Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:6]1)[CH:2]=C.I([O-])(=O)(=O)=[O:39].[Na+]>[Os](=O)(=O)(=O)=O.O1CCCC1.O>[OH:39][CH2:2][CH2:1][O:4][CH:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:15][CH:16]=2)[CH2:9][CH2:8][N:7]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:6]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCO)cc1
Temperature: 25 °C

Procedure:
8.54 g of tert-butyl 3-allyloxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate are initially charged in a 3:1 tetrahydrofuran/water mixture (52 ml) with stirring at room temperature and admixed with 2.07 ml of osmium tetroxide (2.5% by wt. in tert-BuOH). Subsequently, 9.00 g of sodium periodate are added in portions. The reaction mixture is stirred further over 2 hours. The reaction mixture is concentrated by evaporation. The residue is suspended in a 1:1 dichloromethane/methanol mixture (150 ml), cooled to 5° C. and admixed with 3.96 g of sodium borohydride in portions. The reaction mixture is stirred at 5° C. for 1.5 hours and subsequently concentrated by evaporation. The residue is stirred in 200 ml of dichloromethane, filtered through glass fibre filter and washed with dichloromethane. The filtrate is washed with a 1:1 brine/water mixture, filtered through cotton wool, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.17 (1:1 EtOAc-heptane). Rt=5.22.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[C:20]1([C@@H:26]2[CH2:28][C@H:27]2[C:29](Cl)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29]([C@@H:27]3[CH2:28][C@H:26]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:30])[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O)[C@@H]1C[C@H]1c1ccccc1

Procedure:
The product from Example 86A and trans-2-phenyl-1-cyclopropanecarbonyl chloride were treated using a method similar to that described in Example 53 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.69 (s, 1H), 8.39-8.43 (m, 1H), 7.88-8.06 (m, 2H), 7.68-7.82 (m, 1H), 7.64 (s, 4H), 7.28-7.36 (m, 2H), 7.18-7.25 (m, 3H), 2.36-2.45 (m, 1H), 2.05-2.14 (m, 1H), 1.37-1.56 (m, 2H); MS (ESI+) M/Z 416 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([OH:24])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].C(N(C(C)C)CC)(C)C.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39]Br>C(Cl)Cl>[CH3:1][N:2]([O:24][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: CN(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: COCCOCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCON(C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]hydroxyamine (600 mg, 1.65 mmol) in methylene chloride (4 ml) containing diisopropylethylamine (0.43 ml, 1.5 eq.) is added (2-methoxy)ethoxymethyl bromide (310 mg, 1.5 eq.) The mixture is stirred at RT for 16 hours. The reaction mixture is then taken up in methylene chloride, washed, dried, evaporated and purified by prep. TLC to yield N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl](2-methoxy)ethoxymethoxyamine (IXA, R is CH3OCH2CH2OCH2).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:18]1[CH:50]=[CH:49][C:21]([O:22][CH:23]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)[C@@H:24]([C:28]2[CH:41]=[CH:40][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:29]=2)[CH2:25][CH2:26][CH3:27])=[CH:20][C:19]=1[C:51]#[N:52]>CN(C=O)C.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>[Cl:48][C:45]1[CH:44]=[CH:43][C:42]([C@H:23]([O:22][C:21]2[CH:49]=[CH:50][C:18]([C:11]3[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=3)=[C:19]([C:51]#[N:52])[CH:20]=2)[C@@H:24]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:40][CH:41]=2)[CH2:25][CH2:26][CH3:27])=[CH:47][CH:46]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(Oc1ccc(Br)c(C#N)c1)c1ccc(Cl)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)[C@@H](Oc1ccc(-c2ccc(C)cc2)c(C#N)c1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a flask charged with Na2CO3 (2.0 M in water, 132 μL, 0.263 mmol), Pd(PPh3)4 (10.1 mg, 8.77 μmol) and (4-methylphenyl)boronic acid (36.5 mg, 0.175 mmol) was added a solution of the product from Step A (50 mg, 0.088 mmol) in DMF, then the mixture was stirred at 60° C. overnight. After cooling to RT, the mixture was purified by preparative reverse phase HPLC eluting with 50-100% acetonitrile/water+0.1% TFA to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.81 (d, J=8.5 Hz, 2H); 7.43 (d, J=7.5 Hz, 4H); 7.36 (t, J=8.5 Hz, 4H); 7.35 (d, J=8.5 Hz, 1H); 7.28 (d, J=3.0 Hz, 1H); 7.26 (d, J=8.0 Hz, 2H); 7.19 (dd, J=8.5, 2.5 Hz, 1H); 5.77 (d, J=7.0 Hz, 1H); 3.65-3.61 (m, 2H); 3.31 (m, 1H), 3.25 (s, 3H); 2.65 (t, J=6.5 Hz, 2H); 1.88-1.86 (m, 1H); 1.63-1.61 (m, 1H); 1.16-1.11 (m, 2H); 0.79 (t, J=7.0 Hz, 3H); LC1 1.27 min. (M+H)+ 581.
