Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)(=[O:7])=[O:6].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][S:5]([N:8]4[C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=5[O:12][CH2:11][CH2:10][CH2:9]4)(=[O:7])=[O:6])[CH2:37][CH2:38]3)=[CH:29][CH:28]=2)=[CH:24][CH:25]=1
Reactant: O=S(=O)(CCCCl)N1CCCOc2ccccc21
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Product: O=S(=O)(CCCN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1)N1CCCOc2ccccc21

Procedure:
The compound (17) synthesized in Reference Example 17 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:19])=[C:7]([CH3:18])[C:8]=1[C:9]1[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[N:10]=1)=[C:2]=[O:3].[NH:20]1[CH2:27][CH2:26][CH2:25][C@@H:21]1[C:22]([OH:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:7]1[C:8]([C:9]2[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[N:10]=2)=[C:4]([NH:1][C:2]([N:20]2[CH2:27][CH2:26][CH2:25][C@@H:21]2[C:22]([OH:24])=[O:23])=[O:3])[S:5][C:6]=1[CH3:19]
Reactant: Cc1sc(N=C=O)c(-c2nc(C(F)(F)F)no2)c1C
Reactant: O=C(O)[C@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1sc(NC(=O)N2CCC[C@@H]2C(=O)O)c(-c2nc(C(F)(F)F)no2)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.3 %

Procedure:
To a solution of 5-(2-isocyanato-4,5-dimethyl-thiophen-3-yl)-3-trifluoromethyl-[1,2,4]-oxadiazole (178 mg, 0.615 mmol) in CH2Cl2 (10 mL) were added D-proline (142 mg, 1.23 mmol) and triethylamine (0.128 mL, 0.923 mmol) at 25° C. and the reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with 2N aqueous HCl solution (15 mL) followed by H2O (20 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified using silica gel column chromatography using a gradient of CH2Cl2:MeOH (100:0 to 95:5) to furnish the desired compound as an off-white solid (120 mg, 48%). MS (ESI): m/z=403.4 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].Cl.O1CCOCC1>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3c(Cl)cccc3n2COCCOC)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2nc3c(Cl)cccc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a mixture of 1-[4-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.370 g, 0.980 mmol) and EtOH (2.5 mL), was added 4M HCl in dioxane (2.5 mL, 10 mmol). The mixture was stirred for 18 h at 23° C. The resulting white precipitate was filtered and washed with EtOH to yield the titled compound (0.260 g, 93%). MS (ESI/CI): mass calcd. for C13H11ClN4O2, 290.1; m/z found, 291.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.83 (s, 1H), 8.98 (s, 1H), 8.45-8.29 (m, 1H), 7.46 (s, 1H), 7.38-7.16 (m, 2H), 4.59-4.01 (m, 2H), 1.60-1.01 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:27])=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:44].[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][C:54](O)=[O:55])[CH2:47][CH2:46]1>C(Cl)Cl>[ClH:44].[CH3:28][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:27][C:54](=[O:55])[CH2:53][CH2:52][CH2:51][N:48]3[CH2:47][CH2:46][O:45][CH2:50][CH2:49]3)=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CC(CCCc1ccc(F)cc1)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
7.10 g. (18.7 mmoles) of 4,4-dimethyl-9-hydroxy-7-(4-p-fluorophenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta [c] [1]benzopyran, prepared according to the method of Example 6, 4.33 g. (21.0 mmoles) of dicyclohexylcarbodiimide and 4.26 g. (20.3 mmoles) of γ-morpholinobutyric acid hydrochloride are combined with 325 ml. of methylene chloride and stirred at room temperature for a total of 24 hours. The insoluble by-product of dicyclohexylurea is separated by filtration and the methylene chloride is removed using a rotary evaporator. The viscous residue is dissolved in about 100 ml. of benzene and the benzene solution is filtered to remove a small amount of insoluble material. The benzene is removed using a rotary evaporator and the remaining residue is triturated with approximately 250 ml. of ether. The solid which forms is filtered, washed with ether and dried to yield a solid. The material is crystallized from benzene/ether to give the solid product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=1)=[O:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.[CH3:39][N:40]([CH:42]=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:26]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]([NH:19][C:20]2[CH:21]=[N:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=2)=[O:18])[CH:39]=[N:40][CH:42]=1
Reactant: CN(C)C=O
Reactant: O=C(Nc1ccc(C(F)(F)F)nc1)c1nn(C2CCCCO2)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)nc1)c1nn(C2CCCCO2)c2ccc(-c3cncc(F)c3)cc12
Temperature: 90 °C
Yield: 88 %

