Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:8]([O:21][CH3:22])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:23]N(C=NC=[N+](C)C)C.[Cl-].C(O)(=O)C.C([O-])(=O)C.[Na+]>O1CCOCC1>[OH:5][C:4]1[C:3]2[C:2](=[CH:10][C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:8]([O:21][CH3:22])[CH:7]=2)[N:1]=[CH:23][N:6]=1
Reactant: COc1cc(C(N)=O)c(N)cc1OCCCN1CCOCC1
Reactant: CN(C)C=NC=[N+](C)C
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc2c(O)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A mixture of 2-amino-5-methoxy-4-(3-morpholinopropoxy)benzamide (4.57 g, 12.25 mmol) and Gold's reagent (2.6 g, 15.89 mmol) in dioxane (35 ml) was heated at reflux for 5 hours. Acetic acid (0.55 ml) and sodium acetate (1.0 g) were added to the reaction mixture which was heated for a further 3 hours. The mixture was cooled to ambient temperature and the volatiles removed by evaporation. The residue was adjusted to pH7 with 2M sodium hydroxide and then purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with methanol (gradient of 0 to 60%) in water. Concentration of the fractions by evaporation gave a precipitate which was collected by filtration and dried under vacuum over phosphorus pentoxide to give 4-hydroxy-6-methoxy-7-(3-morpholinopropoxy)quinazoline (3.04 g, 78%) as a white solid.
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[O:16]=[C:17]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]1[CH2:34][CH2:35][CH2:36][C:37](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[C:28]1([C:21]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([CH2:34][CH2:35][CH2:36][C:37]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=4)[N:14]=3)[C:17]2=[O:16])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)CCCN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(CCCc2nc(-c3ccc(C(F)(F)F)cc3)no2)CCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
A suspension of (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide (0.233 g, 1.143 mmol), 4-(2-oxo-3,3-diphenylpyrrolidin-1-yl)butanoic acid (0.336 g, 1.039 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.299 g, 1.559 mmol) were stirred together in dichloroethane (5 mL) for 3 hours then heated to 85° C. for 18 hours. The reaction was cooled and concentrated. The reaction was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 4% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.17 (d, J=8.0, 2H), 7.73 (d, J=8.2, 2H), 7.38-7.20 (m, 10H), 3.56 (t, J=7.0, 2H), 3.41 (t, J=6.4, 2H), 2.92 (t, J=7.6, 2H), 2.77 (t, J=6.4, 2H), 2.22-2.09 (m, 2H); MS (ESI+) m/z 492.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11]1
Reactant: CN1CCNCC1
Reactant: Oc1cccc(Cl)n1
Product: CN1CCN(c2cccc(O)n2)CC1
Temperature: 90 °C
Yield: 66 %

Procedure:
To a stirring solution of 1-methyl-piperazine (10 ml) was added 6-chloro-2-pyridinol (1.5 g, 11.57 mmol) and the mixture was heated at 90° C. for 60 h. The reaction mixture was cooled to RT and concentrated under reduced pressure (while heating) to afford the title compound as a brown solid (66%). The crude material was used without further purification. MS (ESI) 194.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:34])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:34])[NH:6][C:7]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:19][CH:20]=1)=[N:8]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc2c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(C4CCNCC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.2 %

Procedure:
To a solution of tert-butyl 4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidine-1-carboxylate (0.210 g, 0.45 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (1 mL). The resulting solution was stirred at room temperature for 5 hours. Then, the mixture was concentrated in vacuo and the resulting material was purified by flash chromatography on silica gel, eluting with 0% to 10% of MeOH/CH2Cl2. The residue was further purified by flash chromatography on silica gel, eluting with 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH followed by 100% of 6:3:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (0.030 g, 18%). 1H NMR (300 MHz, DMSO-d6): δ 8.11 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 6.73 (s, 1H), 6.53 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.92-3.20 (m, 2H), 2.56-2.81 (m, 3H), 2.35-2.57 (m, 2H), 1.67-1.88 (m, 2H), 1.38-1.67 (m, 2H). ESI MS m/z 366 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[NH:7][C:8](=O)[CH3:9]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]([CH3:9])=[N:7][C:6]=2[CH:11]=1
Reactant: CC(=O)Nc1cc(Br)ccc1Nc1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1nc2cc(Br)ccc2n1-c1ccccc1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
Suspending 3.6 g (12 mmol) of 5′-bromo-2′-(N-phenylamino)-acetanilide obtained in the above step (1) into 30 milliliter of xylene, and adding 0.68 g (3.6 mmol) of p-toluenesulfonic acid 1 hydrate, the resultant solution was azeotropically dehydrated while refluxing with heating for 5 hours. The reacted solution was cooled down to room temperature, and the solvent was removed by distillation. Dissolving the resultant solid into ethyl acetate, and after sequentially washing with water, with 10% potassium carbonate aqueous solution and with saturated solution of sodium chloride, it was dried with sulfuric anhydride magnesium, followed by removing the solvent by distillation under reduced pressure, 3.0 g of 5-bromo-2-methyl-1-phenyl-1H-benzimidazole was obtained (yield: 90%).
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:32])[CH2:27][CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.[Cl-].[NH4+]>[CH2:13]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26](=[O:32])[C@H:27]([CH2:28][CH:29]1[CH2:30][CH2:31]1)[CH2:3][CH:1]=[CH2:2])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CCC1CC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC[C@@H](CC1CC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A solution of N,N-diisopropylamine (5.46 mL, 39 mmol) in anhydrous tetrahydrofuran (90 mL) was cooled to −10° C. before adding a solution of n-butyllithium (2.5 M in hexanes, 15 mL, 37.5 mmol) dropwise over 10 minutes maintaining the temperature below 0° C. The reaction mixture was stirred at 0° C. for 10 minutes before cooling to −78° C. A solution of (S)-4-benzyl-3-(3-cyclopropyl-propionyl)-oxazolidin-2-one (8.88 g, 32.5 mmol) in tetrahydrofuran (35 mL) was added dropwise over 10 minutes keeping the temperature below −70° C. The reaction mixture was stirred at −78° C. for 1 h then warmed to −15° C. for 2 h. The reaction mixture was diluted with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (2×60 mL). The extract was dried over anhydrous sodium sulfate, filtered and evaporated to give a yellow gum. The gum was purified by silica gel chromatography using iso-hexanes/ethyl acetate 4:1 to yield the title compound (5.3 g, 52%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 0.01-0.15 (m, 2H), 0.35-0.50 (m, 2H), 0.65-0.82 (m, 1H), 1.50-1.60 (m, 2H), 2.32-2.45 (m, 1H), 2.47-2.60 (m, 1H), 2.66-2.77 (m, 1H), 3.27-3.37 (m, 1H), 4.05-4.25 (m, 3H), 4.65-4.76 (m, 1H), 5.03-5.16 (m, 2H), 5.78-5.93 (m, 1H), 7.20-7.36 (m, 5H). LCMS (m/z) 314.1 [M+H], Tr=2.83 min.
Reaction SMILES: N1C=CC=CC=1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>O>[C:15]([O:14][CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCCCCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1CCCCC1

Procedure:
Under a nitrogen atmosphere, pyridine (934 g) was added to 6-chlorohexanol (800 g). Acetic anhydride (1,200 mL) was added thereto, and after refluxing under heating for 3 hours, the reaction solution was poured into water and extracted with toluene. The organic layer was neutralized with a saturated sodium hydrogencarbonate aqueous solution, and after washing with water, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the concentrated product was purified by distillation under reduced pressure to obtain 6-acetoxycyclohexane (983 g).
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6]([C:8]1[N:16]([CH3:17])[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])=[O:7])C>>[Na+:2].[F:26][C:20]1[CH:21]=[C:22]([I:25])[CH:23]=[CH:24][C:19]=1[NH:18][C:9]1[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[N:16]([CH3:17])[C:8]=1[C:6]([O-:7])=[O:5]
Reactant: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(C(=O)[O-])c(Nc2ccc(I)cc2F)c2cnccc21
Temperature: 60 °C
Yield: 111.4 %

Procedure:
Sodium hydroxide (39 mg, 1.0 mmol) was added to a suspension of 3-(2-fluoro-4-iodo-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (400 mg, 0.91 mmol) in IMS (6 ml) and the reaction heated at 60° C. for 5 hours. The reaction mixture was concentrated in vacuo to yield the title compound as a yellow solid (439 mg, 100%). LCMS (method B): RT=2.19 min, M-Na+H+=412.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:4]=[CH:5][C:6]([F:24])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][C:10]=2[C:17]2[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH:18]=2)[CH:8]=1.S(Cl)([Cl:28])=O>C(Cl)Cl.CN(C=O)C>[Cl:28][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH:8]=[C:3]([CH:2]([F:25])[F:1])[CH:4]=[CH:5][C:6]=2[F:24])=[C:10]([C:17]2[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH:18]=2)[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)CCC=C1c1cc(CO)ccc1-c1cc(C(F)F)ccc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCC=C1c1cc(CCl)ccc1-c1cc(C(F)F)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.1 %

Procedure:
To a solution of 66.50C (0.1666 g, 0.481 mmol) in dry DCM (3 mL) and dry DMF (0.06 mL) was added thionyl chloride (0.07 mL, 0.96 mmol) at 0° C. The resulting solution was warmed to room temperature and monitored with TLC and LCMS. After 45 minutes, the reaction was concentrated and then purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 66.50D (172.1 mg, 98% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.46 (2H, m), 7.39 (1H, m), 7.33 (1H, m), 7.28 (1H, d, J=1.7 Hz), 7.17 (1H, m), 6.62 (1H, t), 5.51 (1H, td, J=2.3, 1.0 Hz), 4.64 (2H, s), 2.24 (2H, td, J=7.1, 2.4 Hz), 1.68 (2H, m), 0.85 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[C:4]([Cl:14])[C:3]=1[NH:15][C:16]1[C:25]2[CH:26]=[CH:27][N:28]=[C:29]([O:30][CH3:31])[C:24]=2[C:23]2[C:18](=[CH:19][CH:20]=[N:21][CH:22]=2)[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:14][C:4]1[CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:15][C:16]1[C:25]2[CH:26]=[CH:27][N:28]=[C:29]([O:30][CH3:31])[C:24]=2[C:23]2[C:18](=[CH:19][CH:20]=[N:21][CH:22]=2)[N:17]=1
Reactant: COc1nccc2c(Nc3c(Cl)cc(C#C[Si](C)(C)C)cc3Cl)nc3ccncc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(Cl)c(Nc2nc3ccncc3c3c(OC)nccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{2,6-dichloro-4-[(trimethylsilyl)ethynyl]phenyl}-10-methoxypyrido[4,3-c]-1,6-naphthyridin-6-amine (118 mg, 0.25 mmol) in methanol (3 mL) was added K2CO3 (38.4 mg, 0.28 mmol) and stirred at room temperature overnight. The solvents were evaporated and the residue was diluted with ethyl acetate and washed with water followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12][CH2:13][CH2:14][CH2:15]O.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:12][CH2:13][CH2:14][CH2:15][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCCCBr
Reactant: Oc1cccc2ccccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-naphthol (3.45 g), 3-bromopropanol (1.75 mL), di-t-butyl-azo-dicarboxylate (5.52 g) and triphenylphosphine (6.28 g) in THF (30 mL) was stirred at room temperature for 16 hours and concentrated. The concentrate was diluted with ethyl acetate, washed with water and brine and dried (MgSO4), filtered, and concentrated. The concentrate was purified by silica gel chromatography with 0-7% ethyl acetate/hexane.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:12]([N:16]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19](Cl)[CH:18]=[N:17]1)([CH3:15])([CH3:14])[CH3:13].O>CN(C)C=O>[C:12]([N:16]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=[N:17]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCc2ccc(F)cc2)cnn(C(C)(C)C)c1=O
Yield: 62.2 %

Procedure:
To a solution of 0.63 g (0.005 mol) of p-fluorobenzyl alcohol dissolved in 20 ml of N,N-dimethylformamide was added 0.24 g of 55% sodium hydride at room temperature under stirring. After addition, the resulting mixture was further stirred at room temperature for fifteen minutes. The reaction liquid was added dropwise with 1.0 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone, and was stirred at room temperature for eight hours. The reaction mixture was poured into 200 ml of water and then extracted with 50 ml of benzene. The resulting benzene layer was washed successively with 50 ml of 10% sodium hydroxide, 50 ml of 1N-hydrochloric acid, and 100 ml of water, dried over anhydrous sodium sulfate, and freed of solvent by distillation to give 1.5 g of crude product. The crude product was recrystallized from 20 ml of hexane to obtain 0.9 g of 2-t-butyl-5-(p-fluorobenzyloxy)-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([N:12]1[CH2:29][CH2:28][C:15]2([CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]2)[CH2:14][CH2:13]1)=[O:11])=[O:7])[CH:2]([CH3:4])[CH3:3].Cl>O1CCOCC1>[CH2:20]1[C:15]2([CH2:28][CH2:29][N:12]([C:10](=[O:11])[CH2:9][NH:8][C:6]([NH:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14]2)[CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CC(C)CNC(=O)NCC(=O)N1CCC2(CCCN(C(=O)OC(C)(C)C)C2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CNC(=O)NCC(=O)N1CCC2(CCCNC2)CC1
Yield: 87.1 %

Procedure:
To a solution of tert-butyl 9-[2-(isobutylcarbamoylamino)acetyl]-4,9-diazaspiro[5.5]undecane-4-carboxylate (0.38 g, 0.93 mmol) in 1,4-dioxane (1.75 mL), add 4M HCl in 1,4-dioxane (8.77 mmol). Stir the reaction at room temperature for 5 hours, then concentrate under reduced pressure. Purify the residue by dissolving in methanol and loading into a SCX (ion exchange) column. Rinse the loaded column with methanol (3×25 mL) then flush the column with 2N ammonia in methanol. Combine and concentrate the ammonia washes to yield the final title compound, 1-[2-(4,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]-3-isobutyl-urea (0.25 g, 0.81 mmol): MS (m/z): 311.0 (M+H).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[Cl:23][C:24]1[C:25]([CH3:33])=[N:26][NH:27][C:28]=1[C:29]([F:32])([F:31])[F:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:23][C:24]1[C:28]([C:29]([F:31])([F:30])[F:32])=[N:27][N:26]([CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:8]=[N:9][N:10]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)[C:11]=3[CH:12]([CH3:14])[CH3:13])[C:3]2=[O:22])[C:25]=1[CH3:33]
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(Cl)cc1
Reactant: Cc1n[nH]c(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1C1CCN(c2cnn(-c3ccc(Cl)cc3)c2C(C)C)C1=O
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 77.9 %

Procedure:
A mixture of 3-bromo-1-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.035 g, 0.095 mmol), 4-chloro-3-methyl-5-(trifluoromethyl)-1H-pyrazole (0.050 g, 0.27 mmol) and K2CO3 (0.050 g, 0.36 mmol) in DMF (0.8 mL) was stirred at 60° C. for 40 min. The mixture was then cooled to room temperature, quenched with water (30 mL), extracted with EtOAc (50 mL), and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to yield the title compound (0.036 g, 78%). 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.47 (m, 2H), 7.34 (m, 2H), 5.05 (dd, J=9.2, 6.0 Hz, 1H), 4.04 (m, 1H), 3.81 (m, 1H), 2.99 (heptet, J=6.8 Hz, 1H), 2.87 (m, 1H), 2.76 (m, 1H), 2.42 (s, 3H), 1.22 (d, J=7.2 Hz, 3H), 1.12 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C21H20Cl2F3N5O [M+H]+486.1. found 486.1.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(F)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])(=O)C>CO.Cl>[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:12]
Reactant: CC(=O)Nc1ccccc1C(=O)C1CCCCC1
Agent: Cl
Solvent: CO
Product: Nc1ccccc1C(=O)C1CCCCC1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of (2-acetamidophenyl) cyclohexyl methanone (0.53 g) in methanol (5 ml) and concentrated hydrochloric acid (15 ml) was heated at 80° C. for 1 h. After this time the solution was cooled to ambient temperature and the solvents removed in vacuo. The residue was dissolved in water (10 ml) and basified with 4N sodium hydroxide solution (20 ml). The mixture was then extracted into ethyl acetate (4×20 ml) and the organic layers combined and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica gel using petrol:ethyl acetate (2:1), to afford the amine (0.40 g). Mp 73°-75° C. 1H NMR (360 MHz, CDCl3) δ 1.23-2.09 (10H, m), 3.27 (1H, m), 6.29 (2H, brs), 6.64 (2H, m), 7.25 (1H, dt, J=6 and 1 Hz), 7.76 (1H, dd, J=7 and 1 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH:23]([N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=N1)([CH3:25])C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.O.[Cl-].[Na+].O>[F:21][CH:20]([F:22])[N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:2]3[CH:28]=[CH:29][C:30]([N:26]4[CH2:23][CH2:25][O:8][CH2:6][CH2:5]4)=[CH:4][CH:3]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](Oc1nc(-c2ccc(N3CCOCC3)cc2)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
Intermediate 2.64 (27 mg, 0.082 mmol), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40 mg, 0.17 mmol), Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (1.8 mg, 0.0025 mmol) and K3PO4 (52 mg, 0.25 mmol) were taken up in 1,4-dioxane (0.9 mL) under Ar. Water (0.1 mL) was added and the resulting stirred mixture was heated to 100° C. After 1.25 h, the reaction mixture was cooled to r.t. and was diluted with EtOAc (2 mL), water (1 mL), and brine (1 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (4×1.5 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (0% to 15% MeOH in DCM) to afford (R)-4-((R)-1-(3-(difluoromethyl)-6-(4-morpholinophenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.25. LCMS-ESI+ (m/z): [M+H]+ calcd for C19H23F2N6O2: 405.2; found 405.1. 1H NMR (400 MHz, Chloroform-d) δ 8.24 (s, 1H), 7.95 (d, J=0.7 Hz, 1H), 7.85 (s, 1H), 7.59 (t, J=61.1 Hz, 1H), 7.48 (s, 1H), 6.12 (s, 1H), 5.71-5.61 (m, 1H), 4.63-4.46 (m, 1H), 3.63-3.50 (m, 1H), 3.37 (dd, J=9.7, 6.1 Hz, 1H), 2.99-2.87 (m, 1H), 2.55 (dd, J=17.2, 9.3 Hz, 1H), 2.45 (dd, J=17.2, 7.4 Hz, 1H), 1.56 (d, J=6.7 Hz, 6H), 1.47 (d, J=6.2 Hz, 3H).