Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12]OC(OC)OC.S(=O)(=O)(O)O.N>CN(C)C(=O)C.CO>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:5])[NH:6][CH:12]=[N:11]2
Reactant: NC(=O)c1c(N)cccc1N
Reactant: COC(OC)OC
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)N(C)C
Solvent: CO
Product: Nc1cccc2nc[nH]c(=O)c12

Procedure:
900 mg (5.958 mmol) 2,6-diaminobenzamide are dissolved in 3.6 ml N,N-dimethylacetamide and combined with 6.3 ml (57.01 mmol) trimethylorthoformate and 792 μl (8.865 mmol) 98% sulphuric acid. After 16 h at 25° C. the reaction mixture is taken up with 20 ml of methanol and the solvent is eliminated in vacuo. The residue is again taken up in 20 ml of methanol, neutralised with concentrated ammonia. The solvent is eliminated in vacuo and the residue purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution are added.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11](Cl)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([NH:28][CH:25]3[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH2:26]3)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2nc(Cl)oc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)oc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.4 %

Procedure:
To a solution of 2-chloro-benzooxazole-7-carboxylic acid methyl ester (1.50 g, 7.08 mmol, 1.0 equiv; example 252/step 3) in acetonitrile (23 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.42 g, 7.08 mmol, 1.0 equiv) and triethylamine (0.79 g, 7.79 mmol, 1.1 equiv). After stirring for 48 h at rt, the reaction mixture was poured on ice, the solution extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with water (2×100 mL) and a conc. solution of sodium chloride (100 mL). The organic phase was dried over MgSO4, concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with hexane/ethyl acetate (1:1) providing 2.27 g (85%) of the title compound. MS (ISP): 376.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][CH:6]([C:9]#[N:10])[C:7]#[N:8].[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][C:6]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:7]#[N:8])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Cl)c(Cl)c1
Yield: 14.7 %

Procedure:
Using 2.00 g of (3,4-dichlorobenzyl)malononitrile, 20 ml of N,N-dimethylformamide, 0.36 g of sodium hydride (60% in oil), and 2.37 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.42 g of 2-(3,4-dichlorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (21)).
Reaction SMILES: [Cl:1][C:2]1[C:14]([N:15]([CH3:17])[CH3:16])=[CH:13][C:5]([CH:6](O)CS(C)(=O)=O)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].C[O-].[Na+].[NH:24]([CH2:31][CH2:32][C:33]#[N:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O>[NH:24]([CH:31]=[C:32]([CH2:6][C:5]1[CH:13]=[C:14]([N:15]([CH3:16])[CH3:17])[C:2]([Cl:1])=[C:3]([N:18]([CH3:19])[CH3:20])[CH:4]=1)[C:33]#[N:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1Cl
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C)c1Cl

Procedure:
A mixture of 15.7 g. of 4-chloro-3,5-bis(dimethylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol, 2.8 g. of sodium methylate and 7.1 g. of β-anilinopropionitrile in 31 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 5 hours at 50° C. The mixture was poured into 200 ml. of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated in vacuo. By purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained α-(anilinomethylene)-4-chloro-3,5-bis(dimethylamino)hydrocinnamonitrile, having a melting point of 168° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][F:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:45]([O:47][C:48]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:46]>C(OCC)(=O)C>[CH2:45]([O:47][C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][F:14])[CH2:54][CH2:55]1)=[O:49])[CH3:46]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CF)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 150 mg (R)-2-tert-Butoxycarbonylamino-3-fluoro-propionic acid were added 0.18 ml N-ethylmorpholine, 237 mg TOTU and 115 mg 1-ethoxycarbonylpiperazine. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product obtained was used without further purification. Yield: 160 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12]S[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[S:32]([O-:36])([O-])(=[O:34])=S.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][S:32](=[O:36])(=[O:34])[CH:10]([C:14]2[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCSC(c2ccc(Br)cc2)C1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCS(=O)(=O)C(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-bromo-phenyl)-thiomorpholine-4-carboxylic acid tert-butyl ester (3.60 g; 10.05 mmol) in CH2Cl2 (100 mL) was added 3-chloroperoxybenzoic acid (5.20 g; 30.14 mmol), at 0° C. The resulting mixture was stirred overnight at RT, and subsequently, a saturated aqueous sodium thiosulfate solution was added and the mixture stirred for another 30 min. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined EtOAc layers were washed twice with an aqueous Na2CO3 solution. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to afford 2-(4-bromo-phenyl)-1,1-dioxo-1λ6-thiomorpholine-4-carboxylic acid tert-butyl ester (4.06 g) which was used as such in the next step.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH:7]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH2:22]([N:24]([CH2:25][CH3:26])[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH:7]=1)[CH3:23]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(CC)c1ccc([N+](=O)[O-])c(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 70.6 %

