Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[CH:3]1([NH:6][C:7]2C(C#N)=C[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4]1.[CH2:15]([OH:18])[CH2:16][CH3:17].Cl>O>[CH:3]1([NH:6][C:7]2[C:16]([C:15]([OH:1])=[O:18])=[CH:17][CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4]1
Reactant: [OH-]
Reactant: CCCO
Reactant: N#Cc1cccnc1NC1CC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1cccnc1NC1CC1
Temperature: 25 °C

Procedure:
A 45% aqueous KOH solution (187g, 1.5 mol) was charged to a mixture of the product from Example 1 and 300 ml of 1-propanol. The mixture was heated at reflux temperature for about 5 hours whereupon TLC analysis showed complete hydrolysis of the nitrile. The reaction mixture was cooled to ambient temperature and treated with 94 g of water that was needed to remove the 1-propanol by azeotropic distillation. About 330 g of water/1-propanol azeotrope was distilled off at 62° C. and 21.1 in. Hg. Water (130 g) was added to the reaction mixture and the mixture chilled to 5-10° C. Concentrated hydrochloric acid (148 g, 1.5 mol) was added at such a rate that the temperature could be maintained below 30° C. After about 80-90% of the acid was added the zwitterion began to precipitate out, making the mixture quite thick. When all the acid had been added, the solid product was collected by filtration, using 90 ml of cold water to rinse out the reaction vessel onto the filter cake. The product was dried to yield 68.12 g. of the zwitterion.
Reaction SMILES: [C:1]([N:4]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:29])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1.O>[C:1]([N:4]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:29])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCC(=O)O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.7 %

Procedure:
Methyl 3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)propanoate (200 mg, 0.4 mmol, 1 equ.) was dissolved in methanol/tetrahydrofuran (2/1) (1.5 ml). A solution of sodium hydroxide (32 mg, 0.8 mmol, 2 eq.) in water (0.5 ml) was added and reaction mixture stirred at room temperature for 20 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 3-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)propanoic acid (190 mg, 97%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[C:13]([CH3:21])([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH3:14])=[CH:8][CH:7]=1.Br[CH2:24][C:25](=[CH2:30])[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:29][O:28][C:26](=[O:27])[C:25]([CH2:30][S:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[C:13]([CH3:14])([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH3:21])=[CH:8][CH:7]=1)=[CH2:24]
Reactant: CC(C)(C(=O)c1ccc(SCCCS)cc1)N1CCOCC1
Reactant: C=C(CBr)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=C(CSCCCSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3.0 g (8.8 mmol) of 1-[4-(3-mercaptopropylthio)phenyl]-2-methyl-2-morpholin-4-yl-propane-1-one are dissolved in 1.50 ml of methanol. To the solution are successively added 1.89 g (10.6 mmol) of methyl 2-(bromomethyl)acrylate and 1.22 g (8.8 mmol) of potassium carbonate, and the reaction mixture is stirred at room temperature for 10 min. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with water, and dried over MgSO4. After distilling off the ethyl acetate, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:3) as an eluent, and an oily product is obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCC.[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[N+:36]([C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH:41]=[O:42])([O-:38])=[O:37]>O1CCCC1>[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]([CH:41]([OH:42])[C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[N+:36]([O-:38])=[O:37])[C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CC1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C1CCN(Cc2ccccc2)CC1)C(O)c1ccccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Diisopropylamine (24.87 mmoles; 3.50 mL) was dissolved in tetrahydrofuran (30.00 mL). Mixture was cooled to −78° C. 2.5 M butyllithium in pentane (24.50 mmoles; 9.80 mL) was added to the mixture drop-wise. Reaction was stirred at −78° C. for 15 minutes. A solution of methyl 2-(1-benzylpiperidin-4-yl)acetate (22.24 mmoles; 5.50 g) in 8 mL THF was then added to the mixture dropwise over 20 minutes. Reaction stirred at −78° C. for 45 minutes. A solution of 2-nitrobenzaldehyde (24.48 mmoles; 3.70 g) in 5 mL THF was then added to the mixture dropwise over 15 minutes. Reaction was stirred at −78° C. for 30 minutes. Reaction was quenched with saturated aqueous ammonium chloride. Mixture was warmed to room temperature. Extracted from the mixture 2× EtOAc. Combined organics were dried (magnesium sulfate), filtered, then concentrated. Silica gel chromatography afforded the desired product in 89% yield as light yellow foam. MS m/e (M+H)+=399.3.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:23])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=2)[C:7]=1[C:24]([O:26]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:23])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=2)[C:7]=1[C:24]([OH:26])=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(C(=O)O)cs3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](Nc3nc(C(=O)O)cs3)[C@H]2SC1
Reaction time: 0.75 h
Yield: 73.2 %

