Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH:13]([CH3:16])[CH2:14]O)[CH2:9][CH2:8]1.P(Br)(Br)[Br:18].O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH:13]([CH3:16])[CH2:14][Br:18])[CH2:9][CH2:8]1
Reactant: CC(CO)N1CCN(c2ccccn2)CC1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(CBr)N1CCN(c2ccccn2)CC1
Temperature: 60 °C

Procedure:
The alcohol prepared in Part (b) hereinabove, (30 grams; 0.136 moles), diluted with 40 ml of chloroform is added dropwise to 15 cc of phosphorus tribromide. The mixture is warmed to about 60° C. for 2 hours. The mixture is then cooled to below 0° C. and the excess of the reagent is decomposed with water. The mixture is made alkaline, the organic phase is separated and the aqueous phase extracted with chloroform. The total organic phase is combined, dried and allowed to evaporate, giving as a residue a yellow solid material, which after recrystallization gives Compound (c) with m.p. 50°-51° C. from n-hexane; Rf=0.54 (from ethyl acetate); IR (nujol) νmax: 1600, 1490, 1445, 1320, 1260, 785 cm-1 ; Br (Schoeninger)--Calculated %: 28.1--Found %: 27.9.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([CH3:25])([OH:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([Br:27])=[C:10]([F:26])[CH:11]=3)[N:6]=1.[CH3:28]S(O)(=O)=O.C([O-])(O)=O.[Na+]>CO>[Br:27][C:9]1[CH:8]=[C:7]2[C:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:24][CH3:28])([CH3:23])[CH3:25])[CH:18]=3)[O:13][C:12]2=[CH:11][C:10]=1[F:26]
Reactant: CS(=O)(=O)O
Reactant: CC(C)(O)C#Cc1cnc2c(c1)C1(COC(N)=N1)c1cc(Br)c(F)cc1O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(C)(C)C#Cc1cnc2c(c1)C1(COC(N)=N1)c1cc(Br)c(F)cc1O2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(2′-amino-7-bromo-8-fluoro-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol (0.580 g, 1.342 mmol) in 10 mL MeOH was treated with methanesulfonic acid (0.871 mL, 13.42 mmol). The resulting solution was allowed to stir at RT for 72 hours and was then heated at 85° C. for 3 hours. The reaction mixture was poured into saturated NaHCO3 (50 mL) and was extracted with EtOAc (3×25 mL). The organics were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatgraphy [0-100% (95:5 EtOAc/MeOH)/CH2Cl2] afforded 7-bromo-8-fluoro-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4](OC)=[O:5].[NH3:27]>>[OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4]([NH2:27])=[O:5]
Reactant: N
Reactant: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Product: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(N)=O)c1O
Temperature: 0 °C
Yield: 92 %

Procedure:
Dissolve compound 8 (1.0 g, 2.84 mmol) in methanolic ammonia (10%, 10 ml), reflux to react for 4-6h, after completion, pour the solution into ice water, extract the solution with ethyl acetate, desiccate the organic layer over anhydrous magnesium sulfate. Filter and concentrate the solution, redissolve the residue, feed the solution into a chromatographic column, evaporate the solvent in the eluent to obtain a white solid as the target product (0.86 g, 92%). 1H NMR (400 MHz, DMSO-d6): 1.79 (s, 3H), 1.81 (s, 3H), 3.25 (d, J=7.6 Hz, 2H), 3.77 (s, 3H), 5.20 (t, J=7.6 Hz, 1H), 6.68 (s, 1H), 6.80 (d, J=16.0 Hz, 1H), 7.24 (d, J=16.0 Hz, 1H), 79 (t, J=7.6 Hz, 2H), 7.36 (s, 1H), 7.44 (t, J=7.6 Hz, 2H), 7.90 (s, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]1[CH2:28]CCC[CH2:24]1.C([Li])CCC.BrCC=C>CCCCCC>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:28][CH:23]=[CH2:24])[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C1CCCCC1
Reactant: c1ccc(C(CC2CC3CCN2CC3)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: CCCCCC
Product: C=CCC(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.91 parts of 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octane in 40 parts by volume of cyclohexane are added under a nitrogen atmosphere 4.6 parts by volume of a 2.5 M solution of butyl lithium in hexane and 1.5 parts by volume of N,N,N'N'-tetramethylethylenediamine. The mixture is heated to reflux, with stirring, for 12/3 hour and then cooled to room temperature. 1.45 Parts of 3-bromopropene is then added during a 5-second period. Stirring is continued for about 6 minutes during which time the internal temperature reaches a maximum of 43° C. and then subsides. The resulting yellow mixture is washed with seven portions of water and then extracted with dilute hydrochloride acid. The acidic, aqueous extract is washed with ethyl ether and then basefied with aqueous sodium hydroxide resulting in the liberation of an oil. This oil is then extracted with ethyl ether. The ethereal extract is dried over anhydrous sodium sulfate and stripped in vacuo to give a light brown oil. This oil is crystallized from methanol and water to afford as a white solid, 2-(2,2-diphenyl-4-pentenyl)-1-azabicyclo[2.2.2]octane melting at about 95.5°-98° C. This compound is represented by the following structural formula: ##STR7##
