Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8](COCC[Si](C)(C)C)[C:9]2[C:10]3[N:17]=[N:16][N:15](COCC[Si](C)(C)C)[C:11]=3[N:12]=[CH:13][N:14]=2)[C:5](=[O:34])[N:4]2[C:35]3([CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[NH:36][C:37](=[O:38])[C:3]=12.FC(F)(F)C(O)=O.[OH-].[K+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]3[N:17]=[N:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C:5](=[O:34])[N:4]2[C:35]3([NH:36][C:37](=[O:38])[C:3]=12)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3
Reactant: C[Si](C)(C)CCOCN(c1cc(Cl)c2n(c1=O)C1(CCCCC1)NC2=O)c1ncnc2c1nnn2COCC[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC2(CCCCC2)n2c1c(Cl)cc(Nc1ncnc3[nH]nnc13)c2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 8-chloro-6-[2-trimethylsilylethoxymethyl-[3-(2-trimethylsilylethoxymethyl)triazolo[4,5-d]pyrimidin-7-yl]amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione (7, 0.3 g, 0.46 mmol) in dichloromethane (15 mL), trifluoroacetic acid (5 mL, 4.63 mmol) was added drop wise at 0° C. The reaction mass was stirred for overnight at room temperature. After completion, reaction mass was concentrated and co-evaporated with diethyl ether. The crude was then dissolved in tetrahydrofuran/ethanol solution and potassium hydroxide (5 mL, 0.46 mmol) solution (3 M in water) was added and stirred the mixture for 16 h. After completion of the reaction the aqueous layer was separated and organic layer was dried over sodium sulfate, filtered and concentrated to get crude. The crude was washed with methanol and n-pentane and dried to afford 8-chloro-6-(3H-triazolo[4,5-d]pyrimidin-7-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione (Cpd. No. 146) as brown solid. Yield: 70 mg, 39%; MS (ESI) m/z 387.39 [M+1]+; 1H NMR: (400 MHz, DMSO-d6) δ 10.45 (brs, 1H), 9.29 (s, 1H), 8.88 (s, 1H), 7.77 (s, 1H), 2.94 (t, J=2.32, 2H), 1.79-1.76 (m, 2H), 1.67-1.51 (m, 5H), 1.27-1.23 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)[CH:7]=1.[C:25]1([CH3:37])[CH:30]=[CH:29][C:28]([S:31]([N:34]=[C:35]=[O:36])(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH3:37][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35](=[O:36])[O:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[CH:7]=[C:2]([Cl:1])[C:3]([C:21]([F:22])([F:23])[F:24])=[CH:4][C:5]=3[N+:18]([O-:20])=[O:19])=[CH:10][CH:11]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Nc1ccc(CCO)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(Nc3cc(Cl)c(C(F)(F)F)cc3[N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a stirred solution of 2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol (step 2 of Example 104, 1.0 g, 2.77 mmol) in dichloromethane (45 ml) was added p-toluenesulfonyl isocyanate (574 mg, 2.91 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was quenched with water (100 ml). The organic layer was separated. The aqueous layer was extracted with dichloromethane (100 ml×3). The combined organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (gradient elution from 2:1 to 1:1) to afford 1.51 g (98%) of the title compound as an orange solid.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:30])[C:14]=2[C:18](=[O:29])[NH:19][CH2:20][C:21]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]1=[O:31])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>>[Cl:30][C:13]1[CH:12]=[CH:11][C:10]2[C:9](=[O:31])[N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[CH:17]=[CH:16][C:15]=2[C:14]=1[C:18]([NH:19][CH2:20][C:21]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:29]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(C(=O)NCC3(O)CCCCCC3)c(Cl)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@H](CO)n1ccc2c(C(=O)NCC3(O)CCCCCC3)c(Cl)ccc2c1=O

