Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1C(=O)[O:11][N:10]=[C:9]1[C:14]1[C:18]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:17][O:16][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[CH2:1]([NH:8][C:9]([C:14]1[C:18]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:17][O:16][N:15]=1)=[N:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1onc(-c2nonc2NCc2ccccc2)n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=C(NCc1ccccc1)c1nonc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A solution of 4-benzyl-3-[4-(benzylamino)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one (12 mg, 34 μmol) in ethanol (1 mL) was treated with 2 M sodium hydroxide in water (300 μL) and stirred at 25° C. for 30 min. The reaction mixture was quenched with acetic acid and purified by preparative HPLC to give the desired product (10 mg, 90%) as a white solid. LCMS for C17H18N5O2 (M+H)+: m/z=324.2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.P(Br)(Br)[Br:15]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Br:15])=[O:8])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Product: O=C(Br)c1ccc(C(F)(F)F)cc1
Yield: 169.7 %

Procedure:
In a 50 ml glass reactor, 30 g of 4-trifluoromethylbenzoic acid and 14.5 g of phosphorus tribromide were reacted at 155° C. for 3 hr. After that the reaction liquid was distilled under reduced pressure to obtain 23 g of 4-trifluoromethylbenzoyl bromide having a boiling point of 88°-89° C. at 18 mmHg. The yield in this reaction was 58%.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.O.[H][H]>[Pd].CO>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)CCNc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CN(C)CCNc1ccccc1N
Reaction time: 20 h

Procedure:
N-(2-(dimethylamino)ethyl)-2-nitrobenzenamine (2.0 g, 14 mmol) and 10% palladium on carbon, wet, 50% water (3.0 g) were combined under nitrogen. 30 mL MeOH was added via syringe, and the atmosphere was replaced with hydrogen from a balloon. The reaction was stirred rapidly for 20 h, at which point the reaction was flushed with nitrogen, and filtered through a pad of Celite®, and concentrated in vacuo to give N1-(2-(dimethylamino)ethyl)benzene-1,2-diamine as a red-brown solid. This material was used without further purification. MS m/z=180 [M+H]+. Calc'd for C10H17N3: 179.3.
Reaction SMILES: CN(C=[N:5][C:6]1[N:7]([CH2:11][CH:12]=[CH2:13])[CH:8]=[CH:9][N:10]=1)C>Cl>[NH2:5][C:6]1[N:7]([CH2:11][CH:12]=[CH2:13])[CH:8]=[CH:9][N:10]=1
Reactant: C=CCn1ccnc1N=CN(C)C
Agent: Cl
Product: C=CCn1ccnc1N

Procedure:
2-(Dimethylaminomethylene)amino-1-(2-propenyl)imidazole (0.2 g) was dissolved in 6N hydrochloric acid (5 ml), and the solution was heated under reflux for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in aqueous saturated sodium carbonate solution (1 ml). The solution was concentrated under reduced pressure, the organic compounds were extracted with chloroform, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: chloroform-methanol-ammonia water=20: 1:0.1) to give 2-amino-1-(2-propenyl)imidazole. This compound was dissolved in dichloromethane, and 4N hydrochloric acid-ethyl acetate (2 ml) was added to form its hydrochloric acid salt. The salt was recrystallized from acetonitrile to give 2-amino-1-(2-propenyl)imidazole hydrochloride (0.19 g, Yield: 71%) as pale yellow needles.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH3:23][N:24]([CH3:39])[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[S:35](Cl)(=[O:37])=[O:36]>C(Cl)(Cl)Cl>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:35]([C:30]3[C:31]4[C:26](=[C:25]([N:24]([CH3:39])[CH3:23])[CH:34]=[CH:33][CH:32]=4)[CH:27]=[CH:28][CH:29]=3)(=[O:37])=[O:36])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: ClC(Cl)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12
Yield: 53.3 %

