Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[C@H:5]([CH3:33])[CH2:6][C@H:7]([NH:21][C:22](=[O:32])[C:23]1[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>CO>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:10][C:9]([CH2:8][C@@H:7]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=2)[CH2:6][C@@H:5]([CH3:33])[C:4]([OH:34])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(F)c(O)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(F)c(O)c(F)c1)C(=O)O
Reaction time: 1 h
Yield: 60.8 %

Procedure:
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-methoxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester (125 mg, 0.260 mmol) in DCM (2.6 mL) is slowly added BBr3 (2.60 mL, 2.60 mmol) under nitrogen. The reaction is stirred for 18 hours at rt. The reaction is quenched with MeOH, diluted with EtOAc, washed with H2O and brine, dried over MgSO4, and concentrated under reduced pressure. The obtained material is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 100 mg (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester (30 mg, 0.064 mmol) in MeOH (2 mL) at room temperature is added aqueous 1M NaOH (4 mL, 4.0 mmol). After stirring for 1 hour the reaction is quenched with aqueous 1M HCl (4 mL, 4.0 mmol). The mixture is concentrated under reduced pressure and filtered to remove NaCl salt. The obtained residue is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 17.1 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid. HPLC Retention time 1.56 minutes (condition G); MS 440 (M+1); 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.19 (d, J=7.07 Hz, 3 H) 1.55 (ddd, J=14.27, 10.74, 3.79 Hz, 1 H) 1.90-1.96 (m, 1 H) 2.54-2.71 (m, 1 H) 2.91 (dd, J=6.69, 3.16 Hz, 2 H) 4.25-4.43 (m, 1 H) 6.49 (d, J=9.60 Hz, 2 H) 6.93 (d, J=8.84 Hz, 1 H) 7.33-7.42 (m, 3 H) 7.49 (t, J=7.71 Hz, 2 H) 7.61 (d, J=8.34 Hz, 2 H) 7.67 (dd, J=8.34, 1.26 Hz, 2 H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1([CH3:12])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[CH3:12][C:6]1([CH:5]=[CH:4][CH2:3][OH:2])[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1
Reactant: COC(=O)C=CC1(C)CCOCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C=CCO)CCOCC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
Into a cooled (−78° C.) solution of 640 mg (3.47 mmol) of 3-(4-methyltetrahydropyran-4-yl)acrylic acid methyl ester obtained in the above 3) in THF was dropped 8.0 mL (8.00 mmol) of 1.0 mol/L diisobutylaluminum hydride in toluene at under an atmosphere of argon, and stirred for 3 hours at −78° C. The reaction mixture was allowed to warm to room temperature, and then an aqueous solution of sodium potassium tartrate was added, followed by a removal of solvent under a reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was removed to obtain 543 mg (yield 71%) of crude 3-(4-methyltetrahydropyran-4-yl)prop-2-ene-1-ol. Its physical property is shown below.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][O:8][CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:29]1([CH2:35][O:36][C:37]2[C:46]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:45][C:44]([S:55]([OH:58])(=[O:57])=[O:56])=[CH:43][C:38]=2[C:39]([NH:41][NH2:42])=[O:40])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>CN(C)C=O.CN(C1C=CN=CC=1)C.O>[CH3:13][C:2]([CH3:1])([O:4][C:5]([NH:7][O:8][CH2:9][C:10]([NH:42][NH:41][C:39](=[O:40])[C:38]1[CH:43]=[C:44]([S:55]([OH:58])(=[O:57])=[O:56])[CH:45]=[C:46]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:37]=1[O:36][CH2:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:12])=[O:6])[CH3:3]
Reactant: NNC(=O)c1cc(S(=O)(=O)O)cc(OCc2ccccc2)c1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NOCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NOCC(=O)NNC(=O)c1cc(S(=O)(=O)O)cc(OCc2ccccc2)c1OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of [(1,1-dimethylethoxy)carbonyl]aminooxy acetic acid (Example 7b, 1.0g, 5.2 mmole) and N-methylmorpholine (0.57 ml, 5.2 mmole) in 10 ml of dimethylformamide at -10° C. was treated dropwise with isobutylchloroformate (0.74 ml, 5.7 mmole). The mixture was stirred at -10° C. for 1 hour, then was treated with a suspension of 2,3-di(phenylmethoxy)-5-sulfobenzoic acid hydrazide (2.24g, 5.2 mmole) in 20 ml of dimethylformamide followed by the dropwise addition of a solution of N-methylmorpholine (0.86 ml, 7.8 mmole) and 4-(N, N-dimethylamino)pyridine (30 mg) in 10 ml of dimethylformamide over 20 minutes. The reaction was stirred for 1 hour at 0° C., then was allowed to warm to ambient temperatures overnight. Evaporation in vacuo gave an oil which was taken up in 30 ml of water. The pH was adjusted to 2 with aqueous hydrochloric acid and the oily product was extracted into ethyl acetate. Drying over magnesium sulfate and evaporation gave a residue which crystallized with hexane. The solid was filtered and dried to give 2.3g. mp 103°-105° C.