Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)\[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>CO>[CH3:19][O:18][C:14]1[CH:13]=[C:12](/[C:7](/[CH2:8][CH2:9][CH2:10][CH3:11])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:20])=[O:2])[CH:17]=[CH:16][CH:15]=1
Reactant: CCCC/C(=C\C=C\C(=O)OC)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC/C(=C\C=C\C(=O)O)c1cccc(OC)c1
Reaction time: 3 h
Yield: 79.9 %

Procedure:
As described in Example 99, (E,E)-5-(3-methoxyphenyl)-2,4-nonadienoic acid methyl ester (6.41 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 3 hours the reaction was worked up in the usual way and the crude acid was crystallized from hexane to furnish 4.86 g of (E,E)-5-(3-methoxyphenyl)-2,4-nonadienoic acid, mp 77.5°-78.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:3]=1.C([Li])CCC.[CH2:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[CH3:18].Cl>O1CCCC1.CCCCCC>[CH2:17]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:3]=2)[CH2:21][CH2:20]1)[CH3:18]
Reactant: CCN1CCC(=O)CC1
Reactant: CC(C)Oc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN1CCC(O)(c2cccc(OC(C)C)c2)CC1
Temperature: -20 °C

Procedure:
To a stirred solution of 1-bromo-3-(1-methylethoxy)benzene (5.0 g, 23 mmol) in anhydrous tetrahydrofuran (50 ml) at −78° C. under an atmosphere of nitrogen was added n-butyllithium (1.6M in hexane, 13.7 ml, 22 mmol) dropwise. The reaction mixture was stirred for 1 h at −78° C., before N-ethyl-4-piperidone (2.95 ml, 22 mmol) was added dropwise at −78° C. over 15 minutes, and the reaction mixture was then warmed to −20° C. over 30 minutes. The solution was poured onto 2N aqueous hydrochloric acid (35 ml) and this was further acidified to pH 1 with concentrated hydrochloric acid. Hexane (50 ml) was added and the two layers were separated. The organic layer was discarded and the pH of the aqueous layer was adjusted to 14 using sodium hydroxide pellets. The basic aqueous layer was extracted with hexane:diethyl ether (1:1, 5×50 ml) and the combined extracts were dried (MgSO4) and concentrated to give the title compound as a crude oil (4.2 g, 73% crude yield) which was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]([C:10](C#N)=C)=[O:9].[C:14](O)(=O)[CH:15]=CC1C=CC=CC=1.N[C@H](C(O)=O)CC1C=CC=CC=1.N[C@H](C(O)=O)CC1C=CC(O)=CC=1.S(=O)(=O)(O)O.N1C=CC=CC=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[C:8]([O:7][C:6]1[CH:1]=[CH:2][C:3]([CH:14]=[CH2:15])=[CH:4][CH:5]=1)(=[O:9])[CH3:10]
Reactant: C=C(C#N)C(=O)OCCCCCC
Reactant: O=C(O)C=Cc1ccccc1
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=Cc1ccc(OC(C)=O)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A 1.0 L jacketed Wheaton CelStir® reactor is charged with 0.335 L of the fermentation supernatant, obtained from a PHCA fermentation, as described in Example 6. The fermentation supernatant contains PHCA, cinnamic acid (CA), phenylalanine, tyrosine (all produced by the recombinant E. coli cells), and salts at pH 6.0. The pH of the pHCA-containing fermentation supernatant is adjusted to pH 6.0 using concentrated sulfuric acid for the enzymatic decarboxylation. Cell-free extract containing PDC2 (0.30 mL, 55 Units; 2.2 mg protein), prepared as described in Example 1, is added along with 0.15 L of reagent grade toluene containing 42 mg of ProStab® 5415 (Ciba Specialty Chemicals, Tarrytown, N.Y.), as a polymerization inhibitor. The reactor is capped, placed on a magnetic stir plate, and stirred at moderate speed. The reaction temperature is set at 40° C. The reaction is allowed to proceed for 2 h before terminating. The contents of the reactor are transferred to a 500 mL separatory funnel and the layers are allowed to separate. If the organic layer contains an emulsion, it is broken by filtering through a glass-fritted Buchner funnel of medium porosity. The filtrate has two immiscible layers, a colorless organic layer and a yellow aqueous layer. The layers are separated by passing through phase-separated cellulose filter paper, which allows the organic layer to selectively pass through into the receiving flask. The organic layer is recovered and immediately transferred to a 250 mL round-bottomed flask containing a stir bar. The flask is charged with pyridine (CAS110-86-1, 0.300 mL, 3.71 mmol) and acetic anhydride (CAS108-24-7, 4.0 mL, 42.4 mmol). The progress of the acetylation reaction is monitored by TLC until all of the pHS is converted and only a single spot appears on the TLC plate. A yellow oil is recovered by rotary evaporation under vacuum (13.3 kPa) with mild heating (30° C.). The isolated oil (1.41 g) is characterized by gas chromatography. Further purification of the acetoxystyrene product could be achieved by known methods (see for example Chosnek et. al. U.S. Pat. No. 5,136,083). This prophetic Example demonstrates how the pHS extracted into the organic medium of the biphasic reaction mixture may be derivatized to give a derivatized product such as para-acetoxystyrene.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:21]=[CH:20][C:9]2[S:10][C:11]([CH2:14][C:15]3[NH:16][CH:17]=[CH:18][N:19]=3)=[C:12]([CH3:13])[C:8]=2[CH:7]=1)=[O:5])C.[ClH:22]>>[ClH:22].[NH:19]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:14][C:11]1[S:10][C:9]2[CH:20]=[CH:21][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[C:12]=1[CH3:13]
Reactant: CCOC(=O)c1ccc2sc(Cc3ncc[nH]3)c(C)c2c1
Agent: Cl
Product: Cc1c(Cc2ncc[nH]2)sc2ccc(C(=O)O)cc12