Procedure:
A mixture of 300 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(4-carboxy-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 1 ml of trifluoroacetic acid, 0.25 ml of anisole and 3 ml of dichloromethane was allowed to stand for 45 minutes, then the solid was collected, washed with ether and petroleum ether and dried, giving 155 mg of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][O:12][C:13]2=[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]2=[O:25])=[CH:9][CH:8]=1.[CH2:32]=O.C([BH3-])#N.[Na+].C[C:39](O)=[O:40]>C(#N)C>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([CH3:32])[C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][O:12][C:13]2=[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:39][OH:40])[C:17]2=[O:25])=[CH:9][CH:8]=1
Reactant: C=O
Reactant: CC(=O)O
Reactant: COc1ccc(CNc2ccc3c(c2)C(=C2C(=O)Nc4ccccc42)OC3)c(OC)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CN(C)c2ccc3c(c2)C(=C2C(=O)N(CO)c4ccccc42)OC3)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 3-[6-(2,4-dimethoxy-benzylamino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (1 g, 2.41 mmol) and 37% formaldehyde aqueous solution (2 ml, 27 mmol) in acetonitrile (30 ml), was added sodium cyanoborohydride (606 mg, 9.64 mmol). The mixture was stirred at room temperature for 2 hours, and 10% AcOH aqueous solution (30 ml) was added. The mixture was continuously stirred for another 10 minutes. The yellow precipitate separated, washed with MeOH and dried under vacuum to give a crude product. Recrystallization of the crude product with MeOH led to 3-{6-[(2,4-dimethoxy-benzyl)-methyl-amino]-3H-isobenzofuran-1-ylidene}-1-hydroxymethyl-1,3-dihydro-indol-2-one as yellow needles (0.9 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.Cl.[NH2:47][C:48]1[S:49][C:50]([CH3:54])=[C:51]([CH3:53])[N:52]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:47][C:48]2[S:49][C:50]([CH3:54])=[C:51]([CH3:53])[N:52]=2)=[O:44])=[C:18]([C:23]([F:25])([F:26])[F:24])[CH:17]=1
Reactant: Cc1nc(N)sc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nc(C)c(C)s4)c(C(F)(F)F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-(trifluoromethyl)aniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-4,5-dimethylthiazole hydrochloride (55 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 43 mg of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]CC(O)=O)=[CH:5][C:4]=1C.[C:16](Cl)(=[O:20])[C:17](Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[CH3:10][C:9]1[CH:17]=[C:16]2[C:4]([C:3](=[O:2])[CH2:8][CH2:7][O:20]2)=[CH:5][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(CCCC(=O)O)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)OCCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A stirred solution of 5.0 grams (0.028 mole) of 3-(3-methylphenoxy)propanoic acid (i) and 5.3 grams (0.042 mole) of oxalyl chloride in 100 mL of methylene chloride was cooled to −5° C. and a few drops of DMF was added. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about two hours. After this time, the reaction mixture was concentrated under reduced pressure to a residue: which was 3-(3-methylphenoxy)propanoic acid chloride. The acid chloride was stored under a nitrogen atmosphere for about 18 hours, and then it was dissolved in 50 mL of methylene chloride. The stirred solution was cooled to −4° C. and 4.1 grams (0.031 mole) of aluminum chloride was added portionwise while maintaining the reaction mixture temperature at 5° C. or less. Upon completion of addition, the reaction mixture was maintained at 5° C. for about three hours. After this time, the reaction mixture was poured into ice and extracted with three 100 mL portions of methylene chloride. The combined extracts were washed with two 50 mL portions of water and dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of ethyl acetate and hexane as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 3.5 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH2:7][CH2:6]2.[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][Cl:19]>O1CCOCC1>[Cl-:19].[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N+:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1
Reactant: COc1cc2c(cc1OC)CCN=C2
Reactant: Cc1ccccc1CCl
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CC[N+](Cc1ccccc1C)=C2
Product: [Cl-]

