Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][N:5]=1)([O-:3])=[O:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.[OH-].[Li+].CN(C=O)C>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[CH:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Reactant: Sc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)cn1

Procedure:
2-Nitro-5-chloropyridine (9.5 grams), 4-chlorothiophenol (8.7 grams), and lithium hydroxide (4 grams) were mixed in 100 ml. of DMF and the reaction mixture was stirred overnight (about 18 hours) at room temperature. The reaction mixture was then poured into water and the product separated by filtration and crystallized from ethanol-hexanes, yield, 10.0 grams, m.p., 96°-98° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:44][O:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:56][C@H:55]([CH2:57][NH:58][C:59](=[O:61])[CH3:60])[O:54][C:53]3=[O:62])=[CH:48][C:47]=2[F:63])([O:14][C:15](=[O:43])[CH:16]([NH:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:64]>CO>[ClH:64].[C:59]([NH:58][CH2:57][C@@H:55]1[O:54][C:53](=[O:62])[N:52]([C:49]2[CH:50]=[CH:51][C:46]([O:45][CH2:44][C:11]3([O:14][C:15](=[O:43])[CH:16]([NH:32][C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:23])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[C:47]([F:63])[CH:48]=2)[CH2:56]1)(=[O:61])[CH3:60]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Agent: Cl
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCNCC3)c(F)c2)C(=O)O1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
200 mg of 4-{4-[5-(5S)-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-4-(2,6-bis-benzyloxycarbonylamino-hexanoyloxy)-piperidine-1-carboxylic acid tert-butyl ester (MW: 977.97, 0.22 mmol) were dissolved in 4 ml of a 1.25M dry hydrochloric acid in methanol. The reaction was stirred at 40° C. for two hours, and the solvent removed by distillation under reduced pressure to leave a off white solid. Yield: 178 mg, quantitative. MS: 778.8 (M+H)+, Method ESI+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[N:17](C(OC(C)(C)C)=O)[N:16]=[C:15]([O:25][CH2:26][C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=2)[CH:14]=1>C1COCC1>[CH3:34][O:33][C:31]1[CH:32]=[C:27]([CH2:26][O:25][C:15]2[CH:14]=[C:13]([NH:12][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:17][N:16]=2)[CH:28]=[C:29]([O:35][CH3:36])[CH:30]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cc(OCc3cc(OC)cc(OC)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
4-Methoxybenzoyl chloride (54 mg, 0.315 mmol, 1.1 eq) in THF (2 ml) was added dropwise to a solution of tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (100 mg, 0.286 mmol, 1 eq) in THF (3 ml) under nitrogen and the solution was heated at reflux for a total of 14 h, then stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by prep. HPLC, using a gradient of 55-75% MeCN in H2O (containing 1% ammonium hydroxide). The product fractions were evaporated to dryness and taken up in DCM (4 ml). 4M HCl in dioxane (1 ml) was added and the mixture stirred at room temperature for 1 h, then evaporated to dryness. The residue was partitioned between ethyl acetate (6 ml) and aqueous NaHCO3 (6 ml), the layers were separated and the aqueous layer was re-extracted with ethyl acetate (3×6 ml). The combined organic extracts were dried over Na2SO4, filtered and evaporated to afford the title compound as an off-white solid (22 mg, 20% yield); 1H NMR (400.132 MHz, DMSO) δ 3.74 (s, 6H), 3.82 (s, 3H), 5.06 (s, 2H), 5.59 (s, 1H), 6.43 (t, 1H), 6.59 (d, 2H), 7.00 (d, 2H), 7.96 (d, 2H) MS: m/z 384 (MH+)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:26]([O:33][CH2:34]I)(=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[I-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH2:34][O:33][C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCCCCC(=O)OCI
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC1=C(C(=O)OCOC(=O)CCCCC)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.9 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate (2.0 g) in N,N-dimethylformamide (20 ml) were added iodomethyl hexanoate (3.4 g) and sodium iodide (3.1 g) in a stream of nitrogen, and the mixture was stirred at ambient temperature for 1.5 hours. After the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (200 ml), the organic layer was separated out, washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate, followed by treating with charcoal. The filtrate was concentrated, and thereto was added diisopropyl ether, followed by collecting the precipitated substance by filtration to obtain hexanoyloxymethyl 7-[2-(2-aminothiazol-4-yl)-acetamido]-3-vinyl-3-cephem-4-carboxylate (1.5 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[C:12]([O:22][CH3:23])[CH:11]=2)[N:3]=1.[CH3:24][O-:25].[Na+]>CO>[CH3:23][O:22][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[N:3]=[C:2]([O:25][CH3:24])[CH:7]=[C:6]([CH3:8])[N:5]=2)[CH:15]=[CH:14][C:13]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 30.7 %