Procedure:
A mixture of 5-fluoro-2-nitro-4′-(trifluoromethoxy)biphenyl (compound of Example 78(1)) (700 mg, 2.32 mmol), diethylamine (339 mg, 4.64 mmol), potassium carbonate (320 mg, 2.32 mmol) and acetonitrile (5 ml) was stirred at 100° for 10 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (580 mg, 70.5%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[C:18](OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH3:18])[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc(CNC)c1

Procedure:
In analogy to the procedures described in example 5D], 5E] and 5F], 2-(3-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester was converted into the corresponding tert-butoxycarbonylamino derivative by treatment with di-tert-butyl dicarbonate and sodium hydrogen carbonate in dioxane/water at r.t., methylated at N and deprotected again to yield the title compound as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][CH2:31][NH2:32].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH2:30][CH2:31][NH:32][C:16]([C:13]([CH3:14])([O:12][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([O:19][CH3:20])[C:3]([OH:2])=[O:21])[CH:11]=[CH:10][CH:9]=1)[CH3:15])=[O:18]
Reactant: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)O)c1)OC
Reactant: NCCc1c(Cl)cccc1Cl
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1cccc(OC(C)(C)C(=O)NCCc2c(Cl)cccc2Cl)c1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (EXAMPLE 56, step 2) and 2-(2,6-dichloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H25ClNO5 [M]+: 454, [M+2]+: 456.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][O:20][CH2:21][C:22](O)=[O:23])=[C:13]([C:26]([O:28]C)=[O:27])[CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][C:13]=1[C:26]([OH:28])=[O:27])=[O:25]
Reactant: NCc1cccc(Br)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)NCc1cccc(Br)c1

Procedure:
Using the same method as in Example 15-(i), 3-bromobenzylamine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 2-[((2-[(3-bromobenzyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester (yield: 78%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[C:23]([CH3:25])=[CH2:24])C1C=CC=CC=1.O.[H][H]>C(O)C.[Pd]>[CH:23]([C:10]1[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=1[OH:8])([CH3:25])[CH3:24]
Reactant: [H][H]
Reactant: C=C(C)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(O)cc1O
Reaction time: 16 h

Procedure:
2,4-Bis-benzyloxy-1-isopropenyl-benzene was taken up in solution in ethanol and added to 10% palladium on carbon, which had been pre-wetted with water. Hydrogen was introduced to the flask and the mixture was allowed to shake for 16 hours. The catalyst was filtered from the reaction mixture, by a suitable method, and the liquor was concentrated in vacuo, to give 4-isopropyl-benzene-1,3-diol as a white crystalline solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(N(CC)CC)C.[CH3:15][C:16]1[C:20]([I:21])=[C:19]([CH3:22])[NH:18][N:17]=1>C(Cl)Cl>[I:21][C:20]1[C:16]([CH3:15])=[N:17][N:18]([C:5](=[O:7])[CH3:6])[C:19]=1[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1n[nH]c(C)c1I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1nc(C)c(I)c1C
Yield: 84.2 %

Procedure:
Acetic anhydride (0.51 mL, 5.4 mmol) and triethylamine (0.75 mL, 5.4 mmol) were added to a solution of 3,5-dimethyl-4-iodopyrazole (1 g, 4.5 mmol) in CH2Cl2. After 1 h the reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layer was washed with 1 N HCl, saturated NaHCO3, brine, dried over Na2SO4, and concentrated to give the title compound as a white solid (1 g, 85%).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16]C(=O)C(F)(F)F)[CH2:6]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH2:16])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@@H]1C[C@H](NC(=O)C(F)(F)F)c2cc(OC)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=CCO[C@@H]1C[C@H](N)c2cc(OC)ccc21
Yield: 87.6 %

