Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][N:7]([CH2:21][C:22]([CH3:27])([S:24][S:25][CH3:26])[CH3:23])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[C:13]([CH2:19][OH:20])[CH:12]=1.[CH3:28]/[CH:29]=[C:30]1\[CH2:31][C@H:32]2[N:43]([CH2:44]\1)[C:41](=[O:42])[C:40]1[C:35](=[CH:36][C:37](O)=[C:38]([O:45][CH3:46])[CH:39]=1)[NH:34][CH:33]2OC.[C:50]([O-:53])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C.O>[CH3:6][N:7]([CH2:21][C:22]([CH3:27])([S:24][S:25][CH3:26])[CH3:23])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][C:37]2[C:38]([O:53][CH3:50])=[CH:39][C:40]3[C:41](=[O:42])[N:43]4[CH2:44][C:30](=[CH:29][CH3:28])[CH2:31][C@H:32]4[CH:33]=[N:34][C:35]=3[CH:36]=2)[N:14]=[C:13]([CH2:19][O:20][C:37]2[C:38]([O:45][CH3:46])=[CH:39][C:40]3[C:41](=[O:42])[N:43]4[CH2:44][C:30](=[CH:29][CH3:28])[CH2:31][C@H:32]4[CH:33]=[N:34][C:35]=3[CH:36]=2)[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: C/C=C1\C[C@@H]2C(OC)Nc3cc(O)c(OC)cc3C(=O)N2C1
Reactant: CSSC(C)(C)CN(C)CCOc1cc(CO)nc(CO)c1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC=C1C[C@H]2C=Nc3cc(OCc4cc(OCCN(C)CC(C)(C)SSC)cc(COc5cc6c(cc5OC)C(=O)N5CC(=CC)C[C@H]5C=N6)n4)c(OC)cc3C(=O)N2C1
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
19.6 μl of methanesulphonyl chloride are added to a solution, cooled to −25° C., of 22 mg of 4-{2-[methyl(2-methyl-2-(methyldisulphanyl)propyl)amino]ethoxy}-2,6-bis(hydroxymethyl)pyridine and of 53 μl of TEA in 0.5 ml of DCM. After stirring for 30 min, the mixture is hydrolysed and the organic phase is washed with water, then dried over MgSO4 and concentrated under RP. The residue thus obtained (22 mg) is added to a solution of 20 mg of tomaymycin in 0.7 ml of DMF, and also 30 mg of K2CO3 and 12 mg of KI. The mixture is stirred at 30° C. for 2 h and then hydrolysed with 4 ml of water. The resulting precipitate is washed with water, dried under vacuum, then dissolved in DCM, concentrated under RP and purified by flash chromatography on silica (Merck SuperVarioFlash 15 g column, Si60 15-40 μm), using a gradient from 0 to 5% of MeOH in DCM. The fractions comprising the desired product are combined and concentrated under RP. 8 mg of 4-{2-[methyl(2-methyl-2-(methyldisulphanyl)propyl)amino]ethoxy}-2,6-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-5-one-8-yloxymethyl]pyridine are thus obtained. 1H NMR (500 MHz, d-chloroform): 1.28 (s, 6H); 1.76 (d, J=6.4 Hz, 6H); 2.39 (s, 3H); 2.43 (s, 3H); 2.60 (s, 2H); 2.91 (s, 2H); 2.97 (s, 4H); 3.91 (d, J=4.2 Hz, 2H); 4.00 (s, 6H); 4.09 (s, 2H); 4.27 (s, 4H); 5.27 (s, 4H); 5.61 (q, J=6.4 Hz, 2H); 6.85 (s, 2H); 7.00 (s, 2H); 7.56 (s, 2H); 7.65 (d, J=4.2 Hz, 2H). LC/MS (A): rt=0.74 min; [M+H]+: m/z 855; [M−H]−: m/z 853.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21](O)[CH:22]=2)[CH:17]=1)=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:21]3[CH:22]=[C:23]4[C:18](=[CH:19][CH:20]=3)[CH:17]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:25]=[CH:24]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: OC1CCC2(CCCC2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Yield: 61 %

Procedure:
The mixture of spiro[4.5]decan-8-ol (0.915 g, 0.00593 mol), 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (1.00 g, 0.00494 mol) and triphenylphosphine (1.56 g, 0.00593 mol) in toluene (10 mL, 0.1 mol) was heated to reflux, and diisopropyl azodicarboxylate (1.17 mL, 0.00593 mol) was added dropwise and was stirred and refluxed for 6 hours. The mixture was taken up into DCM and subjected to chromatography purification with EtOAc/hexane (0:100 to 40:60) to give product as a white solid (1.02 g, 61%). LCMS Rt=2.58 min, m/z=339.34, (M+1, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][Si](C(C)C)(C(C)C)C(C)C)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([SH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Sc1ccc2c(ccn2C(=O)OC(C)(C)C)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2cc(S)ccc21
