Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([N+:24]([O-])=O)[CH:18]=2)[CH:14]=1.C(O)C>O1CCCC1>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([NH2:24])[CH:18]=2)[CH:12]=[N:11][CH:10]=1
Reactant: O=[N+]([O-])c1cc(C#Cc2cncc(Cl)c2)ccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 70 °C
Yield: 78 %

Procedure:
Add tin chloride dihydrate (7.13 mg, 31.6 mmol) to a solution of 3-chloro -5-(4-fluoro-3-nitrophenylethynyl)-pyridine, (prepared as described in EXAMPLE 189) (0.97 g, 3.51 mmol) in 2:1 ethanol:tetrahydrofuran (150 mL). Heat the mixture at 70° C. for 2.5 h. Cool to room temperature and concentrate. Dilute with a 50% solution of aqueous potassium hydroxide (300 g) and extract with diethyl ether (5×150 mL). Wash the combined extracts with water (1×50 mL) and saturated aqueous sodium chloride (1×50 mL). Dry (sodium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 75:25 hexanes:ethyl acetate, to give the title compound as a light yellow solid (670 mg, 78%).
Reaction SMILES: [OH2:1].[OH:2][CH2:3][C@@H:4]1[C:10]([CH3:11])=[CH:9][C@@H:8]2[CH2:12][N:5]1[C:6](=[O:17])[N:7]2[O:13][CH2:14][CH:15]=[CH2:16]>CC#N>[CH3:11][C:10]1[CH:4]([C:3]([OH:1])=[O:2])[N:5]2[CH2:12][CH:8]([CH:9]=1)[N:7]([O:13][CH2:14][CH:15]=[CH2:16])[C:6]2=[O:17]
Reactant: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2CO
Reactant: O
Solvent: CC#N
Product: C=CCON1C(=O)N2CC1C=C(C)C2C(=O)O

Procedure:
To a solution of H5IO6 (12.93 g, 56.71 mmol) in wet CH3CN (150 mL, 0.75% H2O v/v) at r.t. was added CrO3 (128 mg, 1.28 mmol). The mixture was stirred until complete dissolved was achieved. Into a 100-mL round-bottom flask, was placed wet acetonitrile (35 mL), (2S,5R)-2-(hydroxymethyl)-3-methyl-6-(prop-2-en-1-yloxy)-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (Intermediate 149, 740 mg, 3.30 mmol, 1.00 equiv) and it was cooled to 0° C., then the above oxidation solution (35 mL, 3.00 equiv) was added dropwise during 30 min at 0° C. The resulting solution was stirred for 1 h at 0° C. in a water/ice bath and monitor by TLC until the material was consumed completely. Then it was diluted with 200 mL of chloroform and 50 mL of citric acid solution (25%). Separating the organic layer and the organic layer was washed by 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.700 g crude of the title compound as yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10][CH3:11].[Mg].II.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C1(OC(Cl)=O)C=CC=CC=1>O1CCCC1>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[S:10][CH3:11])[CH:18]=1
Reactant: COc1ccc(Br)c(SC)c1
Reactant: COc1ccncc1
Agent: II
Agent: O=C(Cl)Oc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccnc(-c2ccc(OC)cc2SC)c1
Temperature: 25 °C

