Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]1=[O:24])[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.[CH3:35][C:36]1([CH3:48])[O:40][C@H:39]([CH2:41][N:42]2[CH:46]=[CH:45][C:44]([NH2:47])=[N:43]2)[CH2:38][O:37]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH3:35][C:36]1([CH3:48])[O:40][C@H:39]([CH2:41][N:42]2[CH:46]=[CH:45][C:44]([NH:47][C:5](=[O:7])[C@@H:4]([N:8]3[CH2:12][C:11]([O:13][C:14]4[C:23]5[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=5[CH:17]=[CH:16][CH:15]=4)=[CH:10][C:9]3=[O:24])[CH2:3][CH:2]([CH3:25])[CH3:1])=[N:43]2)[CH2:38][O:37]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc3c2CCCC3)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc3c2CCCC3)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A solution of (S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid (59 mg, 0.17 mmol) in N,N-dimethylformamide (1 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.08 mL, 0.51 mmol), a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 41 mg, 0.20 mmol) in N,N-dimethylformamide (0.9 mL) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (115 mg, 0.26 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (25 mL) and was washed with a saturated aqueous ammonium chloride solution (1×25 mL), a saturated aqueous sodium bicarbonate solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, rinsed with ethyl acetate and concentrated in vacuo. Purification by Analogix flash chromatography (24 g, 50-100% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (43 mg, 47%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.33-1.66 (m, 2H), 1.64-1.83 (m, 5H), 2.57 (br. s., 2H), 2.67-2.80 (m, 2H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.5, 6.5 Hz, 1H), 4.07-4.14 (m, 1H), 4.18 (d, J=18.4 Hz, 1H), 4.26-4.41 (m, 1H), 4.56 (d, J=18.4 Hz, 1H), 4.65 (s, 1H), 4.88 (dd, J=10.3, 4.8 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 6.97-7.07 (m, 2H), 7.18 (t, J=8.2 Hz, 1H), 7.59 (d, J=2.1 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C(=O)([O-])[O-].[Na+].[Na+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[NH:33][C:32](=O)[CH2:31][S:30][CH2:29]2)=[CH:24][CH:23]=1>C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[NH:33][C:32](=[S:2])[CH2:31][S:30][CH2:29]2)=[CH:24][CH:23]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CSCC(c2ccc(F)cc2)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(C2CSCC(=S)N2)cc1
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of phosphorus pentasulfide (5.12 g, 11.5 mmol) and sodium carbonate (1.22 g, 11.5 mmol) in THF (30 mL) was stirred at room temperature. A solution of 5-(4-fluoro-phenyl)-thiomorpholin-3-one (2.0 g, 9.5 mmol) in THF (25 mL) was slowly added, and the mixture was stirred at room temperature for 90 minutes. The mixture was diluted with 10% aqueous Na3PO4 solution (40 mL), and stirred at room temperature for five minutes. The mixture was extracted with a 1:4 mixture of ethyl acetate and diethyl ether, and the organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Elution of the residue through silica (15-20% ethyl acetate/hexanes) gave 1.36 g of 5-(4-fluoro-phenyl)-thiomorpholine-3-thione, MP=107-108° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][N:9]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][C:11]=1[NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:5])[CH3:2].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[OH-].[Na+]>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:7][CH2:8][N:9]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:10][C@@H:11]1[NH:12][C@@H:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1N[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
