Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH2:22])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1.[CH3:31][O:32][C:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[O:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[CH:15]([NH:16][C:17]([C:19]4([NH:22][C:38]([C:36]5[O:35][N:34]=[C:33]([O:32][CH3:31])[CH:37]=5)=[O:39])[CH2:21][CH2:20]4)=[O:18])[CH2:14][S:13][C:12]=3[CH:23]=2)[CH:7]=1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(N)CC2)n1
Reactant: COc1cc(C(=O)O)on1
Product: COc1cc(C(=O)NC2(C(=O)NC3CSc4cc(-c5cc(Cl)cc(F)c5-c5nnn(C)n5)ccc43)CC2)on1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-2,3-dihydro-benzo[b]thiophen-3-yl}-amide (example 61) has been coupled with 3-methoxy-isoxazole-5-carboxylic acid to yield the title compound as light yellow oil. MS: 570.1 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([C:22]4(O)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:19][C:18]=3[CH3:29])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:25]1[CH2:24][CH:23]=[C:22]([C:20]2[S:21][C:17]([C:13]3[N:8]4[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[C:7]4=[N:15][C:14]=3[CH3:16])=[C:18]([CH3:29])[N:19]=2)[CH2:27][CH2:26]1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(C4(O)CCOCC4)nc3C)c(C)nc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C4=CCOCC4)nc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
150 mg of 4-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-tetrahydro-pyran-4-ol (0.36 mmol) is dissolved in 5 ml of CH2Cl2 and 112 mg of triethylsilane (0.96 mmol) and 717 mg of trifluoroacetic acid (6.3 mmol) are added. The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is stirred under reflux for 1 h and cooled down to room temperature. The solvent is removed in vacuo. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=10:3:1) to give 64 mg of the title compound. Yield 45%. mass spectrum (m/e): 397 (M+1). 6.94 (s, 1H), 6.71 (s, 1H), 4.41 (d, J=2.6 Hz, 2H), 3.98 (t, J=5.3 Hz, 2H), 3.43 (m, 1H), 2.62 (s, 3H), 2.75 (m, 2H), 2.56 (s, 3H), 2.37 (s, 3H), 1.86 (m, 4H), 0.92 (t, J=8.2 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH:12](O)([CH3:14])[CH3:13]>>[CH:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([OH:11])[CH:4]=1)([CH3:14])[CH3:13]
Reactant: CC(C)O
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Product: CC(C)OC(=O)c1ccc(Cl)c(O)c1
Temperature: 85 °C
Yield: 75 %

Procedure:
4-Chloro-3-hydroxy-benzoic acid (100 mg, 0.58 mmol) and 1 mL of isopropanol were mixed and then heated to 85° C. for overnight. The mixture was then concentrated in vacuum and the resulting residue was purified by flash chromatography (8–20% EtOAc/Hex) to give the desired ester (94 mg, 75%). MS (DCI) m/z 215 (M+H)+, 232 (M+NH4)+.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[O:14]1[CH:16]([CH2:17][CH2:18][CH3:19])[CH2:15]1>>[ClH:1].[OH:14][CH:16]([CH2:17][CH2:18][CH3:19])[CH2:15][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: CCCC1CO1
Agent: Cl
Product: CCCC(O)CNCc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 1, the title compound was synthesized from 4-aminomethylbenzenesulfonamide hydrochloride and 1,2-epoxypentane.
Reaction SMILES: O[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[CH2:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>>[CH2:13]([NH:20][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCN
Reactant: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O
Solvent: O
Product: CCCCCCCNC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 87 %

