Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H][H]>[Rh]>[CH3:1][C:2]1([CH3:14])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8]2)[NH:3]1
Reactant: CC1=CC(C)(C)Nc2c(C)cccc21
Reactant: [H][H]
Agent: [Rh]
Product: CC1CC(C)(C)NC2C(C)CCCC12
Reaction time: 8 h

Procedure:
2,2,4,8-tetramethyldecahydroquinoline was prepared by reacting 74 grams of 2,2,4,8-tetramethyl-1,2-dihydroquinoline with hydrogen in the presence of 2 grams of rhodium at 5% by weight on charcoal at a temperature of 200° C., a pressure of 1000 psig, and over a period of 8 hours. The desired product was confirmed by NMR spectral analysis and carbon, hydrogen, nitrogen analysis (calculated content for C13H25N is the same as above and analyzed contents were 80.03% carbon, 13.38% hydrogen, and 6.09% nitrogen). The product was 90% pure as determined by vapor pressure chromotography and boiled at 65° C. at 0.6 mm of Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[C:6]([Br:8])[CH:7]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:24]4[C:33]5[C:28](=[CH:29][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Nc1ccc(CN2CCN(c3cc(Br)cc(Br)c3)CC2)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: FC(F)(F)c1ccc2c(Nc3ccc(CN4CCN(c5cc(Br)cc(Br)c5)CC4)cc3)ccnc2c1

Procedure:
In the manner given in Example 1C, 1-(3,5-dibromophenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(3,5-dibromophenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.C(N(CC)CC)C.[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[C:27](=[S:28])[O:19][CH2:18]1)=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC)C1C(CO)COC(=S)N1CC2
Yield: 19 %

Procedure:
To a solution of 2.67 g (0.01 mole) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in 150 ml of absolute chloroform a solution of 2.0 g (0.02 mole) of triethyl amine in 10 ml of absolute chloroform is added, and to the mixture 1.15 g (0.01 mole) of thiophosgene are added dropwise with stirring, under cooling with ice. The reaction mixture is stirred for 10 minutes, then it is washed to neutral with 15 ml of a 5% hydrochloric acid solution and subsequently water. The chloroformic phase is dried over sodium sulfate and evaporated to dryness. The residue is taken up in 15 to 20 ml of ethanol, and ether is added to the mixture until slight turbidity. The desired compound is obtained in crystalline form.
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CN(C1C=CC=CN=1)C.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[C:27]([O:17][C:4]1([CH2:1][CH:2]=[CH2:3])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(OC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A solution of tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (3.7 g, 14.51 mmol) in dichloromethane (20 mL) was treated with dimethylaminopyridine (1.8 g, 14.51 mmol), acetic anhydride (4.1 mL, 43.53 mmol) and triethylamine (6.1 mL, 43.53 mmol), and was stirred overnight at 20° C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic extracts were washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure, and purified by a standard method to provide the title compound 44B (3.4 g). LC-MS: m/z 284.4 (M+H)+
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2scnc2c1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4scnc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using benzo[d]thiazole-5-carboxylic acid (Apollo) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.64-7.73 (m, 1 H), 8.35 (s, 1 H), 8.36 (s, 1 H), 8.48 (dt, J=8.1, 2.0, 1.7 Hz, 1 H), 8.83 (dd, J=4.7, 1.7 Hz, 1 H), 9.17 (t, J=1.2 Hz, 1 H), 9.29 (dd, J=2.2, 0.8 Hz, 1 H), 9.66 (s, 1 H) ppm; MS (DCI/NH3) m/z 281 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]([F:16])[F:15])[C@H:10]([O:17][C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)[CH2:9]1)=O)(C)(C)C.[ClH:41]>C(Cl)Cl.O1CCOCC1>[ClH:41].[ClH:41].[CH2:37]([C:21]1[N:20]=[N:19][C:18]([O:17][C@H:10]2[C@H:11]([CH:14]([F:16])[F:15])[CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:23][C:22]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[CH:26][CH:25]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCc1nnc(O[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2C(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(O[C@@H]2CNCC[C@H]2C(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-4-difluoromethyl-piperidine-1-carboxylic acid tert-butyl ester (0.32 mmol, 0.18 g) in DCM (0.75 mL) was added 4 N HCl in dioxane (0.75 mL). The solution was stirred for 1 hour. The solvents were removed with reduced pressure and the salt was triturated with diethyl ether and filtered to give (±)-trans-3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-difluoromethyl-piperidin-3-yloxy)-pyridazine dihydrochloride (0.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[C:6]([OH:8])=[O:7].[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>O>[C:15]([O:12][C:11]1[C:10]([O:13][CH3:14])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C(=O)O)cc(OC)c1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3,5-dimethoxy-4-hydroxybenzoic acid (3.00 g) and acetic anhydride (30 ml) was dropwise added pyridine (15 ml) with ice-cooling over a 5 minutes period. After stirring at room temperature for 30 minutes, the reaction mixture was poured into water and stirred at room temperature for 30 minutes followed by extracting thrice with ethyl acetate. The combined extract was washed with 10% hydrochloric acid, dried and concentrated. The residue was recrystallized from a mixture of methylene chloride and hexane to afford the title compound (3.13 g), melting at 192°-194° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:12]1[CH:13]=[C:14]([CH2:31][NH2:32])[CH:15]=[CH:16][C:17]=1[Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>C1COCC1>[F:34][C:2]([F:1])([F:33])[C:3]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:31][NH:32][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CN)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CNC(=O)CCC(=O)O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Temperature: 20 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
Compound 8 (401 mg, 661 μmol) was dissolved in freshly distilled THF (5 mL) under nitrogen atmosphere and succinic anhydride (165 mg, 1.65 mmol) was added. After stirring 20 h at 20° C., the solvent was removed under reduced pressure and dissolved in n-hexane. The white precipitate was removed by filtration and the filtrate evaporated to dryness. The residue was purified over silica gel by dichloromethane/methanol (9/1) to give 461 mg (661 μmol, 99% yield) of a white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=1.C([Sn](CCCC)(CCCC)[C:38]1[O:39][CH:40]=[CH:41][CH:42]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=[C:2]([C:38]3[O:39][CH:40]=[CH:41][CH:42]=3)[C:7]=2[C:8]1=[O:22]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(Cl)c3C2=O)c(OC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(-c4ccco4)c3C2=O)c(OC)c1
Yield: 58 %

