Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:5]([CH2:4][CH2:3][C:2]([F:20])([F:21])[F:1])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C(CCC(F)(F)F)C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)C(CCC(F)(F)F)c1ccc(CBr)cc1

Procedure:
540 mg (1.79 mmol) of tert-butyl 5,5,5-trifluoro-2-(4-methylphenyl)pentanoate, 333.8 mg (1.78 mmol) of N-bromosuccinimide and 14.7 mg (0.09 mmol) of 2,2′-azobis-2-methylpropionitrile in 10 ml of carbon tetrachloride were stirred under reflux for 2 h. After the reaction had gone to completion, the succinimide was filtered off and the filter residue was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 659 mg (1.72 mmol, 97% of theory) of a yellowish oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].CCOC(C)=O>C1COCC1>[Cl:18][C:13]1[CH:12]=[C:11]([C:9]2[N:8]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:7]=[C:6]([CH2:4][OH:3])[CH:10]=2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CO)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (55.7 g, 0.140 mol) in THF (150 mL) at −78° C. under N2 was slowly added a 1.0 M solution of diisobutylaluminum hydride (DIBAL-H) (350 mL, 0.35 mol) over 45 min. The solution was allowed to stir for 20 min then warmed to rt over 90 min. The mixture was then cooled to 0° C., and a saturated solution of potassium sodium tartrate (300 mL) and EtOAc (400 mL) was added. The slurry mixture was stirred overnight whereupon both layers became clear. The organic layer was extracted with EtOAc (2×75 mL), dried with Na2SO4, filtered and concentrated. The crude product was dried under vacuum to recover 46.8 g (96%) of the title compound. This was used in the next step without further purification. HPLC: Rt=9.16 (Method E). MS (ES+): mass calculated for C17H14Cl2N2O2, 349.21; m/z found 371.1 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.39 (d, J=2.1 Hz, 1H), 7.34 (d, J=3.6 Hz, 1H), 7.20-7.09 (m, 2H), 6.97 (dd, J=8.36, 2.1 Hz,1H), 6.91-6.79 (m, 2H), 6.43 (s, 1H), 4.69 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[C@@H:21]([C:22]4[C:23]([O:29]C)=[N:24][CH:25]=[C:26]([F:28])[CH:27]=4)[CH2:20][O:19][C:18]3=[O:31])=[N:13][C:12]=12)=[O:7]>Cl.O1CCOCC1>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[C@@H:21]([C:22]4[C:23](=[O:29])[NH:24][CH:25]=[C:26]([F:28])[CH:27]=4)[CH2:20][O:19][C:18]3=[O:31])=[N:13][C:12]=12)=[O:7]
Reactant: COc1ncc(F)cc1[C@H]1COC(=O)N1c1ccn2ncc(C(=O)NCCCCl)c2n1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCCCCl)c1cnn2ccc(N3C(=O)OC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 85 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
A suspension of (S)-N-(3-chloropropyl)-5-(4-(5-fluoro-2-methoxypyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (37 mg, 0.08 mmol) in 4N HCl/dioxane (4 mL) was stirred at 85° C. for 17 hours and then at ambient temperature for 48 hours. The resulting solution was concentrated to ½ volume, transferred to a sealed tube, treated with 4N HCl/dioxane (2 mL) and stirred at 100° C. for 2 hours. The heterogeneous mixture was concentrated, dried under reduced pressure and used directly in the next step, assuming 100% yield. MS (apci) m/z=435.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[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:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=3Br)[C@H:14]2[CH3:30])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:33][CH:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[F:1][C:2]([F:32])([F:31])[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:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=3[N:36]3[CH2:37][CH2:38][CH2:39][CH:34]([CH3:33])[CH2:35]3)[C@H:14]2[CH3:30])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC1CCCNC1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc([N+](=O)[O-])ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC1CCCN(c2ccc([N+](=O)[O-])cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)C1

