Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[C:6]([F:8])[CH:7]=1.CN(C)CCN(C)C.C([Li])CCC.[S:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]1>C1COCC1>[OH:36][C:33]1([C:7]2[C:2]([F:1])=[CH:3][C:4]([NH:9][C:10](=[O:16])[O:11][CH2:12][CH:13]([CH3:14])[CH3:15])=[CH:5][C:6]=2[F:8])[CH2:34][CH2:35][S:30][CH2:31][CH2:32]1
Reactant: CC(C)COC(=O)Nc1cc(F)cc(F)c1
Reactant: O=C1CCSCC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)COC(=O)Nc1cc(F)c(C2(O)CCSCC2)c(F)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A stirred solution of isobutyl 3,5-difluorophenylcarbamate (Step A, 10.0 g, 43.6 mmol) and N,N,N′,N′-tetramethylethylenediamine (13.7 mL, 87.3 mmol) in anhydrous THF (87 mL) at −78° C. under N2 is treated n-butyllithium (1.6M in hexanes, 35.8 mL, 89.4 mmol) dropwise over 35 mins. The mixture is stirred at −78° C. for 20 mins and is then treated with a solution of tetrahydro-2H-thiopyran-4-one (5.32 g, 45.8 mmol) in anhydrous THF (15 mL) dropwise over 10 mins. After 45 mins at −78° C., the cooling bath is removed and the mixture is allowed to warm to ambient temperature and is then quenched by the slow addition of saturated aqueous ammonium chloride (50 mL). Water (50 mL) and EtOAc (100 mL) are added, the layers are separated, and the organic phase is washed with water (100 mL) and saline (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product is triturated and filtered from EtOAc (approx. 25 mL) to remove an insoluble impurity, and the filtrate is chromatographed on two Flash 40M 90 g silica gel cartridges, eluting with EtOAc/heptane (20/80). Pooling and concentration of those fractions with an Rf=0.26 by TLC (EtOAc/hexanes, 25/75) gives the title compound, mp 103-104° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].C([O-])([O-])OC.[CH2:28](O)[CH2:29][OH:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C(N(CC)CC)C>[CH2:16]([O:15][C:7]1[CH:6]=[CH:5][C:4]([C:1]2([CH3:2])[O:30][CH2:29][CH2:28][O:3]2)=[CH:9][C:8]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1cc(C(C)=O)ccc1OCc1ccccc1
Reactant: OCCO
Agent: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Cc1cc(C2(C)OCCO2)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
Methyl 2-(5-acetyl-2-benzyloxyphenyl)acetate (9.0 g), 18 ml of methyl orthoformate and 18 ml of ethylene glycol were dissolved in 300 ml of methylene chloride, 60 mg of p-toluenesulfonic acid monohydrate was added to the solution, and the mixture was heated under reflux for 12 hours. After cooling, 0.14 ml of triethylamine was added to the reaction solution and the mixture was stirred for 15 minutes. The reaction solution was partially purified by silica gel flash column chromatography (eluent: methylene chloride) and then further purified by silica gel medium pressure liquid column chromatography (eluent: hexane/diethyl ether=3/2) to give 9.2 g of methyl 2-[2-benzyloxy-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]acetate in an oily form.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[CH3:27][NH2:28]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12]([NH:28][CH3:27])[C:11]=2[CH2:10][CH2:9]1
Reactant: CN
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Solvent: CCO
Product: CNc1nc2c(OC(F)(F)F)cccc2c2c1CCN2c1ccccc1C
Temperature: 170 °C

Procedure:
1-(2-Methylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(300 mg, 0.79 mmol) was dissolved in ethanol(1.0 ml) and aqueous solution of methylamine(40%, 5 ml) was added. The reaction mixture was refluxed in the pressure tube at 170° C. for 20 hours, and the solvent was removed by distillation under low pressure. The residue was diluted in dichloromethane(20 ml), washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 240 mg of desired compound as solid in 81% of yield.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[Br:9]Br.[C:11]([NH:14][C:15]([NH2:17])=[S:16])(=[O:13])[CH3:12].O>CO>[BrH:9].[C:11]([NH:14][C:15]1[S:16][C:5]2[CH2:6][C:1](=[O:8])[CH2:2][CH2:3][C:4]=2[N:17]=1)(=[O:13])[CH3:12]
