Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5]NC1C=CC(C2C=C(C3C=CC(C(OCC)=O)=CC=3)C=CC=2CC=C)=CC=1C(C)(C)C)(=[O:3])C.C12BC(CCC1)CCC2.[OH-].[Na+].OO.[C:50]([CH2:53][CH2:54][NH:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:63]=[C:64]([C:72]3[CH:77]=[CH:76][C:75]([C:78]([O:80][CH2:81][CH3:82])=[O:79])=[CH:74][CH:73]=3)[CH:65]=[CH:66][C:67]=2CCCO)=[CH:58][C:57]=1[C:83]([CH3:86])([CH3:85])[CH3:84])(=[O:52])[CH3:51]>>[C:50]([CH2:53][CH2:54][NH:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:63]=[C:64]([C:72]3[CH:73]=[CH:74][C:75]([CH2:5][CH2:4][CH2:1][OH:3])([C:78]([O:80][CH2:81][CH3:82])=[O:79])[CH2:76][CH:77]=3)[CH:65]=[CH:66][CH:67]=2)=[CH:58][C:57]=1[C:83]([CH3:84])([CH3:85])[CH3:86])(=[O:52])[CH3:51]
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCO)c(-c3ccc(NCCC(C)=O)c(C(C)(C)C)c3)c2)cc1
Reactant: C=CCc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc(NCCC(C)=O)c(C(C)(C)C)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Product: CCOC(=O)C1(CCCO)C=CC(c2cccc(-c3ccc(NCCC(C)=O)c(C(C)(C)C)c3)c2)=CC1
Yield: 100 %

Procedure:
In a manner similar to that of Example 32c, by reacting 0.2 g (0.41 mmol) of ethyl 4″-(acetylethylamino)-4′-allyl-3″-tert-butyl[1,1′;3′,1″]terphenyl-4-carboxylate with 150 mg (1.24 mmol) of 9-borabicyclo[3.3.1]nonane, followed by addition of 1.25 mL (1.28 mmol) of 1N sodium hydroxide solution and 1 g (10.3 mmol) of hydrogen peroxide, 205 mg of ethyl 4″-(acetylethylamino)-3″-tert-butyl-4′-(3-hydroxypropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=100%) in the form of a colorless oil.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)([O-:10])=[O:9].[CH:19]([C:22]1[N:23]=[C:24]([CH3:27])[S:25][CH:26]=1)([CH3:21])[CH3:20]>>[CH:19]([C:22]1[N:23]=[C:24](/[CH:27]=[CH:14]/[C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=2)[S:25][CH:26]=1)([CH3:21])[CH3:20]
Reactant: Cc1nc(C(C)C)cs1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1csc(/C=C/c2cccc([N+](=O)[O-])c2)n1
Yield: 31.9 %

Procedure:
To 11.3 ml of acetic anhydride were added 29.0 g of 3-nitrobenzaldehyde and 27.1 g of 4-isopropyl-2-methylthiazole and the reaction was carried out under nitrogen gas stream at 170° C. for 23 hours. After completion of the reaction, low boiling materials were evaporated under reduced pressure and the residue was recrystallized from ethyl ether-n-hexane to give 16.8 g (yield 32%) of the title compound as yellowish white crystals.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C:19]([CH3:26])([CH2:24][OH:25])[C:20]([O:22][CH3:23])=[O:21]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C:19]([CH3:26])([CH2:24][OH:25])[C:20]([O:22][CH3:23])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Reactant: COC(=O)C(C)(N)CO
Agent: Cl
Product: COC(=O)C(C)(CO)NCc1cccc(O[Si](C)(C)C(C)(C)C)c1
Yield: 97 %

