Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[K+].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.[F:35][C:36]([F:45])([F:44])[C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>CO>[F:35][C:36]([F:44])([F:45])[C:37]1[CH:38]=[CH:39][C:40]([NH:41][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[CH:42][CH:43]=1
Reactant: CC(C)[C@H](Br)C(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O

Procedure:
1.5 Grams (8.3 mmol) of the (S)-2-bromo-3-methylbutanoic acid is titrated with 8 ml of 1 M potassium hydroxide in methanol to a phenolphthalein endpoint. The solution is evaporated under high vacuum at 40° for 1 hour, and 0.51 g (2.33 mmol) of the resulting salt is heated together with 1.52 g (9.43 mmol) of 4-trifluoromethylaniline at 90°-95° under nitrogen for 1 hour. Heating is discontinued and the reaction worked up immediately by partition between ether/5% sodium hydroxide. The layers are separated and the organic phase is extracted with 5% sodium hydroxide (2×). The aqueous layers are combined and washed with ether (2×), then acidified with ice and conc. HCl and extracted with ether (3×). The latter ether extracts are washed with brine, dried over magnesium sulfate, filtered and evaporated, giving (S)-2-(4-trifluoromethylphenylamino)-3-methylbutanoic acid.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>C(O)C>[CH2:2]([O:4][C:8]1[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=1)[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)c1cccnc1Cl
Agent: [K+]
Solvent: CCO
Product: CCOc1ncccc1C(=O)O
Temperature: 170 °C
Yield: 86.3 %

Procedure:
A solution of potassium t-butoxide (44.9 g, 0.40 mol) in absolute ethanol (300 ml) was added slowly to a solution of 2-chloronicotinic acid (30 g, 0.19 mol) in absolute ethanol (100 ml) and the reaction mixture heated in a sealed vessel at 170° C. for 20 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure, the residue dissolved in water (200 ml) and the solution acidified to pH 3 with hydrochloric acid and extracted with dichloromethane (4×200 ml). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give the title compound (27.4 g, 41%) as a white solid. δ (CDCl3): 1.53 (3H,t), 4.69 (2H,q), 7.13 (1H,m), 8.37 (1H,d), 8.48 (1H,d).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:21][CH3:22])=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[CH2:5][NH:4]1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[CH2:37]Cl.[Cl-].[NH4+]>CN(C=O)C.O>[CH2:1]([CH:3]1[CH2:12][CH:11]2[C:6](=[CH:7][C:8]([O:21][CH3:22])=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH2:5][N:4]1[CH2:37][C:36]1[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:34]([O:33][CH3:32])[CH:35]=1)[CH3:2]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CCC1Cc2cc(OCc3ccccc3)c(OC)cc2CN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC1CC2CC(OCc3ccccc3)=C(OC)C=C2CN1Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C

Procedure:
A solution of 261 (297 mg, 1.0 mmol) in anhydrous DMF (3.0 mL), DIPEA (264 mg, 2.0 mmol) and 3,4,5-trimethoxybenzyl chloride (238 mg, 1.1 mmol) was heated to 80° C. for 12 h, cooled to room temperature and poured into water (50 mL) and ammonium chloride (saturated, 2 mL). The mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography using Flashmaster (SiO2: 20 g, hexane 100% to hexane/ethyl acetate 50:50). The title compound was obtained as pale yellow oil (350 mg, 73%). 1H NMR (270 MHz, CDCl3) δ 0.97 (3H, t, J 7.0, CH2CH3), 1.43 (1H, sept, J 7.0, one of CH2CH3), 1.67 (1H, sept, J 7.0, one of CH2CH3), 2.42-2.58 (1H, m, one of ArCH2CH), 2.72-2.95 (2H, m, one of ArCH2CH, CHN), 3.51-3.74 (4H, m, 2×ArCH2N), 3.80 (3H, s, OCH3), 3.83 (6H, s, 2×OCH3), 3.88 (3H, s, OCH3), 5.10 (2H, s, OCH2Ph), 6.45-6.56 (1H, m, CH), 6.56-6.70 (3H, m, 3×CH), 7.24-7.52 (5H, m, OCH2C6H5).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O)=O>C1(C)C=CC=CC=1>[CH:9]1([N:15]=[C:1]([C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)[CH3:2])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC1CCCCC1
Reactant: CC(=O)c1cccs1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CC(=NC1CCCCC1)c1cccs1
Yield: 101.3 %