Procedure:
β-D-galactose (10 g, 1 eq), heptylamine (7.7 g, 1 eq) and water (2 g, 3 eq) were heated in a reaction flask at 80° C. for about 15 minutes. The sample was filtered and washed as described for the decyl derivative to give an 87% yield.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)C.N1C(C)=CC=CC=1C.[CH2:16]([O:23][C:24]1[S:28][N:27]=[C:26]([S:29](C)=O)[N:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>>[CH2:16]([O:23][C:24]1[S:28][N:27]=[C:26]([S:29][CH2:1][O:4][C:5](=[O:7])[CH3:6])[N:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)c1nsc(OCc2ccccc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Product: CC(=O)OCSc1nsc(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
Into 1.5 g of acetic anhydride were added 620 mg of 2,6-lutidine and 500 mg of 5-benzyloxy-3-methylsulfinyl-1,2,4-thiadiazole under ice-cooling. After stirring for 15 hours at room temperature, the reaction mixture was added to saturated sodium hydrogen carbonate aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 376 mg of 5-bezyloxy-3-acetoxymethythio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (44)).
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[N+:27]([O:30][CH:31]([CH2:35][O:36][N+:37]([O-:39])=[O:38])[CH2:32][CH2:33]O)([O-:29])=[O:28].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([O:10][CH2:33][CH2:32][CH:31]([O:30][N+:27]([O-:29])=[O:28])[CH2:35][O:36][N+:37]([O-:39])=[O:38])=[O:9])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])OCC(CCO)O[N+](=O)[O-]
Reactant: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC/C(=C(\C(=O)OCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 1.72 g of (2Z)-4-(acetyloxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 30 mL of CH2Cl2 at 0° C. was added 750 mg of 3,4-bis(nitrooxy)butyl alcohol, 560 mg of DMAP and 880 mg of EDCI. The mixture was stirred at RT for 2 h then quenched by addition of NH4Cl sat., extracted with EtOAc, washed with NaHCO3 sat., brine and dried over sodium sulfate. Purification by flash chromatography afforded 930 mg of the titled compound as a white solid. 1H NMR (acetone-d6, 500 MHz): δ 7.77 (d, 2H), 7.43 (d, 2H), 7.17-7.15 (m, 3H), 7.08 (dd, 2H), 5.56-5.52 (m, 1H), 5.22 (s, 2H), 4.95 (dd, 1H), 4.69 (dd, 1H), 4.47-4.41 (m, 2H), 3.05 (s, 3H), 2.32-2.19 (m, 2H), 1.89 (s, 3H).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[CH3:13][CH:14]1[CH2:18][CH2:17][O:16][C:15]1=[O:19].C(Br)=C>O1CCCC1>[CH3:13][C:14]1([CH:1]=[CH2:2])[CH2:18][CH2:17][O:16][C:15]1=[O:19]
Reactant: CC(C)NC(C)C
Reactant: CC1CCOC1=O
Agent: C=CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC1(C)CCOC1=O
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 47.7 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (4.7 mL, 33.815 mmol, dried over calcium hydride) in anhydrous tetrahydrofuran (20 mL) was treated with a solution of n-butyllithium in hexanes (12.7 mL, 31.702 mmol, 2.5 M). After stirring at −78° C. for 25 minutes, the mixture was treated with 3-methyl-dihydro-furan-2-one (2 mL, 21.135 mmol). After stirring at 0° C. for 1 h, the reaction was subsequently treated with a solution of di-μ-bromobis(tri-tert-butylphosphino)dipalladium(I) (164.2 mg, 0.211 mmol) in anhydrous tetrahydrofuran (5 mL) and a solution of vinyl bromide in tetrahydrofuran (31.7 mL, 81.702 mmol, 1 M). The reaction was slowly warmed to room temperature. After stirring for 16 h, the reaction was quenched with hydrochloric acid (2 M) and water. The aqueous layer was extracted with diethyl ether (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 3:2 to afford the title compound (1.272 g, 48%) as an orange oil. 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 3H), 2.11-2.22 (m, 1H), 2.31-2.41 (m, 1H), 4.20-4.36 (m, 2H), 5.16-5.26 (m, 2H), 5.84-5.96 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[N:14]O)[CH2:12][CH2:13][C:3]1=2.C(=O)([O-])[O-:17].[Na+].[Na+]>O1CCOCC1>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[O:17])[NH:14][CH2:12][CH2:13][C:3]1=2
Reactant: O=C([O-])[O-]
Reactant: Cn1c2c(c3ccccc31)C(=NO)CC2
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1c2c(c3ccccc31)C(=O)NCC2

Procedure:
3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one oxime (1.53 g), polyphosphric acid (450 g) and dioxan (15 ml) were heated at 100°-120° for 2.2 h under nitrogen. The reaction mixture was cooled, and treated with 2N sodium carbonate solution (1 l). The suspension was extracted with ethyl acetate (4×400 ml) and the combined extracts were dried. Evaporation gave a solid (1.43 g) which was recrystallised from ethyl acetate/cyclohexane. This solid was purified by FCC, eluting with System A (200:10:1) to give a solid (1.26 g) which was recrystallised from ethanol to provide the title compound (960 mg), m.p. 234°-238°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([N:26]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:25])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C(O)C>[CH2:1]([O:8][C:9](=[O:37])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH2:26])[CH3:25])=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: CC(N)CCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 75 °C
Yield: 88.5 %

Procedure:
A solution containing compound 25 (0.90 g, 1.81 mmol), hydrazine (0.26 mL, 5.42 mmol) and ethanol (10 mL) was heated at 75° C. for 3 h and then cooled to ambient temperature. The white precipitate was filtered under vacuum and washed with ethanol (3×5 mL). The filtrate and washings were combined and concentrated. The residue was subjected to column chromatography eluting with a mixture of methanol (0-15%), concentrated ammonium hydroxide (0-1.5%) and dichloromethane to afford the desired product 26 (0.59 g, 88%) as a white, waxy solid: 1H NMR (500 MHz, CD3OD) δ 1.08 (d, 3H), 1.36-1.80 (m, 8H), 2.55 (m, 4H), 2.88 (m, 1H), 3.10 (t, 2H), 5.08 (s, 2H), 7.08 (s, 4H), 7.34 (m, 5H); m/z (ESI) 369 [C23H32N2O2+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][C@H:10]([O:12][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9][N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C

Procedure:
To a solution of (4S)-1-(tert-butyloxycarbonyl)-4-hydroxy-L-proline tert-butyl ester (313 mg, 1.09 mmol) in pyridine (2.0 mL) cooled to 0° C. was added methanesulfonyl chloride (0.17 mL, 2.18 mmol). The reaction mixture was allowed to reach room temperature, and after 2 hours was diluted with ethyl acetate (100 mL), washed with saturated sodium hydrogencarbonate solution, 1 M citric acid, water, dried (Na2 SO4), and evaporated. The crude product was purified by flash silica gel chromatography eluting with 15% acetone/hexane; yield 251 mg (52% over 2 steps). 400 MHz 1H NMR (CDCl3): δ1.42-1.48 (3s, 18H); 2.38-2.50 (m, 2H); 2.99 (2s, 3H); 3.69-3.79 (m, 2H); 5.22 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[C:6]=1[NH2:23])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>O1CCCC1.C1(C)C=CC=CC=1.C(O)C.OO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)=[CH:18][CH:17]=2)[C:6]=1[NH2:23])=[O:4]
Reactant: COC(=O)c1c(N)c(-c2ccc(I)cc2)nc2ccc(F)cc12
Reactant: OB(O)c1cccnc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OO
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1c(N)c(-c2ccc(-c3cccnc3)cc2)nc2ccc(F)cc12
Temperature: 20 °C

Procedure:
To a degassed solution of 0.39 g of 3-amino-6-fluoro-2-(4-iodophenyl)-4-quinolinecarboxylic acid methyl ester and 0.035 g of tetrakis(triphenylphosphine) palladium in 10 ml of tetrahydrofuran and 10 ml toluene was added 1.0 ml of 2M aqueous sodium carbonate followed by a solution of 0.148 g of 3-pyridine boronic acid in 2 ml of ethanol. The mixture was stirred at reflux under argon for 5 hours and then cooled to 20° C. Two drops of 30% hydrogen peroxide were added and the mixture stirred for 30 minutes. The reaction mixture was partitioned between water and methylene chloride The organic layers were washed with water and dried over sodium sulfate. The volatiles were removed in vacuo, giving a tan powder. The crude product was purified via silica gel chromatography using toluene/acetone/methanol 78:20:2 as the eluent. The desired compound was obtained as yellow crystals (0.132g), mp 178°-183° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[C:7]([F:16])=[CH:8][C:9]([N+:13]([O-])=O)=[C:10]([NH2:12])[CH:11]=1>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[CH:8][C:7]=1[F:16]
Reactant: CN(C)CCOc1cc(N)c([N+](=O)[O-])cc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)CCOc1cc(N)c(N)cc1F

