Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1)[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(#N)C.C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: CCc1ccc(Cc2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of (4-ethylphenyl)(4-methoxyphenyl)methanone (1) (6.0 g, 25 mmol) in acetonitrile (50 mL) and DCM (50 mL) at 0° C., was added triethylsilane (6.7 g, 57.5 mmol), followed by addition of boron trifluoride etherate (5.3 g, 37.5 mmol). The reaction mixture was stirred at 0° C. for 2 h, then at 50° C. for 3 h. After cooling to rt, the reaction mixture was diluted with DCM (500 mL) and washed with 2N aqueous NaOH (200 mL×2), brine (200 mL×3), dried over MgSO4 and evaporated to give product as a colorless oil, 5.3 g, yield 93.7% 1H NMR (300 MHz, CDCl3) δ 7.06-7.09 (m, 6H), 6.79 (d, J=8.7 Hz, 2H), 3.87 (s, 2H), 3.76 (s, 3H), 2.60 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[C:5]3[CH:12]([CH2:14][N:15]4[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]4)[CH2:13][N:3]1[C:4]=23.Cl>C(Cl)(Cl)Cl>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH:12]2[C:5]3=[CH:6][CH:7]=[N:8][C:9]4[CH:10]=[CH:11][C:2](=[O:1])[N:3]([C:4]=43)[CH2:13]2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2Cn3c(=O)ccc4nccc2c43)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: NC1CCN(CC2Cn3c(=O)ccc4nccc2c43)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl {1-[(7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (91 mg, 0.24 mmol) in chloroform (1 ml) was added HCl (4M in 1,4-dioxane) (2 ml) and the solution was stirred for 1 hour at 25° C. after which time the solvent was evaporated. The dihydrochloride salt of 4-[(4-amino-1-piperidinyl)methyl]-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one was used without further purification.
Reaction SMILES: [CH2:1]([P:7](=[O:10])([OH:9])[OH:8])[CH2:2][P:3](=[O:6])([OH:5])[OH:4].C(Cl)(=O)C(Cl)=O.[F:17][C:18]1([F:34])[C@H:22]([OH:23])[C@@H:21]([CH2:24]O)[O:20][C@H:19]1[N:26]1[CH:33]=[CH:32][C:30]([NH2:31])=[N:29][C:27]1=[O:28]>CN(C=O)C>[CH2:1]([P:7]([O:9][CH2:24][C@H:21]1[O:20][C@@H:19]([N:26]2[CH:33]=[CH:32][C:30]([NH2:31])=[N:29][C:27]2=[O:28])[C:18]([F:17])([F:34])[C@@H:22]1[OH:23])(=[O:8])[OH:10])[CH2:2][P:3](=[O:5])([OH:4])[OH:6]
Reactant: O=P(O)(O)CCP(=O)(O)O
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Nc1ccn([C@@H]2O[C@H](COP(=O)(O)CCP(=O)(O)O)[C@@H](O)C2(F)F)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.9 %

Procedure:
Ethylenediphosphonic acid (173 mg, 0.91 mmol) was treated with oxalyl chloride (2 mL, as solvent) and anhydrous DMF (0.1 ml, cat.). After heating at reflux for 10 minutes under argon, a solution was obtained and after a further 3 h the reaction mixture was cooled to room temperature and evacuated in vacuo. The residue was co-evaporated with anhydrous acetonitrile (3×10 ml). The residue was dissolved in anhydrous trimethyl phosphate (2 mL), cooled to −15° C. and 2′deoxy-2′,2′-difluorocytidine (93 mg, 0.46 mmol) was added under argon. After stirring for 2 h the reaction mixture was quenched with ice-cold TEAB solution (1.0 M, mL) and stirred for 30 minutes. Purification by HPLC gave 7.8 mg of the titled compound 81.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([O:5][CH2:6][CH2:7][C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])O.S(Cl)([Cl:37])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:37][CH:3]([O:5][CH2:6][CH2:7][C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:2]([F:34])([F:33])[F:1]
Reactant: O=S(Cl)Cl
Reactant: OC(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: FC(F)(F)C(Cl)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 3 h
Yield: 63 %

Procedure:
A 1.0 M hexane solution (34 ml) of diisobutylaluminum hydride (hereinafter, referred to as DIBAL) was added, dropwise, at −70° C., to a tetrahydrofuran solution (60 ml) of 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl trifluoroacetate ester (18.3 g) obtained by reaction of trifluoroacetic anhydride and 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecanol, followed by stirring at −70 to −50° C. for 2 hours. The resultant reaction solution was allowed to warm gradually to 0° C., and 1-mol/L aqueous hydrochloric acid (5 ml) was added thereto, followed by stirring at the same temperature for 5 minutes. After extraction with ethyl acetate/1 mol/L-hydrochloric acid, the organic layer was washed with water and an aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was concentrated under reduced pressure, to give crude 2,2,2-trifluoro-1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyloxy)ethanol. The resultant crude alcohol was dispersed in toluene (50 ml), and thionyl chloride (3.5 ml) and pyridine (4.0 ml) were added thereto, dropwise, at room temperature, followed by stirring for 3 hours. After the reaction solution was extracted with ethyl acetate/1 mol/L-aqueous hydrochloric acid, the organic layer was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography (developing solvent: ethyl acetate/hexane=1/9), to give 10-(1-chloro-2,2,2-trifluoroethoxy)-1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluorodecane (11.9 g, 63%).