Procedure:
A Grignard reagent was prepared from the product of step (d) above (12.3 g), magnesium (1.28 g) and iodine (1 crystal) in dry tetrahydrofuran (150 ml). 4-Methoxypyridine (5.76 g) was dissolved in dry tetrahydrofuran (300 ml) and stirred under nitrogen. The solution was cooled to -70°and treated with the above Grignard solution in one portion. After stirring for 10 minutes phenylchloroformate (6.6 ml) was added dropwise. After stirring at -70°for 30 minutes the mixture was allowed to warm up to room temperature. After stirring for 90 minutes the mixture was poured onto water and extracted with ether. The ether was washed with water and brine then dried and evaporated. The residue was taken up in toluene (250 ml) and stirred at room temperature. A solution of 3,4,5,6-tetrachloro-1,2-benzoquinone (13.0 g) in acetic acid (120 ml) was added dropwise. When addition was complete the mixture was stirred for a further 18 hours. The mixture was ice cooled and treated with a cold solution of sodium hydroxide (700 ml of 10%). After stirring for 10 minutes the mixture was filtered and separated. The aqueous filtrates were extracted with ether and the combined organic filtrates were extracted with dilute hydrochloric acid. The extracts were combined and basified with sodium hydroxide solution. The mixture was extracted with ether and the combined extracts washed with brine then dried and evaporated. Flash chromatography (1:1 ethyl acetate/petroleum ether) produced the subtitle compound as a clear oil 5.4 g. NMR (CDCl3) d 8.50 (d,1 H), 7.39 (d,1H), 7.60 (d,1H), 6.85 (d,1H), 6.77 (m,2H), 3.88 (s,3H), 3.86 (s,3H), 2.40 (s,3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1[OH:20].B(F)(F)F.CCOCC>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:18]1[CH:19]=[C:13]([Cl:12])[C:14]([OH:20])=[CH:15][C:16]=1[OH:17])=[O:11]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Oc1ccc(Cl)c(O)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1Br)c1cc(Cl)c(O)cc1O
Reaction time: 2 h

Procedure:
This compounds was synthesised in the same manner as described above. 2-Bromophenylacetic acid (5 g, 23.3 mmol), 4-chlororesorcinol (3.36 g, 23.3 mmol), boron trifloride etherate (20 ml). After standing for two hours a brown precipitate formed (7.4 g, 93.3%); Rf 0.4 hexane/ethyl acetate (70/30). This was shown to be the required product.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[C:22]([OH:24])=O.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:41]([CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:53](=[N:55]O)[NH2:54])[CH:38]=3)[C:33]2=[O:57])=[CH:28][CH:27]=1>CN(C=O)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH:14]1[C:22]1[O:24][N:54]=[C:53]([C:37]2[CH:38]=[C:39]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:57])[N:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[C:41]([CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:40]3)[N:55]=1
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(C(N)=NO)ccc2c(=O)n1-c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(-c3noc(C4Cc5ccccc5C4)n3)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
CDI (21.45 mg, 0.132 mmol) was added to a stirred, room temperature mixture of 2-indanecarboxylic acid (17.88 mg, 0.110 mmol) in DMF (1 mL), and the mixture was stirred at room temperature for 2 h. tert-butyl 5-(2-(4-fluorophenyl)-6-(N′-hydroxycarbamimidoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (50 mg, 0.110 mmol) was added, and the resultant mixture was kept stirring at 100° C. for overnight. The reaction was checked with LCMS and starting material disappeared. The mixture was cooled to room temperature, precipitate formed, filtered and washed with water (20 mL), dried in vacuum oven to give tert-butyl 5-(6-(5-(2,3-dihydro-1H-inden-2-yl)-1,2,4-oxadiazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (51 mg, 0.088 mmol) as a light tan solid.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:9]I.[CH3:11][N:12]([CH:14]=O)[CH3:13]>>[CH3:11][N:12]1[C:13]2[C:2](=[CH:3][CH:4]=[CH:5][CH:1]=2)[CH:9]=[CH:14]1
Reactant: CI
Reactant: O=C1CCCC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cn1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of the cyclopentanone adduct intermediate 1-3 from step 2 (3.81 g, 14.8 mmol) in anhydrous DMF (150 mL) at 0° C., NaH (60% dispersion in oil, 770 mg, 19.2 mmol) was added slowly. The reaction mixture was stirred at 0° C. for 5 min, then MeI (1.2 mL, 19.2 mmol) was added drop-wise and stirring was continued at 0° C. for 3 h. The mixture was allowed to warm-up to RT and was quenched by the addition of aqueous saturated NH4Cl (200 mL). The mixture was extracted with EtOAc (2×500 mL) and the organic layer was washed with aqueous saturated NH4Cl (2×200 mL) H2O (200 mL) and brine (200 mL). The combined organic layers were dried over anhydrous MgSO4, evaporated to dryness and the residue was purified by flash column chromatography (using 30% EtOAc in hexane as the eluent) to isolate the N-methylindole intermediate 1-4 as a beige solid (3.1 g, 77% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: COc1ccc(F)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(F)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101.2 %