Procedure:
The title compound is prepared analogously to Example A from 6,7-dimethoxy-3,4-dihydroisoquinoline and 2-methyl-benzyl chloride in dioxan. Melting point: 193°-195° C. (Decomp., from ethanol-ether).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:25])[C:9]2[CH:21]=[CH:20][C:19]([C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:24])=[CH:18][C:10]1=2
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)c2cc(C(=O)N3CCOCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To the tetrahydrofuran (1 ml) solution of 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid (Compound B2-28, 15 mg, 0.045 mmol), morpholine (6 μl, 1.5 eq.), hexafluorophosphoric acid uronium 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylmethane aminium (HATU) (26 mg, 1.5 eq.), and N,N-diisopropylethylamine (24 μl, 3.0 eq.) were added and the mixture was stirred at room temperature for 3 hr. The reaction solution was filtered to remove insoluble matters and the residues obtained after concentration under reduced pressure were purified by high performance liquid chromatography to obtain the title compound (11 mg, 55%).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[CH:22]1([OH:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>C(OCC)C>[C:1]([O:38][CH:22]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: OC1CCCCCCC=CCCCCCCC1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OC1CCCCCCC=CCCCCCCC1
Yield: 36.1 %

Procedure:
1.8 g of dodecanoyl chloride and 2.0 ml of triethylamine are added to a solution of 1.65 g of 8-cyclohexadecen-1-ol in 25 ml of diethyl ether. After heating to reflux for 5 hours, the mixture is poured into 100 ml of H2O, the organic phase is separated off, the aqueous phase is extracted with 25 ml of diethyl ether, and the combined organic phases are evaporated in vacuo. Purification of the residue by chromatography on silica gel using dichloromethane/hexane 1:3 gives 1.05 g of 8-cyclohexadecen-1-yl dodecanoate as a viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[NH2:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([Cl:20])[N:14]=1.[OH-].[Na+]>O.CC(C)=O>[Cl:20][C:15]1[CH:16]=[C:17]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)[N:18]=[C:13]([NH2:12])[N:14]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Oc1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Nc1nc(Cl)cc(Oc2ccc3ncccc3c2)n1

Procedure:
To a mixture containing 7.25 g (0.05 mol) 6-hydroxy-quinoline, 8.25 g (0.05 mol) 2-amino-4,6-dichloropyrimidine in 300 mL of water/acetone 1:1 are added 2.0 g (0.05 mol) sodium hydroxide. On heating a clear solution is first obtained from which a thick precipitate separates. Stirring under reflux is continued for a total of 6 h. The mixture is cooled, filtered and the solid washed with acetone/water 1.1 and dried. The title compound is obtained as a solid: map. 248-250° C.; MS: [M+1]+=273; HPLC: CtRet=1.30; TLC (dichloromethane/methanol 95:5): Rf=0.46.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.[CH2:27](N(CC)CC)C.O>CN(C)C=O>[CH2:21]([C:22]1[N:23]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:24]=[CH:25][N:26]=1)[CH3:27]
Reactant: Cc1ncc[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
Triphenylmethyl chloride (16.0 g, 57.5 mmol) was added portionwise to a solution of 2-methylimidazole (4.10 g, 50.0 mmol) and Triethylamine (9.02 mL, 64.7 mmol) in 20 ml of N,N-dimethylformamide. The mixture was stirred for 18 hours, mixed with 300 ml of water and extracted with 1000 ml of ethyl acetate. The organic extract was washed with 1 L of water, brine, dried over MgSO4 and concentrate in vacuum to 50 ml volume. A precipitate was collected, washed with ethyl acetate and dried in high vacuum for 18 hours. Weight 15.0 g (92.5%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.29 (m, 9H), 7.16-7.11 (m, 6H), 6.90 (d, J=1.5, 1H), 6.71 (d, J=1.5, 1H), 1.65 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[CH2:10][C:11]1([C:16]([OH:18])=O)[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C@@H:21]([C:35]1[N:39]([CH2:40][CH2:41][C:42]#[N:43])[N:38]=[N:37][N:36]=1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[C:26]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([CH2:22][C@@H:21]([NH:20][C:16]([C:11]2([CH2:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:18])[C:35]2[N:39]([CH2:40][CH2:41][C:42]#[N:43])[N:38]=[N:37][N:36]=2)=[CH:28][CH:27]=1
Reactant: N#CCCn1nnnc1[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(CC1(C(=O)O)CCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#CCCn1nnnc1[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C1(CC(=O)OCc2ccccc2)CCCC1
Reaction time: 2 h
Yield: 44.1 %

