Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=CC[C@H](N[C:12]([CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:31])C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:20][C:17]1([F:21])[CH2:18][CH2:19][CH:14]([C:12]([OH:13])=[O:31])[CH2:15][CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 40 mg (0.1 mmol) of 3-(4-methanesulfonylbenzyl)-bicyclo[3.2.1]-1α,3,8-triaza-spiro[4.5]dodecan-2,4-dione hydrochloride in 1.7 mL of anhydrous DCE were added successively 24 mg (0.1 mmol) of 4,4-difluoro-cyclohexanecarboxylic acid ((S)-3-oxo-1-phenyl-propyl)-amide and 17 μL (0.12 mmol) of triethylamine. The reaction mixture was agitated at room temperature for 10 minutes before adding 26 mg (0.125 mmol) of sodium triacetoxyborohydride. After an overnight agitation, 2 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2×2 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by Bond Elut (ethyl acetate to 5% methanol/DCM) to yield the 4,4-difluoro-cyclohexanecarboxylic acid {(S)-3-[3-(4-methanesulfonylbenzyl)-bicyclo[3.2.1]-2,4-dioxo-1α,3,8-triaza-spiro[4.5]dodec-8-yl]-1-phenyl-propyl}-amide as a white solid (40 mg, 62.3%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)(C)C.C([Li])CCC.CCCCCC.[CH3:30][O:31][C:32]1[C:40]([CH3:41])=[C:39]2[C:35]([C:36](=[O:42])[O:37][CH2:38]2)=[C:34]([O:43]COCCOC)[C:33]=1[CH2:50][CH2:51][CH:52]([CH3:67])[CH2:53][C@H:54](C)[C:55](N1[C@H](C(C)C)COC1=O)=[O:56].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:55](=[O:56])[CH2:54][CH2:53]/[C:52](/[CH3:67])=[CH:51]/[CH2:50][C:33]1[C:34]([OH:43])=[C:35]2[C:39](=[C:40]([CH3:41])[C:32]=1[O:31][CH3:30])[CH2:38][O:37][C:36]2=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOCOc1c(CCC(C)C[C@H](C)C(=O)N2C(=O)OC[C@H]2C(C)C)c(OC)c(C)c2c1C(=O)OC2
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: CCCCCC
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)OC2
Temperature: 0 °C

Procedure:
A solution of (S)-4-benzyl-2-oxazolidinone (177.4 g, 1 mol) and t-butyl alcohol (74.1 g , 1 mol) in anhydrous tetrahydrofuran (2 L) was cooled to -78° C. A 1.6M solution of n-butyllithium in hexane (1280 mL, 2 mol) was added maintaining a temperature below -30° C. After recooling to -78° C. the (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoyl chloride solution (1 mol) was added and the mixture was allowed to warm to 0° C. over 2 hours. 2N Hydrochloric acid (1.5 L) and ethyl acetate (1 L) were added. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate (0.5 L), 2N hydrochloric acid (0.5 L), and brine (1 L). After drying over sodium sulfate, the organic layer was evaporated at reduced pressure to leave the crude imide as a tan solid. Recrystallization from ethyl acetate/hexane (2.5 L/2.5 L) gave (S)-4-benzyl-3-[(E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoyl]-2-oxazolidinone as off-white, shiny plates, m.p. 112°-113° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:46])[C:25]([CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[O:28]1)=[O:26]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[O:28][CH:27]([C:25]([N:24]([CH3:46])[CH3:23])=[O:26])[CH2:36][CH2:35]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CN(C)C(=O)C1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CCC(C(=O)N(C)C)O5)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 7 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromane-2-carboxamide. LCMS (M+H)+=496.0.