Procedure:
A mixture of 2-fluoro-5-methoxy-benzoic acid (4.3 g, 25 mmol) and thionyl chloride (68 mL, 937 mmol) and DMF (1 drop) was stirred at RT for 14 hours. The mixture was then evaporated to afford the title compound (4.77 g, 100%) after repeated azeotroping with toluene.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.Cl>O1CCOCC1.CCOCC>[ClH:21].[NH2:8][CH2:9][CH:10]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)C(CN)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 178.2 %

Procedure:
A solution of methyl 3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoate (451 mg, 1.44 mmol) in dioxane (6.0 mL) was treated with 4M HCl in dioxane (about 6.0 mL, 23.0 mmol) at room temperature. The mixture was stirred for 18 hours to completion, after which the reaction mixture was diluted with ether to afford a precipitate. The slurry was filtered under nitrogen to afford a white solid, which washed with ether. The solid was dried under vacuum to afford the methyl 3-amino-2-(4-chlorophenyl)propanoate hydrochloride as a white solid (321 mg, 89%). LCMS (APCI+) m/z 214.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Br.Br[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[N:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:9])=[CH:4][CH:3]=2)=[CH:25][CH:26]=1
Reactant: BrCc1ccncc1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Agent: Br
Product: O=C(c1ccc(OCc2ccncc2)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-(bromomethyl)pyridine hydrobromide. MS (ES+) 366.2
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:23]C1C=C2C(=CC=1)NC(=O)[C@]12C[C@H]1C1C=C2C(C=NN2)=CC=1>>[F:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:22])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([I:1])=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: O=C1Nc2ccc(F)cc2[C@]12C[C@H]2c1ccc2cn[nH]c2c1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Product: O=C1Nc2ccc(F)cc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Yield: 57 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-2-(3-iodo-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (1R,2S)-5′-fluoro-2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (240 mg, 0.818 mmol). Purification using Biotage Isolera with SNAP 25 g column with 5-90% EtOAc in hexane yielded the title compound as a cream solid (195 mg, 57%; 97% e.e.) with the major (1R,2S) enantiomer eluting at 3.7 min (Phenomenex Lux 5μ Cellulose-2 (150×4.6 mm); isocratic 25% EtOH in n-hexane; 1.5 mL/min; 24° C.; Detection: 254 nm). From the racemic reference standard, the retention time of the (1S,2R) enantiomer was 3.2 min using this method. NMR (400 MHz, CD3OD) δ 7.47 (s, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.88 (dd, J=8.8, 4.4 Hz, 1H), 6.79 (t, J=8.8 Hz, 1H), 5.69 (d, J=8.4 Hz, 1H), 3.38 (t, J=8.8 Hz, 1H), 2.28 (dd, J=8.8, 4.2 Hz, 1H), 2.21 (dd, J=9.2, 4.4 Hz, 1H); MS ESI 420.0 [M+H]+, calcd for [C17H11FIN3O+H]+ 420.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:14])([F:13])[F:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].I[CH3:18]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:13])([F:14])[F:12])=[N:8][N:9]([CH3:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)nc1C(F)(F)F
Temperature: 0 °C
Yield: 81.5 %