Procedure:
378 g (3 moles) of acetylthiophene, 594 g (6 moles) of cyclohexylamine and 6 ml of formic acid are azeotropically dehydrated by means of 1 liter of toluene. When all the water has been removed, the solution is cooled and the toluene and excess amine are removed under reduced pressure of 18 mm of mercury, without exceeding 120° C. in the reactor. In this way, 630 g of acetylthiophene N-cyclohexylimine are obtained, titrating 94.5% by gas phase chromatography, namely a yield of 97%. NMR spectrum in carbon tetrachloride
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[C:20](I)[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])(=[O:11])=[O:10].[ClH:23].C[O:25][C:26](=[O:38])[C@@H:27]([NH2:37])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:14]([C:15]([NH:37][C@@H:27]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([OH:25])=[O:38])=[O:16])=[C:13]([NH:12][S:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])(=[O:11])=[O:10])[CH:21]=1
Reactant: Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
2-(2,6-Difluoro-benzenesulfonylamino)-4-iodo-benzoic acid was coupled to (S)-2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=11.00 min. MS (ESI−): mass calcd. for C22H15Cl3F2N2O5S2, 563.79; m/z found, 561/563 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.45 (s, 1H), 7.75 (d, 1.9, 1H), 7.56-7.45 (m, 1H), 7.36 (d, J=8.2, 1H), 7.29-7.25 (m, 2H), 7.05-6.97 (m, 4H), 6.62 (d, J=7.0, 1H), 5.03 (q, J=5.5, 1H), 3.39-3.17 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[Cl:21][C:22]1[S:26][C:25]([C:27]([C:29]2[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=2)=[O:28])=[CH:24][CH:23]=1>>[Cl:20][C:16]1[CH:15]=[C:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:27]([C:25]4[S:26][C:22]([Cl:21])=[CH:23][CH:24]=4)([C:29]4[N:30]([CH3:34])[CH:31]=[N:32][CH:33]=4)[OH:28])[CH:3]=3)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)s1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)s3)c3cncn3C)ccc2n1
Yield: 99 %