Procedure:
A solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (CXXVIII) (0.469 g, 1 mmol), 5-fluoro-pyridyl-3-boronic acid (CXXIX) (0.156 g, 1.1 mmol), potassium phosphate tribasic (0.318 g, 1.5 mmol) and water (degassed, 1 mL) in DMF (10 mL) was purged with argon. Tetrakis(triphenylphosphine)palladium(0) (0.034 g, 0.03 mmol) was added and the solution was purged again with argon. The reaction was heated to 90° C. for 3 h when TLC showed disappearance of starting material. The solution was cooled to room temperature and excess solvent was removed under vacuum. The residue was treated with water, sonicated briefly and the solids formed were filtered. The solids were washed with cold water and dried under vacuum at room temperature which was purified by silica gel column chromatography (2:8 EtOAc:hexanes→3:7 EtOAc:hexanes) to afford 5-(5-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (CXXX) as a white solid (427 mg, 0.88 mmol, 88% yield). 1H NMR (DMSO-d6) δ ppm 10.95 (s, 1H), 9.25 (d, J=1.8 Hz, 1H), 8.85 (m, 1H), 8.63 (d, J=1.8 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H), 8.53 (m, 1H), 8.16-8.13 (m, 1H), 8.08 (d, J=7.1 Hz, 1H), 7.97-7.94 (m, 2H), 6.11 (dd, J=8.1, 1.8 Hz, 1H), 4.01 (m, 1H), 3.88-3.83 (m, 1H), 2.63-2.60 (m, 1H), 2.11-2.07 (m, 2H), 1.83-1.80 (m, 1H). 1.69-1.65 (m, 2H); ESIMS found for C24H19F4N5O2 m/z 486.0 (M+H).
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)=O.NC1[C:18]([Br:19])=[CH:17][NH:16][N:15]=1>C(O)(=O)C>[Br:19][C:18]1[CH:17]=[N:16][N:15]2[C:5]([C:7]3[CH:11]=[CH:10][S:9][CH:8]=3)=[CH:4][CH:3]=[N:2][C:12]=12
Reactant: CN(C)C=CC(=O)c1ccsc1
Reactant: Nc1n[nH]cc1Br
Solvent: CC(=O)O
Product: Brc1cnn2c(-c3ccsc3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(3-thienyl)-2-propen-1-one and 0.01 mole of 3-amino-4-bromopyrazole in glacial acetic acid is heated at reflux temperature for 8 hours. The solvent is removed in vacuo to give the product of the example.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O=[C:7]1[NH:12][C:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]2[S:23][C:24]([CH3:26])=[CH:25][C:8]1=2.CN(C)C1C=CC=CC=1>>[Cl:3][C:7]1[C:8]2[CH:25]=[C:24]([CH3:26])[S:23][C:9]=2[N:10]=[C:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(-c2nc3sc(C)cc3c(=O)[nH]2)cc1
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1

Procedure:
A mixture of 18 ml of POCl3 with 6 g of methyl 4-(3,4-dihydro-4-oxo-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoate is boiled for 4 hours with the addition of 1.8 ml of N,N-dimethylaniline. Customary working up gives 5 g of methyl 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoate.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH:6]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([OH:20])(=O)=[O:18])=[CH:14][CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8].[Na]>C1S(=O)(=O)CCC1>[O:8]=[C:7]1[C:9](=[O:10])[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:17]([Cl:3])(=[O:20])=[O:18])[CH:12]=2)[NH:6]1
Reactant: O=C1Nc2ccc(S(=O)(=O)O)cc2C1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na]
Solvent: O=S1(=O)CCCC1
Product: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Temperature: 60 °C
Yield: 83 %

