Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[NH:9][C@@H:10]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:9][C@@H:10]([C:12]2[CH:13]=[C:14]([F:20])[C:15]([F:19])=[C:16]([F:18])[CH:17]=2)[CH3:11])[C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1cc(F)c(F)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](NC(c1ccc(F)cc1)c1cccc(N)c1)c1cc(F)c(F)c(F)c1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 2.46 g of N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-(3,4,5-trifluorophenyl)ethyl]amine [prepared as described in step (a) above], 2.90 g of nickel chloride hexahydrate and 927 mg of sodium borohydride were reacted, to obtain 760 mg of isomer A and 716 mg of isomer B of the title compound, each as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][O:6][CH:5]([CH2:8][OH:9])[CH2:4][O:3]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][S:12]([O:9][CH2:8][CH:5]1[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7][O:6]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)COC(CO)CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)COC(COS(C)(=O)=O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
(5,5-Dimethyl-1,4-dioxan-2-yl)methanol (740 mg, 5.06 mmol) and TEA (0.988 mL, 7.09 mmol) were dissolved in DCM (20 mL). At 0° C. MsCl (0.473 mL, 6.07 mmol) was added dropwise. After the addition the solution was warmed to ambient temperature and stirred for 1 hr. Saturated NaHCO3 solution was added and the two layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 4:1 to 1:1) to give the product as a colorless oil (805 mg, 71%). 1H NMR (400 MHz, CDCl3) δ ppm 4.18-4.19 (2H, m), 3.71-3.76 (1H, m), 3.66 (1H, t, J=10.8 Hz), 3.52-3.57 (2H, m), 3.37 (1H, d, J=11.6 Hz), 3.03 (3H, s), 1.28 (3H, s), 1.09 (3H, s).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])[S:10][C:6]=2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.[S:22]([CH2:26][C:27](O)=O)(=[O:25])(=[O:24])[NH2:23]>>[F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][C:12]3[O:13][C:27]([CH2:26][S:22]([NH2:23])(=[O:25])=[O:24])=[N:15][N:14]=3)[S:10][C:6]=2[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: NNC(=O)Cc1nc2c(F)cc(-c3ccccc3)cc2s1
Reactant: NS(=O)(=O)CC(=O)O
Product: NS(=O)(=O)Cc1nnc(Cc2nc3c(F)cc(-c4ccccc4)cc3s2)o1

Procedure:
Compound 90e was prepared from Compound 90d and 2-sulfamoylacetic acid using the procedure given for Compound 1b. LCMS=1.78 min using analytical method (Q), 405.1 (M+H). 1H NMR (500 MHz, CD3OD) δ 8.07 (d, J=1.7 Hz, 1H), 7.74-7.67 (m, 2H), 7.56 (dd, J=12.0, 1.5 Hz, 1H), 7.52-7.43 (m, 2H), 7.43-7.36 (m, 1H), 4.94-4.88 (m, 2H), 4.78-4.74 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[C:7](OC)[C:6]([CH3:12])=[CH:5][N:4]=1.P(Br)(Br)[Br:14].CN(C=O)C.[NH4+].[OH-]>>[Br:14][C:7]1[C:6]([CH3:12])=[CH:5][N:4]=[C:3]([CH2:2][Cl:1])[C:8]=1[CH3:9]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: BrP(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cnc(CCl)c(C)c1Br
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 44.1 %

Procedure:
A suspension of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (3.24 g, 14.6 mmol) in PBr3 (8.0 ml, 85.1 mmol, 5.8 equiv.) was heated to 80° C. under nitrogen. A catalytic amount of DMF (0.50 ml, 6.4 mmol, 0.44 equiv.) was added, whereupon the suspension rapidly turned into an orange solution. After 40 min., the reaction was still incomplete as judged by HPLC. The temperature was raised to 110° C. and the reaction was prolonged for 30 min, at which point it was complete. The mixture was poured over ice, made basic with conc. aq. NH4OH and extracted into EtOAc. Washing with water, drying (brine, MgSO4) and concentration gave the title compound as a pink solid (1.51 g, 44%) containing 10% of an impurity by 1H-NMR. The crude was used without further purification. 1H-NMR (CDCl3) δ 8.19 (s, 1H), 4.59 (s, 2H), 2.48 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39].Cl.O1CCOCC1>CN1C(=O)CCC1>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=4[F:31])[N:24]=[C:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[C:22]=3[CH3:39])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (118 mg, 0.45 mmol; described herein), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (130 mg, 0.45 mmol; described herein), 4.0M hydrogen chloride in 1,4-dioxane (110 μL, 0.45 mmol), and NMP (450 μL). Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 8.66-8.74 (1H, m), 7.85-7.94 (2H, m), 7.73 (1H, d, J=11.0 Hz), 7.57-7.66 (2H, m), 7.38 (1H, ddd, J=6.0, 4.9, 2.8 Hz), 7.02 (1H, ddd, J=13.4, 8.5, 2.6 Hz), 6.44 (1H, d, J=2.9 Hz), 3.86-3.98 (4H, m), 3.76-3.85 (4H, m), 2.91-3.47 (8H, m), 2.21 (3H, s). Mass Spectrum (ESI) m/e=519.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28]([OH:30])=O)=[N:11][C:12]([I:27])=[C:13]2[C:18]=1[N:17]=[CH:16][C:15]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[CH3:41][O:42][CH2:43][CH2:44][NH2:45].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH3:41][O:42][CH2:43][CH2:44][NH:45][C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]2[C:13]([CH:14]=[C:15]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:16]=[N:17]2)=[C:12]([I:27])[N:11]=1)=[O:30]
Reactant: O=C(O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCCNC(=O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To the above Compound 9 (7.0 g, 13.6 mmol), 1-hydroxybenzotriazole (208 mg, 1.36 mmol) was added dichloromethane (75 ml) to give suspension, and was added 2-methoxyethyl amine (1.42 ml, 16.3 mmol) in nitrogen gas flow under stirring on ice, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.13 g, 16.3 mmol). 30 minutes later, the solution was stirred at room temperature. After 3 hours, the reaction solution was subjected to distillation under reduced pressure, and to the residue (12 g) was added and solved ethyl acetate (150 ml) and water (100 ml), and followed by 2N hydrochloric acid aqueous solution (5.7 ml, 11.4 mmol). Then the solution was shaken for separation, washed once with water and with sodium chloride aqueous solution, dried over sodium sulfate and subjected to distillation under reduced pressure. The resultant residue (7.97 g) was solved in methanol (5 ml), and added with diisopropyl ether (35 ml) little by little under warming and left at room temperature. Then the product was collected by filtering and washed with diisopropyl ether, to give Compound 10 (6.31 g, 81.1%). The filtrate was subjected to silica gel silica gel chromatography, to give 8-benzyloxy-3-(4-fluorobenzyl)-5-iodo[1,6]naphthyridine-7-carboxylic acid (2-methoxyethyl)amide 10 (437 mg, 5.6%).
Reaction SMILES: [OH:1][CH:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][CH:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].CO.OO>O>[OH:1][CH:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=[C:3]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1c2ccccc2NC(c2ccccc2)C1O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2N=C(c2ccccc2)C1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
To a solution of 0.23 g (0.96 mmol) 3-hydroxy-2-phenyl-2H, 3H, 4H-1-benzopyridin-4-one, 0.94 g NaOH (in 4 mL water) and 35 mL MeOH was added 15 mL of H2O2 over ice bath. The yellow solution was then stirred at room temperature for 4 hours before the mixture was poured into 300 mL of water. The resulting mixture was extracted with CH2Cl2 and the solvent was removed from the organic phase. The resulting residue was recrystallized form toluene which gave the desired product in 17% yield. MP: 260°-262° C. Quantum yield (relative to 3-hydroxyflavone in CH2Cl2) 1.4. Extinction coefficient εmax (M-1 cm-1) 10,000. λmax (abs)=343 nm and λmax (em)=510 nm.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].[H-].[Na+].[Br:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25](Cl)[S:26][C:22]=2[CH:21]=1>CN(C=O)C.O>[Br:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([O:16][CH:13]3[CH2:14][CH2:15][N:10]([C:7]4[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=4)[CH2:11][CH2:12]3)[S:26][C:22]=2[CH:21]=1
Reactant: CCCc1cnc(N2CCC(O)CC2)nc1