Reaction SMILES: [N+](C1C=CC(B(O)O)=CC=1)([O-])=O.IC1C2C(=NC=NC=2N)N(C(C)C)N=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:33]([N:36]1[C:40]2=[N:41][CH:42]=[N:43][C:44]([NH2:45])=[C:39]2[C:38]([C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-])=O)=[CH:48][CH:47]=2)=[N:37]1)([CH3:35])[CH3:34]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].[Zn].CC(O)=O.C1COCC1.CCO>[NH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:38]2[C:39]3[C:40](=[N:41][CH:42]=[N:43][C:44]=3[NH2:45])[N:36]([CH:33]([CH3:35])[CH3:34])[N:37]=2)=[CH:47][CH:48]=1
Reactant: CC(C)n1nc(-c2ccc([N+](=O)[O-])cc2)c2c(N)ncnc21
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)n1nc(I)c2c(N)ncnc21
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)n1nc(-c2ccc(N)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
With reference to Scheme 5, 4-nitrophenyl boronic acid (100 mg, 0.330 mmol; Sigma-Aldrich), was coupled to 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (140 mg, 0.8248 mmol; Apsel et al., 2008) via the Suzuki reaction in 6 mL 1,2 methoxy ethane, 1 mL of saturated sodium carbonate, 1.65 mL EtOH, and 200 mg of polymer-bound tetrakis Palladium. The reaction was stirred under argon for 12 hours at room temperature, filtered through Whatman paper to remove Palladium, mixed with brine, extracted in chloroform and the product was subsequently purified on silica in EtOAc and concentrated in vacuo. The purified solid 1-isopropyl-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 299.1, calculated 299.1; 100 mg, 0.336 mmol) was combined with Zinc dust, 5 mL THF, 0.4 mL HOAc for 12 hours at room temperature under Argon. Then the reaction mixture was filtered through Celite®, extracted with EtOAc and concentrated in vacuo to yield 3-(4-aminophenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 269.1, calculated 269.1). To this reduced product, molar equivalents of 3-(trifluoromethyl)phenyl isocyanate (Sigma-Aldrich) were added dropwise in ice-cold CH2Cl2. The reaction proceeded until completion as judged by TLC, was concentrated in vacuo, resuspended in 50:50 H20-CH3CN, and purified on a C18 column in CH3CN/H20/0.1% TFA (1-100% gradient) to yield Cmpd 5 1-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (ESI-MS m/z [M+H]+ found 455.2, calculated 455.2; 1H NMR (400 MHz, DMSO): δ 9.48 (s, 1H), 9.42 (s, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.70 (d, J=8 Hz, 2H), 7.60 (d, J=8 Hz, 2H), 7.60-7.64 (m, 1H), 7.53 (t, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 5.10 (septet, J=6.8 Hz, 1H), 1.51 (d, J=6 Hz, 6H), 3.10 (q, J=4 Hz, 1.5H, trace triethylamine), 1.18 (t, J=8 Hz, 2H, trace triethylamine). 13C NMR (400 MHz, DMSO): δ 9.08 (trace triethylamine), 22.23, 46.20 (trace triethylamine), 49.17, 97.40, 115.45, 116.0 (d), 119.20, 122.34, 124.70 (q), 126.19, 129.35, 130.00 (q), 130.40, 140.85, 141.09, 145.20, 151.70, 152.35, 153.00, 155.72, 159.41 (q)).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7](O)[C:8]#[CH:9].C(C1C=C(O)C(=CC=1)O)(C)(C)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[C:1]([O:6][CH2:9][C:8]#[CH:7])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C#CCO
Reactant: C=C(C)C(=O)O
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C#CCOC(=O)C(=C)C
Yield: 75 %

Procedure:
A solution of 86 g. (1 mole) of methacrylic acid in 120 ml. benzene was reacted with 67.2 g. (1.2 moles) of propargyl alcohol in the presence of 4 g. of p-toluenesulfonic acid as a catalyst and 0.4 g. p-tertbutylcatechol as an inhibitor. The reaction mixture was stirred and heated to reflux under nitrogen until 18 g. of water was azeotroped over into a Dean-Stark trap. The reaction mixture was neutralized with saturated sodium carbonate aqueous solution, washed with deionized water three times and dried over sodium carbonate. The solvent was removed on a Rotavapor. Vacuum distillation of the residue in the presence of the inhibitor gave a 75% yield of propargyl methacrylate obtained as a clear colorless liquid.
Reaction SMILES: C([Si](CC)(CC)O[C:5]1([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:9][C:8](=O)[CH:7]=[CH:6]1)C.Cl.[NH2:21]CC(OCC)=O.C(=O)(O)[O-].[Na+].C(O)C>O>[F:13][C:12]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][C:8]([NH2:21])=[CH:7][CH:6]=1
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=CC(=O)C=C1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A mixture of 400 mg (1.4 mmol) of 4-triethylsiloxy-4-trifluoromethyl-2,5-cyclohexadien-1-one, 572 mg (4.2 mmol) of ethyl glycinate hydrochloride, 298 mg (3.6 mmol) of sodium bicarbonate, and 10 mL of 95% ethanol was heated to reflux for 6 hours, allowed to cool to room temperature, and poured into 25 mL of water. The resulting aqueous mixture was extracted with three 10 mL portions of dichloromethane. The organic layers were combined and extracted with six 5 mL portions of 1N HCl. Combination of the aqueous layers and treatment with solid sodium bicarbonate until neutral to pH paper gave a cloudy mixture that was extracted with three 10 mL portions of dichloromethane. The organic layers were combined, dried (MgSO4), and stripped to give a residue which was purified by PTLC (one 2 mm silica gel plate eluted with dichloromethane), affording 160 mg (73% yield) of 4-trifluoromethylaniline.
