Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].CN.[CH3:37][N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([NH:38][CH3:37])=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(-c2nc(NCCN(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 69.2 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (15 mg, 0.03 mmol) in CH2Cl2 (3 mL) were added methylamine (2.0 M soln. in THF, 0.018 mL, 0.036 mmol), HATU (13 mg, 0.034 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (10 mg, 65%). LC-MS m/z 482 (M+H)+; 1H-NMR (MeOD) δ 2.16 (s, 6H), 2.38 (m, 2H), 2.96 (s, 3H), 3.22 (m, 2H), 4.45 (s, 2H), 7.16 (m, 2H), 7.50 (m, 1H), 7.64 (m, 1H), 7.74 (d, 1H), 7.95 (d, 1H), 8.00 (s, 1H).
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-:2].[Na+:5].[OH-].[Na+].[C:8](=[O:11])([OH:10])[O-:9].[OH-].[C:13](=[O:16])([O-:15])[O-:14].[Na+].[Na+]>O>[C:1](=[O:2])([OH:4])[OH:3].[Na+:5].[C:8](=[O:9])([O-:11])[O-:10].[C:13](=[O:14])([OH:16])[OH:15].[Na+:5]
Reactant: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)O

Procedure:
According to U.S. Pat. No. 3,334,963 sodium carbonate is produced by mixing crude wet sodium bicarbonate crystals with an aqueous solution of sodium hydroxide, the ratio of bicarbonate to hydroxide in terms of sodium carbonate equivalents being from 6:1 to 1:1 in the presence of a total of 15-40% by weight of water thereby forming substantial amounts of sodium sesquicarbonate. The mixture thus obtained is then calcined to yield low density anhydrous sodium carbonate having a large particle size and excellent absorptive capacity.
Reaction SMILES: FC(F)[C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([CH2:14][CH2:15][CH3:16])[C:6]([C:17]([O:19]CC)=[O:18])=[C:5]([C:22]([F:25])([F:24])[F:23])[N:4]=1.[OH-].[K+]>CO>[CH2:14]([C:7]1[C:6]([C:17]([OH:19])=[O:18])=[C:5]([C:22]([F:23])([F:24])[F:25])[N:4]=[CH:3][C:8]=1[C:9]([OH:11])=[O:10])[CH2:15][CH3:16]
Reactant: CCCc1c(C(=O)OCC)c(C(F)F)nc(C(F)(F)F)c1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(=O)O)cnc(C(F)(F)F)c1C(=O)O
Yield: 28.9 %

Procedure:
A mixture of 20.1 g (0.0525 mole) of the product of Example 13, 11.4 g of 85% KOH, and 100 ml of methanol is held at reflux for 19 hours and concentrated. The residue is treated with 200 ml of water and extracted with ether. The aqueous layer is separated and acidified with 30 ml of concentrated HCl. The oily precipitate is extracted into ether and the ether extract is dried and concentrated. The residue is recrystallized from chloroform to give 4.2 g (24%) of the desired product, m.p. 235.5°-236.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[CH:7]=[C:8](Br)[CH:9]=1)=[O:4].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)cn1C
Reactant: OB(O)c1ccccc1
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
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)cn1C
Temperature: 70 °C
Yield: 10.4 %

