Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([F:16])([F:15])[CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O.P(Br)(Br)[Br:18]>O>[Cl:1][C:2]([F:16])([F:15])[CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:18]
Reactant: BrP(Br)Br
Reactant: OCCCCCCCCCC=CC(F)(F)Cl
Solvent: O
Product: FC(F)(Cl)C=CCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 197.9 %

Procedure:
Under an argon atmosphere 4.8 grams (0.019 mole) of 12-chloro-12,12-difluoro-10-dodecen-1-ol (prepared in Example 1) was stirred, and 0.65 ml (0.007 mole) of phosphorus tribromide was added dropwise using a syringe. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 18 hours. After this time the reaction mixture was poured into 100 ml of ice/water with stirring. An additional 300 ml of water was added to the gelatinous mixture, and stirring was continued for 18 hours. The mixture was extracted with pentane, and the extract was washed with aqueous sodium bicarbonate. Additional water was added to help separate the layers. The organic layer was washed with an aqueous solution saturated with sodium chloride and then was dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure yielding 4.4 grams of 12-chloro-12,12-difluoro-10-dodecenyl bromide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:11][C:12]1[O:16][N:15]=[C:14]([CH:17]2[CH2:19][CH2:18]2)[N:13]=1)(=[O:10])=[O:9].[F:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=1>>[CH:17]1([C:14]2[N:13]=[C:12]([CH2:11][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:25]3[CH:24]=[CH:23][C:22]([C:36]4[CH:41]=[N:40][C:39]([NH2:42])=[N:38][CH:37]=4)=[C:21]([F:20])[CH:26]=3)(=[O:10])=[O:9])[O:16][N:15]=2)[CH2:19][CH2:18]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(Cc1nc(C2CC2)no1)c1ccccc1Br
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)Cc3nc(C4CC4)no3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 5-(((2-bromophenyl)sulfonyl)methyl)-3-cyclopropyl-1,2,4-oxadiazole and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine. MS (ESI): mass calcd. for C22H18FN5O3S, 451.11; m/z found, 452.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.56 (s, 1H), 7.98-7.94 (m, 1H), 7.85-7.77 (dd, J=8.2, 6.9, 1H), 7.67-7.61 (m, 1H), 7.61-7.57 (m, 1H), 7.52-7.46 (d, J=7.6, 1H), 7.39-7.35 (dd, J=7.9, 1.6, 1H), 7.35-7.31 (m, 1H), 2.05-1.94 (m, 1H), 1.04-0.94 (m, 1H), 0.79-0.72 (m, 1H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:42])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(N(C)Cc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 58 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-hexyl chloroformate. Yield: 58% of theory, C35H43N7O5 (641.2); Rf value: 0.42 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=642; (M+H+Na)++=332.7.
Reaction SMILES: [C:1]1(C2(C(O)=O)CCCC2)[CH:6]=CC=C[CH:2]=1.[CH3:15][CH:16]([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH:40]1([CH:17]([CH:16]2[CH2:46][CH2:6][CH2:1][CH2:2][CH2:15]2)[C:18]([NH:20][C@@H:21]2[C@H:28]3[C@H:24]([CH2:25][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=4)[CH2:27]3)[CH2:23][CH2:22]2)=[O:19])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C(C1CCCCC1)C1CCCCC1

Procedure:
The title compound was prepared by substituting 2,2-dicyclohexylacetic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (400 MHz, pyridine-d5) δ ppm 7.73 (s, 1H), 7.65 (d, J=7.6, 1H), 7.57-7.44 (m, 3H), 4.46 (dt, J=6.4, 12.6, 1H), 3.55 (d, J=12.9, 1H), 3.47 (d, J=12.8, 1H), 2.75 (d, J=8.1, 2H), 2.53-2.39 (m, 2H), 2.32 (t, J=8.2, 1H), 2.21 (t, J=8.3, 1H), 1.97-1.53 (m, 15H), 1.50-1.04 (m, 11H), 0.98 (dd, J=11.3, 23.1, 1H); MS (ESI+) m/z 491 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5]1.C(N(C(C)C)CC)(C)C.[C:30]([N:38]=[C:39]=[S:40])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C1COCC1>[CH2:13]([O:12][C:11](=[O:20])[NH:10][CH:7]1[CH2:8][CH2:9][CH:4]([CH2:3][NH:2][C:39]([NH:38][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[S:40])[CH2:5][CH2:6]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCC1CCC(NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCC(CNC(=S)NC(=O)c2ccccc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101.8 %