Procedure:
Prepare as in Example 12-9c from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and methyl 2-amino-3-hydroxy-2-methylpropanoate hydrochloride. Yield 97%, yellowish oil. MS 354 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:5][N:4]=1)[CH3:2].[I:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.CCCCCC>[CH2:1]([C:3]1[S:7][C:6](=[N:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[N:5]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([I:15])=[CH:17][CH:18]=2)[N:4]=1)[CH3:2]
Reactant: BrCc1ccc(I)cc1
Reactant: CCc1nnc(NC(=O)C(F)(F)F)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(I)cc2)c(=NC(=O)C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of 5-ethyl-2-trifluoroacetylamino-1,3,4-thiadiazole (22.5 g) and 4-iodobenzyl bromide (32.7 g) in N,N-dimethylformamide (100 ml) was added potassium carbonate (13.8 g), followed by stirring at room temperature overnight. To the reaction mixture, ethyl acetate (500 ml) was added. The resulting mixture was washed three times with 10% aqueous citric acid solution, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off. The oily substance so obtained was separated by column chromatography on silica gel. The crystals so obtained were dispersed in n-hexane, collected by filtration and then dried, whereby 33.9 g of the title compound was obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[O:13]=[C:14]1[NH:18][C:17]([C:19]([F:22])([F:21])[F:20])=[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:15]1.[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:33]=CC=C[CH:29]=1.C(O)C#C>O.O1CCCC1>[O:13]=[C:14]1[N:18]([CH2:33][C:28]#[CH:29])[C:17]([C:19]([F:20])([F:21])[F:22])=[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:15]1
Reactant: CCOC(=O)c1oc(=O)[nH]c1C(F)(F)F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: C#CCO
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: C#CCn1c(C(F)(F)F)c(C(=O)OCC)oc1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
5.4 ml of diethyl azodicarboxylate were added at 10 C to a solution of 7 g of ethyl 2,3-dihydro-2-oxo-4-trifluoromethyl-oxazol-5-carboxylate [prepared as in Patent No. EP 027,020], 70 ml of tetrahydrofuran, 8.15 g of triphenylphosphine and 3.3 ml of propargyl alcohol and the mixture was stirred for one hour at 20° C. The mixture was poured into water and was extracted with ethyl acetate, dried, filtered and concentrated. The residue was chromatographed on silica and eluted with a hexaneethyl acetate mixture (85-15) to obtain 4.6 g of the expected product melting at 72° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]2[CH3:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:20].[Na+:21]>O>[OH2:8].[NH2:16][C:17]1[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[CH:14]([CH3:19])[C:15]([O-:20])=[O:18].[Na+:21]
Reactant: [OH-]
Reactant: CC1C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Agent: [Na+]
Solvent: O
Product: CC(C(=O)[O-])c1cccc(C(=O)c2ccccc2)c1N

Procedure:
A suspension of 9 g. (0.036 mole) of 7-benzoyl-3-methylindolin-2-one in 100 ml. of 3N sodium hydroxide was refluxed for 18 hrs. under nitrogen. The mixture was filtered and stripped under water pump vacuum to yield a gummy mixture of sodium hydroxide, water, and product. The mixture was triturated with boiling isopropanol and filtered. The isopropanol solution was cooled and filtered to separate the bright yellow product. The product weighed 4.0 g. and melted at 218° C. (dec.)
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=2)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:24]([N:3]([CH2:1][CH3:2])[C:4]1[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH3:25]
Reactant: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Reaction time: 0.17 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(diethylamino)-2-phenylquinoxaline-6-carboxylate (117 mg, 0.35 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (69.9 mg, 1.75 mmol, 5.00 equiv) in water (2 mL) dropwise with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The crude product (110 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and methanol (70% methanol up to 90% in 10 min); Detector, UV 254 nm. This resulted in 70 mg (62%) of 3-(diethylamino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:16]([CH3:17])=[C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:14]([CH2:24][O:25][CH3:26])[C:13]=1[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=O)C>[Cl-].[NH4+]>[OH:9][CH2:10][C:12]1[C:16]([CH3:17])=[C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:14]([CH2:24][O:25][CH3:26])[C:13]=1[C:27]1[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1c(C)c(-c2ccncc2)n(COC)c1-c1ccncc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: COCn1c(-c2ccncc2)c(C)c(CO)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
To a stirred suspension of lithium aluminum hydride (LAH) (88 mg, 2.31 mmol) was added 3-ethoxycarbonyl-1-methoxymethyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole (270 mg, 0.77 mmol) at 0° C. under nitrogen. After stirring for 2 hours, the reaction mixture was allowed to warm to room temperature and stirred for 3 days. Saturated aqueous ammonium chloride solution (50 mL) was added to the mixture, and the whole was extracted with ethyl acetate (70 mL×2). Combined organic layers were washed. with brine (50 mL), dried over MgSO4, and concentrated il vacuo to afford the subtitle compound (180 mg, 5.8% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([S:29]([C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:5]=[CH:6][CH:7]=1.[C:39]([O:43][C:44]([NH:46][CH2:47][C:48](O)=[O:49])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCN(C(C)C)C(C)C.[Cl-].ClC1N(C)C=C[N+]=1C>C(Cl)Cl>[C:39]([O:43][C:44](=[O:45])[NH:46][CH2:47][C:48]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([S:29]([C:32]5[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=5)(=[O:31])=[O:30])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][S:11]3)[CH:3]=1)=[O:49])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reaction time: 1.5 h
Yield: 55.5 %

Procedure:
The 4-[6-(3-aminophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-{(3R)-1-[(4-chlorophenyl)-sulfonyl]piperidin-3-yl}pyrimidin-2-amine (0.1 g, 0.177 mmol) and N-(tert-butoxycarbonyl)glycine (34 mg, 0.194 mmol) were dissolved in DCM (5 ml) and treated with Hunig's base (92 uL, 0.53 mmol) and 2-chloro-1,3-dimethyl-1H-imidazol-3-ium chloride (33 mg, 0.194 mmol). The mixture was kept at room temperature for 90 minutes then was diluted with DCM (10 ml). The organic phase was washed with water (2×10 ml) and with an aqueous sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo, giving a yellow oil. The product was purified by flash chromatography (gradient 70%-100% EtOAc/hexanes), affording the title compound as a pale yellow solid (71 mg). 400 MHz 1H NMR (DMSO-d6) δ: 9.86 (s, 1H), 8.73 (br. s, 1H), 8.11 (d, J=5.5 Hz, 1H), 7.84 (s, 1H), 7.79-7.75 (m, 2H), 7.70-7.65 (m, 3H), 7.45-7.37 (m, 2H), 7.26 (d, J=7.4 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.82 (br. s, 1H), 6.42 (d, J=6.9 Hz, 1H), 4.00-3.90 (m, 1H), 3.78-3.70 (m, 3H), 3.52-3.44 (m, 1H), 3.18 (s, 2H), 2.34 (t, J=10.2 Hz, 1H), 1.94-1.81 (m, 2H), 1.65-1.52 (m, 1H), 1.39 (s, 9H). LCMS: 723 [M+H].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[C@H:31]([OH:33])[CH3:32].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)=[C:25]([C@H:31]([OH:33])[CH3:32])[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C[C@@H](O)c1cc(Cl)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](O)c1cc(Cl)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 74537.5 %

Procedure:
A vigorously stirred mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1-4) (34.0 g, 0.110 mol), (1R)-1-(2-bromo-5-chlorophenyl)ethanol (3-4) (25.8 g, 0.110 mmol), potassium phosphate tribasic (70.0 g, 0.330 mol) and tetrakis(triphenylphosphine)palladium(0) (2.54 g, 2.20 mmol) in N,N-dimethylformamide (440 mL) was degassed via three vacuum/nitrogen ingress cycles and then heated at 100° C. for approximately 18 h. After cooling to room temperature, the reaction mixture was poured into ice/water (˜1:1) and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (25% ethyl acetate/hexanes as eluent) afforded 3-5 (27.7 g) as a pale yellow foam.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[Cl:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC4CCCCC4)c23)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)c(Nc2ncnc3cc(O)cc(OC4CCCCC4)c23)c1

Procedure:
Using an analogous procedure to that described in Example 20, 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-cyclohexyloxyquinazoline was reacted with trifluoroacetic acid to give 4-(2-chloro-5-methoxyanilino)-5-cyclohexyloxy-7-hydroxyquinazoline; NMR Spectrum: (DMSOd6 and CF3CO2D) 1.2–1.35 (m, 1H), 1.4–1.55 (m, 2H), 1.55–1.65 (m, 1H), 1.7–1.85 (m, 4H), 2.15 (m, 2H), 3.82 (s, 3H), 4.85 (m, 1H), 6.8 (s, 1H), 7.0 (s, 1H), 7.05 (m, 1H), 7.55 (d, 1H), 7.6 (d, 1H), 8.82 (s, 1H); Mass Spectrum: M+H+ 400 and 402.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]([OH:16])=O)[CH2:11][C:10]2([CH3:13])[CH3:12])=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]([Cl:19])=[O:16])[CH2:11][C:10]2([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C(=O)O)CC2(C)C)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2(C(=O)Cl)CC2(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(4-methoxyphenyl)-2,2-dimethylcyclopropanecarboxylic acid (44 mg, 0.20 mmol), thionyl chloride (44 μL, 0.60 mmol) and DMF (1 drop) was stirred at room temperature for 30 minutes. The mixture was concentrated and the resultant acid chloride was used without further purification.
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:17][NH:18][C@@H:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])([O:10]C2C=CC=CC=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(#N)C>[C:1]1([O:7][P:8]([CH2:17][NH:18][C@@H:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:33][CH:34]=2)[C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Product: O=C(O)CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(O)Oc1ccccc1

Procedure:
(S)-N-[2-(Diphenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionic acid (100 mg, 0.18 mmol) is dissolved in acetonitrile (10 mL) containing 5% 1N HCl. The mixture is refluxed for 3 hours. The precipitate is filtered and triturated with aqueous methanol to yield (S)-N-[2-(monophenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionic acid as a monohydrate, m.p. 222°-223°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].C[O:16][C:17](=[O:50])[C@@H:18]([CH2:45][C:46]([O:48]C)=[O:47])[NH:19][C:20](=[O:44])[C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][C:27]1[O:28][C:29]([C:32]([O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[NH:43])[NH2:42])=[CH:37][CH:36]=2)=[O:33])=[CH:30][CH:31]=1.Cl>O1CCOCC1.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:41]([C:38]1[CH:37]=[CH:36][C:35]([O:34][C:32]([C:29]2[O:28][C:27]([CH2:26][N:22]3[CH2:23][CH2:24][CH2:25][C@@H:21]3[C:20]([NH:19][C@@H:18]([C:17]([OH:50])=[O:16])[CH2:45][C:46]([OH:48])=[O:47])=[O:44])=[CH:31][CH:30]=2)=[O:33])=[CH:40][CH:39]=1)(=[NH:42])[NH2:43]
Reactant: COC(=O)C[C@@H](NC(=O)[C@H]1CCCN1Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2)o1)C(=O)OC
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: N=C(N)c1ccc(OC(=O)c2ccc(CN3CCC[C@@H]3C(=O)N[C@H](CC(=O)O)C(=O)O)o2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 5 %

Procedure:
To the compound obtained in step 1 were added 4N hydrochloric acid in 1,4-dioxane and water (1/1), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (2 steps yield 5%).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[C:12]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])/[CH:13]=[CH:14]/[CH3:15].[OH-].C([N+](CC)(CC)CC1C=CC=CC=1)C>>[CH:7](=[CH:15]/[CH:14]=[CH:13]/[C:12]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])[C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C/C=C/C(=O)N1CCCCC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Product: O=C(/C=C/C=Cc1ccc2c(c1)OCO2)N1CCCCC1

Procedure:
1 mol of piperonal is reacted with 1.1 mols of crotonic acid piperidide in the presence of 0.09 mol of triethylbenzylammonium hydroxide in 100 parts by volume of one of the solvents indicated in Table 3 which follows, under the conditions described in Example 1 to give piperonylidenecrotonic acid piperidide. The yields achieved are likewise indicated in Table 3.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12]Cl)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[I-:15].[Na+]>C(C(C)=O)C>[CH3:1][C:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12][I:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)(C)CCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)CC(C)(C)CCCCI

Procedure:
To a solution of 3.57 g. (0.0162 mole) of ethyl 3,3-dimethyl-7-chloroheptanoate in 100 ml. of methyl ethyl ketone is added 4 g. of sodium iodide and the mixture heated at reflux for 18 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between ether and water. The aqueous phase is extracted several times with ether. The extract is washed with sodium bisulfite solution, water and saline. The organic solution is dried over magnesium sulfate and concentrated to give 4.182 g. of a yellow oil. The material is purified by distillation, b.p. 86°-87° C. (0.18 Torr).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21]([OH:23])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.[F:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][CH2:51][CH2:52][CH2:53][N:54]1[N:58]=[N:57][CH:56]=[N:55]1>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:23])[N:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[F:43])[CH2:51][CH2:52][CH2:53][N:54]2[N:58]=[N:57][CH:56]=[N:55]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:9])([CH3:8])[CH3:10]
Reactant: Fc1ccccc1NCCCn1ncnn1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCn2ncnn2)c2ccccc2F)c1)c1ccncc1
Yield: 64.8 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.110 ml) and dry DMF (0.002 ml) were added to a stirred suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g) in dry dichloromethane (1 ml) under nitrogen. After 5 min DIPEA (0.090 ml) was added followed after a further 40 min by 2-fluorophenyl-(3-tetrazol-2-yl-propyl)-amine (0.066 g) and DMAP (0.002 g). After 40 h the solvent was evaporated and the residue was purified by flash chromatography, eluting with dichloromethane:methanol (98:2 v/v) to give the title compound as a viscous yellow oil (0.059 g).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:31])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:30][CH2:29][CH2:28][C@H:13]2[C:14]([NH:16][C@H:17]([C:25]([NH2:27])=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C1COCC1>[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([NH:27][C:25](=[O:26])[C@H:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:16][C:14](=[O:15])[C@@H:13]2[CH2:28][CH2:29][CH2:30][N:12]2[S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH3:31])=[CH:4][CH:5]=2)(=[O:11])=[O:10])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(N)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-(Toluene-4-sulfonyl)-L-proline was reacted with L-phenylalanine amide using the procedure described in Method 12 to yield N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide. To a solution of NaH (60% mineral oil—prewashed with THF) in THF at 0° C. was added N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine amide and the reaction was stirred at 0° C. for 45 minutes. Toluene-4-sulfonyl chloride was added and the reaction was stirred for 16 hours at room temperature. The reaction mixture was extracted with EtOAc (3×50 mL) and 0.2 N HCl (50 mL), and the combined organic layers were washed successively with sat. NaHCO3 (50 mL), and sat. NaCl (2×50 mL), dried over MgSO4, filtered, and concentrated to yield the title compound as an oil.