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]2[O:6][C:7]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1.N1C=CC=CC=1>ClC(Cl)C>[C:35]([O:1][C:2]1[CH:34]=[CH:33][C:5]2[O:6][C:7]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([CH:18]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[CH2:16][CH2:17]3)=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1
Reactant: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: O=C(Cl)c1cccnc1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=C(Oc1ccc2c(c1)OC=C(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2)c1cccnc1
Yield: 95 %

Procedure:
Heat at reflux for 8 hours, under a nitrogen atmosphere, a solution of 1.37 mmol of 6-hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin, 4.5 mmol of nicotinoyl chloride and 3.42 mmol of anhydrous pyridine in 25 cm3 of dichloroethane. After cooling, the reaction mixture is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate and then concentrated under reduced pressure. The crude product is then purified by chromatography on a silica column (eluant: petroleum ether/ethyl acetate, 70:30). 6-Nicotinoyloxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin is thereby obtained in a yield of 95%. Melting point: 142° C. ##STR77##
Reaction SMILES: C1[O:18][CH2:17][CH2:16]OCCOCCOCCOCCOC1.C([O-])(=O)C.[K+].[Cl:24][C:25]1[CH:32]=[CH:31]C=C(F)[C:26]=1[C:27]#[N:28].[OH-].[Na+]>C(#N)C.O>[Cl:24][C:25]1[C:26]([C:27]#[N:28])=[C:17]([OH:18])[CH:16]=[CH:31][CH:32]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: N#Cc1c(F)cccc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1c(O)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 18-crown-6 (3.96 g, 15 mmol) in 30 mL of acetonitrile were added dry potassium acetate (1.47 g, 15 mmol) and 2-chloro-6-fluorobenzonitrile (1.56 g, 10 mmol). The reaction was refluxed under nitrogen for 25 hours, then cooled to room temperature. Sodium hydroxide (2 mL of a 10 M solution, 20 mmol) and water (5 mL) were added, and the reaction stirred at room temperature for two hours. The acetonitrile was removed on a rotary evaporator, and the residue was taken up in ether and water. The basic aqueous layer was washed three times with ether. The aqueous layer was then made acidic with HCl, and the product extracted into ether. The ether layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting solid was crystallized from water/methanol to yield 1.11 g of 3-chloro-2-cyanophenol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([C:23](O)=[O:24])=[CH:14]2.CCOCC.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:24][CH2:23][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[C:18]([O:19][CH3:20])[C:9]=2[O:8][CH3:7])[CH:14]=1
Reactant: COc1cc2cc(C(=O)O)ccc2c(OC)c1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1cc2cc(CO)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Lithium aluminum hydride (579 mg) was added to dry THF (40 mL) under an argon atmosphere and ice cooling, a solution of 5,6,7-trimethoxynaphthalene-2-carboxylic acid (4.0 g) in dry THF (40 mL) was then added dropwise thereto, and the mixture was stirred at room temperature for 4 hours. Ether (150 mL) was added to the reaction mixture, sodium sulfate decahydrate was added thereto, and the resultant mixture was stirred for 15 minutes. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.CON(C)[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:20]1([C:19](=[O:26])[CH2:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: Cc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Lithium diisopropyl amide (16.9 mL, 1.5 M in cyclohexane, 25.4 mmol) was added to THF (40 mL) at −78° C. A solution of 4-picoline (2.50 mL, 25.4 mmol) in THF (30.0 mL) was added dropwise to the LDA solution. The dry ice bath was removed. The reaction mixture was stirred at 0° C. for 30 minutes, and cooled down to −78° C. A solution of N-methoxy-N-methylbenzamide (1) (5.00 g, 29.6 mmol) in THF (20.0 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was quenched with water, and extracted with ethyl acetate (3×). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered, and the solvent was removed under vacuum to give the crude product. The crude material was triturated with hot hexane, and filtered to give 1-phenyl-2-(pyridin-4-yl)ethanone (2) as a yellow solid (3.53 g, 17.9 mmol, 70% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:11]1(C(O)=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].FC(F)(F)C(O)=O.[OH-].[Na+]>ClC1C=CC=CC=1.[N+]([O-])([O-])=O.[Ag+].O>[CH:11]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)C1CCCCC1
Reactant: c1ccc2ncccc2c1
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Clc1ccccc1
Product: c1ccc2nc(C3CCCCC3)ccc2c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
To a solution of quinoline (11.84 ml, 100 mmol) in chlorobenzene (300 ml) was added sequentially water (300 ml), cyclohexanecarboxylic acid (35.88 g, 280 mmol), silver nitrate (1.36 g, 8.0 mmol), ammonium persulfate (22.82 g, 100 mmol) and trifluoroacetic acid (7.67 g, 100 mmol). The mixture was heated to 140° C. with stirring for 3 h. The mixture was then cooled to room temperature, basified with solid sodium hydroxide and the solvent removed in vacuo. The residue was then subjected to a continuous extraction with isohexane for 18 h, the solvent evaporated under reduced pressure and the residue purified by flash chromatography eluting with 20% (v/v) ethyl acetate in isohexane to afford 2-cyclohexylquinoline as a yellow oil (2.66 g, 12.61 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:26][CH:27]([CH3:29])[CH3:28])=[N+:11]([O-:25])[C:12]([O:23][CH3:24])=[C:13]([CH2:15][O:16]C2CCCCO2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>Cl.C(OCC)C>[CH2:1]([O:8][C:9]1[C:10]([CH2:26][CH:27]([CH3:29])[CH3:28])=[N+:11]([O-:25])[C:12]([O:23][CH3:24])=[C:13]([CH2:15][OH:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(COC2CCCCO2)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1c(CO)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
There was stirred, for 30 minutes at room temperature, a mixture of 80 mg of 3-benzyloxy-2-isobutyl-6-methoxy-5-(2-tetrahydropyranyloxymethyl)pyrazine 1-oxide, 1 ml of methanol and one drop of concentrated hydrochloric acid. The reaction mixture was mixed with diethyl ether, then the mixture was washed with an aqueous solution saturated over sodium hydrogen carbonate, and dried over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by a silica gel thin layer chromatography (developing solvent: 50% by volume of ethyl acetate-n-hexane), followed by recrystallization from diethyl ether-n-hexane to obtain 63 mg of 3-benzyloxy-5-hydroxymethyl-2-isobutyl-6-methoxypyrazine 1-oxide (Compound B-16) as colorless needle-like crystals having a melting point of 68.0°-69.2° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[O:3][CH2:4][C:5]#[CH:6].C([Mg]Br)C.[O:13]=[C: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.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.O>[OH:13][C:14]1([C:6]#[C:5][CH2:4][O:3][Si:2]([CH3:8])([CH3:7])[CH3:1])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C#CCO[Si](C)(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C#CCO[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Trimethyl(2-propynyloxy)silane (11.54 ml, 9.62 g, 75 mmol) was added dropwise to a stirred, cooled (−5° C.) solution of ethyl magnesium bromide (1M in tetrahydrofuran, 75 ml, 75 mmol) in tetrahydrofuran (150 ml), maintaining the internal temperature below 0° C. The mixture was stirred at 0° C. for 30 minutes, then at room temperature for 90 minutes. The mixture was cooled to −5° C. and 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (15.0 g, 75 mmol) was added slowly, maintaining the internal temperature below 0° C. The mixture was stirred at 0° C. for 3 hours then at room temperature for 96 hours. Saturated aqueous ammonium chloride (300 ml), water (100 ml) and ethyl acetate (300 ml) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (200 ml) and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (24.4 g, 100%).