Procedure:
A mixture of (R)-2-(6-Chloro-5-((1-hydroxycycloheptyl)methylcarbamoyl)-1-oxoisoquinolin-2(1H)-yl)propyl acetate (620 mg, 0.0012 mol) and potassium carbonate (300 mg, 0.002 mol) was stirred in methanol (50 mL, 1 mol) at room temperature for 1 h. The mixture was concentrated, and the residue was purified by reverse phase preparative HPLC and then by flash chromatography to afford the desired product as a white solid.
Reaction SMILES: [CH:1]1[N:5]=[C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[N:3]2[CH2:19][CH2:20][CH2:21][C:2]=12.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH:8]1[CH2:9][CH2:10][CH2:11][CH:6]([C:4]2[N:3]3[CH2:19][CH2:20][CH2:21][C:2]3=[CH:1][N:5]=2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ncc3n2CCC3)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1nc(C2CCCNC2)n2c1CCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
t-Butyl 3-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)piperidine-1-carboxylate (65 mg, 0.1 mmol) was dissolved into a 20% trifluoroacetic acid in dichloromethane solution (2.4 mL). The reaction mixture was stirred at room temperature for 2.5 h. The solvent was removed under reduced pressure to afford 3-(piperidin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole trifluoroacetate salt as an oil (94 mg, 100%). The material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][C:13]([C:17](OC)=[O:18])([CH2:14][CH2:15]1)[CH2:12][CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1>[OH:18][CH2:17][C:13]12[CH2:16][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])([CH2:15][CH2:14]1)[CH2:10][CH2:11][CH2:12]2
Reactant: COC(=O)C12CCCC(NC(=O)OC(C)(C)C)(CC1)C2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC12CCCC(CO)(CC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of methyl 5-(tert-butoxycarbonylamino)bicyclo[3.2.1]octane-1-carboxylate (7.8 g, 27.6 mmol) in THF (65 mL) was added LiBH4 (2.0 M in THF, 28 mL, 56.0 mmol) dropwise at 0° C. under N2. The solution was warmed up to room temperature gradually and stirred overnight. The reaction mixture was quenched with Sat. NH4Cl and extracted with ethyl acetate (3×150 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 7.0 g (90%) of the crude title compound, tert-Butyl 5-(hydroxymethyl)bicyclo[3.2.1]octan-1-ylcarbamate, as colorless oil, which was used in the next step without further purification. ESI-MS m/z: 200 (M-55)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=1N)([O-:3])=[O:2].Cl.N([O-])=O.[Na+]>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:5]=2)[CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(-c2ccccc2)c1
Reaction time: 1 h

Procedure:
A suspension of 2-nitro-5-methoxyaniline (3.7 g) in water (25 ml) was heated at 80° C. with 36% hydrochloric acid (7.7 ml) for 30 minutes. It was then treated dropwise with aqueous sodium nitrite solution (1.8 g in 5 ml H2O) at 0° C. After 1 hour, the mixture was filtered and the filtrate added at 23° C. to a solution of dimethylamine (35% aqueous solution, 3.9 ml) and sodium carbonate (8.2 g) in water (340 ml). After 12 hours at 23° C. a solid was collected by filtration and dissolved in benzene (100 ml). The solution was heated under reflux and treated with p-toluene sulphonic acid (4.0 g) and heated under reflux for 4 hours in a Dean-Stark water separator. The reaction mixture stood for 48 hours and was then partitioned between cold 10% aqueous sodium hydroxide solution and dichloromethane. Evaporation of the organic layer left an oil which was purified on silica column using ethylacetate:hexane as eluant to furnish 5-methoxy-2-nitrobiphenyl which was dissolved in ethanol (30 ml) and heated under reflux with sodium sulphide (5.3 g) for 8 hours. Purification of the product on a silica column gave 2-amino-5-methoxybiphenyl which was converted into its hydro-chloride salt (m.p. 167° C.).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:2]=[O:3].C(N(C(C)C)C(C)C)C.[CH:51]([OH:54])([CH3:53])[CH3:52]>C(Cl)Cl>[CH:51]([O:54][C:2](=[O:3])[NH:1][C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6](=[O:7])[N:8]([CH3:9])[CH3:10])([CH3:53])[CH3:52]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12
Reactant: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)OC(C)C)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Yield: 48.7 %