Procedure:
A solution of (R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanamide (150 mg, 0.323 mmol), tributyl(furan-2-yl)stannane (138 mg, 0.387 mmol), and tetrakis(triphenylphosphine)palladium(0) (373 mg, 0.323 mmol) in toluene (1 mL) was heated to 102° C. overnight. After removal of the solvent, the residue was diluted in MeOH/DCM (10 mL) and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (45-60% gradient, 0.035% TFA). The collected fractions were stripped to dryness via rotary evaporation to give the title compound (93.1 mg, 58%). [M+H] calc'd for C26H29FN4O5, 498. found 498.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.[CH3:39][N:40]([CH3:45])[CH2:41][C:42](O)=[O:43].CCN=C=NCCCN(C)C>C(Cl)Cl>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:25]([CH:26]2[CH2:27][CH2:28][N:29]([C:42](=[O:43])[CH2:41][N:40]([CH3:45])[CH3:39])[CH2:30][CH2:31]2)[CH3:32])=[O:24])[C:10]([CH2:9][OH:8])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCC(N(C)C(=O)N2CC(c3cc(F)ccc3F)=CC2(CO)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 30 mg (0.055 mmol) of amine 7-2 in CH2Cl2 was added 10 mg (0.097 mmol) of N,N-dimethylglycine and 15 mg (0.078 mmol) of EDCI. After stirring overnight at room temperature, the mixture was partitioned between CH2Cl2 and saturated NaHCO3, the layers were separated, the organic phase was washed with water, dried over Na2SO4, and concentrated by rotary evaporation. The residue was dissolved in dry CH3CN and ˜500 μL of 3HF-TEA was added and the mixture was stirred overnight at room temperature. The reaction was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was purified by reverse phase HPLC to provide 7-3 as a white solid. Data for 7-3: HRMS (ES) calc'd M+H for C28H34F2N4O3: 513.2672. Found: 513.2673.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([CH:28]2[NH:27][C@H:26]([C:24]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([O:16][C:15]4[CH:39]=[CH:40][C:12]([F:11])=[CH:13][CH:14]=4)=[CH:22][CH:21]=3)=[O:25])[CH2:30][C@H:29]2[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(O)Cn1ccnn1
Reactant: Cc1ccc(C[C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)cc1
Agent: Cl
Product: Cc1ccc(C[C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)NC2C(=O)Cn2ccnn2)cc1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide, gave Compound 3, (2S,4R)-5-(2-(1H-1,2,3-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(4-methylbenzyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): σ 8.96 (br s, 1H), 7.77 (s, 1H), 7.74 (s, 1H), 7.42 (m, 2H), 7.13 (d, 2H), 7.08 (d, 2H), 7.03-6.98 (m, 2H), 6.94-6.87 (m, 4H), 5.27 (d, 1H), 5.13 (d, 1H), 4.76 (d, 1H), 3.66 (m, 1H), 3.26 (t, 1H), 3.02-2.85 (m, 2H), 2.66-2.57 (m, 2H), 2.33 (s, 3H), 1.76-1.68 (m, 1H); MS (EI) for C29H28FN5O3. found 514.1 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:32]([C:36]1[CH:61]=[CH:60][C:39]([C:40]([NH:42][C@@H:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52](/[C:55](=[N:58]/[H])/[NH:56]O)=[CH:51][CH:50]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[C:32]([C:36]1[CH:61]=[CH:60][C:39]([C:40]([NH:42][C@@H:43]([CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:55](=[NH:56])[NH:58][O:14][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=3)=[CH:53][CH:54]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: [H]/N=C(\NO)c1ccc(C[C@H](NC(=O)c2ccc(C(C)(C)C)cc2)C(=O)OC)cc1
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCCCCOc1ccc(C(=O)ONC(=N)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Reaction time: 2 h

