Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12](O)(=[O:24])/[CH:13]=[CH:14]/[C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:24])/[CH:13]=[CH:14]/[C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1
Reactant: CCCCCCCCCCO
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCOC(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
n-Decanol (1.58 g, 10.0 mmol), ferulic acid (1.94 g, 10.0 mmol) and triphenylphosphine (2.88 g, 11.0 mmol) were dissolved in THF (20 ml), and DIAD (40% solution of diisopropyl azodicarboxylate in toluene, 5.56 g, 11.0 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 16 hr and concentrated under reduced pressure. Ethyl acetate (100 ml) was added to the residue, and the mixture was washed with 5% aqueous citric acid solution (25 ml×3) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (n-hexane:ethyl acetate=2:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give n-decanyl ferulate (2.55 g, yield 76.2%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(O)=O.[CH2:24]([NH2:27])[CH2:25][CH3:26].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][CH:16]([NH:27][CH2:24][CH2:25][CH3:26])[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: O=C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCNC1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A solution of compound 119 (0.75 g, 2.926 mmol) in 1,2-dichloroethane (20 mL) was treated with AcOH (0.16 mL, 2.926 mmol), n-propylamine (0.24 g, 2.926 mmol), NaBH(OAc)3 (0.93 g, 4.390 mmol) at room temperature and stirred for over night (16 h). The reaction was basified with 2 N NaOH (25 mL) and product was extracted into ethyl acetate (3×50 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 133 (0.58 g, 66%) as a brown semi-solid. 1H NMR (DMSO-d6) δ 0.89 (t, 3H, J=7.2 Hz), 1.37-1.51 (m, 4H), 1.91-2.00 (m, 2H), 2.44-2.57 (m, 4H), 2.68-2.76 (m, 1H), 6.14 (s, 1H), 7.80 (s, 1H), 7.86-7.97 (m, 2H), 8.30 (d, 1H, J=2.1 Hz), 11.82 (brs, 1H); ESI-MS (m/z, %) 300 (MH+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([F:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1cccc(F)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3cccc(F)c3)c2cn1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (215 mg, 1.12 mmol) and 3-fluoroaniline (1.16 g, 10.4 mmol) is stirred at 160° C. for 30 min. The resulting product is chromatographed over silica gel (6-7% MeOH/CH2Cl2) to give 7-amino-4-(3-fluoroanilino)pyrido[4,3-d]pyrimidine (185 mg, 65%) as a white solid. 1H NMR (DMSO) δ 9.94 (1H, brs), 9.36 (1H, s), 8.46 (1H, s), 7.91 (1H, brd, J=11.9 Hz), 7.63 (1H, brd, J=8.1 Hz), 7.41 (1H, dd, J=15.7, 7.7 Hz), 6.93 (1H, dt, Jt=8.5 Hz, Jd=2.4 Hz), 6.68 (2H, brs), 6.38 (1H, s).
Reaction SMILES: C([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[CH:6]1)CCC.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].CCCCCC.[I:27]I.[Cl-].[NH4+]>C1COCC1>[CH2:16]([C:9]1[NH:5][C:6]([I:27])=[N:7][C:8]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:17][CH2:18][CH3:19]
Reactant: [Li]CCCC
Reactant: CCCCn1cnc(-c2ccccc2)c1
Reactant: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCc1[nH]c(I)nc1-c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-butyl-4-phenylimidazole (4.0 g, 20 mmol) in 60 ml of anhydrous THF at −78° C. under nitrogen is added a solution of n-butyllithium in hexane (1.6M, 13.13 ml, 21 mmol, 1.05 eq.) dropwise. The resulting mixture is stirred at −78° C. for 1 h followed by dropwise addition of a solution of iodine (5.33 g, 21 mmol, 1.05 eq.) in 40 ml of THF. The resulting solution is stirred at −78° C. for 30 min. and then warmed to room temperature. Saturated ammonium chloride (30 mL) is added to quench the reaction. The resulting mixture is evaporated a reduced pressure to remove THF, extracted with ethyl acetate, washed with water and brine, dried over Na2-SO4, filtered and evaporated. Purification by silica gel chromatography (hexanes/ethyl acetate, from 8:1 to 5:1) affords 5.73 g of butyl-2-iodo-4-phenylimidazole. 1H NMR (400 MHz, CDCl3) δ 7.73 (2H, dd, J=1.2, 8.4 Hz), 7.36 (2H, m), 7.30 (1H, s), 7.24 (1H, m), 3.91 (2H, t, J=7.2 Hz), 179 (2H, m), 1.41 (2H, m), 0.98 (3H, t, J=7.2Hz); MS (+VE) m/z 327 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:20].C(Cl)Cl.CCOC(C)=O>C(O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])[NH:20][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1cc(C(F)F)[nH]cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