Procedure:
Into a 3 mL reaction vial were added 2-isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (30 mg, 0.053 mmol), methylene chloride (1 mL), iPr2EtN (21 μL, 0.060 mmol), and isopropyl alcohol (50 μL, 6.5 mmol). The solution was stirred at room temperature for at least 12 h and monitored by HPLC. The reaction mixture was concentrated then re-dissolved in MeOH (1 mL), and cooled to 0° C. and treated with 100 μL 50% (w/w) aqueous KOH for 30 min or until Ts-removal was complete. The reaction was quenched by addition of 500 μL glacial acetic acid and then concentrated in vacuum. Purification by mass-triggered HPLC (formic acid ACN/H2O gradient) followed by lyophilization provided 12.2 mg of the title compound as a white powder. 1H-NMR (500 MHz, d6-DMSO) δ=11.91 (br.s, 1H), 8.96 (br.s., 1H), 8.53 (d, J=2.0 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.73 (m, 3H), 7.60 (d, J=9.0 Hz, 1H), 7.59 (s, 1H), 7.29 (dd, J=1.5, 7.2 Hz, 1H), 7.12 (d, J=7 Hz, 1H), 7.04 (t, J=7 Hz, 1H), 4.84 (m, 1H), 3.81 (s, 3H), 2.97, 2.92 (br s, 6H), 1.23 (d, J=6, 6H); MS: m/z 473.1 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[CH3:12].[CH3:18]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.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]>[CH3:17][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=2[CH3:12])=[C:2]([CH3:18])[CH:3]=[N:4]1
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2c(C)cnn2C)c(C)s1
Temperature: 110 °C
Yield: 58.4 %

Procedure:
To a 350 mL sealed flask reactor was added methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (2.57 g, 8.15 mmol), trimethylboroxine (2.27 ml, 16.31 mmol), K2CO3 (3.47 g, 25.1 mmol) and Pd(dppf)Cl2 (426 mg, 0.83 mmol) in N,N-Dimethylformamide (DMF) (41 ml). The reaction was heated at 110° C. for 1 hour. The mixture was partitioned between CHCl3/H2O, organic layer separated and dried with Na2SO4. The resulting material was adsorbed onto silica and purified via column chromatography (0-15% EtOAc/Hexane) affording the title compound (1.3 g, 4.76 mmol, 58%): LC-MS (ES) m/z=251 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[N:9]=1)([CH3:7])[CH3:6])C.[OH-].[K+]>CO>[CH3:15][O:14][C:10]1[N:9]=[C:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:16])=[O:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)(C)c1cccc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C(C)(C)C(=O)O)n1
Yield: 76.2 %

Procedure:
2-(6-Methoxy-pyridin-2-yl)-2-methyl-propionic acid ethyl ester (5.33 g) was dissolved in methanol (200 ml), added with 5 N aqueous solution of potassium hydroxide (25 ml), and then stirred under reflux. The reaction mixture was concentrated and neutralized with 2 N hydrochloric acid. The precipitated matters were collected by filtration and dried to obtain the title compound (3.55 g).
Reaction SMILES: [OH:1][C:2]1(/[CH:17]=[CH:18]/[C:19](/[C:26]([F:29])([F:28])[F:27])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([CH3:15])([CH3:14])[CH2:12][C:5]2(OC(C)C(C)[O:6]2)[CH:4]=[C:3]1[CH3:16].Cl.O>CC(C)=O>[OH:1][C:2]1(/[CH:17]=[CH:18]/[C:19](/[C:26]([F:27])([F:28])[F:29])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([CH3:14])([CH3:15])[CH2:12][C:5](=[O:6])[CH:4]=[C:3]1[CH3:16]
Reactant: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC(=O)CC1(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.2 %

