Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[ClH:12].[H][H]>C(O)C.[Pd]>[ClH:12].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: [H][H]
Reactant: COc1cc(F)ccc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc(F)ccc1CN
Reaction time: 40 h
Yield: 88.1 %

Procedure:
To a mixture of intermediate 127, 4-fluoro-2-methoxybenzonitrile, (800 mg, 5.3 mmol) and conc.HCl (0.53 mL, 6.36 mmol, 1.2 eq.) in ethanol (20 mL) was added 10% Pd—C (100 mg; Aldrich), and the mixture hydrogenated at 1 atm hydrogen for 15 hrs at room temperature. To this mixture was added an additional amount of conc.HCl (1 mL) and 10% Pd—C (200 mg) and the reaction allowed to continue for another 40 hrs. The mixture was filtered through Celite and the filtrate concentrated in vacuo to dryness. The residue was triturated with ether to provide the title compound (895 mg, Yield 88%) as a white powder: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.84 (3H, s, OMe), 3.91 (2H, d, J=5.5 Hz, N—CH2), 6.81 (1H, dt, J=2.5 Hz, J=J=8.5 Hz, Ar—H), 6.99 (1H, dd, J=2.5 Hz, J=11.3 Hz, Ar—H), 7.47 (1H, dd, J=7 Hz, J=8.5 Hz, Ar—H); 13C NMR (CDCl3, 125.8 Hz) δ ppm: 36.76, 56.03, 99.30, 99.51 106.28, 106.45, 117.93, 117.95, 131.60, 131.69, 158.56, 158.64, 162.28, 164.22. HRMS (ESI) calcd for C8H11FNO (M+H) 156.0825, found 156.0830.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[O:9][CH2:10][C:11]([F:24])([F:23])[C@:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH2:22])[N:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[C:28]([C:37](O)=[O:38])=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O.CC(OC)(C)C>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[O:9][CH2:10][C:11]([F:23])([F:24])[C@:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH:22][C:37]([C:28]3[C:27]([Cl:26])=[CH:32][C:31]([C:33]([F:35])([F:34])[F:36])=[CH:30][N:29]=3)=[O:38])[N:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(N)ccc2F)C(F)(F)CO1
Agent: On1nnc2cccnc21
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)C(F)(F)CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of [(R)-4-(6-amino-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester (134 mg, 0.372 mmol) in DMF (1.3 ml) was added 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid (101 mg, 0.446 mmol) and HOAt (91 mg, 0.669 mmol). The mixture was cooled to 0° C., EDC*HCl (107 mg, 0.558) was added and the mixture stirred for 1 h while allowing to warm to rt. To the reaction mixture was added TBME and water, the layers were separated and the aq. layer extracted with TBME. The combined organic layers were washed with sat. aq. NaHCO3, sat. aq. NaCl, dried with MgSO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc 6:1 to 5:1) to provide the title compound as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[NH:8][CH:7]=1)=[O:5])[CH3:2].C(O[CH:18](OC(C)C)[N:19]([CH3:21])[CH3:20])(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=[O:13])/[CH:12]=[CH:18]/[N:19]([CH3:21])[CH3:20])[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)OC(OC(C)C)N(C)C
Reactant: CCOC(=O)c1c[nH]c(C(C)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c(C(=O)/C=C/N(C)C)c1
Temperature: 65 °C
Reaction time: 6 h
Yield: 72.5 %

Procedure:
To a solution of 5-Acetyl-1H-pyrrole-3-carboxylic acid ethyl ester (0.560 g, 3.1 mmol) in 5 mL of dimethylformamide, N,N-dimethylformamide diisopropyl acetal (1.9 mL, 9.3 mmol) was added. The mixture was stirred for at 65° C. for 6 hrs. After cooling to room temperature an aqueous solution of NaHCO3 2% (30 mL) was added and extracted with ethyl acetate (50 mL×2). Organic layer was separated and washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentered in vacuo to give 0.531 g (72%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]#[CH:10].[CH2:11]([O:13][C:14]([C:16]1[N:17]([CH3:23])[C:18](Br)=[N:19][C:20]=1[CH3:21])=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[N:17]([CH3:23])[C:18]([C:10]#[C:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:19][C:20]=1[CH3:21])=[O:15])[CH3:12]
Reactant: C#Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Product: CCOC(=O)c1c(C)nc(C#Cc2c(Cl)cccc2Cl)n1C