Reaction SMILES: Cl.I[CH2:3]I.[C:5]1([C@@H:11]2[C@@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:14][C:13]3([CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]3)[O:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.[Zn].[Cu].[Zn].II>[C:5]1([C@@H:11]2[C@@H:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:14][C:13]3([CH2:26][CH2:25][CH2:24][C@H:23]4[C@@H:22]3[CH2:3]4)[O:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1=CC2(CCC1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Reactant: ICI
Agent: [Cu]
Agent: Cl
Agent: II
Solvent: CCOCC
Product: c1ccc([C@H]2OC3(CCC[C@@H]4C[C@@H]43)O[C@@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.6 %

Procedure:
The zinc/copper couple was freshly prepared by quickly washing zinc dust with 1N HCl (4×100 mL), then washing with distilled water (4×120 mL), 2 mol % CuSO4 solution (2×200 mL), water (4×120 mL), EtOH (4×120 mL) and Et2O (5×100 mL). The washings were done in a flask with decanting of the liquid. The Et2O washes were poured onto a funnel and dried by vacuum filtration. The resulting solid was added to a 2 L flask and dried under vacuum at 115° C. for 30 min, then cooled to RT. The flask was fitted with an addition funnel and reflux condenser, then purged with nitrogen and kept under N2 throughout the reaction. Next, 400 mL of Et2O was added followed by I2 (0.551 g, 2.172 mmol), and the solution was stirred and heated to reflux. Once at reflux, heating was stopped and diiodomethane (87 mL, 1086 mmol) was slowly added making sure to not allow the reaction to reflux out of control. (2R,3R)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-6-ene (127 g, 434 mmol) was then added in 350 mL ether, followed by an additional 0.5 eq of diiodomethane. The reaction was heated to reflux and the reaction monitored by LCMS. After 1.5 h the reaction was cooled to RT and quenched with saturated aq Na2CO3 (230 g in 900 mL water). The mixture was stirred for 30 min, then filtered through celite. The inorganics were washed with Et2O (2 L), then the combined organics were washed with saturated aq NH4Cl (1 L), saturated aq NaHCO3 (1 L), brine (1 L). The organic layers were dried over MgSO4, filtered and concentrated to afford the crude product (176.45 g). To the residue was added Et2O (250 mL) and the suspension was heated to reflux, then allowed to cool to RT to crystallize the product. The suspension was put in the freezer for 3 days, then the ether decanted off. Drying of the solids gave (1S,4′R,5′R,6R)-4′,5′-diphenylspiro[bicyclo[4.1.0]heptane-2,2′-[1,3]dioxolane] (112.5 g, 85% yield). The material was used as an intermediate without further purification.
Reaction SMILES: Cl.[Br:2][C:3]1[S:7][C:6]2=[N:8][C:9]([NH2:11])=[CH:10][N:5]2[CH:4]=1.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28](O)=[O:29])=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:12]([O:16][C:17](=[O:18])[NH:19][C@@H:20]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28](=[O:29])[NH:11][C:9]1[N:8]=[C:6]2[N:5]([CH:10]=1)[CH:4]=[C:3]([Br:2])[S:7]2)=[O:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Reactant: Nc1cn2cc(Br)sc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
To a mixture of compound 11 (0.137 mmol), compound 3a (0.206 mmol), and HATU (0.206 mmol) in dimethylformamide (1.5 mL) was added TEA (0.55 mmol) dropwise. The reaction mixture was stirred at 40° C. for 4 hrs. The solvent was removed under reduced pressure and the residue dissolved in a mixture of dichloromethane/methanol (9/1). This mixture was passed through a SCX-2 column and the column was washed three times with the same eluent. The filtrate was concentrated and the residue was purified by chromatography on a silica gel column to give compound 12a as a yellow orange solid in 18% yield. MS (ESI, EI+) m/z=548.24-550.20 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]#[N:43])[CH:37]=3)=[CH:32][C:31]=2[C:44]2[CH:49]=[CH:48][N:47]=[N:46][CH:45]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.Cl>CO.O1CCOCC1>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]#[N:43])[CH:37]=3)=[CH:32][C:31]=2[C:44]2[CH:49]=[CH:48][N:47]=[N:46][CH:45]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4cccc(C#N)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1cccc(-c2ccc(Oc3cc(F)c(S(=O)(=O)Nc4nncs4)cc3Cl)c(-c3ccnnc3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
5-Chloro-4-(3′-cyano-3-(pyridazin-4-yl)biphenyl-4-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 118, 550 mg, 0.77 mmol) was dissolved in methanol (2 mL) and a 4M solution of hydrogen chloride in 1,4-dioxane (10 mL) was added. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was co-evaporated with methanol and then purified by reverse phase chromatography (acetonitrile/water both with 0.1% formic acid) to give the title compound (303 mg, 70%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[CH2:25][NH:24][CH2:23]4)[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH3-][C:45]#N.[Na+].CC(O)=O.C=O>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][C:28]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:36])[CH3:37])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[CH2:25][N:24]([CH3:45])[CH2:23]4)[C@H:14]2[CH3:41])[CH:4]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:8]=1
Reactant: [BH3-]C#N
Reactant: COc1cc(F)c(C(C)C)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]1C)CNC2
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(F)c(C(C)C)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]1C)CN(C)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (8.3 mg, 0.0136 mmol) in MeOH (0.2 mL), was added NaCNBH3 (1.0 mg, 0.0163 mmol), AcOH (3.85 uL, 0.068 mmol) and formaldehyde (38%) (1.3 uL, 0.0176 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was washed with sat. aq. NaHCO3. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-2-methyl-2,3-dihydro-1H-isoindol-5-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calc. 625.2; found=624.9 (M+H)+.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[C:27]1([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39]O)[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.CCCCC>[C:27]1([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39][I:25])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: II
Reactant: OCC1CCC(c2ccccc2)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: ICC1CCC(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
Imidazole (4.4 g, 0.065 mol) is added in one portion to a solution of triphenylphosphine (17.0 g, 0.065 mol) in dichloromethane (300 mL) at 25° C. After all of the solids dissolved, iodine (16.5 g, 0.065 mol) is added in four portions. The mixture is stirred for 10 min. then a solution of 4-phenylcyclohexylmethanol (10.5 g, 0.055 mol) is added dropwise and the mixture is stirred at 25° C. for 18 h. The reaction mixture is poured into pentane and the resulting solids filtered. The filtrate is concentrated in vacuo and the residue is dissolved in dichloromethane. This solution is poured into hexanes, the solids were filtered, and the filtrate is concentrated in vacuo. The residue is passed through a pad of silica gel using hexanes as eluent to afford 14.6 g (89%) of 4-phenylcyclohexylmethyl iodide as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29](F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.N[C:35]1C(C#N)=C(N2CCC(C3N(CCNC)C=C(C4C=CC(F)=C(C)C=4)N=3)CC2)N=[CH:37][N:36]=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[N:18]([CH2:33][CH2:35][NH:36][CH3:37])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=4)[N:21]=3)[CH2:15][CH2:16]2)[N:5]=[CH:4][N:3]=1
Reactant: CNCCn1cc(-c2ccc(F)c(C)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: CNCCn1cc(-c2ccc(F)c(C)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=453, obsd.=453).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]=[C:21]=[O:23])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1ccc(CN=C=O)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 69.7 %

Procedure:
4t-butylbenzylamine (3.2 g) was dissolved in dichloromethane (10 ml) and to the solution was added triethylamine (2.79 ml), followed by cooling to 0° C. and slowly adding dropwise a solution of triphosgene (1.98 g) in dichloromethane (5 ml). The mixture was stirred at room temperature for 5 hours and water (10 ml) was added thereto. The resulting mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by column-chromatography (hexane/ethyl acetate=20/1) to yield 4-t-butylbenzylisocyanate (880 mg) as a solid. The obtained compound (400 mg) and 3-fluorophenethylamine (290 mg) were dissolved in dichloromethane (20 ml) and the solution was stirred at room temperature for 22 hours. The solvent was removed therefrom and the residue was purified by column-chromatography (hexane/ethyl acetate=4/1) to yield the compound 29 (400 mg, 58%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:20][NH:21][S@@](C(C)(C)C)=O.Cl>CO>[ClH:1].[NH2:21][CH2:20][C:3]1[C:2]([Cl:1])=[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)[CH:6]=[N:5][CH:4]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN[S@](=O)C(C)(C)C)c3Cl)ccc21
Agent: Cl
Solvent: CO
Product: CN1C(=O)CCc2cc(-c3cncc(CN)c3Cl)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 42, reaction of (R)-2-methyl-propane-2-sulfinic acid [4-chloro-5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-amide (example 217) with hydrogen chloride (in dixoane) in methanol gave the title compound as a yellow solid. MS: 302.4 (M+H+).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13]CC)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[NH2:2].[OH-].[Li+]>CCO.O>[C:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)C(c1ccccc1)N1CCC(C(N)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)C1CCN(C(C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
Ethyl 2-(4-carbamoylpiperidin-1-yl)-2-phenylacetate (202 mg, 0.69 mmol) was dissolved in a mixture EtOH (4.6 ml) and water (2.3 ml), and lithium hydroxide (50.0 mg, 2.09 mmol) was added. The reaction was stirred at room temperature overnight. LiOH (33.3 mg, 1.39 mmol) was added in two portions in the following two days. EtOH was evaporated and 1N HCl was added dropwise to the aqueous solution till pH 6-7. The solution was evaporated and the residue was purified by flash chromatography (DCM/MeOH=7/3 to 6/4) to obtain 2-(4-carbamoylpiperidin-1-yl)-2-phenylacetic acid (155 mg, 85% yield) as a white solid.