Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH2:11][C@H:12]2[N:15]([C:16](=P(CCCC)(CCCC)CCCC)[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[C:14](=[O:36])[C@@H:13]2[C@H:37]([OH:39])[CH3:38])=O)=[N:4]1)[CH3:2].C1(C=CC(O)=CC=1)O.C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:39][C@@H:37]([C@H:13]1[C:14](=[O:36])[N:15]2[C:16]([C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])=[C:9]([C:5]3[CH:6]=[C:7]([CH3:8])[N:3]([CH2:1][CH3:2])[N:4]=3)[CH2:11][C@H:12]12)[CH3:38]
Reactant: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O)[C@H]1CC(=O)c1cc(C)n(CC)n1)=P(CCCC)(CCCC)CCCC
Agent: Oc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1=C(c2cc(C)n(CC)n2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 64 h

Procedure:
Allyl 2-{(3S,4R)-4-[(1-ethyl-5-methylpyrazol-3-yl)carbonylmethyl]-3-[(R)-1-hydroxyethyl]-2-oxoazetidinyl}-2-(tri-n-butylphosphoranylidene)acetate (2.6), in toluene (120 ml) containing hydroquinone (20 mg) was heated under reflux in an argon atmosphere for 4 h, allowed to stand for 64 h, and then heated under reflux for a further 2 h. The mixture was cooled and then loaded onto a column (4.5×12 cm) of silica gel (particle size 0.040-0.063 mm), elutin with ethyl acetate/hexane mixtures; 1:1; 6:4; 7:3; 8:2; 9:1 (250 ml of each), followed by ethyl acetate. This Dave the carbapenem (436 mg); υmax(CH2Cl2) 3604, 2976, 1774, 1716, 1600, 1546, 1311, 1189 cm−1; λmax(EtOH)/nm 321.5 (ε/dm3 mol−1 cm−1 14,856), δ(CDCl3) 1.36 (d, J 6.3 Hz), 1.39 (t, J7.3 Hz) (together 5H), 1.80 (1H, d, J 5.0 Hz), 2.28 (3H,s), 3.19 (1H, dd J 2.7 & 6.7 Hz), 3.28 (1H, dd, J 9.0 & 18.6 Hz), 3.60 (1H, dd, J 9.9 & 18.5 Hz), 4.08 (2H, q, J 7.3 Hz), 4.16-4.30 (2H, m), 4.68-4.90 (2H, m), 5.27 (1H, m, approx d, J ca. 12 Hz), 5.46 (m, approx d, J ca. 17 Hz), 5.93-6.08 (1H, m), 7.00 (1H, s) ppm; [Found m/z 345.1693. C18H23N3O4 requires m/z 345.1689].
Reaction SMILES: FC(F)(F)C(O[I:6](OC(=O)C(F)(F)F)[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=O.FC(F)(F)C(O)=O.[F:30][C:31]([F:37])([F:36])[S:32]([OH:35])(=[O:34])=[O:33].[CH:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[F:30][C:31]([F:37])([F:36])[S:32]([O-:35])(=[O:34])=[O:33].[F:13][C:7]([I+:6][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([F:12])[C:8]([F:9])([F:10])[F:11]
Reactant: c1ccccc1
Reactant: O=C(OI(OC(=O)C(F)(F)F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C(F)(F)[I+]c1ccccc1
Product: O=S(=O)([O-])C(F)(F)F
Yield: 55 %

Procedure:
To a mixture of 6.05 g of di(trifluoroacetoxy)iodopentafluoroethane and 45 ml of trifluoroacetic acid was added 1.1 ml of trifluoromethanesulfonic acid while cooling in an ice bath and stirring, and thereafter 1.2 ml of benzene was added dropwise to the mixture. After completion of the addition, the mixture was stirred for 4.5 hours and the solvent was distilled off to obtain a crystalline solid which was then recrystallized from chloroform to obtain 3.32 g (55% yield) of pentafluoroethylphenyliodonium trifluoromethanesulfonate as colorless flake crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.B(OC)(OC)[O:17]C.OO>O1CCCC1.CCCCCC.O>[OH:17][CH2:1][C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COB(OC)OC
Reactant: Cc1cccnc1N(C)C
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)c1ncccc1CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 18.8 %

Procedure:
To a cold (ca. −78° C.) solution of 2.9 g (21 mmole) of 3-methyl-2-(N,N-dimethylamino)pyridine in 35 ml of tetrahydrofuran was added dropwise 15 ml (23 mmole) of 1.55 M butyllithium in hexane. The mixture was stirred at 0° C. for four hours and then recooled to ca. −78° C. Trimethyl borate (2.65 ml, ca. 23 mmole) was added dropwise and the mixture was stirred at 0° C. After one hour 2.9 ml of 30% hydrogen peroxide was added and the mixture was stirred at 25° C. After another hour, the reaction mixture was poured into water and extracted with several portions of diethyl ether. The combined ether extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel (using ethanol-toluene as eluent) yielded 600 mg of 3-hydroxymethyl-2-(N,N-dimethylamino)pyridine, as confirmed by the nmr and infrared spectra. Using the method of Example 79 with 3-hydroxymethyl-2-(N,N-dimethylamino) pyridinamine instead of 3-hydroxymethyl-2-pyridinamine yielded the title compound, which was used in subsequent reactions without further purification. Structure assignment was supported by the nmr and infrared spectra.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19]>[Cu]I.O1CCOCC1>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[CH:9]=1
Reactant: O=C1CCCN1
Reactant: Ic1cccnc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1CCCN1c1cccnc1
Temperature: 125 °C
Yield: 93.7 %

Procedure:
In a sealed flask, a stirred mixture of CuI (37 mg, ˜0.2 mmol) and potassium carbonate (2.70 g, 19.5 mmol) was degassed for 15 min. N,N,N′,N1-tetramethylethylenediamine (146 μL, ˜1.0 mmol), 3-iodopyridine (2.00 g, 9.8 mmol), 2-pyrrolidinone (˜1 g, 11.7 mmol) and 1,4-dioxane (10 mL) were added, respectively (A. Klapars. J. C. Antilla. X. Huang. S. L. Buchwald J. Am. Chem. Soc. 2001, 123, 7727-7729). The flow of nitrogen was removed, and the reaction mixture was then heated at 125° C. for 18 h. After cooling to room temperature the reaction mixture was filtered, rinsed with ethyl acetate, and concentrated. The crude product was purified by flash column chromatography (eluents MeOH/CH2Cl2: 2/98 to 5/95) to afford title compound 349 (1.49 g, 94% yield) as a yellow oily liquid. MS (m/z): 163.1 (M+H)+..
Reaction SMILES: C(OC(=O)NC1C=CC=[C:10]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([Cl:39])[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)C=1)(C)(C)C.C(Cl)(=O)C(Cl)=O.[CH:48]([O:51]CCN1C=CC(N)=N1)([CH3:50])[CH3:49].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Cl:39][C:31]1[CH:30]=[C:29]([C@@H:22]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:21]([NH:20][C:17]2[CH:18]=[CH:19][N:15]([CH2:14][CH2:10][O:51][CH:48]([CH3:50])[CH3:49])[N:16]=2)=[O:40])[CH:34]=[CH:33][C:32]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CC(C)OCCn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 120 mg, 0.36 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 210 μL, 0.42 mmol) which produced gas evolution and it was then allowed to warm to 25° C. and stirred 1 h at 25° C. After this time, the reaction was concentrated in vacuo to ⅓ of the original volume. In a separate flask, a solution of 1-(2-isopropoxy-ethyl)-1H-pyrazol-3-ylamine (67 mg, 0.40 mmol), 2,6-lutidine (63 μL, 0.54 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride, diluted with another portion of methylene chloride (2 mL), dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction mixture was diluted with methylene chloride (10 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 40% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-isopropoxy-ethyl)-1H-pyrazol-3-yl]-propionamide (168 mg, 96%) as a white foam: [α]28589=+10.0° (c=0.43, methylene chloride); ES-HRMS m/e calcd for C23H32N3O4SCl (M+H)+ 482.1875, observed 482.1874; 1H NMR (300 MHz, DMSO-d6) δ 1.01 (d, J=6.1 Hz, 6H, 2×CH3), 1.11 (m, 2H, CH2), 1.38-1.80 (m, 8H, 4×CH2), 2.09 (m, 1H, CH), 3.34 (s, 3 H, SO2CH3), 3.47 (m, 1H, OCH), 3.64 (t, J=5.5 Hz, 2H, OCH2), 3.91 (m, 1H, ArCHCO), 4.08 (t, J=5.5 Hz, 2H, NCH2), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.54 (d, J=2.2 Hz, 1H, Ar), 7.59 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 7.70 (d, Jm=1.6 Hz, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.Cl[C:21]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=[C:23]([S:32][CH3:33])[N:22]=1>O1CCCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([NH:10][C:25]2[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][N:22]=[C:23]([S:32][CH3:33])[N:24]=2)=[N:12]1
Reactant: Nc1n[nH]c2ccccc12
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1Nc1n[nH]c2ccccc12
Temperature: 25 °C
Yield: 86.8 %

Procedure:
N,N-diisopropylethylamine (19.4 g) and 3-aminoindazole (6.66 g) were added to a tetrahydrofuran (0.2 L) solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (12.22 g), and stirred with heating under reflux for 15 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, water (50 mL) was added to the residue and the precipitated solid was collected through filtration, washed with distilled water and ethyl acetate in that order, and dried to give the title compound as a white solid (14.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:10][C:11]([NH:14][NH:15][C:16](=O)[CH2:17][C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)=[N:12][CH:13]=1.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:10][C:11]2[N:12]([C:16]([CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)=[N:15][N:14]=2)[CH:13]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)nc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Solvent: CCO
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)cn23)cn1
Temperature: 25 °C

Procedure:
A solution of N′-(5-(2-chlorophenyl)-4-(4-chlorophenyl)pyridin-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetohydrazide (40 mg, 0.075 mmol) and acetic acid (0.25 mL) in ethanol (0.5 mL) was heated in a microwave oven at 180° C. for 45 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was taken into EtOAc, and the solution was washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-70%) in hexanes to obtain the product with about 85% purity as an oil. The product was further purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 50% to 100% B, 10 min gradient, 100% B hold for 4 min, (A=90% H2O, 10% MeOH, 0.1% TFA and B=10% H2O, 90% MeOH, 0.1% TFA); Flow rate at 20 mL/min, UV detection at 220 nm) to yield the desired product, which was taken into EtOAc, washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The residue was lyophilized in acetonitrile to afford 9 mg (24% yield, 99% pure) of the title compound as a white powder. HPLC/MS (method A): retention time=3.88 min, [M+H]+=499.0.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][OH:25])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=2[Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:33]2[CH:42]=[CH:41][CH:40]=[C:35]([C:36]([O:38][CH3:39])=[O:37])[CH:34]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[C:12]=2[Cl:21])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reaction time: 18 h
Yield: 26 %

Procedure:
A solution of N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-hydroxypropylamine (186 mg, 0.42 mmole) and methyl 3-hydroxybenzoate (63 mg, 0.42 mmole) in 15 mL of THF was treated with Ph3P (110 mg, 0.42 mmole) and diisopropylazodicarboxylate (93 mg, 0.46 mmole). The reaction was stirred for 18 hours, diluted with H2O, and extracted with Et2O. The extracts were washed with H2O, dried, and the solvent evaporated. The residue was chromatographed on a silica gel column, and elution with 10% EtOAc in hexane gave the titled product, 64 mg (26% yield). MS (ESI) 583 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][N:27]([CH3:36])[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]1[CH2:29][CH2:28][N:27]([CH3:26])[CH3:36])=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CN(C)CCC1CCCCN1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCCC2CCN(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(2-dimethylaminoethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.01 minutes; C26H31Cl2N5O2 (516.47); mass spectrum: (M−H)−=515/517 (chlorine isotope).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:20]1>CCCCCC.CS(C)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:33][CH:32]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (88 mg, 2.2 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (10 ml). The obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (0.40 g, 2 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-(4-methoxyphenethyl)homopiperidine (0.59 g, 2.2 mmol) in dimethyl sulfoxide (5 ml) was added dropwise into the obtained solution, and they were stirred at 50° C. for 2 hours. The reaction liquid was distributed in saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (6:1) and then with hexane and ethyl acetate (3:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(4-methoxyphenethyl) piperidine-2-ylmethyl] dibenzo[b,e][1,4]oxazepine in the form of a light yellow solid (0.63 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=3[C:17]3[C:25]4[C:20](=[CH:21][C:22]([N+:26]([O-])=O)=[CH:23][CH:24]=4)[N:19]([CH3:29])[CH:18]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.O.NN>C(O)C.O1CCCC1.[Pd]>[NH2:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([C:16]3[C:15](=[O:30])[NH:14][C:13](=[O:31])[C:12]=3[C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[CH:7]=3)=[CH:18][N:19]2[CH3:29])=[CH:24][CH:23]=1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccc(F)cc21
Agent: [Pd]
Agent: Cl
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cn1cc(C2=C(c3cn(C)c4cc(F)ccc34)C(=O)NC2=O)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (2.39 mmole) of 3-(6-fluoro-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione in 20 ml of ethanol and 10 mL of tetrahydrofuran was added 0.55 g of 10% Pd/C and 0.54 mL of 5% hydrochloric acid. The mixture was cooled in an ice bath, and 0.54 mL (14.34 mmole) of hydrazine hydrate (85%) was added dropwise over 5 min. The reaction mixture was allowed to warm to room temp as it was stirred for two hours. The catalyst was removed by filtration over Celite. The filtrate was evaporated and the residue was crystallized from ethyl acetate/tetrahydrofuran/hexane to give 708 mg (76%) of )3-(6-amino-1-methyl-1H-indol-3-yl)-4-(6-fluoro-1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Product: O=C(Cc1cccc(Cl)c1)Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 68B and 2-(3-chlorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.87-11.90 (m, 1H), 8.56 (d, J=8.1 Hz, 1H), 8.38 (dd, J=7.9, 1.3 Hz, 1H), 8.09-8.14 (m, 1H), 7.99-8.03 (m, 3H), 7.78-7.83 (m, 1H), 7.66-7.70 (m, 2H), 7.34-7.41 (m, 3H), 7.24-7.27 (m, 1H), 3.71 (s, 2H); MS (APCI+) M/Z 454 (M+H)+.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][O:28][CH:29]([O:35][CH3:36])[CH2:30][C:31](OC)=[O:32]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH:29]([O:35][CH3:36])[O:28][CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: COC(=O)CC(OC)OC
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: COC(CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)OC