Procedure:
A mixture of (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (99 mg, 0.3 mmol) and sodium methoxide (25 mg, 0.45 mmol) in methanol (3 mL) was heated for 30 min to 160° C. in a microwave oven. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound as a yellow solid (30 mg, 31%). MS ISP (m/e): 326.2 (100) [(M+H)+].
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][C:3]#[CH:4].C([Li])CCC.[CH3:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].ICCCCCC>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[C:1]([OH:6])(=[O:5])[CH2:2][C:3]#[C:4][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC
Reactant: C#CCC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCCI
Product: CCCCCCC#CCC(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 6.8 g (70 mmol) of 3-butynoic acid dissolved in 150 ml of 1:1 tetrahydrofuran (THF): hexamethyl phosphoric triamide (HMPA) and cooled to -20° C. is added via syringe a solution of n-butyl lithium in hexane (1.6N, 2 equiv). The mixture was allowed to warm to 0° C. The mixture is stirred for 30 minutes at this temperature and then 150 g (1.1 equiv) of 1-iodohexane is added dropwise as a solution in 20 ml of THF. The mixture is allowed to warm to room temperature and then is partitioned between ether and water. The aqueous layer is acidified with 3N H2SO4 and extracted with ether. The combined organic extracts are washed with brine and dried (Na2SO4). Evaporation of the volatiles in vacuo and chromatography of the crude on silica gel (ethyl acetate/hexane/acetic acid; 10:90:0.1) affords 4.5 g of pure 3-decynoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:9][CH2:10]1
Reactant: Fc1cccc(N2CCNCC2)c1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Fc1cccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)c1

Procedure:
80 mg of the target compound (0.23 mmol, 28.0%) was obtained using 1-(3-fluorophenyl)piperazine (296 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]([C:38]([O:40]C)=[O:39])([CH3:37])[CH3:36])=[C:6]([C@@H:8]2[C@:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[C@H:12]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[CH2:11][C:10](=[O:32])[NH:9]2)[CH:7]=1.[OH-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]([C:38]([OH:40])=[O:39])([CH3:37])[CH3:36])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[CH2:11][C:10](=[O:32])[NH:9]2)[CH:7]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1[C@H]1NC(=O)C[C@@H](c2cc(Cl)ccc2C)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Br)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 40.9 %

Procedure:
A mixture of (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg), NaOH (40 mg), H2O (5 mL) and THF (2 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified to “pH” 2 by concentrated aqueous HCl (1.5 mL). The white precipitate was collected by filtration to give the title compound as a white solid (Yield: 20 mg).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([CH3:21])[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].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.O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[C:14]([CH3:21])[CH:13]=1
Reactant: COc1ccc(B(O)O)c(C)c1
Reactant: Cc1oc(Br)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cc(C=O)c(C)o2)c(C)c1
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.5 g), 4-methoxy-2-methylphenylboronic acid (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), 2N aqueous sodium carbonate solution (10 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.7 g, 94%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][C:21]1[N:22]([CH2:29][CH2:30][NH2:31])[C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=1>>[CH3:20][C:21]1[N:22]([CH2:29][CH2:30][NH:31][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[C:23]([N+:26]([O-:28])=[O:27])=[CH:24][N:25]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCN
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCCn3c([N+](=O)[O-])cnc3C)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl-amine to afford the title compound. MS: m/e=411 (M+H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:18]1(/[CH:21]=[CH:22]/[C:23](Cl)=[O:24])[CH2:20][CH2:19]1.[NH4+].[Cl-]>C1COCC1>[CH:18]1(/[CH:21]=[CH:22]/[C:23]([N:8]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:10][C:9]2=[O:12])=[O:24])[CH2:20][CH2:19]1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: O=C(Cl)/C=C/C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(/C=C/C1CC1)N1C(=O)OC[C@H]1c1ccccc1
Temperature: -78 °C