Procedure:
Ethyl (2E,4E)-5-(8-hydroxy-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)-3-(trifluoromethyl)penta-2,4-dienoate (150 mg, 0.36 mmol) was dissolved in acetone (5 ml) under argon in a round-bottom flask, and 10% strength hydrochloric acid was added. The resulting reaction solution was stirred at room temperature for 40 minutes, and water was then added. After removing acetone under reduced pressure, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2E,4E)-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)-3-(trifluoromethyl)penta-2,4-dienoate (80 mg, 61% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.55 (d, 1H), 6.37 (d, 1H), 6.33 (s, 1H), 5.97 (s, 1H), 4.25 (q, 2H), 2.47 (d, 1H), 2.34 (d, 1H), 1.92 (s, 3H), 1.90 (br. s, 1H, OH), 1.33 (t, 3H), 1.11 (s, 3H), 1.02 (s, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][CH:9]([CH2:17][CH3:18])[CH2:10][CH2:11][CH2:12][C:13](OC)=[O:14]>O(CC)CC>[CH3:7][O:8][CH:9]([CH2:17][CH3:18])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: CCC(CCCC(=O)OC)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC(CCCCO)OC
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
A stirred suspension of LiAlH4 (15.2 g, 0.40 mole) in dry OEt2 (700 mL) was cooled to 0° C. Methyl 5-methoxyheptanoate (Compound XXII, 34.8 g, 0.20 mole) in dry OEt2 (100 mL) was added dropwise over 1/2 h. The reaction was allowed to slowly warm to room temperature and stirred for an additional 12 h. The excess hydride was destroyed by dropwise addition of sat. aqueous Na2SO4 (extremely vigorous reaction) to the rapidly stirred reaction mixture until the gray color was completely destroyed and only a snow white precipitate remained (further addition of sat. Na2SO4 increased the water content of the product and necessitated drying before the next reaction). The precipitate was filtered and washed with dry OEt2 (5×300 mL). Removal of the ether gave 5-methoxy-1-heptanol (Compound XXIII, 29.2 g, 100%) as a colorless oil, sufficiently pure for further reactions: IR (film) cm-1 3390, 2970, 2945, 2875, 2830, 1465, 1440, 1380, 1200, 1170, 1135, 1094, 1060, 1040, 918; 1H NMR (200 MHz, CDCl3) δ 3.66 (m, 2H), 3.33 (s, 3H), 3.10 (rough pentet, 1H), 1.74 (s, 1H), 1.3-1.7 (complex, 8H), 0.89 (t, 7.4 Hz, 3); 13C NMR (22.5 MHz, CDCl3) δ 82.2, 62.4, 56.4, 32.8, 32.8, 25.8, 21.6, 9.4; high resolution mass spectrum (70 eV) m/e 146 (M+, not observed), 117.0918 (M+ - CH3CH2., calculated 117.0916 for C6H13O2); TLC (OEt2, vanillin dip) Rf =0.30.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:19][CH3:20])[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)=O.CO[CH:34](OC)[CH2:35][NH2:36].Cl>CC(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([N:10]2[CH:34]=[CH:35][N:36]=[C:11]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:19][CH3:20])[CH:3]=1
Reactant: CCc1cc(Br)cc(CC)c1NC(=O)c1ccccc1
Reactant: COC(CN)OC
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cc(Br)cc(CC)c1-n1ccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.6 %

Procedure:
In a 250 mL round-bottom flask added N-(4-bromo-2,6-diethylphenyl)benzamide (7.64 g, 23 mmol), phosphorus pentachloride (4.79 g, 23 mmol), and phosphorus oxychloride (40 mL). The reaction was heated up to reflux under nitrogen. After 2.5 h, the reaction mixture was cooled and phosphorus oxychloride was distilled off using short path distillation apparatus. 2-propanol (40 mL) and 2,2-dimethoxyethanamine (48.4 g, 460 mmol) was added. The reaction was stirred at room temperature for 4 h. Concentrated hydrochloric acid (40 mL) was added carefully, and the reaction was heated to reflux overnight. The solution was decanted from black solid and neutralized with 10% sodium hydroxide solution, extracted with ethyl acetate. The organic layers were dried over magnesium sulfate. The residue was purified by silica gel column chromatography eluting with 20 and 30% ethyl acetate/hexanes. 6.75 g (83% yield) of product was obtained after purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][CH2:18][OH:19].O[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:31]=[O:32])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:17][CH2:18][O:19][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:31]=[O:32])=[CH:23][CH:22]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc(C=O)c2ccccc12
Reaction time: 2 h

