Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:33]([F:36])([F:35])[F:34])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:32])[CH2:24][N:23]([C:25]([CH:27]5[CH2:30][S:29](=[O:31])[CH2:28]5)=[O:26])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[OH:37]OS([O-])=O.[K+]>CO.O>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:33]([F:35])([F:36])[F:34])[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4([F:32])[CH2:22][N:23]([C:25]([CH:27]5[CH2:28][S:29](=[O:37])(=[O:31])[CH2:30]5)=[O:26])[CH2:24]4)=[CH:19][CH:20]=3)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: O=C(C1CS(=O)C1)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(C1CS(=O)(=O)C1)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidin-1-yl)(1-oxidothietan-3-yl)methanone (30 mg) in methanol (2 mL) was added to a solution of oxone (160 mg) in water (1 mL) cooled with an ice bath. Reaction allowed to warm slowly to ambient then stirred at ambient temperature for 16 hours. Majority of methanol removed under reduced pressure then remaining aqueous extracted with DCM (2×5 mL). Organic phase collected and condensed. The crude material was adsorbed on silica and chromatographed on a 4 g silica column, eluting with a gradient of 0% to 100% ethyl acetate in heptane. Fractions containing the desired material were combined and concentrated. Placing the flask on high vacuum overnight resulted in formation of a white foam. Yield 15.7 mg (51%). 1H NMR (DMSO-D6) δ 7.82 (m, 4H), 7.69 (m, 2H), 4.67 (d, 2H), 4.46-4.29 (m, 8H), 3.56-3.43 (m, 1H). LC/MS retention time=3.455 minutes, MS calculated for (C23H17Cl2F5N2O4S), 582.02; nd M+H+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH3:13][C@H:14]([NH:23][CH3:24])[C@@H:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]2[N:23]([CH3:24])[C@@H:14]([CH3:13])[C@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12]2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: O=Cc1cc(Br)cc2c1OCC2
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Solvent: c1ccccc1
Product: C[C@H]1[C@H](c2ccccc2)OC(c2cc(Br)cc3c2OCC3)N1C
Yield: 77.5 %

Procedure:
A sample of 20 (650 mg, 2.9 mmol) and (1S,2S) pseudoephedrine (500 mg, 3.0 mmol) in 40 mL of benzene was refluxed overnight using a Dean-Stark trap. Solvent removal yielded yellow crystals which were recrystallized from a minimum of hot hexanes to give white crystals of 21 (841 mg, 79%), mp=83.5-85.5° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:24][CH3:25])[N:3]=[C:2]([NH:34][CH2:33][CH2:32][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[N:11]=[C:10]2[N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13]
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3cc(OC)c(OC)cc23)cc1
Product: COc1ccc(N(C)c2nc(NCCN3CCOCC3)nc3cc(OC)c(OC)cc23)cc1

Procedure:
The title compound was prepared from (2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg, 0.139 mmol) and 2-morpholin-4-yl-ethylamine (25 μL, 0.167 mmol) by a procedure similar to Example 10 and was isolated as white powder (27 mg, 54%). 1H NMR (CDCl3): 7.21 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.93 (s, 1H), 6.13 (s, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.77-3.74 (m, 4H), 3.71-3.66 (m, 2H), 3.60 (s, 3H), 3.25 (s, 3H), 2.70 (t, J=7.2 Hz, 2H), 2.59-2.56 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH:14]1([C:20]([OH:22])=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.Cl.[NH2:25][C:26]1[CH:58]=[CH:57][C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:38]=[C:37]([CH2:39][O:40][C:41]4[CH:54]=[CH:53][C:44]([CH2:45][CH:46]5[S:50][C:49](=[O:51])[NH:48][C:47]5=[O:52])=[CH:43][CH:42]=4)[N:36]([CH3:55])[C:35]=3[CH:56]=2)=[CH:28][CH:27]=1>CN(C)C=O>[O:51]=[C:49]1[NH:48][C:47](=[O:52])[CH:46]([CH2:45][C:44]2[CH:43]=[CH:42][C:41]([O:40][CH2:39][C:37]3[N:36]([CH3:55])[C:35]4[CH:56]=[C:31]([O:30][C:29]5[CH:57]=[CH:58][C:26]([NH:25][C:20]([CH:14]6[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]6)=[O:22])=[CH:27][CH:28]=5)[CH:32]=[CH:33][C:34]=4[N:38]=3)=[CH:54][CH:53]=2)[S:50]1
Reactant: O=C(O)C1CCCCC1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)C4CCCCC4)cc3)cc21
Reaction time: 1.5 h

Procedure:
