Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=1[CH2:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:58]1[C:62]2([CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]2)[CH2:61][C:60]([C:68](O)=[O:69])=[N:59]1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([CH2:19][CH2:20][C:21]([OH:23])([CH3:24])[CH3:22])=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:16])([F:17])[F:18])=[CH:6][C:7]=1[NH:8][C:68]([C:60]1[CH2:61][C:62]2([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]2)[O:58][N:59]=1)=[O:69]
Reactant: CC(C)(O)CCc1cc(-c2ccccc2C(F)(F)F)cc(N)c1N
Reactant: O=C(O)C1=NOC2(CCCCC2)C1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CCc1cc(-c2ccccc2C(F)(F)F)cc(NC(=O)C2=NOC3(CCCCC3)C2)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
4-(4,5-Diamino-2′-trifluoromethyl-biphenyl-3-yl)-2-methyl-butan-2-ol (57.5 mg, 0.170 mmol, as prepared in the previous step) was placed in a 50 mL round-bottom flask equipped with a magnetic stir bar. DCM (15 mL), PyBrOP (95.0 mg, 0.204 mmol), and DIPEA (36.0 μL, 0.204 mmol) were added via syringe. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (31.0 mg, 0.170 mmol, as prepared in Example 1, step B) in DCM (10 mL) was placed in an addition funnel and added dropwise over 2 h. After completion of the addition, the mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure. The residue was chromatographed on a 40-g pre-packed SiO2 column eluting with EtOAc/heptane, 0:1 to 3:7, v/v over 20 min, yielding 34.4 mg (40%) of the title compound. Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H32F3N3O3: 504.2 (M+H). Found 504.1.
Reaction SMILES: [Cl:1][CH2:2]C(CCl)=O.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Na]>CO.O1CCCC1>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:26]([OH:28])[CH2:2][Cl:1])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(CCl)CCl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
To a solution of 75.0 g (0.226 mol) of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of 807 mL of methanol and 807 mL of tetrahydrofuran at -2° C., was added 13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borehydride over one hundred minutes. The solvents were removed under reduced pressure at 40° C. and the residue dissolved in ethyl acetate (approx. 1L). The solution was washed sequentially with 1M potassium hydrogen sulfate, saturated sodium bicarbonate and then saturated sodium chloride solutions. After drying over anhydrous magnesium sulfate and filtering, the solution was removed under reduced pressure. To the resulting oil was added hexane (approx. 1L) and the mixture warmed to 60° C. with swirling. After cooling to room temperature, the solids were collected and washed with 2L of hexane. The resulting solid was recrystallized from hot ethyl acetate and hexane to afford 32.3 g (43% yield) of N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp 150°-151° C. and M+Li+ =340.
Reaction SMILES: O.NN.CCO.O=C1C2C(=CC=CC=2)C(=O)[N:9]1[C@H:18]([C:20]1[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH3:39])(=[O:38])=[O:37])=[N:28][C:27]2[C:26]([C:40]#[N:41])=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1)[CH3:19].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:9][C@H:18]([C:20]1[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH3:39])(=[O:38])=[O:37])=[N:28][C:27]2[C:26]([C:40]#[N:41])=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1)[CH3:19]
Reactant: C[C@@H](c1nc2cccc(C#N)c2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: C[C@H](N)c1nc2cccc(C#N)c2nc1-c1ccccc1S(C)(=O)=O
Yield: 93.4 %