Procedure:
(16) Phosphorus oxychloride (13.2 mL, 141.6 mmol) was added to a solution of 5-isatinsulfonic acid (5), sodium salt hydrate (8.0 g, 30.0 mmol) in tetramethylene sulfone (40 mL). The mixture was heated to 60° C. for 3 h, then cooled to 0° C. The reaction mixture was poured into 150 g of ice. The solid was filtered out and washed with cold water, then the solid was dissolved in ethyl acetate (100 mL), washed with water (50 mL×2) and saturated NaCl (50 mL), and dried over Na2SO4. The ethyl acetate was evaporated in reduced pressure to afford 6.12 g (83%) of 6 as a pale yellow solid, mp 188.2-190.1° C. 1H NMR (300 MHz, DMSO) δ 11.1 (s, 1H), 7.82 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 7.60 (s, 1H), 6.89 (d, J=8.1 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@H:25]3[C@H:32]4[C@H:28]([O:29][C:30]([CH3:34])([CH3:33])[O:31]4)[C@@H:27]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH2:26]3)=[C:18]([NH:40][CH2:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:17]=2)[CH2:12]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@H:25]3[C@@H:32]4[O:31][C:30]([CH3:34])([CH3:33])[O:29][C@@H:28]4[C@@H:27]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH2:26]3)=[C:18]([NH:40][CH2:41][CH:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:17]=2)[CH2:12]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reaction time: 8 h

Procedure:
To a solution of {(R)-1-[9-((3aS,4R,6S,6aR)-2,2-dimethyl-6-propionylamino-tetrahydro-cyclopenta[1,3]dioxol-4-yl)-6-(2,2-diphenyl- ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid benzyl ester (0.598 g, 0.79 mmol) in ethanol (7.5 ml) under an inert atmosphere of Argon is added palladium hydroxide on carbon (10 mg). The reaction mixture is purged with Argon and placed under an atmosphere of hydrogen overnight. The mixture is filtered and purified by chromatography on silica eluting with 5% MeOH in DCM to yield the title d compound. [MH+ 611].
Reaction SMILES: C([O:6][CH2:7][C@@H:8]1[O:17][C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])(=O)CCC.[OH-].[K+].CO>>[O:17]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C@@H:8]1[CH2:7][OH:6]
Reactant: CCCC(=O)OC[C@@H]1O[C@@H]1CCCCC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCCC[C@H]1O[C@H]1CO
Yield: 93.8 %

Procedure:
3.6 g of (-)-(2S,3R)-1-butyroxy-2,3-epoxy-8-methylnonane was hydrolyzed with potassium hydroxide/methanol to yield 2.4 g of (-)-(2S,3R)-2,3-epoxy-8-methyl-1-nonanol.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]>ClCCl.FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccc(C#N)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Yield: 69.7 %

Procedure:
The solution of tert-butyl 4-(4-cyanophenoxy)benzoate (80 mg, 0.27 mmol) in dichloromethane: trifluoroacetic acid (4:1, 3 mL) was stirred overnight at room temperature. The solvent was evaporated in vacuo to give 4-(4-cyanophenoxy)benzoic acid (45 mg, 70%). LRMS (M+H+) m/z: calcd 239.06. found 239.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][O:12]C)=[CH:6][CH:5]=1.Cl>C1COCC1.O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[O:12])=[CH:6][CH:5]=1
Reactant: COC=Cc1ccc(C(=O)OC)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CC=O)cc1
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a 0° C. solution of 4-(2-Methoxy-vinyl)-benzoic acid methyl ester (930 mg, 4.84 mmol) in THF (50 mL) is added conc. HCl (7 mL) dropwise. After 2 h, the reaction is diluted with water and the pH is adjusted to 7. The aqueous layer is extracted with Et2O (2×200 mL). The combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated, and chromatographed (0% to 30% EtOAC/Hex) to yield the title compound (613 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 9.77 (t, 1H, J=2.2 Hz), 8.04 (d, 2H, J=8.4 Hz), 7.30 (d, 2H, J=8.8 Hz), 3.92 (s, 3H), 3.77 (d, 2H, J=2.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[S:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1>[N+](C1C=CC=CC=1)([O-])=O>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][C:4]=2[N:10]=[C:14]2[CH2:15][CH2:16][S:11][CH2:12][C:13]=12
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: O=C1CCSCC1
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc2c(N)c3c(nc2c1)CCSC3
Temperature: 50 °C
Yield: 61.2 %