Procedure:
The title compound, MS: m/e=197.4 (M+H+) was prepared in accordance with the general method of example 1b from 1,3-dichloro-2-ethynyl-benzene and 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C[Al](C)C.C([O:15][C:16]([C:18]1[N:19]=[C:20]([CH3:31])[S:21][C:22]=1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[C:27]([O:26][C:24](=[O:25])[NH:23][C:22]1[S:21][C:20]([CH3:31])=[N:19][C:18]=1[C:16](=[O:15])[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)c1nc(C)sc1NC(=O)OC(C)(C)C
Reactant: Cc1cc(N)ccn1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NC(=O)c2nc(C)sc2NC(=O)OC(C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 2-methyl-pyridin-4-ylamine (0.623 g, 5.77 mmol) in 20 ml dry dioxane was treated at 0° C. with trimethylaluminium (2M in hexane, 2.88 ml, 5.77 mmol). The mixture was stirred at room temperature for 1 h. 5-tert-Butoxycarbonylamino-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.55 g, 1.92 mmol) was added and the reaction mixture was refluxed for 4 h. 1 ml water and 2 g sodium sulfate were sequentially added and filtered. The filtrate was evaporated and the residue purified by flash chromatography on silica gel with heptane/ethyl acetate 100:0→0:100 to yield [2-methyl-4-(2-methyl-pyridin-4-ylcarbamoyl)-thiazol-5-yl]-carbamic acid tert-butyl ester (0.555 g, 83%) as a light yellow solid, MS (ISP): m/e=349.5 (M+H+).
Reaction SMILES: [C:1]1(Cl)[C:7](=[O:8])[C:6]([Cl:9])=[C:5]([Cl:10])[C:3](=[O:4])[C:2]=1[Cl:11].C(=O)([O-])O.[Na+].[CH:18]([OH:21])([CH3:20])[CH3:19]>CC(CC)=O>[Cl:9][C:6]1[C:7](=[O:8])[C:1]([O:21][CH:18]([CH3:20])[CH3:19])=[C:2]([Cl:11])[C:3](=[O:4])[C:5]=1[Cl:10]
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: CC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(C)OC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O
Temperature: 55 °C

Procedure:
Chloranil (0.06 mole) and sodium hydrogen carbonate (0.075 mole) were added to 300 ml of methylethylketone (MEK). the mixture was heated to 55° C. before adding iso-propanol (0.5 mole) dropwise with stirring. When the reaction was complete (as judged by HPLC) the MEK solvent was removed from the product mixture under vacuum. The resultant orange gum was recrystallised from petroleum ether to give 2,3,5-trichloro-6-isopropoxy-1,4-benzoquinone as product.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:15])[NH2:14])[CH:8]=1)=[O:5].[F:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[Cu](I)I.O>[C:13]([C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[O:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:15])[NH2:14]
Reactant: Oc1ccc(F)cc1
Reactant: NC(=O)c1cccc(NC(=O)c2ccccc2Br)c1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NC(=O)c2ccccc2Oc2ccc(F)cc2)c1
Reaction time: 0.25 h

Procedure:
To a mixture of 2-bromo-N-(3-carbamoylphenyl)benzamide (100 mg, 0.28 mmol), 4-fluorophenol (47.1 mg, 0.28 mmol), potassium phosphate (119 mg, 0.56 mmol), copper iodide (53 mg, 0.28 mmol) in a microwave vial was added 0.9 μL of DMF and 19 μL of water. The reaction was subjected to microwaves at 150° C. for 15 min. The reaction was cooled, the solids were filtered and the residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give N-(3-carbamoylphenyl)-2-(4-fluorophenoxy)benzamide. LC/MS: m/z 351.0 (M+H)+ at 2.90 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.I.O>O1CCOCC1>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:27][C:24]3[CH:25]=[N:26][C:21]([C:20]([F:29])([F:19])[F:28])=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Agent: I
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Temperature: 130 °C
Yield: 95 %

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.5 g, 1.93 mmol) was dissolved in anhydrous dioxane (3 mL) and 6-trifluoromethylpyridin-3-ylamine was added (469 mg, 2.9 mmol); followed by HI/H2O (0.3 mL, 47%). The mixture was heated at 130° C. for 600 s in a Personal Chemistry microwave. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the product as an orange solid (700 mg, 95% crude). The crude product was used for the subsequent step.
Reaction SMILES: [CH:1]1([NH:11][C:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[N:17][C:18]([Cl:25])=[CH:19][C:20]=3[CH3:24])[NH:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.IC.N1[CH2:29]CCN2CCCCCC=12>CN(C=O)C>[CH:1]1([NH:11][C:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[N:17][C:18]([Cl:25])=[CH:19][C:20]=3[CH3:24])[N:15]2[CH3:29])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1cc(Cl)nc2[nH]n(C(=O)NC3CCCc4ccccc43)c(=O)c12
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(Cl)nc2c1c(=O)n(C(=O)NC1CCCc3ccccc31)n2C

Procedure:
In analogy to example 2, 50 mg (0.14 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydro-pyrazolo[3,4-b]pyridine-2-carboxylic acid (1,2,3,4-tetrahydronaphthalen-1-yl)amide were reacted with 23.85 mg (0.168 mmol) of iodomethane in DMF with 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU) at RT. Yield: 12 mg (23%), M+H+: 371.42.
Reaction SMILES: [CH3:1][CH:2]([SH:5])[CH2:3][CH3:4]>C(#N)C>[CH3:1][CH:2]([S:5][S:5][CH:2]([CH3:1])[CH2:3][CH3:4])[CH2:3][CH3:4]
Reactant: CCC(C)S
Solvent: CC#N
Product: CCC(C)SSC(C)CC
Reaction time: 2 h

Procedure:
A solution of 150 μg of LL-E33288γ1 -I in 1 ml of acetonitrile was treated with 50 μl of a 1 μmole/ml solution of 1-methyl-1-propyl mercaptan. After 2 hours, the reaction was complete, giving the desired 1-methyl-1-propyl disulfide of LL-E33288γ1 -I.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[C:19]3[S:20][CH2:21][CH2:22][N:18]3[N:17]=2)[C:10]=1[F:30])C1C=CC=CC=1.FC(F)(F)S(O)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:30][C:10]1[C:11]([C:16]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[C:19]3[S:20][CH2:21][CH2:22][N:18]3[N:17]=2)=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1nn2c(c1-c1ccncc1)SCC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1ccc(F)c(-c2nn3c(c2-c2ccncc2)SCC3)c1F
Temperature: 120 °C

Procedure:
To dibenzyl-[2,4-difluoro-3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenyl]-amine (180 mg, 0.34 mmol) in toluene (2 mL) was added trifluoro-methanesulfonic acid (3.5 mL) in a sealable vial under nitrogen atmosphere. The mixture was stirred under microwave irradiation at 120° C. for ten minutes. The crude was diluted with ethyl acetate and washed with NaHCO3 saturated solution twice. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was isolated by column chromatography eluting with ethyl acetate: hexane (1: 1) (115 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:18])[NH:9][C@H:10]([CH2:16][OH:17])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:6])([CH3:5])[CH3:4].IC.[C:21]([O-])(O)=O.[Na+]>C1COCC1>[C:3]([O:7][C:8](=[O:18])[NH:9][C@H:10]([CH2:16][O:17][CH3:21])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (51.3 mg, 1.284 mmol) in THF (10 mL) cooled at 0° C. under Argon atmosphere was slowly added ((S)-1-hydroxymethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (300 mg, 1.167 mmol). The mixture was stirred at 0° C. for 30 min and iodomethane (0.095 ml, 1.517 mmol) was added. The reaction mixture was allowed to reach RT and further stirred overnight. To complete the reaction, NaH (24 mg, 0.584 mmol) was again added at 0° C. followed 30 min later by the addition of iodomethane (36 μL, 0.584 mmol). The reaction mixture was stirred at RT for 6 h, then poured into a sat. aq. solution of NaHCO3 and extracted twice with CH2Cl2. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash chromatography on silica gel (c-hexane to c-hexane/EtOAc 8:2) to give the desired material as a white powder. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 6.60 (m, 1H), 3.66 (m, 1H), 3.23 (s, 3H), 3.14 (m, 1H), 3.05 (m, 1H), 1.38 (s, 9H), 1.30 (m, 2H), 0.88 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)([S:16][CH3:17])[CH2:13][C@H:12]1[C:30]([OH:32])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]O>>[C:21]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C@@:14]2([S:16][CH3:17])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C@H:12]([C:30]([O:32][CH3:33])=[O:31])[CH2:13]2)=[CH:23][CH:22]=1
Reactant: CO
Reactant: CS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Product: COC(=O)[C@@H]1C[C@@](SC)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To an iced colorless solution of (2S,4R)-1-(benzyloxycarbonyl)-4-(biphenyl-4-yl)-4-(methylthio)pyrrolidine-2-carboxylic acid (288 mg, 0.644 mmol) in MeOH (5 mL) was added (trimethylslyl)diazomethane (3.54 mL, 7.08 mmol) dropwise until it turned into light yellow (bubble was generated). The formed light yellow solution was stirred at room temperature overnight. Diluted with EtOAc, washed with 5% citric acid, and brine, dried over MgSO4, filtered, evaporated, to afford the desired product (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-(methylthio)pyrrolidine-1,2-dicarboxylate (267 mg, 0.578 mmol, 90% yield) as a white wax. LC-MS (retention time: 3.25 min, method B), MS m/z 462 (M+H), 414 (M-MeSH).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[NH2:19]>>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([NH:19][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[OH:13])[CH:20]=[C:21]([C:23]([F:24])([F:26])[F:25])[CH:22]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc([N+](=O)[O-])ccc1O
Yield: 57.2 %

Procedure:
Using 5-nitrosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=O)[C:7](=[CH:11][CH:12]=1)[C:8](O)=[O:9])([O-:3])=[O:2].P([O-])([O-])([O-])=O.[OH:21][NH3+:22].O[NH3+].O[NH3+]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:13](=[O:15])[N:22]([OH:21])[C:8](=[O:9])[C:7]2=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: [NH3+]O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: O=P([O-])([O-])[O-]
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1O

Procedure:
Analogous to Example 4, but from 500 mg (2.37 mmol) of 4-nitrophthalic acid (tech., contaminated with approximately 10% of 3-nitrophthalic acid) and 187 mg (0.974 mmol) of hydroxylammonium phosphate at a bath temperature of 130° C. The yield was 332 mg (67%, approximately 5% contaminated).
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][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2].[CH2:54]([Al](CC)CC)[CH3:55].CCCCCC.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCOCC1.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.C(=O)([O-])[O-].[Ag+2].[Cu]Cl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([CH2:54][CH3:55])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:35]=[C:34]([C:42]([F:43])([F:45])[F:44])[CH:33]=3)[C:28]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2]
Reactant: CC[Al](CC)CC
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: Cl[Cu]
Agent: [Ag+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1c2ccc(CC)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (250 mg) is dissolved in 1,4-dioxane (3 ml), and thereto are added a catalytic amount of tetrakis(triphenylphosphine)palladium, a catalytic amount of silver carbonate and a catalytic amount of copper (I) chloride under nitrogen flow. After adding dropwise a triethylaluminum-hexane solution (1M, 480 μl), the mixture is stirred at 60° C. for 30 minutes. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate are added to the reaction solution. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane: ethyl acetate=9:1→4:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)-pyrimidin-2-yl]}amino-2,6-diethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (83 mg); MS (m/z): 667 [M+H]+ and (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (77mg). MS (m/z): 639 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:23]1[CH:24]=[N:25][C:26]([C:30]#[N:31])=[CH:27][C:28]=1[CH3:29].I([O-])(=O)(=O)=[O:33].[Na+]>C(#N)C.ClCCl.O.CO.[Ru](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH3:9])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][C:19]([OH:33])=[O:20])=[O:7])=[CH:4][C:3]=1[C:23]1[CH:24]=[N:25][C:26]([C:30]#[N:31])=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1cc(C#N)ncc1-c1cc(C(=O)N(C)c2ccccc2OCCCO)ccc1Cl
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc(C#N)ncc1-c1cc(C(=O)N(C)c2ccccc2OCCC(=O)O)ccc1Cl
Reaction time: 0.25 h

Procedure:
To a mixture of 4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-[2-(3-hydroxy-propoxy)-phenyl]-N-methyl-benzamide 9-1 (30 mg, 0.07 mmol) in acetonitile (0.25 mL) and dichloromethane (0.25 mL), a solution of sodium periodate (40 mg, 0.19 mmol) in water (0.4 mL) was added followed by ruthenium (III) chloride (2 mg, 0.0096 mmol). The mixture was stirred 15 min, diluted with MeOH, stirred for 15 min and filtered. The filtrate was purified by prep. LCMS to yield 3-(2-{[4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 11-1. MS [M+H]+: 449.8; tR=6.76 min. (method 2)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[C:10]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[N:12]=[C:11]([CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[C:10]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)C1=C(CN2C(=O)c3ccccc3C2=O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Product: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(C)c(C(=O)OC)c1-c1cccc(Cl)c1Cl

Procedure:
Analogously to the procedure for Example I, 2.3 g (4.3 mmol) of the compound from Example II are oxidized by 10 g of manganese dioxide at RT for 1 h to give 2.0 g (88% of theory) of the title compound.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]4[CH:18]=[C:19]([C:21]5[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][N:22]=5)[N:20]=[C:13]4[C:12]=3[CH:29]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.C[O:32]CCOC>>[CH:26]([N:25]1[C:21]([C:19]2[N:20]=[C:13]3[C:12]4[CH:29]=[C:8]([C:7]5[C:2](=[O:32])[NH:3][CH:4]=[CH:5][CH:6]=5)[CH:9]=[CH:10][C:11]=4[O:17][CH2:16][CH2:15][N:14]3[CH:18]=2)=[N:22][CH:23]=[N:24]1)([CH3:28])[CH3:27]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3cccnc3F)ccc1OCC2
Reactant: COCCOC
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3ccc[nH]c3=O)ccc1OCC2
Temperature: 80 °C
Yield: 55 %

Procedure:
To a solution of 10-(2-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.047 g, 0.12 mmol) in DME (2 mL) was added 10% aq HCl (2 mL). The reaction mixture was allowed to stir and heat at 80° C. for 18 hours before cooling and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 203 (25 mg, 55%). 1H NMR (400 MHz, DMSO) δ 11.82 (s, 1H), 8.88 (d, J=2.3, 1H), 7.92 (d, J=6.7, 2H), 7.67 (ddd, J=9.0, 7.7, 2.2, 2H), 7.38 (d, J=4.8, 1H), 7.07 (d, J=8.6, 1H), 6.31 (t, J=6.7, 1H), 5.81 (dt, J=13.2, 6.6, 1H), 4.54 (q, J=5.8, 4H), 1.48 (d, J=6.6, 6H). MS (ESI(+)): m/z 389.1 (M+H)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[BH:12]([OH:14])[OH:13]>>[C:10]([C:4]1[CH:3]=[C:2]([B:12]([OH:14])[OH:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])#[N:11]
Reactant: OBO
Reactant: N#Cc1ccc(I)cc1C#N
Product: N#Cc1ccc(B(O)O)cc1C#N

Procedure:
The title compound was prepared according to Preparation 102 using 4-iodophthalonitrile to provide a mixture of the boronic acid and boronic ester. The mixture was taken on to the next step as crude.