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-methyl-1,3-oxazolidin-2-one (42 mg, 0.083 mmol), 3-methylpiperidine (13 mg, 0.126 mmol), palladium(II) acetate (1.0 mg, 5%), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (2-6 mg, 7.5%), cesium carbonate (55 mg, 0.17 mmol) and THF (1 mL) were sealed in a microwave vessel. The reaction mixture was irradiated by microwave at 150° C. for 1 hour. Reaction crude was purified by SiO2 to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(3-methylpiperidin-1-yl)-5-nitrobenzyl]-1,3-oxazolidin-2-one. LCMS calc.=546.17; found=546.23 (M+1)+. 1H NMR signals are doubled because of atropoisomerism 1H NMR (CDCl3, 500 MHz) δ 8.22 (d, J=2.5 Hz, 1H), 8.16 (d, J=3 Hz, 0.5H), 8.14 (d, J=2.5 Hz, 0.5H), 7.89 (s, 1H), 7.78 (s, 2H), 7.14 (d, J=4 Hz, 0.5H), 7.12 (d, J=4.0 Hz, 0.5H), 5.76 (d, J=8 Hz, 1H), 4.84 (d, J=4.5 Hz, 0.5H), 4.81 (d, J=4.5 Hz, 0.5H), 4.40 (d, J=3.5 Hz, 0.5H), 4.36 (d, J=3.5 Hz, 0.5H), 3.87-3.83 (m, 1H), 7.14 (s, 1H), 3.09 (s, 2H), 3.02 (d, J=12.5 Hz, 1H), 2.84 (t, J=10 Hz, 1H), 2.60 (t, J=12.5 Hz, 1H), 2.54 (t, J=11 Hz, 0.5H), 2.33 (t, J=11 Hz, 1H), 1.16-1.07 (m, 1H), 0.96 (d, J=6.5 Hz, 0.5H), 0.94 (d, J=6.5 Hz, 1.5H), 0.70 (s, 1.5H), 0.69 (s, 1.5H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][CH:9]([CH3:12])[C:8]2[CH:7]=[C:6]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C([O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)(=O)C.[OH-].[Na+].Cl>CO>[CH3:1][CH:2]1[CH2:11][CH2:10][CH:9]([CH3:12])[C:8]2[CH:7]=[C:6]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH:24][CH2:32][CH2:31][CH2:30][CH2:29][OH:28])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1CCC(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCC(C)c2cc(-c3csc(N4CCC(NCCCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as described starting from 218 mg (0.58 mmol) of 1-[4-(5,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine and 126 μl (0.58 mmol) of 4-bromobutyl acetate. The protecting group is cleaved off by means of a 1N NaOH solution in methanol. The product is in the form of the hydrochloride.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH:12]1([CH2:15][N:16]([C:24]2[C:25]([CH2:33][CH3:34])=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=23)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][CH2:13]1.[Br:35]C(F)(F)C(F)(F)Br.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:35][C:32]1[N:27]2[N:26]=[C:25]([CH2:33][CH3:34])[C:24]([N:16]([CH2:15][CH:12]3[CH2:13][CH2:14]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:28]2[CH:29]=[CH:30][CH:31]=1
Reactant: CCc1nn2ccccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Reactant: FC(F)(Br)C(F)(F)Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1nn2c(Br)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Yield: 87.9 %

Procedure:
A solution of n-butyllithium in hexane (1.6M, 3.88 mL, 6.18 mmol) was added dropwise to a solution of tert-butyl N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)carbamate (1.5 g, 4.76 mmol) in tetrahydrofuran (15 mL) at −70° C. After stirring the reaction mixture for 50 minutes at the same temperature, 1,2-dibromotetrafluoroethane (1.0 mL, 8.33 mmol) was added dropwise to the reaction mixture. The temperature of the reaction mixture was slowly increased and aqueous sodium bicarbonate was added at 0° C. The reaction mixture was extracted with ethyl acetate, and the organic extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to afford 1.65 g of the title compound as a yellow oil (87.8% yield).
Reaction SMILES: Cl[C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][CH2:5][N:6]([C:11]1[N:16]=[C:15]2[O:17][C:18]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:19]([C:20]([NH:22][CH3:23])=[O:21])[C:14]2=[CH:13][C:12]=1[CH:31]1[CH2:33][CH2:32]1)[S:7]([CH3:10])(=[O:9])=[O:8].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:46]1COC[CH2:47]1.O>[Pd]>[CH:31]1([C:12]2[CH:13]=[C:14]3[C:19]([C:20]([NH:22][CH3:23])=[O:21])=[C:18]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[O:17][C:15]3=[N:16][C:11]=2[N:6]([CH2:5][CH2:4][C:3]2[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=2[CH:46]=[CH2:47])[S:7]([CH3:10])(=[O:8])=[O:9])[CH2:32][CH2:33]1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCc3ccccc3Cl)S(C)(=O)=O)c(C3CC3)cc12
Reactant: C1CCOC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1ccccc1CCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Temperature: 120 °C