Procedure:
Using the general method of Example 245 except that chloroform was used as the solvent, 1-(3-aminopropyl)-2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with 5-dimethylamino-1-naphthalenesulfonyl chloride (5.87 mmol) to provide 1.45 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-5-(dimethylamino)naphthalene-1-sulfonamide as a yellow solid, m.p. 210-215° C. Analysis: Calculated for C28H32N6O3S.1.50 H2O: %C, 60.09; %N, 15.02; Found: %C, 59.89; %H, 6.22; %N, 14.86.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:8]=[C:9]=[O:10])([CH3:7])[CH3:6].[C-]#N.[CH3:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([NH:8][C:9](=[O:10])[N:17]([CH3:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:7])[CH3:6]
Reactant: CCCCCNC
Reactant: CC(C)(N=C=O)c1cccc(Cl)c1
Agent: [C-]#N
Solvent: CCCCCC
Product: CCCCCN(C)C(=O)NC(C)(C)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A solution of 3.9 g of m-chloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, in 10 ml of n-hexane was added to 4 g of N-methyl-N-pentylamine and the mixture was allowed to stand overnight. The precipitated crystals were separated by filtration and washed thoroughly with n-hexane to obtain 5.4 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([NH:17]N)[CH:9]=1.[C:19]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]2[C:9]=1[C:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=1[NH:17]2
Reactant: NNc1cc(-c2ccccc2F)ccc1C(=O)O
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2ccccc2F)c2c3c([nH]c12)CCCC3
Temperature: 25 °C
Yield: 34.4 %

Procedure:
Step 4 A solution of 2′-fluoro-3-hydrazinylbiphenyl-4-carboxylic acid (0.306 g, 1.24 mmol) and cyclohexanone (0.183 g, 1.86 mmol) in acetic acid (6.2 mL) was heated at reflux under nitrogen for 2 h. The mixture was cooled to rt and concentrated. The residue was partitioned between EtOAc and 1 M hydrochloric acid. The organic layer was washed with brine, dried and concentrated. The residue was triturated with EtOAc and DCM to give 5-(2-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (0.132 g) as a white solid. The filtrate was purified by column chromatography (eluting with a gradient from hexane to 50:50 EtOAc-hexane) to give additional product (0.029 g, 41% total). 1H NMR (400 MHz, DMSO-d6) δ 12.95 (br s, 1H), 10.79 (s, 1H), 7.68 (d, J=7.15, 1H), 7.42-7.51 (m, 1H), 7.24-7.34 (m, 3H), 6.87 (d, J=7.15, 1H), 2.67-2.82 (m, 2H), 1.89-2.10 (m, 2H), 1.65-1.81 (m, 2H), 1.44-1.63 (m, 2H). Mass spectrum m/z 310.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[Li+].CC([N-]C(C)C)C.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Br>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C:4]1([CH2:26][C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[CH3:29])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]1
Reactant: Cc1ccccc1CBr
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-t-butoxycarbonyl isonipecotic acid methyl ester (10.1 g 41.8 mmol) in 140 ml of dry THF at -78° C. was added LDA (59 ml of a 1.0M solution in THF, 59 mmol) over 15 min. The resulting orange solution was stirred at -78° C. for 1 hr and then treated dropwise with 2-methylbenzyl bromide (6.80 ml, 50.7 mmol) and then allowed to warm slowly to room temperature over 16 hrs. The reaction was quenched with saturated aqueous NH4Cl, diluted with H2O, and extracted with EtOAc. The combined organic extracts were washed with brine, and concentrated in vacuo to an orange gum. Chromatography (SiO2, eluting with 20 to 30% EtOAc in hexanes) and evaporation of solvent in vacuo, afforded the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:24][C:25]([O:27]C)=[O:26])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=2.Cl>O>[Br:1][C:2]1[N:3]([CH2:24][C:25]([OH:27])=[O:26])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH:5]=2
Reactant: COC(=O)Cn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Agent: Cl
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)O)c2c1
Temperature: 50 °C