Reactant: O=C1CCC(=O)CC1
Reactant: BrBr
Reactant: CC(=O)NC(N)=S
Solvent: CO
Solvent: O
Product: Br
Product: CC(=O)Nc1nc2c(s1)CC(=O)CC2
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
8.8 g of 1,4-cyclohexanedione was dissolved in 40 ml of methanol. The solution was cooled on an ice bath to 10° C. and 4.4 ml of bromine was added dropwise in 10 minutes. The solution was stirred at the same temperature for 1.5 hours and then the temperature was allowed to rise to ambient. After the colour disappeared, 11.1 g of N-acetylthiourea and 20 ml of water were added and the solution was heated under reflux for 2 hours. Hot reaction mixture was filtered, the filtration cake was washed with hot methanol and the combined filtrates were heated to reflux with activated charcoal. The hot suspension was filtered and the filtrate was concentrated in vacuo to yield 3.4 g of a solid product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].S(=O)(=O)(O)[OH:14]>FC(F)(F)C(O)=O>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)=[O:14]
Reactant: N#Cc1cccc(CC(=O)O)c1
Reactant: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
A solution of 3-cyanophenylacetic acid (0.2 g, 1.24 mmol) in a mixture of trifluoroacetic acid (1 ml) and concentrated sulfuric acid (0.5 ml) was stirred at room temperature for 16 h. The reaction mixture was then poured into ice-cold water and the resulting solid was filtered, washed with water and dried under vacuum to give 2-[3-(aminocarbonyl)phenyl]acetic acid (0.167 g, 75% yield). MS (EI) for C9H9NO3: 178 (M−H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[N+:27]([C:30]1[C:35]2=[N:36][O:37][N:38]=[C:34]2[C:33](N)=[CH:32][CH:31]=1)([O-:29])=[O:28].O>C1COCC1>[CH3:7][CH:5]([CH3:6])[CH2:4][C@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:13]([O:22][CH2:23][CH:24]2[CH2:25][CH2:26]2)[N:12]=1)=[O:10])[CH2:2][NH:1][C:33]1[C:34]2=[N:38][O:37][N:36]=[C:35]2[C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1
Reactant: CC(C)C[C@@H](CN)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Reactant: Nc1ccc([N+](=O)[O-])c2nonc12
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](CNc1ccc([N+](=O)[O-])c2nonc12)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a colorless solution of 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-aminomethyl-3-methyl-butyl)-amide (30 mg, 83.2 μmol) in THF (555 μl) was added 7-nitro-2,1,3-benzoxadiazol-4-amine (CAN 10199-91-4, 19.9 mg, 100 μmol). The reaction mixture was stirred at room temperature for 30 minutes, followed by stirring at reflux temperature for 2 hours. After cooling to room temperature the mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with brine; and the aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried with Na2SO4, and concentrated in vacuo. The black, solid residue was purified by flash chromatography (basic silica gel, 10 g, 0% to 100% ethyl acetate in a 1:1 mixture of dichloromethane and heptane) to give the title compound (25 mg, 57%) as brown solid; LC-MS (UV peak area/ESI) 100%, 524.2609 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:22]=1)[C:7](=[O:21])[N:8](O)[C:9]3=[O:19].C1C(=O)N([Cl:30])C(=O)C1.O>C(O)(=O)C>[Br:1][C:2]1[CH:22]=[C:6]2[C:5]3=[C:10]([CH:11]=[C:12]([Cl:30])[C:13]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:4]3[CH:3]=1)[C:9](=[O:19])[NH:8][C:7]2=[O:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1c2ccc(N3CCCC3)c3cc(Br)cc(c23)C(=O)N1O
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=O)c2cc(Cl)c(N3CCCC3)c3cc(Br)cc1c23
Yield: 45.2 %

Procedure:
A mixture of 5-bromo-2-hydroxy-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.15 g, 0.42 mmol, from Example 59) and NCS (0.072 g, 0.54 mmol) in acetic acid (12 mL) was reacted at 100° C. for 3 hours. The reaction mixture was cooled and poured into water. The resulting precipitate was collected by filtration, washed with water, and dried to give 0.072 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[C@H:10]([CH3:36])[CH2:9]2)=[C:4]([C:37]([F:40])([F:39])[F:38])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:36])[CH2:9]2)=[C:4]([C:37]([F:40])([F:38])[F:39])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of tert-butyl 4-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]piperidine-1-carboxylate (540 mg, 0.923 mmol) in DCM (15 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 2 h and washed with aq. Na2CO3. The organic layer was dried over Na2SO4, concentrated and redissolved in Et2O and acidified with 1N HCl in Et2O to give the titled compound as a white solid (427 mg, 89%). HRMS: calcd for C23H27F4N3O2S+H+, 486.18328. found (ESI-FTMS, [M+H]1+), 486.18382.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21]>C1COCC1.C(OCC)(=O)C>[F:20][C:19]1[C:14]2[NH:13][C:1](=[O:2])[O:21][C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(O)cccc1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c2c(F)cccc2o1
Temperature: 60 °C

Procedure:
1,1′-Carbonyldiimidazole (11.4 g, 0.0703 mol) is added portionwise to a solution of 2-amino-3-fluorophenol (Step 3, 8.94 g, 0.0703 mol) in THF (200 ml) and warmed at 60° C. for 2 h. The reaction mixture is diluted with ethyl acetate (200 ml), washed with 2N HCl and saline, dried (MgSO4), and evaporated to give product as a white solid suitable for use in the next step (10.6 g, 99%); mp 131-3° C.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:12]=1.[I:22]I.O>O1CCCC1.C(OCC)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]#[C:13][C:11]2[CH:10]=[N:9][CH:8]=[C:7]([I:22])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(C#Cc2cncc(Br)c2)cc1
Reactant: II
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(C#Cc2cncc(I)c2)cc1
Reaction time: 1 h
Yield: 53 %

Procedure:
Add a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (81 mL, 161.7 mmol) to a solution of 3-bromo-5-(4-fluorophenylethynyl)-pyridine, (prepared essentially as described in PREPARATION 24), (40.5 g, 147 mmol) in anhydrous tetrahydrofuran (400 mL) at room temperature under nitrogen. Stir for 1 h, add a solution of iodine (41 g, 161.7 mmol) in anhydrous tetrahydrofuran (250 mL) and stir for an additional 16 h. Add water (200 mL) to the reaction mixture, dilute with diethyl ether (400 mL) and separate the layers. Sequentially wash the organic layer with a 10% aqueous solution of sodium thiosulfate (150 mL), water (200 mL) and an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 15:1 hexanes:ethyl acetate, to give the title compound as a pale yellow solid (25.4 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].[Br:14]Br.[Cl-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:14][C:10]([CH3:11])([CH3:12])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:13]
Reactant: CC(C)C(=O)c1ccc(F)cc1F
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
In 260 ml of methylene chloride was dissolved 145.5 g (0.79 mol) of 1-(2,4-difluorophenyl)-2-methylpropan-1-one, and 134.2 g (0.84 mol) of bromine was slowly added dropwise thereto at 20° C. or lower. The mixture was warmed to room temperature and stirred for 1 hour. A saturated sodium chloride aqueous solution and a saturated sodium thiosulfate aqueous solution were added to the reaction mixture. The organic layer was separated, washed successively with a saturated sodium chloride aqueous solution, a saturated sodium hydrogencarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation under reduced pressure to obtain 205.7 g (99%) of 2-bromo-1-(2,4-difluorophenyl)-2-methylpropan-1-one as a pale yellow oily substance.