Triethylamine (0.32 ml) and ethyl chloroformate (0.08 ml) were added dropwise to a solution of cyclohexanecarboxylic acid (0.09 ml) in anhydrous N,N-dimethylformamide (8 ml). After stirring the mixture for 90 minutes, 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) was added and this mixture was stirred at room temperature for 2 hours and then for 90 minutes in an oil bath at 50° C. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate to afford the title compound (262 mg, pale orange powder, mp 182-184° C.).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Si]([O:34][CH2:35][CH2:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1)(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+].O1CCOCC1>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>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:40]4[CH:39]=[N:38][N:37]([CH2:36][CH2:35][OH:34])[CH:41]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
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: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3cnn(CCO)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was concentrated. The residue was treated with methanol. The solid was filtered off. The filtrate was concentrated. The resulting residue was dissolved in 1.5 ml of 1% HCl ethanol solution, and stirred at r.t. overnight. Then it was purified with RP-HPLC (pH=10) to afford the desired product (4.6 mg). LCMS (M+H)+: m/z=449.3.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>O1CCCC1.C(O)(C)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:33][CH3:34])=[O:19])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc3cccnc3n2CC(=O)O)s1
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(C)s2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A solution of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183 mole) in tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with a stream of nitrogen bubbling through it. A solution of dipropylamine (5.56 g, 0.055 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was stirred overnight at room temperature. The solvents were evaporated and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. The organic layer was dried over magnesium sulfate, treated with charcoal, filtered, and evaporated to give a solid which was dissolved in hot isopropyl alcohol and filtered while hot. Addition of water and cooling caused a solid to precipitate. The solid was dissolved again in hot isopropyl alcohol with charcoal, filtered while hot and brought to the cloud point by addition of water. Upon cooling, solid precipitated which was collected by filtration, rinsed with water, and dried under high vacuum at 50° C. overnight to give 2.28 g (35%) of title compound, mp 125°-127° C.
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].Br[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O>C(O)C>[SH:4][C:1]1[S:3][C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:2]=1
Reactant: NC(=S)[S-]
Reactant: O=C1CCCCC1Br
Agent: [NH4+]
Solvent: CCO
Product: Sc1nc2c(s1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To a solution of ammonium dithiocarbamate (1.4 g, 12.4 mmol) in 25 mL of ethanol was added 2-bromocyclohexanone (2.2 g, 12.4 mmol). The reaction was stirred at rt overnight. The next morning the reaction was heated at 70° C. for 1 h. The solvent was removed under reduced pressure. The product was subjected to flash chromatography (3:1 hexane/ethyl acetate) to recover a yellow solid. Recrystallization from ethyl acetate afforded 0.54 g of 2-mercapto-4,5,6,7-tetrahydrobenzothiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure BB and using 3,4-dichlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid haying a melting point of 811-83° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: NC1C=CC(C#N)=NC=1N.ClC1C=C(C=CC=1Cl)[O:15]C1C=CC(C=O)=CC=1.CN(C)C(=O)C.[Cl:34][C:35]1[CH:36]=[C:37]([CH:56]=[CH:57][C:58]=1[Cl:59])[O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[NH:46][C:47]3[C:48]([N:55]=2)=[N:49][C:50]([C:53]#[N:54])=[CH:51][CH:52]=3)=[CH:41][CH:40]=1>O.[OH-].[Na+]>[Cl:34][C:35]1[CH:36]=[C:37]([CH:56]=[CH:57][C:58]=1[Cl:59])[O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[NH:46][C:47]3[C:48]([N:55]=2)=[N:49][C:50]([C:53]([NH2:54])=[O:15])=[CH:51][CH:52]=3)=[CH:41][CH:40]=1
Reactant: N#Cc1ccc2[nH]c(-c3ccc(Oc4ccc(Cl)c(Cl)c4)cc3)nc2n1