Procedure:
Following the same procedure as described in example 1E, 6-bromo-4-(3-chloro-phenyl)-2-methoxy-quinoline (1.0 g, 1.87 mmol) and (5-chloro-thiophen-2-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (170 mg, 3.44 mmol) generated the title compound of 18A as a yellow solid (919 mg, 65% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:17]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=S.[CH:25]1([C:28]([NH:30][NH2:31])=O)[CH2:27][CH2:26]1>O1CCCC1.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH:25]1([C:28]2[N:2]([CH3:1])[C:3]([C:5]3[CH:6]=[C:7]([CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[CH:17]=3)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:31][N:30]=2)[CH2:27][CH2:26]1
Reactant: CNC(=S)c1cc(C(=O)OC(C)(C)C)cc(-c2ccc(C)cn2)c1
Reactant: NNC(=O)C1CC1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(-c3nnc(C4CC4)n3C)c2)nc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 3-[(methylamino)carbonothioyl]-5-(5-methylpyridin-2-yl)benzoate (0.56 g, 1.64 mmol) in tetrahydrofuran (15 mL) were added cyclopropanecarbohydrazide (0.49 g, 4.92 mmol) and mercury(II) acetate (1.05 g, 3.28 mmol). The reaction mixture was heated to 40° C. After 18 h, the mixture was cooled to ambient temperature. The mixture was filtered and the filtrate was concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound. MS 391.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH2:16].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1Cl>CN(C)C1C=CN=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:22]1[CH:21]=[CH:20][C:19]2[C:18](=[CH:11][CH:2]=[CH:3][CH:4]=2)[CH:23]=1
Reactant: Clc1ccccc1Cl
Reactant: O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Product: COc1cc2nccc(Oc3ccc4ccccc4c3)c2cc1OC
Temperature: 150 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-1-naphthonic acid (252 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 150° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (41 mg, yield 28%).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]#[N:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][Cl:24].O>CN(C=O)C.C(OCC)(=O)C>[Cl:24][CH2:23][CH2:22][CH2:21][C:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([C:16]#[N:17])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: ClCCCBr
Reactant: N#CC1c2ccccc2C=Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1c2ccccc2C=Cc2c(CCCCl)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5H-dibenzo[a,d]cycloheptene-5-carbonitrile (described in J. Med Chem. 1994, 37, 804-810) (500mg) in DMF (10 ml) were added 60% sodium hydride (110 mg) and 1-bromo-3- chloropropane (0.30 ml) and the mixture was stirred at room temperature for 1 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 5-(3-chloropropyl-5H-dibenzo[a,d]cycloheptene-5-carbonitrile. Without purification, to a solution obtained chloride in DMF (10 ml) were added 4-(4-chlorophenyl)-4- hydroxypiperidine (650 mg), potassium carbonate (950 mg), and potassium iodide (50 mg) and the mixture was stirred at 70° C. for 24 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (700 mg). 1H-NMR (CDCl3) d: 1.22-1.34(2H,m), 1.60-1.80(3H,m), 1.93-1.99(2H,m), 2.16-2.28(6H,m), 2.56-2.60(2H,m), 6.98(2H,s), 7.25-7.47(10H,m), 8.00-8.03(2H,m). MS m/z: 469(M+1)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.ClCCl.BrN1C(=O)CCC1=O.[CH3:41][C:42]([CH3:47])([CH3:46])[C:43](=[S:45])[NH2:44]>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:45][C:43]([C:42]([CH3:47])([CH3:46])[CH3:41])=[N:44][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: CC(C)(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 10 °C
Reaction time: 0.21 h
Yield: 481.8 %

Procedure:
To a reactor vessel was charged N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (30 g, 1 eq) followed by dichloromethane (300 mL). The reaction slurry was cooled to ˜10° C. and N-bromosuccinimide (“NBS”) (12.09 g, 1 eq) was added in 3 approximately equal portions, stirring for 10-15 minutes between each addition. After the final addition of NBS, the reaction mixture was warmed to ˜20° C. and stirred for 45 min. Water (5 vol) was then added to the reaction vessel and the mixture was stirred and then the layers separated. Water (5 vol) was again added to the dichloromethane layer and the mixture was stirred and the layers separated. The dichloromethane layers were concentrated to ˜120 mL. Ethyl acetate (7 vol) was added to the reaction mixture and concentrated to ˜120 mL. Dimethylacetamide (270 mL) was then added to the reaction mixture and cooled to ˜10° C. 2,2-Dimethylpropanethioamide (1.3 g, 0.5 eq) in 2 equal portions was added to the reactor contents with stirring for ˜5 minutes between additions. The reaction was warmed to 20-25° C. After 45 min, the vessel contents were heated to 75° C. and held for 1.75 hours. The reaction mixture was then cooled to 5° C. and water (270 ml) was slowly charged keeping the temperature below 30° C. Ethyl acetate (4 vol) was then charged and the mixture was stirred and layers separated. Ethyl acetate (7 vol) was again charged to the aqueous layer and the contents were stirred and separated. Ethyl acetate (7 vol) was charged again to the aqueous layer and the contents were stirred and separated. The organic layers were combined and washed with water (4 vol) 4 times and stirred overnight at 20-25° C. The organic layers were then concentrated under heat and vacuum to 120 mL. The vessel contents were then heated to 50° C. and heptanes (120 mL) were added slowly. After addition of heptanes, the vessel contents were heated to reflux then cooled to 0° C. and held for ˜2 hrs. The solids were filtered and rinsed with heptanes (2×2 vol). The solid product was then dried under vacuum at 30° C. to obtain N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (28.8 g, 80%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([NH2:14])[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])(=O)C.N1C=CC=CC=1>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([NH:14][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(=O)N1c2cccnc2C(N)CC1C
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)N1c2cccnc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
[Step 4] 15 mg of the 1-acetyl-4-amino-2-methyl-3,4-dihydro-2H-[1,5] naphthyridine and 23 mg of 4-chlorophenylboronic acid were dissolved in 0.3 mL of DMF followed by adding 27 mg of divalent capper acetate and 18 μL of pyridine and stirring for 5 hours at room temperature in the presence of air. Following completion of the reaction, the solution was filtered with celite followed by the addition of water and extracting three times with ethyl acetate. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:1) to obtain 13 mg of the target compound in the form of a pale yellow solid (57%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34](Cl)=[N:33][CH:32]=1.C(N(CC)CC)C.N12CCN(CC1)CC2>CN(C=O)C.O>[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:33][CH:32]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)nc1
Reaction time: 0.17 h
Yield: 16 %

