Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19]C)=[O:18])[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:7][C:4]2([CH2:6][CH2:5]2)[CH2:3]1.O[Li].O>O1CCOCC1.O>[C:13]([O:12][C:10]([N:9]1[CH2:8][CH2:7][C:4]2([CH2:5][CH2:6]2)[CH2:3][C:2]1([CH3:1])[C:17]([OH:19])=[O:18])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)C1(C)CC2(CCN1C(=O)OC(C)(C)C)CC2
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC2)CC1(C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
6-tert-butyl 5-methyl 5-methyl-6-azaspiro[2.5]octane-5,6-dicarboxylate (D5) (320 mg, 1.13 mmol) was partitioned between dioxane/water (8/8 ml) prior addition of LiOH H2O (190 mg, 4.52 mmol). The mixture was stirred at RT for 18 hrs then heated at 150° C. under microwave irradiation 40 min (4 cycles of 10 min each). Organic solvent was evaporated off and the aqueous solution washed with EtOAc (2×10 ml), acidified to pH˜4 with citric acid sat. sol. and extracted with EtOAc (3×10 ml). The organic phases were washed with NaCl sat. sol, dried over Na2SO4 and evaporated to reduced pressure to afford the title compound (D6) (114 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7](=[O:18])[NH:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7](=[O:18])[NH:8][CH2:9][CH2:10][S:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CCCN1C(=O)NCCSc1ccccn1
Solvent: ClCCl
Product: O=C1CCCN1C(=O)NCCS(=O)c1ccccn1
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
To a solution of 2.0 g (7.54 mmol) of 2-oxo-1-[[2-(pyridin-2-ylthio)ethyl]carbamoyl]pyrrolidine in 35 ml of CH2Cl2 was added 1.63 g (7.54 mmol) of m-CPBA (content 80%) under ice-cooling. Then the mixture was stirred for 1.5 hr. at room temperature. The reaction solution was washed with aqueous NaHCO3 and water. After drying, the solvent was removed by evaporration. The residue was refined by silica gel column chromatography, then the crystalline objective compound was obtained from the eluate with benzene/ethyl acetate (3/1-1/1 v/v). The compound was washed with Et2O and collected by filtration, whereby 0.93 g of the crystalline compound (Ib-3) melting at 119.5°-120.5° C. was obtained. Yield: 43.9%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.[N:11]1[NH:12][C:13](=[O:17])[CH:14]=CC=1>>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([C:2]2[CH:1]=[CH:14][C:13](=[O:17])[NH:12][N:11]=2)=[CH:9][CH:8]=1
Reactant: O=c1cccn[nH]1
Reactant: CC(=O)c1ccc(O)cc1
Product: O=c1ccc(-c2ccc(O)cc2)n[nH]1

Procedure:
50 g of 4-hydroxyacetophenone are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([S:7]([C:10]1[CH:11]=[CH:12][C:13]([O:34]C)=[C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH:24]=3)[C:19](=[O:32])[N:18]([CH3:33])[CH:17]=2)[CH:15]=1)(=[O:9])=[O:8])[CH3:6]>C(Cl)Cl>[CH2:5]([S:7]([C:10]1[CH:11]=[CH:12][C:13]([OH:34])=[C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH:24]=3)[C:19](=[O:32])[N:18]([CH3:33])[CH:17]=2)[CH:15]=1)(=[O:8])=[O:9])[CH3:6]
Reactant: CCS(=O)(=O)c1ccc(OC)c(-c2cn(C)c(=O)c3ccc(-c4cnn(C)c4)cc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(O)c(-c2cn(C)c(=O)c3ccc(-c4cnn(C)c4)cc23)c1
Yield: 36.1 %