Reaction SMILES: C12CC3CC(CC(C3)C1)C2.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2N=N1.[CH3:45][O:46][C:47]1[C:52]([O:53][CH3:54])=[CH:51][C:50]([CH2:55][C:56]([OH:58])=[O:57])=[C:49]([CH2:59][N:60](C2C=CC=CC=2)[C:61]([CH3:63])=[O:62])[CH:48]=1>CN(C=O)C>[CH3:45][O:46][C:47]1[C:52]([O:53][CH3:54])=[CH:51][C:50]([CH2:55][C:56]([OH:58])=[O:57])=[C:49]([CH2:59][NH:60][C:61](=[O:62])[CH2:63][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:48]=1
Reactant: COc1cc(CC(=O)O)c(CN(C(C)=O)c2ccccc2)cc1OC
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: C1C2CC3CC1CC(C2)C3
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CNC(=O)Cc2ccccc2)c(CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
2-[1-(3-Hydroxy)phenyl)-1-methoxymethylene]tricyclo[3.3.1.13,7]decane 3a (520 mg), triethylamine (800 μl) and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (950 mg) were added to a solution of 4,5-dimethoxy-2-[(phenylacetamino)methyl]phenylacetic acid 7 (656 mg, 1.91 mmol) in anhydrous DMF (10 ml). The reaction mixture was stirred at ambient temperature for 6 hours. The mixture was concentrated under vacuum. Chromatography on silica gel using cyclohexane/EtOAc (v/v:40/60) as eluent gave the ether of 3-(adamantan-2-ylidene-methoxymethyl)phenyl enol ester of [4,5-dimethoxy-2-(phenylacetylaminomethyl)phenyl]-acetic acid 2 (606 mg, 53%) in the form of a white powder. M.p. 95° C. 1H NMR (CDCl3, 300 MHz) δ 7.21 (t, J=7.9 Hz, 1H), 7.15-7.00 (m, 6H), 6.91 (t, J=2.3 Hz, 1H), 6.84 (ddd, J=7.9 Hz, 2.3 Hz, 0.8 Hz, 1H), 6.80 (s, 1H), 6.77 (s, 1H), 4.44 (d, J=5.3 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 2H), 3.81 (s, 3H), 3.53 (s, 2H), 3.30 (s, 3H), 3.25 (br s, 1H), 2.66 (br s, 1H), 1.90-1.55 (m, 12H). 13C NMR (CDCl3, 75 MHz) δ 150.6, 148.6, 148.5, 142.6, 137.3, 134.9, 132.9, 129.4, 129.1, 128.9, 127.3, 127.1, 124.1, 122.1, 120.4, 113.5, 112.9, 58.0, 56.1, 56.0, 43.9, 41.4, 39.3, 39.1, 38.3, 37.2, 32.2, 30.3, 28.3. M.S. (Maldi-T of, positive mode) m/z 634.27 [M+K]+, 618.30 [M+Na]+. Analysis calculated for C37H41NO6: C=74.60, H=6.94 and N=2.35. Analysis measured: C=74.25, H=7.09 and N=2.41.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[C:13]([O:17][C@H:18]([CH3:45])[C@H:19]([NH:22][C:23]1[CH:28]=[C:27]([F:29])[N:26]=[C:25]([NH:30][C@H:31]([C:33]2[CH:34]=[N:35][N:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:37]=2)[CH3:32])[N:24]=1)CO)([CH3:16])([CH3:15])[CH3:14].N1C(C)=CC=CC=1C>C(Cl)Cl.[Cl-].[Na+]>[C:13]([O:17][C@@H:18]([C@H:19]1[CH2:7][O:6][C:5](=[O:11])[N:22]1[C:23]1[CH:28]=[C:27]([F:29])[N:26]=[C:25]([NH:30][C@H:31]([C:33]2[CH:34]=[N:35][N:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:37]=2)[CH3:32])[N:24]=1)[CH3:45])([CH3:15])([CH3:16])[CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](Nc1nc(F)cc(N[C@H](CO)[C@@H](C)OC(C)(C)C)n1)c1cnn(-c2ccc(F)cc2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C[C@H](Nc1nc(F)cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1cnn(-c2ccc(F)cc2)c1