Procedure:
Prepared using General Procedure 5: To a solution of 4-(heptyloxy)benzoic acid (400.0 mg, 1.54 mmol) in anhydrous DMF (6 mL) were added HOBt (312.3 mg, 2.31 mmol) and EDC (442.75 mg, 2.31 mmol). After stirring for 2 h, (S,Z)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)-propanoate, INT-2 (673.3 mg, 1.69 mmol) was added. The reaction mixture was stirred at RT for 2 h, partitioned between saturated aqueous NaHCO3 (15 mL) and EA (15 mL), and concentrated under reduced pressure to afford the intermediate (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N-((4-(heptyloxy)benzoyl)oxy) carbamimidoyl)phenyl)propanoate. The intermediate was dissolved in DMF (10 mL) and heated to 100° C. for 18 h. The reaction mixture was cooled to RT and partitioned between EA (10 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was extracted with water (2×10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and concentrated. The brown oil was purified by chromatography (EA/hexanes) to afford 710 mg (77%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)-propanoate as a white solid. LCMS-ESI (m/z) calculated for C36H43N3O5: 597.3; no m/z observed, tR=12.80 min (Method 2). 1H NMR (400 MHz, DMSO) δ 8.84 (d, J=8.0 Hz, 1H), 8.08 (t, J=17.2 Hz, 2H), 7.97 (dd, J=18.2, 8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.50 (dd, J=18.6, 8.3 Hz, 4H), 7.18 (d, J=8.9 Hz, 2H), 4.85-4.63 (m, 1H), 4.09 (dd, J=13.8, 7.3 Hz, 2H), 3.67 (s, 3H), 3.24 (ddd, J=23.8, 15.7, 7.3 Hz, 4H), 2.08 (s, 4H), 1.74 (dd, J=14.1, 6.9 Hz, 2H), 1.42 (dd, J=13.6, 6.3 Hz, 2H), 1.30 (d, J=14.5 Hz, 9H), 0.88 (t, J=6.8 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 174.05, 170.87, 133.81, 165.14, 161.43, 153.21, 140.51, 129.70, 128.85, 128.78, 126.06, 125.84, 123.93, 123.39, 114.36, 114.25, 66.86, 52.66, 50.88, 34.32, 33.47, 30.06, 29.74, 27.33, 27.24, 24.23, 20.89, 12.80.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)(=O)C>[C:16]([NH:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:18])[CH3:17]
Reactant: Nc1cc(O)ccc1Oc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(O)ccc1Oc1ccccc1
Reaction time: 1 h
Yield: 93 %

Procedure:
20.1 g of 3-amino-4-phenoxyphenol was dissolved in 60 ml of acetic acid. 30 ml of acetic anhydride was added thereto with ice cooling. Stirring was conducted at 20°-25° C. for 1 hour. The mixture was subjected to distillation under reduced pressure to remove the solvent. The resulting crystal was recrystallized from toluene to obtain 22.6 g (yield: 93%) of 3-acetylamino-4-phenoxyphenol having a melting point of 151°-153° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[H-].[Na+].[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]3[CH:20]([CH:21]([CH3:23])[CH3:22])[CH:19]4[C:24]([CH3:37])([CH3:36])[N:25]([CH3:35])[CH:26]([C:27]5[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=5)[CH:18]4[C:17]3=[O:38])=[CH:14][C:9]=2[O:8][CH2:7]1>CN(C=O)C>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]3[CH:20]([CH:21]([CH3:23])[CH3:22])[CH:19]4[C:24]([CH3:36])([CH3:37])[N:25]([CH3:35])[CH:26]([C:27]5[CH:28]=[CH:29][C:30]([C:31](=[NH:32])[NH:2][OH:3])=[CH:33][CH:34]=5)[CH:18]4[C:17]3=[O:38])=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: NO
Reactant: CC(C)C1C2C(C(=O)N1Cc1ccc3c(c1)OCO3)C(c1ccc(C#N)cc1)N(C)C2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C1C2C(C(=O)N1Cc1ccc3c(c1)OCO3)C(c1ccc(C(=N)NO)cc1)N(C)C2(C)C
Temperature: 0 °C
Reaction time: 120 h
Yield: 66 %

