Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:15]([O:19][C:20](=[O:23])[CH2:21][NH2:22])([CH3:18])([CH3:17])[CH3:16].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:23])=[O:6]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 178.7 %

Procedure:
Preparation I7, Step 1: A solution of 2-fluoro-5-trifluoromethylbenzoic acid (5.80 g) in N,N-dimethylformamide (190 mL) was treated sequentially with glycine t-butyl ester (5.50 g), BOP reagent (18.50 g), and N-methylmorpholine (9.20 mL). The mixture was stirred at rt for 12 h, then was diluted with ethyl acetate. The organic layer was washed with 1 M HCl, saturated aqueous NaHCO3, 5% aqueous LiCl, and brine, then was dried over Na2SO4 and concentrated under vacuum to provide tert-butyl 2-(2-fluoro-5-(trifluoromethyl)benzamido)acetate (16 g) as a white solid. MS found: (M+H)+=322.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].[CH2:42]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1B(O)O)[CH2:43][CH:44]=[CH2:45].C([O-])([O-])=O.[Na+].[Na+]>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>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:47]6[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=6[CH2:42][CH2:43][CH:44]=[CH2:45])[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:31])[C:16]=3[C@H:32]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]([O:35][CH3:36])=[O:34])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCCc1ccccc1B(O)O
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(Br)c5)nn34)c(Cl)c21
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: C=CCCc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c4ccc5c(c4Cl)N(CC=C)CCO5)n3n2)c1
Temperature: 90 °C
Yield: 100 %

Procedure:
A solution of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.092 g, 0.143 mmol), (2-(but-3-en-1-yl)phenyl)boronic acid (0.050 g, 0.286 mmol) and 2.0 M aq. Na2CO3 (0.179 mL, 0.358 mmol) in DMF (4 mL) was sparged with nitrogen for 10 min, treated with Pd(Ph3P)4 (0.012 g, 10.01 μmol), sparged for 5 min, then heated (90° C.) for 5 h. The reaction was cooled, then diltued with EtOAc (20 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated and the residue was purified by biotage (Isco 4 g SiO2, 0% (5 CV), 0-60% (20 CV), 60% (5 CV), EtOAc in hexanes) to afford the desired product (0.099 g, 0.143 mmol, 100% yield). LCMS (M+H)=691.4.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[N+:21]([O-:23])=[O:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C.CO.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>ClCCCl.O.C(N(CC)CC)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: COc1ccc(C2CCN(Cc3ccccc3)C2)c([N+](=O)[O-])c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: COc1ccc(C2CCNC2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
By referring to the synthetic method of J. Org. Chem., 1984, 49, 2081, to a solution of 1-benzyl-3-(4-methoxy-2-nitrophenyl)pyrrolidine (647 mg) in 1,2-dichloroethane (15 ml) was added chloroformic acid 1-chloroethyl ester (0.33 ml) on an ice bath, the solution was stirred for 2 hours at 80° C., and then stirred for 2.5 hours at 100° C. Methanol (5 ml) was added thereto, the solution was stirred for 3 hours at 80° C., then triethylamine (1 ml) and di-tert-butyl dicarbonate (0.7 ml) were sequentially added thereto on an ice bath, and the solution was stirred for 40 minutes at room temperature. Water was added thereto followed by stirring. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by silica gel column chromatography (hexane-ethyl acetate system), 3-(4-methoxy-2-nitrophenyl)pyrrolidine-1-carboxylic acid tert-butyl ester (436 mg) was dissolved in trifluoroacetic acid (2 ml), the solution was stirred for 1 hour at room temperature, and neutralized with ammonia solution. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo to provide the title compound (207 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(C1C=CC(N=NC2C=CC(OCC(O)=O)=CC=2)=CC=1)#N>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)COc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: N#Cc1ccc(N=Nc2ccc(OCC(=O)O)cc2)cc1
Product: O=C(O)COc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
2-[4-(4-Nitrophenylazo)phenoxy]-ethanoic acid was prepared by hydrolysis of ethyl 2-[4-(4-nitrophenylazo)phenoxy]-ethanoate analogous with the preparation of 2-[4-(4-cyanophenyl-azo)phenoxy]-ethanoic acid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Br:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18]>>[Br:7][C:8]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:9]=1[O:18][CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CBr
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Product: COC(=O)COc1ccc(C(F)(F)F)cc1Br