Procedure:
A solution of LiOH monohydrate (4 eq) in H2O (0.05 M) was added to a solution of tert-butyl 2-bromo-3-cyclohexyl-1-(2-methoxy-2-oxoethyl)-1H-indole-6-carboxylate (1 eq) in a mixture THF: CH3OH (1:1) (from Step 6, 0.05 M). The reaction was heated at 50° C. for 2 h, before being allowed to cool to RT and reducing the volatiles in vacuo. The residue was then acidified with aqueous HCl (1 N) and the resultant precipitate filtered off, washed with water and dried in vacuo to afford the title compound (quant.); MS (ES+) m/z 436 (M+H)+, 438 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:15])[C@H:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:10]=1.[H-].[Na+].[CH3:38]I>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:38])[CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[O:15])[C@H:11]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)N2CC(c3cc(F)ccc3F)=C[C@H]2c2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Crude 18-3 (100 mg, 0.2 mmol) was dissolved in anhydrous DMF (3 mL) and cooled to 0° C. under N2. NaH (28 mg, 1.17 mmol) was added neat and the reaction was stirred 30 minutes at 0° C. Following cessation of H2 evolution, MeI (0.15 mL, 2.4 mmol) was added and the reaction was stirred 12 hours at 25° C. Upon completion, the reaction was diluted with EtOAc (10 mL), and the organic layer was washed successively with 5% NH4Cl (1×10 mL), H2O (3×5 mL) and brine (1×10 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude oil was dissolved in anhydrous CH2Cl2 (10 mL). The resulting solution was treated with trifluoroacetic acid (5 mL) and stirred 1 hour at 25° C. Upon completion, the reaction was concentrated and directly subjected to reverse-phase column chromatography to provide 18-4: 1H NMR (300 MHz, CD3OD) δ 7.33 (m, 4H), 7.25 (m, 2H), 7.17 (m, 1H), 7.08 (m, 1H), 6.41 (s, 1H), 6.00 (t, J=2.7 Hz, 1H), 5.07 (ddd, J=14.0, 5.6, 1.7 Hz, 1H), 4.55 (d, J=14.0 Hz, 1H), 3.82 (m, 1H), 3.40 (m, 2H), 3.03 (dt, J=12.5, 3.9 Hz, 1H), 2.88 (s, 3H), 2.81 (dt, J=13.1, 2.9 Hz, 1H), 1.90 (m, 4H); LRMS m/z (M+H) 398.0 found, 398.2 required.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[H-].[K+].C([Li])(C)(C)C.C(O[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)(C)C>C1COCC1>[CH3:11][C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)=[CH:10][CH:9]=2
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
A solution of 5-bromo-2-methyl-1H-indole (5.04 g, 24 mmol) in THF (25 mL) was added dropwise to a suspension of potassium hydride (3.2 g, 24 mmol) in THF at 0° C. After fifteen minutes at 0° C., the solution was cooled to −78° C. and a t-butyl lithium solution (1.7 M in pentane, 28.2 mL, 48 mmol) was added dropwise via syringe while maintaining the temperature below −55° C. After an additional 15 minutes, the solution was cooled to −78° C. and treated with a 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (9.8 mL, 48 mmol) dropwise via syringe. The solution was stirred at −78° C. for 1.5 hours, allowed to warm to room temperature and quenched with saturated aqueous ammonium chloride. The solution was diluted with ethyl acetate and filtered to remove inorganic material. The filtrate was extracted with ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and concentrated. The concentrate was purified by flash chromatography on silica gel using 10% ethyl acetate/hexanes to give 3.9 g (63% yield) of the desired product. MS (ESI(+)) m/e 258 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:17][N:18]3[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:21]=4[N:20]([CH:27]4[CH2:29][CH2:28]4)[C:19]3=[O:30])[N:10]([CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15])[C:5]2=[CH:4][CH:3]=1.[Li][CH3:32]>C1COCC1.O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:17][N:18]3[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:21]=4[N:20]([CH:27]4[CH2:29][CH2:28]4)[C:19]3=[O:30])[N:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])([CH3:32])[CH3:15])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ketone 75-1 (210 mg, 0.497 mmole) in THF was added MeLi (0.466 mL, 1.5 eq, 1.6 M in THF) dropwise, at 0° C. The resulting mixture was stirred at RT overnight, then was heated at 50° C. for 2 hours. After cooling to RT, the reaction mixture was poured in water, extracted with dichloromethane, dried over MgSO4 and concentrated. The residue was purified by column chromatography using dichloromethane and methanol, followed by a purification by prep HPLC on RP SunFire Prep C18 OBD-10 μm,30×150 mm, and mobile phase (0.25% NH4HCO3 solution in water, CH3CN) to give 11 mg of the desired compound 75. LCMS m/z=441 (M+H)+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97-1.05 (m, 2 H), 1.11-1.22 (m, 2 H), 1.17 (s, 6 H), 1.43-1.53 (m, 2 H), 1.74 (br. s., 1 H), 1.79-1.91 (m, 2 H), 2.82-3.05 (m, 1 H), 4.40 (t, J=7.5 Hz, 2 H), 5.39 (s, 2 H), 7.11 (d, J=5.0 Hz, 1 H), 7.20 (d, J=8.3 Hz, 1 H), 7.64 (d, J=8.3 Hz, 1 H), 8.31 (d, J=5.0 Hz, 1 H), 8.70 (s, 1 H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1)([OH:3])=[O:2].[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1)([O:3][CH2:15][CH3:16])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCCCCC1=CCCC1=O
Solvent: CCO
Product: CCOC(=O)CCCCCC1=CCCC1=O