Procedure:
Combined 6-(N-(2-chlorophenethyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-(p-tolyl)furo[2,3-b]pyridine-3-carboxamide (38 mg, 0.071 mmol), Potassium phosphate Tribasic (nH2O) (244 mg, 1.059 mmol) and Pd-catalyst (42.4 mg, 0.071 mmol) in 3.4 mL 2:1 THF/water. Heated at 120° C. μwave for 20 min. Added water 50 mL and extracted 4× with EtOAc. Conc on vac. Taken up in DMF/ACN/drop of water Purified via HPLC C18 40-75% ACN/water (0.1% NH4OH)40 mL/min over 20 min to give 10.4 mg 5-cyclopropyl-N-methyl-2-(p-tolyl)-6-(N-(2-vinylphenethyl)methylsulfonamido)furo[2,3-b]pyridine-3-carboxamide
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[NH:13][C:14](=O)[CH2:15][CH2:16][CH:17]1[CH2:20][C:19](=[O:21])[CH2:18]1>C(O)(=O)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]2[N:13]=[C:14]([CH2:15][CH2:16][CH:17]3[CH2:20][C:19](=[O:21])[CH2:18]3)[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CCC1CC(=O)C1
Solvent: CC(=O)O
Product: O=C1CC(CCc2nc3cc(C(F)(F)F)c(Cl)cc3[nH]2)C1
Temperature: 65 °C
Yield: 66.1 %

Procedure:
N-(2-amino-4-chloro-5-(trifluoromethyl)phenyl)-3-(3-oxocyclobutyl)propanamide (72 mg, mmol) was taken up in acetic acid (3.2 mL) and the solution was heated at 65° C. for 26 h, upon which HPLC indicated the starting material was consumed and a new product had formed. The reaction mixture was cooled and the solvent was removed under high vac. The light brown residue was taken up in 20 mL ethyl acetate and the organic phase was washed with 10 mL portions of sat NaHCO3 and H2O. The organic phase was dried over Na2SO4, filtered and concentrated to yield a light brown glass. The crude material was purified by prep TLC (20 cm×20 cm×1.0 mm prep TLC plate, 3% MeOH/EA) to yield the title compound (45 mg, 66%) as a tan glass: MS (ESI+) for C14H12ClF3N2O m/z 317.2 (M+H)+; MS (ESI−) for C14H12ClF3N2O m/z 315.2 (M−H)−; HPLC purity 84.1% (ret. time, 2.98 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[OH:37].N1C=CC=[CH:40][CH:39]=1.C(B1OB(C=C)OB(C=C)O1)=C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([NH:30][S@:31]([C:33]([CH3:34])([CH3:36])[CH3:35])=[O:32])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[O:37][CH:39]=[CH2:40]
Reactant: c1ccncc1
Reactant: CC(C)(C)[S@](=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(O)c1
Agent: [Cu+2]
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: C=COc1cc([C@@](Cc2ccccc2)(N[S@@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of (S)—N—((R)-1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide prepared as described in Procedure 3, 4, 5, 6 and 59 (0.545 g, 1 mmol) in CH2Cl2 (10 mL) was added Cu(OAc)2 (0.182 g, 1 mmol), followed by pyridine (0.79 g, 10 mmol) and 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (0.159 g, 0.66 mmol). The reaction mixture was stirred overnight under ambient air and filtered through a plug of celite and neutral alumina. The solid was washed with ethyl acetate and the filtrate was concentrated under reduced pressure to yield (S)—N—((R)-1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide as an off-white foam (0.495 g, 87% yield). LCMS: RT=3.653 min [M+H] 572.2 (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueous acetonitrile containing 0.1% trifluoroacetic acid over a 4 minute gradient, monitoring at 220 nM). 1H NMR (CDCl3) ppm 7.2-7.1 (m, 5H), 7.02 (d, J=6.2 Hz, 1 H), 6.89 (d, J=6.2 Hz, 2H), 6.82 (d, J=8.8 Hz, 1H), 6.68 (br, 2H), 6.54 (dd, J=6.2 Hz, 13.6 Hz, 1H), 5.84 (t, J=52.7 Hz, 1H), 4.62 (dd, J=2.2 Hz, 13.6 Hz, 1H), 4.40 (dd, J=2.2 Hz, 5.7 Hz, 1H), 4.21 (s, 1H), 3.95 (d, J=12.8 Hz, 1H), 3.55 (d, J=12.7 Hz, 1H), 1.19 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[B][B][B][B][B][B][B][B][B][B].CCOC(C)=O.CCCCCC>CO>[O:15]1[CH2:20][CH2:19][CH:18]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:16]1
Reactant: O=C1CCOCC1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C(F)(F)F)cc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
To a solution of 500 mg (2.46 mmol) 1-(2-amino-4-(trifluoromethyl)phenyl)ethanone in methanol (18 ml) was added 250 μl (2.70 mmol) dihydro-2H-pyran-4(3H)-one at RT followed by the addition of 90 mg (0.73 mmol) decaborane. The reaction mixture was stirred at RT for 16 h. The mixture was evaporated under vacuum and residue diluted with ethyl acetate (20 ml). The organic layer was washed with water (20 ml), brine (20 ml), dried over anhydrous Na2SO4 and concentrated in vacuum. After CC (EtOAc/hexane 1:24) of the residue, 240 mg (0.83 mmol, 34%) 1-(2-(tetrahydro-2H-pyran-4-ylamino)-4-(trifluoromethyl)phenyl)ethanone were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11](=O)[CH:12]([CH3:18])[C:13](OCC)=[O:14]>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[C:11]([C:10]([F:21])([F:20])[F:9])[C:12]([CH3:18])=[C:13]2[OH:14]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Reactant: Nc1ccc(Cl)cc1
Product: Cc1c(C(F)(F)F)nc2ccc(Cl)cc2c1O