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of 1-(5-propylpyrimidin-2-yl)piperidin-4-ol (160 mg, 0.724 mmol) in DMF (5 mL) was added NaH (36.2 mg, 0.905 mmol) at 0° C. Upon completion of addition, the reaction mixture was allowed to warm to rt and then 6-bromo-2-chlorobenzo[d]thiazole (150 mg, 0.604 mmol) was added. The resulting mixture was heated to 90° C., where it stirred overnight. At the conclusion of this period, the reaction mixture was cooled to rt, diluted with water and then extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4. The resulting mixture was filtered and concentrated under reduced pressure to yield the crude product. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford Compound 1C (194 mg, 0.448 mmol, 74.2% yield).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=1)(=O)=O.[C:21]1([C:27]2[S:31][C:30](B(O)O)=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.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>[CH3:18][O:17][C:9]1[CH:8]=[C:7]([C:30]2[S:31][C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:28][CH:29]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: OB(O)c1ccc(-c2ccccc2)s1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)c2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccc(-c3ccccc3)s2)c2ccccc2c1
Yield: 67 %

Procedure:
A mixture of 3-methoxynaphthalene-1-yl trifluoromethanesulfonate (2.7 g, 8.82 mmol), 5-phenyl-2-thiopheneboronic acid (2.7 g, 13.24 mmol), sodium carbonate (1.4 g, 13.24 mmol) was mixed in de-gassed toluene (50 ml) and ethanol (50 ml), under nitrogen. Pd(PPh3)4 (153 mg, 1 mol %) was added and the mixture heated to reflux for 18 h. The solution was allowed to cool, poured into water (200 ml), extracted with dichloromethane (2×100 ml), dried (Na2SO4), and the solvent removed under reduced pressure. The resulting residue was dissolved in DCM and filtered through a short plug of silica. The solvent was removed under reduced pressure to give a red/brown solid, which was flash chromatographed on silica using EtOAc-hexane (1:9). The fractions were combined and the solvent removed to give the title compound (1.87 g, 67%) as a green solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:14])=[CH:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12]>CN(C)C=O>[F:5][C:6]([F:14])=[CH:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:3])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCC=C(F)F
Solvent: CN(C)C=O
Product: O=C(Cl)CCCC=C(F)F

Procedure:
6.5 ml of thionyl chloride are added dropwise, at room temperature, with stirring, to 7.5 g of 6,6-difluorohex-5-enoic acid and a drop of dimethylformamide. The mixture is then stirred at reflux temperature for 5 hours, the excess thionyl chloride is evaporated off in a rotary evaporator and the residue is distilled at 86° and 100 mbar. The title product is obtained in the form of a colourless fluid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:27][C:28]([F:44])([F:43])[C:29](=[O:42])[CH2:30][C:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41])([CH3:33])[CH3:32]>C(Cl)(Cl)(Cl)Cl>[F:27][C:28]([F:43])([F:44])[C:29](=[O:42])[CH2:30][C:31]([C:34]1[CH:39]=[C:38]([Br:1])[CH:37]=[CH:36][C:35]=1[O:40][CH3:41])([CH3:33])[CH3:32]
Reactant: COc1ccccc1C(C)(C)CC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)cc1C(C)(C)CC(=O)C(F)(F)F

Procedure:
A mixture of N-bromosuccinimide (6.84 g, 38.42 mmol), benzoylperoxide (catalytic amount) and 1,1,1-trifluoro-4-(2-methoxyphenyl)-4-methylpentan-2-one (10.0 g, 38.42 mmol) in carbon tetrachloride (120 mL) and was refluxed for two days. After cooling, the solution was washed with water (60 mL) and 1.0M NaOH (60 mL), dried over sodium sulfate (Na2SO4), and concentrated in vacuo giving 1,1,1-trifluoro-4-(5-bromo-2-methoxyphenyl)-4-methylpentan-2-one and the starting material as 3:1 mixture (13.0 g).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C([Li])CCC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[N:19]2[CH2:22][CH:21]([C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)=[O:24])[CH2:20]2)=[CH:14][CH:13]=1.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[N:19]2[CH2:22][CH:21]([C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=3)([OH:24])[C:2]([CH3:4])([CH3:3])[C:1]#[N:5])[CH2:20]2)=[CH:14][CH:13]=1
Reactant: O=C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: CC(C)C#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C#N)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reaction time: 0.83 h