Reaction SMILES: N[C@H]([C:8]([OH:10])=[O:9])CCCCN.NN.[CH:13]1[C:18](N=C=S)=[CH:17][C:16]2[C:22]([O:24][C:25]3([C:35]4[CH:36]=[CH:37][C:38]([OH:40])=[CH:39][C:34]=4[O:33][C:27]4[CH:28]=[C:29]([OH:32])[CH:30]=[CH:31][C:26]3=4)[C:15]=2[CH:14]=1)=[O:23].C(N(C(C)C)CC)(C)C.C1C=CC(C(O)=O)=C(C2C3C=CC(O)=CC=3OC3C=2C=CC(C=3)=O)C=1>CN(C=O)C>[CH:13]1[C:18]([C:8]([OH:10])=[O:9])=[CH:17][C:16]2[C:22]([O:24][C:25]3([C:35]4[CH:36]=[CH:37][C:38]([OH:40])=[CH:39][C:34]=4[O:33][C:27]4[CH:28]=[C:29]([OH:32])[CH:30]=[CH:31][C:26]3=4)[C:15]=2[CH:14]=1)=[O:23]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: NN
Agent: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Reaction time: 12 h

Procedure:
Peptide-resin obtained via from Method 5, containing an ivDde protecting group on the epsilon nitrogen of lysine, was mixed with a solution of hydrazine in DMF (10% hydrazine/DMF, 2×10 mL, 10 min) to remove the ivDde group. The epsilon nitrogen of the lysine was labeled with fluorescein-5-isothiocyanate (0.12 mmol) and diisopropylethylamine (0.12 mmol) in DMF. The mixture was agitated for 12 h (fluorescein-containing compounds were protected from light). The resin was then washed with DMF (3×10 mL) and twice with CH2Cl2 (10 mL) and dried under nitrogen for 1 h. The peptide was cleaved from the resin using Reagent B for 4 h and the solution collected by filtration. The volatiles were removed under reduced pressure and the residue was dried under vacuum. The peptide was precipitated with ether, collected and the precipitate was dried under a stream of nitrogen. The precipitate was added to water (1 mg/mL) and the pH of the mixture was adjusted to 8 with 10% aqueous meglumine. Cyclization of the peptide was carried out for 48 h and the solution was freeze-dried. The crude cyclic peptide was dissolved in water and purified by RP-HPLC on a C18 column with linear gradient of acetonitrile into water (both phases contained 0.1% TFA). Fractions containing the pure product were collected and freeze dried. The peptides were characterized by ES-MS and the purity was determined by RP-HPLC (linear gradient of acetonitrile into water/0.1% TFA).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: Nc1ccc2ncccc2c1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3ncccc3c2)cc1
Reaction time: 0.08 h
Yield: 92.7 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (159 mg, 0.728 mmol) in dichloromethane (4 mL) was added pyridine (140 μL, 1.74 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinoline (100 mg, 0.694 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (210 mg, 93%), single spot at Rf 0.71 (ethyl acetate). mp 180.1-180.7° C., HPLC purity 99+% (tR 2.37 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.83 (1H, dd, J=4.2, 1.7 Hz), 8.05 (1H, d, J=8.4 Hz), 7.97 (1H, d, J=9.2 Hz), 7.70 (2H, d, J=8.2 Hz), 7.57 (1H, d, J=2.5 Hz), 7.40-7.34 (2H, m), 7.22 (2H, m), 6.85 (1H, s, N—H, 2.57 (2H, t, J=7.2 Hz), 1.57 (2H, sextet, J=7.2 Hz), 0.87 (3H, t, J=7.3 Hz). LCMS: 325.23 (M−). FAB-MS (MH+, C18H18N2O2S): calcd 327.1167, found 327.1167.
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:7][C:6](=[O:8])[NH:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].I[C:18]1[CH:36]=[CH:35][C:21]([C:22]([NH:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH2:15]([C:3]1([CH2:1][CH3:2])[O:7][C:6](=[O:8])[N:5]([C:18]2[CH:36]=[CH:35][C:21]([C:22]([NH:24][C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)=[O:23])=[CH:20][CH:19]=2)[C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:16]
Reactant: O=C(Nc1cccc2cccnc12)c1ccc(I)cc1
Reactant: CCC1(CC)OC(=O)N[C@H]1c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCC1(CC)OC(=O)N(c2ccc(C(=O)Nc3cccc4cccnc34)cc2)[C@H]1c1ccccc1
Temperature: 90 °C
Yield: 7.9 %

Procedure:
To a 25 mL round bottom flask were added (S)-5,5-diethyl-4-phenyloxazolidin-2-one (0.3 g, 1.36 mmol), 4-iodo-N-(quinolin-8-yl)benzamide (0.560 g, 1.5 mmol), Cs2CO3 (0.972 g, 3.0 mmol), X-Phos (35 mg, 0.068 mmol), Pd2(dba)3 (62 mg, 0.068 mmol) and 1,4-dioxane (2 mL). The mixture was purged with N2 gas for 15 minutes. The reaction mixture was then heated at 90° C. for 6 hours. After completion of reaction (monitored by TLC, TLC eluent: 30% EtOAc in hexane), the reaction mixture was cooled to ambient temperature and treated with water (5 mL) and the mixture extracted with EtOAc (5 mL). The aqueous layer was back extracted with EtOAc (5 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude material was purified with HPLC (column: AG/AD/C18-027, ramping ACN in H2O, 40-50% B, 0-2 minutes, 50-90% B, 2-10 minutes, flow rate 20 mL/min) to afford 50 mg of (S)-4-(5,5-diethyl-2-oxo-4-phenyloxazolidin-3-yl)-N-(quinolin-8-yl)benzamide as a brown solid. 1H NMR (300 MHz, CDCl3) δ: 10.67 (s, 1H), 8.96-8.80 (m, 2H), 8.20 (dd, J=8.3, 1.6 Hz, 1H), 7.99 (d, J=9 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 7.62-7.56 (m, 2H), 7.57-7.47 (m, 1H), 7.40-7.36 (m, 3H), 7.28-7.24 (m, 2H), 5.15 (s, 1H), 2.04-1.96 (m, 2H), 1.39-1.20 (m, 2H), 1.12 (t, J=7.5 Hz, 3H), 0.85 (t, J=7.4 Hz, 3H). m/z (ESI) 466.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=5)=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2].C=O.[C:49](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[CH3:49][N:27]([CH:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C@H:8]3[O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]4[CH2:10][CH2:9]3)=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:40][CH:41]=2)=[CH:30][CH:29]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@H](COc1ccc(N3CCC(Nc4ccc(OCc5ccc(OC(F)(F)F)cc5)cc4)CC3)cc1)CC2
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1)C1CCN(c2ccc(OC[C@@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
N-{1-[4-((S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethoxybenzyloxy)phenyl]amine (0.30 g) was suspended in 1,2-dichloroethane (2 ml). A 37% formaldehyde aqueous solution (0.362 ml) and sodium triacetoxyborohydride (149 mg) were added to the suspension and stirred at room temperature overnight. A 37% formaldehyde aqueous solution (0.362 ml) and sodium triacetoxyborohydride (149 mg) were further added thereto and stirred at room temperature for 1 day. A sodium hydrogen carbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1→methylene chloride:methanol=4:1) and crystallized from ether to afford the title compound as a pale yellow powder (130 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][N:22]=3)[N:17]([CH2:24][CH3:25])[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[CH2:24]([N:17]1[C:18]2=[N:19][CH:20]=[CH:21][N:22]=[C:23]2[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1)[CH3:25]
Reactant: CCn1nc(-c2ccc(OCc3ccccc3)cc2)c2nccnc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCn1nc(-c2ccc(O)cc2)c2nccnc21
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-1H-pyrazolo[3,4-b]pyrazine (570 mg) and 10% Pd—C (50% wet, 200 mg) in MeOH (8 mL) and AcOEt (8 mL) was hydrogenated under balloon pressure at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (240 mg).