Procedure:
At −78° C., a 4 M solution of BBr3 (2.3 mL, 9.2 mmol) in CH2Cl2 was added to the title compound of Example 79 (200.0 mg, 0.458 mmol) in dry CH2Cl2 (8 mL). The mixture was refluxed for 18 h. Extractive work up with CH2Cl2 and purification by silica gel chromatography (DCM:MeOH=100:1 to 20:1) gave the title compound (70 mg, 36.1%) as a brown solid. 1H NMR (CDCl3, 400 MHz) δ 8.39 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.87 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.80 (s, 1H), 7.79 (s, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J=1.2 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 3.91 (s, 3H), 3.67 (s, 3H), 3.25 (q, J=7.6 Hz, 2H), 1.27 (t, J=7.6 Hz, 3H). LCMS: 424.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:40])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[N:27](C(OC(C)(C)C)=O)[C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:40])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: CCOC(=O)c1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)COC)c2)n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(-c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@@H](C)COC)c2)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
1-t-Butyl 2-ethyl 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-1,2-dicarboxylate (9.44 g, 16.5 mmol) synthesized in Example (17c) was dissolved in dichloromethane (90 mL), and cooled to 0° C. Trifluoroacetic acid (45 mL) was added dropwise with stirring under nitrogen atmosphere, and stirring was carried out at room temperature for 1 hour. The solvent was distilled off under reduced pressure, followed by dilution with ethyl acetate (300 mL), a saturated aqueous sodium hydrogencarbonate solution (200 mL) was added, and the solution was separated. 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: ethyl acetate/hexane=10%-50%) to afford the desired compound (6.34 g, yield 81%) as a pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5](B(O)O)[CH:4]=1)=[O:2].[N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]([C:3]1[S:7][CH:6]=[C:5]([N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH:4]=1)=[O:2]
Reactant: O=Cc1cc(B(O)O)cs1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C=O)c1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 86 %

Procedure:
To a solution of 5-formylthiophen-3-ylboronic acid (2 g, 12.82 mmol) and di-tert-butyl azodicarboxylate (1.476 g, 6.41 mmol) in THF (12 mL) under nitrogen was added copper(II) acetate (0.116 g, 0.641 mmol) in one portion according to the procedure of T. Uemura and N. Chatani (J. Org. Chem. 2005, 70, 8631-8634). The suspension was then stirred for 18.5 hours at room temperature. The resulting brown solution was then concentrated and the residue was dissolved in DCM and methanol and loaded on silica and applied to a 40M Biotage column. Elution with a gradient of 10 to 20% ethyl acetate in hexanes gave compound 11 (1.888 g, 86%) as a yellow crust. LRMS (ESI): calc. 342.12; found 365.2 (MNa)+.
Reaction SMILES: [OH-].[K+].CO.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[C:16]([N:20]=[N:21][C:22](Cl)([CH2:24][C:25]([CH3:33])([O:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:26])[CH3:23])([CH3:19])([CH3:18])[CH3:17]>O>[C:16]([N:20]=[N:21][C:22]([S:15][C:12]1[CH:11]=[CH:10][C:9]([C:5]([CH3:8])([CH3:6])[CH3:7])=[CH:14][CH:13]=1)([CH2:24][C:25]([CH3:26])([O:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:33])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: CC(C)(C)N=NC(C)(Cl)CC(C)(C)OOC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)N=NC(C)(CC(C)(C)OOC(C)(C)C)Sc1ccc(C(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a stirred solution of 1.38 g (0.021 moles) of 85% potassium hydroxide in 25 ml. of methanol in a 125 ml. erlenmeyer flask was added dropwise 3.66 grams (0.022 moles) of p-t-butylthiophenol. The reaction was stirred an additional 30 minutes and then 6.0 grams (0.0205 moles) of 2-(t-butylazo)-2-chloro-4-methyl-4-(t-butylperoxy)pentane from Example 23 was added dropwise over 30 minutes, holding the reaction temperature at 15° C with a cold water bath. The reaction was stirred an additional hour at room temperature and poured into 100 ml. of water. The product was extracted with 50 ml. of pentane, the pentane solution washed with water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated on a flash evaporator. The residue weighed 8.65 g (72% yield) and its infrared spectrum was in agreement with that of the desired product.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=3)[N:8]=[N:7][C:6]=2[C:21](O)=[O:22])[CH2:3][CH2:2]1.C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:6]2[N:7]=[N:8][N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=3)[C:5]=2[CH2:4][CH:1]2[CH2:3][CH2:2]2)=[O:22])[CH2:29][CH2:27]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 183.8 %