Procedure:
841 mg (12.12 mmol) of hydroxylamine hydrochloride are suspended in 4 ml of DMF and cooled to 0° C. 303 mg (10.1 mmol) of 80% sodium hydride are added slowly. 500 mg (1.13 mmol) of (1RS,3aSR,4RS,6aSR)-4-(5-benzo[1,3]dioxol-5-ylmethyl-4-isopropyl-2,3,3-trimethyl-6-oxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile are dissolved in DMF and added to the reaction mixture. The cooling is thereafter no longer applied. The mixture is stirred at room temperature for 5 days. Thereafter, it is filtered and the solvent is removed in a high vacuum. The mixture is purified by chromatography (RP18, gradient from water to methanol). (1RS,3aSR,4RS,6aSR)-4-(5-Benzo[1,3]dioxol-5-ylmethyl-4-isopropyl-2,3,3-trimethyl-6-oxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-N-hydroxy-benzimidamide is isolated in 66% yield. Colourless solid. ISP-MS: 479.4 ([M+H]+, 100).
Reaction SMILES: ClC1C=CC(C(OO)=[O:9])=CC=1.[CH3:12][S:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH2:27][N:28]3[CH2:32][CH:31]([CH2:33][CH2:34][CH3:35])[CH2:30][C:29]3=[O:36])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=2)[N:19]=1>C(Cl)(Cl)Cl>[CH3:12][S:13]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH2:27][N:28]3[CH2:32][CH:31]([CH2:33][CH2:34][CH3:35])[CH2:30][C:29]3=[O:36])=[C:21]([C:23]([F:25])([F:24])[F:26])[N:22]=2)[N:19]=1)=[O:9]
Reactant: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(SC)nn23)C1
Reactant: O=C(OO)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(S(C)=O)nn23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
4-chloroperbenzoic acid (36 mg, 0.134 mmol, 1 eq) is added to a solution of 1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 33 (50 mg, 0.134 mmol) in chloroform (2 ml) at −30° C. After 30 minutes, the mixture is warmed to room temperature then stirred for additional 16 hours. After hydrolysis with a saturated aqueous NaHCO3 solution (2 ml) and extraction with CHCl3 (2 ml), the cumulated organic layers are dried over MgSO4 and condensed under reduced pressure. The resulting crude product is purified by reverse phase liquid chromatography (gradient acetonitrile/water/TFA) to yield 1-{[6-(methylsulfinyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 82.
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH:8]([C:20]([OH:22])=O)[CH2:7]1)=[O:5])[CH3:2].O[N:25]=[C:26]([NH2:34])[CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:7][CH:8]([C:20]2[O:22][N:34]=[C:26]([CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:25]=2)[CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:11]1)=[O:5])[CH3:2]
Reactant: NC(CN1CCOCC1)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N(C)CC)C2)cc1
Product: CCc1ccc(C2CC(c3nc(CN4CCOCC4)no3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
63 mg (0.20 mmol) of 1-[ethyl(methyl)carbamoyl]-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 45A) and 35 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-2-morpholin-4-ylethanimidamide were reacted according to the General Method 1. Yield: 5 mg (5% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[OH:35][C:29]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([F:37])([F:21])[F:36])[CH2:34][CH2:33][N:32]([C:14]([C@@:11]2([CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]2)=[O:16])[CH2:31][CH2:30]1
Reactant: OC1(c2ccccc2C(F)(F)F)CCNCC1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3C(F)(F)F)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 2.5 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (150 mg, 0.55 mmol), 4-[2-(trifluoromethyl)phenyl]piperidin-4-ol hydrochloride (170 mg, 0.60 mmol), and triethylamine (0.17 g, 1.6 mmol) in methylene chloride (3 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.31 g, 0.60 mmol). After being stirred for 2.5 h, the reaction was quenched by addition of a saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. The crude product was carried on to the next step without purification. MS calculated for C26H37F3N2O4: (M+H) 499; found 499.2.