Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]([OH:21])[C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=2[F:20])[CH2:5][CH2:4]1)[CH3:2].[H][H]>[C].[Pd].C(OCC)(=O)C>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]([OH:21])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=2[F:20])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](C(O)C#Cc2ccc(F)c(F)c2F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@H]1CC[C@H](C(O)CCc2ccc(F)c(F)c2F)CC1

Procedure:
A 200-ml ethyl acetate mixture containing 1-(trans-4-ethylcyclohexyl)-3-(2,3,4-trifluorophenyl)-2-propyne-1-ol (38 g) and 5% palladium carbon (50% in water, 2 g) was stirred for 4 hours at room temperature at a hydrogen pressure of 4 atm. After palladium carbon was removed by filtration using Celite, the filtrate was concentrated to obtain 1-(trans-4-ethylcyclohexyl)-3-(2,3,4-trifluorophenyl)-1-propanol (38 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.CCN(C(C)C)C(C)C.[CH:29]1[N:33]=[CH:32][N:31]([C:34](N2C=NC=C2)=O)[CH:30]=1.CN(C)CCN>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([NH:33][CH2:29][CH2:30][N:31]([CH3:34])[CH3:32])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=C(O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.2 %

Procedure:
295 (60 mg, 0.22 mol), DIEA (0.08 mL, 0.44 mmol), and CDI (71 mg, 0.44 mmol) were suspended in DMF (2 mL) and stirred for 4 h at room temperature. N1,N1-Dimethylethane-1,2-diamine (77 mg, 0.87 mmol) was added, and the reaction mixture was stirred for another 3 h. The reaction mixture was quenched with water. The resulting precipitate was filtered, washed with MeOH and H2O, and dried under vacuum to produce provide 296 (61 mg, 81% yield) as a solid. LC-MS (M+H=345, obsd.=345).
Reaction SMILES: [CH3:1]O.[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9]([OH:11])=[O:10])([O-:5])=[O:4].S(=O)(=O)(O)O>>[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9]([O:11][CH3:1])=[O:10])([O-:5])=[O:4]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 91.9 %

Procedure:
In a 72-liter, round-bottomed flask equipped with mechanical stirrer and condenser were combined methyl alcohol (27.97 kg, 873 moles, 35.4 liters), 3,5-dinitrobenzoic acid (15 kg, 70.72 moles), and sulfuric acid (2.6 kg, 26.56 moles, 1.42 liters). The mixture was heated and stirred at reflux by means of a heating mantle for approximately 26 hours and then was allowed to cool to 25° (approximately 18 hours). The precipated solid was isolated by centrifugation (Tolhurst 12-in. centrifuge); each of the four loads collected was washed with methyl alcohol (4 liters). The wet solid was air dried for 16-18 hours to give 14.7 kg (92% of theory) of methyl 3,5-dinitrobenzoate (I). Tlc analysis (toluene/acetone/HOAc; 90/5/2; utilizing a plate marketed by Mallinckrodt under the trade designation ChromAR 7GF plate) showed the product to be homogenous and identical to an authentic sample.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.O.[NH3:27].O1CCOCC1>O>[NH2:27][CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Reactant: N
Solvent: O
Solvent: C1COCCO1
Product: NCC1CCn2c(nc3ccccc32)S1
Temperature: 120 °C
Yield: 35.1 %