5-Benzyloxy-2-difluoromethyl-pyran-4-one (0.47 g, 1.9 mmol) was dissolved in ethanol (15 mL) to give a slightly yellow clear solution. Ammonium hydroxide (28-30% aqueous solution, 15 mL, 235 mmol) was added at room temperature. The resulting solution was stirred at ambient temperature for 24 hours. The progress of the reaction was monitored by TLC (CH2Cl2/EtOAc, 7/3, v/v) and HPLC Method 2. Volatiles were removed in vacuo and the residue was purified by column chromatography on silica (95/5 then 85/15 CH2Cl2/MeOH, v/v) to give the title compound as a light yellow solid (0.35 g, 74%) with a HPLC purity (peak percent area) of 98.2%. 1H NMR (300 MHz, DMSO-D6) δ (ppm): 10.99 (br. s, 1H), 8.22 (s, 1H), 7.32-7.32 (m, 5H), 7.06 (s, 1H), 6.75 (t, J=55.4 Hz, 1H), 5.23 (s, 2H); MS (m/z) 252 [M+1]+, 192.2, 91.3 (100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](C2C=NN(C)C=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1B(O)O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:18]=2[CH3:17])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccncc1B(O)O
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2cnccc2C)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using (4-methylpyridin-3-yl)boronic acid. ESI-MS (m/z): 228 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20].C(OCC)(=O)C>N1C=CC=CC=1.C(O)C>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(/C=C/c2ccncc2)cc1
Reactant: O=C(O)CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(/C=C/c2ccncc2)cc1
Yield: 46.6 %

Procedure:
To a solution of 4-[(E)-2-(4-pyridyl)vinyl]benzaldehyde (50 mg) in pyridine (0.025 ml) and ethanol (0.075 ml) was added malonic acid (27.4 mg), and the mixture was refluxed for 7 hours. After cooling, ethyl acetate was added thereto, the resulting precipitates were collected by filtration to give 4-[(E)-2-(4-pyridyl)vinyl]cinnamic acid (28 mg).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]1)=[O:9].[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:35][C@@H:36]([C:45]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[C:51]2[C:46]=1[CH:47]=[CH:48][C:49](=[O:63])[NH:50]2)[O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl>O.CN(C)C=O>[CH2:64]([N:34]([CH2:35][C@@H:36]([C:45]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[C:51]2[C:46]=1[CH:47]=[CH:48][C:49](=[O:63])[NH:50]2)[O:37][Si:38]([C:41]([CH3:42])([CH3:43])[CH3:44])([CH3:40])[CH3:39])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:19]([CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][CH:11]([O:10][C:8](=[O:9])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:16][CH2:15]1)=[O:20])[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCCCCN)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCCCCNC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)Cc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A mixture of the product of step (e) (3.68 g, 10 mmol) and N,N-dimethylformamide (50 mL) was heated at 60° C. until the solid completely dissolved and then cooled to room temperature. The product of step (d) (6 g, 10 mmol) and diisopropylethylamine (3.5 mL) was added and the reaction mixture was cooled to 0° C. PyBOP (6.25 g, 12 mmol) was added in one portion and the reaction mixture was stirred at 0° C. to room temperature for 2 hours. The reaction mixture was then poured into cold water (500 mL) with stirring and the pH of the resulting mixture was adjusted to about 2 using aqueous 1 M hydrochloric acid. This mixture was stirred for 15 min and then filtered to collect the solid, which was washed with water (100 mL) and dried to afford the title compound (8.7 g, HPLC purity >95%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([CH3:16])=[C:14]3[N:10]([CH2:11][CH2:12][CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([CH3:16])=[C:14]3[N:10]([C:9]=2[CH:20]2[CH:21]=[CH:22][N:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:19]2)[CH2:11][CH2:12][CH2:13]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccncc1
Reactant: Cc1c(-c2ccc(F)cc2)cn2c1CCC2
Solvent: ClCCl