Procedure:
(R)-(-)-4-Phenyl-2-oxazolidinone (39.12 g, 0.240 mmol, Aldrich) was dissolved in THF (600 mL), and the solution was cooled to -78° C. and flushed with N2. n-Butyllithium (2.5M in THF, 96.0 mL, 0.240 mmol) was introduced over 25 minutes. The compound from step 1b (0.276 mmol) was added while maintaining the temperature at -78° C., and the mixture was stirred at this temperature for half an hour. The mixture was stirred as it was allowed to warm to room temperature. Saturated aqueous NH4Cl solution was added, the mixture was stirred for 10 minutes and the THF was removed under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water, 5% aqueous NaHCO3 and brine, then dried over Na2SO4. The solvent was removed to afford the title compound, which was recrystallized from ethyl acetate:hexane to give the title product (54.660 g, 89% yield). MS m/z 258 (M+H)+, 275 (M+NH4)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH3:7].[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C1CCCCC1.C(OCC)(=O)C>[C:9]([C:11](=[C:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: CCCC(=O)CCC
Reactant: CCOC(=O)CC#N
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCCC(CCC)=C(C#N)C(=O)OCC
Yield: 80000 %

Procedure:
In a 100 mL round-bottom flask was dissolved 4-heptanone (11.4 g, 0.10 mmole) and ethyl cyanoacetate (11.30 g, 0.100 mole) in cyclohexane (25 mL). Acetic add (1.0 mL) and NH4OAc (2.0 g) were added. The solution was magnetically stirred and heated to reflux with a Dean-Stark trap in place overnight under N2. The reaction was cooled to ambient, diluted with ethyl acetate (100 mL) washed with H2O (2×50 mL) and brine (25 mL). The organic extracts were dried (Na2SO4, filtered and concentrated under vacuum to give an oil that was distilled (bp. 135°-137° C., 20 mmHg) to give Ethyl α-cyano-α-(4-heptylidene)acetate (16.65 g, 0.080 mole, 80%). IR (neat film) 2950, 2910, 2860, 2200, 1725, 1570, 1235, 1085 cm-1 ; 1H NMR (400 MHz, CDCl3 δ 4.15 (q, J=9 Hz, 2H), 2.60 (t, J=10 Hz, 2H), 2.38 (t, J=10 Hz, 2H), 1.25 (t, J=9 Hz, 2H), 1.40 (sextet, J=9 Hz, 2H), 1.25 (t, J=9 Hz, 3H), 0.88 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 181.2, 161.5, 115.5, 104.6, 61.4, 40.2, 35.2, 21.9, 21.4, 14.1, 13.8 (one carbon not observed due to overlap); MS (CI) m/e 211 (14.5), 210 (100), 209 (3.59), 182 (3.5), 164 (2.8); HRMS (CI) calcd for C12H20NO2 (M+H) m/e 210.1484, found 210.1491.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](=[O:11])[CH:10]=1)=[N+]=[N-]>CO>[NH2:1][CH2:4][C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](=[O:11])[CH:10]=1
Reactant: [N-]=[N+]=NCc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Solvent: CO
Product: NCc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Yield: 96.1 %