Procedure:
5-(Cyclopropylmethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (503 mg, 1.60 mmol) obtained in Example 96b), HOBt (109 mg, 0.800 mmol, 0.5 eq.) and cyclopropylamine (0.149 ml, 2.08 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 8 ml), WSC (376 mg, 1.92 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 ml) and washed with 2% aqueous sodium carbonate solution (×2), 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (3:1, 40 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (518 mg, 1.47 mmol, 91.6%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16].C(O)C.O>C(O)C>[CH3:15][NH:16][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: O
Solvent: CCO
Product: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 96.9 %

Procedure:
4-Fluoro-3-nitrobenzotrifluoride (25 g) was dissolved in ethanol (50 mL), and 30% methylamine-ethanol solution (97.9 g) was gradually added dropwise under ice-cooling, and the mixture was stirred at room temperature for 40 min. The reaction mixture was added to water, and the precipitated solid was collected by filtration to give 4-methylamino-3-nitrobenzotrifluoride (25.5 g) as yellow crystals.
Reaction SMILES: O=[CH:2][CH2:3][NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6].[CH2:17]([NH:20][CH:21]1[CH2:29][CH2:28][C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH2:22]1)[CH2:18]C>>[CH2:17]([N:20]([CH:21]1[CH2:29][CH2:28][C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH2:22]1)[CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6])[CH3:18]
Reactant: O=CCNC(=O)c1ccc2ccccc2c1
Reactant: CCCNC1CCc2ncsc2C1
Product: CCN(CCNC(=O)c1ccc2ccccc2c1)C1CCc2ncsc2C1
Yield: 34 %

Procedure:
Compound 32 is prepared from 32B and 1C as described for 1. The salt of oxalic acid is crystallized from ethanol/diethylether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C:32]([CH3:37])([CH2:35][OH:36])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:31][C:32]([CH2:35][OH:36])([CH3:37])[CH2:33][OH:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Reactant: CC(N)(CO)CO
Product: Cc1cc(F)ccc1-c1nc(NC(C)(CO)CO)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 61.7 %

Procedure:
Following the general procedure outlined in Example 60, the product of Example 121 (200 mg, 0.47 mmol) and 2-amino-2-methyl-1,3-propanediol (494 mg, 4.7 mmol) were reacted to give the crude material, which was purified as described in Example 126 to give the desired product 130 mg (62%). LC-MS: 449.0 (MH+, m/z), 1.67 (Rt, min).
Reaction SMILES: [OH:1][C@@H:2]([CH2:12][C:13]([N:15]1[CH2:22][CH2:21][C:18]2([CH2:20][CH2:19]2)[C@H:17]([OH:23])[CH2:16]1)=[O:14])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][C@@H:6]([CH3:10])[C:5]1=[O:11].[Cl:24][C:25]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[CH:28]=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>>[Cl:24][C:25]1[CH:30]=[C:29]([NH:31][C:32]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:12][C:13]([N:15]3[CH2:22][CH2:21][C:18]4([CH2:19][CH2:20]4)[C@H:17]([OH:23])[CH2:16]3)=[O:14])[C:5](=[O:11])[C@@H:6]2[CH3:10])=[O:33])[CH:28]=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]
Reactant: C[C@@H]1NCCN(C[C@@H](O)CC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1ccc(C(F)(F)F)c(Cl)c1
Product: C[C@H]1C(=O)N(C[C@@H](O)CC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(C(F)(F)F)c(Cl)c1
Yield: 36 %