Procedure:
Prepared according to procedure R using 4-chloroaniline (6.44 g, 50.47 mmol) and ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate (10 g, 50.47 mmol) to give 6-chloro-3-methyl-2-(trifluoromethyl)quinolin-4-ol as an off-white solid: Mass Spectrum (ESI) m/e=262.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][CH2:24][CH2:25][OH:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].Cl>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][CH2:24][CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(COCCO)ccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Chloro-5-[(2-hydroxyethoxy)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.228 g, Example 25a) and triethylamine (0.21 ml) in dichloromethane (10 ml) were cooled to 5° C. under nitrogen and methanesulfonyl chloride (0.1 ml) was added. The mixture was stirred at room temperature for 20 h then poured into 2N hydrochloric acid, and extracted into ethyl acetate. The combined extracts were washed with 2N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution then brine, and dried over magnesium sulfate. The organics were filtered and concentrated under reduced pressure to afford the subtitled compound as a white solid (0.160 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-nitrophenol (1 g, 7.12 mmol, 1.00 equip, 99%), tert-butyl 2-bromoacetate (1.68 g, 8.53 mmol, 1.00 equip), potassium carbonate (1.49 g, 10.60 mmol, 1.50 equip, 99%), and tetrahydrofuran (50 mL). The resulting solution was stirred for 4 h at 70° C. in an oil bath. The resulting solution was diluted with water (150 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined. The resulting mixture was washed with water (1×100 mL) and brine (1×100 mL). The resulting mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20) to yield tert-butyl 2-(4-nitrophenoxy)acetate as a yellow solid.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[C:15]([Br:20])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[Br:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH2:12][CH3:13])[C:9]=2[CH:14]=1
Reactant: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)c(Br)cc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC1CNCCc2cc(OC)c(Br)cc21
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.561 g, 1.48 mmol) in methanol (30 mL) was treated with 15% aqueous NaOH (30 mL), and stirred overnight at 20 C. The product mixture was diluted with brine (100 mL), extracted twice with EtOAc (200 mL), dried with MgSO4, and concentrated to give 0.412 g of a clear oil. 1H NMR (400 MHz, CD3OD) d 7.24 (s, 1 H), 6.76 (s, 1 H), 3.83 (s, 3 H), 3.02 (m, 3 H), 2.91 (s, 1 H), 2.85-2.76 (m, 3 H), 2.63 (m, 1 H), 1.78 (m, 1 H), 1.72 (m, 1 H), 0.94 (dd, J=8, 8 Hz, 3 H). MS calculated for C13H18BrNO+H: 284, observed: 284.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](I)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].[C:13]([O:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:21]2[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C:28]3[C:23]([CH:22]=2)=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: O=C1NCc2c(Cl)ccc(I)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2ccccc21
Yield: 43.7 %

Procedure:
In a similar manner to Step 2 of Example 1, 4-chloro-7-iodoisoindolinone (100 mg, 0.341 mmol) was dissolved in acetonitrile (7 mL), and the solution was treated with 1-(tert-butoxycarbonyl)indol-2-boronic acid (178 mg, 0.682 mmol), palladium acetate (6.1 mg, 0.027 mmol), tri(o-tolyl)phosphine (17 mg, 0.055 mmol) and triethylamine (0.475-mL, 3.41 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=30/1) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)indol-2-yl)isoindolinone (57 mg, yield 44%).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]([C:65]2[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=2)[CH2:61][CH2:62][CH2:63][NH2:64])=[CH:56][CH:55]=1>CN(C=O)C.C(OCC)C>[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]([C:65]2[CH:66]=[CH:67][C:68]([F:71])=[CH:69][CH:70]=2)[CH2:61][CH2:62][CH2:63][NH:64][C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH:15]([CH3:18])[CH2:16][CH3:17])=[O:14])=[CH:56][CH:55]=1
Reactant: CCC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)[C@H](NC(=O)N1CCCCCC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-3-methyl-pentanoic acid (0.300 g, 1.24 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.647 mL, 3.71 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.470 g, 1.24 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.369 g, 1.24 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 25 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 0.50 g (81%) of the pure titled compound as a white foam; mp 50-60° C. APCI-MS m/z 500.3 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([N:32]5[CH:36]=[CH:35][N:34]=[CH:33]5)[CH:27]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1ccnc(-n2ccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2ccnc(-n3ccnc3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4′-fluoro-3-[3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K43) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (209 mg).