Temperature: 25 °C

Procedure:
Triphosgene (18 mg, 0.062 mmol, 0.5 equiv) was added to a solution of (2R,3R)-3-(tert-butoxy)-2-((6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)amino)butan-1-ol (57 mg, 0.12 mmol) in DCM (1.2 mL) at −78° C., followed by the dropwise addition of 2,6-lutidine (0.058 mL, 0.49 mmol, 4 equiv). The solution was allowed to warm to room temperature and was then heated at 35° C. for 30 min. The reaction was then cooled to room temperature and diluted with DCM (30 mL) and saturated aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to give crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-fluoro-2-(((S)-1-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one, which was used without further purification. MS m/z 487.4 (M+H)+; Rt-1.12 min.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]([NH:27][C:13](=[O:15])[CH2:12][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:11][CH:10]=2)[CH3:26])=[N:23][CH:24]=1
Reactant: O=C(O)Cc1ccc(N2CCCC2)cc1
Reactant: COc1ccc([C@@H](C)N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)NC(=O)Cc2ccc(N3CCCC3)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of (4-pyrrolidin-1-ylphenyl)acetic acid (U.S. Pat. No. 3,641,040) (0.50 g, 2.4 mmol), (1R)-1-(5-methoxypyridin-2-yl)ethylamine hydrochloride (0.57 g, 3.0 mmol), and HATU (1.2 g, 3.1 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (1.7 mL, 9.7 mmol) and the mixture was stirred at room temperature for 16 h. The solution was concentrated and the crude residue was partitioned between water and EtOAc. The organic layer was washed with brine and water, dried over MgSO4, and purified by normal phase chromatography (10-100% EtOAc/hexanes) to give N-[(1R)-1-(5-methoxypyridin-2-yl)ethyl]-2-(4-pyrrolidin-1-ylphenyl)acetamide as a tan solid. 1H NMR (400 MHz, CDCl3) δ 8.16 (m, 1H), 7.11 (m, 4H), 6.54 (m, 3H), 5.09 (m, 1H) 3.83 (s, 3H), 3.48 (d, J=3.2 Hz, 2H), 3.28 (t, J=6.4 Hz, 4H), 2.01 (m, 4H), 1.36 (d, J=6.4 Hz, 3H); MS (Electrospray): m/z 340.4 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:24]=3)[CH:14]=2)[N:11]=[C:10]([C:32]([C:38]([F:41])([F:40])[F:39])([C:34]([F:37])([F:36])[F:35])[OH:33])[CH2:9]1.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)[CH:14]=2)[N:11]=[C:10]([C:32]([C:38]([F:41])([F:39])[F:40])([C:34]([F:35])([F:36])[F:37])[OH:33])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(C1=NN(c2cccc(C3=CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 208.5 %

Procedure:
5-(2-Chloro-phenyl)-1-[3-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (350.0 mg, 0.71 mmol) prepared in Example 433 was added to a saturated solution of hydrochloric acid in ethyl acetate (3.0 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 400.0 mg of 5-(2-chloro-phenyl)-1-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride as a yellow liquid.