Procedure:
5-[2-(2-Chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (150 mg, obtained in Example 172) was added to a solution of methyl-6-chloro-nicotinate (64 mg, [CAS Reg. No. 73781-91-6]) in DMF (1.9 mL) followed by the addition of triethylamine (0.067 mL). Stirring was continued for 10 minutes at r.t. Then 1,4-diazabicyclo[2.2.2]octane (6 mg) was added. The mixture was stirred over night at r.t. and then 4 hours at 60° C. The reaction mixture was poured into water, extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the desired compound as a colorless foam (33 mg, 16%). MS (m/e)=537.2 [M+H+].
Reaction SMILES: I[CH:2]([CH2:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[Br:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:16]=[N+:17]=[N-:18].[Na+].C(O)C.N(C(CC(F)(F)C(F)(F)Br)C([O-])=O)=[N+]=[N-]>O>[N:16]([CH:2]([CH2:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[Br:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:17]=[N-:18]
Reactant: CCOC(=O)C(I)CC(F)(F)C(F)(F)Br
Reactant: [N-]=[N+]=[N-]
Agent: [N-]=[N+]=NC(CC(F)(F)C(F)(F)Br)C(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC(F)(F)C(F)(F)Br)N=[N+]=[N-]
Reaction time: 1 h
Yield: 58.3 %

Procedure:
Subsequently, 9.7 g (0.024 mol) of ethyl 2-iodo-4,4,5,5-tetrafluoro-5-bromopentanoate and 2.73 g (0.042 mol) of sodium azide were added to 40 ml of 80% ethanol and were refluxed while under stirring at an elevated temperature for one hour. Then water was added to the resultant mixture and 2-azido-4,4,5,5-tetrafluoro-5-bromopentanoate was extracted with ether, whereafter the ether was removed by drying. The residual liquid was vacuum distilled to afford 4.54 g (0.014 mol, yield of 60%) of ethyl 2-azido-4,4,5,5-tetrafluoro-5-bromopentanoate having b.p. 78° to 79° C./4 mm, nD20 1.4291, d420 1.564, νN3 2120 cm-1 and νC=O 1746 cm-1.
Reaction SMILES: NC1C=CC(C([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15]C)[CH2:11][CH2:10]2)=O)=CC=1Cl.[NH2:20][C:21]1[C:29]([O:30][CH3:31])=[CH:28][C:24]([C:25]([OH:27])=O)=[C:23]([Cl:32])[CH:22]=1.CN1CCC(N)CC1>>[NH2:20][C:21]1[C:29]([O:30][CH3:31])=[CH:28][C:24]([C:25]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[O:27])=[C:23]([Cl:32])[CH:22]=1
Reactant: CCN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Reactant: COc1cc(C(=O)O)c(Cl)cc1N
Agent: CN1CCC(N)CC1
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(Cl)cc1N

