Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O-:15][C:16]#[N:17].[K+].Cl[O-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:15])[NH:17][C:10]([CH3:11])=[N:9]2)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: N#C[O-]
Reactant: CC=NNc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1nn(-c2ccc(Cl)c([N+](=O)[O-])c2)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a stirred solution of 5.25 g (00246 mole) of acetaldehyde 4-chloro-3-nitrophenylhydrazone in 25 ml of acetic acid was added dropwise a solution of 2.0 g (0.0246 mole) of potassium cyanate in 5 ml of water. After complete addition, 50 ml of an aqueous 5% sodium hypochlorite solution was added dropwise, forming a precipitate. After about 1/2 hour, the solid was collected by filtration and dried to yield 5.4 g of 1-(4-chloro-3-nitrophenyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one.
Reaction SMILES: C(OO)(=[O:3])C.C([O-])(=O)C.[Na+].[CH3:11][C:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[C:13]=1[CH:20]([OH:24])[CH:21]=[CH:22][CH3:23].C(Cl)Cl>O>[CH3:11][C:12]12[O:3][C:13]1([CH:20]([OH:24])/[CH:21]=[CH:22]/[CH3:23])[C:14]([CH3:18])([CH3:19])[CH2:15][CH2:16][CH2:17]2
Reactant: CC=CC(O)C1=C(C)CCCC1(C)C
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C/C=C/C(O)C12OC1(C)CCCC2(C)C

Procedure:
21 g. of 40 % peracetic acid and 0.6 g. of sodium acetate were added under nitrogen to a suspension of 2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene (19.4 g.) and 12 g. of sodium acetate in 35 ml. of CH2Cl2 at 20°. The reaction mixture was left 2 more hours with stirring and it was then poured into 250 ml. of water.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][N:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[NH:25]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].O>>[NH:25]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][NH:12][C:13]4[C:22]5[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][N:21]=5)[N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:7]=2)[CH:27]=[N:26]1
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Reactant: OB(O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc2c(NCc3nnc4ccc(-c5cn[nH]c5)nn34)ccnc2c1

Procedure:
A 48 mL sealed tube was charged with N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (0.150 g, 0.439 mmol), 1H-pyrazol-4-ylboronic acid (0.0737 g, 0.658 mmol), and DMF (3.00 ml, 38.6 mmol). A solution of potassium carbonate (0.182 g, 1.32 mmol) and water (0.696 ml, 38.6 mmol) was added, followed by PdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol). The tube was flushed with argon, sealed, then placed in a 90° C. oil bath for 5 hours. The mixture was concentrated and the black solid was triturated with water to remove K2CO3, then purified by column chromatography using a 40 g RediSep column, eluting with 30-70% (90:10:1 DCM:MeOH:NH4OH solution) in DCM over 40 minutes. Pure fractions were collected to give N-((6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine as a white solid.
Reaction SMILES: Cl.C(=N)OCC.[C:7]([NH2:11])([CH3:10])([CH3:9])[CH3:8].C1(N2[C:19]([CH:20]=[O:21])=[CH:18][N:17]=[C:16]2C)CC1>>[C:7]([N:11]1[C:19]([CH:20]=[O:21])=[CH:18][N:17]=[CH:16]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1ncc(C=O)n1C1CC1
Reactant: CC(C)(C)N
Agent: CCOC=N
Agent: Cl
Product: CC(C)(C)n1cncc1C=O

Procedure:
3-tert-Butyl-3H-imidazole-4-carbaldehyde was prepared from ethyl formimidate hydrochloride (Aldrich) and tert-butylamine in the same manner as 3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4][C:3]=1[CH:14]=[O:15].[OH-:16].[Na+]>[N+]([O-])([O-])=O.[Ag+].C(O)C>[CH3:1][C:2]1[CH:6]=[C:5]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: Cc1cc(Oc2ccccc2)sc1C=O
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Oc2ccccc2)sc1C(=O)O

Procedure:
3-Methyl-5-phenoxy-thiophene-2-carbaldehyde, (example 22.a, 5.68 g, 25.9 mmol) was added to 26 mL of ethanol. To the mixture were added 21 mL of 5 N NaOH(aq) and silver nitrate (8.81 g, 52 mmol), and the resultant mixture was stirred for 19 hours at room temperature. The mixture was filtered through a pad of celite, washing the solid with ca. 50-100 mL portions of 1 N NaOH solution three times. The basic solution was washed with ethyl ether, then acidified with concentrated H2SO4, and extracted twice with ethyl acetate. The organic fractions were dried over anhydrous sodium sulfate and concentrated under high vacuum to 5.7 g of a yellow solid: MS: (−) m/z 232.9 (M−1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18](O)=[N:19][CH:20]=[N:21][CH:22]=4)=[C:11]3[O:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:18]1[C:17]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=23)=[CH:22][N:21]=[CH:20][N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncncc1-c1ccnc2c(-c3ccc(F)cc3)noc12
Product: Fc1ccc(-c2noc3c(-c4cncnc4Cl)ccnc23)cc1
Temperature: 90 °C
Yield: 100.6 %

Procedure:
A suspension of 5-(3-(4-fluorophenyl)isoxazolo[4,5-b]pyridin-7-yl)pyrimidin-4-ol (45 mg, 0.146 mmol) in phosphorus oxychloride (503 μl, 5.40 mmol) was heated at 90° C. for 1 h, then allowed to cool to room temperature. The solvent was evaporated to afford the title compound (48 mg, 100%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[O:25]([C:32]1[CH:42]=[CH:41][C:35]([CH:36]=[CH:37][C:38](O)=[O:39])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:25]([C:32]1[CH:33]=[CH:34][C:35]([CH:36]=[CH:37][C:38]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:39])=[CH:41][CH:42]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(Oc2ccccc2)cc1
Yield: 94.4 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 4-phenoxycinnamic acid (3.4 g), WSC.HCl (2.7 g, 14.1 mmol), and methylene chloride (80 mL), to give the captioned compound (4.9 g, 94%) as an oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:24][CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:27]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(NC(=O)C(Cl)c3ccccc3)cn2)nc(O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 16 (0.10 g, 0.42 mmol) in THF (10 mL), was added triethylamine (0.064 g, 0.63 mmol) and 2-chloro-2-phenyl acetyl chloride (0.119 g, 0.63 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5 methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[CH2:29][NH2:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]3[C:15]=2[CH2:29][NH:30][C:39](=[O:41])[N:21]3[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(NCc3ccccc3)c2CN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc3c2CNC(=O)N3Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The crude 4-(2-aminomethyl-3-benzylamino-6-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester of step 3 was dissolved in 10 mL dichloromethane and cooled to 0° C. Triethylamine (293 μL, 3 eq., 2.1 mmol) and 69 mg (1 eq., 0.233 mmol) triphosgene were added. The reaction mixture was stirred for 10 minutes. The mixture partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated. Column chromatography, eluting with acetone/dichlorometane provided 141 mg of 4-(1-benzyl-6-fluoro-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:19]=[O:20].Cl>C(#N)C>[OH:8][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[CH:19]=[O:20]
Reactant: C=O
Reactant: Oc1cccc(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=Cc1ccc(F)cc1O
Yield: 72 %

Procedure:
To the mixture of 3-fluorophenol (10 mL, 102 mmole), anhydrous magnesium chloride (28.2 g, 744.6 mmole) in 500 mL of anhydrous acetonitrile was added anhydrous triethylamine (67 mL, 382.5 mmole) and paraformaldehyde (22.3 g, 744.6 mmole). The mixture was then heated to reflux for five hours. After cooling to r.t, 500 mL of 5% aqueous hydrochloric acid was added. The product was extracted with ethyl acetate. The combined organic extracts were washed with 5% hydrochloric acid (×3), brine, and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was a light pink solid. 11 g, yield 72%. M.P: 67.5-69.0° C. ESHRMS m/z 139.0211(M−H, C7H4FO2 calc'd 139.0201). 1H NMR (CDCl3/300 MHz) 11.40 (s, 1H), 9.86 (s, 1H), 7.62-7.57 (m, 1H ), 6.79-6.67 (m, 2H). 3C (CDCl3/300 MH) 195.4, 168.3 (d, J=258 Hz), 164.4 (d, J=14.9 Hz), 136.3 (d, J=12.6 Hz), 118.2 (d, J=2.0 Hz), 108.5 (d, J=23.3 Hz), 104.9 (d, J=24.4 Hz). 19F (CDCl3/400 MHz) −97.9 (m).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:12][O:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]1[CH:18]=[C:19]([OH:34])[CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH3:12][O:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:34][C:2]1[N:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Reactant: CS(=O)(=O)c1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nn2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
3-Chloro-6-(methylsulfonyl)pyridazine (41 mg, 0.27 mmol) synthesized in Example (118c) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (80 mg, 0.24 mmol) synthesized in Example (116d) were dissolved in acetonitrile (2 mL), and cesium carbonate (158 mg, 0.48 mmol) was added, followed by stirring for 1 hour under nitrogen atmosphere. To the reaction solution, water (10 mL) was added, and extraction was carried out with ethyl acetate (10 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-4%) to afford the desired compound (116 mg, yield 98%) as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[CH3:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[CH:26][C:27]([CH3:28])=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2)cc1C

Procedure:
199 mg (87%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(3,4-dimethylphenyl)piperazine (52 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]([F:24])([C:18]2[O:19][C:20]([CH3:23])=[N:21][N:22]=2)[CH:12]2[CH2:16][CH2:15][C:14](=O)[CH2:13]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.ClC1C2C3(CCC=2)C(=CC=1)NC(C(S(C1C=CC=C(Cl)C=1)(=O)=O)(F)C1OC(C)=NN=1)C3>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]2[NH:33][C:14]3[CH2:13][CH:12]([C:11]([S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)(=[O:10])=[O:9])([F:24])[C:18]4[O:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH2:16][C:15]=3[C:29]=2[CH:28]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: Cc1nnc(C(F)(C2CCC(=O)C2)S(=O)(=O)c2cccc(Cl)c2)o1
Agent: Cc1nnc(C(F)(C2CC34CCC=C3C(Cl)=CC=C4N2)S(=O)(=O)c2cccc(Cl)c2)o1
Agent: Cl
Product: Cc1nnc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2cccc(Cl)c2)o1

Procedure:
In analogy to example 74.6, from (RS,SR)-3-[(3-chloro-benzenesulfonyl)-fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone and (4-chloro-phenyl)-hydrazine hydrochloride was prepared (RS,SR)-7-chloro-2-[(3-chloro-benzenesulfonyl)-fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)-methyl]-1,2,3,4-tetrahydro-cyclopenta[D]indole as a light brown solid, MS: 480 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16](=[O:33])[NH:17][C:18]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([NH:17][C:18]1[CH:31]=[CH:30][C:29]2[NH:28][C:27](=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)NCCCCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCCNCC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
(6-{[(6-oxo-5,6-dihydro-phenanthridin-2-ylcarbamoyl)-methyl]-amino}-hexyl)-carbamic acid tert-butyl ester was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at room temperature overnight, evaporated, taken up with diethyl ether, filtered and the collected solid was dried under vacuum to afford 30 mg (65% yield) of the title compound as a light-yellow solid.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:35][CH2:36][C:37]([NH:39][C@H:40]([C:44]([NH:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38].[Na+].[Cl-]>CN(C)C=O>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:35][CH2:36][C:37]([NH:39][C@H:40]([C:44]([NH:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@H](NC(=O)CN)C(=O)NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Boc-Phe-OH (9.16 g, 34.54 mmol) was dissolved in 100 ml of dimethylformamide (DMF), cooled to 0° C. and N-methylmorpholine (NMM) (3.83 ml) added. The solution was cooled to -15° C. and isobutyl chloroformate (IBCF) (3.96 ml, 30 mmol) was added slowly under stirring while maintaining the temperature at -15°±1° C. After stirring at this temperature for 15 minutes, a precooled solution of II (9.4 g, 21.59 mmol) and NMM (2.4 ml) in DMF (40 ml) was added and stirring continued for two hours at ice-bath temperature. A saturated solution of KHCO3 was added to bring the pH to 8.0 and stirred for an additional 30 minutes. The reaction mixture was poured into a cold 90% saturated NaCl solution (1000 ml) and the precipitate obtained was filtered, washed with satd. NaCl, H2O and dried. The peptide was crystallized from ethyl acetate to give 10 g of III (yield: 81.5%). Rf2 0.83 Anal. Calcd. for C30H40N4O7 : C 63.35, H 7.09, N 9.85%. Found: C 62.96, H 7.37, N 9.86%.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:17])[C:15]=1[CH3:16].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].CC(O)=O>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:17])[C:15]=1[CH2:16][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1c(Br)cncc1Br
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(Br)cncc1Br
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 31.8 %

Procedure:
To a solution of LDA (0.308 mol) [generated from N,N-diisopropylamine (31.2 g, 0.308 mol) and n-BuLi (123 mL, 0.308 mol, 2.5M in hexane) in 800 mL THF] was added slowly a solution of 3,5-dibromo-4-methylpyridine (70 g, 0.28 mol) in THF (300 mL) while the inner temperature was maintained below −70° C. After the addition, the resulting mixture was stirred for another 30 min at −78° C. before ethyl bromoacetate (116.9 g, 0.7 mol) was slowly added and the reaction mixture was stirred at −78° C. for another 1.5 h. 10% aq. AcOH was added (resulting pH=4-5), and the reaction was allowed to warm up to room temperature. After evaporation of solvent, the residue was poured into sat. aq. NaHCO3 solution, and was extracted with EtOAc (1 L×3). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by column chromatography (n-pentane:EtOAc=15:1˜5:1) to afford the title compound (30 g, 32%) as a gray solid. MS: 337.7 (M+H+, 2 Br).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:9]([C:14]([O:16]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[N:10][CH:11]=[CH:12][CH:13]=1.[F:28][C:29]([F:42])([F:41])[O:30][C:31]1[CH:32]=[C:33]([CH2:37][C:38](Cl)=[O:39])[CH:34]=[CH:35][CH:36]=1>C(#N)C.O>[OH:16][C:14]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[O:7][C:38](=[O:39])[C:37]=1[C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:29]([F:28])([F:41])[F:42])[CH:32]=1
Reactant: O=C(Cl)Cc1cccc(OC(F)(F)F)c1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=c1oc2cccnc2c(O)c1-c1cccc(OC(F)(F)F)c1
Temperature: 22.5 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
3.5 g of K2CO3 were added to a solution of 0.64 g of pentafluorophenyl 3-hydroxy-pyridine-2-carboxylate (from step 1) and 0.5 g of (3-trifluoromethoxyphenyl)acetyl chloride in 150 ml of acetonitrile, and the mixture was stirred at 20-25° C. under an atmosphere of nitrogen for about 12 hours. After filtration, the solvent was removed from the filtrate and the residue obtained was taken up in water and, after acidification to pH<4, extracted with CH2Cl2. The organic phase was dried, then freed from the solvent. The residue gave, after preparative HPLC [column: Luna (2), from Phenomenex, 300*50 mm 10 μm; mobile phase: water (+0.0375% trifluoroacetic acid) and acetonitrile in mixing ratios of 80:20 and 50:50; flow rate 80 ml/min; detection at 220 and 254 nm), 20-25° C.], 300 mg of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:10]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)=[N:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([C:3]1[C:10]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([C:26]([F:28])([F:29])[F:27])[CH:17]=3)=[N:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1)[CH3:2]
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
To a solution of 2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}benzaldehyde (D72) (60 mg), 3-azetidinecarboxylic acid (28.9 mg) and acetic acid (0.1 mL) in dichloromethane (DCM) (3 mL) stirred under nitrogen at room temperature for 1 h was added sodium triacetoxyborohydride (60.6 mg) in one charge. The reaction was stirred at room temperature overnight. The mixture was partitioned with DCM and water, washed with saturated brine and the organic phase was dried and evaporated, the residue was purified by Mass Directed AutoPrep to afford 1-[(2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}phenyl)methyl]-3-azetidinecarboxylic acid (E31) (14 mg). δH (DMSO-d6, 400 MHz): 1.06 (3H, t), 1.33 (6H, d), 2.73 (2H, m), 3.22 (5H, m), 3.63 (2H, s), 4.89 (1H, m), 7.26 (2H, m), 7.39 (1H, d), 7.45 (1H, d), 7.84 (1H, s), 8.15 (2H, m). δF (DMSO-d6, 376 MHz): −61.3. MS (ES): C26H27F3N2O3S requires 504. found 505.1 (M+H+).