Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].C(N(CC)C(C)C)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:1]([N:3]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCN(C(=O)c1ccccc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (100 mg) in 1,4-dioxane (3 ml) were sequentially added N,N-diisopropylethylamine (0.34 ml) and benzoyl chloride (0.05 ml), and the solution was stirred for 1 hour at 100° C. The solution was let to cool down, then a saturated aqueous solution of sodium bicarbonate was added thereto, the soution was extracted with ethyl acetate, then sequentially washed with an aqueous solution of 10% citric acid and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate-tetrahydrofuran system) to provide the title compound (133 mg).
Reaction SMILES: [Cl-].[Li+].[CH:3](NC(C)C)(C)[CH3:4].C([Li])CCC.[OH:15][CH:16]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:17]([N:19]([CH3:29])[C:20](=[O:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:18].C(I)C.[Si](O[Si](C)(C)C)(C)(C)C>O1CCCC1>[CH2:3]([CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:20]([N:19]([CH:17]([CH3:18])[CH:16]([OH:15])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])=[O:28])[CH3:4]
Reactant: CC(C(O)c1ccccc1)N(C)C(=O)Cc1ccccc1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: CCC(C(=O)N(C)C(C)C(O)c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A dry 500 mL round-bottomed flask was charged with lithium chloride (4.24 g, 100 mmol, 10.0 equiv), diisopropylamine (3.1 mL, 22.1 mmol, 2.21 equiv), and tetrahydrofuran (35 mL). The suspension was cooled to -78° C., and n-butyllithium (2.04M in hexanes, 10.20 mL, 20.8 mmol, 2.08 equiv) was added via cannula, and the mixture was briefly warmed to 0° C. and then recooled to -78° C. [1S-[1R*, 2R*]]-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl benzeneacetamide (2.83 g, 10.0 mmol, 1.0 equiv) was added as a solution in tetrahydrofuran (50 mL), and the mixture was stirred at -78° C. for 1 hour, 0° C. for 10 minutes, and 23° C. for 4 minutes, then cooled to 0° C. Ethyl iodide (3.2 mL, 40 mmol, 4.0 equiv) was added, and the reaction was quenched after 40 minutes with saturated ammonium chloride. The amide was extracted from saturated ammonium chloride (800 mL) with ethyl acetate (3×100 mL), and the combined organic extracts were dried over sodium sulfate. After removal of the solvent under reduced pressure, flash column chromatography (50% ethyl acetate/hexanes) of the oily residue afforded a colorless oil which slowly solidified (2.85 g, 92 % yield). GC analysis of the TMS ether indicated a diastereomeric purity of the amide of greater than 98% de: mp 65°-66° C.; 1H NMR (300 MHz, C6D6) δ6.9-7.4 (m, 5H), 4.95 (br, 1H), 4.51 (t, 1H, J=6.9 Hz), 4.03 (m, 1H), 3.82 (m, 1H), 3.11 (dd, 1H, J=7.5 Hz, 7.0 Hz), 2.78 (s, 3H), 2.48 (m, 2H), 2.25 (m, 1H), 2.12 (s, 3H), 1.90 (m, 1H), 1.73 (m, 2H), 0.98 (d, 3H, J=6.8 Hz), 0.97 (m, 3H), 0.82 (t, 3H, J =7.3 Hz), 0.30 (d, 3H, J=6.5 Hz); 13C NMR (75.5 MHz, CDCl3) δ 175.4, 174.2, 142.3, 141.3, 140.5, 139.6, 128.8, 128.7, 128.7, 128.3, 128.2, 127.8, 127.7, 127.4, 126.9, 126.7, 126.6, 126.3; FTIR (neat film) cm-1: 3384 (br, m), 3027 (m), 2966 (m), 2922 (m), 2873 (m), 1620 (s), 1491 (m), 1453 (m), 1406 (m), 761 (m), 701 (m); HRMS (FAB) Calcd for C20H26NO2 (MH+): 312. 1965. Found: 312. 1962.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]2([F:19])[CH2:18][O:17][CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:21][C:22]1([F:30])[CH2:26][NH:25][C@H:24]([C:27]([NH2:29])=[O:28])[CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[CH2:26][C:22]([F:30])([F:21])[CH2:23][C@H:24]3[C:27]([NH2:29])=[O:28])=[O:14])[CH:9]=[CH:8][C:7]=2[C:15]2([F:19])[CH2:18][O:17][CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Reactant: O=C(O)c1ccc(C2(F)COC2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(C2(F)COC2)c(OCC2CC2)n1
Yield: 53.6 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-(cyclopropylmethoxy)-5-(3-fluorooxetan-3-yl)pyridine-2-carboxylic acid (Example 134 f, 25 mg, 93.5 μmol) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1, 20.9 mg, 112 μmol) to give the title compound (20 mg, 54%) as colorless oil, MS (EI): m/e=400.2 [MH+].
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CCCC4)cc3c2)cc1

