Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[N:6][CH:5]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[N:12]1([C:8]2[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([O:2][CH3:1])=[O:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cncc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cncc(N2CCOCC2)c1
Temperature: 110 °C
Yield: 42 %

Procedure:
To a mixture of methyl-5-bromonicotinate (10 g, 0.045 mol) and morpholine (4.6 g, 0.054 mol) in dry toluene (100 mL) was added fused CsCO3 (30 g, 0.09 mol) with stirring under argon. To this mixture was added BINAP (0.45 g, 0.0005 mol), Pd2(dba)3 (0.22 g, 0.00015 mol) and then the reaction mixture was refluxed at 110° C. for 50 h. The reaction mixture was cooled down to r.t. and diluted with diethyl ether (400 ml) and filtered through celite. The filtrate was concentrated under vacuum and purified by flash column chromatography (CHCl3/MeOH, 4:1) to give 4.2 g (41%) of methyl 5-morpholin-4-ylnicotinate as a liquid. TLC—Chloroform/Methanol (8/2): Rf=0.7.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:19]3[CH:20]=[CH:21][C:22]([O:24][C:25]4[S:26][C:27]5[C:28]([N:33]=4)=[N:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][C:18]=3[O:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>C(Cl)Cl>[ClH:34].[N:11]1([CH2:14][C:15]2[C:19]3[CH:20]=[CH:21][C:22]([O:24][C:25]4[S:26][C:27]5[C:28]([N:33]=4)=[N:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][C:18]=3[O:17][CH:16]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2coc3cc(Oc4nc5ncccc5s4)ccc23)CC1
Agent: Cl
Solvent: ClCCl
Product: c1cnc2nc(Oc3ccc4c(CN5CCNCC5)coc4c3)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 129 %

Procedure:
To a solution of 4-[6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (0.22 g, 0.47 mmol) in DCM (5 mL) is added HCl (4 M in dioxane, 1 mL, 8.5 equiv.) and the solution was stirred (rt, 1 h). The reaction mixture was concentrated in vacuo to provide the desired product as a white solid (0.25 g, 129%). [Note: the mass recovery of 129% was attributed to additional HCl that could not be removed by standard evaporation under reduced pressure]. MS (ESI): mass calcd. for C19H18N4O2S, 366.44; m/z found, 367.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[OH-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:10])[CH3:9]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a solution of 1-(5-bromo-2-hydroxyphenyl)ethan-1-one (10 g, 46.50 mmol) in N,N-dimethylformamide (80 mL) was added sodium hydroxide (2.23 g, 92.92 mmol) and then stirred for 1 hour at room temperature. Ethyl 2-bromoacetate (8.24 g, 49.34 mmol) was added dropwise and stirred overnight at room temperature. The reaction mixture was quenched by the addition of water (200 mL), adjusted to pH 5 with HCl (3N), extracted with ethyl acetate (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue which was purified by silica gel chromatography (5% ethyl acetate in petroleum ether) to afford ethyl 2-(2-acetyl-4-bromophenoxy)acetate as a light yellow oil (8.9 g, 64%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1.CCN(CC)CC.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=[O:21].ClC1C=CC=CC=1CO.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=[O:21])=[O:11]
Reactant: COC(=O)[C@@H]1CCCCN1
Reactant: O=C(Cl)OCc1ccccc1Cl
Agent: Cl
Agent: OCc1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To a vigorously stirred solution of (S)-pipecolic acid methyl ester hydrochloride (500 mg, 2.79 mmol) in dry DCM (10 mL) cooled in an ice-bath, was added dropwise Et3N (705 mg, 6.96 mmol) followed by 2-chlorobenzyl chloroformate (made from 2-chlorobenzyl alcohol using the method described in J. Med. Chem., 1998, 41, 1315–1343) (857 mg, 4.18 mmol). The resulting suspension was stirred at 0° C. for a further 0.75 h, diluted with ethyl acetate (30 mL) and poured into 1.0-M HCl (30 mL). The organic layer was separated and washed sequentially with 1.0-M HCl (20 mL), aq.NaHCO3 (20 mL) and brine (20 mL). The organic layer was then dried (NaSO4), filtered and concentrated under reduced pressure to give a colorless oil. The oil was purified by column chromatography (15% ethyl acetate in hexane) to give the title compound as a colorless viscous oil (824 mg, 95%): 1H NMR (400 MHz, CDCl3) 1.2–1.4 (1H, m), 1.4–1.6 (1H, m), 1.6–1.8 (3H, m), 2.2–2.3 (1H, m), 2.9–3.2 (1H, m), 3.7–3.8 (3H, m), 4.0–4.2 (1H, m), 4.8–5.0 (1H, m), 5.2–5.4 (2H, m), 7.2–7.3 (2H, m), 7.3–7.5 (2H, m)
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]([O:23][CH3:24])=[O:22])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:32](O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(COCC)C=C2)CO)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([C:21]([O:23][CH2:24][CH3:32])=[O:22])[CH:14]=[CH:13]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Reactant: COC(=O)c1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1
Product: CCOC(=O)c1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(C)cc2n1