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Agent: N#Cc1ccc(N)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: NC(=O)c1ccc2[nH]c(-c3ccc(Oc4ccc(Cl)c(Cl)c4)cc3)nc2n1
Temperature: 120 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
2-[4-(3,4-Dichloro-phenoxy)-phenyl]-1H-imidazo[4,5-b]pyridine-5-carboxylic acid amide. A flask containing 6-amino-5-nitro-pyridine-2-carbonitrile (67 mg, 0.40 mmol), 10% palladium on carbon (catalytic) and ethanol (2.0 mL) was put under an atmosphere of H2 using a balloon. The mixture was stirred at room temperature for 3 h, and filtered through a pad of celite. The filtrate was concentrated to provide crude 5,6-diamino-pyridine-2-carbonitrile. A portion of this 5,6-diamino-pyridine-2-carbonitrile (89 mg, 0.66 mmol) was treated with 4-(3,4-dichloro-phenoxy)-benzaldehyde (177 mg, 0.66 mmol), Na2S2O5 (188 mg, 0.99 mmol) and N,N-dimethylacetamide (3.0 mL). The mixture was stirred at 120° C. for 24 h. The reaction mixture was then diluted with water (8 mL), and the resulting precipitate was collected by filtration. The crude filtrate, 2-[4-(3,4-dichloro-phenoxy)-phenyl]-1H-imidazo[4,5-b]pyridine-5-carbonitrile (35 mg, 0.09 mmol), was treated with boron trifluoride/acetic acid complex (461 μL) and water (10 μL), and held at 115° C. for 30 min. The reaction mixture was cooled to room temperature and diluted with 4 N NaOH (10 mL). The resulting precipitate was collected by filtration, washed with water, and dried to provide 34 mg (94%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(O[BH-](O[C:24](=[O:26])[CH3:25])OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:6][C:5]2[O:26][C:24]3[C:25](=[N:8][CH:3]=[CH:2][CH:7]=3)[CH:4]=2)[CH2:10][CH2:9]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Fc1ccccc1N1CCNCC1
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Fc1ccccc1N1CCN(Cc2cc3ncccc3o2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-(2-Fluorophenyl)piperazine (0.18 g, 1.0 mmol) and sodium triacetoxyborohydride (0.32 g, 1.5 mmol) in dichloroethane (2 mL) were treated with the product from Example 35B (2 mL, 1.0 mmol) as a 0.5M solution in dichloroethane dropwise. The mixture was allowed to stir at room temperature for 17 hours. The mixture was diluted with dichloromethane (10 mL) and washed with 1N NaOH. The organic layer was dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica (dichloromethane to 2% methanol in dichloromethane) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 2.81 (br, 4H), 3.19 (br, 4H), 3.85 (s, 2H), 6.89 (s, 1H), 7.00 (m, 4H), 7.20 (dd, J=4.75, 8.14 Hz, 1H), 7.74 (d, J=8.48 Hz, 1H), 8.52 (d, J=4.75 Hz, 1H); MS (DCI/NH3) m/z 312.2 (M+H)+; Anal. Calcd for C18H18FN3O: C, 69.44; H, 5.83; N, 13.50. Found: C, 69.36; H, 5.59; N, 13.28.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:7]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.FC(F)(F)C(O)=O.CO[CH2:30][N:31]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:32][Si](C)(C)C>C(Cl)Cl>[CH2:37]([N:31]1[CH2:32][C@@H:5]([C:6]2[C:7]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=2)[C@H:4]([C:3]([O:2][CH3:1])=[O:20])[CH2:30]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)/C=C/c1cc2ccccc2cc1C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2ccccc2cc1[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
To a solution of (E)-methyl 3-(3-methoxy-3-oxoprop-1-enyl)-2-naphthoate (1.65 g, 6.09 mmol) in 15 mL of methylene chloride was added trifluoroacetic acid (0.07 mL, 0.91 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (2.34 mL, 9.13 mmol). The reaction mixture was allowed to stir at ambient temperature for 18 h. The solution was concentrated in vacuo and purified (ISCO, elution with 0-25% EtOAc/hexane) to afford 2.1 g (86%) of the title compound as an oil. 1H NMR (CDCl3): δ 8.34 (s, 1H), 8.15 (s, 1H), 7.87-7.80 (m, 2H), 7.58-7.53 (m, 1H), 7.50-7.41 (m, 3H), 7.39-7.33 (m, 2H), 7.30-7.25 (m, 1H), 4.57-4.51 (m, 1H), 3.94 (s, 3H), 3.74 (ABq, 2H), 3.68 (s, 3H), 3.36-3.31 (m, 1H), 3.27-3.20 (m, 1H), 3.07-3.02 (m, 2H), 2.80-2.75 (m, 1H). LRMS (ESI): 404.