Procedure:
A solution of benzyl N-[4-(aminomethyl)cyclohexyl]carbamate HCl (3.46 g, 11.6 mmol) and diisopropylethylamine (6.0 ml) in anhydrous THF (90 ml) was stirred at room temperature for 20 minutes. To this solution was added benzoylisothiocyanate (2.00 g, 12.3 mmol) and the reaction mixture stirred at room temperature for 14 hours. The solution was poured into water (200 ml) and extracted with Et2O (2×150 ml). The organic layer was dried over MgSO4, filtered and evaporated to yield a solid. The solid was triturated with hexane and filtered to yield 99% (5.023 g) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[F:11][C:12]([F:23])([F:22])[O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.CC[O:26][C:27]([C:29]([CH2:31][C:32]([CH3:34])=[O:33])=[O:30])=O>>[C:32]([CH:31]1[CH:17]([C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([O:13][C:12]([F:23])([F:22])[F:11])[CH:15]=2)[N:1]([C:2]2[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:27](=[O:26])[C:29]1=[O:30])(=[O:33])[CH3:34]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Product: CC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 57.1 using 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2), 3-trifluoromethoxy-benzaldehyde and ethyl acetopyruvate at 110° C. for 4 hr. tR: 0.79 min (LC-MS 2); ESI-MS: 423 [M+H]+ (LC-MS 2); ESI-MS: 421 [M−H]− (LC-MS 2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CS[C:9]1[N:10]=[N:11][CH:12]=[CH:13][N:14]=1.C(N(CC)CC)C.C(OCC)(=O)C>C(O)CCC>[N:1]1([C:9]2[N:10]=[N:11][CH:12]=[CH:13][N:14]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CSc1nccnn1
Reactant: C1CNCCN1
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: c1cnc(N2CCNCC2)nn1
Temperature: 120 °C
Yield: 68.7 %

Procedure:
3.45 g (40.1 mmoles) of piperazine is placed in the presence of 1.7 g (13.4 mmoles) of intermediate 2a in 1-butanol. 6.5 ml (47 mmoles) of triethylamine is added and the mixture is heated for 24 hours at 120° C. After concentrating the reaction medium, the residue obtained is taken up with ethyl acetate and washed with water. After drying on MgSC4, the organic phase is concentrated to dryness. The residue obtained is purified by flash chromatography (CH2Cl2-MeOH-NH4OH gradient: 100-0-0 to 90-9-1). 1.52 g of intermediate 5a is obtained in brown oil form (yield: 69%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]2=O)[CH3:2].O.[NH2:22][NH2:23]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:6]2[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][NH:23][N:22]=2)[C:10]([OH:9])=[CH:11][C:12]=1[OH:13])[CH3:2]
Reactant: CCc1cc2c(=O)c(-c3ccccc3)coc2cc1O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCc1cc(-c2n[nH]cc2-c2ccccc2)c(O)cc1O

Procedure:
This compounds was synthesised in the same manner as described above. 6-Ethyl-7-hydroxy-3-phenyl-chromen-4-one (0.29 g, 1.1 mmol), hydrazine hydrate (4 ml), ethanol (20 ml). The crude product was columned to give 4-Ethyl-6-(4-phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol as a off white solid (0.23 g, 74.73%); Rf 0.7 Cf SM 0.9 ethyl acetate/hexane (70/30).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([OH:16])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[C:18]1([C:24]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:32]3[CH:28]([CH2:29][NH:30][CH2:31]3)[C:27](=[O:33])[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[C:34]1([C:24]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:32]3[CH:28]([CH2:29][N:30]([C:14](=[O:16])[CH2:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH2:31]3)[C:27](=[O:33])[CH2:26][CH2:25]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)Cc1ccccc1N1CCOCC1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3N3CCOCC3)CC12
Reaction time: 1.25 h
Yield: 25.2 %