Product: CCOC(=O)N1C=CC(c2c(-c3ccc(F)cc3)c(C)c3n2CCC3)C=C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine (1.72 g, 8.0 mmol) in CH2Cl2 (55 ml) is firstly treated at 0° C. (ice bath) with pyridine (1.6 ml, 1.58 g, 20 mmol) and dropwise with the solution of ethyl chloroformate (2.1 g, 19.5 mmol) in CH2Cl2 (25 ml) (10 min). After a temperature rise to 3-6° C., the cooling agent is removed and the mixture is stirred for 1 h at RT, then heated to boiling temperature (36° C.) for 15 min. Then and after refluxing for a further hour, in each case 2 further portions of pyridine (each 0.8 ml, 10 mmol) and chloroformic acid (each 1.05 g, 10 mmol) are added dropwise and after a total of 3 h the reaction is terminated. The dark-colored batch solution is poured onto ice water (100 ml), stirred for 15 min and then the phases are separated. The water phase is extracted with CH2Cl2 (100 ml) and the combined organic phase is washed with water (50 ml), dried (Na2SO4 sicc.) and concentrated. As a residue, 2.69 g of dark oil (91.9% crude) remain which still contains residues of unreacted 6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine and was employed without further purification in the next stage.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][Cl:25])[CH:20]=2)[NH:15][C:14]=1[CH3:26])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:3]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][Cl:25])[CH:20]=2)[N:15]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]=1[CH3:26])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OCc2ccccc2)c2cc(OCCCl)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a suspension of NaH (0.959 mmol, 0.038 g, 60% in mineral oil, rinsed twice with hexanes) in 5 mL of DMF at 0° C. under N2 was added a solution of 5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.873 mmol, 0.300 g, Example 1, Step A) in 3.73 mL of DMF. The ice bath was removed and the solution was stirred for 2 hours at room temperature. Benzyl bromide (0.959 mmol, 0.114 mL, Aldrich) was added dropwise via syringe and the solution was stirred for 19 hours. Water (10 mL) was added and the mixture was stirred for 30 minutes. The resulting precipitate was filtered off, the filtrate was extracted with ethyl acetate (3×10 mL), and the extracts were washed with brine (1×10 mL), dried over MgSO4, and concentrated. The residue was combined with the solid and purified by silica gel flash column chromatography (10-20% ethyl acetate/hexanes) to give an off-white solid (0.236 g, 62%): 1HNMR (400 MHz, DMSO-d6) δ 2.64 (s, 3H, ArCH3),3.86-3.89 (m, 2H, CH2Cl), 4.09-4.12 (m, 2H, CH2OAr), 5.30 (s, 2H, CO2CH2Ph), 5.46 (s, 2H, NCH2Ph), 6.78 (dm, J=8.79 Hz, 1H, ArH), 6.96 (d, J=7.33 Hz, 2H, ArH), 7.18-7.30 (m, 3H, ArH), 7.32-7.40 (m, 4H, ArH), 7.44-7.49 (m, 3H, ArH); MS(APCI+): m/z 434.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:20])([CH2:17][CH2:18][CH3:19])[CH2:3][C@H:4]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.Cl.[NH2:22][CH:23]([CH2:34][CH3:35])[C@@H:24]([C:26]1[O:30][N:29]=[C:28]([CH:31]2[CH2:33][CH2:32]2)[N:27]=1)[OH:25].C(NC(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH:31]1([C:28]2[N:27]=[C:26]([CH:24]([OH:25])[CH:23]([NH:22][C:5]([CH:4]([NH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:10])[CH2:3][C:2]([F:1])([F:20])[CH2:17][CH2:18][CH3:19])=[O:7])[CH2:34][CH3:35])[O:30][N:29]=2)[CH2:32][CH2:33]1
Reactant: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)O
Reactant: CCC(N)[C@H](O)c1nc(C2CC2)no1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCCC(F)(F)CC(NC(=O)N1CCOCC1)C(=O)NC(CC)C(O)c1nc(C2CC2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a mixture of (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid (104 mg, 0.35 mmol), (S)-2-amino-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-butan-1-ol hydrochloride (86.7 mg, 0.37 mmol) and diisopropyl amine (219 mg, 0.42 mmol) in dry dichloromethane (5 mL) is added PyBOP (113 mg, 0.87 mmol). The mixture is stirred at room temperature for 16 hr and the evaporated in vacuum. The residue is diluted with ethyl acetate (25 mL) and washed with saturated NaHCO3 (30 mL), dilute HCl (30 mL), then saturated NaHCO3 (30 mL). The organic layer is dried over magnesium sulfate and concentrated in vacuum. The residue is purified over 12 g silica gel, eluting with ethyl acetate: heptane (2:1 then 1:0) to afford morpholine-4-carboxylic acid (1-{1-[(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-3,3-difluoro-hexyl)-amide (146 mg, 88%) as a solid. LC/MS shows 2 isomers, total 100% M+1 474.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:14])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Cl:14])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cl)cc1