Procedure:
A mixture of 4-methylanthranilonitrile (4.46 g) and freshly fused zinc (6.8 g) in 20 ml of nitrobenzene was heated at 50° C. for 1 hour. To this was added tetrahydrothiopyran-4-one (5.1 g) and the mixture was heated to 130° C. for 1.5 hours. After cooling, the zinc complex was filtered, rinsed with ethyl ether and partitioned between 2-butanone (MEK) and NH4OH. The aqueous phase was extracted with MEK and the organics were washed with water and dried (saturated NaCl, MgSO4). This was concentrated to give 4.76 g of an off-white powder, m.p. 239°-245° C. d., which was recrystallized from ethyl acetate to give 2.95 g of an off-white powder, m.p. 243°-246° C. d.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:38][CH:39]([CH3:56])[CH2:40][C@@H:41]([B:43]1[O:47][C@@H:46]2[CH2:48][C@@H:49]3[CH2:52][C@H:51]([C@:45]2([CH3:55])[O:44]1)[C:50]3([CH3:54])[CH3:53])[NH2:42].FC(F)(F)C([O-])=O.CCN(C(C)C)C(C)C>CN(C)C=O>[F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:42][C@H:41]([B:43]1[O:47][C@H:46]2[CH2:48][C@H:49]3[CH2:52][C@@H:51]([C@@:45]2([CH3:55])[O:44]1)[C:50]3([CH3:53])[CH3:54])[CH2:40][CH:39]([CH3:56])[CH3:38])=[O:10])=[O:5]
Reactant: O=C(O)CNC(=O)c1cccc(F)c1F
Reactant: CC(C)C[C@H](N)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)CNC(=O)c1cccc(F)c1F)B1O[C@H]2C[C@H]3C[C@H](C3(C)C)[C@@]2(C)O1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of [(2,3-difluorobenzoyl)amino]acetic acid (0.205 g, 0.95 mmol) in dimethylformamide (10 mL) were added TBTU (0.337 g, 1.0 mmol) and (1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butan-1-amine as its trifluoroacetate salt (0.362 g, 0.95 mmol). The mixture was allowed to cool to 0° C. and DIEA (0.498 mL, 2.9 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (100 mL) and the product partitioned into DCM. The organic layer was dried over sodium sulfate and the solvent removed to give 2,3-difluoro-N-[2-({(1R)-3-methyl-1-[(3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].O.[F:6][CH:7]([F:21])[O:8][C:9]1[C:10]([F:20])=[C:11]([CH:15]=[C:16]([F:19])[C:17]=1[F:18])[C:12]([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:21][CH:7]([F:6])[O:8][C:9]1[C:10]([F:20])=[C:11]([C:15]([N+:1]([O-:4])=[O:2])=[C:16]([F:19])[C:17]=1[F:18])[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
20 ml of concentrated aqueous nitric acid (d=1.42) were added dropwise, whilst stirring and cooling with water, to a solution of 15.0 g (0.062 moles) of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid [(XXV), X=X'=F] (prepared as described in Preparation 1, 2 or 3) in 40 ml of concentrated aqueous sulfuric acid, and the mixture was stirred at 60° C. for 7 hours. At the end of this time, it was allowed to stand to cool to room temperature, and then the reaction mixture was poured into ice-water, and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure, to give 16.6 g of 3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoic acid as a yellow powder, melting at 77°-80° C.
Reaction SMILES: [CH2:1]([C:7]1[N:8]2[C:12](=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=1[C:15](=O)[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:11][CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].O.NN>C(O)COCCO>[CH2:1]([C:7]1[N:8]2[C:12](=[C:13]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:11][CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1c(C(=O)CCCC(=O)O)c(-c2ccccc2)c2n1CCC2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCCCc1c(CCCCC(=O)O)c(-c2ccccc2)c2n1CCC2