Procedure:
A 5 L three-necked round-bottomed flask equipped with a nitrogen inlet, overhead stirrer and thermocouple was charged with hydrazine hydrate (381 mL, 783 mmol) and EtOH (3.0 L). To the solution was then added 2-((S)-1-(1,3-dioxoisoindolin-2-yl)ethyl)-3-(2-(methylsulfonyl)phenyl)quinoxaline-5-carbonitrile (378 g, 783 mmol) in one portion and heated to 80° C. The reaction was monitored by LC, and deemed complete once the reaction again reached 80° C. The reaction was cooled to room temp (20-21° C.), when DCM (3.0 L) and satd. NaHCO3 solution (600 mL) were added. After phase separation, the organic layer was washed with brine (2×600 mL), concentrated and dried under vacuum and N2 flow for 24 h to afford the product as a light yellow solid 257.7 g with 94.4% LC purity, (no R enantiomer detected) and 93% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45-8.54 (m, 2H), 8.18 (dt, J=7.7, 1.5 Hz, 1H), 8.05 (dd, J=8.5, 7.4 Hz, 1H), 7.76-8.00 (m, 3H), 3.83-4.03 (m, 1H), 3.25-3.32 (m, 3H), 1.19-1.39 (m, 3H) Mass Spectrum (ESI) m/z=353.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:18]([C:22]1[CH:23]=[CH:24][C:25]([OH:35])=[C:26]([C:28]2[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)[CH:27]=1)([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C.C(O)(=O)C.C(N)CN.S([O-])(O)=O.[Na+]>CO>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([OH:35])=[C:26]([C:28]2[O:32][C:31]([CH:33]=[C:6]3[S:5][C:4](=[S:7])[N:3]([NH:8][C:9]4[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=4[C:11]([OH:13])=[O:12])[C:2]3=[O:1])=[CH:30][CH:29]=2)[CH:27]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(O)c(-c2ccc(C=O)o2)c1
Reactant: O=C(O)c1ccccc1NN1C(=O)CSC1=S
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: NCCN
Solvent: CO
Product: CC(C)(C)c1ccc(O)c(-c2ccc(C=C3SC(=S)N(Nc4ccccc4C(=O)O)C3=O)o2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A mixture of 2-(4-oxo-2-thioxo-thiazolidin-3-ylamino)-benzoic acid (0.078 g, 0.29 mmol), 5-(5-tert-butyl-2-hydroxy-phenyl)-furan-2-carbaldehyde and (0.075 g, 0.31 mmol) and ethylenediamine diacetate (0.056 g, 0.031 mmol) in methanol (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into stirred 0.6 N aq sodium hydrogensulfite (50 mL). The mixture was vigorously stirred for 30 min. The solid product was filtered off and washed on funnel successively with 0.6 N aq sodium hydrogensulfite (1 mL), water (2×2 mL), ether (2×1 mL) and hexanes (2 mL). The material was dried in a vacuum oven at 65° C. for 17 h to afford 2-{5-[1-[5-(5-tert-Butyl-2-hydroxy-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-ylamino}-benzoic acid (135 mg, 94%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.37 (9H, s), 6.98 (1H, d, J=8.4 Hz), 7.23 (1H, d, J=3.6 Hz), 7.34 (1H, dd, J=8.8, 2.8 Hz), 7.39 (1H, d, J=3.6 Hz), 7.70 (2H, m), 7.74 (1H, s), 7.94 (1H, d, J=2.4 Hz), 8.01 (1H, m), 8.07 (1H, m). LC/MS. APCI 493.1, HPLC 100%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](F)=[C:22]([F:27])[CH:21]=1)=[O:19]>C(OCC)(=O)C.O>[F:27][C:22]1[CH:21]=[C:20]([C:18](=[O:19])[CH3:17])[CH:25]=[CH:24][C:23]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)c1ccc(F)c(F)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2ccnc2)c(F)c1

Procedure:
Imidazole (543 mg) and potassium carbonate (1.80 g) were added to a DMF (15 mL) solution of 3,4-difluoroacetophenone (1.0 mL). After agitating reaction solution at 80° C. for 4 hours, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane:ethyl acetate=5:1->ethyl acetate), and 1.40 g of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[N:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:30]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=Cc1ccncc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2oc(-c3ccc4c(c3)nc(-c3ccncc3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.15 g, 0.484 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 4-pyridinecarboxaldehyde (0.06 g, 0.561 mmol) was added followed by oxone (0.19 g, 0.310 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.09 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (117 mg, 60.9% yield) as white crystals.
Reaction SMILES: [OH:1][C:2]1([CH2:13][CH:14]=O)[CH:9]2[CH2:10][CH:5]3[CH2:6][C:7]([OH:12])([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][CH2:14][CH2:13][C:2]2([OH:1])[CH:9]3[CH2:8][C:7]4([OH:12])[CH2:6][CH:5]([CH2:4][CH:3]2[CH2:11]4)[CH2:10]3)[CH3:24])=[CH:19][CH:18]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: O=CCC1(O)C2CC3CC1CC(O)(C3)C2
Product: C[C@H](NCCC1(O)C2CC3CC1CC(O)(C3)C2)c1ccc(Br)cc1