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>C1COCC1>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccc(C(F)(F)F)cc2)CC1
Reaction time: 1 h
Yield: 76.3 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (1.88 g, 9.34 mmol) was dissolved in THF (20 ml). Sodium hydride (411 mg, 10.3 mmol) was added to this solution while cooling in an ice-bath, and the mixture was stirred for 1 hour. 4-(Trifluoromethyl) benzylbromide (2.23 g, 9.34 mmol) was added to the mixture, which was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was extracted with methylene chloride. The extract was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford tert-butyl 4-(4-trifluoromethylbenzyloxy)piperidine-1-carboxylate (2.56 g, yield 76%) as a pale yellow oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[O:48])=[CH:42][CH:41]=1>O1CCCC1>[CH2:12]([O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:22][C:47](=[O:48])[NH:46][C:43]1[CH:44]=[CH:45][C:40]([C:39]([F:38])([F:50])[F:49])=[CH:41][CH:42]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a solution of L-phenylalanine benzyl ester p-toluenesulfonic acid salt (1.71 g) and triethylamine (405 mg) in dry tetrahydrofuran (30 ml), which was cooled to 0° C., was added 4-trifluoromethylphenyl isocyanate (748 mg). The mixture was stirred at the same temperature for 30 minutes. After evaporation of the solvent, the residue was washed with 5% hydrochloric acid, saturated sodium bicarbonate solution and water successively, dried over magnesium sulfate and concentrated under reduced pressure to give N-(4-trifluoromethylphenylcarbamoyl)-L-phenylalanine benzyl ester (1.62 g) as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:36]([CH3:35])(=[O:38])=[O:37])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(C)(=O)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (69.1 mg, 150 μmol; Example 6) was initially charged in THF (2 ml), and sodium hydride (60% in mineral oil; 7.2 mg, 180 μmol) was added at 0° C. The mixture was warmed to RT and stirred for 20 min. A solution of methanesulfonyl chloride (20.6 mg, 180 μmol, 1.2 eq.) in THF (1 ml) was then slowly added dropwise. After a reaction time of 16 h, more methanesulfonyl chloride (6.7 mg, 60 μmol, 0.4 eq.) was added, and the mixture was again stirred at RT for 60 min. The reaction mixture was then concentrated, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). This gave the title compound as a colorless solid (47 mg, 58% of theory).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([C:14]([OH:16])=[O:15])[CH2:12][OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>CN(C=O)C>[N+:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:13][CH2:12][C@H:11]([C:14]([OH:16])=[O:15])[NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 1.84 g (0.0768M) of sodium hydride (NaH) in 50 mL of DMF at 0° C. under a nitrogen atmosphere was added dropwise a slurry of 7.39 g (0.0360M) of N-t-butoxycarbonyl-D-serine. After addition was complete, the reaction was warmed to room temperature and stirred for 45 minutes. The reaction was cooled to -5° C. and 4.04 mL (0.0384M) of 2-fluoronitrobenzene was added dropwise. The reaction was then warmed to room temperature and stirred for 1 hour. The reaction was quenched with an equal volume of water and extracted with ethyl acetate. The ethyl acetate extracts were reextracted with water (pH=9). The water layer was then adjusted to pH=7 and extracted with ethyl acetate. The water layer was then adjusted to pH=2 and extracted with ethyl acetate. The pH=2 ethyl acetate extracts were combined, dried, and evaporated to yield 8.98 g of product as an oil.