Procedure:
Meanwhile, the 4-methylbenzoyl chloride acylating agent was prepared by suspending 3.314 g (24.3 mmol) of ρ-toluic acid in 200 ml benzene. To this solution was added 2.0 equiv. (4.25 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at O° C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:4]=2[CH2:3]1.[Li+].O.ON1C2C=CC=CC=2N=N1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36]([NH:38][C@@H:39]1[CH2:42][CH2:41][C@@H:40]1[NH2:43])=[O:37])=[CH:30]2>CN(C)C=O>[ClH:26].[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36]([NH:38][C@@H:39]1[CH2:42][CH2:41][C@@H:40]1[NH:43][C:11]([C:9]1[S:10][C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][C:5]=3[N:8]=1)=[O:13])=[O:37])=[CH:30]2
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: N[C@H]1CC[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2nc(C(=O)N[C@H]3CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
Lithium 5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylate (136 mg), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (255 mg) and 1-hydroxybenzotriazole monohydrate (90 mg) were added to a solution with (±)-cis-N-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclobutanediamine (117 mg) dissolved in N,N-dimethylformamide (5 ml), and the mixture was stirred overnight at room temperature. The solvent was then distilled off under reduced pressure using a vacuum pump, and dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue to conduct liquid separation. The resultant organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography on silica gel (methanol:dichloromethane=7:93). After ethyl acetate and a 1N ethanol solution of hydrochloric acid were added to the thus-obtained compound to acidify it, and the solvent was distilled off under reduced pressure. Ethyl acetate was added again, and precipitate formed was collected by filtration and dried to obtain the title compound (56 mg) as a colorless powder.
Reaction SMILES: O.O.[O:3]=[C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][CH:6]=[C:5]1[O:11][CH2:12][C:13]([OH:15])=[O:14].[Cl:16]N1C(=[O:23])N(Cl)C(=O)N(Cl)C1=O>CO.O>[OH2:3].[OH2:23].[O:3]=[C:4]1[C:9]([Cl:16])=[C:8]([CH3:10])[NH:7][CH:6]=[C:5]1[O:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Cc1cc(=O)c(OCC(=O)O)c[nH]1
Solvent: O
Solvent: CO
Product: Cc1[nH]cc(OCC(=O)O)c(=O)c1Cl

Procedure:
2-(4-oxo-6-methyl-1,4-dihydropyridin-3-yloxy)acetic acid dihydrate (2.2 g) was dissolved in a mixture of methanol (120 ml) and water (170 ml) under heating on a water bath. The solution was stirred at 65° to 70° C. and trichloroisocyanuric acid (1.1 g) was added thereto. The resultant mixture was stirred for 65° to 70° C. for 1.5 hours. The reaction mixture was left to cool to room temperature with removal of the water bath and filtered. The obtained precipitates were washed with water and dried. The resultant crystals (2.0 g) were dried at 100° C. for 6 hours in vacuo over phosphorus pentoxide to give crystals of 2-(4-oxo-5-chloro-6-methyl-1,4-dihydropyridin-3-yloxy)acetic acid dihydrate, mp 240° to 242° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])[CH2:26][CH2:27][CH3:28].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:10](=[O:12])[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[CH2:34][CH2:33]1)=[O:31])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)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: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 9.06 g (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester in 100 ml DMF were added 5.00 g piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate, 13.7 ml N-ethylmorpholine and 8.8 g TOTU. After stirring for 12 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%) and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 15.8 g.