Reaction SMILES: FC(F)(F)C1C(CC2C=CC(N)=CC=2)=CC=CN=1.FC(F)(F)[C:21]1[CH:26]=[C:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH:24]=[CH:23][N:22]=1.C(OC(=O)CC1C=CC([N+]([O-])=O)=CC=1)C.[Cl:52]C1C=C([N+]([O-])=O)C=CN=1>>[Cl:52][C:21]1[CH:26]=[C:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH:24]=[CH:23][N:22]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Nc1ccc(Cc2ccnc(C(F)(F)F)c2)cc1
Agent: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: Nc1ccc(Cc2cccnc2C(F)(F)F)cc1
Product: Nc1ccc(Cc2ccnc(Cl)c2)cc1

Procedure:
4-(2-Chloro-pyridin-4-ylmethyl)-phenylamine was prepared by a method analogous to that described for 4-(2-trifluoromethyl-pyridinylmethyl)-phenylamine (Intermediate 2P), starting from ethyl(4-nitrophenyl)acetate and 2-chloro-4-nitro-pyridine. 1H NMR (CHCl3-d) δ 8.23 (dd, J=5.1, 0.5 Hz, 1H), 7.11 (m, 1H), 7.01 (m, 1H), 6.95 (m, 2H), 6.65 (m, 2H), 3.83 (s, 2H).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[C:40]([O:41][CH3:42])=[CH:39][C:28]2[CH2:29][C:30](=[O:38])[N:31]([CH2:34][CH2:35][CH2:36]Cl)[CH2:32][CH2:33][C:27]=2[CH:26]=1>C(Cl)Cl>[CH3:23][O:24][C:25]1[C:40]([O:41][CH3:42])=[CH:39][C:28]2[CH2:29][C:30](=[O:38])[N:31]([CH2:34][CH2:35][CH2:36][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]3[CH2:18][CH2:17][C:16]4[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=4)[CH2:10]3)[CH2:32][CH2:33][C:27]=2[CH:26]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: COc1cc2c(cc1OC)CC(NCc1ccccc1)CC2
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(Cc1ccccc1)C1CCc3cc(OC)c(OC)cc3C1)CC2

Procedure:
The title compound is prepared analogously to Example 1 by reacting 2-benzylamino-6,7-dimethoxy-1,2,3,4-tetrahydronaphthalene with 1-(7,8-dimethoxy-1,3,4,5-tetra hydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane. IR spectrum (methylene chloride): 1645 cm-1 (C=O).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6]([CH2:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)([C:11]#[N:12])[CH3:10])[CH:7]=1.[NH4+].[OH-]>CO.[Ni]>[NH2:12][CH2:11][C:9]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:17][CH:18]=1)([CH3:10])[CH2:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([C:26]([CH3:28])([CH3:29])[CH3:27])[C:5]=1[O:24][CH3:25]
Reactant: COc1c(CC(C)(C#N)c2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1c(CC(C)(CN)c2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Yield: 83.9 %

Procedure:
step 1—To a solution of 288 (150 mg, 0.313 mmol) in MeOH (20 mL) in a Parr bottle was added Raney Nickel (50% solution in water, 1 mL) and NH4OH (0.5 mL) and the mixture was hydrogenated at 45 psi on a Parr shaker overnight. LCMS indicated some remaining starting material. Additional Raney Nickel (1 mL) and NH4OH (0.5 mL) were added and the hydrogenation was continued for another day. The crude mixture was filtered through CELITE and the filtrate was concentrated. The crude product was purified by SiO2 chromatography eluting with 10% MeOH/DCM to afford 127 mg (84%) of N-{4-[1-aminomethyl-2-(5-bromo-3-tert-butyl-2-methoxy-phenyl)-1-methyl-ethyl]-phenyl}-methanesulfonamide (290).