Procedure:
To a solution of 1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxylic acid (49.4 mg, 0.188 mmol) and (R)-3-(5-(1-amino-2-(biphenyl-4-yl)ethyl)-1H-tetrazol-1-yl)propanenitrile (50 mg, 0.157 mmol) in DMF (1.5 mL) were added EDC.HCl (36 mg, 0.188 mmol), HOAt (26 mg, 0.188 mmol) and triethylamine (0.033 mL, 0.236 mmol). After being stirred for 2 hours, the reaction mixture was diluted with EtOAc. The mixture was washed with H2O2O and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel flash column chromatography (eluent; EtOAc/heptane) to give (R)-benzyl 2-(1-(2-(biphenyl-4-yl)-1-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)ethylcarbamoyl)cyclopentyl)acetate (39 mg). LCMS (condition A) δ 563 (M+1); retention time=1.85 min.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]([F:15])=[N:13][CH:14]=1)=O)(C)(C)C.O.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[C:10]([C:16]([OH:18])=[O:17])=[CH:11][C:12]([F:15])=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(F)cc1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1cnc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.5 %

Procedure:
A suspension of 36.6 g (140 mM) of 5-[N-(tert-butoxycarbonyl) amino]-2-fluoropyridine-4-carboxylic acid hydrated with 0.3 equivalents of water in 280 mL of dichloromethane was cooled in an ice bath then treated dropwise over 15 minutes with 140 mL of trifluoroacetic acid. The bath was removed, and the resultant mixture was stirred at room temperature for 14 hours, then concentrated. The yellow-orange solids were triturated in 125 mL of warm 1:1 diethyl ether:dichloromethane. After cooling, the yellow solids were collected, washed with 100 mL of the diethyl ether:dichloromethane mixture, and dried to afford 19.3 g of product. Processing of the filtrate afforded 1.7 g of a second crop. Total yield=21 g (94%). Recrystallization of a small sample from ethyl acetate provided product of mp 259° C. (dec). 1H NMR [(CD3)2SO]: δ8.86 (m, 3H), 7.81 (d, JH-F=1.1 Hz, 1H), 7.20 (d, JH-F=2.3 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][C:23]=1[CH3:30]>[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:19])[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[C:23]([CH3:30])[CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc([Mg]Br)cc1C
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
A solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 11.02 mmol in 30 mL THF) was cooled to 0° C., then (4-methoxy-3-methylphenyl)magnesium bromide was added dropwise via a syringe under N2 and the reaction mixture was stirred at the same temperature for 1.5 h, then gradually warmed up to room temperature over 1 h when the reaction was judged complete by LCMS. 40 mL of saturated aqueous NH4Cl was added slowly then the aqueous solution was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over Na2SO4 and the solvent was removed to yield the crude product. Purification by flash chromatography gave the title compound as a white solid (1.97 g, 5.62 mmol, 51% yield). MS (ESI) m/z 334.4 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.57 min. 1H NMR (400 MHz, CDCL3) δ ppm 1.48 (s, 9H) 1.62-1.91 (m, 4H) 2.27 (s, 3H) 2.78-3.02 (m, 2H) 3.27-3.46 (m, 1H) 3.91 (s, 3H) 4.12-4.27 (m, 2H) 6.87 (d, J=8.59 Hz, 1H) 7.77 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:13]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([C:9]([Cl:13])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)ccc(N)c1C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
To a solution of methyl 3-amino-2-methylbenzoate (25.0 g, 151 mmol) in N,N-dimethylformamide (757 mL) was added N-chlorosuccinimide (20.2 g, 151 mmol) at room temperature, and the mixture was stirred for 3 days. The reaction mixture was concentrated under reduced pressure to a half volume, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/5) to give the title compound (13.5 g, yield 45%).