Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[O:2](CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:3]1C=CC=C[CH:4]=1.Cl.[OH:26][C@H:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47](C(C)(C)C)=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([O:2][CH2:3][CH3:4])=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: CCOc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 358 (M−15, 0.1), 253 (17), 252 (100), 163 (6), 121 (21), 114 (8), 108 (8).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([N+:11]([O-])=O)=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1>C1COCC1.[Zn]>[NH2:11][C:5]1[C:4]([O:14][CH3:15])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[CH2:8][C:9]#[N:10]
Reactant: COc1cc(Cl)cc(CC#N)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: COc1cc(Cl)cc(CC#N)c1N
Yield: 96.5 %

Procedure:
In accordance with Example No. 3, 22.7 g of (5-chloro-3-methoxy-2-nitrophenyl)acetonitrile dissolved in a 100 ml/70 ml mixture of THF/37% HCl were reduced with 26 g of zinc powder. 19 g of (2-amino-5-chloro-3-methoxyphenyl)acetonitrile were obtained (yield=97%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][NH:10][C:9]3([Br:23])[C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[O:16])=[N:2]1.[C:24]1([C:30](Cl)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O>[Br:23][C:9]1([C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[O:16])[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:3]3[N:4]=[CH:5][N:1]([C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:2]=3)[CH:7]=2)[NH:11][NH:10]1
Reactant: O=C(C1CCCCO1)C1(Br)NNc2ccc(-c3nc[nH]n3)cc21
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C1CCCCO1)C1(Br)NNc2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc21
Temperature: 80 °C

Procedure:
To a solution of 2-(5-(1H-1,2,4-triazol-3-yl)-3-bromo-1H-indazoyl)perhydro-2H-pyran in 60 mL in dimethyl formamide, was added triphenylmethyl chloride (3.48 g, 12.5 mmol), and triethyl amine (4.64 mL, 33.32 mmol). The reaction mixture was heated to 80° C. for 12 hours. The solvent was removed under reduced pressure and the crude reaction mixture was partitioned between water and ethyl acetate. The oil resulting from evaporation of the extracts was purified by column chromatography (SiO2, 25% ethyl acetate in hexanes (2.90 g, 61% over 4 steps): 1H NMR (CDCl3) δ 8.3 (s, 1H), 8.2 (d, 1H), 7.9 (s, 1H), 7.5 (d, 1H), 7.4-8.1 (m, 15H), 5.68 (dd, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 2.5 (m, 1H), 2.1 (m, 2H), 1.7 (m, 3H); ES-MS (m/z) 592 [M+2]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[Br:13]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:13][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Cc1ccc(CO)cc1
Solvent: CC#N
Product: CC(=O)Cc1ccc(CBr)cc1

Procedure:
A mixture of 1-(4-hydroxymethylphenyl)propan-2-one (3.15 g) and dibromotriphenylphosphorane (8.11 g) was refluxed in acetonitrile (50 ml) for 1 hour. The solvent was removed and the residue chromatographed on silica. Elution with ether gave 1-(4-bromomethylphenyl)propan-2-one, 3.4 g. τ(CDCl3) 7.92 (3H, s), 6.4 (2H, s), 5.6 (2H, s), 2.9 (2H, d, J=8 Hz), 2.65 (2H, d, J=8 Hz). This was ketalised in an analogous manner to that described in Description 2 to give the title compound, 3.73 g. τ(CDCl3) 8.7 (3H, s), 7.1 (2H, s), 5.9-6.3 (4H, m), 5.54 (2H, s), 2.75 (4H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]>C(O)C.[Pd]>[NH2:18][C:17]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(N)c(OC)c1)OCC
Reaction time: 16 h