Reaction SMILES: C([O:8][C:9]([C:11]1[NH:12][C:13]([CH3:23])=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15]=1[CH3:16])=[O:10])C1C=CC=CC=1>CO>[CH3:22][O:21][C:19]([CH2:18][CH2:17][C:14]1[C:15]([CH3:16])=[C:11]([C:9]([OH:10])=[O:8])[NH:12][C:13]=1[CH3:23])=[O:20]
Reactant: COC(=O)CCc1c(C)[nH]c(C(=O)OCc2ccccc2)c1C
Solvent: CO
Product: COC(=O)CCc1c(C)[nH]c(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
4-(2-methoxycarbonyl-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid benzyl ester (390 mg, 1.24 mmol) was dissolved in anhydrous MeOH (20 mL). The solution was evacuated and rinsed with argon several times. 120 mg of palladium on charcoal (10%) were added and again the mixture was evacuated and rinsed with argon several times. Finally argon was exchanged by hydrogen (balloon filled with hydrogen) and the mixture was stirred for 3 h at room temperature. The reaction mixture was filtered over celite and the filter residue was washed with MeOH (150 mL). The filtrate was concentrated in vacuo to give pure 4-(2-methoxycarbonyl-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid as a colorless solid (263 mg). MS (ESI−): m/e=225 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[C:3]([O:5]C)=[O:4].C[Si](C)(C)[O-].[Na+:17]>C(Cl)Cl>[F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[C:3]([O-:5])=[O:4].[Na+:17]
Reactant: COC(=O)C(F)(F)C(F)(F)F
Agent: C[Si](C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C([O-])C(F)(F)C(F)(F)F
Yield: 91.9 %

Procedure:
The procedure of Example 1 was followed using methyl perfluoropropionate (3 mL, 23.4 mmol), sodium trimethylsilanolate (2.63 g, 23.4 mmol), dry methylene chloride (100 mL), and a 1 h reaction time. Sodium perfluoropropionate (4.0 g, 92% yield) was obtained as a white solid: 1H NMR (D2O) δ -82.4 (t, J=2 Hz, CF3, 3F), -120.1 ppm (q, J=2 Hz, CF2, 2F).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.C(O)C.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:31]=[CH:32][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:34][CH:35]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4ccccc4)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
Ethyl (2-{7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (1.0 g) was dissolved in a mixed solvent of tetrahydrofuran (6 mL)-ethanol (6 mL), 1M aqueous sodium hydroxide solution (6 mL) was added, and the mixture was stirred at room temperature for 10 min. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid, and filtered. The obtained solid was washed successively with water, ethanol and diethyl ether to give the title compound (640 mg, yield 67%) as a pale-orange solid. The obtained solid was recrystallized from ethanol-hexane to give colorless crystals. melting point 218-219° C. MS 537 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:21][CH2:22][CH3:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7]2.C1COCC1.CCO.O[Li].O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:21][CH2:22][CH3:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(OCC)cc(Cl)c2OC1C(F)(F)F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOc1cc(Cl)c2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
To a solution of the ester from Step 4 (250 mg, 0.713 mmole) in a 7:2:1 THF:EtOH:H2O mixture (10 mL) was added LiOH.H2O (44.9 mg, 1.07 mmole). The mixture was stirred room temperature for 15 minutes and then at 50° C. for 75 minutes. After standing at room temperature for 2.75 days, the solvent was removed in vacuo. The residue was redissolved in H2O (20 mL) and washed with ethyl ether (20 mL). The aqueous layer was concentrated to a volume of 5 mL and acidified with 1 N HCl. The resulting solid was filtered, washed with H2O and dried in vacuo to give 216 mg (94% yield) of the product as a yellow crystalline solid: ESHRMS m/z 321.0135 (M−H, C13H9ClF3O4, Calc'd 321.0136). 1H NMR (dmso-d6/300 MHz) 13.45 (brs, 1H), 7.88 (s, 1H), 7.13-7.16 (m, 2H), 6.02 (q, 1H, J=7.3 Hz), 4.03 (q, 2H, J=6.9 Hz), 1.32 (t, 3H, J=6.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Reactant: Clc1nccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2nccc3ccccc23)CC1
Yield: 2.7 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 1-chloroisoquinoline (131 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (4 mg), a beige solid, in 3% yield.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)=[N:6][CH:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].Cl.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH:33]1[C:38]([OH:40])=[O:39]>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)[NH:8][C:3]([CH2:2][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH:33]2[C:38]([OH:40])=[O:39])=[C:4]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc(C(F)(F)F)cs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nc(C(F)(F)F)cs2)=NC1c1ccc(Cl)cc1Cl
Yield: 84.3 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(4-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.1 g, 0.18 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.03 g, 0.18 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.09 g, 80%). The compound was characterized by the following spectroscopic data: