Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.Cl[C:17]([F:23])([F:22])C(OC)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(C(C)=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH:17]([F:23])[F:22])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: COC(=O)c1cc(OC(F)F)cc(C(=O)OC)c1
Temperature: 25 °C
Yield: 37.1 %

Procedure:
React 5-hydroxy-isophthalic acid dimethyl ester (5.88 g, 28 mmol), methyl 2-chloro-2,2-difluoroacetate (5.9 mL, 56 mmol), cesium carbonate (18.2 g, 56 mmol) in methyl ethyl ketone at reflux for 2 days. Cool to room temperature, filter though a filtering agent, wash with ethyl acetate, concentrate and purify (silica gel chromatography, eluting with 10:90 to 30:70 ethyl acetate:hexanes) to give the title compound (2.7 g, 37%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[F:42])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Fc1ccccc1Cc1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Cc5ccccc5F)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(2-fluoro-benzyl)-pyridine.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C([O-])([O-])=O.[Cs+].[Cs+].[Cs].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO.O.CN(C=O)C>[NH2:1][C@H:2]([C:10]([O:12][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Cs]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: N=C(N)NCCC[C@H](N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Water (2 ml) was added to a solution of Boc-Arg-OH (2.5 mmol) in methanol (20 ml). The solution was neutralised with a 20% solution of Cs2CO3 in water and then evaporated in vacuo to dryness. Residual water was removed by repeated addition and evaporation of toluene. The solid cesium salt of Boc-arginine was treated with DMF (25 ml) and benzyl bromide (3 mmol) and stirred at room temperature for 6 h. The DMF was removed in vacuo and the product was dissolved in acetone and filtered. The filtrate was evaporated in vacuo and the product was treated with 95% trifluoroactetic acid (TFA) (4 ml). The resulting product H-Arg-OBzl was isolated by tituration by diethyl ether. The salt of H-Arg-OBzl was isolated by treating the product with para-toluenesulfonic acid (5 mmol) in ether.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:32]=[C:14]3[C:15]4[C:20]([CH2:21][CH2:22][N:13]3[C:12](=[O:33])[CH2:11][N:10]=2)=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:17][CH:16]=4)[CH:8]=1.[OH:34]O>COCCOC>[OH:34][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH2:21][CH2:22][N:13]1[C:12](=[O:33])[CH2:11][N:10]=[C:9]([N:7]3[CH:8]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=[CH:6]3)[CH:32]=[C:14]12
Reactant: COCc1cn(C2=NCC(=O)N3CCc4c(B5OC(C)(C)C(C)(C)O5)cccc4C3=C2)cn1
Reactant: OO
Solvent: COCCOC
Product: COCc1cn(C2=NCC(=O)N3CCc4c(O)cccc4C3=C2)cn1
Reaction time: 8 h

Procedure:
Example 142-2. 2-(4-(methoxymethyl)-1H-imidazol-1-yl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (413 mg, 0.737 mmol) was dissolved in DME (10 mL) and hydrogen peroxide (30%, 3.40 mL, 33.3 mmol) was added at rt. The mixture was stirred overnight and the resulting crystals were filtered off (62 mg). UPLC-MS: MS 339.2 (M+H+); UPLC rt 0.63 min.
Reaction SMILES: CN1CCCCC1.[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[Cl:30][C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][CH:37]([NH2:39])[CH3:38])=[CH:33][CH:32]=1>C(Cl)Cl.O>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][CH3:21])[C:17]([NH:39][CH:37]([CH3:38])[CH2:36][O:35][C:34]1[CH:40]=[CH:41][C:31]([Cl:30])=[CH:32][CH:33]=1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(N)COc1ccc(Cl)cc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)NC(C)COc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
2.0 g of N-methylpiperidine was added to a solution containing 4.1 g of (2S)-2-tert-butoxycarbonylaminobutyric acid dissolved in 60 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 2.7 g of isobutyl chloroformate was added to the mixture at -40° C., and stirred for 1 hour at -20° C. 3.7 g of 2-(4-chlorophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 5.6 g of the desired product in the form of a colorless glutinous substance (yield: 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][N:5]=1.S(=O)(=O)(O)O.[N+:17]([O-])([O-:19])=[O:18].[K+]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([N+:17]([O-:19])=[O:18])=[CH:6][N:5]=1
Reactant: COC(=O)c1cc(N)ccn1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc(N)c([N+](=O)[O-])cn1