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 212, on a 3.06 mmol scale utilising 4-amino-2-chloro-5-methoxy-benzoic acid (Intermediate 217; 617 mg, 3.06 mmol) and 1-methylpiperidin-4-amine (Fluorochem; 385 mg, 3.37 mmol), as an off-white solid (845 mg, 93%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([N:31]3[CH2:34][CH2:33][CH:32]3[C:35](O)=[O:36])[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl-].[NH4+].C[N:41](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@H:25]2[CH2:26][CH2:27][C@H:28]([N:31]3[CH2:34][CH2:33][CH:32]3[C:35]([NH2:41])=[O:36])[CH2:29][CH2:30]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:20])([F:21])[F:22])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CCN1[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)C1CCN1[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(trans-4-{[(5-nitro-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidin-4-yl)amino]methyl}cyclohexyl)azetidine-2-carboxylic acid (170 mg, 0.27 mmol) in DMF (1.5 mL) were added ammonium chloride (170 mg, 3.2 mmol), HATU (303 mg, 0.80 mmol) and DIPEA (370 μL, 2.1 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3, water (×3) and brine. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 7 mg of the title compound, m/z 522.6 [M−1]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[NH:14][C:15](=[O:22])[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=3[CH:11]=[C:10]([C:23](O)=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:27][C:28]1[N:32]=[C:31]([C@H:33]([NH2:35])[CH3:34])[O:30][N:29]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[NH:14][C:15](=[O:22])[N:16]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=3[CH:11]=[C:10]([C:23]([NH:35][C@@H:33]([C:31]3[O:30][N:29]=[C:28]([CH3:27])[N:32]=3)[CH3:34])=[O:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: CC(C)(O)Cn1c(=O)[nH]c2c(-c3ccc(F)cc3)cc(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3)c3[nH]c(=O)n(CC(C)(C)O)c3c2)n1
Temperature: 50 °C
Yield: 39.9 %

Procedure:
To a mixture of 7-(4-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (40 mg, 0.069 mmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride (13.6 mg, 0.083 mmol), 1-hydroxy-7-azabenzotriazol (1.88 mg, 0.014 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (23.2 mg, 0.121 mmol) was added N,N-dimethylformamide (0.138 mL) followed by triethylamine (0.048 mL, 0.346 mmol). Reaction heated at 50° C. for 1.5 h. Reaction cooled and filtered. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TPA) gave the title compound (12.5 mg): LC-MS [M+1]=454.4; HRMS [M+1] found=454.1884; 1H NMR (500 MHz, CHCl3-d): δ 7.65 (1H, s), 7.51-7.47 (3H, m), 7.22-7.15 (2H, m), 6.97 (1H, d, J=7.81 Hz), 5.60-5.52 (1H, m), 3.85 (2H, s), 3.12 (1H, s), 2.35 (3H, s), 1.69 (3H, d, J=7.10 Hz), 1.29 (6H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:14]2=[CH:15][CH:16]=[N:17][CH:18]=[C:13]2[C:5]2[C:6]([OH:12])=[CH:7][C:8]([CH2:10][CH3:11])=[CH:9][C:4]=2[O:3]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:12][C:6]1[C:5]2[C:13]3[C:14]([C:2]([CH3:1])([CH3:19])[O:3][C:4]=2[CH:9]=[C:8]([CH2:10][CH3:11])[CH:7]=1)=[CH:15][CH:16]=[N:17][CH:18]=3)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Solvent: c1ccncc1
Product: CCc1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-ethyl-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-ethyl-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.