Procedure:
The title compound is prepared from (2,5-dihydroxy-adamantan-2-yl)-acetaldehyde and (S)-1-(4-bromo-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2; the title compound is obtained as a mixture of 2 diastereomers. Yield: 20% of theory; Mass spectrum (ESI+): m/z=394/396 (Br) [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]([Cl:27])(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[ClH:27].[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCCCSc1ccncc1
Yield: 84.3 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.61 ml (4.96 mmol) of pivaloyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.01 g of the desired compound (free base) (96.4%, yellow oil).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:36][NH:37][O:38][CH3:39].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[N:37]([O:38][CH3:39])[CH3:36])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid (24.85 g, 93.66 mmol) in dichloromethane (150 mL) was added N-methylmorpholine (10.3 mL, 93.66 mmol), followed by addition of isobutyl chloroformate (12.25 mL, 93.66 mmol) at 0° C. The reaction mixture was stirred for 20 min. then N,O-dimethylhydroxylamine hydrochloride (9.14 g, 93.66 mmol) in one portion was added. Subsequently, triethylamine (13 mL, 93.66 mmol) was added dropwise over 15 min. The reaction mixture was stirred for another hour, then it was quenched with 1N HCl (100 mL) and the organic phase was washed with saturated NaHCO3 and brine (500 mL). The organic layers were dried over (MgSO4), filtered, and concentrated in vacua to give the Weinreb amide of Formula VII(a), [(S)-1-(methoxy-methyl-carbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester as a clear sticky oil (29.3 g, 100%). 1H NMR (400 MHz, d6-DMSO): δ (ppm) 7.33-7.09 (m, 6H), 4.61-4.47 (m, 1H), 3.70 (s, 3H), 3.08 (s, 3H), 2.89-2.78 (m, 1H), 2.75-2.63 (m, 1H), 1.29 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:3]=1.[C:23]1([CH:29]([NH2:35])[C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[ClH:1].[NH2:35][CH:29]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:30]([CH3:34])([CH3:33])[CH2:31][NH:32][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: Cc1cccc(-c2c(-c3ccncc3)nc(Cl)n(C)c2=O)c1
Reactant: CC(C)(CN)C(N)c1ccccc1
Solvent: CCO
Product: Cc1cccc(-c2c(-c3ccncc3)nc(NCC(C)(C)C(N)c3ccccc3)n(C)c2=O)c1
Product: Cl

Procedure:
A solution of 2-chloro-3-methyl-5-(3-methylphenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone (228 mg, 0.73 mmol) and 3-phenyl-2,2-dimethyl-1,3-propanediamine (178 mg, 1 mmol) (prepared according to: W. Ten Hoeve and H. Wynberg, Synth. Commun. 24 (15), 2215-2221, 1994) in ethanol (4 ml) was stirred at room temperature for 16 h. The solvent was evaporated and the crude product purified by column chromatography on silica gel. MS (m/z): 454 (M+H)+; C28H31N5O requir. 453.6 (free base).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([OH:13])=O)#[CH:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Pb](SC#N)[S:26][C:27]#[N:28]>ClCCl>[C:1]([C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([N:28]=[C:27]=[S:26])=[O:13])#[CH:2]
Reactant: C#Cc1cc(F)ccc1CC(=O)O
Reactant: N#CS[Pb]SC#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#Cc1cc(F)ccc1CC(=O)N=C=S
Reaction time: 1 h