Procedure:
To a stirred solution of methyl-4-bromo-1-methyl-1H-pyrrole-2-carboxylate (2.5 g, 11.5 mmol) in DMF (35 mL) under argon were added sequentially Pd(PPh3)4 (0.66 g, 0.58 mmol) and phenyl boronic acid (3.46 g, 28.4 mmol). The reaction mixture was heated to 70° C., and Na2CO3 (11 g, 104 mmol) dissolved in water (30 mL) was added. The reaction mixture was heated to 110° C. (14 h), cooled to room temperature, diluted with water (250 mL), and extracted with diethyl ether (250 mL×3). The combined organic layers were dried and concentrated in vacuo. The residue was purified by silica chromatography (eluted with petroleum ether:ethyl acetate=40:1) to afford methyl-1-methyl-4-phenyl-1H-pyrrole-2-carboxylate as a white crystalline solid (0.257 g). The ester (0.26 g, 1.2 mmol) was then combined with LiOH/H2O (0.15 g, 3.6 mmol) in THF (5 mL), CH3OH (5 mL) and H2O (2.5 mL) and was stirred at 40° C. (4 h). Water (25 mL) was added and the mixture was washed with DCM (15 mL). The pH of the aqueous phase was adjusted to 5-7 using HCl (1N). The water was removed and the residue was dissolved in MeOH (100 mL) and then filtered. The filtrate was concentrated in vacuo to give 1-methyl-4-phenyl-1H-pyrrole-2-carboxylic acid as white solid. (0.419 g) 1H-NMR (CDCl3, 400 MHz): δ 4.01 (s, 3H), 7.16 (d, J=1.6 Hz, 1H), 7.23 (t, J=7.2 Hz, 1H), 7.38 (m, 3H), 7.53 (dd, J=7.2, 8.4 Hz, 2H)
Reaction SMILES: C([N:3]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]([CH3:17])[CH2:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+].O1CC[CH2:36][CH2:35]1>>[CH2:35]([CH:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:5][CH:4]([NH:3][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:17])[CH3:36]
Reactant: C1CCOC1
Reactant: CCCCCCCN(CC)C(C)CC(=O)NCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CCCCCCCNC(C)CC(CC)NCCc1ccccc1

Procedure:
Dissolve 3.0 g (9 mmol) of 3-[ethyl(heptyl)amino]-N-(2-phenylethyl)butanamide in 50 mL of anhydrous tetrahydrofuran. Add this solution dropwise to a suspension of 0.68 g (18 mmol) of lithium aluminum hydride in 20 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere. After the addition is complete heat the reaction mixture to reflux. Follow the progress of the reaction by thin layer chromatography on silica gel. At the completion of the reaction add successively dropwise 0.7 mL of water, 0.7 mL of 15% aqueous sodium hydroxide solution and 2.1 mL of water. Filter the resulting solids and wash with 20 mL of tetrahydrofuran. Evaporate the solvent in vacuo and dissolve the residue in 100 mL of methylene chloride. Wash the methylene chloride solution with 20 mL of water and 20 mL of saturated sodium chloride solution then dry over anhydrous sodium sulfate. Remove the drying agent and evaporate the solvent to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([N:20]1[C:25](=[O:26])[C:24]2=[C:27]([Cl:30])[CH:28]=[CH:29][N:23]2[N:22]=[C:21]1[CH:31](Cl)[CH:32]1[CH2:34][CH2:33]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:31]([C:21]1[N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:25](=[O:26])[C:24]2=[C:27]([Cl:30])[CH:28]=[CH:29][N:23]2[N:22]=1)[CH:32]1[CH2:33][CH2:34]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1c2c(Cl)ccn2nc(C(Cl)C2CC2)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCCCNC(c1nn2ccc(Cl)c2c(=O)n1Cc1ccccc1)C1CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
(3-Amino-propyl)-carbamic acid tert-butyl ester (Fluka, 0.527 mL, 3.02 mmol) was added to a solution of 3-benzyl-5-chloro-2-(chloro-cyclopropyl-methyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (0.35 g, 1.01 mmol) in NMP (3.3 mL) at room temperature. The reaction mixture was degassed with N2 and then stirred at 100° C. for 12 h. The reaction mixture was cooled to room temperature and the crude product was purified by loading directly onto a reverse phase C-18 HPLC with a 30 min gradient eluting with 45–90% aqueous methanol with 0.1% TFA to afford the title compound (0.397 g, 81%) as a solid: 1H NMR (DMF-d7) 7.74 (m, 1H), 7.35–7.49 (m, 5H), 6.85 (m, 2H), 5.85 (m, 1H), 5.45 (m, 1H), 3.15–3.25 (m, 3H), 2.70–2.85 (m, 2H), 2.55 (br m, 1H), 1.55–165 (m, 2H), 1.47 (s, 9H), 1.40 (br m, 1H), 0.65–0.75 (m, 1H), 0.41–0.46 (m, 2H), 0.15 (br m, 1H); MS (ESI+) 486 (M++H); HRMS (ESI+) calculated: 486.2272 (M++H). found: 486.2256 (M++H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:8]#[N:9].C([N:30]([CH2:34][CH3:35])[CH:31]([CH3:33])C)(C)C>C(#N)C>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:31][CH2:33][C:22]3[C:35](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:34]2)[C:8]#[N:9])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(C(C#N)(CCCCCBr)Sc2ccccn2)cc1OC
Solvent: CC#N
Product: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccccn2)cc1OC

Procedure:
A mixture, under argon, of 1.5 g of product from Example 118, 0.790 g of 6,7-dtmethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, 7 ml of N,N-diisopropyl ethylamine and 60 ml of acetonitrile is heated at reflux temperature overnight. The reaction is cooled and concentrated tn yacuo to give an oil. The oil is purified by chromatography (silica gel: 1 and 2% methyl alcohol/methylene chloride) to give 1.1 g of the desired product as a glassy yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].CS(O[CH:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)(=O)=O>CN(C=O)C>[O:18]1[C:17]2([CH2:22][CH2:23][CH:14]([N:1]3[CH2:5][CH2:4][CH2:3][C:2]3=[O:6])[CH2:15][CH2:16]2)[O:21][CH2:20][CH2:19]1
Reactant: O=C1CCCN1
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCN1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
Pyrrolidin-2-one (720 mg, 8.46 mmol) in DMF (5 mL) was treated with NaH (203 mg, 8.46 mmol) at room temperature. The mixture allowed to stir for 30 min. 1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (500 mg, 2.12 mmol) from above step A, in DMF (3 mL) was added to the mixture and stirred at 130° C. for 3 h. The mixture was cooled to room temperature, quenched with NH4Cl, and extracted into EtOAc. Washed the EtOAc layer with saturated NaCl, dried over Na2SO4 and evaporated. Purified by silica prep TLC to give 55 mg (11.5%) of 1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-2-one.
Reaction SMILES: [C:1]([C:3]1[C:4]([C@@H:21]2[CH2:23][C@H:22]2[C:24](O)=[O:25])=[C:5]2[C:19]([CH3:20])=[N:18][NH:17][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16])#[N:2].[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.N1(O)C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[C:4]([C@@H:21]2[CH2:23][C@H:22]2[C:24]([NH:27][CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]2)=[O:25])=[C:5]2[C:19]([CH3:20])=[N:18][NH:17][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)c(C#N)c([C@@H]3C[C@H]3C(=O)O)c12
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)c(C#N)c([C@@H]3C[C@H]3C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.9 %

Procedure:
To 200 mg (0.57 mmol) of (1R,2R)-2-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)cyclopropane carboxylic acid diluted in 4 ml of anhydrous dimethylformamide are added, at 0° C., 121 mg (0.57 mmol) of tert-butyl 4-aminopiperidine-1-carboxylate, 76 mg (0.62 mmol) of N,N-dimethylpyridine-4-amine (DMAP), 110 mg (0.62 mmol of N,N-dimethyl-N-[(methylimino)methylene]propane-1,3-diamine hydrochloride (EDCI) and 84 mg (0.62 mmol) of 1H-benzo[d][1,2,3]triazole-1-ol (HOBT). The reaction mixture is stirred 20 h at room temperature. The solvent is concentrated, water is added and the product extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 5:5 to 3:7) to give 158 mg of tert-butyl 4-((1R,2R)-2-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)cyclopropanecarboxamido)piperidine-1-carboxylate in the form of a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[CH:15][C:16]=1[C:17]([NH2:19])=[O:18]>>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:14]1[S:13][C:12]([NH:11][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([OH:10])[CH3:9])[N:7]=2)=[C:16]([C:17]([NH2:19])=[O:18])[CH:15]=1
Reactant: NC(=O)c1cc(-c2ccccc2F)sc1N
Reactant: CC(O)c1cccc(Br)n1
Product: CC(O)c1cccc(Nc2sc(-c3ccccc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 1-(6-bromopyridin-2-yl)ethanol (65.0 mg, 0.322 mmol) and 2-amino-5-(2-fluorophenyl)thiophene-3-carboxamide (78.0 mg, 0.330 mmol) as the starting materials.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1>C1(C)C=CC=CC=1>[NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC(N)=O)c2cccc(Cl)c2)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Temperature: 0 °C
Reaction time: 12 h
Yield: 109.5 %

Procedure:
(R)-tert-Butyl 3-((R)-(2-amino-2-oxoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (1.10 g, 2.60 mmol) was dissolved in anhydrous toluene (30 mL) and cooled to 0° C. Red-A1 (65% in toluene, 2.6 mL, 8.64 mmol) was added dropwise. After the addition, the reaction was stirred at rt for 12 h and quenched by adding water slowly. The resulting mixture was filtered through Celite, washing with THF. The filtrate was evaporated under reduced pressure to give crude (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (1.05 g), which was used for next step without further purification.
Reaction SMILES: O1CCC=N1.[F:6][C:7]([F:31])([C:12]([F:30])([F:29])[C:13]([F:28])([F:27])[C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[C:8](OC)=[O:9].[F:32][C:33]([C:54]([CH3:56])=[O:55])([F:53])[C:34]([F:52])([F:51])[C:35]([F:50])([F:49])[C:36]([F:48])([F:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40]>CC(C)=O>[F:32][C:33]([F:53])([C:54](=[O:55])[CH2:56][C:8]([C:7]([F:6])([F:31])[C:12]([F:29])([F:30])[C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[O:9])[C:34]([F:51])([F:52])[C:35]([F:49])([F:50])[C:36]([F:47])([F:48])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40]
Reactant: CC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C1=NOCC1
Solvent: CC(C)=O
Product: O=C(CC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
The beta-diketones which are used in carrying out this invention can be prepared by perfluoroacylation of appropriate ketones by esters or acid chlorides of perfluorocarboxylic acids, as in the reaction of methyl perfluorocaprylate with methyl tertiary butyl ketone to make 1-perfluoroheptyl-3 tertiary butyl-1,3 propanedione. Or a methyl perfluoroalkyl ketone can be acylated by an appropriate carboxylic derivative, as in the reaction of methyl phenylacetate with methyl perfluoropentyl ketone to give 1-perfluoropentyl-3-phenyl-1,3-propanedione; or in order to have two perfluorinated groups in the eventual isoxazoline, a methyl ketone containing also a perfluoroalkyl group can be acylated by an ester of a perfluorinated carboxylic acid, as when methyl perfluorocaprylate is reacted with methyl perfluoroheptyl ketone to produce 1,3-di(perfluoroheptyl)-1,3-propanedione.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].[F:9][C:10]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:25][C:24]([C:30]4[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=4)([C:26]([F:29])([F:28])[F:27])[O:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:13][CH:12]([NH2:14])[CH2:11]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:9][C:10]1([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH2:25][C:24]([C:30]4[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=4)([C:26]([F:27])([F:28])[F:29])[O:23][N:22]=3)=[CH:19][CH:20]=2)[CH2:13][CH:12]([NH:14][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:11]1
Reactant: NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)CC(=O)NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.2 %

Procedure:
2-(methylsulfonyl)acetic acid (22 mg, 0.16 mmol) was added to 3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)cyclobutanamine (Preparation 16, 50.0 mg, 0.10 mmol) in DMF (1.5 mL) along with DIPEA (54 μL, 0.31 mmol) and HATU (61 mg, 0.16 mmol). The mixture is stirred for 3 days at room temperature. The reaction mixture is partitioned between brine (5 mL) and EtOAc (5 mL). The organics are separated, dried over MgSO4, filtered and evaporated to give a residue, which is purified on regular silica eluting from neat DCM to 15% MeOH/DCM to give the title compound (20 mg): 1H NMR (DMSO-d6) δ: 8.83 (1H, d), 7.85 (2H, s), 7.79 (2H, d), 7.58 (2H, d), 4.60-4.51 (1H, m), 4.42-4.30 (2H, m), 4.04 (2H, s), 3.12 (3H, s), 2.96-2.86 (2H, m), 2.65-2.54 (2H, m); m/z (Cl) 602.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]1[C@H:20]2[C@H:15]([CH2:16][CH2:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=32)[NH:14][CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:11]1[C@H:20]2[C@H:15]([CH2:16][CH2:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=32)[N:14]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[O:8])[CH2:13][CH2:12]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(O)cc1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 28 %

Procedure:
The title compound is prepared from 4-hydroxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 28% of theory; LC (method 4): tR=1.93 min; Mass spectrum (ESI+): m/z=308 [M+H]+.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[C:6]([OH:16])(=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]C(C)C.C1(O)C=CC=CC=1>>[CH:7]1[C:6]([OH:16])=[CH:11][CH:10]=[C:9]([S:2]([OH:5])(=[O:4])=[O:3])[CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)CCCCCC(=O)O
Solvent: Oc1ccccc1
Product: O=S(=O)(O)c1ccc(O)cc1
Temperature: 95 °C
Reaction time: 0.12 h
Yield: 93.3 %

Procedure:
In the equipment according to FIG. 1, a mixture of 178.8 g (1.53 mole) of chlorosulfonic acid and 136.5 g (0.86 mole) of isononanoic acid was placed into one of the two graduated funnels and a mixture of 143 g (1.52 mole) of phenol and 104 g (0.66 mole) of isononanoic acid was placed into the other, and the two mixtures were added under control to the continuous-flow reactor in such a way that the residence time was about 7 minutes. The total time for adding the starting compounds to the reactor under control was about 2 hours. The reactor, heated to 95° C. under thermostatic control, had a length of 60 cm and was packed with glass rings. Throughout the reaction period, 10 liters of nitrogen per hour were passed through the receiver and through the reactor. This gave a 93.3% yield of crude phenolsulfonic acid diluted with isononanoic acid, of the following composition:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:4]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:5]([O:7]CC)=[O:6].[OH-].[K+]>C(O)C>[Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:4]([CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1cc(C(F)(F)F)cc(Br)c1N1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(C(F)(F)F)cc(Br)c1N1CCCCC1
Yield: 78 %

Procedure:
To a solution of ethyl 3-bromo-2-piperid-1-yl-5-trifluoromethylbenzoate (830 mg; 1 eq.) in ethanol (30 ml) is added potassium hydroxide (610 mg; 5 eq.). After stirring at reflux for 2 hours, the reaction medium is evaporated to dryness, taken up in water (20 ml) and acidified with 1N HCl. The precipitate is filtered off by suction, washed with water and dried. 600 mg of 3-bromo-2-piperid-1-yl-5-trifluoromethylbenzoic acid are obtained in the form of a white solid.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([S:16]([C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:30])([CH3:29])[C@H:7]1[OH:31].[CH:32]([C:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]=1[C:36](OC)=O)=[O:33].C(=O)([O-])O.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[F:26][C:20]([F:25])([C:21]([F:22])([F:23])[F:24])[C:19]([F:28])([F:27])[S:16]([C:13]1[CH:14]=[CH:15][C:10]2[O:9][C:8]([CH3:29])([CH3:30])[C@@H:7]([OH:31])[C@H:6]([N:5]3[CH2:36][C:35]4[C:34](=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:32]3=[O:33])[C:11]=2[CH:12]=1)(=[O:18])=[O:17]
Reactant: COC(=O)c1ccccc1C=O
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)F)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A solution of 0.142 g of zinc chloride and 0.065 g of sodium cyanoborohydride in 3 ml of methanol was added to a solution of 0.40 g of trans-4-amino-6-heptafluoropropylsulfonyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (prepared as described in Preparation 4) and 0.156 g of methyl 2-formylbenzoate in 6 ml of methanol, and the resulting mixture was stirred at room temperature for 1 hour and then at 50° C. for 24 hours. At the end of this time, the mixture was cooled with ice and then mixed with a saturated aqueous solution of sodium hydrogencarbonate. The methanol was then removed by distillation under reduced pressure, and the resulting residue was diluted with water and extracted with methylene chloride. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate; the solvent was then removed by distillation under reduced pressure. The resulting residue was recrystallized from ethyl acetate, to afford 0.356 g of the title compound, melting at 241°-249° C.