Procedure:
Step U (2): N-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (1.28 g, 4.06 mmol) from Step U (1), potassium carbonate (2.85 g, 20.8 mmol) and MeOH (92 mL)/H2O (6 mL) were heated at reflux for 16 h. The reaction mixture was concentrated in vacuo. Added water to the residue, extracted with EtOAc, washed the organic layers with brine, dried over Na2SO4, filtered and concentrated to afford 780 mg (quantitative yield) of the title compound as light brown oil. HRMS (M+H)+=220.1336; [α]D +18.72 (c=8.86 mg/mL, ethanol) 1H NMR (500 MHz, CDCl3) δ ppm 1.66 (s, 1H) 1.76 (d, J=12.82 Hz, 1H) 2.74-2.83 (m, 1H) 3.81 (s, 3H) 4.04-4.18 (m, 3H) 4.77 (t, J=5.80 Hz, 1H) 5.18 (dd, J=10.38, 1.53 Hz, 1H) 5.32 (dd, J=17.24, 1.68 Hz, 1H) 5.97 (dd, 1H) 6.90 (d, J=2.44 Hz, 1H) 7.30 (d, J=8.24 Hz, 1H).
Reaction SMILES: [C:1]([O:4][O:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[C:8]([Br:23])[C:7]=1[CH2:24][CH3:25])(=[O:3])[CH3:2].C(O)C>C(OC(=O)C)C.Cl[Zn]Cl>[C:1]([O:4][O:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[C:8]([Br:23])[C:7]=1[CH2:24][CH3:25])(=[O:3])[CH3:2]
Reactant: CCc1c(OOC(C)=O)cc(Br)c(Oc2ccc([N+](=O)[O-])cc2)c1Br
Agent: Cl[Zn]Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1c(OOC(C)=O)cc(Br)c(Oc2ccc(N)cc2)c1Br
Temperature: 25 °C
Yield: 88.9 %

Procedure:
Ethyl(3,5-dibromo-4-[4-nitrophenoxy]phenoxy) acetate (2.4 g), zink chloride (5.7 g), ethylacetate (30 mL) and ethanol (30 mL) was heated at reflux for two hours. After cooling down to room temperature, the reaction mixture was diluted with ethylacetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and the organic phase dried over potassium carbonate. After concentration, 2.0 g of ethyl(3,5-dibromo-4-[4-aminophenoxy]phenoxy) acetate was obtained as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](O)=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1.C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.CCN(CC)CC>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:29]=[N+:30]=[N-:31])=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: COc1cc(F)ccc1/C=C/C(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(F)ccc1/C=C/C(=O)N=[N+]=[N-]
Reaction time: 16 h
Yield: 76.5 %

Procedure:
(E)-3-(4-fluoro-2-methoxyphenyl)acrylic acid (1.22 g, 6.22 mmol), diphenylphosphinyl azide (1.273 mL, 5.91 mmol), and Et3N (1.734 mL, 12.44 mmol) were dissolved in benzene and stirred for 16 h. The solution was concentrated under vacuum and the residue was purified by silica gel chromatography using 20% EtOAc/Hexanes to give (E)-3-(4-fluoro-2-methoxyphenyl)acryloyl azide (1.0 g, 73% yield).
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=[O:6])C(C)(C)C.[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]1[N:58]=[N:59][N:60]=[C:52]1[CH:51]=[CH:50]2)[CH2:45][OH:46])([CH3:42])([CH3:41])[CH3:40].C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)CO)(C)(C)C>>[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]1[N:58]=[N:59][N:60]=[C:52]1[CH:51]=[CH:50]2)[C:45]([OH:6])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1cc2c(ccc3nnnn32)c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2c(ccc3nnnn32)c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin-7-yl)acetic acid (4.9 mg) was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin-7-yl)ethanol instead of ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. 1H-NMR 400 MHz (CD3OD) 8.61 (s, 1 H), 7.75 (d, J=9.6 Hz, 1 H), 7.67-7.55 (m, 4 H), 7.39 (d, J=9.2 HZ, 1 H), 5.2 (s, 1 H), 2.79 (s, 3 H), 1.00 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C22H22ClN4O3: 425.1. Found: 425.1.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[C:11]([N:18]1[CH2:22][CH2:21][C:20](=O)[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[S:1]1[CH2:6][CH2:5][N:4]([CH:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:22]2)[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: c1ccc2c(c1)NCCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3ccccc32)C1
Temperature: 0 °C
Reaction time: 11 h
Yield: 19.4 %

Procedure:
A mixture of 3,4-dihydro-2H-benzo[b][1,4]thiazine (1.00 g, 6.61 mmol), N-boc-3-pyrrolidinone (1.34 g, 7.27 mmol), and acetic acid (0.94 mL, 16.52 mmol) in 1,2-dichloroethane (20 mL) was cooled to 0° C. and then treated with solid sodium triacetoxyborohydride (2.10 g, 9.92 mmol). The reaction was brought to room temperature and was stirred for 11 hours. Additional equivalents of each of sodium triacetoxyborohydride (1.40 g, 6.61 mmol) and N-boc-3-pyrrolidinone (1.22 g, 6.61 mmol) were added to the reaction mixture. The reaction was stirred for 2 more days and was then quenched with 3 N NaOH (50 mL). The mixture was transferred to a separatory funnel and extracted with EtOAc (2×50 mL). The organic phase was washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (10% EtOAc/hexanes then 20% EtOAc/hexanes). The sample was subject to additional flash chromatography on silica gel (7.5-15% EtOAc/hexanes) to give viscous oil (0.41 g, 19%). 1H NMR (CDCl3) δ 7.08 (dd, J=0.9, 7.5 Hz, 1H), 7.04-6.99 (m, 1H), 6.77 (d, J=8.1 Hz, 1H), 6.67-6.72 (m, 1H), 4.39-4.36 (m, 1H), 3.73-3.72 (m, 6H), 3.10-3.06 (m, 2H), 2.20-2.00 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %): 345, 343 (M+Na, 4), 322, 320 (MH+, 3), 267, 265 (100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[CH2:4][C@@H:5]([NH:35]C(OCC1C=CC=CC=1)=O)[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[C:17]([O:32][CH3:33])[CH:16]=2)=[CH:8][CH:7]=1.C(O)C>[Pd].C(O)=O>[CH3:1][O:2][C:3](=[O:46])[CH2:4][C@@H:5]([NH2:35])[C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[C:17]([O:32][CH3:33])[CH:16]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Product: COC(=O)C[C@@H](N)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
A mixture of (R)-3-benzyloxycarbonylamino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}phenyl)-propanoic acid methyl ester (18.55 g), ethanol (750 ml) and formic acid (18 ml), under an atmosphere of hydrogen, was heated at reflux. The reaction was treated portionwise with 10% palladium on charcoal (3.0 g) over a period of 1 hour and then heated at reflux for a further 1 hour. The reaction mixture was filtered through a short pad of diatomaceous earth and the filter pad was washed three times with ethanol (75 ml) and water (75 ml). The combined filtrate and washings were evaporated. The residue was treated carefully with aqueous solution of sodium bicarbonate (600 ml, 0.6M) followed by stirring for 15 minutes. The resultant white solid was collected, washed twice with water (100 ml), then boiled in acetonitrile in the presence of activated charcoal (150 mg). The mixture was filtered through a short pad of diatomaceous earth while hot and the filtrate cooled in ice to yield the title compound (7.6 g) as a white solid m.p. 189-191° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][NH:7][C:5](=[O:6])[CH2:4]1.[C:10]([S:13][CH2:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:16](O)=[O:17])(=[O:12])[CH3:11].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:10]([S:13][CH2:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:16]([NH:2][C@H:3]1[CH2:9][CH2:8][NH:7][C:5](=[O:6])[CH2:4]1)=[O:17])(=[O:12])[CH3:11]
Reactant: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)O
Reactant: N[C@H]1CCNC(=O)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)N[C@H]1CCNC(=O)C1
Reaction time: 18 h

Procedure:
Prepare 3(S)-amino-δ-valerolactam hydrochloride according to the procedure of J. Chem. Soc. Dalton Trans., 1987, p. 1127. Combine this lactam (0.29 g,2.0 mmol), 2(S)-acetylthiomethyl-3-(2-methylphenyl)propionic acid (0.50 g,2.0 mmol), triethylamine (0.03 g,3.0 mmol), and HOBT (0.30 g,2.0 mmol) in DMF (20 ml). Add DEC (0.38 g,2.0 mmol). Stir 18 hr, partition between EtOAc and H2O, dry and concentrate. Chromatograph on silica, eluting with 3% MeOH/CH2Cl2 to obtain the title compound as a foam, [α]D26 =-28.6° (EtOH)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][NH:13][CH3:12])[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1cccc2cc[nH]c12
Reaction time: 3 h
Yield: 88.9 %

Procedure:
Indole-7-carbaldehyde (500 mg, 3.4 mmol) was dissolved in anhydrous methanol (10 mL). Methylamine (5.1 mL of 2M solution in methanol, 9.55 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (10 mL). Sodium borohydride (131 mg, 3.45 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated. Sodium hydroxide (5 mL, 1N) was added and the indole was extracted with ethyl acetate (3×20 mL), dried over MgSO4 and concentrated to afford the tide compound as a yellow oil (484 mg, 92%). 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.29-7.17 (m, 2H), 7.04 (d, J=3.1 Hz, 1H), 6.44 (d, J=3.1 Hz, 1H), 3.84 (s, 2H), 2.46 (s, 3H).