Procedure:
To 2.24 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole, were added 5 g of 25% ammonia water and 40 ml of dioxane. The mixturewere heated in a sealed tube, at 120° C., for 75 hours. The reactionmixture was then condensed under reduced pressure. The residue was added with water and then extracted with chloroform, and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.46 g (yield: 35.1%) of the intended product, m.p. 217°-222° C.; IR νmaxKBr cm-1 3300-2600, 1440; Anal. Calcd. for C11H13N3S: C, 60.25; H, 5.97; N, 19.16; S, 14.62; Found: C, 60.28; H, 5.99; N, 19.60; S, 14.13.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([SH:10])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>O>[CH3:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([S:10][CH3:19])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COS(=O)(=O)OC
Reactant: Cc1c(C#N)ccc(S)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc(C#N)c(C)c1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 g (0.29 mol) of 3-methyl-2,4-dicyanothiophenol were added to a solution of 23 g (0.58 mol) of NaOH in 400 ml of water, and 73 g (0.58 mol) of dimethyl sulfate were then added dropwise at 25-35° C. The mixture was stirred at 25° C. for 16 h, after which a solid had precipitated out, which was filtered off with suction, washed twice with water and then recrystallized from glacial acetic acid/water. Yield: 43 g (80%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]([C:18]1[CH:23]=[C:22]([SH:24])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])[CH3:16].C(N(CC)CC)C.Cl>C(#N)C>[CH3:28][C:25]([C:20]1[CH:21]=[C:22]([S:24][CH2:2][C:3]([NH:5][C:6]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:13])=[O:4])[CH:23]=[C:18]([C:15]([CH3:17])([CH3:16])[CH3:14])[C:19]=1[OH:29])([CH3:26])[CH3:27]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by dissolving 2-chloro-N-(2,6-dimethylphenyl)acetamide (1.8 g, 0.0091 mole) and 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.17 g, 0.0091 mole) in acetonitrile (20 ml) under argon. Triethylamine (1.25 ml) was added and the solution stirred at room temperature under argon for 12 hours. The solution was acidified with 10% hydrochloric acid with stirring, extracted with ethyl acetate (3×), the extracts combined, washed with water and dried over sodium sulfate. The solvent was removed on a rotary evaporator and the product purified by chromatography over silica and recrystallized from ethyl acetate/benzene. m.p. ca. 137.7° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH3:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([Cl:12])=[CH:7]2.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][CH:18]=1.[OH-].[Na+]>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[N:13]([CH2:14][CH3:15])[C:3]3[CH:4]=[CH:5][C:6]4[CH:7]=[C:8]([Cl:12])[CH:9]=[N:10][C:11]=4[C:2]=3[N:1]=2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCNc1ccc2cc(Cl)cnc2c1N
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(-c2ccc(Cl)cc2)nc2c3ncc(Cl)cc3ccc21
Temperature: 120 °C

Procedure:
A mixture of 4.1 g (20 mmol) of 8-amino-3-chloro-7-ethylaminoquinoline, 3.1 g (20 mmol) of 4-chlorobenzoic acid and 20 ml of polyphosphoric acid is heated at 120° C. for 1 hour. It is allowed to cool to 90° C., and 100 g of ice are slowly added to the solution. The mixture is then poured into 200 g of ice, and the pH is adjusted to 12 with concentrated sodium hydroxide solution. The precipitate is filtered off with suction, washed thoroughly with hot water, dried at 70° C. under reduced pressure and recrystallized from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1.CC1(C)C(C)(C)OB([C:48]2[CH:49]=[N:50][O:51][CH:52]=2)O1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36]([C:48]3[CH:49]=[N:50][O:51][CH:52]=3)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: CC1(C)OB(c2cnoc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(Br)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(-c4cnoc4)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Temperature: 150 °C
Yield: 14.5 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole (57.5 mg, 0.3 mmol), 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and was purified by preparative HPLC to give 20 mg of (S)-3-(4-{2-amino-6-[(S)-2,2,2-trifluoro-1-(4-isoxazol-4-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino propionic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1.[CH3:27][N:28]([CH3:34])[C@@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:15]([C:17]3[S:21][C:20]([N:31]4[CH2:32][CH2:33][C@@H:29]([N:28]([CH3:34])[CH3:27])[CH2:30]4)=[N:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=1
Reactant: O=C(NCC1(c2cccnc2)CCCCC1)c1sc(Br)nc1C(F)(F)F
Reactant: CN(C)[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C)[C@@H]1CCN(c2nc(C(F)(F)F)c(C(=O)NCC3(c4cccnc4)CCCCC3)s2)C1
Temperature: 80 °C

Procedure:
A mixture of 2-bromo-4-trifluoromethyl-thiazole-5-carboxylic acid (1-pyridin-3-yl-cyclohexylmethyl)-amide (44.8 mg), dimethyl-(R)-pyrrolidin-3-yl-amine (12.6 mg), and potassium carbonate (15.2 mg) in ACN (1 mL) is heated at 80° C. for 1 h. The mixture is cooled, poured into water and extracted with EtOAc. The extract is concentrated in vacuo and the residue is purified by PTLC (silica gel, 5% MeOH in methylene chloride) to give the title compound. MS (M+1)=482.24; RT=1.03 min. *IC50.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.[C:30](Cl)(=[O:37])[O:31][CH2:32][CH2:33][CH2:34][CH2:35][Cl:36]>ClCCl>[CH3:1][N:2]1[C:6](/[C:7](=[N:14]\[O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:30](=[O:37])[O:31][CH2:32][CH2:33][CH2:34][CH2:35][Cl:36])[CH:20]=[CH:19][CH:18]=2)/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: O=C(Cl)OCCCCCl
Reactant: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1nnnc1/C(=N\OCc1cccc(NC(=O)OCCCCCl)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
To a stirred solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)-methyl]pyridin-2-amine (150 mg, 0.485 mmol) in dichloromethane (5 mL), was added pyridine (0.078 mL), 4-chlorobutyl carbonochloridate (166 mg, 0.970 mmol). The reaction mixture was stirred for 5 hours at room temperature, concentrated in vacuo, and then purified by silica gel chromatography to yield to 4-chlorobutyl {6-[({[(Z)-(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate [200 mg; 90% of purity; 84% of to theory; HPLC/MS: m/z=344 (M+H); log P(HCOOH)=3.67].
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[Cl:10][C:11]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([CH:22]=1)[C:19]([NH2:21])=[O:20]>C(Cl)Cl>[Cl:10][C:11]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:23]([O-:25])=[O:24])=[C:18]([CH:22]=1)[C:19](=[NH:21])[O:20][CH3:6]
Reactant: NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=N)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 94.9 %

Procedure:
A solution containing trimethyloxonium tetrafluoroborate (100 g; 0.68 mol) and methylene chloride (2 liters) is prepared. It is stirred and 5-[2'-chloro-4'-(trifluoromethyl)phenoxy]-2-nitrobenzamide (220 g; 0.61 mol) is then added in portions at ambient temperature. The stirring is continued for 24 hours at ambient temperature. The solution is then washed with a 10% aqueous solution of sodium carbonate (cooled beforehand) and dried over sodium sulphate. The methylene chloride is removed by evaporation to leave a yellow solid of methyl 5-[2'-chloro-4'-(trifluoromethyl)phenoxy]-2-nitrobenzimidate (217 g; yield 95%) melting at 46° C. and having the formula: ##STR20##
Reaction SMILES: [CH3:1][C@H:2]([NH2:11])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:11][C@@H:2]([CH3:1])[C@@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[OH:10])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)N[C@@H](C)[C@H](O)c2ccccc2)cc1
Yield: 37.8 %

Procedure:
Following a procedure similar to that described in Example 6, but using 3 g of (1R,2S)-(-)-norephedrine, 4.36 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 3.41 g of sodium cyanoborohydride, 2.65 g of the title compound were obtained as crystals, melting at 124° C. (after recrystallization from a mixture of ethyl acetate and hexane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:26].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH2:14][CH2:15][I:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1(CCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCI)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 39.9 %

Procedure:
To a solution of 4-ethoxycarbonyl-4-(2-methanesulfonyloxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (2.38 g) in dimethylformamide (24 ml) was added sodium iodide (4.77 g), and the mixture was stirred at 70° C. for 7 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and dried under reduced pressure to give the title compound (1.03 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([Cl:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>CN(C=O)C>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=3)[CH:3]=[C:4]([F:21])[C:5]=2[Cl:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)cc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)cc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a mixture of (4S,6S)-4-(5-amino-2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.060 g, 0.184 mmol) and 5-chloropicolinic acid (0.035 g, 0.221 mmol) in DMF (1.5 mL) at 0° C. was added 1-propanephosphonic acid cyclic anhydride, 50% solution in ethyl acetate (0.130 mL, 0.221 mmol). The reaction was gradually warmed to rt and stirred for 2 h. The reaction mixture was partitioned between EtOAc and saturated solution of NaHCO3. The organic layer was separated, washed twice with water, then washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (12 g, 0-100% EtOAc/DCM in 15 min). The fractions were combined and concentrated in vacuo. The resulting white solid was dissolved in MeOH and purified by reverse phase prep HPLC: 10-80% MeCH in Water (with 0.1% TFA). The fractions were collected and neutralized with solid Na2CO3, extracted with DCM three times. The organic solution was dried over sodium sulfate and concentrated in vacuo to give N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-chloro-5-fluorophenyl)-5-chloropicolinamide (20 mg, 23.3% yield). MS m/z=465 [M+H]+. Calculated for C18H14Cl2F4N4O2: 465.2.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].C(OC([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4][N:3]3[CH2:1][CH3:2])=[C:8]([CH3:16])[C:9]=2[F:15])[CH2:30]1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(F)c(F)c21
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(N3CCC(N)C3)c(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 0.36 g (1.25 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.26 g (1.39 mmol) of 3-(t-butoxycarbonyl) aminopyrrolidine, 0.38 g (3.76 mmol) of triethylamine, and 20 mL of acetonitrile was refluxed for 5 hours, then stirred at room temperature overnight. The solids were collected by filtration and washed with acetonitrile and ether. The crude product was dissolved in 5 mL of 6N hydrochloric acid and 5 mL of glacial acetic acid and stirred for 5 hours at room temperature. The solution was concentrated to a solid which was suspended in water, made basic (pH 12), filtered through a fiberglass pad, and neutralized (pH 6.8). The solids were collected by filtration, washed with water, and dried in vacuo to give 0.32 g of white solid, mp 218°-220° C.
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].C([O-])([O-])=O.[K+].[K+].[CH:36]1(Br)[CH2:40]C[CH2:38][CH2:37]1>C(#N)C>[CH:17]1([N:14]2[CH2:15][CH2:16][C:11]3([CH2:10][C:9](=[O:28])[C:8]4[C:25](=[CH:26][CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:2])=[O:29])[CH:7]=4)[O:24]3)[CH2:12][CH2:13]2)[CH2:38][CH2:37][CH2:36][CH2:40]1
Reactant: BrC1CCCC1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C3CCCC3)CC1)O2
Temperature: 75 °C
Yield: 95.1 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (500 mg, 1.48 mmol, Intermediate 1, hydrochloride salt) was suspended in acetonitrile (65 ml). K2CO3 (818 mg, 5.92 mmol) and cyclopentyl bromide (882 mg, 5.92 mmol) were subsequently added and the mixture was heated at 75° C. for 14 h. The solvent was then evaporated and the residue was diluted with water and extracted with ethyl acetate, which was dried and evaporated. The crude orange solid (540 mg) was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-cyclopentyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (500 mg) as a light brown solid. The acid was suspended in DCM (16 ml), TEA (0.30 ml) was added and the resulting clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-cyclopentyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as an orange solid (360 mg). The protected hydroxamic acid was dissolved in DCM (4 ml) and treated with 1 M HCl in diethyl ether (4 ml, 4 mmol) as described in Example 2, Step D, giving a light pink solid (247 mg, trifluoroacetate salt) after purification by preparative HPLC.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].O[C:17]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:18]=1[CH:19]=O>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:13](=[O:15])[O:14][C:21]3[C:18]([CH:19]=2)=[CH:17][CH:24]=[C:23]([OH:25])[CH:22]=3)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(CC(=O)O)cc1
Reactant: O=Cc1ccc(O)cc1O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(-c2cc3ccc(O)cc3oc2=O)cc1
Temperature: 0 °C

Procedure:
89.5 g (0.43 mol) of 4-butoxyphenylacetic acid (prepared by the method of McElvain, Carney; J. Am. Chem. Soc. 1946 (68), 2592-2599) and 30.0 g (0.22 mol) of 2,4-dihydroxybenzaldehyde are heated at 120° C. for 5 h in 100 ml of acetic anhydride and 120 ml of triethylamine. The still-hot solution is subsequently added to 3 l of ice-water, and the precipitated product is filtered off with suction and suspended in 1 l of water and 1.4 l of ethanol. After dropwise addition of 190 ml of conc. sulfuric acid, the batch is heated under reflux for 4 h and added to 3 l of water, and the precipitated product is filtered off with suction. The crude product is filtered through silica gel with hot toluene/ethyl acetate (1:1), the solvent is evaporated in vacuo, and the residue is recrystallised from toluene, giving 3-(4-butoxyphenyl)-7-hydroxychromen-2-one as colourless crystals.