Procedure:
The product from Example 1C and pyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ7.7 (m, 5H), 7.50 (d, J=8.7 Hz, 1H), 7.42 (dd, J=8.7, 1.5 Hz, 1H), 6.51 (s, 1H), 3.1 (m 2H), 2.95 (m, 2H), 2.65 (m, 4H), 1.9 (m, 4H); MS (DCI) m/z 317 (M+H)+;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]([OH:23])=[O:22])[C:10]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Rh]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][CH:13]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:12]2[N:11]([CH2:20][C:21]([OH:23])=[O:22])[C:10]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccccc2N(CC(=O)O)C1=O
Agent: [Rh]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCC2CCCCC2N(CC(=O)O)C1=O

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-1-carboxymethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (5 g) in ethanol (100 ml) was hydrogenated at 45 psi using 5% rhodium on carbon (2 g) as catalyst, until uptake ceased. The catalyst was filtered off (celite) and the solvent removed under pressure to give 3-(S)-t-butyloxycarbonylamino-1-carboxymethyl-2,3,4,5,5a,6,7,8,9,9a-decahydro-1H-[1]benzazepin-2-one which was used without further purification for the next synthetic step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[NH2:8][C@@H:9]([CH2:20][CH2:21][C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:26]=1)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>O1CCCC1.C(OCC)(=O)C>[C:27]1([C:25]2[N:26]=[C:22]([CH2:21][CH2:20][C@H:9]([NH:8][CH2:6][C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[NH:23][CH:24]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N[C@@H](CCc1nc(-c2ccccc2)c[nH]1)C(=O)OCc1ccccc1
Reactant: O=Cc1ccsc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](CCc1nc(-c2ccccc2)c[nH]1)NCc1ccsc1
Temperature: 20 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
Thiophene-3-carboxaldehyde (1 ml; 1 eq.) is added to a solution of benzyl (2S)-2-amino-4-(4-phenyl-1H-imidazol-2-yl)butanoate in the form of a free base (3.6 g; 1 eq.) in tetrahydrofuran (hereafter THF, 40 ml). The mixture is stirred for 15 hours at approximately 20° C. and diluted by adding 50 ml of tetrahydrofuran. NaBH(OAc)3 (4.73 g; 2 eq.) is then added. After 1 hour of stirring at approximately 20° C., the reaction is stopped by adding water (40 ml) and ethyl acetate is then added (100 ml). After decantation and extraction, the combined organic phases are washed with salt water, dried over Na2SO4 then evaporated under reduced pressure at 40° C. Flash chromatography purification on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound in the form of a yellow oil (3.08 g; 66% yield).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCC[CH2:17]1>>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[CH2:2][NH:1][CH3:17])[CH3:9]
Reactant: C1CCOC1
Reactant: CCN1CCC[C@H]1CN
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCN1CCC[C@H]1CNC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the compound obtained in (1) mentioned above in tetrahydrofuran (10 ml) was added dropwise to a suspension of lithium aluminum hydride (590.5 mg) in tetrahydrofuran (20 ml), and the resulting mixture was stirred at room temperature for 0.5 hour, and under reflux by heating for 6 hours. The reaction mixture was cooled to room temperature, then distilled water, 25% aqueous sodium hydroxide and distilled water were added to the reaction mixture in this order under ice cooling, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered thorough Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (510 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[C:6]2O.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1ccc2ncc([N+](=O)[O-])c(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2ncc([N+](=O)[O-])c(Cl)c2c1