Procedure:
A solution of intermediate 180 (220 mg, 0.904 mmol) in acetic acid (3.6 mL) was degassed and put under N2 atmosphere. A catalytic amount of Pd(OH)2 was added and the black mixture was hydrogenated (1 atm) at rt for 16 h, filtered through a celite pad and rinsed with MeOH. The filtrate was concentrated in vacuo at 80° C. to afford the title compound 181 as a mixture with AcONHEt3 (252 mg, 75%). 1H NMR: (CD3OD) δ (ppm): 6.54 (d, J=7.8 Hz, 1H), 6.51 (d, J=12.3 Hz, 1H), 4.21 (t, J=5.1 Hz, 2H), 3.40 (t, J=5.1 Hz, 2H), 2.89 (s, 6H). m/z: 214.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][N:14]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[N:15]2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][N:14]2[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cn2ccc([N+](=O)[O-])n2)COC1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@H](Cn2ccc(N)n2)COC1(C)C
Yield: 97.3 %

Procedure:
In a Parr shaker bottle was placed (R)-2,2-dimethyl-4-(3-nitro-pyrazol-1-ylmethyl)-oxazolidine-3-carboxylic acid t-butyl ester (1.21 g, 3.71 mmol), 10% palladium on carbon (500 mg) and ethanol (25 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 5 h. The reaction was then filtered through a pad of celite and washed with ethanol and concentrated in vacuo to afford (R)-4-(3-amino-pyrazol-1-ylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester (1.07 g, 97%) as a yellow oil: LR-ES-MS m/z calculated for C14H24N4O3 [M]+ 296, observed 297 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]([C:15]3[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[C:34]([CH3:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:31][C:32]2[CH:33]=[C:34]([CH3:40])[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=2)[C:9]2[C:10]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:11][N:12]([C:15]3[C:16]([O:23][CH3:24])=[N:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-methyl-1H-pyrazole-3-carboxylate (Step 55.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.59 min (HPLC 1); tR: 1.06 min (LC-MS 2); ESI-MS: 553 [M+H]+ (LC-MS 2); Rf=0.40 (CH2Cl2/MeOH 9:1).
Reaction SMILES: C([O:8][C:9]1[CH:20]=[CH:19][C:12]2[C:13](=O)[C:14]([CH3:17])([CH3:16])[O:15][C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH3:16][C:14]1([CH3:17])[CH2:13][C:12]2[CH:19]=[CH:20][C:9]([OH:8])=[CH:10][C:11]=2[O:15]1
Reactant: [H][H]
Reactant: CC1(C)Oc2cc(OCc3ccccc3)ccc2C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2ccc(O)cc2O1
Yield: 87.5 %

Procedure:
To a solution of 6-(benzyloxy)-2,2-dimethylbenzofuran-3(2H)-one (0.85 g, 3.20 mmol) in methanol (100 mL) was added palladium hydroxide (0.22 g, 20 wt. % loading, 0.32 mmol). The resulting mixture was hydrogenated for 16 hours under 60 psi of hydrogen. The reaction mixture was filtered through celite, washed with methanol. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/5) to give the title compound (0.46 g, 88%): 1H NMR (300 MHz, CDCl3) δ 6.92 (d, 1H), 6.30-6.21 (m, 2H), 4.77 (s, 1H), 2.90 (s, 2H), 1.44 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:42]/[O:43][C:44]2([C:47]([OH:49])=[O:48])[CH2:46][CH2:45]2)/[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]([S:16]([OH:19])(=[O:18])=[O:17])[C@@H:12]2[CH2:20][N:21]2[N:25]=[C:24]([CH2:26][NH:27][C:28](=[NH:41])[NH:29][CH2:30][CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)[CH:23]=[N:22]2)=[O:9])[N:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][CH2:30][NH:29][C:28](=[NH:41])[NH:27][CH2:26][C:24]1[CH:23]=[N:22][N:21]([CH2:20][C@@H:12]2[C@H:11]([NH:10][C:8](=[O:9])/[C:7](=[N:42]\[O:43][C:44]3([C:47]([OH:49])=[O:48])[CH2:45][CH2:46]3)/[C:5]3[N:6]=[C:2]([NH2:1])[S:3][CH:4]=3)[C:14](=[O:15])[N:13]2[S:16]([OH:19])(=[O:18])=[O:17])[N:25]=1
Reactant: CC(C)(C)OC(=O)NCCCNC(=N)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(NCCCN)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Yield: 55.1 %

Procedure:
Followed the general procedure for the acid mediated deprotection using 1-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((4-(3-imino-11,11-dimethyl-9-oxo-10-oxa-2,4,8-triazadodecyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid (37 mg, 15 μmol), DCM (0.8 mL), and TFA (0.2 mL, 2.60 mmol) for 1.5 h. The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min) affording the title compound (5.2 mg, 20%). LCMS: Rt=0.39 min, m/z=629.2 (M+1), Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 7.77 (s, 1H), 7.15 (s, 1H), 5.63 (d, J=5.7 Hz, 1H), 5.06-4.99 (m, 1H), 4.98-4.89 (m, 2H), 4.57 (s, 2H), 3.39-3.34 (m, 2H), 3.14-3.06 (m, 2H), 2.01 (p, J=7.2 Hz, 2H), 1.39-1.29 (m, 2H), 1.26-1.15 (m, 2H).
Reaction SMILES: CCCCCC.[C:7]([O:11][C:12](=[O:22])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1Br)([CH3:10])([CH3:9])[CH3:8].[CH:23](=[O:25])[CH3:24].[Cl-].[NH4+]>C1COCC1.O>[C:7]([O:11][C:12](=[O:22])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH:23]([OH:25])[CH3:24])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1Br
Reactant: CC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)c1cc(Cl)ccc1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
At −78° C. under nitrogen 1.6 M butyllithium solution in hexane (4.89 ml, 7.8 mmol) were added dropwise to [2-bromo-4-chloro-phenyl]-carbamic acid tert-butyl ester (1.09 g, 3.56 mmol) in THF (20 ml). The reaction was stirred for 15 minutes at −78° C. and acetaldehyde (235 mg, 5.33 mmol) was added dropwise. After stirring for 15 minutes at −78° C. saturated aqueous ammonium chloride solution was added and the reaction was allowed to warm to room temperature. The reaction was diluted with water and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated to yield the crude product which was purified by column chromatography (heptane:ethyl acetate=4:1). The product was isolated as a colorless viscous oil (525 mg, 54%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:5][C@H:4]([CH3:16])[N:3]1[C:17]1[O:18][C:19]2[C:20](=[C:22]([C:26]([O:28]C)=[O:27])[CH:23]=[CH:24][CH:25]=2)[N:21]=1.[I-].[Li+]>N1C=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][N:6]([C:8]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:9])[CH2:5][C@H:4]([CH3:16])[N:3]1[C:17]1[O:18][C:19]2[C:20](=[C:22]([C:26]([OH:28])=[O:27])[CH:23]=[CH:24][CH:25]=2)[N:21]=1
Reactant: COC(=O)c1cccc2oc(N3[C@@H](C)CN(C(=O)N4CCCCC4)C[C@@H]3C)nc12
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: C[C@H]1CN(C(=O)N2CCCCC2)C[C@H](C)N1c1nc2c(C(=O)O)cccc2o1
Temperature: 110 °C

Procedure:
To a solution of methyl 2-((2S,6S)-2,6-dimethyl-4-(piperidine-1-carbonyl)piperazin-1-yl)benzoxazole-4-carboxylate (200 mg, 0.52 mmol) in pyridine (2 mL) was added lithium iodide (495 mg, 3.70 mmol). The mixture was heated at 110° C. for 18 h and allowed to cool to ambient temperature before partitioning with 9:1 dichloromethane/2-propanol (100 mL) and 1 N HCl (50 mL). The non-homogenous organic layer was washed with brine and concentrated in vacuo. The residue was treated with 9:1 mixture of toluene and methanol (100 mL) and concentrated under reduced pressure to afford crude 2-((2S,6S)-2,6-dimethyl-4-(piperidine-1-carbonyl)piperazin-1-yl)benzoxazole-4-carboxylic acid as a brown solid which was directly elaborated without purification.