Procedure:
In analogy to the procedure described in Example 30, (S)—(S)-1-[2-hydroxy-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 25) and 1.2 eq. of 2-chloro-4-isocyanato-1-trifluoromethyl-benzene (intermediate 16) gave the titled compound in 36% yield as white powder. MS: 547.19 (MH+, Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[N:17][OH:18])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(C)(C)C(=NO)CC2
Temperature: 80 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (used as a crude from example 1, step1, 128.8 g, 0.63 mol) and hydroxylamine hydrochloride (350 g, 5.04 mol) in pyridine (360 ml) were heated up to 80° C. The reaction mixture was stirred for 15 h at 80-90° C. Pyridine was removed under reduced pressure. The residue was partitioned between ethylacetate (2.5 l) and water (1 l). Water layer was separated and washed with ethyl acetate (1 l). Ethyl acetate solution was washed with 10% aq. KHSO4 (1 l), dried over Na2SO4. Ethyl acetate was removed under reduced pressure and the residue was crystallized from acetone to give 101.2 g of target compound. Mother liquid was concentrated to dryness and crystallized from acetone to give second crop (11.4 g). 112.6 g (82%) of the desired product was obtained. 1H NMR (CDCl3), d 9.15 (s, 1H), 7.06 (d, 1H, J=7.4 Hz) 6.92 (1H, d, J=2.4 Hz), 6.75 (dd, 1H, J=7.4 and 2.4 Hz), 3.82 (s, 3H), 2.78-2.95 (m, 4H), 1.5 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH:14]2[CH2:13][O:12][CH2:11][C:10](=[S:16])[NH:9]3)[CH:5]=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](O)=[O:25])=[N:22][CH:23]=1>>[S:16]=[C:10]1[CH2:11][O:12][CH2:13][CH:14]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:24]([C:21]4[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][N:22]=4)=[O:25])[CH:7]=[CH:6][CH:5]=3)([CH2:15]2)[NH:9]1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: Nc1cccc(C23CC2COCC(=S)N3)c1
Product: O=C(Nc1cccc(C23CC2COCC(=S)N3)c1)c1ccc(Cl)cn1

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (1SR,7RS)-1-(3-amino-phenyl)-5-oxa-2-aza-bicyclo[5.1.0]octane-3-thione (intermediate B13B) (230 mg, 0.98 mmol) and commercially available 5-chloro-pyridine-2-carboxylic acid [CAS-no 86873-60-1] (172 mg, 1.09 mmol). The title compound was obtained as a light yellow foam (310 mg, 76%). MS (ISP): m/z=374.1 [(M+H)+]and 376.0 [(M+2+H)+].
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([OH:11])[CH:10]=1)=[O:5])C.CCO.O>>[OH:11][N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[N:8]1
Reactant: CCOC(=O)c1cn(O)nn1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Hydroxy-1H-1,2,3-triazole-4-carboxylic acid was prepared by combining 1-hydroxy-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (2.0 g, 13 mmol), EtOH (25 mL, 430 mmol), and a pre-dissolved solution of LiOH monohydrate (1.6 g, 38.2 mmol) and water (10 mL, 600 mmol). The mixture was stirred at room temperature for 4 hours, then partially concentrated and acidified with HCl to cause precipitation. The solid was filtered and dried under vacuum to give 1.3 g of the desired acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])=[CH:8][S:7][CH:6]=1)=[O:4].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:12]([CH3:13])[C:11]([NH:10][C:9]2[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][CH:8]=2)=[O:15])=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COC(=O)c1cscc1NC(=O)C(C)Cl
Product: CC(Oc1ccc(C(C)(C)C)cc1)C(=O)Nc1cscc1C(=O)O