Procedure:
To a solution of 84 uL (0.928 mmol) of isobutyronitrile in 2 mL of THF was added a solution of 370 uL (0.928 mmol) of butyllithium (2.5M solution in hexanes), followed by stirring for 50 minutes at −55° C. to −40° C. Then a solution of 334 mg (0.773 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)methanone (as in Preparation 6) in THF was added at −78° C. and the solution was stirred for 5 h at −60° C. to −50° C. A solution of 2 mL of saturated NH4Cl was added to quench the reaction and the reaction mixture was poured into 30 mL of ether and washed with 5 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate=4:1 to afford the title compound. 1NMR(CDCl3) δ 1.24 (s, 3H), 1.34 (S, 3H), 2.58 (br, 1H), 3.12 (br, 1H), 3.40 (br, 2H), 3.60 (br, 1H), 4.26 (m, 1h) 4.43 (s, 1H), 6.76 (m, 1H), 7.06 (m, 2H), 7.25-7.34 (m, 8H); Mass Spectrum: m/e=501 (M+1 35Cl, 38Cl) and 503 (M+1 35Cl, 37Cl).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:27]1=[CH:28][C:29]2[C:30]([CH:35]([O:38][Si](C(C)C)(C(C)C)C(C)C)[CH2:36][CH2:37]1)=[N:31][CH:32]=[CH:33][CH:34]=2>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[C:27]1=[CH:28][C:29]2[C:30]([CH:35]([OH:38])[CH2:36][CH2:37]1)=[N:31][CH:32]=[CH:33][CH:34]=2
Reactant: CC(C)[Si](OC1CCC(c2cc(F)ccc2F)=Cc2cccnc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC1CCC(c2cc(F)ccc2F)=Cc2cccnc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
TBAF (0.954 mL, 0.954 mmol) was added to the THF (5 mL) solution of (E)-6-(2,5-difluorophenyl)-9-(triisopropylsilyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridine (0.2049 g, 0.477 mmol) at rt. The reaction was stirred at room temperature for 6 hours. The solvent was removed via vacuum and the product was purified by flash column eluted with ethyl acetate in hexane from 0 to 50% to 100% (102.2 mg, 78%). MS (ESI)[M+H+]=274.23 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.37 (dd, J=4.78, 1.26 Hz, 1H) 7.51 (dd, J=7.81, 1.26 Hz, 1H) 7.17-7.27 (m, 1H) 6.87-7.05 (m, 3H) 6.44 (s, 1H) 5.74 (br. s., 1H) 4.77 (dd, J=10.45, 2.64 Hz, 1H) 2.79-2.93 (m, 1H) 2.66-2.77 (m, 1H) 2.48-2.60 (m, J=13.53, 5.45, 5.45, 2.77 Hz, 1H) 1.97-2.11 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:20]=[N:21][N:22]([C:24]3([CH2:28][C:29]#[N:30])[CH2:27][NH:26][CH2:25]3)[CH:23]=2)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.O=[C:32]1[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.O1CCOCC1>C1COCC1>[F:1][C:2]1[C:3]([C:19]2[CH:20]=[N:21][N:22]([C:24]3([CH2:28][C:29]#[N:30])[CH2:27][N:26]([CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[CH2:25]3)[CH:23]=2)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)c(F)cnc21
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)c(F)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile.2[HCl] (3.10 g, 5.78 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (1.152 g, 5.784 mmol) and N,N-diisopropylethylamine (3.022 mL, 17.35 mmol) in THF (100.0 mL) was added sodium triacetoxyborohydride (2.452 g, 11.57 mmol). The mixture was stirred at room temperature for 2 hours and quenched with brine. The resulting solution was extracted with EtOAc (2 times). The combined extracts were washed with water, brine and dried over Na2SO4. After filtration and evaporation, the residue was purified by flash chromatography on silica gel eluting with 50-100% EtOAc/hexanes. The purified intermediate ([M+H]+=610.3) was dissolved in THF (50 mL). To the solution at 10° C. was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (50.0 mL, 200 mmol). The mixture was stirred at room temperature for 2 hours and concentrated to give 3.57 g of {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile.3[HCl] as an off-white solid. LC/MS found: 510.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6), δ 9.41 (s, 1H), 8.81 (s, 1H), 8.72 (s, 1H), 8.35 (d, 1H), 8.32 (s, 1H), 7.85 (d, 1H), 7.00 (d, 1H), 5.63 (s, 2H), 4.93 (d, 2H), 4.55 (d, 2H), 3.78-3.60 (m, 1H), 3.55 (s, 2H), 3.51 (t, 2H), 3.47-3.37 (m, 2H), 2.79 (m, 2H), 2.11 (m, 2H), 1.80 (m, 2H), 0.81 (t, 2H), −0.12 (s, 9H).