Procedure:
2-(Azidomethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone (1.0 g, 2.89 mmol) was dissolved in 50 ml of methanol and 0.10 g of platinic oxide was added. Hydrogen was bubbled through the mixture for 30 minutes and the catalyst filtered off by suction over Hyflo. The filtrate was evaporated in vacuo and the oily residue triturated with ether to afford crystalline title compound (0.89 g), melting point 207° C.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH:8]([CH3:16])[CH:9]2[O:14][CH3:15].[C:17]([OH:20])(=O)[CH3:18]>C1COCC1>[CH3:15][O:14][CH:9]1[C:10]2[C:6](=[C:5]([CH2:4][CH2:3][C:17]3([OH:20])[CH2:18][C:13]4[C:5](=[CH:6][CH:10]=[CH:11][CH:12]=4)[CH2:4]3)[CH:13]=[CH:12][CH:11]=2)[CH2:7][CH:8]1[CH3:16]
Reactant: CC(=O)O
Reactant: COC1c2cccc(CCBr)c2CC1C
Agent: [Mg]
Solvent: C1CCOC1
Product: COC1c2cccc(CCC3(O)Cc4ccccc4C3)c2CC1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 2.26 g (93.0 mmol) of magnesium turnings in 20 ml of THF a solution of 16.7 g (62.0 mmol) of 4-(2-bromoethyl)-1-methoxy-2-methylindane in 80 ml of THF was added dropwise at reflux. The resulting mixture was additionally refluxed for 1 h, and then this Grignard reagent was titrated. To a suspension of 10.9 g (44.1 mmol) of anhydrous CeCl3 in 160 ml of THF 100 ml (44.1 mmol) of 0.441 M solution of the Grignard reagent was added at vigorous stirring for 15 min at 0° C., and then the reaction mixture was stirred at this temperature for 1.5 h. Further on, 5.83 g (44.1 mmol) of indanone-2 was added at 0° C. This mixture was stirred overnight at room temperature, and then 300 ml of 10% acetic acid was added. The product was extracted by 3×100 ml of ether. The combined extract was washed by brain and aqueous Na2CO3. The organic layer was separated, dried over Na2SO4, and evaporated to dryness. The title product was isolated by flash chromatography on Silica Gel 60 (40-63 um, d 50 mm, l 300 mm, eluent: hexanes/ether=3/1). Yield 10.7 g (75%) of a one diastereomer (as the starting material was one pure diastereomer).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[N:41]=[CH:42][N:43]([CH2:45][CH2:46]OS(C)(=O)=O)[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:52][NH:53][CH3:54]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[N:41]=[CH:42][N:43]([CH2:45][CH2:46][N:53]([CH3:54])[CH3:52])[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cn(CCOS(C)(=O)=O)cn2)n1
Solvent: C1CCOC1
Product: CN(C)CCn1cnc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
To a solution of Intermediate 119f (0.10 mmol) in THF (2 mL) was added dimethylamine (2M in MeOH, 0.4 mL, 0.8 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM followed by HPLC (XBridge C18 column, 30-98% MeCN in H2O, 0.1% NH4OH), to give the title compound (12 mg, 18%). LCMS (Method 5): Rt 3.43 min, m/z 666 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.21 (9H, s), 1.54-1.60 (2H, m), 1.65-1.71 (4H, m), 1.86-1.94 (2H, m), 1.95-2.05 (1H, m) 2.13 (6H, s), 2.13-2.16 (1H, m), 2.55 (2H, t, J=6.3 Hz), 3.10 (4H, t, J=5.2 Hz), 4.05 (2H, t, J=7.1 Hz), 4.86 (1H, td, J=8.4, 5.5 Hz), 5.51 (1H, t, J=4.5 Hz), 6.32 (1H, s), 7.12 (1H, dd, J=10.0, 1.9 Hz), 7.20-7.25 (2H, m), 7.28-7.36 (3H, m), 7.56-7.59 (2H, m), 7.63 (1H, d, J=1.4 Hz), 7.90 (1H, d, J=8.6 Hz), 9.63 (1H, br s).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.C(N(CC)CC)C.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:36]1([NH:35][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:3])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (32.2 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (62 μL), aniline (25 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62.7 mg) and 4-dimethylaminopyridine (˜1 mg) were added in that order. Mixture stirred 16 h at room temperature then 2 mL more CH2Cl2 added (reaction had gone dry overnight) and thin layer chromatography showed complete conversion of starting material. Concentrated under reduced pressure then purified by silica gel chromatography (98:2 CH2Cl2:MeOH) to yield 16.9 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.48 (br s, 1H); 8.48 (br s, 1H); 8.41 (d, J=5.5 Hz, 1H); 8.00 (s, 1H); 7.75-7.84 (m, 3H); 7.61-7.66 (m, 3H); 7.51 (t, J=7.8 Hz, 1H); 7.33-7.41 (m, 4H); 7.17 (t, J=7.5 Hz, 1H); 6.81 (d, J=5.5 Hz, 1H); 5.73 (br s, 1H); 5.28 (br s, 1H); 1.68 (d, J=6.8 Hz, 3H). Mass Spectrum (ESI): m/e 435.1 (M+1).