Procedure:
A mixture of 2-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-5-carboxylic acid ethyl ester (1.0 g) and 6N hydrochloric acid (80 ml) was heated on a steam bath for 5 hours and then cooled. The solid was filtered off, dried and crystallized from ethanol ether to give 2-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-5-carboxylic acid hydrochloride (0.72 g), m.p. 298°-299° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([CH2:22][O:23][CH3:24])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([CH2:22][O:23][CH3:24])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:34])[NH2:14])=[CH:8]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCc1ccc(Oc2cc(OC)c3[nH]c(C(N)=O)cc3c2)cn1
Solvent: C1CCOC1
Product: COCc1ccc(Oc2cc(OC)c3[nH]c(C(N)=S)cc3c2)cn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 104.5 %

Procedure:
To a solution of 7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (1.86 g) in tetrahydrofuran (40 mL) was added Lawesson's reagent (2.3 g), and the mixture was stirred at 50° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=30/70 to 90/10, volume ratio) to give the title compound (2.04 g, 100%) as a yellow amorphous solid. MS 344 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[OH:8].[C:13](Cl)(Cl)=[S:14]>C1COCC1>[SH:14][C:13]1[O:8][C:7]2[CH:6]=[CH:5][C:4]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:3][C:2]=2[N:1]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(S(N)(=O)=O)ccc1O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc2oc(S)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-amino-4-hydroxy-benzenesulfonamide (5.00 g, 26.6 mmol, 1.0 equiv) in anhydrous THF (250 mL) was added slowly thiophosgene (3.67 g, 2.43 mL, 31.9 mmol, 1.2 equiv) via syringe pump over a time period of 1 h. After stirring for 4 h at rt, excess thiophosgene was quenched by addition of a conc. solution of ammonium chloride (100 mL) and the majority of solvent removed by evaporation under reduced pressure. The residue was extracted with ethyl acetate (3×100 mL) and the combined organic phases dried over MgSO4 yielding 6.1 g (92%) of crude product, which was used in the subsequent reaction step without further purification. 1H NMR (300 MHz, DMSO): δ 7.51 (br s, 2H), 7.68 (s, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 14.21 (br s, 1H). 13C NMR (75 MHz, DMSO): δ 106.29, 108.47, 120.06, 129.91, 139.54, 148.16, 179.38. MS (ISP): 230.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:27])[CH2:11]/[CH:12]=[CH:13]\[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](Cl)Cl>>[CH2:1]([O:8][CH2:9][C@H:10]([OH:27])[CH2:11][C@H:12]1[CH2:28][C@H:13]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C\C[C@@H](O)COCc2ccccc2)CC1
Reactant: ClCCl
Product: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2C[C@@H](O)COCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of the commercially available (S,S) dioxaborolane ligand (7.37 g, 27.3 mmol) in DCM (20 mL) was added. The mixture was stirred for 10 minutes. The precipitate dissolves yielding a clear solution. A solution of the alkene from step B of this example (8.53 g, 22.7 mmol) in DCM (20 mL) was added. The solution was warmed to 0° C. and stirred for 24 hours. The solution remains clear after stirring for 24 hours. The reaction was quenched after 24 hr by addition of 50 ml of sat'd aq. NH4Cl. The mixture was placed in a separatory funnel, 250 ml DCM and 200 ml 10% HCl (aq) added, shaken, and the layers separated. The aqueous layer was re-extracted with DCM (2×150 ml), the organic layers combined, transferred to a Morton flask. 2N NaOH (300 ml) and 50 ml of 30% H2O2 were added. The biphasic solution was stirred vigorously for 12 hours. The layers were separated and the aqueous phase was re-extracted with DCM (2×150 ml), the organic phases were combined, washed with 10% HCl (aq, 250 ml), 1N Na2S2O3 (250 ml), sat'd NaHCO3 (250 ml), brine (250 ml), dried over MgSO4, filtered and stripped. The material was purified by chromatography on SiO2 eluting with 30% EtOAc:Hexanes. The desired product is obtained as a mixture with the minor diastereomer and the residual SM. The desired diastereomer was isolated by Chiralpak IA stationary phase chromatography.