Procedure:
To a solution of acid 327 (2.10 g, 11.8 mmol) in dry dichloromethane (50 mL) was added oxalyl chloride (2.0 mL, 2.9 g, 23 mmol) and dry DMF (0.1 mL). The mixture was stirred for 1 h, then concentrated under reduced pressure. The residue was re-dissolved in toluene (75 mL) and lead thiocyanate (4.0 g, 12 mmol) was added. The resulting suspension was heated to reflux with vigorous stirring for 3 h, then cooled, filtered through celite, and concentrated to afford crude 321 which was used without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2)#[N:4].[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.C(O)(=O)C>O1CCCC1.ClCCl>[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][CH2:5][C:3]#[N:4])[CH:12]=[CH:13]1
Reactant: BrCc1cccc(C2OCCO2)c1
Reactant: N#CCOc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CCOc1cccc2ccn(Cc3cccc(C4OCCO4)c3)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60% Sodium hydride dispersion in mineral oil (90 mg, 2.25 mmol) was added to a stirred, cooled solution of 7-cyanomethoxyindole (Example 1a) (0.32 g., 1.86 mmol) in tetrahydrofuran (8 ml). The dark mixture was stirred for 15 minutes at room temperature then cooled again whilst a solution of 3-(1,3-dioxolan-2-yl)benzyl bromide (0.50 g., 2.06 mmol) in tetrahydrofuran (2 ml) was added. The mixture was stirred at room temperature for 20 hours then treated with glacial acetic acid (130 μl), diluted with dichloromethane, washed with water, dried and evaporated. The residue was chromatographed on silica in ethyl acetate-hexane (1:3).
Reaction SMILES: CC(N=N[C:8]([C:11]#N)(C)C)(C#N)C.[Cl:13]CC=CC1C=CC=CC=1.[C:23]1([CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Cl:13][CH2:29][C:23]1[CH:28]=[CH:27][C:26]([CH:8]=[CH2:11])=[CH:25][CH:24]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: ClCC=Cc1ccccc1
Product: C=Cc1ccc(CCl)cc1
Temperature: 79 °C
Reaction time: 22 h

Procedure:
A flame dried 1-L round bottom flask was charged with AIBN (1.9 g, 11.6 mmol) and 50 mL of anhydrous toluene. To this stirred solution was added chloromethylstyrene (76.25 g, 500 mmol) in toluene (430 mL). Argon was bubbled through the mixture; it was then warmed to 78-80° C. with stirring for 22 hrs under a blanket of argon. Approximately 50 mL of hexane was added to the flask and the whole mixture was then poured into 750 ml of hexane. A taffy-like precipitate formed. The precipitate was collected and washed a couple of times with water. The precipitate was then dissolved in THF. The THF solution was filtered. Adding petroleum ether precipitated the product that was then separated from the mother liquor. The solid was dissolved again in THF, and finally precipitated in methanol. The product was collected and dried overnight at 50° C. in a vacuum oven. This gave the title compound as a brittle, white powder (36.16 g). GPC analysis that gave the following results:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=O)[CH2:17]1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[N:30]1([C:23]([C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[CH:18]2[CH2:19][CH2:20][N:16]([CH2:15][CH2:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C:2]3=[O:1])[CH2:17]2)=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccccc1C1CCN(CCc2ccccc2N2CCCCC2=O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1C1CCN(CCc2ccccc2N2CCCCC2=O)C1)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12 %