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:41]=[CH:42][CH:43]=[CH:44][C:26]=2[C:25]2[CH:45]=[CH:46][CH:47]=[CH:48][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:27]2[CH:41]=[CH:42][CH:43]=[CH:44][C:26]=2[C:25]2[CH:45]=[CH:46][CH:47]=[CH:48][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: CC(C)[C@H](N)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-U), the title compound was prepared. The product was purified by chromatography (silica, 1-2% MeOH/CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[CH:20]=[C:21]([CH:25]=[C:26]([N:28]5[CH2:32][CH2:31][O:30][C:29]5=[O:33])[CH:27]=4)[C:22]([O-:24])=[O:23])[C:11]3=[O:34])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]4[CH:20]=[C:21]([CH:25]=[C:26]([N:28]5[CH2:32][CH2:31][O:30][C:29]5=[O:33])[CH:27]=4)[C:22]([OH:24])=[O:23])[C:11]3=[O:34])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])c1cc(N2CCOC2=O)cc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(N2CCOC2=O)cc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a solution of (1S,2S) and (1R,2R)-3-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)-5-(2-oxooxazolidin-3-yl)benzoate (43 mg, 0.088 mmol) in MeOH (2 mL) and H2O (0.2 mL) was added lithium hydroxide (18 mg, 0.44 mmol). The reaction mixture was stirred at room temperature until TLC indicated no further reaction. The methanol was removed under reduced pressure. After quenching with concentrated HCl (3.0 N), the mixture was extracted with ethyl acetate for three times. The organic layers were dried over anhydrous Na2SO4 and concentrated to give the crude product. Purification by preparative HPLC gave desired product as white solid (29 mg, 70%). LC/MS m/e calcd. for C26H19ClN2O5: 474, observed (M+H)+: 475.1 1H NMR (400 MHz, MeOD-d4) δppm 2.22-2.33 (m, 2 H) 3.35-3.39 (m, 1 H) 4.22 (t, J=8.08 Hz, 2H) 4.56 (t, J=7.96 Hz, 2 H) 6.15 (d, J=7.07 Hz, 1 H) 6.81 (t, J=7.20 Hz, 1 H) 6.96 (d, J=7.83 Hz, 1 H) 7.15 (t, J=7.33 Hz, 1 H) 7.33 (q, J=8.51 Hz, 4 H) 7.91 (s, 1 H) 8.11 (t, J=2.02 Hz, 1 H) 8.26 (s, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([O:18][CH3:19])[CH:13]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:12]2.[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([O:18][CH3:19])[CH:13]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:12]2)[CH2:37][C:33]1[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=1
Reactant: CCCN(CCC)CCCCC1Cc2cc(CNCc3ncc[nH]3)ccc2C1OC
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCC1Cc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2C1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (54.8 mg) obtained in Example 127-14 was dissolved in methanol (2.74 ml) and added with 1-methyl-2-imidazole carboxaldehyde (21.9 mg) and sodium cyanoborohydride (16.7 mg). Then, the solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and added with saturated saline solution. The solution was subjected to separation/extraction with chloroform. The extract was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (35.9 mg) of the subject compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:10].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(=O)([O-])O.[Na+]>ClCCl>[CH3:20][S:21]([O:1][CH2:2][CH2:3][C:4]1([CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:10])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCCCC1(CO)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(COS(C)(=O)=O)CCCNC1=O
Temperature: 0 °C

Procedure:
A solution of 1 mmol of 3-(2-hydroxy-ethyl)-3-hydroxymethyl-piperidin-2-one in 3 ml of dichloromethane is admixed at 0° C. with 3 mmol of triethylamine, followed by 2.2 mmol of methanesulphonyl chloride. The reaction mixture is stirred at 0° C. for an hour and then at room temperature for an hour. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (2×). The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[CH:22][C:23]([F:28])=[C:24]([CH:27]=1)[C:25]#[N:26].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:28][C:23]1[CH:22]=[CH:21][C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(-c2cccc3[nH]ccc23)ccc1F
Temperature: 83 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (4 g, 16.4 mmol), and 5-bromo-2-fluorobenzonitrile (3.28 g, 16.4 mmol) in THF (564 mL) were added Palladium catalyst Pd(PPh3)4 (0.6 g, 0.5 mmol) and the freshly prepared sodium carbonate solution (5.22 g in 23 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 83° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 2.18 g (56%) of 2-fluoro-5-(1H-indol-4-yl)-benzonitrile.