Reaction SMILES: [CH2:1]([S:16]([CH:19]([CH2:25][CH3:26])[C:20]([O:22]CC)=[O:21])(=[O:18])=[O:17])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15].[Li+].[OH-].O.Cl>C(O)C>[CH2:1]([S:16]([CH:19]([CH2:25][CH3:26])[C:20]([OH:22])=[O:21])(=[O:17])=[O:18])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\CCS(=O)(=O)C(CC)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CCS(=O)(=O)C(CC)C(=O)O
Temperature: 60 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
Ethyl 2-((3Z,6Z,9Z,12Z)-pentadeca-3,6,9,12-tetraenylsulfonyl)butanoate (370 mg, 0.97 mmol) was dissolved in ethanol (10 mL) and added a solution of LiOH in H2O (1 M, 3.9 mL, 3.9 mmol). The resulting mixture was stirred at 60° C. for three hours, cooled, added 0.1 M HCl until pH=2 and extracted twice with diethyl ether (15 mL each). The combined organic layer was washed with brine (15 mL), dried, filtrated, concentrated in vacuo and purified by flash chromatography on silica gel (heptane:EtOAc w/5% HCOOH 4:1). Concentration of the appropriate fractions afforded 250 mg (73% yield) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:12])=[C:5]([CH3:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8].OC1[CH2:19][C:18]([CH3:21])([CH3:20])[N:17]([CH3:22])[C:16]([CH3:24])([CH3:23])[CH2:15]1>>[CH3:1][C:2]1[O:3][C:4]([CH3:12])=[C:5]([CH3:11])[C:6]=1[C:7]([O:9][CH:10]1[CH2:19][C:18]([CH3:21])([CH3:20])[N:17]([CH3:22])[C:16]([CH3:24])([CH3:23])[CH2:15]1)=[O:8]
Reactant: COC(=O)c1c(C)oc(C)c1C
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Product: Cc1oc(C)c(C(=O)OC2CC(C)(C)N(C)C(C)(C)C2)c1C

Procedure:
If methyl 2,4,5-trimethylfuran-3-carboxylate and 4-hydroxy-1,2,2,6,6-pentamethylpiperidine are reacted by the method given in Example 1, the product obtained is a virtually colorless oil of boiling point 138°-140° C./0.4 mm; this solidifies to a solid of melting point 55°-56° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=O)=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[OH:7][CH:4]([CH2:5][OH:6])[CH2:3][N:2]([CH3:1])[C:22]([C:21]1[CH:25]=[CH:26][N:27]=[CH:28][C:20]=1[NH:19][C:17]([C:15]1[C:14]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:13][CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10]2)[N:16]=1)=[O:18])=[O:24]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CNCC(O)CO
Product: CN(CC(O)CO)C(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 19 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3-methylamino-propan-1,2-diol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (19%) as sticky yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21])[C:16]([OH:18])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:46][O:47][C:48]1[CH:61]=[CH:60][C:51]([CH2:52][N:53]2[C:57]([NH:58][CH3:59])=[N:56][N:55]=[N:54]2)=[CH:50][CH:49]=1>ClCCl.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH2:25]([O:24][C:22](=[O:23])[C@@H:20]([NH:19][C@H:15]([C:16](=[O:18])[N:58]([C:57]1[N:53]([CH2:52][C:51]2[CH:60]=[CH:61][C:48]([O:47][CH3:46])=[CH:49][CH:50]=2)[N:54]=[N:55][N:56]=1)[CH3:59])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9][CH:10]=1)[CH3:21])[CH3:26]