Procedure:
1 mmole of 71 is reacted in 10 ml of diethyleneglycol with 50 mmoles (2.8 g) of KOH and 30 mmoles (1.5 g) of hydrazine hydrate similarly to the procedure for reducing the 4-(diphenyl-2,3-dihydro-1H-pyrrolizinyl)-4-oxobutyric acids. Product purification is by means of column chromatography (silica gel/diisopropylether). After concentrating the eluates, 72 remains as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[C:1]([O:5][C:6](=[O:32])[N:7]([CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([C:39]([C:38]2[S:37][C:36]3[CH:42]=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:13][CH2:14]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(C)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C)nc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared from amine (281) (200 mg, 0.45 mmol) and acid chloride 6 (170 mg, 6.8 mmol) following Method D.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A suspension of 2-methyl-5-nitrobenzotrifluoride (3.90 g, 19 mmol), N-bromosuccinimide (NBS, 3.56 g, 20 mmol), and 2,2′-azobis(2-methylpropionitrile) (AIBN, 0.094 g, 0.6 mmol) in 40 mL of CCl4 was heated at reflux under N2 for 16 h. HPLC indicated ca. 50% conversion. Additional NBS (10 mmol) and AIBN (0.6 mmol) were added and the mixture was heated at reflux for another 14 h. HPLC indicated ca. 80% conversion. The reaction mixture was cooled to ambient temperature, and the solid was filtered and washed with EtOAc. The combined filtrate was washed with aq. NaHCO3, dried over Na2SO4, filtered, concentrated on rotovap, and further dried under vacuum. 1H NMR indicated the ratio of desired product to unreacted 2-methyl-5-nitrobenzotrifluoride to be 75:25. This material was used directly in the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].ClC(Cl)(Cl)[C:11]([C:13]([F:16])([F:15])[F:14])=[O:12]>CS(C)=O>[F:14][C:13]([F:16])([F:15])[C:11]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:12]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(C(F)(F)F)C(Cl)(Cl)Cl
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
A mixture of 7.4 mmol of L-valine, 10 ml of dimethyl sulfoxide and 23 mmol of sym-trichlorotrifluoroacetone was stirred at room temperature for 24 hours in a flask protected from atmospheric moisture. A complete solution was obtained within the first hour. The progress of the reaction was followed by taking samples periodically and submitting them to gas-liquid chromatographic analysis. The reaction mixture was poured into 50 ml of ice water and the resultant mixture was extracted thrice with n-butanol and chromatographed on a column packed with silica gel. N-trifluoroacetylvaline, melting at 88°-89° C., was obtained in a yield of 94 percent.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:32])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([C:20]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])=O)[CH:11]=[CH:10][C:9]1=2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][C:8]1([CH3:32])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([C:20]([C:22]3[CH:23]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:29]=[CH:30][CH:31]=3)=[CH2:1])[CH:11]=[CH:10][C:9]1=2
Reactant: COC(=O)c1cccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: C=C(c1cccc(C(=O)OC)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (3 g, 26.5 mmol) is added to a solution of methyl 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylcarbonyl)benzoate (6.6 g, 18.9 mmol) and methyltriphenylphosphonium bromide (9.4 g, 26.3 mmol) in THP (60 ml). The mixture is stirred for 1 h at room temperature. The solution is extracted with ethyl acetate. After separation of the phases by settling, the organic phase is washed twice with 40 ml of water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica.