C5CCNCC5)n4)n[nH]c3cn2)c1
Yield: 10.9 %

Procedure:
Tert-butyl 4-(3-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (17.0 mg, 0.032 mmol) in Dioxane (5 mL) was treated with 4.0 M of Hydrogen chloride in 1,4-Dioxane (5 mL) overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse phase HPLC to afford 215 as an off-white solid (1.2 mg, 18%). 1H NMR (400 MHz, DMSO) δ 9.28 (s, 1H), 9.19 (s, 1H), 8.70-8.57 (m, 2H), 8.44 (d, J=7.6 Hz, 1H), 8.30 (s, 1H), 7.94 (s, 1H), 7.59-7.51 (m, 1H), 6.84 (s, 1H), 4.47 (s, 1H), 3.22 (d, J=12.7 Hz, 2H), 2.82 (t, J=12.0 Hz, 2H), 2.15 (d, J=11.5 Hz, 2H), 2.04 (d, J=9.0 Hz, 2H). ESI MS m/z=346.1 (M+1)
Reaction SMILES: [F:1][C:2]1[C:31]([N:32]2[CH2:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:30][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH:14][C:15](=[O:23])[N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:12][N:11](C4CCCCO4)[N:10]=3)=[N:8][C:4]=2[CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[C:31]([N:32]2[CH2:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:30][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH:14][C:15](=[O:23])[N:16]([CH:17]([CH3:18])[CH3:19])[CH:20]([CH3:22])[CH3:21])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)N(C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCCOCC3)cc2[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N(C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N3CCCOCC3)cc2[nH]1)C(C)C
Yield: 9.5 %

Procedure:
A solution of 600 mg of 3-[3-(5-fluoro-6-perhydro-1,4-oxazepin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]-1,1-diisopropylurea in solution in 5 mL of a 4N solution of hydrochloric acid in dioxane is stirred at 22° C. for 4 hours. After evaporation, the reaction crude is purified by preparative HPLC and then by preparative LC/MS, with, as eluent, a gradient of water, with acetonitrile, containing respectively 0.07% of trifluoroacetic acid. 48 mg of 3-[3-(5-fluoro-6-perhydro-1,4-oxazepin-4-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-1,1-diisopropylurea are obtained in the form of a brown solid. 1H NMR (400 MHz, DMSO-d6, δ in ppm): 1.35 (d, J=7.0 Hz, 12H); 1.98 (m, 2H); 3.33 (m, 4H); 3.78 (m, 4H); 4.06 (m, 2H); 7.08 (broad d J=8.0 Hz, 1H); 7.28 (broad d, J=12.0 Hz, 1H); 8.01 (s, 1H); 9.56 (s, 1H); 12.85 (broad m, 2H).
Reaction SMILES: Cl.[CH2:2]([C:4]1([C:13]2NC=N[CH:14]=2)[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[CH3:3].CC(=[O:23])CC=C>>[CH:13]([C:4]1([C:2](=[O:23])[CH3:3])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[CH2:14]
Reactant: C=CCC(C)=O
Reactant: CCC1(c2cnc[nH]2)Cc2ccccc2C1
Agent: Cl
Product: C=CC1(C(C)=O)Cc2ccccc2C1