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[N:25][C:26]([N:29]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[N:30]3)=[CH:27][CH:28]=2)[C:8]2[CH:21]=[CH:20][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[CH:41]([NH2:44])([CH3:43])[CH3:42]>C(=O)=O>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[N:25][C:26]([N:29]3[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[N:30]3)=[CH:27][CH:28]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])=[CH:20][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:41]([NH3+:44])([CH3:43])[CH3:42]
Reactant: CC(C)N
Agent: O=C(O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)C2CCCCC2)cc1
Agent: O=C=O
Solvent: CCO
Product: CC(C)[NH3+]

Procedure:
(+/−)-3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid (Example 101) was resolved by SFC (Column: Chiralpak AD-H 25×4.6 mm; mobile phase: 25% ethanol in CO2; modifier: 0.2% isopropylamine; flow rate: 2.5 mL/min) to provide 3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, Isomer 1 (retention time: 6.93 min) and 3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido) propanoic acid, Isomer 2 (retention time: 9.58 min) as their isopropylammonium salts. The salts were dissolved in water and the pH adjusted to 3.5 by addition of 1N aqueous HCl. The mixtures were extracted with dichloromethane. The organic layers were dried over MgSO4 and concentrated to provide 3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, Isomer 1 and 3-(4-(cyclohexyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, Isomer 2. Spectral data for Isomer 1: 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.77 (s, 1H), 7.65-7.72 (m, 3H), 7.60 (d, J=8.8 Hz), 7.32 (d, J=8.2 Hz, 2H), 6.82-6.88 (m, 1H), 6.71-6.78 (m, 1H), 4.15 (d, J=6.2 Hz, 1H), 3.65-3.73 (m, 2H), 2.63-2.73 (m, 2H), 1.83-1.93 (m, 1H), 1.59-1.82 (m, 4H), 1.46-1.56 (m, 1H), 0.94-1.28 (m, 6H). MS (M+H)=516.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22](OC)=[O:23])=[CH:20][CH:19]=1.O>C1(C)C=CC=CC=1>[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:23])=[CH:20][CH:19]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)c1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Yield: 38.7 %

Procedure:
3.98 g (0.02 mol) of 1-benzyl-4-hydroxy-piperidine in 70 ml of toluene were treated with 0.624 g of NaH (50%) and heated at reflux for 1 1/2 hr. while gassing with argon. Subsequently, 3.32 g (0.022 mol) of methyl 4-amino-benzoate dissolved in 80 ml of toluene were added dropwise over 1/2 hr. and the mixture was heated at reflux for a further 2 hrs. The suspension obtained was added to 400 mi of water and the mixture was stirred. The precipitate was filtered off under suction and washed with toluene and hexane. The organic phase of the filtrate was separated, washed three times with water, dried over MgSO4 and evaporated and the residue was combined with the filter material. Chromatography was carried out over silica gel with chloroform as the eluent and recrystallization was carried out from ethyl acetate/hexane. 2.4 g (38.7%) of 1-benzyl-piperidin-4-yl 4-amino-benzoate were obtained as colorless crystals; m.p. 119°-120° C.