Reaction time: 0.25 h
Yield: 33.6 %

Procedure:
A solution of the product of Example 59B (203.7 mg, 0.502 mmol) in anhydrous tetrahydrofuran (4 mL) at −20° under a nitrogen atmosphere was treated with a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.552 mL, 0.552 mmol) and the reaction stirred at −20° for 15 minutes. The reaction was diluted with ethyl acetate (50 mL) and washed with water (2×25 mL) and brine (25 mL). The organic was dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation under vacuum to provide a yellow oil. Purification by silica gel flash chromatography using 5% ethyl acetate/hexanes as eluent afforded the title compound (42 mg, 33%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].C([Li])CCC.C([CH:22]1[CH2:25][NH:24][C:23]1=[O:26])(=O)C1C=CC=CC=1>CCCCCC.C1COCC1>[C:3]1([C:1]#[C:2][CH:22]2[CH2:25][NH:24][C:23]2=[O:26])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1NCC1C(=O)c1ccccc1
Reactant: C#Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1NCC1C#Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 500 mL, three necked round bottomed flash with a stirring bar, low temperature thermometer, argon inlet and a septum was added dry THF (100 mL) and ethynylbenzene (60 mmol, 6.1 mL). This solution was cooled to -78° C. and n-butyllithium (60 mmol, 24 mL of a 2.5M solution in hexane) was added with a syringe at such a rate that the temperature was maintained below -50° C. When the addition was complete, the solution was aged 30 min then a solution of 3(R,S)-benzoylazetidinone (15 mmol, 2.87 g) in THF (50 mL) was added slowly with a syringe, maintaining the temperature below -60° C. The resulting solution was aged 1 h at -78° C. then warmed to 0°C. The reaction was quenched at 0°C. by addition of saturated, aqueous NH4Cl solution. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with H2O and brine. Drying (MgSO4), filtration and removal of the solvents in vacuo gave 3(R,S)-phenylethynylazetidinone (15-2) as a crystalline solid, which was used in Step B without further purification. ##STR139##
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7].[NH:18]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([N:18]1[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:19]1)=[O:12])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of the carboxylic acid (2.7 g, 11 mmol) from step A and tert-butyl (3S)-pyrrolidin-3-ylcarbamate (2.0 g, 11 mmol) in DMF (30 mL) cooled in an ice bath was added BOP (5 g, 11 mmol) followed by triethylamine (3 mL, 22 mmol). The mixture was allowed to warm to temperature and stirred overnight. Ethyl acetate (150 mL) was added. The resulting solution was washed with NaHCO3 and brine each three times, dried over MgSO4 and concentrated. Chromatography on silica gel eluting with EtOAc provided 4.4 g (96%) of the desired product. MS (M-Boc+H)+ 316.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11](OS(C(F)(F)F)(=O)=O)=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:26]3[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=3[F:33])[C:5]2=[O:34])[CH2:3][CH2:2]1.[NH2:35][C:36]1[CH:37]=[C:38]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=1.CN(C)C(=O)C.N1C(C)=CC=CC=1C>CO>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([NH:35][C:36]4[CH:37]=[C:38]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=4)=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:26]3[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=3[F:33])[C:5]2=[O:34])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Solvent: Cc1cccc(C)n1
Solvent: CC(=O)N(C)C
Solvent: CO
Product: Cc1c(Nc2cccc(NS(C)(=O)=O)c2)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