In a dry flask (R)-5-(1-phenyl-ethylamino)-3,6-dihydro-2H-pyridine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (5.78 g, 15.4 mmol) was dissolved in acetonitrile (25 mL) and glacial acetic acid (25 mL) and cooled to 0° C. Triacetoxyborohydride (9.82 g, 46.3 mmol) was added over a 5-minute period. The reaction mixture was allowed to stir at 0° C. for 2 hours. Concentrated aqueous sodium hydroxide was carefully added to maintain the internal temperature of the flask below 10° C. The resulting solid sodium acetate was filtered and the mixture was extracted with ethyl acetate 3 times (50 mL). The combined organic extracts were dried with magnesium sulfate, filtered, concentrated in vacuo, and then purified by flash chromatography with 20% ethyl acetate in hexanes to give a colorless oil (2.6 g, 47%). The 1H NMR showed a mixture of two rotation isomers. The major compound had the following 1H NMR (300 MHz, CDCl3), δ: 7.28 (t, J=5, 2H), 7.25 (t, J=2, 1H), 7.23 (d, J=4, 2H), 4.35 (m, 2H), 4.24 (q, 2H, J=7), 3.96 (m, 2H), 3.15 (bs, 1H), 2.99 (m, 1H), 2.75 (m, 1H) 2.48 (dt, 2H, J=10, 4), 1.86 (m, 1H), 1.68 (m, 1H), 1.39 (s, 9H), 1.26 (d, 3H, J=6), 1.26 (t, 3H, J=7).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([O:22]C)=O)[CH:17]=[C:16]([CH:24]=[CH2:25])[CH:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:26]>CO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]([NH2:26])=[O:22])[CH:17]=[C:16]([CH:24]=[CH2:25])[CH:15]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C=Cc1cc(C(=O)OC)nc(-c2ccc(-c3ccc(F)cc3)cc2)c1
Reactant: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=Cc1cc(C(N)=O)nc(-c2ccc(-c3ccc(F)cc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 6-(4′-fluoro-[1,1′-biphenyl]-4-yl)-4-vinylpicolinate (600 mg, 1.8 mmol) was dissolved in 10 mL of methanol in a pressure tube. Into the tube was condensed about 10 mL ammonia at −20° C. to −30° C. The pressure tube was tightly closed and the resulting solution was stirred at room temperature for overnight. TLC (silica gel, 10% methanol in chloroform) showed the reaction had gone to completion. The ammonia was removed by nitrogen purge and the methanol was removed under reduced pressure to obtain 300 mg of 6-(4′-fluoro-[1,1′-biphenyl]-4-yl)-4-vinylpicolinamide which was pure enough to take to next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[C:10]2[S:11][C:12]([C:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH:15]=3)=[CH:13][C:9]=2C=[CH:7][CH:6]=1.[NH4+:30].[Cl-].O>CCO.[Fe]>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:6]=[CH:7][N:30]=[C:9]3[CH:13]=[C:12]([C:14]4[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH:15]=4)[S:11][C:10]=23)=[C:2]([F:1])[CH:26]=1
Reactant: CC(=O)N1CC=C(c2cc3cccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reaction time: 0.67 h
Yield: 90.4 %

Procedure:
To a mixture of the nitro compound 390 (358.2 mg, 0.87 mmol) and NH4Cl (39.4 mg, 0.74 mmol) in EtOH (8.7 mL)/water (4.3 mL) at 100° C. Fe powder (411.3 mg, 7.36 mmol) was added in one portion and the mixture was heated to reflux under vigorous stirring for 40 min. It was then filtered through Celite®, the Celite® was washed with EtOH and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in DCM, washed with water, dried (anhydrous Na2SO4) and concentrated under reduced pressure affording 391 (256.5 mg, 77% yield) as a white solid. LCMS:(M+H) 384.2.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][O:7][C:8]1[C:9](=[O:19])[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16](=[O:18])[CH:17]=1.[N-:20]=[N+]=[N-].[Na+]>CO>[CH3:6][O:7][C:8]1[C:9](=[O:19])[NH:20][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:16](=[O:18])[CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=CC(=O)C2=C(CCCC2)C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1cc(=O)c2c([nH]c1=O)CCCC2
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
