Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>C(O)C>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:34]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[O:35])=[CH:37][CH:38]=1
Reactant: C[C@H]1COCCN1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCO
Product: C[C@H]1COCCN1C(=O)c1ccc(N)nc1
Reaction time: 18 h
Yield: 30.1 %

Procedure:
To a solution of (S)-3-methylmorpholine (1.5 g, 15.0 mmol) in ethanol (20 mL) was added EDCI (3.33 g, 17.4 mmol), HOBt (2.35 g, 17.4 mmol), and 6-aminonicotinic acid (2.07 g, 15.0 mmol) at room temperature. After stirring for 18 h, the resulting suspension was filtered. The solid was purified by silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to straight ethyl acetate to afford 256a (1.0 g, 30%) as white solid. MS-ESI: 222.3 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([C:15]3[N:19]=[C:18](C(Cl)(Cl)Cl)[O:17][N:16]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl.[F:34][C:35]([F:46])([F:45])[CH2:36][O:37][CH2:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C=O)C>[C:1]1([NH:7][C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([C:15]3[N:19]=[C:18]([N:42]4[CH2:41][CH2:40][CH:39]([CH2:38][O:37][CH2:36][C:35]([F:34])([F:45])[F:46])[CH2:44][CH2:43]4)[O:17][N:16]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nc(Nc2ccccc2)nc(-c2noc(C(Cl)(Cl)Cl)n2)n1
Reactant: FC(F)(F)COCC1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Nc2ccccc2)nc(-c2noc(N3CCC(COCC(F)(F)F)CC3)n2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.9 %

Procedure:
To 2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (Intermediate 134, 0.100 g, 0.268 mmol) in DMF (2 mL) was added DIPEA (93.6 μL, 0.537 mmol) at the mixture was stirred at room temperature for 5 min. 4-[(2,2,2-trifluoroethoxy)methyl]piperidine hydrochloride (Intermediate 179, 0.063 g, 0.268 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was then heated to 50 C for 18 h and to 70 C for 36 h. The reaction mixture was concentrated under reduced pressure, dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC, Method C, to afford the title compound (10.8 mg, 8.9%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: C1COCCN1
Solvent: O
Product: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Temperature: 25 °C
Yield: 96 %

Procedure:
As shown in Scheme 3 above, a mixture of 2,6-dichloropurine (1.90 g, 10 mmol) and morpholine (2.34 g, 30 mmol) in water (25 mL) was heated under reflux for 15 min. Solidified reaction mixture was cooled to room temperature. Solid was filtered out and washed with water, methanol and ether. The 2-chloro-6-morpholin-4-yl-9H-purine was obtained in 96% yield (2.30 g). A mixture of 2-chloro-6-morpholin-4-yl-9H-purine (1.92 g, 8 mmol) and 2-(3,4-dimethoxyphenyl)ethylamine (4.35 g, 24 mmol) in sealed tube and under nitrogen was stirred at 190–195° C. for 1 hour. The reaction mixture turned to clear solution initially and then formed a slurry. The reaction mixture was cooled to room temperature diluted with methanol (8 mL) and the solid was collected by filtration, washed with methanol and Et2O and dried to afford 2.30 g (74% yield) of [2-(3,4-dimethoxy-phenyl)-ethyl]-(6-morpholin-4-yl-9H-purin-2-yl)amine.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:36][C:37]1[CH:38]=[CH:39][C:40]([Cl:44])=[C:41]([Pb+3])[CH:42]=1>ClCCl.Cl>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:44])=[C:39]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])[CH:38]=1
Reactant: Clc1ccc(Br)cc1[Pb+3]
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(Br)ccc2Cl)C1=O
Temperature: 80 °C
Yield: 7.5 %

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (2.78 g, 16.3 mmol) and N,N-dimethylaminopyridine (9.97 g, 81.6 mmol) is added anhydrous chloroform (120 ml). To this solution is added anhydrous toluene (30 ml), followed by 5-bromo-2-chlorophenyllead triacetate (10.32 g, 18 mmol) in one portion and the reaction mixture is heated at 80° C. overnight. The mixture is allowed to cool to room temperature, then diluted with dichloromethane (120 ml) and 2M aqueous hydrochloric acid (250 ml), followed by filtration through diatomaceous earth to remove inorganic residues. The filter cake is washed with dichloromethane, and all organic fractions are combined, washed with 2M hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate then concentrated in vacuo. This material is finally purified by flash column chromatography on silica gel to afford 4-(5-bromo-2-chlorophenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.44 g) of sufficient purity to use directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13](C)C)=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([C:28]([F:31])([F:30])[F:29])=[N:20][N:21]([CH2:24][C:25](O)=[O:26])[C:22]=1[CH3:23].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:17][C:18]1[C:19]([C:28]([F:30])([F:29])[F:31])=[N:20][N:21]([CH2:24][C:25]([NH:16][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:26])[C:22]=1[CH3:23]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)Nc1cnn(-c2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.03 g, 0.16 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetic acid (0.038 g, 0.16 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.067 g, 0.18 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.02 g, 0.048 mmol, 30%). 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.37 (dd, J=8.9, 4.7 Hz, 1H), 7.26 (d, J=0.4 Hz, 2H), 7.18 (dd, J=8.9, 8.1 Hz, 2H), 4.94 (s, 2H), 2.39 (s, 3H), 2.16 (s, 3H); MS: (ES) m/z calculated for C17H14ClF4N5O [M+H]+416.1, found 416.0.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N:13](C(=O)C)[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[CH:6]=1>O1CCCC1.CO>[CH3:2][O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[CH:6]=1
Reactant: COC(=O)c1ccc(OC)c(N(C(C)=O)c2cc(Cl)cc(Cl)c2)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)c(Nc2cc(Cl)cc(Cl)c2)c1
Reaction time: 72 h
Yield: 23.6 %

Procedure:
Concentrated HCl (45 mL) was added to a solution of 3-[acetyl-(3,5-dichlorophenyl)-amino]-4-methoxybenzoic acid methyl ester (11.46 g, 31.12 mmol) in a mixture of tetrahydrofuran (75 mL) and methanol (75 mL). The reaction was heated to reflux. After 3 days, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and dried (MgSO4). The ethyl acetate was removed under reduced pressure to give the product (2.4 g); m.p. 134-135° C. after chromatography on silica gel in ethyl acetate followed by recrystallization from ether/hexane 1:9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:21]([CH3:23])[CH3:22])[CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C.[F:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[C:62]([N:70]3[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]3)=[C:63]3[CH:69]=[CH:68][NH:67][C:64]3=[N:65][CH:66]=2)=[CH:57][CH:56]=1>C(Cl)Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:10]([C:11]([N:73]2[CH2:74][CH2:75][N:70]([C:62]3[C:61]([C:58]4[CH:59]=[CH:60][C:55]([F:54])=[CH:56][CH:57]=4)=[CH:66][N:65]=[C:64]4[NH:67][CH:68]=[CH:69][C:63]=34)[CH2:71][CH2:72]2)=[O:12])[CH2:9][N:8]([CH:21]([CH3:23])[CH3:22])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:15][CH:16]=1
Reactant: Fc1ccc(-c2cnc3[nH]ccc3c2N2CCNCC2)cc1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3ccc(F)cc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 39.8 %

Procedure:
(S)-3-(tert-Butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (87 mg, 0.25 mmol, see Example H), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (65 mg, 0.34 mmol), HOBt-H2O (52 mg, 0.34 mmol) and triethylamine (51 mg, 0.51 mmol) were added to 5-(4-fluorophenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.17 mmol) in DCM (10 mL). The reaction was stirred for 18 hours. The reaction was then diluted with DCM (50 mL) and washed with 1N HCl, 10% K2CO3 and brine. After drying with MgSO4 and concentration, the resulting residue was purified by chromatography (SP4, 12+M, water/ACN 80/20→0/100, 20CV) to yield (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (42 mg, 40% yield) as a solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C@@H:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16](O)=[O:17])=[O:13])[CH:9]=[CH:8][C:7]=2[N:23]2[CH2:26][C:25]([F:28])([F:27])[CH2:24]2)[CH2:3][CH2:2]1.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1>>[F:30][C:31]1([F:35])[CH2:34][N:33]([C:16]([C@@H:15]([NH:14][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:23]3[CH2:26][C:25]([F:28])([F:27])[CH2:24]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[N:11]=2)=[O:13])[C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:32]1
Reactant: FC1(F)CNC1
Reactant: CC(C)(C)[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)O
Agent: Cl
Product: CC(C)(C)[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)N1CC(F)(F)C1