Procedure:
Prepared analogously to example 83b from methyl-4-aminopicolinate, conc. sulphuric acid and potassium nitrate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[C:5]([C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(Cl)Cl>C1(C)C=CC=CC=1.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].O.O1CCOCC1>[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]4)[C:5]([C:28]([F:31])([F:29])[F:30])=[CH:4][CH:3]=2)=[CH:42][CH:41]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ccc3C(F)(F)F)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(-c4ccc(OC)cc4)ccc3C(F)(F)F)ccc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
To a solution of ethyl [(1S)-5-(3-{[6-chloro-3-(trifluoromethyl)-2-pyridinyl]amino}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 306) (0.08 g, 0.18 mmol) in a mixture of toluene (3.75 mL), 1,4-dioxane (0.75 mL), and water (0.88 mL) were added sodium carbonate (0.15 g, 1.38 mmol), 4-methoxyphenyl boronic acid (0.11 g, 0.70 mmol), and PdCl2(dppf).CH2Cl2 (0.03 g, 0.04 mmol). The mixture was stirred at 80° C. for 4 h, and then concentrated under reduced pressure. The product (0.065 g, 70%) was isolated after by silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 1H NMR (400 MHz, CD2Cl2) δ 8.03 (d, 2H), 7.68 (d, 1H), 7.05 (dd, 2H), 6.97 (d, 2H), 6.77 (s, 1H), 6.71 (dd, 1H), 5.39 (b, 1H), 4.15 (q, 2H), 4.09 (t, 2H), 3.90-3.80 (m, 5H), 3.51 (qt, 1H), 2.95-2.78 (m, 2H), 2.71 (dd, 1H), 2.45-2.33 (m, 2H), 2.22-2.10 (m, 2H), 1.80-1.70 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CO>[O:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CNCCN1
Reactant: Clc1ccncc1Oc1ccccc1
Solvent: CO
Product: c1ccc(Oc2cnccc2N2CCNCC2)cc1

Procedure:
To a solution of 13 g of 4-chloro-3-phenoxypyridine in 25 ml of methanol is added 30 g of piperazine and the solution is stirred and heated for 72 hours. The resulting mixture is concentrated at reduced pressure. The residue is shaken with 500 ml of ether and excess dilute aqueous sodium hydroxide. The organic phase is separated, dried and filtered. The filtrate is concentrated and the product distilled to give 3-phenoxy-4-piperazinylpyridine; bp 134°-135° C./0.2 mm, solidified and has a mp of 74°-77° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:34])[N:8](CC2C=CC(OC)=CC=2)[C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH:35](/B(O)O)=[CH:36]\[CH2:37][CH2:38][CH3:39].C([O-])(O)=O.[Na+].COCCOC.O>O.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]([O:3][C:4]([C:6]1[C:7](=[O:34])[NH:8][C:9]2[C:14]([C:15]=1[CH:35]=[CH:36][CH2:37][CH2:38][CH3:39])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Reactant: CCC/C=C/B(O)O
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: O
Solvent: COCCOC
Product: CCCC=Cc1c(C(=O)OCC)c(=O)[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A solution of 11 (0.10 g, 0.19 mmol), E-penten-1-ylboronic acid (44.0 mg, 0.38 mmol), tetrakis(triphenylphosphine)palladium (22.0 mg, 0.023 mmol), and NaHCO3 (41.0 mg, 0.38 mmol) in 1:1 DME/H2O (3 mL) was heated at 100° C. for 1 h. The reaction was allowed to cool to room temperature, diluted with H2O, extracted with EtOAc, dried (Na2SO4), filtered, and concentrated. Chromatography (SiO2, 3:1 Hex/EtOAc) gave 12 (43.0 mg, 51%) as a colorless film.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH:4]([C:10](=[S:12])[NH2:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>C(O)C>[CH3:13][CH:2]([CH3:1])[CH2:3][CH:4]([C:10]1[S:12][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(CC(C)C)C(N)=S
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)c1nc(-c2ccccc2)cs1