Procedure:
EP 0247764 B (ORION-YHTYMÄ OY) Feb. 12, 1987 disclosed the following process for preparation of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole hydrochloride. The process starts by reaction of alpha, alpha′-dibromo-o-xylene with 4-penten-2-one to obtain 1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)ethanone. The obtained intermediate was brominated, e.g. with bromine, methylene chloride was used as solvent and 2-bromo-1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)-ethanone was obtained, which is thereafter reacted with formamide in excess formamide to give a 4(5)-(2,3-dihydro-2-vinyl-1H-inden-2-ylimidazole hydrochloride. As the last step the vinyl group was catalytically hydrogenated to an ethyl group so as to form a product 4(5)-(2,3-dihydro-2-ethyl-1H-inden-2-yl) imidazole.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([SH:6])=[N:2]1.C[O-].[Na+].CS(O[CH2:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)(=O)=O>CO>[NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:15][CH:16]2[CH2:19][CH2:18][CH2:17]2)=[N:2]1
Reactant: CS(=O)(=O)OCC1CCC1
Reactant: Sc1nc[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc(SCC2CCC2)n[nH]1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
To a solution of 1,2,4-triazole-3-thiol (20.2 g; 0.20 mol) and sodium methoxide (11.8 g; 0.22 mol) in methanol (250 ml) is added cyclobutylmethyl methanesulfonate (36.4 g; 0.22 mol). The mixture was refluxed for 27 h under dry nitrogen, allowed to cool to 25° C. and filtered. The solid was washed with ethyl acetate and the organic solutions combined and evaporated. The residue was dissolved in water (250 ml) and extracted into ethyl acetate (250 ml) and dichloromethane (100 ml). The extracts were combined, dried (Na2SO4), filtered and evaporated to afford crude cyclobutylmethyl 1,2,4-triazol-3-yl sulfide (21.8 g; 65%) as a white, sticky solid. NMR -d(CDCl3 ; 60 MHz) 1.5-2.8 (m), 3.2 (2H, d, J=7 Hz), 8.0 (1H, s) and 12.4 (1H, br s).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH:11]1([CH2:14][C:15](Cl)=[O:16])[CH2:13][CH2:12]1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][N:34]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>>[CH2:25]([NH:24][C:22](=[O:23])[C:21]1[CH:32]=[CH:33][N:34]=[C:19]([NH:18][C:15](=[O:16])[CH2:14][CH:11]2[CH2:13][CH2:12]2)[CH:20]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)CC1CC1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(CC1CC1)Nc1cc(C(=O)NCc2ccccc2)ccn1
Yield: 57 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 2-cyclopropylacetyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(2-cyclopropylacetamido)isonicotinamide was obtained as a colorless solid in 57% yield: 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.48 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 7.53 (dd, J=5.1, 1.4 Hz, 1H), 7.31-7.24 (m, 5H), 6.87 (br s, 1H), 4.60 (d, J=5.8 Hz, 2H), 2.31 (d, J=7.2 Hz, 2H), 1.08-0.99 (m, 1H), 0.70-0.62 (m, 2H), 0.25 (q, J=4.9 Hz, 2H); MS (ES+) m/z 310.6 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:32]([N:34]([CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)[CH:35]([CH3:37])[CH3:36])=[O:33])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=O>>[CH2:1]([O:8][C:9]1[C:10]([C:32]([N:34]([CH2:38][CH2:39][OH:40])[CH:35]([CH3:37])[CH3:36])=[O:33])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3cccc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-6-hydroxy-N-(2-hydroxyethyl)-N-isopropyl-2-((1-(3-(trifluoromethyl)phenyl)cyclo-pentyl)methyl)pyrimidine-4-carboxamide (477) was synthesized from 5-(benzyloxy)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-hydroxy-N-isopropyl-2-((1-(3-(trifluoromethyl)phenyl)cyclo-pentyl)methyl)pyrimidine-4-carboxamide (476) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (246).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][O:8][C:5]1[C:4]([NH2:10])=[CH:3][C:2]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)=[CH:7][N:6]=1
Reactant: COc1ncc(Br)cc1N
Reactant: OB(O)c1ccncc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ncc(-c2ccncc2)cc1N
Temperature: 110 °C
Yield: 74 %

Procedure:
To a flask were weighed 5-bromo-2-methoxypyridin-3-amine, 11.1.A, (1 g, 4.9 mmol), pyridin-4-ylboronic acid (0.73 g, 5.9 mmol), X-Phos (0.47 g, 0.99 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.22 g, 0.25 mmol), and Potassium phosphate tribasic (3.13 g, 14.8 mmol). N-butanol was added as a solvent and the reaction mixture was heated at 110° C. for 3 hr. The solids were filtered off through a pad of celite. The filtrate was concentrated and chromatographed by gradient EtOAc/DCM and then 10% MeOH/DCM to afford 730 mg of 11.1.B (74%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]([NH:15][C:16](=[O:22])[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][NH:7][C:8](=[O:14])[O:9][CH2:10][CH:11]([CH3:13])[CH3:12].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:30][S:31]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]([NH:15][C:16]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:22])[CH2:6][NH:7][C:8]([O:9][CH2:10][CH:11]([CH3:12])[CH3:13])=[O:14])(=[O:33])=[O:32]
Reactant: CC(C)COC(=O)NC[C@H](CCCO)NC(=O)OCC(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)COC(=O)NC[C@H](CCCOS(C)(=O)=O)NC(=O)OCC(C)C
Temperature: -78 °C

Procedure:
A round bottom flask was charged with (S)-diisobutyl (5-hydroxypentane-1,2-diyl)dicarbamate (5.0 g, 15.7 mmol), CH2Cl2 (80 mL), and triethylamine (5.3 mL, 38 mmol), and cooled to −78° C. Methanesulfonyl chloride (2.3 mL, 30 mmol) was added dropwise with stirring and the cold bath was allowed to warm to 0° C. over the course of 5 h. Aqueous citric acid (20%, 140 mL) and CH2Cl2 (150 mL) were added and the phases were separated. The organic phase was washed with saturated NaHCO3 solution, and then dried on anhydrous Na2SO4. The solvent was removed by rotary evaporation and dried in oil pump vacuum. The product (S)-4,5-bis((isobutoxycarbonyl)amino)pentyl methanesulfonate was obtained as a yellowish white solid. The crude product was used without further purification in the next procedure.