Procedure:
A solution of 1.309 g. (0.00668 mole) of 2-(5-carboxypentyl)-2-cyclopentenone (Example 26) and 90 mg. of p-toluensulfonic acid in 150 ml. of ethanol is refluxed for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The organic phase is washed with water, sodium bicarbonate solution, and saturated saline solution, dried (MgSO4), and evaporated to give 1.371 g. of a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([O:10]COC)=[CH:8][C:7]([O:14]COC)=[CH:6][C:5]=1[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C(O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([OH:10])=[CH:8][C:7]([OH:14])=[CH:6][C:5]=1[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCOc1cc(COCc2ccccc2)c(C(=O)OC)c(OCOC)c1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1c(O)cc(O)cc1COCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 154.2 %

Procedure:
The above-obtained 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzoic acid methyl ester (10 mg, 0.027 mmol) was dissolved in ethanol (4 mL) and the obtained solution was added with concentrated hydrochloric acid (0.10 mL) and stirred at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=20/1) to obtain Compound 22 (12 mg, 100%).
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][CH:8]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])C(OCC)=O)=[CH:5][CH:4]=1.Br.O>C(O)(=O)C>[F:16][C:15]([F:17])([F:18])[C:14](=[O:19])[CH2:8][CH2:7][C:6]1[CH:20]=[CH:21][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(=O)C(F)(F)F
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCc1ccc(O)cc1)C(F)(F)F
Temperature: 120 °C