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(ethoxycarbonyl)-7-methylquinolin-6-yl)acetic acid was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxycarbonyl)-7-methylquinolin-6-yl)acetic acid of Example 12, except that (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(ethoxymethyl)-7-methylquinolin-6-yl)ethanol was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxymethyl)-7-methylquinolin-6-yl)ethanol. 1H-NMR 300 MHz, (CD3OD) δ8.10-8.00 (m, 2H), 7.90 (d, 1H), 7.70-7.57 (m, 3H), 7.35 (d, 1H), 5.23 (s, 1H), 4.50 (q, 2H), 2.70 (s, 3H), 1.46 (t, 3H) 0.98 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C25H26ClNO5: 456.9. Found: 456.2, 458.2.
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:20][CH2:21][CH3:22])[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([C:16]([O:18]C)=[O:17])[CH:10]=[CH:11][CH:12]=2)[CH2:7]1)[CH2:3][CH3:4].[OH-].[Na+].CO>O>[C:16]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH:6]([N:5]([CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3][CH3:4])[CH2:15][CH2:14]2)([OH:18])=[O:17]
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)OC)c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(CCC)C1CCc2cccc(C(=O)O)c2C1
Yield: 97.1 %

Procedure:
A solution of methyl 2-(dipropylamino)tetralin-8-carboxylate hydrochloride (1.5 g, 4.6 mmol), sodium hydroxide (736 mg, 18.4 mmol), methanol (25 ml) and water (4 ml) was stirred overnight, The methanol was evaporated. Concentrated hydrochloric acid was added until the pH became about 6. The solution was extracted with chloroform. The organic layer was dried (sodium sulfate) and concentrated to give 1.23 g (97%) of pure 8-carboxy-2-(dipropylamino)tetralin as an oil. The hydrochloride melts at 245°-247° C., which could bse recrystallised from methanol/diethylether.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([OH:12])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3].I[CH3:20]>[Ag]=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([O:12][CH3:20])[CH2:9][C@H:8]1[CH:13]=[C:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[O:6])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCOC(=O)N1C[C@@H](O)C[C@H]1C=C(C)C(C)=O
Agent: O=[Ag]
Product: C=CCOC(=O)N1C[C@@H](OC)C[C@H]1C=C(C)C(C)=O
Reaction time: 48 h