To trifluoromethanesulfonic acid 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 43 (30.0 g) obtained in the same manner in Example 4-2, Step 6 to be mentioned later and N-(3-aminophenyl)methanesulfonamide 44 (10.9 g) were added N,N-dimethylacetamide (60.0 ml) and 2,6-lutidine (6.82 ml), and the mixture was stirred at 130° C. for 3.5 hrs. After allowing to cool to room temperature, methanol (60 ml) was added with stirring and the mixture was stirred for 2 hrs. The crystals were collected by filtration and dried is to give N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide 45 (30.5 g, yield 96%) as colorless crystals.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[CH3:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][N:9]3[CH2:8][CH2:7][N:6]([CH3:5])[CH2:11][CH2:10]3)=[CH:21][CH:20]=2)=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Thionyl chloride (53.3 g, 448 mmol) is added over a period of 15 min to a suspension of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (70.0 g, 299 mmol) in toluene (300 ml) at 0° C. At the end of the addition, the reaction mixture is heated at 23° C. over a period of 45 min. The excess of SOCl2 is removed by co-distillation with toluene under reduced pressure at 40° C. At the end of the distillation, the resulting suspension id cooled down to 0° C. and the benzoyl chloride is filtered off, washed with toluene (2×50 ml) and dried in vacuo at 45° C. overnight. Yield: 55.0 g, 79% of theory based on the di-hydrochloride salt of the benzoylchloride, white solid. The dried benzoyl chloride (55 g) is then resuspended in toluene (100 ml). A solution of 4-methyl-3-nitroaniline (22.75 g, 145 mmol) and pyridine (34.4 g, 435 mmol) in toluene (60 ml) is added dropwise at 23° C. over a period of 15 min. The resulting orange-brown reaction mixture is heated at 45° C. and is stirred for 6 hrs. The suspension is filtrated and the filtercake is washed successively with toluene (300 ml) and acetone (350 ml), and is then suspended in water (350 ml). Aqueous NaOH (30%) is added until the pH of the suspension reaches 11 and remains stable. The suspension is further stirred for 1 h at 40° C. before being filtrated. The filtercake is washed with water (5×50 ml) and dried in vacuo to give 51.3 g of the title compound (96%) as beige crystals, (98.7% area by HPLC).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[F:13].[Cl:14]OC(C)(C)C.O.[OH-].[NH4+]>C(OCC)C.ClOC(C)(C)C>[NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])([CH3:12])[CH2:7][C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[F:13]
Reactant: CC1(C)Cc2ccc(F)c(N)c2O1
Reactant: CC(C)(C)OCl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC1(C)Cc2c(Cl)cc(F)c(N)c2O1
Reaction time: 0.33 h
Yield: 86 %

Procedure:
A solution of 39.27 g (0.217 mole) of 7-amino-2,3-dihydro-2,2-dimethyl-6-fluorobenzofuran in 750 mL of diethyl ether was cooled to -5° C to 0° C., and 23.54 g (0.217 mole) of t-butyl hypochlorite was added in a dropwise manner during a fifteen minute period. The temperature rose to 10° C., but was lowered to 0°-5° C. at which the reaction mixture stirred for 20 minutes. Gas chromatographic analysis showed that the reaction was incomplete, and an additional 4.54 g (0.042 mole) of t-butyl hypochlorite was added. The mixture was stirred at 0°-5° C. for an hour after which gas chromatographic analysis showed that the reaction was still incomplete. Therefore, an additional 1.82 g (0.017 mole) of t-butyl hypochlorite was added to the reaction mixture, and stirring was continued for one more hour. At the conclusion of this period the reaction was determined to have been completed, and it was poured into 400 mL of water. To this mixture was added 100 mL of 10% ammonium hydroxide. The aqueous and organic phases were separated. The aqueous phase was washed with diethyl ether, and this wash was combined with the organic phase. The combined material was dried over anhydrous sodium sulfate, filtered, and the solvent 20 evaporated from the filtrate under reduced pressure, leaving a dark red oil as the residue. This oil was passed through a column of silica gel, eluting with petroleum ether:diethyl ether (9:1). Product-containing fractions were combined, and the solvent was evaporated under reduced pressure, yielding 40.24 g of 7-amino-4-chloro-2,3-dihydro-2,2-dimethyl-6-fluorobenzofuran as a red oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](O[C@@H]3CCC[C@H](N4C(=O)C5C(=CC=CC=5)C4=O)C3)=[CH:7][CH:8]=2)C=N1.O[C@@H]1CCC[C@H](N2C(=O)C3C(=CC=CC=3)C2=O)C1.