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:3]1[NH:14][C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])=[S:16].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CS(C)=O.[OH-].[Na+]>O>[NH:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:3]1[NH:14][C:15](=[N:17][C:18]([O:20][CH3:21])=[O:19])[S:16][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)NC(=S)NC1C(=N)C=CC=C1Cc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)N=C(NC1C(=N)C=CC=C1Cc1ccco1)SCc1ccccc1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
To 100.0 g (0.33 mole) of imino(2-furylmethyl)-2-(3-carbomethoxythioureido) benzene and 50.0 g. (0.395 mole) of benzyl chloride in 275 ml. of dimethyl sulfoxide is slowly added 15.0 g (0.375 mole) of sodium hydroxide in 260 g. of water. The resulting mixture is stirred for 1/2 hour and the yellow precipitate is separated by filtration and recrystallized from 800 ml of methylene chloride-hexane (1:1) to give 91.1 g (70.1%) of 1-imino-(2-furylmethyl)-2-(3-carbomethoxy-S-benzylisothioureido)benzene m.p. 112°-114° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[CH2:11][C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:28]C([N-]C(C)C)C.IC>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C@H:11]([CH3:28])[C@@:12]([CH3:23])([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C(=O)C[C@@](C)(c2cccc([N+](=O)[O-])c2)N=C1NC(=O)OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H]1C(=O)N(C)C(NC(=O)OC(C)(C)C)=N[C@]1(C)c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
To a solution of [(S)-1,4-dimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (110 mg, intermediate E1) in THF (3.0 ml) was added at −78° C. a solution of LDA (3 eq., 1.95 ml) and stirring was continued for 1 h. The mixture was treated at −78° C. with a solution of iodomethane (38 μl) in THF (2.0 ml) and stirring was continued at the same temperature for 1.5 h. The mixture was quenched with saturated aqueous NH4Cl, extracted with diethyl ether, the organic layer was dried and evaporated. The residue was chromatographed on silica using n-heptane/ethyl acetate (5:1) to give [(4S,5R)-1,4,5-trimethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (72 mg) as a colorless foam. MS (ESI): m/z=377.4 [ M+H]+. The hydrogenation of the nitro group to give the aniline (intermediate F) was carried out as described in Scheme 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2F)CC1
Reaction time: 2.5 h

Procedure:
A solution of 4-(2-fluoro-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (9.30 g, 28.6 mmol) in EtOH (80 mL) was treated with hydrogen (H2, 50 psi) in the presence of 10% Pd/C (0.50 g). After 2.5 h, the reaction mixture was filtered and the filtrate was concentrated to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[OH:15].[Cl:16][CH2:17][C:18](Cl)=[O:19]>CC(C)CC(=O)C.O>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[OH:15])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)C(C)c1ccc(N)c(O)c1
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CCOC(=O)C(C)c1ccc(NC(=O)CCl)c(O)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of Ethyl 2-(4-amino-3-hydroxyphenyl)propanoate (101 mg, 0.483 mmol) in 4-methyl-2-pentanone (4 mL) was added chloroacetyl chloride (58 mg, 0.514 mmol) in 4-methyl-2-pentanone (2 mL) at room temperature. The reaction mixture was stirred for 12 hrs at 80° C. then cooled to room temperature. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluant.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].[C:13](=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH3:13][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C=O)ccc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 95.6 %

Procedure:
3-Hydroxy-4-nitrobenzaldehyde (500 mg, 2.99 mmol) and potassium carbonate (0.42 g, 3.0 mmol) were dissolved in 6.0 mL of N,N-dimethylormamide. After addition of iodemethane (0.38 mL, 6.0 mmol) at room temperature, the mixture was stirred for 5 h at the same temperature. The reaction mixture was diluted with ethyl acetate and water, and separated. The organic layer was washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/1) to obtain the title compound as a pale yellow powder (518 mg, 96%).