To stirred, ice bath cold, concd H2SO4 (10 mL, Baker), there was added 2-methoxy-5,6,7,8-tetrahydronaphthalene-1,4-dione (600 mg, 3.12 mmol) in portions. A deep red solution resulted. To this cold solution, NaN3 (406 mg, 6.24 mmol, Aldrich) was added in portions. The reaction was allowed to slowly attain rt with stirring under N2. Gas evolution was noted. After 16 h, the reaction was judged complete by TLC analysis (10% MeOH/90% CHCl3). The reaction was added to crushed ice (100 mL) to give a yellow/brown solution. This was extracted with 30% MeOH/70% CHCl3 (4×30 mL) and CHCl3 (2×30 mL). The extract was washed with water (1×20 mL), saturated NaHCO3 (1×20 mL) and brine (1×20 mL), filtered through cotton and the solvent removed in vacuo to give a red solid (280 mg). An additional portion was obtained in exactly the same manner (350 mg). The combined solids were subjected to vacuum chromatography (silica gel, 2.5×25 cm, initial CHCl3 elution to remove mobile impurities, 2% EtOH/98% CHCl3 elution to remove product) to yield a pink solid. Crystallization from 95% EtOH (dissolved in 20 mL, hot filtered, concd to 8 mL, allowed to cool to rt) yielded a pink solid (242 mg, 19%, >95% pure by 1H NMR, mp 227.5°-228.5° C.). A sample was further purified by recrystallization from 95% EtOH (25 mg dissolved in 2 mL, allowed to cool to rt, yielded a pale pink solid, 14 mg, 56% recovery); mp 228.5°-229.5° C.;
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH3:30][C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][N:8]1[C:7]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:23])([CH3:21])[CH3:22])[CH2:16][CH2:15]2)=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:32]1[C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=[C:31]1[CH3:30])=[N:3][C:4]=2[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Cn1c(CCN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CCC(C(C)(C)O)CC3)n(C)c2n1
Temperature: 150 °C
Yield: 43.8 %

Procedure:
A mixture of 2-{1-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-piperidin-4-yl}propan-2-ol (47 mg, 0.11 mmol), 2-methylbenzimidazole (16 mg, 0.12 mmol), Pd2(dba)3 (2.5 mg, 2.5 mol %), Xphos (5.0 mg, 10 mol %) and Cs2CO3 (54 mg, 0.17 mmol) in dioxane (1.0 mL) was purged with argon gas then heated at 150° C., for 30 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (RediSep amine cartridge, 0-5% MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 30-50%) to give 344 (25 mg, 43%) as a white solid. LCMS: (Method G): RT 5.64 min; [M+H]+ 519.3. 1H NMR (400 MHz, CHCl3-d): δ 8.09-8.04 (m, 1 H), 7.73-7.69 (m, 1 H), 7.29-7.24 (m, 2 H), 4.48-4.16 (m, 4 H), 3.87 (t, J=4.7 Hz, 4 H), 3.79 (s, 3 H), 3.23-1.05 (m, 4 H), 2.93 (s, 3 H), 2.93-2.75 (m, 2 H), 2.11 (s, 3 H), 1.90-1.75 (m, 2 H), 1.55-1.25 (m, 3 H), 1.20 (s, 6 H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of 1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol (7 g, 23.5 mmol) in DCM (150 mL) was added trifluoroacetic acid (2.68 g, 23.5 mmol) and the reaction mixture was stirred at rt overnight. The mixture was then evaporated under reduced pressure and partitioned between 500 mL saturated aqueous sodium bicarbonate and 500 mL of ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure to yield 1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (5.9 g, 88% yield). LCMS (method F) RT 2.84 min, 100% AP, m/z 280.4 (M+H+).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C@@H:22]3[CH2:24][C@H:23]3[C:25](N(OC)C)=[O:26])=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.C(C1C=C2C(=CC=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2[C@@H]1C[C@H]1C=O)#N>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C@@H:22]3[CH2:24][C@H:23]3[CH:25]=[O:26])=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1c1cn(S(=O)(=O)c2ccc(C)cc2)c2cc(C(F)(F)F)ccc12
Agent: Cc1ccc(S(=O)(=O)n2cc([C@@H]3C[C@H]3C=O)c3cc(C#N)ccc32)cc1
Product: Cc1ccc(S(=O)(=O)n2cc([C@@H]3C[C@H]3C=O)c3ccc(C(F)(F)F)cc32)cc1
Yield: 89 %

Procedure:
Racemic [trans-2-[6-trifluoromethyl-1-(p-toluenesulfonyl)indol-3-yl]-cyclopropane-carboxaldehyde was prepared in an 89% yield from racemic [trans-2-[6-trifluoromethyl-1-(p-toluenesulfonyl)indol-3-yl]cycloprop-1-yl]-N-methoxy-N-methyl-carboxamide in a similar manner to [trans-2-[5-cyano-1-(p-toluenesulfonyl)indol-3-yl]cyclopropane-carboxaldehyde in Example 1. 1H NMR (400 MHz, DMSO-d6) 9.12 (1H, d, J=5.4 Hz), 8.15 (1H, s), 7.92 (4H, m), 7.64 (1H, dd, J=8.3, 1.1 Hz), 7.41 (2H, d, J=8.1 Hz), 2.78 (1H, m), 2.32 (3H, s), 2.15 (1H, m), 1.71 (2H, m); MS m/e 406 (M−H)−. Anal calcd. for C20H16F3NO3S: C, 58.96; H, 3.95; N, 3.43. Found: C, 58.93; H, 3.93; N, 3.25.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[C:5]([F:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[F:19]C(F)(F)S(O[Si](C)(C)C)(=O)=O.F[B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C1(C)C=CC=CC=1.C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH2:10][F:19])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cc(Br)cnc1F