Reaction SMILES: O1CCCC1.CS(C)=O.[C:10](Cl)(=[O:14])[C:11](Cl)=O.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([N:33]3[C@@H:38](CO)[CH2:37][O:36][CH2:35][C@H:34]3[C:41]3[CH:46]=[CH:45][C:44]([F:47])=[C:43]([F:48])[CH:42]=3)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>[Cl-].[NH4+].C(N(CC)CC)C>[CH:25]1[C:26]2[CH:27]([CH2:29][O:30][C:31]([N:33]3[C@@H:38]([CH:10]([OH:14])[CH3:11])[CH2:37][O:36][CH2:35][C@H:34]3[C:41]3[CH:46]=[CH:45][C:44]([F:47])=[C:43]([F:48])[CH:42]=3)=[O:32])[C:28]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1[C@@H](CO)COC[C@H]1c1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(O)[C@H]1COC[C@@H](c2ccc(F)c(F)c2)N1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a tetrahydrofuran (35 mL) solution containing dimethylsulfoxide (530 μL) was cooled to −78° C. To the reaction solution was then dropwise added oxalyl chloride (608 μL), and this solution was stirred at the same temperature for 5 minutes. A solution of tetrahydrofuran (25 mL) containing (3R,5S)-3-(3,4-difluorophenyl)-5-hydroxymethylmorpholine-4-carboxylic acid 9H-fluorene-9-ylmethyl ester (2.5 g) was then dropwise added thereto, and the solution was stirred at the same temperature for 30 minutes. To the reaction solution was then added triethylamine (3.7 mL), and the reaction mixture was stirred at the same temperature for 30 minutes followed by stirring at room temperature for 1 hour. The resultant solution was diluted with saturated aqueous ammonium chloride, and this solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure. The resultant residue was diluted with tetrahydrofuran (15 mL), and the resultant solution was cooled to −78° C. To the reaction solution was dropwise added methylmagnesium bromide (8.33 mL, 0.97 M tetrahydrofuran solution), and the resultant solution was stirred at the same temperature for 1 hour. The solution was then diluted with saturated aqueous ammonium chloride and ethyl acetate, and the organic layer was partitioned. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate 95/5→1/1), to thereby obtain the titled compound (950 mg). The physical properties of this crude product were as follows.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cc(F)ccc2F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cc(F)ccc3F)cc2=O)n1
Yield: 63 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2,5-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 46) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2,5-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.76 g, 63%); ES+-HRMS m/e calcd for C25H29N5O4F2 [M+H+] 502.2261 found 502.2259. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.08 (m, 1H), 1.24-1.77 (m, 8H), 1.92 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.68 (s, 1H), 5.47 (dd, J=4.1, J=11.0 Hz, 1H), 6.00 (d, J=2.7 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.24-7.35 (m, 1H), 7.53 (d, J=2.1 Hz, 1H), 7.53-7.62 (m, 2H), 8.21 (d, J=2.7 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][NH:18]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[CH2:1]([N:8]1[CH2:16][CH2:17][NH:18][CH:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/CN(CCNC(c1ccccc1)(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1
Temperature: 50 °C

Procedure:
To a solution of Example 12B (160 g, 326 mmol) in methanol (652 mL) was added 4 M HCl in dioxane (408 mL, 1630 mmol) and the mixture was heated at 50° C. for 3 hours. The solvent was then evaporated and water was added. A solid precipitates. The water layer was decanted and washed once with ethyl acetate. The solid was dissolved in ethyl acetate and extracted with water once. The water layers were combined and treated with 1 N NaOH (1 L) until pH=10. The free amine was extracted twice with dichloromethane, dried over sodium sulfate and concentrated to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.34-7.20 (m, 5H), 3.57 (s, 3H), 3.42 (q, J=13.4 Hz, 2H), 2.96 (qd, J=2.7 Hz, 6.9 Hz, 1H), 2.78 (dt, J=2.9 Hz, 11.9 Hz, 1H), 2.69-2.60 (m, 2H), 2.55 (d, J=10.8 Hz, 1H), 2.30 (dd, J=3.2 Hz, 6.7 Hz, 2H), 1.92 (td, J=2.8 Hz, 10.6 Hz, 1H), 1.68 (t, J=10.0 Hz, 1H); MS (ESI) m/z 249.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH2:43][CH3:44])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH2:43][CH3:44])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K34) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light yellow substance (332 mg, 80%).
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[NH2:24][C:25]1[C:26]([C:32]([NH:34][CH3:35])=[O:33])=[N:27][C:28](Br)=[CH:29][CH:30]=1.[CH2:36]([O:43][CH2:44][C:45]([F:62])([F:61])[CH2:46][N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[NH2:24][C:25]1[C:26]([C:32]([NH:34][CH3:35])=[O:33])=[N:27][C:28]([C:50]2[CH:49]=[N:48][N:47]([CH2:46][C:45]([F:62])([F:61])[CH2:44][O:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:51]=2)=[CH:29][CH:30]=1
Reactant: CNC(=O)c1nc(Br)ccc1N
Reactant: CC1(C)OB(c2cnn(CC(F)(F)COCc3ccccc3)c2)OC1(C)C
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cnn(CC(F)(F)COCc3ccccc3)c2)ccc1N
Yield: 63.6 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-6-bromo-N-methylpyridine-2-carboxamide (Compound 6D, 359 mg, 1.56 mmol) and 1-[3-(benzyloxy)-2,2-difluoropropyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 59E, 650 mg, 1.72 mmol) to afford 398 mg of the title compound (64%). MS (ESI): m/z=402.16 [M+H]+. UPLC: tR=0.93 min (UPLC-TOF: polar—2 min).