Procedure:
N,N'-Carbonyldiimidazole (0.35 g) is added to a solution of 2-[2-(4-morpholinyl)phenyl]acetic acid (0.48 g) in dry dichloromethane (25 cc), cooled to +5° C. The mixture is stirred for 75 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (0.71 g) and triethylamine (0.6 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 1 hour at +5° C. and then for 8 hours at 20° C. It is washed with distilled water (3×100 cc) and with saturated sodium chloride solution (100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 2.2 cm, height 12 cm), eluting with a mixture of ethyl acetate and cyclohexane (70/30 by volume) under a nitrogen pressure of 0.7 bar and collecting 50 cc fractions. Fractions 4 and 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from ethylene oxide (2 cc). The crystals are drained, washed with isopropyl ether (1 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-[2-(4-morpholinyl)phenyl]acetyl]-4-perhydroisoindolone (0.27 g) melting at 167° C. is obtained.
Reaction SMILES: [CH2:1]1[O:19][C:18]2[C:3](=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[C:6]([CH:17]=2)[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]([OH:16])=[O:15])=[O:8])[O:2]1.CO.[CH2:25](O)[CH3:26]>>[CH2:1]1[O:19][C:18]2[C:3](=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[C:6]([CH:17]=2)[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]([O:16][CH2:25][CH3:26])=[O:15])=[O:8])[O:2]1
Reactant: O=C(O)C1CCCN1C(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: CCO
Solvent: CO
Product: CCOC(=O)C1CCCN1C(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Yield: 85 %

Procedure:
By carrying out the procedure as in Example 11, but replacing 4-hydroxy-1-(3,4-methylenedioxybenzoyl)pyrrolidine-2-carboxylic acid by 1-(4,5-methylenedioxy-2-nitrobenzoyl)pyrrolidine-2-carboxylic acid and methanol by ethanol, the title product is obtained.
Reaction SMILES: Cl.[F:2][C:3]1[C:8](F)=[C:7]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[CH:6]=[CH:5][C:4]=1[C:15]1[S:19][C:18]([N:20]2[CH2:23][C:22]3([CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH2:21]2)=[N:17][N:16]=1.[OH2:36]>O1CCOCC1.CO.CS(C)=O>[CH2:21]1[C:22]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:23][N:20]1[C:18]1[S:19][C:15]([C:4]2[C:3]([F:2])=[CH:8][C:7]([C:10]3[CH:11]=[N:12][NH:13][CH:14]=3)=[CH:6][C:5]=2[OH:36])=[N:16][N:17]=1
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(-c4cn[nH]c4)c(F)c3F)s1)C2
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: Oc1cc(-c2cn[nH]c2)cc(F)c1-c1nnc(N2CC3(CCNCC3)C2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
HCl (4M solution in dioxane, 545 μL, 2.179 mmol) was added to a stirred suspension of tert-butyl 2-(5-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (53 mg, 0.109 mmol) in dioxane (4 mL). The reaction mixture was stirred at room temperature for 2 hours then diluted with dioxane (2 mL), MeOH (5 mL), DMSO (5 mL) and a small amount of water, then loaded onto a 2 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (15 mL) then flushed with 10% DCM in [7M NH3 in MeOH] (20 mL). The DCM/MeOH/NH3 was removed in vacuo to afford the crude product as a brown solid. The crude material was heated in MeOH (5 mL) and the resulting suspension was cooled to room temperature then filtered under vacuum and rinsed with MeOH to afford the title compound as a pale brown solid (23 mg, 55% yield). LC-MS: Rt 0.68 min; MS m/z 387.2 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 8.17 (s, 2H), 7.15-7.05 (m, 2H), 3.87 (s, 4H), 2.70 (t, J=5.1 Hz, 4H), 1.73 (t, J=5.3 Hz, 4H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=O)[CH2:23][CH:24]1[CH2:27][CH:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25]1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][C:22]([CH2:23][CH:24]2[CH2:25][CH:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27]2)=[N:21][N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(Cc2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclobutylcarbamate (1.0 g, 1.99 mmol) in DCM (20 mL) was added pyridine (1.5 mL). (CF3SO2)2O (1.4 g, 4.97 mmol) was added slowly at −10° C. The reaction mixture was stirred at 0° C. for 1 h. Sat. NaHCO3 was added at 0° C. very slowly. The organic layer was separated and the water layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10˜50% EtOAc/petroleum ether) to afford tert-butyl 3-((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutylcarbamate (0.7 g, 48%) as a slight yellow solid. ESI-MS (EI+, m/z): 484.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)=[O:7])[CH3:4].[CH3:13][O:14][C:15](=[O:30])[C:16]1[CH:21]=[C:20](F)[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=1[N+:27]([O-:29])=[O:28].O>CN1CCCC1=O>[CH2:3]([O:5][C:6]([C:8]1[N:12]=[CH:11][N:10]([C:20]2[CH:21]=[C:16]([C:15]([O:14][CH3:13])=[O:30])[C:17]([N+:27]([O-:29])=[O:28])=[CH:18][C:19]=2[C:23]([F:24])([F:26])[F:25])[N:9]=1)=[O:7])[CH3:4]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ncn(-c2cc(C(=O)OC)c([N+](=O)[O-])cc2C(F)(F)F)n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A solution of 613 mg (14.0 mmol) of sodium hydride in 10 ml of 1-methyl-2-pyrrolidinone is cooled to 0-5° C. and treated dropwise with a solution of 1.74 g (12.4 mmol) of 1H-[1,2,4]triazole-3-carboxylic acid ethyl ester in 10 ml of 1-methyl-2-pyrrolidinone over 8 minutes. The mixture is stirred for 1 hour at 0-5° C. and a solution of 3.00 g (11.2 mmol) of 5-fluoro-2-nitro4-trifluoromethyl-benzoic acid methyl ester in 10 ml of 1-methyl-2-pyrrolidinone is added. The mixture is allowed to warm slowly to room temperature and stirred for 18 hours under N2. It is poured into water and extracted with ethyl acetate. The organic phase is separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, hexane/ethyl acetate 1:1) and the mixed fractions are recrystallized in toluene to provide overall 3.12 g (71%) of 1-(5-methoxycarbonyl-4-nitro-2-trifluoromethyl-phenyl)-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester, m.p. 190-192° C.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[N:23](C(C)(C)C)[C:22](=[O:31])[CH2:21]2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=O)(C)(C)C.[CH:32](N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.Cl.[NH2:66][CH2:67][CH2:68][CH2:69][CH2:70][O:71][C:72]1[CH:81]=[CH:80][CH:79]=[C:78]([OH:82])[C:73]=1[C:74]([O:76][CH3:77])=[O:75]>CN(C)C=O>[C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:31])[CH2:21]2)=[CH:16][CH:15]=1)[C:10]([NH:66][CH2:67][CH2:68][CH2:69][CH2:70][O:71][C:72]1[CH:81]=[CH:80][CH:79]=[C:78]([OH:82])[C:73]=1[C:74]([O:76][CH3:77])=[O:75])=[O:11])(=[O:5])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)C(=O)O
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)NC(C)=O
Reaction time: 2 h
Yield: 20.3 %