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-3,3-dimethylbutanoic acid and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7)) as starting materials. MS (EI): m/e=473.0 [M+H]+.
Reaction SMILES: Cl.C(N([CH2:13][CH3:14])CCCN=C=NCC)C.[OH:15]N1C2C=CC=CC=2N=N1.Cl.[NH2:26][C@H:27]([C:30]1[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1)[CH2:28][OH:29].C(N(CC)C(C)C)(C)C>C1COCC1.O>[OH:29][CH2:28][C@H:27]([NH2:26])[C:30]1[CH:31]=[N:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=1.[C:35]1([C@H:30]2[CH2:31][C@@H:27]2[C:28]([OH:15])=[O:29])[CH:14]=[CH:13][CH:36]=[CH:33][CH:34]=1
Reactant: CCN=C=NCCCN(CC)CC
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: N[C@@H](CO)c1ccc(C(F)(F)F)nc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@H]1C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-Diethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.39 g, 2.03 mmol) and 1-hydroxybenzotriazole (0.366 g, 2.71 mmol) were added to a stirred mixture of IM46 (0.22 g, 1.36 mmol) and commercially available (R)-2-amino-2-(6-trifluoromethyl-pyridin-3-yl)-ethanol hydrochloride (Supplier Netchem Inc., Catalog No 517882) (0.494 g, 2.03 mmol) and N,N-diisopropylethylamine (0.472 ml, 2.71 mmol) in THF (20 ml). The solution was stirred at rt overnight. Water was added and the mixture was extracted with EtOAc (3×80 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered and the solvent was evaporated of in vac. The crude product was purified by silica gel chromatography (EtOAc in heptanes 10:1). Yield of Compound 22 475 mg (78%). 1H-NMR (500 MHz, DMSO) δ 8.77 (d, 1H), 8.74 (s, 1H), 8.00 (d, 1H), 7.88 (d, 1H), 7.27 (m, 2H), 7.18 (m, 1H), 7.13 (d, 2H), 5.04 (m, 2H), 3.64 (m, 2H), 2.22 (m, 1H), 2.07 (m, 1H), 1.37 (m, 1H), 1.37 (m, 1H), 1.23 (m, 1H). LC-MS (m/z) 351.1 (MH+), tR=1.51 min (method A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:30](=[O:32])[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH2:10][CH2:9]1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:30]([OH:32])[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])=[O:29])[CH2:12][CH2:13]1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(C)O)cc2F)CC1
Temperature: 25 °C

Procedure:
0.086 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone was dissolved in 1 ml ethanol and 0.26 mmol sodium borohydride was added The mixture was refluxed for 40 min., cooled to room temperature, quenched with water, acidified with HCl 1N and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified on silica eluting with heptane/ethylacetate to yield after evaporation the title compound. MS (m/e): 465.4 (M+H+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[F:53][C:54]1[CH:59]=[CH:58][C:57]([S:60]([NH2:63])(=[O:62])=[O:61])=[CH:56][CH:55]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([NH:63][S:60]([C:57]5[CH:56]=[CH:55][C:54]([F:53])=[CH:59][CH:58]=5)(=[O:61])=[O:62])=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2(C(=O)O)CCC2)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2(C(=O)NS(=O)(=O)c3ccc(F)cc3)CCC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.4 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.086 mmol) and CDI (28 mg, 0.17 mmol) in DMF (0.5 mL) was heated at 60° C. for 30 min, and then cooled to root temperature. To this solution was added a mixture of 4-fluoro-benzenesulfonamide (175 mg, 1 mmol) and NaH (40 mg, 60%, 1 mmol) in DMF (1 mL). The resulting mixture was stirred at room temperature for 10 min, purified by prep-HPLC to give the title compound as a white solid (20 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8](Cl)([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[OH-:25].[Na+]>Cl>[CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([OH:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCN(CC)CCNC(=O)C(Cl)(c1ccccc1)C1CCCCC1
Agent: Cl
Agent: [Na+]
Product: CCN(CC)CCNC(=O)C(O)(c1ccccc1)C1CCCCC1
Temperature: 55 °C

Procedure:
A mixture of N-[2-(diethylamino)ethyl]-2-chloro-2-cyclohexyl-2-phenylacetamide (6.35 g) and 1N hydrochloric acid (100 ml) was heated at 55° C. for 2 hours. After being cooled, the solution was made alkaline with 6N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated under reduced pressure. And the residue was triturated with a mixture of n-hexane and diisopropyl ether to give N-[2-(diethylamino)ethyl]-2-cyclohexyl-2-hydroxy-2-phenylacetamide (4.98 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([Br:26])[C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[Br:26][C:20]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:17]([NH:16][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:18][CH:19]=1
Reactant: COC(=O)c1c(Br)csc1N
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Product: COC(=O)c1c(Br)csc1NC(=O)CN1C(=O)CCc2ccccc21

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (447 mg, 2.18 mmol) and methyl 2-amino-4-bromothiophene-3-carboxylate (516 mg, 2.18 mmol) according to protocol A. Retention time (min)=2.528, method [1], MS (ESI) 423.0 (M+H).
Reaction SMILES: [C:1]1([C:7]2([C:11]([Cl:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][OH:20])([CH3:16])[CH3:15]>>[ClH:13].[C:1]1([C:7]2([C:11]([O:20][CH2:19][CH2:18][N:17]([CH:21]([CH3:23])[CH3:22])[CH:14]([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N(CCO)C(C)C
Reactant: O=C(Cl)C1(c2ccccc2)CCC1
Product: CC(C)N(CCOC(=O)C1(c2ccccc2)CCC1)C(C)C
Product: Cl

Procedure:
The title compound was prepared in an analogous manner to that in Example 36 by reacting 1-phenylcyclobutanecarbonyl chloride with 2-diisopropylaminoethanol at 80° C. for 17 h. The undissolved oil was separated from the reaction mixture and the toluene solution was chromatographed on silica gel using toluene-Et3N 98:2 as eluent. The yield was 1.5 g (77%); mp 110-114° C.; 1H NMR (D2O) δ 1.33 (d, 12H), 1.97 (m, 1H), 2.11 (m, 1H), 2.63 (m, 2H), 2.89 (m, 2H), 3.47 (t, 2H), 3.70 (m, 2H), 4.46 (t, 2H), 7.44 (m, 1H), 7.48 (m, 2H), 7.53 (m, 2H). Anal. (C19H29NO2 HCl) C, H, N.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[Cl:10][CH2:11][Si:12]([Cl:15])(Cl)Cl.[CH:16](O)([CH3:18])[CH3:17]>CCOCC>[Cl:15][Si:12]([CH2:11][Cl:10])([C:16]1[CH:18]=[CH:7][C:6]([F:9])=[CH:5][CH:17]=1)[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1
Reactant: ClC[Si](Cl)(Cl)Cl
Reactant: CC(C)O
Reactant: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: Fc1ccc([Si](Cl)(CCl)c2ccc(F)cc2)cc1
Reaction time: 0.08 h
Yield: 61 %

Procedure:
A suspension of 7.0 g (0.288 mol) of magnesium turnings in 50 ml of ether was stirred under nitrogen while a solution of 50.2 g (0.287 mol) of 4-bromofluorobenzene in 200 ml of ether was added dropwise at a rate that maintained gentle reflux. After another 2 hours at reflux, the mixture was chilled in ice and a solution of 12.0 ml (0.096 mol) of chloromethyltrichlorosilane in 30 ml of ether was added dropwise. The resulting mixture was refluxed for 4 hours, chilled in ice, treated with a solution of 7.5 ml of isopropanol in 20 ml of ether, stirred 5 minutes, and filtered. The filtrate was evaporated to leave a viscous oil that was stirred with hexanes to give a slurry. Filtration under nitrogen and evaporation of the filtrate left a mobile oil that was distilled to give 17.6 g (61%) of the title compound: bp 100°-140° (0.1 mm); nmr (CDCl3) 3.3 (2H, s), 7.1 (4H, t), 7.7 (4H, d of d).
Reaction SMILES: [C:1]1([O:7][CH:8]([CH2:10][O:11][CH:12]([CH2:14][OH:15])C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCCC>S(=O)(=O)(O)O.O>[C:16]([O:15][CH2:14][CH2:12][O:11][CH2:10][CH2:8][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(CO)OCC(C)Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: O
Product: O=C(OCCOCCOc1ccccc1)c1ccccc1
Temperature: 115 °C

Procedure:
In a 2-L one-neck flask equipped with a magnetic stirrer, a heating mantle, and a Dean-Stark trap connected to a nitrogen purged condenser were placed 517.5 g dipropylene glycol phenyl ether technical grade containing a total hydroxyl content of 3.0 moles, 363.3 g (2.97 mole) benzoic acid, 300 ml heptane, and 20 drops concentrated sulfuric acid. The flask was heated to 115° C. to establish a constant heptane reflux through the trap where the water of esterification was collected. The reaction was allowed to continue for a total of 48 hours, at which point the theoretical amount of water was collected. The reaction mixture was cooled to 25° C. and then filtered through a small bed of activated basic alumina to neutralize the catalyst. The filtrate was placed in a boiling flask and the heptane removed at low pressure in a Büchi rotary evaporator. The residue was flash distilled under vacuum to isolate the diethylene glycol phenyl ether benzoate boiling at 165° C. @ 0.1 mmHg. The boiling point at reduced pressure was corrected to the normal boiling by means of a computer program that fits vapor pressure data to an Antoine equation of the form log P=A−B/(T+C). The normal boiling point was calculated at approximately 440° C. A sample of the product was then tested as specified by EPA Method 24 and found to contain only 0.7 percent volatiles.