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CF)c1cc(Br)cnc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
A solution of 1-(5-bromo-2-fluoropyridin-3-yl)ethanone (200 mg, 0.92 mmol) and triethylamine (140 μl, 1.01 mmol) in toluene (2 mL) was treated with trimethylsilyl trifluoromethanesulfonate (182 μl, 1.01 mmol) under nitrogen atmosphere. The reaction mixture was heated to 80° C. for 2 h, the upper toluene phase was isolated (e.g. by decanting) and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in acetonitrile (2 mL) and added to a suspension of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-(2.2.2)octane bis(tetrafluoroborate) (325 mg, 0.92 mmol) in acetonitrile (2 mL) at room temperature. After 1 h, the solvent was removed under reduced pressure. The residue was partitioned between brine and EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure to obtain 1-(5-bromo-2-fluoropyridin-3-yl)-2-fluoroethanone (170 mg, 0.72 mmol, 79% yield, 90% purity) as a light yellow solid. This material was used in the next step without purification. MS m/z=237.9 [M+H]+. Calculated for C7H4BrF2NO: 236.01.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:11][CH2:10][CH2:9][CH2:8][O:7][CH3:6])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COCCCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
Methanesulphonyl chloride (1.75 ml, 22 mmol) was added to a solution of 3-methoxy-1-propanol (1.81 g, 20 mmol) and triethylamine (3.35 ml, 24 mmol) in DCM (40 ml) cooled in an ice bath and the mixture stirred at ambient temperature for 18 hours. DCM (25 ml) and water (50 ml) were added and the phases separated and the aqueous layer was extracted with DCM (25 ml). The extracts were combined, washed with water (50 ml) and brine (50 ml), dried (Chemelut column CE1010) and evaporated to give the title compound 3.25 g (97%) as a pale yellow oil. NMR 2.00 (m, 2H), 3.01 (s, 3H), 3.35 (s, 3H), 3.49 (t, 2H), 4.38 (t, 2H).
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][C:10]([NH:12][CH2:13][CH:14]1[O:28][C:17]2=[C:18]3[C:23](=[C:24]([CH3:26])[CH:25]=[C:16]2[CH2:15]1)[NH:22][C:21](=[O:27])[CH:20]=[CH:19]3)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:6][NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]1[O:28][C:17]2=[C:18]3[C:23](=[C:24]([CH3:26])[CH:25]=[C:16]2[CH2:15]1)[NH:22][C:21](=[O:27])[CH:20]=[CH:19]3)=[O:11]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)CN(C)C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Product: CNCC(=O)NCC1Cc2cc(C)c3[nH]c(=O)ccc3c2O1
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
The compound obtained in Example 232 (2.75 g, 6.9 mmol) was added to trifluoroacetic acid (15 ml) under cooling conditions, and the mixture was stirred for 30 minutes. The reaction mixture was subjected to distillation under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol =3:1). The obtained crystals were dissolved in chloroform-methanol (3:1, 20 ml), and 5% HCl-methanol (10 ml) was added thereto while cooling on ice. The mixture was condensed under reduced pressure. The resultant residue was recrystallized from methanol--ether. 2.0 g of the title compound was obtained as pale yellow crystals (86.0%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1nc(C(=O)N2CCCC(C)C2CN)c(-c2ccc(F)cc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c(-c2ccc(F)cc2)s1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-chloro-5-(trifluoromethyl)pyridine, and K2CO3 in DMAC was stirred at 120° C. overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a pale yellow oil which solidified. MS (ESI) 493.01 (M+H).
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][N:8]2[CH:13]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][CH2:11][CH2:10][CH:9]2[C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[NH:3][CH:2]=1.[H-].[Na+].[CH3:30]I>C1COCC1>[CH3:27][C:26]1[C:21]([CH:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:8]2[CH2:7][CH2:6][C:4]2[N:3]=[CH:2][N:1]([CH3:30])[CH:5]=2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: CI
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCc1cnc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCc1cn(C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of 1′-[2-(3H-imidazol-4-yl)-ethyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (167 mg, 0.46 mmol) in THF (5 mL) at 0° C. was added NaH (60%, 7 mg, 0.17 mmol). After 30 min at 0° C., MeI (10 mL, 0.15 mmol) was added and the reaction mixture was warmed to room temperature and stirred overnight. The next day the mixture was concentrated to afford a yellow foam. Purification by radial chromatography on silica gel (1 mm plate; using CH2Cl2/MeOH/NH4OH; 50:1:1→10:1:1) afforded the product as a yellow oil (23 mg, 41%). 1H NMR (CDCl3) δ 1.57-1.72 (m, 3H), 1.94-2.16 (m, 3H), 2.48-2.53 (m, 8H), 3.41 (s, 3H), 3.71 (s, 2H), 4.13 (d, 2H, J=9.0 Hz), 5.94 (br 2, 1H), 7.02-7.06 (m, 3H), 7.40 (d, 2H, J=9.0 Hz), 8.45 (br s, 2H). 13C NMR (CDCl3) δ 19.25, 23.34, 25.40, 32.42, 33.46, 50.08, 62.13, 115.93, 122.07, 132.50, 136.91, 138.83, 141.50, 147.32, 160.82. ES-MS m/z 376 [M+H]+. Anal. Calcd. for C1753H29N5.1.4H2O.0.4CH2Cl2: C, 64.65; H, 7.56; N, 16.11. Found: C, 65.01; H, 7.67; N, 15.99.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[N:35](C3CCCCO3)[N:34]=[CH:33][C:32]=2[CH3:42])=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.[NH:43]1[CH2:47][CH2:46][C@@H:45]([OH:48])[CH2:44]1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.CCOC(C)=O>[Cl:28][C:25]([F:26])([F:27])[O:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:29]=[C:30]([C:31]3[NH:35][N:34]=[CH:33][C:32]=3[CH3:42])[C:11]([N:43]3[CH2:47][CH2:46][C@@H:45]([OH:48])[CH2:44]3)=[N:12][CH:13]=2)=[CH:23][CH:22]=1
Reactant: O[C@@H]1CCNC1
Reactant: Cc1cnn(C2CCCCO2)c1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn[nH]c1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
DIPEA (77 μL, 0.44 mmol) was added to a solution of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 33.1, 99 mg, 0.2 mmol) and (R)-pyrrolidin-3-ol, 20.9 mg, 0.24 mmol) in iPrOH (200 μL) in a vial, which was sealed and the RM mixture was stirred at 140° C. for 1.5 h. After cooling at RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was dissolved in DCM (1.1 mL), cooled to 0° C., treated with TFA (0.616 mL, 8 mmol) and stirred at RT for 3 h. The RM was poured in to 10% aq. Na2CO3 (10 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® silica gel column, DCM/MeOH from 2% to 10% MeOH) to afford the title compound as a beige powder. HPLC (Condition 4) tR=4.79 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=464 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.92 (m, 5H) 2.81-2.96 (m, 1H) 3.05-3.41 (m, 3H) 4.17 (br. s, 1H) 4.81 (br. s, 1H) 7.30 (d, J=8.60 Hz, 2H) 7.58 (s, 1H) 7.79-8.02 (m, 3H) 8.73 (s, 1H) 10.15 (s, 1H) 12.58-12.85 (m, 1H).