Procedure:
In analogy to Example 2, the title compound was prepared using rac-4-(2-chloro-propionylamino)-thiophene-3-carboxylic acid methyl ester and 4-tert-butylphenol. MS (m/e): 346.2 (M−H).
Reaction SMILES: [CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][NH:5][C@H:4]1[CH3:8])[CH3:2].[F:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[C:15]([F:20])[C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][N:5]([C:17]2[CH:18]=[C:11]([F:10])[C:12]([C:13]#[N:14])=[C:15]([F:20])[CH:16]=2)[C@H:4]1[CH3:8])[CH3:2]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: CC[C@]1(O)CCN[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2cc(F)c(C#N)c(F)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-methylpyrrolidin-3-ol 0.5 oxalate (257 mg), 2,4,6-trifluorobenzonitrile (464 mg) and lithium carbonate (218 mg), the title compound was obtained as a colorless solid (yield: 207 mg, yield: 53%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]=[C:29]1[C@H:35]2[CH2:36][C@H:31]([CH2:32][CH2:33][C@@H:34]2[C:37]([OH:39])=O)[O:30]1.[C:40]1([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[C:40]1([N:46]2[CH2:51][CH2:50][N:49]([C:37]([C@H:34]3[CH2:33][CH2:32][C@H:31]4[CH2:36][C@@H:35]3[C:29](=[O:28])[O:30]4)=[O:39])[CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)[C@H]1CC[C@H]2C[C@@H]1C(=O)O2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1O[C@H]2CC[C@H](C(=O)N3CCN(c4ccccc4)CC3)[C@@H]1C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (7.0 g, 0.016 mol) was added to a solution of (1S,2S,5S)-7-oxo-6-oxabicyclo[3.2.1]octane-2-carboxylic acid (14.4 mmol, 0.0144 mol) and 1-Phenylpiperazine (2.4 mL, 0.016 mol) in N,N-dimethylformamide (30 mL, 0.4 mol) at 0 Celsius. After 5 minutes, N,N-diisopropylethylamine (7.5 mL, 0.043 mol) was added at 0 Celsius. The mixture was stirred at RT for overnight. The product was purified by flash chromatography on silica gel column (ethyl acetate in hexanes: 60%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:36]1[CH:37]=[CH:38][C:39]([O:42][CH:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[N:40][CH:41]=1>>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:36]3[CH:41]=[N:40][C:39]([O:42][CH:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:38][CH:37]=3)[CH:12]=2)[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:33])[CH3:34])=[CH:27][CH:26]=2)[C:6]=1[C:4]([OH:3])=[O:5]
Reactant: Brc1ccc(OC2CCCC2)nc1
Reactant: CCOC(=O)c1c(Cl)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(OC(C)C)cc1
Product: CC(C)Oc1ccc(-n2c(C(=O)O)c(Cl)c3cc(-c4ccc(OC5CCCC5)nc4)ccc32)cc1

Procedure:
The title compound was prepared in accordance with Example 8(b) from 3-chloro-1-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 35(c)) and 5-bromo-2-cyclopentoxypyridine (see Example 36(b)), followed by ester hydrolysis in accordance with Example 1(c).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][C:37]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:38])[C@H:31]2[C:46]2[CH:60]=[CH:59][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56](O)=[O:57])=[O:53])=[CH:48][CH:47]=2)=[CH:26][CH:25]=1.CN1CCOCC1.[NH2:68][C@@H:69]([C:74]([OH:76])=[O:75])[C:70]([CH3:73])([CH3:72])[CH3:71]>C(Cl)Cl>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][CH:37]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[OH:38])[C@H:31]2[C:46]2[CH:47]=[CH:48][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([NH:68][C@@H:69]([C:74]([OH:76])=[O:75])[C:70]([CH3:73])([CH3:72])[CH3:71])=[O:57])=[O:53])=[CH:59][CH:60]=2)=[CH:28][CH:29]=1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 1.5 h

Procedure:
TBTU (0.021 g, 0.067 mmol) was added to a solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.030 g, 0.056 mmol) and N-methyl morpholine (0.017 g, 0.166 mmol) in CH2Cl2 (5 ml) at 30° C. After 1.5 h, D-tert-leucine (0.011 g, 0.083 mmol) was added. Full conversion to the corresponding amide was obtained after 30 minutes. The reaction was quenched by the addition of water (1 ml). After 10 minutes, MeOH (3 ml) and NaBH (0.042 g, 1.11 mmol) were added. After 5 minutes, the reaction was quenched by the addition of 0.1M NH4OAc buffer (1 ml). The reaction mixture was concentrated and purified by preparative HPLC using an eluent of 0-50% CH3CN in 0.1M N4OAc buffer. The title compound (0.025 g, 69%) was obtained as a colourless solid. M/z: 654.0 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 0.86 (s, 9H), 2.82-2.98 (m, 2H), 3.76-3.81 (m, 2H), 3.92-3.96 (m, 1H), 4.26-4.33 (m, 1H), 4.52 (s, 2H), 4.68-4.76 (m, 1H), 5.02-5.07 (m, 1H), 6.97-7.37 (m, 12H), 7.58-7.63 (m, 1H), 8.29-8.34 (m, 1H).