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[S:26][CH:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[N:29]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:40]>C(OCC)(=O)C>[ClH:40].[NH2:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[S:26][CH:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[N:29]=1)=[CH:14][CH:13]=2
Reactant: CC(=O)Nc1csc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1csc(-c2ccc3c(=O)n(CC(C)C)c(CN)c(-c4ccccc4)c3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Tert-butyl{6-[4-(acetylamino)-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.14 g, 0.25 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give N-{2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazol-4-yl}acetamide hydrochloride (0.11 g, 91.7%) as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>>[N:14]1([CH2:13][CH2:12][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OCc1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCc1ccc(OCCN2CCCCC2)cc1

Procedure:
Schemes IX through XII exemplify the synthesis of 2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol utilizing intermediates of the present invention. Scheme IIa, described above, can be considered the first step of Scheme IX or a step prior thereto. In this step 4hydroxybenzyl alcohol is treated with a desired aryl amino alkyl chloride to afford the corresponding alkoxy benzyl alcohol. In the specific example of Scheme IIa, 4-hydroxybenzyl alcohol is treated with 1-(2-chloroethyl)-piperidine hydrochloride in the presence of K2CO3/Me2CO to yield 4-(2-piperidinylethoxy)benzyl alcohol. Toluene and brine can be added to the resulting alcohol mixture to separate its phases. The toluene phase can then be washed successively with aqueous alkali and brine. The resulting batch can then be concentrated and ethylene dichloride added to form a solution of the intermediate, 4-(2-piperidinylethoxy)benzyl alcohol.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:7]=2[C:8](O)=[O:9])=O)[CH2:3][CH2:2]1.O.[NH2:18][NH2:19]>>[CH:1]1([C:4]2[C:6]3[C:7](=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:8](=[O:9])[NH:19][N:18]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)C2CC2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(C3CC3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-cyclopropanecarbonyl-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][C@@H:9]([CH3:14])[C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[OH-].[Li+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C@@H:9]([CH3:14])[C:10]([OH:12])=[O:11])=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H](C)OCc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CO[C@@H](C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of (S)-methyl 2-((4-methoxybenzyl)oxy)propanoate (1 g, 4.46 mmol) in THF (20 mL) and MeOH (6 mL) at 0° C. was added lithium hydroxide (0.225 g, 9.38 mmol) and stirred for 3 h. Then warmed to room temperature in 30 min. After completion of starting material (by TLC), reaction mixture was concentrated and the resultant residue was taken EtOAc (100 ml), acidified by 1.5N HCl (up to pH 1) and extracted into EtOAc (2×100 ml). Combined organic extracts were dried over anhydrous Na2SO4, concentrated to give (S)-2-((4-methoxybenzyl)oxy)propanoic acid (0.6 g) was obtained as a gummy liquid.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:20][C:21]1[N:30]=C(C)C2C(=O)CC(C3C=CC(F)=CC=3)CC=2[N:22]=1>>[NH2:30][C:21]1[N:22]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[CH2:6][C:5]=2[N:20]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Reactant: COc1ccccc1C1CC(=O)C(C(C)=O)C(=O)C1
Product: COc1ccccc1C1CC(=O)c2c(C)nc(N)nc2C1

Procedure:
The title compound was prepared from 2-acetyl-5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (872 mg, 3.35 mmol), from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/a stage 2/3) except that the title compound was further purified by recrystallisation in methanol.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[F:25][C:26](=[C:32]([F:34])[F:33])[CH2:27][CH2:28][C:29](O)=[O:30]>C(Cl)Cl>[F:25][C:26](=[C:32]([F:34])[F:33])[CH2:27][CH2:28][C:29]([N:3]([O:4][CH3:5])[CH3:2])=[O:30]
Reactant: CNOC
Reactant: O=C(O)CCC(F)=C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CCC(F)=C(F)F
Reaction time: 8 h

Procedure:
N,O-dimethylhydroxyamine hydrochloride (3.5 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.9 g) and triethylamine (9.2 mL) were added to a solution of 4,5,5-trifluoropent-4-enoic acid (CAS No. 110003-22-0 (5.0 g)) in methylene chloride solution (64 mL) in a cold-water bath and stirring was carried out at room temperature overnight. The reaction solution was concentrated and diluted with ethyl acetate. The dilute solution was washed with 1 N hydrochloric acid, water and saturated brine; dried with anhydrous sodium sulfate; and concentrated to obtain the title compound (6.4 g) having the following physical properties:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[C:24](OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(OCC)(=O)C>[CH3:24][O:18][C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](Cc1cccnc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of N-(t-butoxycarbonyl)-3-(3-pyridyl)alanine (20) (5.0 g, 18.8 mmole) in methanol (100 mL) was added thionyl chloride (2M solution in dichloromethane, 66 mL, 132 mmole). The resulting solution was stirred overnight at ambient temperature. The methanol was removed under reduced pressure to a minimum volume and ethyl acetate (100 mL) was added. The resulting white precipitate was collected in a fritted funnel. To a solution of the collected precipitate in a mixture of tetrahydrofuran/water (40 mL each) was added di-tert-butyl dicarbonate (4.8 g, 21.99 mmole) and sodium carbonate (1.95 g, 18.4 mmole). After stirring for 12 hours at ambient temperature, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with a solution of saturated sodium bicarbonate (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give crude product. This product was subjected to flash column chromatography on silica gel (230-400 mesh) using a 8×52 cm column and eluting with a 10:90 mixture of ethyl acetate/hexane followed by a 60:40 mixture of ethyl acetate/hexane. 4 g (74%) of the title compound was obtained as an oil. Thin-layer chromatography (silica gel; ethyl acetate), Rf=0.68.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@H:11]([CH2:21][N:22]3[N:26]=[N:25][C:24]([CH2:27][C:28](OCC)=[O:29])=[N:23]3)[O:10][C:9]2=[O:33])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@H:11]([CH2:21][N:22]3[N:26]=[N:25][C:24]([CH2:27][CH2:28][OH:29])=[N:23]3)[O:10][C:9]2=[O:33])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nnn(C[C@@H]2OC(=O)N(c3ccc(Cl)cc3)[C@H]2c2cccc(OC)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc([C@H]2[C@H](Cn3nnc(CCO)n3)OC(=O)N2c2ccc(Cl)cc2)c1

Procedure:
A solution of ethyl 2-(2-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-2H-tetrazol-5-yl)acetate (50 mg, 0.11 mmol) [Example 379] in MeOH (1 mL) is treated with excess sodium borohydride at room temperature for 30 min. The reaction is quenched with 1 mL 0.1 M HCl and extracted with EtOAc (3×5 mL). The combined organics are dried over MgSO4, filtered and concentrated to give the title compound. 1H NMR (acetone-d6, 400 MHz) δ 7.47-7.43 (m, 2H), 7.33-7.29 (m, 3H), 7.04 (app t, J=2.0 Hz, 1H), 7.00-6.98 (app d, J=7.7 Hz, 1H), 6.90 (ddd, J=8.3, 2.6, 0.9 Hz, 1H), 5.60 (d, J=5.2 Hz, 1H), 5.33 (dd, J=14.6, 6.2 Hz, 1H), 5.25 (dd, J=14.6, 4.1 Hz, 1H), 4.99 (ddd, J=6.2, 5.2, 4.1 Hz, 1H), 3.89-3.76 (m, 6H), 2.99 (t, J=6.3 Hz, 2H), HPLC-MS calculated C20H20ClN5O4 (M+H+) 430.1, found 430.1.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[CH:21]([NH:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:20][CH2:19]4)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:29]2[CH2:30][CH2:31][CH:26]([NH:25][CH:21]3[C:22]4[C:18](=[CH:17][C:16]([O:15][CH:12]5[CH2:13][CH2:14][N:9]([C:6]6[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:32])[F:33])=[CH:4][CH:5]=6)[CH2:10][CH2:11]5)=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)[CH2:27][CH2:28]2)=[CH:37][CH:38]=1
Reactant: FC(F)(F)c1ccc(N2CCC(Oc3ccc4c(c3)CCC4NC3CCNCC3)CC2)cc1
Reactant: Fc1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Fc1ccc(CN2CCC(NC3CCc4cc(OC5CCN(c6ccc(C(F)(F)F)cc6)CC5)ccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred mixture of N-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-2,3-dihydro-1H-inden-1-yl)piperidin-4-amine.3HCl (0.06 g, 0.1 mmol) in anhydrous dimethylformamide (0.5 mL) at room temperature was added 1-bromomethyl-4-fluorobenzene (0.02 g, 0.1 mmol) and N,N-diisopropylethylamine (0.07 g, 0.5 mmol). The resulting mixture was stirred at room temperature overnight. After this time the mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, methylene chloride/methanol/30% ammonium hydroxide=20/1/0.05) to afford the title compound as a off-white solid (0.05 g, 88%). 1H NMR (CDCl3, 300 MHz) 7.46 (m, 2H), 7.25 (m, 3H), 6.96 (m, 4H), 6.75 (m, 2H), 4.47 (m, 1H), 4.29 (m, 1H), 3.58 (m, 2H), 3.48 (s, 2H), 3.06-2.54 (m, 6H), 2.38 (m, 1H), 2.14-1.74 (m, 9H), 1.49 (m, 2H) ppm; MS (ES) 568.6 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH:28]2[CH2:30][CH2:29]2)[C:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)=[N:9][C:10]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:5])C.[OH-].[Na+:32]>CCO>[Na+:32].[CH:28]1([N:7]2[C:6]([C:4]([O-:5])=[O:3])=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:9]=[C:8]2[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:19][CH:18]=2)[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1c(-c2cccnc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1c(-c2cccnc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1

Procedure:
To 0.9 g (2 mmol) 3-cyclopropyl-5-pyridin-3-yl-2-(4-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid ethyl ester in 5 ml of EtOH was added 0.4 ml of 6 M sodium hydroxide solution (2 mmol) and the mixture heated to reflux for 6 h. The solvent was then evaporated, affording 1.0 g (quant.) of the title compound as a white solid. MS: 390.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH:3]=1.Cl>CC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)[CH:3]=1
Reactant: Clc1cc(N2CCC3(CC2)OCCO3)ncn1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCN(c2cc(Cl)ncn2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 8-(6-chloropyrimidine-4-yl)-1,4-dioxa-8-azaspiro[4,5]decane (12.79 g) in acetone (50 ml) was added 4N hydrochloric acid (50 ml), and the mixture was stirred at 50° C. for 1 hour. Under reduced pressure, acetone was removed, and the residue was neutralized with 2N sodium hydroxide solution and was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated, and the residue was crystallized from diethylether to give colorless crystals of 1-(6-chloropyrimidine-4-yl)piperidin-4-one (10.09 g).