Procedure:
Dissolve 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.0 g, 9.61 mmol) in N,N-dimethylformamide (20 mL) and cool to 0° C. Add sodium hydride (0.58 g, 14.42 mmol, 60% dispersion in oil) and stir at 0° C. for 20 min. Add iodomethane (0.90 mL, 14.42 mmol) and allow to warm to room temperature over 18 hr. Partition between ethyl acetate (100 mL) and water (50 mL). Separate the organic layer and wash with water (5×50 mL) and saturated aqueous sodium chloride solution (50 mL). Dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 90:10 hexanes:ethyl acetate), to give 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.74 g, 81.7%). 1H-NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 4.27 (q, 2H), 3.95 (s, 3H), 1.33 (t, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([Cl:27])[CH:33]=4)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(I)cc3)nc2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
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: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(Cl)c4)cc3)nc2)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a sealed tube was added N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-iodophenyl)acetamide 177-2 (100 mg, 0.22 mmol), 2-chloropyridin-4-ylboronic acid 177-3 (52 mg, 0.33 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), saturated Na2CO3 (1 mL), ethanol (1 mL) and toluene (3 mL). The reaction was heated to 110° C. and stirred for 16 hours. The reaction was cooled down to room temperature, then extracted with ethyl acetate. The crude product was purified by silica-gel flash chromatography, eluted with ethyl acetate to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-fluoropyridin-4-yl)phenyl)acetamide 177 as off-white solid. MS m/z 450.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.51 (s, 1H), 8.40 (d, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.78 (d, 1H), 7.76 (d, 2H), 7.69 (dd, 1H), 7.43 (d, 2H), 7.37 (dd, 1H), 3.68 (s, 2H), 3.52 (m, 4H), 3.09 (t, 2H), 3.02 (t, 2H), 1.97 (s, 3H).
Reaction SMILES: C([S:4][CH2:5][CH:6]([C:21]([F:24])([F:23])[F:22])[C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH:6]([C:21]([F:24])([F:22])[F:23])[C:7]([N:9]1[CH2:16][C:15]([O:17][CH3:18])([O:19][CH3:20])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(CSC(C)=O)C(F)(F)F)C1
Agent: N
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(CS)C(F)(F)F)C1

Procedure:
Each individual isomer product from Example 19 is hydrolyzed with concentrated ammonia according to the procedure of Example 4 to yield 1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4,4-dimethoxy-L-proline, isomer A and 1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4,4-dimethoxy-L-proline, isomer B.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NC1CCN(CCCO)CC1)c1ccccc1
Product: O=C(NC1CCN(CCCOC(=O)c2ccccc2)CC1)c1ccccc1
Yield: 92.5 %