Procedure:
2-(1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)benzoic acid enantiomer 2 a6-8 (2.72 g, 6.97 mmol, 1 eq) is dissolved in dichloromethane (100 ml). Pyrrolidine (0.69 ml, 8.36 mmol, 1.2 eq) is added followed by BOP reagent (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate; 4.62 g, 10.45 mmol, 1.5 eq) and the reaction mixture is stirred at room temperature for 4 h. The mixture is evaporated to dryness, redissolved in dichloromethane and the organic layer is washed with HCl 1N and water, dried over MgSO4 and evaporated. The residue is purified by reverse phase HPLC (gradient: acetonitrile/H2O/ammonium formate from 5% to 95% of acetonitrile in 8 minutes) to afford 385 mg of (−)-1-[2-(2-{3-[2-(pyrrolidin-1-ylcarbonyl)phenyl]pyrrolidin-1-yl}ethyl)phenyl]piperidin-2-one 17.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:15][O:14][C:12](=[O:13])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]C(C)C)(C)C>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:9][C@H:10]([CH2:15][OH:14])[CH2:11][CH:12]=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](OC(=O)c2ccccc2)CO1
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=CC[C@@H](CO)OC(=O)c1ccccc1
Temperature: -78 °C
Yield: 73.7 %

Procedure:
To a solution of 101 (0.780 g, 3.8 mmol) in 13 mL dry THF was slowly dropwise added 1.0 M diisopropyl aluminiumhydride (4.7 mL, 4.7 mmol) in toluene at −78° C. The reaction mixture was stirred at −78° C., and as soon as the starting material was completely consumed (TLC, 2 hours), methanol (2 mL) was slowly added in order to quench the reaction. The cooling bath was removed, 15 mL of a saturated aqueous sodium potassium tartrate solution and 25 mL of EtOAc were added and the mixture stirred vigorously for 3 hours. The organic layer was washed with water and brine, and concentrated under vacuo. The residue was purified by chromatography on a silica gel column (n-hexane/EtOAc=8:2) to afford 102 (590 mg, 2.8 mmol) as a colorless oil, in 75% yield, which was characterized as follows:
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].N1CCOCC1.Cl.[N:64]1([CH2:70][CH2:71][CH2:72][N:73]2[CH2:78][CH2:77][NH:76][CH2:75][C:74]2=[O:79])[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([N:76]1[CH2:77][CH2:78][N:73]([CH2:72][CH2:71][CH2:70][N:64]2[CH2:69][CH2:68][O:67][CH2:66][CH2:65]2)[C:74](=[O:79])[CH2:75]1)(=[O:54])=[O:55]
Reactant: O=C1CNCCN1CCCN1CCOCC1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCN1
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCN(CCCN2CCOCC2)C(=O)C1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2carboxylate, and morpholine with 1-(3-morpholin-4-ylpropyl)piperazin-2-one hydrochloride, the title compound was obtained. ESI+MS: 528.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:10]([NH:16][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCCCCCN
Product: CCCCCCNC(=O)C(F)(F)F

Procedure:
In a manner similar to Example 6, ethyl trifluoroacetate (131 g, 0.92 m) was reacted with n-hexylamine. The resulting amide distilled at 64° C./0.2 mm Hg and amounted to 154 g.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:7][CH:6]=[C:5]([CH:8]=[O:9])[CH:4]=1.B(F)(F)F.CCOCC.[CH3:21][C:22]([CH:29]=[CH2:30])=[CH:23][O:24][Si](C)(C)C>C(Cl)Cl>[OH:9][CH:8]([C:5]1[CH:4]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:7][CH:6]=1)[CH2:30][CH:29]=[C:22]([CH3:21])[CH:23]=[O:24]
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: C=CC(C)=CO[Si](C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C=O)=CCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-trimethylsilyl-3-furaldehyde (0.382 g., 2.27 mmol) in dry methylene chloride (15 ml) at -50° under argon was added dropwise boron trifloride etherate (0.28 ml, 2.3 mmol). This addition was followed by the dropwise addition of 2-methyl-l-trimethylsilyloxy-1,3-butadiene (0.356 g., 2.3 mmol). The solution was stirred at -50° to -60° for 18 hours, quenched by the addition of several ml saturated sodium bicarbonate solution, warmed to room temperature and poured into methylene chloride. The organic portion was washed once with saturated bicarbonate solution, once with water, once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil which consisted of several components by TLC. The mixture was applied to a chromatography column (silica) and eluted with 30% ethyl acetate/hexane. Eluted last was the desired alcohol, which was concentrated to give a yellow gum.