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (4.00 g) in iodomethane (20 ml) was added silver oxide (20 g), and the mixture was allowed to stand at ambient temperature for 2 days. The resulting precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel (50 ml) eluting with a mixture of n-hexane and ethyl acetate (6:4 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-methoxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (2.31 g).
Reaction SMILES: [NH:1]1[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.[N+:9]([O-])([O-:11])=[O:10].[K+]>S(=O)(=O)(O)O>[N+:9]([C:7]1[CH:6]=[N:5][N:4]2[CH2:3][CH2:2][NH:1][C:8]=12)([O-:11])=[O:10]
Reactant: O=[N+]([O-])[O-]
Reactant: c1cc2n(n1)CCN2
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cnn2c1NCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
To a solution of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (120 g) in sulfuric acid (500 ml) was added potassium nitrate (111 g) under ice-cooling. The mixture was stirred at room temperature for 48 hours. The reaction mixture was added to ice (2.0 kg). The crystalline residue was collected by filtration and dried in vacuo to give 7-nitro-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (132 g) as a solid.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1.[C:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])#[CH:22].C(N(CC)CC)C>O1CCCC1.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:4]2[C:5]([N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[N:6][C:2]([C:22]#[C:21][Si:23]([CH3:26])([CH3:25])[CH3:24])=[N:3]2)=[CH:14][CH:15]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Cn2nc(Br)nc2N2CCCC2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C#C[Si](C)(C)C)nc2N2CCCC2)cc1
Temperature: 75 °C
Yield: 45.9 %

Procedure:
A mixture of 3-bromo-1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (197 mg, 584 μmol, Eq: 1.00), ethynyltrimethylsilane (115 mg, 164 μl, 1.17 mmol, Eq: 2) and triethylamine (88.7 mg, 122 μl, 876 μmol, Eq: 1.5) in tetrahydrofuran (3 ml) was purged for 5 minutes with nitrogen. Then copper (I) iodide (1.11 mg, 5.84 μmol, Eq: 0.01), bis(triphenylphosphine) palladium(II) chloride (4.1 mg, 5.84 μmol, Eq: 0.01) and triphenylphosphine (1.53 mg, 5.84 μmol, Eq: 0.01) were added, the vessel was capped and heated to 75° C. for 18 hours. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 10-30% as eluent affording 1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-3-trimethylsilanylethynyl-1H-[1,2,4]triazole (95 mg/45.9%) as an orange oil. MS: m/e=355.4 (M+H+)
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][C:5]1=[O:17])(=[O:3])[CH3:2].[CH3:18][CH2:19][O:20][C:21](OCC)(OCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:21]([O:20][CH2:19][CH3:18])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]1=[O:17])(=[O:3])[CH3:2]
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: COc1cc2c(cc1OC)N(C(C)=O)C(=O)C2
Solvent: CC(=O)OC(C)=O
Product: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1

Procedure:
10.0 g of 1-acetyl-5,6-dimethoxy-2-indolinone, 29.2 ml of triethyl orthobenzoate and 100 ml of acetic anhydride are stirred for 48 hours at 120° C. The solvent is eliminated and the residue evaporated with toluene, combined with ether and the precipitate formed (starting compounds is suction filtered. The filtrate is concentrated by evaporation and separated through a silica gel column with toluene, then with toluene/ethyl acetate (10:1). The product is triturated with ether, suction filtered and dried in vacuo at 100° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:14](=[O:31])[CH2:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>N1C=CC=CC=1>[C:32]([NH:2][CH:3]([C:14](=[O:31])[CH2:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:18]=1)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reaction time: 16 h