Reaction SMILES: C([O:8][C:9](=[O:46])[CH:10]([O:43][CH2:44][CH3:45])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:35])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:23][CH:22]=2)=[C:14]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:13]=1)C1C=CC=CC=1.CCO>CCOC(C)=O>[CH2:36]([C:14]1[CH:13]=[C:12]([CH2:11][CH:10]([O:43][CH2:44][CH3:45])[C:9]([OH:46])=[O:8])[CH:17]=[CH:16][C:15]=1[O:18][C:19](=[O:35])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])=[CH:23][CH:22]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(Cc1ccc(OC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(Cc1ccc(OC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccccc2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-{3-benzyl-4-[2-(4-tert-butoxycarbonylamino-phenyl)-acetoxy]-phenyl}-2-ethoxy-propionic acid benzyl ester (0.06 g, 0.096 mmol) in the same manner as described for example 1 with the difference that EtOH was used as the solvent instead of EtOAc. The crude product was purified by column chromatography using DCM/MeOH (9:1) as the eluent and the title compound was obtained as an oil (0.047 g, 24.2%). 1H NMR (400 MHz, CDCl3): δ 9.28 (s, 1H), 7.38-7.29 (d, 2H), 7.02-7.21 (m, 9H), 6.88-6.91 (d, 1H), 3.79 (s, 2H), 3.50-3.55 (m, 1H), 3.15-3.19 (m, 1H), 2.85-2.87 (dd, 1H), 2.64-2.69 (m, 1H), 2.48-2.50 (m, 1H), 1.45 (s, 9H), 0.91-0.95 (t, 3H). Mass spectrum: M−H+ 531.93.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:15]([O:19][C:20](=[O:31])[NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][CH:29]=O)[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:15]([O:19][C:20](=[O:31])[NH:21][C@H:22]1[CH2:23][CH2:24][C@H:25]([CH2:28][CH2:29][N:10]2[CH2:9][CH2:8][CH:7]([O:6][C:5]3[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:26][CH2:27]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(F)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
A mixture of 4-(4-fluorophenoxy)piperidine (0.150 g, 0.485 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (0.117 g, 0.48 mmol), in 1, 2 dichloroethane (3 mL) and methanol (0.500 mL) was stirred for 4 hours at room temperature. Sodium triacetoxyborohydride (0.175 g, 0.829 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2-CH2Cl2/CH3OH (1-9:1). The product fractions were concentrated to give 0.176 g (0.45 mmol, 92.5% yield) of a light yellow solid. MS (m/e): 393.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[C:25]([F:26])=[CH:24][C:23](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:22][C:21]=1[F:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:23]3[CH:24]=[C:25]([F:26])[C:20]([Cl:19])=[C:21]([F:32])[CH:22]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1cc(F)c(Cl)c(F)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3cc(F)c(Cl)c(F)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-chloro-3,5-difluoro-phenyl)-acrylic acid. LC-MS-conditions 01b: tR=0.97 min; [M+H]+=406.11.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8]N=C2CCCNC2=O)[CH:5]=[CH:6][CH:7]=1.[C:17](=[O:20])([O-])[O-].[Na+].[Na+]>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:2]3[CH2:3][CH2:4][NH:8][C:17](=[O:20])[C:7]=3[NH:8]2)=[CH:6][CH:7]=1
Reactant: O=C1NCCCC1=NNc1cccc(Br)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Product: O=C1NCCc2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of 2,3-piperidinedione 3-(3-bromophenyl) hydrazone (2.5 g, 22.3 mmol) in formic acid (40 mL) is refluxed for 1 h then cooled to room temperature. The reaction mixture is neutralized with sodium carbonate to basic condition. The resulting precipitate is filtered and collected. Recrystallization with ethanol provides 1.0 g (56%) of the title compound as a yellow solid.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C@H:16]3[CH2:15]2)=[O:13])=[CH:5][CH:4]=1.[F:24][C:25]([F:36])([F:35])C1C=C(CCO)C=CC=1>>[F:24][C:25]([F:36])([F:35])[C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][O:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C@@H:16]3[CH2:15]2)=[O:13])[CH:7]=[CH:8][CH:3]=1
Reactant: OCCc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(CCOC(=O)N2CCN3CCCC[C@H]3C2)cc1
Product: O=C(OCCc1cccc(C(F)(F)F)c1)N1CCN2CCCC[C@@H]2C1

Procedure:
48 mg of the title compound was prepared as described for (S)-octahydropyrido[1,2-a]pyrazine-2-carboxylic acid 2-(4-methoxyphenyl)ethyl ester, using 2-(3-(trifluoromethyl)-phenyl)ethanol instead of 2-(4-methoxyphenyl)ethanol.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[ClH:12].[N:13]1([CH2:18][CH2:19][CH2:20][C:21](=[S:23])[NH2:22])[CH:17]=[CH:16][N:15]=[CH:14]1>>[ClH:12].[ClH:12].[N:13]1([CH2:18][CH2:19][CH2:20][C:21]2[S:23][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:22]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: NC(=S)CCCn1ccnc1
Reactant: O=C1c2ccccc2CC1Br
Agent: Cl
Product: c1ccc2c(c1)Cc1sc(CCCn3ccnc3)nc1-2

Procedure:
Starting compounds: 2-bromo-1-indanone, 4-(1-imidazolyl)butanethioamide hydrochloride