Reactant: CNc1nnnn1Cc1ccc(OC)cc1
Reactant: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)N(C)c1nnnn1Cc1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
To a suspension of (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid (225 mg, 0.599 mmol) in dichloromethane (4 mL) and saturated aqueous NaHCO3 (1 mL) was added triphosgene (178 mg, 0.599 mmol). After vigorously stirred for 10 min, the reaction mixture was diluted with EtOAc and partially concentrated under reduced pressure. Excess of triphosgene was quenched by adding saturated aqueous NaHCO3 and stirred for 0.5 hour. The mixture was extracted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (5 mL). To the mixture were added triethylamine (0.167 mL, 1.197 mmol) and [1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-amine (197 mg, 0.898 mmol) and stirred at 45° C. overnight. Additional triethylamine (0.167 mL, 1.197 mmol) and [1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-amine (197 mg, 0.898 mmol) were added and stirred at 45° C. for 30 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: 10% MeOH in DCM) to give (S)-2-((S)-2-(3′-chloro-biphenyl-4-yl)-1-{[1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-carbamoyl}-ethylamino)-propionic acid ethyl ester (261 mg). MS: m/z (MH+) 577; HPLC retention time 1.36 min (HPLC condition C).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]([C:12]1[S:13][C:14]([Br:17])=[CH:15][CH:16]=1)(=[O:11])[CH3:10].Cl>C1COCC1.O>[Br:17][C:14]1[S:13][C:12]([C:9](=[O:11])[CH2:10][C:3]([O:6][CH3:7])=[O:8])=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(Br)s1
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(=O)c1ccc(Br)s1
Yield: 99 %

Procedure:
Sodium hydride (1.95 g of 60% dispersion in oil, 0.045 mol), dimethyl carbonate (50 mL) and THF (40 mL) were added to a flame dried flask equipped with stirrer and dropping funnel. 2-Acetyl-5-bromothiophene (5.0 g, 0.024 mol) in 20 mL THF was added dropwise. The mixture was then heated at reflux for 2 hours, then poured into 250 mL of water, acidified to pH 2.0 with 1N HCl and extracted 3×200 mL ether. The organic layers were combined, dried (MgSO4) and stripped to yield 6.4 g (99%) of present title product as an oil; tlc Rf 0.42 (CHCl3).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[NH2:7][C:3]1[CH:2]=[C:1]([CH:6]=[CH:5][CH:4]=1)[NH:8][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Nc1cccc(N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1cccc(N)c1)C(=O)OCC
Reaction time: 30 h

Procedure:
10.8 Grams of m-phenylenediamine are dissolved in 80 ml of ethyl alcohol, 21.6 grams of diethyl ethoxymethylenemalonate are added and the mixture is heated under reflux for 40 minutes. After filtration hot, 50 ml of water are added and the mixture is left for 24 to 36 hours at room temperature with stirring. The precipitate formed is filtered off, washed with an ethanol/water (1:1) mixture and dried at 60° C. The product is recrystallized in a benzene/hexane (2:1) mixture and 10.5 grams of a solid are obtained, of melting point 71°-74° C.