Procedure:
The compound of Example 11 (0.55 g) was dissolved in pyridine (10 ml) and benzoyl chloride (0.17 g) was added. The reaction was stirred for 16 hours and then partitioned between 10% citric acid (50 ml) and ethyl acetate (100 ml). The organic phase was washed with water (100 ml) and sodium bicarbonate solution (100 ml), dried (MgSO4) and evaporated to yield an oil which was purified by chromatography on silica using petroleum ether/ethyl acetate (1:3) to yield the title compound as a white solid, mp=119°-122° C.; found: C, 63.28; H, 4.25; N, 5.14; C28H22F6N2O2 requires C, 63.16, H, 4.16; N, 5.26%.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]([CH3:19])([CH3:18])[CH2:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([N:30]1[CH2:34][C@@H:33]([F:35])[CH2:32][C@H:31]1[C:36]#[N:37])=[O:29]>C1COCC1>[CH3:18][C:9]([NH:8][CH2:27][C:28]([N:30]1[CH2:34][C@@H:33]([F:35])[CH2:32][C@H:31]1[C:36]#[N:37])=[O:29])([CH3:19])[CH2:10][C:11](=[O:12])[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Reactant: CC(C)(N)CC(=O)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC(=O)N1CCCC1)NCC(=O)N1C[C@@H](F)C[C@H]1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a stirred solution of 3-amino-3-methyl-1-pyrrolidin-1-yl-butan-1-one trifluoroacetic acid (0.28 g, 1 mmol) in anhydrous THF (5 mL) was added potassium carbonate (0.55 g, 4 mmol). After stirred at room temperature for 1 h, the mixture was filtered through a Celite pad, and rinsed with ethyl acetate (5 mL). To the above filtrate was added (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (0.12 g, 0.5 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 12 h. Most of solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (20 mL) and H2O (5 mL). The aqueous layer was further extracted with CH2Cl2 (10 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a crude viscous oil. The crude oil was purified by chromatography (silica gel, 4 to 10% CH3OH/CH2Cl2 gradient) to give compound 1 (0.12 g, 74% overall yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][CH2:25][CH2:26][CH3:27])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:32][CH:31]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[CH3:40][O:39][C:37](=[O:38])[CH2:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:28][N:18]([CH2:17][CH2:16][CH2:15][N:14]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])=[CH:35][CH:34]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCCN(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCN(C)C)Cc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product from step (vi) (0.25 g), methyl (4-formylphenyl)acetate (0.15 g) and sodium triacetoxyborohydride (0.2 g) in NMP (10 mL) was stirred at rt for 18 h then heated at 45° C. for 3 h. A further portion of methyl(4-formylphenyl)acetate (0.1 g) and sodium triacetoxyborohydride (0.2 g) were added then stirred at 45° C. for 6 h. The mixture was purified by RPHPLC, yield 0.035 g.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[CH2:2]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCBr
Reactant: C1CCNC1
Solvent: CC#N
Product: CCCCCCCCCCCCCCN1CCCC1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
In a 250-mL round bottom flask, equipped with a magnetic stirrer, a heating mantle and reflux condenser, were placed 1-bromotetradecane (10 g, 36 mmol), acetonitrile (100 mL) and pyrrolidine (5.1 g, 72 mmol). The reaction mixture was refluxed for 3 hrs. The reaction mixture was cooled to room temperature and was concentrated on a rotary evaporator to a residue. Water and ethyl acetate were added. The organic phase was separated and washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated to dryness affording 7.2 g (75% yield) of 1-tetradecylpyrrolidine, as a light yellow semi-solid. This intermediate was subjected to the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:55]=[CH:54][CH:53]=[CH:52][C:5]=1[CH2:6][O:7][C:8]([NH:10][CH:11]1[CH:14]([CH2:15][CH2:16][OH:17])[N:13]([P:18]([CH2:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[N+:48]([O-:50])=[O:49])=[O:39])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]1=[O:51])=[O:9])([O-:3])=[O:2].CC(C)=[O:58].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>C(Cl)Cl>[N+:1]([C:4]1[CH:55]=[CH:54][CH:53]=[CH:52][C:5]=1[CH2:6][O:7][C:8]([NH:10][CH:11]1[CH:14]([CH2:15][C:16]([OH:58])=[O:17])[N:13]([P:18]([CH2:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[N+:48]([O-:50])=[O:49])=[O:39])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]1=[O:51])=[O:9])([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: O=C(CP(c1ccccc1)(c1ccccc1)(c1ccccc1)N1C(=O)C(NC(=O)OCc2ccccc2[N+](=O)[O-])C1CCO)OCc1ccccc1[N+](=O)[O-]
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(O)CC1C(NC(=O)OCc2ccccc2[N+](=O)[O-])C(=O)N1P(CC(=O)OCc1ccccc1[N+](=O)[O-])(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
One gram of 3-(o-nitrobenzyloxycarbonylamino)-1-(o-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4-(2-hydroxyethyl)-2-azetidinone is dissolved in 20 ml. acetone and cooled to 0° C. Jones Reagent (1 ml., 4 N solution) is added dropwise over 5 min. and the resulting solution is stirred at 0° C. for 10 min. Isopropanol (0.1 ml.) is added. The mixture is stirred for another 2 min. The reaction mixture is diluted with CH2Cl2 and filtered. The filtrate is washed with saturated NaCl solutin, dried and evaporated to give the title compound which is used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]([CH:27](O)[O:28]C)([F:26])([F:25])[F:24]>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:27]([OH:28])[C:23]([F:26])([F:25])[F:24])=[CH:12][NH:11][C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(O)C(F)(F)F
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Temperature: 120 °C
Yield: 37.8 %

Procedure:
3-Benzyloxy-2-methyl-1H-pyridin-4-one (1 g, 4.64 mmol) was mixed with potassium carbonate (0.2 g, 1.45 mmol) and CF3CH(OCH3)OH (4.34 g, 33.36 mmol) in sealed parallel synthesizer reactor and heated at 120° C. metal block temperature for 2 days. The mixture was cooled, and an additional amount of potassium carbonate (2 g, 14.5 mmol) and CF3CH(OCH3)OH (2 g, 15.30 mmol) was added. The mixture was again heated in a sealed tube at 120° C. for 60 hours. The mixture was cooled to room temperature and then evaporated to dryness. The residual material was purified by column chromatography (5% MeOH: dichloromethane) to give 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (0.55 g, 37.8% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH3:24])=[C:16]2[C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:8][CH:7]=1)=[O:5])C.C([O-])(O)=O.[Na+].CCOCC.[ClH:41]>>[ClH:41].[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH3:24])=[C:16]2[C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(SCCn2c(-c3cccnc3)c(C)c3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1c(-c2cccnc2)n(CCSc2ccc(C(=O)O)cc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
A mixture of 6.39 g of 1-[2-(4-ethoxycarbonylphenylthio)ethyl]-2-(3-pyridyl)-3-methylindole in 260 ml of 2 N HCl is heated at reflux temperature for 6 hours. After cooling the pH is adjusted to 6-7 with saturated aqueopus NaHCO3 (ca 500 ml). About 200 ml of ether is added and the mixture is stirred for 0.5 hour. A solid is collected, first washed with water, then ether, and then dissolved in 100 ml hot absolute ethanol. The solution is filtered, and while still hot treated with 1.68 ml of 6.5 N ethanolic HCl. The solution is cooled and diluted with ca 100 ml ether. The resulting product is collected to yield 1-[2-(4-carboxyphenylthio)ethyl]-2-(3-pyridyl)-3-methylindole hydrochloride, m.p. 222°-224°.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C@@H:3]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:33][CH2:32][C:22]3([CH2:31][CH2:30][C:25]4(OCC[O:26]4)[CH2:24][CH2:23]3)[C:21]2=[O:34])=[CH:16][CH:15]=1)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.Cl>C1COCC1>[F:36][C:2]([F:1])([F:35])[C@@H:3]([C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:33][CH2:32][C:22]3([CH2:31][CH2:30][C:25](=[O:26])[CH2:24][CH2:23]3)[C:21]2=[O:34])=[CH:18][CH:19]=1)[O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1
Reactant: COc1ccc(CO[C@H](c2ccc(N3CCC4(CCC5(CC4)OCCO5)C3=O)cc2)C(F)(F)F)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CO[C@H](c2ccc(N3CCC4(CCC(=O)CC4)C3=O)cc2)C(F)(F)F)cc1

Procedure:
The title compound was prepared in analogy to example 1, step 5 from 10-{4-[(R)-2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-ethyl]-phenyl}-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (4.91 g) by treatment with 2 M HCl (58.3 ml) in THF (68.2 ml) as a white solid. (3.5 g).