Reaction SMILES: C(C(NC(C1C=C(C)C=CC=1S[S:20][N:21]([C:30](=[O:38])[C:31]1[CH:36]=[C:35](C)[CH:34]=[CH:33][CH:32]=1)[CH:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=O)CC(C)C)(O)=O.BrBr.[C:41](#N)C>ClCCl>[CH3:29][CH:27]([CH3:28])[CH2:26][C@H:22]([N:21]1[C:30](=[O:38])[C:31]2[CH:32]=[CH:33][C:34]([CH3:41])=[CH:35][C:36]=2[S:20]1)[C:23]([OH:25])=[O:24]
Reactant: CC#N
Reactant: Cc1cccc(C(=O)N(SSc2ccc(C)cc2C(=O)NC(CC(C)C)C(=O)O)C(CC(C)C)C(=O)O)c1
Agent: BrBr
Solvent: ClCCl
Product: Cc1ccc2c(=O)n([C@@H](CC(C)C)C(=O)O)sc2c1

Procedure:
Following the general method of Example 3, a slurry of [s-(R*,R*)]-2-[-[2-(1-carboxy-3-methyl-butylcarbamoyl)-4-methylphenyldisulfanyl]-5-methylbenzoylamino]-4-methyl-pentanoic acid (1.8 g, 3.2 mmol) (from Preparation 22) in 5 mL acetonitrile and 20 mL dichloromethane was reacted with bromine (0.6 g, 3.7 mmol) in 10 mL dichloromethane. The crude product was recrystallized from methanol/water to afford 1.3 g of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])[CH:8]=[CH:9][CH:10]=1.[CH3:17][N:18]([CH:20](OC)OC)[CH3:19].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])CN>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:12](=[O:16])[C:13]([C:14]#[N:15])=[CH:20][N:18]([CH2:17][C:32]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[C:34]([O:35][CH3:36])[CH:33]=3)[CH:19]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)Cc1cccc(OCCCl)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(C#N)c(=O)c(-c3cccc(OCCCl)c3)c2)cc1OC
Temperature: 100 °C
Yield: 41.5 %

Procedure:
To a stirred solution of 4-[3-(2-chloroethoxy)phenyl]-3-oxo-butyronitrile (16.0 g, 67.0 mmol) in 100 mL anhydrous DMF was added DMF-DMA (19.7 mL, 148 mmol) and TEA (9.4 mL, 67.0 mmol), and the solution was heated at 100° C. for 2.5 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2, passed through Magnesol® and concentrated. The crude material was then stirred with 3,4-dimethoxybenzylamine (11 mL, 74 mmol) in 100 mL of anhydrous toluene at reflux for 2 h. The reaction was cooled, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with EtOAc to yield 11.8 g (41% yield) of 5-[3-(2-chloroethoxy)phenyl]-1-(3,4-dimethoxybenzyl)-4-oxo-1,4-dihydro-pyridine-3-carbonitrile as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:14]([O:15][CH3:16])[C@H:13]([O:17]C2C=CC(OC)=CC=2)[C@H:12]2[CH2:26][O:27][C@@H:10]1[O:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[Ce].[NH4+]>C1COCC1.O.ClCCl>[CH2:1]([O:8][C@H:9]1[C@@H:14]([O:15][CH3:16])[C@H:13]([OH:17])[C@H:12]2[CH2:26][O:27][C@@H:10]1[O:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(O[C@H]2[C@H](OC)[C@H](OCc3ccccc3)[C@@H]3OC[C@H]2O3)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CO[C@H]1[C@H](O)[C@H]2CO[C@H](O2)[C@H]1OCc1ccccc1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The above crude compound 92 is dissolved in a THF/water mixture (311 ml, 17/1) and ammonium cerium nitrate (76 g, 138 mmol) is then added at 0° C. After stirring for 30 minutes, the reaction mixture is diluted with dichloromethane (1 l) and then washed with aqueous 2% sodium hydrogen carbonate solution, and then with water. After drying, filtration and concentration, the residue is purified on silica to give compound 93 (6.63 g, 72% over two steps).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:4]=2[N:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[CH:32]=[C:31]([OH:34])[CH:30]=[CH:29]2>>[CH2:7]([N:6]1[C:5]2[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:4]=2[N:3]=[C:2]1[NH:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[CH:32]=[C:31]([OH:34])[CH:30]=[CH:29]2)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: FC(F)(F)c1ccc2c(c1)nc(Cl)n2CCc1ccccc1
Reactant: Nc1cccc2ccc(O)cc12
Product: Oc1ccc2cccc(Nc3nc4cc(C(F)(F)F)ccc4n3CCc3ccccc3)c2c1

Procedure:
The reaction of 2-chloro-1-phenethyl-5-(trifluoromethyl)-1H-benzo[d]imidazole from step (b) above (98 mg, 0.3 mol) with 8-amino-naphthalen-2-ol (64 mg, 0.2 mmol, Aldrich) under the condition of Example 21(b) afforded the title compound. MS (ESI, pos. ion) m/z: 448(M+1).