Procedure:
The title compound is prepared in analogy to Example 19c starting from 3.5 g (15.89 mmol) 6-methoxy-3-nitro-quinolin-4-ol (Example 44f) and 24 ml POCl3. mp: 281-283° C.; MS: 239 (M++1); HPLC: t-=12.29 min (Grad 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[NH:17][C:18](=[O:27])[CH:19]=[CH:20]C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClC1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[C:4]2[C:3]=1[NH:17][C:18](=[O:27])[CH:19]=[CH:20]2
Reactant: O=C(C=Cc1ccccc1)Nc1cc(OCCN2CCOCC2)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Clc1ccccc1
Product: O=c1ccc2c(OCCN3CCOCC3)ccc(Cl)c2[nH]1
Temperature: 125 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
N-(2-chloro-5-(2-morpholinoethoxy)phenyl)cinnamamide (800 mg, 2.1 mmol, 1 eq.) was placed in chlorobenzene (1.9 mL), in the presence of aluminium trichloride (1.6 g, 12.4 mmol, 6 eq.). The reaction mixture was heated at 125° C. and stirred for 2 hours. After cooling down to room temperature, it was diluted with a water and ice mixture and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 8-chloro-5-(2-morpholinoethoxy)quinolin-2(1H)-one (220 mg, 34%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:34][C:35]([CH3:39])([CH3:38])[C:36]#[CH:37]>CN(C)C=O.C(OCC)(=O)C.[Cu]I.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:34][C:35]([CH3:39])([CH3:38])[C:36]#[C:37][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)C
Reactant: Cc1ccc(NS(=O)(=O)CCc2ccc(Br)cc2)c(S(N)(=O)=O)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NS(=O)(=O)CCc2ccc(C#CC(C)(C)C)cc2)c(S(N)(=O)=O)c1
Temperature: 80 °C
Yield: 25.6 %

Procedure:
A mixture of 2-[2-(4-bromo-phenyl)-ethanesulfonylamino]-5-methyl-benzenesulfonamide (0.08 g, 0.18 mmol), N,N-diisopropylethylamine (0.1 mL, 0.55 mmol), and copper(I) iodide (7 mg, 0.04 mmol) in anhydrous N,N-dimethylformamide (2 mL) was degassed with nitrogen for 30 min. (1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (14 mg, 0.02 mmol) and 3,3-dimethyl-1-butyne (0.045 mL, 0.37 mmol) were added and the reaction mixture was heated in a sealed tube at 80° C. overnight. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC, using 5% methanol in dichloromethane as the eluent, to give 20 mg (25% yield) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=O)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24](=[O:25])[N:16]2[CH2:15][CH2:14][CH2:13][N:10]2[CH2:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(Nc2ccc(Cl)cc2)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 6 h
Yield: 54 %

Procedure:
Para-toluenesulphonic acid (50 mg) is added to an agitated solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (10 g) and 4-chlorophenylamine (4.6 g) in xylene (230 cc) at a temperature close to 20° C. in a Dean Stark apparatus. Agitation is continued for 6 hours at a temperature close to 135° C. After cooling to a temperature close to 20° C., the precipitate formed is filtered, washed with xylene (2×50 cc), dried under reduced pressure (20 mm Hg; 2.7 kPa) and recrystallized from boiling acetonitrile (360 cc). 7.1 g of 3-(4-chlorophenylamino)-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone are obtained, melting at 188° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:40]=[C:39]([F:41])[C:31]5[N:32]=[C:33]([CH3:38])[N:34]([CH:35]([CH3:37])[CH3:36])[C:30]=5[CH:29]=4)[C:25]([F:42])=[CH:24][N:23]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CO.O1CCOCC1>[F:42][C:25]1[C:26]([C:28]2[CH:40]=[C:39]([F:41])[C:31]3[N:32]=[C:33]([CH3:38])[N:34]([CH:35]([CH3:37])[CH3:36])[C:30]=3[CH:29]=2)=[N:27][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:16][N:17]=2)=[N:23][CH:24]=1
Reactant: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CN5CCN(C(=O)OC(C)(C)C)CC5)cn4)ncc3F)cc2n1C(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CN5CCNCC5)cn4)ncc3F)cc2n1C(C)C
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
To a mixture of 4-{6-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-ylamino]-pyridin-3-ylmethyl}-piperazine-1-carboxylic acid tert-butyl ester (150 mg) in DCM (10 mL) and methanol (10 mL) add hydrogen chloride 4M in dioxane (194 μL). Stir 10 min and remove the solvent under vacuum. Purify by strong cation exchange cartridge (SCX) eluting with methanol and then methanol-NH3 2M followed by silica gel column chromatography eluting with DCM/methanol-NH3 2M (3%) to afford 120 mg of the title compound. MS (ES+): m/z=479 (M+H)+.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].CI.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[C:26]([OH:27])[C:21]3=[CH:20][N:19]=2)=[O:17])=[CH:12][C:11]=1[O:28][CH3:29].C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:1])[C:21]3=[CH:20][N:19]=2)=[O:17])=[CH:12][C:11]=1[O:28][CH3:29]
Reactant: COc1cc(C(=O)c2ncc3c(O)cccn23)ccc1N
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2ncc3c(OC)cccn23)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.79 g (2.43 mmol) of cesium carbonate and then 0.05 ml (0.84 mmol) of methyl iodide are added to 0.22 g (0.76 mmol) of (4-amino-3-methoxyphenyl)(8-hydroxy-imidazo[1,5-a]pyridin-3-yl)methanone obtained in example 147 in 5 ml of DMF. The reaction medium is stirred at ambient temperature for 4 hours. After addition of a saturated sodium hydrogencarbonate solution, the reaction medium is extracted with ethyl acetate. The organic phase obtained is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel, elution being carried out with dichloromethane. 0.2 g of an orangy-yellow solid is collected. Melting point: 229° C.; 1H NMR (CDCl3): 3.86 (3H, s), 4.01 (3H, s), 5.80 (2H, m), 6.69 (1H, m), 6.69-6.72 (1H, m), 7.03-7.09 (1H, t), 7.78 (1H, s), 7.92 (1H, s), 8.24 (1H, m), 9.25-9.28 (1H, m)
Reaction SMILES: C(C1C=CC([C:9]([C:11]([O:13]CC)=[O:12])=[O:10])=CC=1)C(C)C.C1C=CC([C@H](N)CO)=CC=1.[CH2:28]([C:32]1[CH:37]=[CH:36][C:35]([C@H:38]([CH3:43])[C:39]([O:41]C)=O)=[CH:34][CH:33]=1)[CH:29]([CH3:31])[CH3:30]>>[OH:10][C:9]1[C:11](=[O:12])[O:13][C@@:38]([CH3:43])([C:35]2[CH:34]=[CH:33][C:32]([CH2:28][CH:29]([CH3:30])[CH3:31])=[CH:37][CH:36]=2)[C:39]=1[OH:41]
Reactant: COC(=O)[C@@H](C)c1ccc(CC(C)C)cc1
Reactant: CCOC(=O)C(=O)c1ccc(CC(C)C)cc1
Agent: N[C@H](CO)c1ccccc1
Product: CC(C)Cc1ccc([C@]2(C)OC(=O)C(O)=C2O)cc1
Yield: 19 %

Procedure:
(S)-(+)-3,4-Dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone was synthesized in an analogous manner used for the production of(R)-(-)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone starting with ethyl 4-isobutylbenzoylformate. (S)-(+)-Phenylglycinol was used to resolve the methyl (S)-(+)-2-(4-isobutylphenyl)propionate enantiomer, of which 1.2 g (5 mmol) was converted into 250 mg (19% yield) of (S)-(+)-3,4-dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone as a white crystalline material: mp 175-177° C. dec. (CHCl3 /hexanes); [α]25D +132° (c=1.55; MeOH) 1H NMR (acetone-d6) δ 7.44-7.14 (m, 4H), 2.48 (d, 2H, J=7.1 Hz), 1.87-1.82 (m, 1H), 1.83 (s, 3H), 0.88 (d, 6H, J=6.5 Hz). Anal Calcd for C15H18O4 : C, 68.68; H, 6.92. Found: C, 68.08; H, 6.90.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[N:25]1([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: Fc1ccc2nnc(N3CCCCC3)n2c1
Reactant: N[C@H]1CC[C@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@H](Oc2ccc3nnc(N4CCCCC4)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Intermediate B (74.0 mg, 454 μmol) was added to a mixture of NaH (60% in mineral oil, 27.2 mg, 681 μmol) in DMF (2.5 mL) at RT and stirred for 15 min. Intermediate 3b (100 mg, 454 μmol) was then added and the resulting mixture heated to 60° C. for 1 h. After cooling, the reaction was quenched with sat. aq. NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were concentrated in vacuo. The resulting residue was purified by FCC, using 0 to 10% [2M NH3 in MeOH] in DCM, to afford the title compound as an orange residue (122 mg, 74%). LCMS (Method 3): Rt 2.13 min, m/z 364 [MH+].
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:33]([NH2:42])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>CN(C=O)C>[Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:42][C:33]([CH3:35])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:34])=[O:6]
Reactant: O=C(O)c1cccnc1Br
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1cccnc1Br)c1ccccc1
Yield: 76 %

Procedure:
In a similar manner to Step 1 of Example 137, 2-bromonicotinic acid (2.42 g, 12.0 mmol) was dissolved in DMF (48 mL), and the solution was treated with EDCI (3.45 g, 18.0 mmol), HOBT monohydrate (917 mg, 5.99 mmol) and cumylamine (3.40 mL, 24.0 mmol), followed by purification by flash column chromatography (chloroform/methanol=100/1 to 98/2) to obtain 2-bromo-N-(1-methyl-1-phenylethyl)nicotinamide (2.91 g, yield 76%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[CH2:20][N:19]([C@H:29]([CH2:33][CH:34]4[CH2:37][CH2:36][CH2:35]4)[C:30]([OH:32])=[O:31])[CH2:18]3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]1([CH2:44]CCC2CCNCC2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl>>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[CH2:20][N:19]([C@H:29]([CH2:33][CH:34]4[CH2:35][CH2:36][CH2:37]4)[C:30]([O:32][CH2:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:31])[CH2:18]3)[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2cccc(F)c2)C1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: Cl
Product: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2cccc(F)c2)C1
Yield: 102.1 %

Procedure:
The title compound was prepared from 23.2 mg (0.052 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, benzyl ester (from EXAMPLE 26, Step A) and 12.8 mg (0.052 mmol) of 4-(3-phenylpropyl)piperidine.HCl using a procedure analogous to that described in EXAMPLE 1, Step J to provide 31.7 mg (96%) of the title compound: RF: 0.57 (1:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.13-3.27 (m, 33H), 5.14 (s, 2H), 6.86-6.99 (m, 3H), 7.14-7.38 (m, 11H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[Na+]>Cl>[F:18][C:14]1([F:17])[CH2:15][CH2:16][N:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH2:12][CH2:13]1
Reactant: FC1(F)CCN(C2CCC3(CC2)OCCO3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCC(N2CCC(F)(F)CC2)CC1
Yield: 96.4 %

Procedure:
Stir a solution of 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4,4-difluoro-piperidine (2.41 g, 9.22 mmol) in 4 mL of 6M hydrochloric acid at room temperature for 48 h. Neutralize the mixture with the addition of 30% NaOH solution and extract with 5×CH2Cl2. Dry the combined extracts with MgSO4 and evaporate to give 1.93 g, 96% yield of 4-(4,4-difluoro-piperidin-1-yl)-cyclohexanone as a colorless liquid.