Procedure:
A 100 mL round bottom flask, fitted with reflux condenser, magnetic stirrer and argon inlet was charged with 2.05 g (6.7 mmol) of ethyl 2-(4-methoxybenzyl)-3-oxo-4,4,4-trifluorobutanoate (I), 20 mL of 31% (w/v) hydrogen bromide in acetic acid, and 10 mL of water. This mixture was heated overnight at 120° C., cooled, concentrated under reduced pressure and partitioned between dichloromethane and water. The organic layer was extracted sequentially with aqueous bisulfite, and saturated sodium bicarbonate, and then dried over anhydrous magnesium sulfate. Solvent was removed under reduced pressure. The crude reaction mixture was chromatographed on a 50 mm×300 mm silica gel column with ethyl acetate/hexane (50/50). Similar fractions were combined and the solvent was removed under reduced pressure to yield 600 mg (41%) as a clear oil. NMR(CDCl3): 2.95(m,4H), 5.40(bs, 1H), 6.93(dd,4H) J=4, 60 Hz.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:28][C@@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:33]2[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)ccc2N2C[C@H](O)[C@@H](O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 7 using 3-bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 7.1) and (6-methylpyridin-3-yl)boronic acid to afford a yellow solid. UPLC-MS (condition 1) tR=1.65 min, m/z=474.0 [M+H]+, m/z=472.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H) 2.74 (d, J=10.76 Hz, 2H) 3.25 (dd, J=10.51, 3.67 Hz, 2H) 3.85 (br. s, 2H) 5.03 (br. s, 2H) 6.90 (d, J=8.80 Hz, 1H) 7.27-7.38 (m, 3H) 7.68 (dd, J=7.82, 2.20 Hz, 1H) 7.77 (d, J=2.20 Hz, 1H) 7.85-7.88 (m, 2H) 7.87-7.91 (m, 1H) 8.48 (d, J=2.20 Hz, 1H) 10.09 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](=[O:16])[O:13][C@@H:14]([CH3:15])[C@@H:7]1[CH2:6][CH2:5]2.Br[CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:15][C@H:14]1[C@@H:7]2[CH2:6][CH2:5][C:4]3[C:9]([N:8]2[C:12](=[O:16])[O:13]1)=[CH:10][CH:11]=[C:2]([O:1][CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:3]=3
Reactant: FC(F)(F)CCCBr
Reactant: C[C@@H]1OC(=O)N2c3ccc(O)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1OC(=O)N2c3ccc(OCCCC(F)(F)F)cc3CC[C@@H]12
Temperature: 90 °C
Yield: 75.9 %

Procedure:
To a solution of 0.70 g (3.2 mmol) of cis-(±)-7-hydroxy-3-methyl-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one in 15 ml of dimethylformamide are added 0.90 g (4.8 mmol) of 1-bromo-4,4,4-trifluorobutane and 0.90 g (6.4 mmol) of potassium carbonate. The mixture is heated at 90° C. for 4 hours and then diluted with ethyl acetate and washed with water. The organic phase is then dried over sodium sulphate and concentrated under reduced pressure, and the residue is chromatographed on a column of silica, with cyclohexane containing 20% of ethyl acetate. After trituration in diisopropyl ether, 0.80 g of product is obtained.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]2[CH3:21])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:22]([OH:25])[CH2:23][OH:24].CC([O-])(C)C.[K+]>CS(C)=O>[OH:24][CH2:23][CH2:22][O:25][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]2[CH3:21])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OCCO
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1OCCO
Temperature: 50 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A mixture of tert-butyl (3R)-4-(3-chloropyrazin-2-yl)-3-methylpiperazine-1-carboxylate* (35 g, 0.11 mol), ethylene glycol (100 g, 1.61 mol) and t-BuOK (25 g, 0.22 mol) in DMSO (150 g) was stirred at 50° C. for 3 h. After this time, the reaction mixture was partitioned between EtOAc (500 g) and water (500 g) and sodium chloride (20 g) was added. The organic layer was concentrated in vacuo to furnish 32.5 g (87%) of the title product. HPLC purity: 75%. HRMS m/z calcd for C16H26N4O4 (M)+ 338.1954, found 338.1959. *Described in WO 00/76984, Example 172, Step 2.
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=5[C:32]([OH:34])=O)[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[CH:40]1([NH2:43])[CH2:42][CH2:41]1.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[F:39][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=5[C:32]([NH:43][CH:40]5[CH2:42][CH2:41]5)=[O:34])[O:27][N:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: NC1CC1
Reactant: O=C(O)c1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CC1)c1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoic acid (105 mg) in dichloromethane (10 ml) are added, at room temperature, cyclopropanamine (11 mg), 4-dimethylaminopyridine (2 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (37 mg). The mixture is stirred at room temperature for 3 hours and then admixed with water. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}-N-cyclopropylbenzamide (78 mg).