[CH3:46][C:47]1[C:55]([OH:56])=[CH:54][CH:53]=[C:52]2[C:48]=1[CH:49]=[N:50][NH:51]2>>[CH3:46][C:47]1[C:55]([O:56][C@H:6]2[CH2:5][CH2:4][C@H:9]([NH2:1])[CH2:8][CH2:7]2)=[CH:54][CH:53]=[C:52]2[C:48]=1[CH:49]=[N:50][NH:51]2
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@@H](Oc2ccc3[nH]ncc3c2)C1
Reactant: Cc1c(O)ccc2[nH]ncc12
Agent: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@@H](O)C1
Product: Cc1c(O[C@H]2CC[C@H](N)CC2)ccc2[nH]ncc12

Procedure:
The following compound of Example 409 was synthesized by carrying out reaction according to the method described in Example 385, except for using the cis-2-[3-(1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dione obtained in Example 326, (d) and the 4-methyl-1H-indazol-5-ol obtained in Example 402, as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C:12]3[NH:11][C:10](=[O:16])[CH2:9][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][C:10](=[O:16])[NH:11]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CCC1=C2CC(=O)N1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1CC[C@@H]1NC(=O)C[C@H]21
Yield: 80.9 %

Procedure:
A suspension of 150 g (0.7 mol) of 1,3,4,5-tetrahydro-6-methoxy-2H-benzo[e]indol-2-one in 1.5 l of methylene chloride was treated with 333 ml (2.1 mol) of triethylsilane and then slowly dropwise at 0° and while stirring with 240 ml of trifluoroacetic acid. After stirring for three hours 400 ml of 20% sodium hydroxide solution were added slowly while cooling until a pH of 14 had been reached. Subsequently, the mixture was poured into water and extracted with methylene chloride. The organic phase was washed with sodium chloride solution, dried with sodium sulphate, filtered and evaporated. The residue was treated with 500 ml of ether, whereupon the solid was filtered off and dried at 50°/20 Torr. There were obtained 123 g (81%) of rac-cis-1,3,3a, 4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one with m.p. 192°-194°. The material showed a Rf value of 0.14 in a thin-layer chromatogram (silica gel, ethyl acetate).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])([O-:3])=[O:2].CC(O)=O.[C:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:37]3[CH2:36][CH2:35][N:34]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:39][CH2:38]3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])([O-:3])=[O:2]
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])c(OCC(F)(F)F)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(c3ccc([N+](=O)[O-])c(OCC(F)(F)F)c3)CC2)CC1
Reaction time: 1 h
Yield: 54 %

Procedure:
1-{4-Nitro-3-[(2,2,2-trifluoroethyl)oxy]phenyl}-4-piperidinone (1.63 g, 5.12 mmol) was dissolved in 20 mL of acetonitrile with stirring. HOAc (0.44 mL, 7.7 mmol) was added, and 20 mL of toluene was added. TEA (1.78 mL, 12.8 mmol) was added followed by 1-BOC-piperazine (1.91 g, 10.3 mmol). Sodium triacetoxyborohydride (2.71 g, 12.8 mmol) was added. After 1 h, 40 mL of acetonitrile and 20 mL of toluene were added, and the reaction was stirred overnight. The reaction was quenched with 1N NaOH and poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers was dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded 1.35 g (54%) of the title compound of step D. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (d, J=9.5 Hz, 1H), 6.63 (dd, J=9.6, 2.3 Hz, 1H), 6.56 (d, J=2.2 Hz, 1H), 4.88 (q, J=8.7 Hz, 2H), 3.98-4.10 (m, 2H), 3.27 (s, 4H), 2.84-2.97 (m, 2H), 2.33-2.55 (m, 5H), 1.76 (br. s., 2H), 1.29-1.45 (m, 11H).