Procedure:
2.00 g of 2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol (7.37 mmol) was dissolved in 37 ml of toluene and treated successively at 0° C. with 1.27 g of 4-hydroxy-naphthalene-1-carbaldehyde (7.37 mmol), 1.93 g of triphenylphosphine (7.37 mmol), and 1.49 g (7.37 mmol) of DIAD. The cooling bath was then removed and stirring continued for 2 h. The reaction mixture was then evaporated to dryness in vacuo. Flash chromatography (SiO2, hexane/AcOEt=75/25), followed by boiling up in ether, delivered 1.28 g of the title compound as off-white crystals.
Reaction SMILES: C([O:8][C:9](=[O:28])[CH2:10][CH2:11][NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)C1C=CC=CC=1.[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[OH:32]>>[OH:32][C@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[CH2:30][NH:29][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:8])=[O:28])=[O:27])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=C1CCN(c2ccc(C(=O)NCCC(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)NCCC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 3-[4-(4-oxo-piperidine-1-yl)-benzoylamino]-propionic acid benzyl ester (which was obtained in Example 159) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a white solid; mp >170° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.45 (m, 2H), 1.80-1.95 (m, 2H), 2.43 (t, J=7.0 Hz, 2H), 2.60-2.90 (m, 5H), 2.90 (s, 3H), 3.00-3.40 (m, 2H), 3.70-3.85 (m, 2H), 4.50 (dd, J=8.0, 4.2 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 7.01 (dd, J=8.3, 1.9 Hz, 1H), 7.18 (d, J=1.9 Hz, 1H), 7.68 (d, J=8.9 Hz, 2H), 8.26 (t, J=5.2 Hz, 1H); MS (ES) m/z: 521.2 (MH+); HRMS Calcd. for C24H33N4O7S(MH+): 521.2064. Found: 521.2056.
Reaction SMILES: [C:1]1([C:7]2([CH2:13]OS(C)(=O)=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:19]#[N:20].[Na+]>CS(C)=O.O>[C:1]1([C:7]2([CH2:13][C:19]#[N:20])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1(c2ccccc2)CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1(c2ccccc2)CCCCC1
Temperature: 140 °C
Reaction time: 16 h
Yield: 16.2 %

Procedure:
To a stirred solution of methanesulfonic acid 1-phenyl-cyclohexylmethyl ester (252) (20.0 g, 74.52 mmol) in dimethyl sulfoxide (100.0 mL) were added KI (1.24 g, 7.45 mmol) and NaCN (5.48 g, 111.78 mmol) and the reaction mixture was stirred at 140° C. for 16 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was then dried over Na2SO4 and concentrated. The crude product was purified by normal silica gel column chromatography (using 5% ethyl acetate in hexane) to get (1-phenyl-cyclohexyl)-acetonitrile (253) (2.4 g, 16.1%) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[CH3:22][N:23]1[C:27]([CH:28]=[O:29])=[CH:26][CH:25]=[N:24]1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:28]([OH:29])[C:27]4[N:23]([CH3:22])[N:24]=[CH:25][CH:26]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: Cn1nccc1C=O
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: COC(=O)c1nc2n(c1C(O)c1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 87 %

Procedure:
Methyl 10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with 1-methylpyrazole-5-carbaldehyde to afford 342 mg (87% yield) of the title compound.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[F:37]>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[F:37]
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccncc3F)c2)OC1(C)C
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Fc1cnccc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F
Yield: 35 %

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled to 4-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3-fluoropyridine using the method of Example 65 to give 3-[4-fluoro-3-(3-fluoropyridin-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid (130 mg, 35%): δH (400 MHz, CDCl3) 7.28 (1H, d, J 7), 7.43-7.48 (2H, m), 7.63-7.68 (2H, m), 8.11 (1H, s), 8.55 (1H, d, J 5), 8.64 (1H, d, J 1), 8.77 (1H, d, J 7).