Procedure:
A solution of diethyl (3-methoxy-4-nitrobenzyl)phosphonate (Compound 1G, 1.07 g, 3.54 mmol) in ethanol (10.0 mL) was charged with palladium 10% wt on activated carbon (0.38 g). The reaction mixture was evacuated and purged with hydrogen gas (3×) and allowed to stir under hydrogen for 16 h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to afford the title compound as 0.78 g of an orange oil (80%). This material was used in successive reactions without further purification. MS (ESI): m/z 274.01 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH2:21][CH2:22][O:23][CH3:24])[C:19]3[C:25]([O:32][CH3:33])=[CH:26][C:27]([CH:29]([OH:31])[CH3:30])=[CH:28][C:18]=3[N:17]=2)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].C(N(CC)CC)C>ClCCl.CS(C)=O>[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH2:21][CH2:22][O:23][CH3:24])[C:19]3[C:25]([O:32][CH3:33])=[CH:26][C:27]([C:29](=[O:31])[CH3:30])=[CH:28][C:18]=3[N:17]=2)=[CH:12][CH:11]=1)([CH3:9])[CH3:8]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(C)O)cc(OC)c21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(C)=O)cc(OC)c21
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 0.17 ml oxalylchloride in 4 ml dichloromethane, 0.285 ml DMSO (in 0.8 ml dichloromethane is slowly added at −60° C. This mixture is stirred under argon at −60° C. for 0.5 h. Then 180 mg (0.488 mmol) 1-[2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-ethanol (in 2 ml dichloromethane) are added and stirring is continued at −60° C. for 1 h. 1 ml triethylamine is added and the reaction mixture is allowed to warm to room temperature, poured on water and extracted (3×) with dichloromethane. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 163 mg of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:14]([CH2:26][CH3:27])[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1)[CH3:13].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[CH2:26]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:9](=[O:11])[C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:22][CH:23]=1)[CH3:27]
Reactant: CCN(CC)CCOc1ccc(CN)cc1
Reactant: O=C(O)C#Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(CNC(=O)C#Cc2ccccc2)cc1

Procedure:
A solution of 0.29 g (2 mmol) of phenylpropynoic acid, 0.44 g (2 mmol) of [4-(2-diethylaminoethoxy)phenyl]methylamine, 0.7 g (2.2 mmol) of TBTU, 0.29 g (2.2 mmol) of HOBT and 0.51 mL (3 mmol) of Hünig base in 30 mL of THF and 2 mL of DMF is stirred for 14 hours at ambient temperature. The reaction mixture is evaporated down. The purification is carried out by column chromatography on silica gel (dichloromethane/methanol (80:20)). Yield: 130 mg (18.5% of theory); C22H26N2O2 (M=350.46); calc.: molecular ion peak (M+H)+: 351; found: molecular ion peak (M+H)+: 351; Rf value: 0.39 (silica gel, dichloromethane/methanol (80:20)).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][CH:14]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[N:26][O:27][CH3:28])[CH2:21][CH2:20]3)=O)=[CH:8][CH:7]=1.C([O-])(=O)C.[NH4+:41]>C(O)(=O)C>[CH3:28][O:27][N:26]=[C:22]1[C:23]2[C:19](=[CH:18][C:17]([C:15]3[NH:41][C:12]([C:9]4[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:36])=[CH:11][CH:10]=4)=[CH:13][C:14]=3[C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:21]1
Reactant: [NH4+]
Reactant: CON=C1CCc2cc(C(=O)C(CC(=O)c3ccc(OCCN(C)C)cc3)c3ccncc3)ccc21
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CON=C1CCc2cc(-c3[nH]c(-c4ccc(OCCN(C)C)cc4)cc3-c3ccncc3)ccc21
Temperature: 25 °C
Yield: 100.7 %

Procedure:
A solution of the product of Step 4 (0.45 g, 1 mmol) and ammonium acetate (0.77 g, 10 mmol) in glacial acetic acid (15 ml) was heated under reflux for 3 hours. After cooling to room temperature the reaction mixture was concentrated in vacuo and saturated sodium hydrogen carbonate solution was added. The mixture was extracted with chloroform and the organic phase washed with water and brine, dried and concentrated in vacuo to afford the title compound (0.47 g, 100%); MS(ES+) m/e 467 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[F:11].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[F:11]
Reactant: CC(O)c1ccc(Br)c(F)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 1-(4-bromo-3-fluorophenyl)ethanol oil (from Step 1) in DCM (100 mL) was added pyridinium dichromate (8.96 g, 23.82 mmol). The mixture was stirred overnight at room temperature. To the mixture was added celite, the reaction mixture was filtered through a celite pad and rinsed several times with DCM. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate] providing 1-(4-bromo-3-fluorophenyl)ethanone (3.08 g) as a white solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>C1COCC1>[CH3:10][S:11]([O:3][C@@H:2]([CH2:4][C:5]([OH:7])=[O:6])[C:1]([OH:9])=[O:8])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(O)C[C@H](O)C(=O)O
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H](CC(=O)O)C(=O)O
Yield: 99 %

Procedure:
A solution of 8.04 g (0.060 mol) of (S)-malic acid and 9.2 mL (0.120 mol) of methanesulphonyl chloride in 60.0 mL of THF was refluxed for 10 hours. After cooling, the solution was vacuum evaporated to dryness to obtain 12.60 g (99%) of the title compound. H-NMR in DMSO-d6: δ 2.41 (3H, s, CH3SO3), 2.90 (2H, m, CH2), 5.47 (1H, t, CHOSO2).
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([O:28]CC)=[O:27])[CH2:21]2)=[O:19])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CCO>O.O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([OH:28])=[O:27])[CH2:21]2)=[O:19])[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A solution of LiOH (0.32 g) in H2O (20 ml) was added to a solution of ethyl (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylate (4.46 g) in tetrahydrofuran (20 ml)-EtOH (20 ml) at 0° C. The reaction mixture was stirred for 3 hours at the same condition, and the solvent was evaporated in vacuo. The residue was resolved in ethyl acetate-water, and acidified with 10% aq. KHSO4. The whole was washed with water, brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was recrystallized from diethyl ether to give (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylic acid as a white solid (3.07 g).
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[S:19])=[C:6]([C:9]3[O:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:7][S:8][C@H:3]12.[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59](/[C:61](=[N:65]/[O:66][CH3:67])/[C:62](O)=[O:63])[N:60]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl.O>[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59](/[C:61](=[N:65]/[O:66][CH3:67])/[C:62]([NH:1][CH:2]2[C:34](=[O:35])[N:4]3[C:5]([C:18]([O:20][CH:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[S:19])=[C:6]([C:9]4[O:10][C:11]5[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=5[N:13]=4)[CH2:7][S:8][C@H:3]23)=[O:63])[N:60]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4o3)CS[C@H]12
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4o3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
A 207 mg portion of diphenylmethyl 7-amino-3-(benzoxazol-2-yl)thio-3-cephem-4-carboxylate was dissolved in 4 ml of methylene chloride and the resulting solution was cooled to -20° C. To this were added 213 mg of (Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoaceticacid, 0.13 ml of pyridine and 45 μl of phosphorous oxychloride, followed by 20 minutes of stirring at the same temperature. The resulting solution was mixed with 4 ml of water, stirred for additional 1 hour at room temperature, and then subjected to organic layer separation. After drying the resulting organic layer on anhydrous magnesium sulfate and distilling off the solvent under a reduced pressure, the residue was purified by a column chromatography (30 g silica gel, toluene:ethyl acetate =3:1) to obtain 272 mg of the title compound (yield, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[CH:59][CH:58]=1>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:56][C:57]2[CH:58]=[CH:59][C:60]([CH2:63][CH2:64][CH2:65][C:66]([O:68][CH3:69])=[O:67])=[CH:61][CH:62]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCc1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Reaction time: 2 h

Procedure:
A solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.9 mg, 0.130 mmol) in dichloromethane (3 ml) were added DIPEA (66.8 mg, 0.514 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (78.2 mg, 0.324 mmol). The mixture was stirred for 20 mins under argon before methyl 4-(4-aminophenyl)butanoate (24.7 mg, 0.128 mmol) was added. After 2 hrs, the reaction mixture was diluted with dichloromethane and extracted with water then with sat. NaHCO3, water, and sat. NaCl. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral methyl 4-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)phenyl)butanoate (79.2 mg., 96%) as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 642.2. found: 642.1.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][C:12](=[O:17])[CH2:13]2)=[O:7])(C)(C)C.Br[C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][CH:24]=1>>[N+:25]([C:22]1[N:23]=[CH:24][C:19]([N:11]2[C:12](=[O:17])[CH2:13][CH:14]3[N:8]([C:6]([OH:5])=[O:7])[CH:9]([CH2:16][CH2:15]3)[CH2:10]2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)NC2
Product: O=C1CC2CCC(CN1c1ccc([N+](=O)[O-])nc1)N2C(=O)O
Yield: 58 %

Procedure:
Following general N—C coupling procedure 1, 4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester, 1.86 g (7.72 mmoles) was combined with 5-Bromo-2-nitro-pyridine, 1.51 g (7.42 mmoles), which after recrystallized from CH2Cl2-Heptanes gave 3-(6-Nitro-pyridin-3-yl)-4-oxo-3,9-diaza bicyclo[4.2.1]nonane-9-carboxylic acid tea-butyl ester, (1.59 g) in 58% yield. TLC Rf ˜0.45 (75% Ethyl acetate-Heptane)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)=[C:15]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][C:42]#[N:43])=[CH:34][CH:33]=3)[S:14][C:13]=2[CH:44]=1)C1C=CC=CC=1.[NH4+].[OH-]>C(Cl)(Cl)Cl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:23]=3)=[C:15]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][C:42]#[N:43])=[CH:36][CH:37]=3)[S:14][C:13]=2[CH:44]=1
Reactant: N#CCCCOc1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: N#CCCCOc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Yield: 71 %

Procedure:
By essentially following the proceedure described in Example 8, Part F, the title compound was prepared as an oil starting from 6-benzyloxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]-2-[4-(3-cyanopropyloxy)phenyl]benzo[b]thiophene (Part E) in 71% yield following radial chromatography (SiO2; 1.0% in CHCl3 sat'd with NH4OH).
Reaction SMILES: I[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[CH2:16]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH2:18]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1)[CH:17]=[CH2:16]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: [O-][n+]1nc(I)nc2cc3c(cc21)CCC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: C=CCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 85.1 %

Procedure:
Pd(PPh3)4 (0.89 g, 0.77 mmol) was added to a stirred, degassed solution of iodide 66 (4.80 g, 15.3 mmol) and allyltributyltin (5.2 mL, 16.9 mmol) in DME (100 mL), and the mixture stirred at reflux temperature for 8 h. The solvent was evaporated and the residue purified by chromatography, eluting with 10% EtOAc/pet. ether, to give 1-oxide 69 (2.96 g, 85%) as white solid: mp (EtOAc/pet. ether) 60-61° C.; 1H NMR δ 8.26 (s, 1H, H-9), 7.77 (s, 1H, H-5), 6.12-6.23 (m, 1H, H-2′), 5.29 (dd, J=17.1, 1.5 Hz, 1H, H-3′), 5.22 (dd, J=10.1, 1.3 Hz, 1H, H-3′), 3.77 (br d, J=6.9 Hz, 2H, H-1′), 3.08-3.14 (m, 4H, H-6, H-8), 2.21 (p, J=7.5 Hz, 2H, H-7); 13C NMR δ 164.1, 154.8, 149.0, 147.5, 133.0, 132.3, 122.7, 118.2, 114.3, 41.6, 33.2, 32.8, 25.7. Anal. calcd for C13H13N3O: C, 68.7; H, 5.8; N, 18.5. Found: C, 68.7; H, 5.9; N, 18.7%.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])([OH:4])(=[O:3])=O.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH:21]([CH3:23])[CH3:22]>CC(N(C)C)=O>[CH3:20][CH:21]([CH3:23])[CH2:22][S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:3])=[O:4]
Reactant: CC(C)CI
Reactant: O=C(O)c1cccc(S(=O)(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)CS(=O)(=O)c1cccc(C(=O)O)c1

Procedure:
To a suspension of 3-sulfo-benzoic acid (1 g) and potassium carbonate (1.2 g) in dimethylacetamide (10 ml) was added iso-butyl iodide (0.65 ml). The mixture was heated by microwaves (600W) at 150° C. for 15 minutes. The reaction mixture was partitioned between water (100 ml) and ethyl acetate (100 ml), the aqueous layer was separated, acidified to pH 1 with HCl (2N) and extracted with ethyl acetate (100 ml). The extract was evaporated to leave a residue which was purified by flash chromatography (Biotage 12S eluting with ethyl acetate:hexane:acetic acid, 29:70:1) to give the title product as a white solid (0.34 g).
Reaction SMILES: N.C(OC([N:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[N:20]([N:21]([CH3:25])[C:22](=[O:24])[CH3:23])[C:19]3[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.ClCCl.[IH:33]>C(OCC)C>[IH:33].[CH3:25][N:21]([N:20]1[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[N:17]=[C:16]1[N:12]1[CH2:13][CH2:14][CH2:15][NH:9][CH2:10][CH2:11]1)[C:22](=[O:24])[CH3:23]
Reactant: CC(=O)N(C)n1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Agent: N
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)N(C)n1c(N2CCCNCC2)nc2ccccc21
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-1H-benzimidazol-2-yl)[1,4]diazepane (0.10 g, 0.32 mmol) and dimethylformamide (2 mL). Add sodium hydride (0.015 g, 0.62 mmol) and stir. After the gas evolution ceases, add N-methyl chloroacetamide (0.034 g, 0.32 mmol). After 12 hours, dilute the reaction mixture with water and extract with dichloromethane. Separate the layers and extract the aqueous layer with dichloromethane. Combine the organic layer and extract five times with water and then brine. Dry the organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 0.5% concentrated aqueous ammonia/1.5% methanol/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.34 (silica gel, 0.5% concentrated aqueous ammonia/5% methanol/dichloromethane). Combine 1-(t-butoxycarbonyl)-4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane (0.6 mmol) and dichloromethane (10 mL). Add aqueous 48% hydriodic acid solution (1.2 mmol). Heat to 40° C. After 6 hours, cool to ambient temperature dilute with diethyl ether (40 mL), and collect the solid to give the title compound.