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](O)=[O:5])#[N:2].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([Cl:16])=[O:5])#[N:2]
Reactant: N#CC(=Cc1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: N#CC(=Cc1ccccc1)C(=O)Cl

Procedure:
100 ml of benzene was added to 17.3 grams of α-cyanocinnamic acid. 12 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 70° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH2:64])[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1.[F:65][C:66]1[CH:67]=[C:68]2[C:72](=[CH:73][CH:74]=1)[NH:71][CH:70]=[C:69]2[CH2:75][C:76](O)=[O:77]>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH:64][C:76](=[O:77])[CH2:75][C:69]2[C:68]3[C:72](=[CH:73][CH:74]=[C:66]([F:65])[CH:67]=3)[NH:71][CH:70]=2)[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Reactant: NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: O=C(Cc1c[nH]c2ccc(F)cc12)NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 33G and 2-(5-fluoro-1H-indol-3-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.76 (d, J=8.3 Hz, 1H), 8.47 (s, 1H), 7.63 (d, J=7.9 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.26 (dd, J=8.8, 4.6 Hz, 1H), 7.08 (d, J=12.4 Hz, 2H), 6.91-6.83 (m, 4H), 5.31 (d, J=7.9 Hz, 1H), 3.44 (s, 2H), 3.22-3.11 (m, 1H), 3.06 (dd, J=13.3, 7.0 Hz, 1H). MS (m/z) 510.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:3].[H-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17]I>CN(C)C=O.CCCCCC.C(OCC)C>[Cl:14][CH2:15][CH2:16][CH2:17][O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:2](=[O:3])[CH3:1])=[CH:10][CH:9]=1
Reactant: ClCCCI
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc(OCCCCl)cc1
Reaction time: 0.05 h

Procedure:
A 4.50 g portion of p-hydroxyphenylacetone, prepared above, was dissolved in 80 mL of anhydrous dimethylformamide under a dry nitrogen atmosphere. With stirring 1.26 g of sodium hydride (as a 60% dispersion in oil) was added to the solution. After 3 minutes, 9.40 g of 1-chloro-3-iodopropane was quickly added. After stirring for approximately 18 hours, the reactionwas diluted with 300 mL hexane and 100 mL diethyl ether. The resulting mixture was washed with distilled water, 5% sodium hydroxide solution, andbrine. The remaining organic phase was dried and evaporated to dryness in vacuo. The yellow oil was purified by column chromatography over silica gel, using 22% ethyl acetate and 78% hexane. Appropriate fractions were pooled and solvents removed in vacuo to yield 3.06 g of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CCOC(C)=O.O.C(Cl)(Cl)[Cl:31]>CN(C=O)C>[CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][Cl:31])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1cccc(-c2ccc(CO)cc2)c1
Reactant: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1cccc(-c2ccc(CCl)cc2)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product of step 2 (419 mg, 1.3 mmol) in CHCl3 (1 mL) was added a solution of POCL3 in DMF (0.39 mL, 3.6 mM) at 0° C. The mixture was stirred at 0° C. for 1.5 h. The reaction mixture was partionned between EtOAc and H2O. The organic phase was separated, dried over NaSO4, filtered and evaporated under reduced pressure. The title compound was obtained after flash chromatography (338 mg, 77%). Step 4: [4′-(2-benzotriazol-1-yl-3-4-[(di-tert-butoxy-phosphoryl)-difluoro-methyl]-phenyl}-2-phenyl-propyl)-biphenyl-3-yl]-phosphonic Acid Diethyl Ester