Reaction SMILES: N[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[BrH:13].N([O-])=O.[Na+]>O.[Cu]Br>[Br:13][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: CC1(C)Cc2cccc(N)c2O1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)Cc2cccc(Br)c2O1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 10.0 grams (0.061 mole) of 7-amino-2,3-dihydro-2,2-dimethylbenzofuran was stirred and cooled in an ice-water bath. To this was added 17.4 mL (0.153 mole) of aqueous 48% hydrobromic acid, followed by the dropwise addition of a solution of 4.2 grams (0.061 mole) of sodium nitrite in 50 mL of water. The reaction mixture temperature was maintained at below 10° C. throughout the addition. In a separate reaction vessel, a stirred mixture of 4.8 grams (0.034 mole) of copper(I) bromide and 4.2 mL (0.037 mole) of aqueous 48% hydrobromic acid was heated to 60°-70° C., and the diazonium salt prepared above was added slowly dropwise. Upon completion of addition, the reaction mixture was warmed to 80° C. where it was stirred for one hour. After this time the reaction mixture was allowed to cool to ambient temperature as it stirred for about 18 hours. The reaction mixture was poured into 300 mL of water and the mixture was extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 7.0 grams of 7-bromo-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: O[CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:25])[CH:24]=2)[CH2:3]1.C1CCN2C(=NCCC2)CC1.[B-](F)(F)(F)F.CCN([S+](F)F)CC>C(Cl)Cl>[O:19]=[C:5]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:2]=[CH:3][N:4]1[C:20]1[CH2:21][O:22][C:23](=[O:25])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(C1=CC(=O)OC1)CC2O
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(C=CN(C3=CC(=O)OC3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-hydroxy-1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (210 mg, 0.596 mmol) in DCM (6 mL) at 0° C. was added DBU (269 μA, 1.79 mmol), and XtalFluor-E® (409 mg, 1.79 mmol). The reaction mixture was stirred overnight while warming up to rt, then quenched with aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with DCM (30 mL). The combined organic layers were dried (MgSO4) and purified by column chromatography (0-100% EtOAc/hex) to give the title compound. LCMS: [(M+1)]+=335;
Reaction SMILES: [F:1][C:2]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35]CCCC)=[O:34])[CH2:29][CH2:28]1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3].[OH-].[Na+].Cl>CO.O.C(OCC)(=O)C>[F:1][C:2]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3]
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)(F)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(F)[C@H]3CC[C@H](C(=O)O)CC3)s2)c1
Temperature: 60 °C

Procedure:
To a solution of butyl trans-4-{1-fluoro-1-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylate (80 mg, 0.14 mmol) in methanol (1.5 mL) was added sodium hydroxide (1.0 M in H2O, 0.28 mL, 0.28 mmol) and the reaction was heated to 60° C. overnight. Then, the reaction was cooled to room temperature, acidified to a pH of ˜3 with HCl (1.0 M in water) and diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford racemic trans-4-{1-fluoro-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid. MS ESI calc'd. for C24H25F4N4O2S [M+H]+ 509. found 509. 1H NMR (500 MHz, DMSO-d6) 12.01 (s, 1H), 10.28 (s, 1H), 8.84 (d, J=4.8, 1H), 8.07 (d, J=3.3, 1H), 8.02 (s, 1H), 7.47 (s, 1H), 7.29 (d, J=4.9, 1H), 7.19 (s, 1H), 2.32 (s, 3H), 2.16-2.01 (m, 1H), 2.00-1.87 (m, 4H), 1.85 (s, 1H), 1.67 (s, 3H), 1.35-1.19 (m, 4H).