Procedure:
The title compound, white solid (71 mg, 64%), MS (ISP) m/z=443.4 [(M+H)+], mp 148° C., was prepared in accordance with the general method of example 46 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and methyl 3,3-dimethoxy-propanoate.
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:9]1[CH:14]=[C:13]([N:4]2[CH2:5][CH2:6][C:2]([F:7])([F:1])[CH2:3]2)[N:12]=[CH:11][N:10]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: FC1(F)CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: FC1(F)CCN(c2cc(Cl)ncn2)C1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A solution of 3,3-difluoropyrrolidine (215 mg, 1.5 mmol), 4,6-dichloro-pyrimidine (223 mg, 1.5 mmol) and DIPEA (194 mg, 1.5 mmol) in 1,4-dioxane (3.0 mL) was heated at 100° C. for 16 hours. The reaction was cooled to room temperature and then partitioned between EtOAc and water. The organic phase was separated and washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue was separated with flash chromatography (25+S Biotage, 20% EtOAc/pentane) to afford 160 mg (48.6%) of 4-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyrimidine as a solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]1([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>FC(F)(F)C(O)=O>[C:15]1([CH:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCCCCCCCCCS
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCCCCCCCCSC(c1ccccc1)c1ccccc1
Yield: 44 %

Procedure:
A solution of 11-mercaptoundecanoic acid (300 mg, 1.3 mmol) and diphenylmethanol (255 mg, 1.3 mmol) in trifluoroacetic acid was stirred at RT, under nitrogen for 30 min. Trifluoroacetic acid was evaporated under high vacuum, the residue dissolved in ether (20 ml), washed with water (3×20 ml), dried and evaporated. The residue was purified by chromatography (light pet—ethyl acetate, 80:20-50:50) on silica to give the desired product (220 mg, 42%), m.p. (Found C, 74.55; H, 8.77. C24H34O2S requires C, 74.96; H, 8.39) ms (EI) 384.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.C(OP([CH2:24][C:25]1[C:26]2[C:31]([C:32]([CH2:39]P(OCC)(OCC)=O)=[C:33]3[C:38]=1[CH:37]=[CH:36][CH:35]=[CH:34]3)=[CH:30][CH:29]=[CH:28][CH:27]=2)(OCC)=O)C.[C:48](O[K])([CH3:51])([CH3:50])C.S(=O)(=O)(O)O>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:24][C:25]2[C:26]3[C:27]([C:28]([CH:29]=[C:30]([C:31]4[CH:10]=[CH:9][CH:8]=[CH:39][CH:32]=4)[C:50]4[CH:48]=[CH:51][CH:3]=[C:2]([Br:1])[CH:15]=4)=[C:37]4[C:38]=2[CH:33]=[CH:34][CH:35]=[CH:36]4)=[CH:13][CH:4]=[CH:5][CH:7]=3)[CH:13]=[CH:14][CH:15]=1
Reactant: CCOP(=O)(Cc1c2ccccc2c(CP(=O)(OCC)OCC)c2ccccc12)OCC
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Reactant: CC(C)(C)O[K]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: Brc1cccc(C(=Cc2c3ccccc3c(C=C(c3ccccc3)c3cccc(Br)c3)c3ccccc23)c2ccccc2)c1
Reaction time: 3.5 h

Procedure:
Under an inert atmosphere, 3-bromobenzophenone (3.917 g, 15 mmol), and 9,10-bis(diethylphosphonomethyl)anthracene (2.942 g, 6.17 mmol) are dissolved in tetrahydrofuran (40 g). At room temperature, tetrahydrofuran (16.38 g) solution of tert-butoxy potassium (2.070 g, 18.45 mmol) is added dropwise for 5 minutes, and successively stirred for 3.5 hours. The reaction mixture is charged into water (200 ml) and neutralized with 5% sulfuric acid. After neutralization, a hydrophobic solvent is added and the organic layer is partitioned. The organic layer is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the resultant raw product is purified by silica gel chromatography or recrystallization to give a desired product.