Procedure:
A solution comprised of ethyl 4-methyl-2-thiocarbamoylpentanoate (410 mg, 2 mmol) in ethanol (5 mL) was treated with 2-bromo-1-phenylethanone (400 mg, 2 mmol). The mixture was refluxed for 30 minutes and concentrated to provide ethyl 4-methyl-2-(4-phenylthiazol-2-yl)pentanoate as a crude product. The crude product was dissolved in methanol (5 mL, tech. grade) and the solution was treated with sodium hydroxide (100 mg, 2.5 mmol). The mixture was stirred for 2 hours and diluted with 0.1 M hydrochloric acid solution. The dilution was extracted with ethyl acetate (25 mL) and the extract was washed with water and brine, dried (MgSO4) and concentrated. Product was purified from the residue by flash column on silica gel (60° A) with 33% ethyl acetate in hexane to provide 4-methyl-2-(4-phenylthiazol-2-yl)pentanoic acid (500 mg, 1.8 mmol). Rf 0.33. 1H NMR (DMSO-d6): 0.96 (d, 6H), 1.71-1.79 (m, 3H), 3.61 (m, 1H), 7.12 (s, 1H), 7.32-7.41 (m, 5H). LCMS: 275.91 (M+H+).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[C:7]([S:17](Cl)(=[O:19])=[O:18])=[CH:6]1)(=[O:3])[NH2:2].[OH-].[NH4+:22]>C(Cl)Cl>[N+:14]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH:6]=[C:7]2[S:17](=[O:19])(=[O:18])[NH2:22])([O-:16])=[O:15]
Reactant: NC(=O)Cn1cc(S(=O)(=O)Cl)c2cc([N+](=O)[O-])ccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)Cn1cc(S(N)(=O)=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
The 1-carbamoylmethyl-5-nitro-1H-indole-3-sulfonyl chloride (0.37 g, 1.165 mmole) of Step 2 was suspended in methylene chloride (2 ml) and added to ammonium hydroxide (4 ml) at room temperature. After stirring for 2 h at room temperature, the reaction flask was heated on a steam bath for 35 min and then allowed to cool to room temperature. The yellow solid which precipitated was filtered off and dried to afford 0.24 g (0.81 mmole, 69% yield) of 2-(5-nitro-3-sulfamoyl-indol-1-yl)-acetamide. Step 4
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[NH2:27])[N:15]=[CH:14]2.[C:28](O)(=[O:31])[C:29]#[CH:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:27][C:28](=[O:31])[C:29]#[CH:30])[N:15]=[CH:14]2
Reactant: COc1ccc(F)c(-c2ccc3nc(N[C@@H]4CCC[C@@H]4N)ncc3c2)c1F
Reactant: C#CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(-c3c(F)ccc(OC)c3F)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A mixture of (1R,2S)—N1-(6-(2,6-difluoro-3-methoxyphenyl)quinazolin-2-yl)cyclopentane-1,2-diamine (0.045 mmol), propiolic acid (0.004 mL, 0.067 mmol), HATU (25 mg, 0.067 mmol) and DIEA (0.023 mL, 0.135 mmol) in dichloromethane (1 mL) was stirred at room temperature for 60 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R)-2-((6-(2,6-difluoro-3-methoxyphenyl)quinazolin-2-yl)amino)cyclopentyl)propiolamide (Compound 2) (13 mg, 68%). MS (ES+) C27H27N5O3 requires: 422, found: 423 [M+H]+.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[OH:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([N:16]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[N:11]3)=[CH:6][NH:7]2)=[N:23][CH:22]=1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: NNc1ccc(CO)cn1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: O=c1c(-n2ccnn2)c[nH]n1-c1ccc(CO)cn1
Temperature: 25 °C

Procedure:
15.1 g (71.9 mmol) of the compound from Example 3A and 10.0 g (71.9 mmol) of the compound from Example 4A are dissolved in 375 ml ethanol and 1.7 g (7.2 mmol) camphor-10-sulfonic acid are added. The mixture is heated under reflux for 16 h. After cooling to RT, the reaction mixture is concentrated and the residue is purified by column chromatography over silica gel (mobile phase: methylene chloride/methanol 9:1, then 1:1). The product fraction is concentrated in vacuo and the residue is stirred in diisopropyl ether, filtered off and dried in vacuo.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][CH3:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][CH3:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: CCc1c(C)c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 6.81 %

Procedure:
Prepared in 6.81% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethyl-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.17-8.10 (m, 1H), 7.99 (s, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.23-7.13 (m, 3H), 6.00 (br. s., 1H), 4.61 (br. s., 1H), 3.83 (t, J=11.7 Hz, 1H), 3.63 (t, J=10.8 Hz, 1H), 3.44 (d, J=7.3 Hz, 2H), 3.12 (d, J=8.4 Hz, 1H), 3.07-2.97 (m, 2H), 2.64 (d, J=8.1 Hz, 1H), 2.33 (s, 3H), 1.90-1.59 (m, 9H), 1.52 (br. s., 1H), 1.19 (br. s., 5H), 1.16 (s, 9H), 1.07 (d, J=6.2 Hz, 3H); LCMS (ESI, M+1): 672.4.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromo-thiophene-2-carboxylic acid (2.00 g, 10.47 mmol) was dissolved in DCM (10 mL) to which was added oxalyl chloride (1.99 g, 15.71 mmol) and a catalytic amount of DMF (100 μL). This reaction mixture was stirred at room temperature for 1 hr at which time the solvent was removed under vacuum and taken forward immediately.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(O)(O)(=O)=O.[CH3:33][O:34][C:35](=[NH:37])[NH2:36].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:37][C:35]([O:34][CH3:33])=[N:36][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:26])([F:27])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:23]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: COC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC#N
Product: COC(N)=NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C

Procedure:
To a solution of 1.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylbenzoyl-chloride synthesized in Process 4 of Synthetic Example 1 in 20 mL of acetonitrile, 0.85 g of O-methylisourea sulfate and 1.26 g of potassium carbonate were added and the resultant mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, the insoluble substance was filtered off and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:1) to obtain 0.40 g of the objective substance as a yellow resin-state substance.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[C:7]([C:12]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[CH:18]1([C:21]([NH2:23])=[O:22])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[OH:17][C:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][N:11]=[C:2]([NH:23][C:21]([CH:18]4[CH2:20][CH2:19]4)=[O:22])[CH:3]=3)[N:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OC1(c2ccc3cc(Cl)ncc3n2)CCCC1
Reactant: NC(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2ccc(C3(O)CCCC3)nc2cn1)C1CC1
Temperature: 90 °C
Yield: 45.3 %

Procedure:
A mixture of 1-(6-chloro-1,7-naphthyridin-2-yl)cyclopentanol (65 mg, 0.26 mmol), cyclopropanecarboxamide (67 mg, 0.8 mmol), Chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-1-pr-1,1′-biphenyl)][2-(2-aminoethyl )Ph]Pd(II) (31 mg, 0.04 mmol), (dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-i-pr-1,1′-biphenyl (21 mg, 0.04 mmol), and cesium carbonate (170 mg, 0.52 mmol) in 1,4-dioxane (1.5 mL) was heated at 90° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (35 mg, 45%). 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.12 (s, 1H), 8.47 (s, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 5.32 (s, 1H), 2.29-2.17 (m, 2H), 2.11-2.03 (m, 1H), 1.95-1.75 (m, 6H), 0.91-0.78 (m, 4H). LCMS (Method E): RT=3.811 min, M+H+=298.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][CH3:20])=[C:5]([CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][CH3:20])=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[C:14](=[O:16])[CH2:13][CH:12]([CH3:17])[CH2:11]2
Reactant: CCCc1c(CC(C)CC(=O)O)ccc(OC)c1OC
Solvent: ClCCl
Product: CCCc1c2c(cc(OC)c1OC)C(=O)CC(C)C2
Yield: 86 %

Procedure:
Compound 15b (7.0 g, 25 mmol) was added to 35 g of polyphosphoric ester in 100 mL of methylene chloride and refluxed for 1 h. The reaction mixture was poured onto ice, stirred, and extracted with ether. The ether was evaporated, and the residual oil was chromatographed on silica gel using ethyl acetate/hexane to give 5.63 g (21.5 mmol, 86% yield) of 16b as white crystals: 1H NMR:(ppm) 7.49 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.00-2.23 (mult, 7H), 1.50 (mult, 2H), 1.15 (d, 3H), 1.01 (t, 3H). Anal. (C16H22O3) C,H.