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid (12 mg, 0.035 mmol) in N,N-dimethylformamide (1.0 mL,) was added N,N-diisopropylethylamine (0.018 mL, 0.10 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (16 mg, 0.042 mmol) and premixed for 5 minutes. Methyl 2-(4-aminobutoxy)-6-hydroxybenzoate hydrochloride (12 mg, 0.042 mmol) was added and the mixture was stirred for 2 h. The product was purified by preparative LCMS to afford the desired product (4.0 mg, 20%). 1H NMR (500 MHz, CD3OD): δ 7.43–7.45 (m, 2H), 7.35–7.36 (m, 2H), 7.27(t, J=8.3 Hz), 6.49–6.53 (m, 2H), 5.12–5.17 (m, 1H), 4.55–4.59 (m, 1H), 3.96–3.99 (m, 2H), 3.90 (s, 3H), 2.89–3.89 (m, 4H), 1.95 (s, 3H), 1.64–1.68 (m, 2H), 1.57–1.61 (m, 2H); LCMS found for C26H32N3O9S (M+H)+: m/z=562.2.
Reaction SMILES: [OH2:1].[NH2:2][NH2:3].CO[C:6](=[O:39])[C@@H:7]([CH3:38])[NH:8][C:9](=[O:37])[C@H:10]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C(O)C.O1CCCC1>[NH:11]([C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C@H:10]([C:9]([NH:8][C@@H:7]([C:6]([NH:2][NH2:3])=[O:39])[CH3:38])=[O:37])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:1])=[CH:27][CH:28]=1
Reactant: O
Reactant: COC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1
Reactant: NN
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(OC(=O)c2ccccc2)cc1)NC(=O)OCc1ccccc1)C(=O)NN
Temperature: 25 °C

Procedure:
A solution of hydrazine hydrate (5.05 ml.) in ethanol (45 ml.) was added to a solution of (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl)-D-alanine methyl ester (15.18 g.) in tetrahydrofuran (135 ml.). The resulting solution was stirred at room temperature and seeded. (N-Benzyloxycarbonyl-O-benzyl-L-tyrosyl)-D-alanyl hydrazide (13.2 g.; m.r. 216°-218° C.; [α]D25 -21.4°, c=2, dimethylformamide) separated from the solution as a crystalline solid.
Reaction SMILES: C[CH:2]1[C:11]2[C:10]3[CH:12]=[CH:13][CH2:14][CH2:15][C:9]=3[CH:8]=[CH:7][C:6]=2[NH:5][CH2:4][CH2:3]1.N.[Li].[CH2:18](O)C>CCOCC.O>[CH3:18][N:5]1[CH:6]2[CH:11]([C:10]3[CH2:12][CH:13]=[CH:14][CH2:15][C:9]=3[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC1CCNc2ccc3c(c21)C=CCC3
Reactant: CCO
Agent: N
Agent: [Li]
Solvent: O
Solvent: CCOCC
Product: CN1CCCC2C3=C(CC=CC3)CCC21

Procedure:
1-Methyl-1,2,3,4,7,8-hexahydrobenzo[f]-quinoline is dissolved in 200 ml of ether and added to 1.5 l of liquid ammonia. Lithium ribbon (16 g) is added portionwise over a period of 15 minutes. After stirring a few minutes, absolute ethanol is added dropwise until the color is discharged (500 ml added over a period of 2.5 hours). More ether is added and the ammonia is boiled off. While cooling in an ice bath, the mixture is diluted to about 1500 ml with water. The layers are separated and the aqueous layer is reextracted with ether. The combined organic layers are dried over potassium carbonate, filtered and the solvent is removed in vacuo leaving the title compound as a crude product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:13]([OH:16])[CH:14]=[CH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:26](OC)([CH3:28])[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:13]([CH:14]=[CH2:15])[O:16][C:26]1([CH3:28])[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: C=CC(O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
983 mg of (3RS,4S)-4-(benzyloxycarbonyl)amino-5-cyclohexylpentene-3-ol was dissolved in 5 ml of dichloromethane, and 4 ml of 2,2-dimethoxypropane and 30 mg of dry p-toluenesulfonic acid were added thereto. The mixture was stirred at room temperature overnight. Then, 100 ml of ethyl acetate was added to the reaction mixture. The mixture was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by-silica gel column chromatography (n-hexane/ethyl acetate=20/1) to obtain 967 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-5-ethenyl-2,2-dimethyloxazolidine as colorless oily substance.