Procedure:
Treatment of 4-benzamido-1-(3-hydroxypropyl) piperidine with benzoyl chloride as in the previous example gave 3.4 grams (92.5% yield) of the title compound, m.p. 146°-7° C. Crystallisation from ethanolic hydrogen chloride afforded the hydrochloride, m.p. 211°-212° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:12][CH:11]([NH2:13])[CH2:10]2)=[N:7][CH:8]=1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:13][CH:11]1[CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:8][N:7]=2)[CH2:12]1)=[O:25]
Reactant: NC1CN(c2ccc(C(F)(F)F)cn2)C1
Reactant: O=C=Nc1ccccc1Br
Solvent: ClCCl
Product: O=C(Nc1ccccc1Br)NC1CN(c2ccc(C(F)(F)F)cn2)C1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
D7 (100 mg, 0.46 mmol) in dichloromethane (2 ml) at ambient temperature was treated with 2-bromophenyl isocyanate (91 mg, 0.46 mmol) in dichloromethane (1 ml). The reaction mixture was maintained at ambient temperature overnight. The white solid was removed by centrifugation and washed with diethyl ether, and dried in vacuo, to give the title compound, (160 mg). MH+ 415, 417.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(N([CH:18]([CH3:20])[CH3:19])CC)(C)C.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](Cl)=[O:30]>ClCCl.O>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29]([N:1]([C:29](=[O:30])[CH2:28][C:23]1[CH:22]=[CH:27][CH:26]=[CH:20][C:18]=1[CH3:19])[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)=[O:30]
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccccc1CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(N(C(=O)Cc2ccccc2C)C(=O)Cc2ccccc2C)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a chilled solution (0° C.) of 5.0 g of methyl 6-aminopyridine-3-carboxylate and 12.6 ml of diisopropylethylamine in 40 ml of dichloromethane under argon is added 12.2 g of 2-methylbenzeneacetyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature 16 hours and diluted with 200 ml of dichloromethane and 50 ml of water. The organic layer is separated and washed with 50 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue (9.0 g) is purified by chromatography on silica gel with hexaneethyl acetate (3:1) as eluent to give 0.70 g of methyl 6-[[bis(2-methylbenzeneacetyl)]amino]pyridine-3-carboxylate and 8.6 g of a mixture of methyl 6-[(2-methylbenzeneacetyl)amino]pyridine-3-carboxylate and the bis acylated product. The above mixture (8.6 g) of mono and bis acylated product is dissolved in 60 ml of tetrahydrofuran-methanol (1:1) and 23 ml of 5N NaOH is added. The solution is stirred at room temperature for 16 hours, concentrated under vacuum, diluted with 25 ml of H2O and acidified with cold 1N HCl. The precipitated solid is filtered off and dried to give 5.9 g of white solid.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[N:5]\[O:6][CH3:7].C1(C)C=CC=C(OC2C=CC=CC=2OC(=O)[CH:38]=[N:39]OC)C=1.CN>>[CH3:38][NH:39][C:3](=[O:2])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[N:5]\[O:6][CH3:7]
Reactant: CO/N=C(\C(=O)OC)c1ccccc1Oc1cccc(C)c1
Reactant: CON=CC(=O)Oc1ccccc1Oc1cccc(C)c1
Agent: CN
Product: CNC(=O)/C(=N\OC)c1ccccc1Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To Product (A') (286 mg), i.e. methyl-(Z)-2-[2-(3-tolyloxy)phenyl]-2-methoxyiminoacetate, [2-(3-tolyloxy)phenyl]-2-methoxyiminoacetate, 30 % methanolic methylamine (197 mg) was added, followed by stirring at room temperature for 12 hours. Excess amine and methanol were removed from the mixture, which was subjected to silica gel column chromatography with a mixture of hexane and ethyl acetate to give 201 mg of (Z)-N-methyl-2-[2-(3-tolyloxy)phenyl]-2-methoxyiminoacetamide (Compound No. 5).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]3[CH2:20][CH:19]([OH:21])[CH:18]([OH:22])[CH2:17]3)=[CH:15][C:10]=2[O:9][CH2:8]1>C1COCC1.O>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([CH2:20][CH:19]=[O:21])[CH2:17][CH:18]=[O:22])=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: OC1CC(c2ccc3c(c2)OCO3)CC1O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=CCC(CC=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of sodium periodate (1.91 mmol, 0.41 g) in THF (3 mL) and H2O (2 mL) at 0° C. was added diol 99 (1.91 mmol, 0.42 g). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered, and the resulting dialdehyde 100 was used as is, as an aqueous solution.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Ca+2].FC(F)(F)S([O-])(=O)=O.[C:18]1([S:24]([N:27]2[C:39]3[CH2:38][NH:37][CH2:36][CH2:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O:40]1[CH2:42][CH:41]1[CH:43]1[CH2:52][CH2:51][C:46]2([O:50][CH2:49][CH2:48][O:47]2)[CH2:45][CH2:44]1>O1CCCC1>[C:18]1([S:24]([N:27]2[C:39]3[CH2:38][N:37]([CH2:42][CH:41]([CH:43]4[CH2:52][CH2:51][C:46]5([O:50][CH2:49][CH2:48][O:47]5)[CH2:45][CH2:44]4)[OH:40])[CH2:36][CH2:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(c1ccccc1)n1c2c(c3ccccc31)CCNC2
Reactant: C1COC2(CCC(C3CO3)CC2)O1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ca+2]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c2c(c3ccccc31)CCN(CC(O)C1CCC3(CC1)OCCO3)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Calcium trifluoromethanesulfonate (1.22 g, 3.60 mmol) was added to a solution of the product from stage 3 (2.51 g, 8.05 mmol) and 8-oxiranyl-1,4-dioxaspiro[4.5]decane (1.34 g, 7.30 mmol) in anhydrous tetrahydrofuran (50 ml) and the mixture was stirred at room temperature for 48 h. The tetrahydrofuran was removed i. vac. The residue was taken up in methylene chloride (40 ml) and the mixture was washed with 25% potassium carbonate solution (2×25 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (4.31 g) was purified by flash chromatography with cyclohexane/ethyl acetate (1:2).