Procedure:
The sub-title compound was prepared by the method of Example 2 step a) using methyl bromoacetate and 2-bromo-4-(trifluoromethyl)phenol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[NH:26][C:27]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:28]
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2cccc(Cl)c2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 3-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:37])[CH2:12][S:13][C@H:14]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C@@H:15]2[C:26]2[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:67][CH2:68][C:69]([NH:71][C@@H:72]([C:80]([OH:82])=[O:81])[CH2:73][CH:74]1[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]1)=[O:70].[BH4-].[Na+]>CN(C=O)C.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:37])[CH2:12][S:13][C@H:14]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C@@H:15]2[C:26]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][C:32]([NH:67][CH2:68][C:69]([NH:71][C@@H:72]([C:80]([OH:82])=[O:81])[CH2:73][CH:74]3[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]3)=[O:70])=[O:33])=[CH:35][CH:36]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)O)cc2)cc1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@H](CC3CCCCC3)C(=O)O)cc2)cc1
Reaction time: 18 h
Yield: 35.9 %

Procedure:
To a solution of {4-[(2R,3R)-3-{[2-(4-tert-butylphenyl)-2-oxoethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (0.020 g, 0.038 mmol) and NMM (0.013 ml, 0.118 mmol) in DMF (3 ml) at RT was added TBTU (0.019 g, 0.059 mmol). After 90 min glycyl-3-cyclohexyl-D-alanine (0.009 g, 0.039 mmol) was added and the mixture was stirred for 18 h before the reaction was quenched by the addition of water (1 ml). The mixture was diluted with MeOH (1 ml) and NaBH4 (0.025 g, 0.661 mmol) was added. After 10 min the reaction was quenched by the addition of a 0.1M ammonium acetate buffer (2 ml) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product as a white solid (0.010 g, 36% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](O)=[O:14])[CH:9]=2)[N:4]=1.CN(C)C=O.C(Cl)(=O)C([Cl:26])=O>ClCCl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([Cl:26])=[O:14])[CH:9]=2)[N:4]=1
Reactant: O=C(O)c1ccc2nc(C(F)(F)F)ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2nc(C(F)(F)F)ccc2c1
Reaction time: 2 h

Procedure:
2-(Trifluoromethyl)quinoline-6-carboxylic acid (0.20 g) was dissolved in dichloromethane. To this solution, a small amount of N,N-dimethylformamide (300 μL) and oxalyl chloride (0.17 g) were added at room temperature and stirred for two hours. After refluxing for 20 minutes, the solvent was distilled off under the reduced pressure and 2-(trifluoromethyl)quinoline-6-carbonyl chloride was obtained as a crude product. To this crude product, 4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylaniline (0.49 g) dissolved in pyridine was added and refluxed for 5 hours. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and washed with 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The residue was purified by column chromatography to obtain N-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-2,6-dimethylphenyl]-2-(trifluoromethyl)quinoline-6-carboxamide (0.10 g, yield 24%).
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.I[C:38]1[CH:43]=[CH:42][N:41]([CH:44]([CH3:46])[CH3:45])[C:40](=[O:47])[CH:39]=1>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:38]3[CH:43]=[CH:42][N:41]([CH:44]([CH3:46])[CH3:45])[C:40](=[O:47])[CH:39]=3)=[CH:18][CH:19]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)n1ccc(I)cc1=O
Product: CC(C)n1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-iodo-1-isopropylpyridin-2(1H)-one following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 2 tR=1.846 min, m/z=489.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.24 (s, 3H), 1.39 (d, 6H), 1.52 (d, 3H), 2.17-2.31 (m, 4H), 2.35-2.46 (m, 1H), 2.88 (m, 1H), 5.27 (m, 1H), 5.69 (m, 1H), 6.49 (d, 1H), 6.88 (s, 1H), 7.00 (d, 2H), 7.29-7.38 (m, 7H), 7.40 (d, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[C:39](O)[CH:38]=[C:37]([O:42][CH2:43][CH3:44])[CH:36]=1.[O:46]1[CH2:51][CH2:50][CH:49]([OH:52])[CH2:48][CH2:47]1>C1COCC1>[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[C:39]([O:52][CH:49]2[CH2:50][CH2:51][O:46][CH2:47][CH2:48]2)[CH:38]=[C:37]([O:42][CH2:43][CH3:44])[CH:36]=1
Reactant: OC1CCOCC1
Reactant: CCOc1cc(O)cc(C(=O)OC)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1cc(OC2CCOCC2)cc(C(=O)OC)c1
Reaction time: 6 h
Yield: 56 %

Procedure:
To a mixture of triphenylphosphine (1.18 g, 4.49 mmol, 1.1 equiv) and DEAD (0.76 mL, 0.85 g, 4.89 mmol, 1.2 equiv) in anhydrous THF (10 mL) was added 3-ethoxy-5-hydroxy-benzoic acid methyl ester (0.8 g, 4.08 mmol, 1.0 equiv; prepared as described in WO 99/05123 A1, Astra Pharmaceuticals Ltd.) and tetrahydro-pyran-4-ol (0.42 g, 4.08 mmol, 1.0 equiv), dissolved in THF (10 mL), at 0° C. under Ar. After stirring for 6 h, the solvent was partially removed by evaporation under reduced pressure, water (50 mL) added and the reaction mixture extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material yielding 0.64 g (56%) of the title compound which was directly used in the next step. 1H NMR (300 MHz, CDCl3): δ 1.32 (t, J=7.0 Hz, 3H), 1.67-1.72 (m, 2H), 1.91-1.97 (m, 2H), 3.48-3.53 (m, 2H), 3.81 (s, 3H), 3.85-3.91 (m, 2H), 3.96 (q, J=7.0 Hz, 2H), 4.40-4.44 (m, 1H), 6.56-6.58 (m, 1H), 7.08-7.10 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 14.59, 31.68, 51.99, 63.69, 64.89, 71.86, 107.82, 108.06, 109.09, 131.98, 158.17, 160.05, 166.61. MS (ISP): 281.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][CH:25]([C:40]2[N:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][N:49]([C:52](=[O:54])[CH3:53])[CH2:48][CH2:47]3)=[CH:42][N:41]=2)[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[CH2:8][C@H:7]1[CH2:55][CH3:56])=[O:5])[CH3:2].C(N(CC)CC)C.C(O)=O.O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C@@H:9]([NH:24][CH:25]([C:40]2[N:45]=[CH:44][C:43]([N:46]3[CH2:47][CH2:48][N:49]([C:52](=[O:54])[CH3:53])[CH2:50][CH2:51]3)=[CH:42][N:41]=2)[C:26]2[CH:27]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=2)[CH2:8][C@H:7]1[CH2:55][CH3:56])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C(C)=O)CC3)cn2)C[C@H]1CC
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1c2cccnc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C(C)=O)CC3)cn2)C[C@H]1CC
Temperature: 60 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
(2R,4S)-4-{[5-(4-Acetylpiperazin-1-yl)pyrimidin-2-yl]-[3,5-bis-(trifluoromethyl)benzyl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (250 mg), palladium acetate (34 mg), 1,1′-bis(diphenylphosphino)ferrocene (84 mg) and triethylamine (126 μl) are dissolved in N,N-dimethylformamide (2 ml), and thereto is added formic acid (28 μl). The mixture is stirred at 60° C. for 1 hour under nitrogen flow. To the reaction solution are added water and ethyl acetate, and then the organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane:ethyl acetate=1:2→0:1) to give (2R,4S)-4-{[5-(4-acetylpiperazin-1-yl)pyrimidin-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (195 mg). MS (m/z): 680 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([N:13]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[O:12])=[C:4]2[CH:3]=1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].[F:71][C:72]1[CH:73]=[C:74]([C@@H:78]2[NH:82][CH2:81][C@H:80]([OH:83])[CH2:79]2)[CH:75]=[CH:76][CH:77]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(O)(C)C>[F:71][C:72]1[CH:73]=[C:74]([C@H:78]2[CH2:79][C@@H:80]([OH:83])[CH2:81][N:82]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([N:13]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[O:12])=[C:4]3[CH:3]=2)[CH:75]=[CH:76][CH:77]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(Br)cc23)cc1
Reactant: O[C@H]1CN[C@@H](c2cccc(F)c2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)(C)O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@H](O)C[C@@H]4c4cccc(F)c4)cc23)cc1
Temperature: 120 °C

Procedure:
A N2 purged flask was charged with 5-bromo-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-26) (0.19 g, 0.39 mmol), palladium acetate (3 mg, 12 μmol), RuPhos (11 mg, 24 μmol), cesium carbonate (0.25 g, 0.78 mmol), tBuOH (1 mL) and (3R,5R)-5-(3-fluorophenyl)pyrrolidin-3-ol (I-32) (71 mg, 0.39 mmol). The contents were heated to 120° C. overnight in an oil bath. Upon cooling to room temperature the reaction was filtered through celite and concentrated. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-33). 1H NMR (400 MHz, CDCl3) δ 7.96-7.84 (m, 1 H), 7.65-7.49 (m, 1 H), 7.09-7.04 (m, 3 H), 7.01-6.95 (m, 3 H), 6.92-6.81 (m, 3 H), 6.72-6.64 (m, 4 H), 6.05-5.92 (m, 1 H), 4.79-4.69 (m, 1 H), 4.56-4.41 (m, 3 H), 4.38-4.26 (m, 2 H), 3.96-3.86 (m, 1 H), 3.66-3.59 (m, 6 H), 2.63-2.49 (m, 1 H), 2.06-1.94 (m, 1 H), 1.87-1.79 (m, 1 H). MS m/z 581.2 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[C:15]([F:22])=[CH:16][C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1.[Cl-].[NH4+].O.C(O)C>C1COCC1.[Fe]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:2]=2[F:1])=[C:6]([C:14]2[C:15]([F:22])=[CH:16][C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)[CH:7]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccc(F)cc2F)c(F)cc1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)c(F)cc1=O
Temperature: 50 °C
Yield: 90.2 %

Procedure:
A mixture of 5-[2-(2,4-difluorophenoxy)-5-nitrophenyl]-4-fluoro-1-methylpyridin-2-one (90 mg, 0.24 mmol), ammonium chloride (26 mg, 0.48 mmol), iron powder (67 mg, 1.2 mmol) suspended in THF (500 μL), water (180 mL) and ethanol (500 mL) was heated to 100° C. using microwave irradiation (normal) for 3 h. The crude reaction mixture was filtered through a short plug of celite and the celite plug was washed with heated (50° C.) MeOH (˜10 mL). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (20 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, 5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-4-fluoro-1-methylpyridin-2-one (75 mg, 90%). LCMS (M+H)+=347. The material was carried forward without any further purification.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1OB(O)O)#[N:15].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:17]2[C:16]([C:14]#[N:15])=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: N#Cc1ccccc1OB(O)O
Reactant: O=Cc1ccc(Br)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc(C=O)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
A mixture of 4-bromo-2-(trifluoromethyl)benzaldehyde (9 g), 2-cyano-phenylboric acid (9.5 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (2.9 g), tetrabutylammonium bromide (1.15 g), 2M aqueous sodium carbonate solution (30 mL) and toluene (100 mL) was stirred at 100° C. overnight under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3.2 g, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=2)=O)=[CH:4][C:3]=1[O:32][CH3:33].C([O-])(=O)C.[NH4+:38]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:38][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=3)=[CH:10][C:9]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:4][C:3]=1[O:32][CH3:33]
Reactant: COc1cc(C(=O)C(CC(=O)c2ccc(OCCN(C)C)cc2)c2ccncc2)ccc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(-c2[nH]c(-c3ccc(OCCN(C)C)cc3)cc2-c2ccncc2)ccc1Cl
Temperature: 25 °C

Procedure:
A solution of the product of Example 1 Step 2 (420 mg, 0.9 mmol) and ammonium acetate (750 mg, 9.7 mmol) in glacial acetic acid (15 ml) was heated under reflux for 16 hours. After cooling to room temperature, the reaction mixture was concentrated and aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with chloroform and the organic phase washed with water and brine, dried and concentrated in vacuo to give the title compound; MS(ES+) m/e 448,450 [+H]+.