Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.N1C=CC=CC=1.[CH:19]([N:22]([CH:35]([CH3:37])[CH3:36])[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=1[O:33][CH3:34])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:8])[N:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][N:22]([CH:19]([CH3:21])[CH3:20])[CH:35]([CH3:37])[CH3:36])=[C:27]([O:33][CH3:34])[CH:28]=1)[C:9]2=[O:10]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: COc1cc(N)ccc1OCCN(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1cc(N2C(=O)c3ccc(Br)cc3C2=O)ccc1OCCN(C(C)C)C(C)C
Temperature: 85 °C
Yield: 64.2 %

Procedure:
4-Bromophthalic anhydride [Apin] (2.27 g, 10 mmol) was dissolved in 1,2-dichloromethane (8 ml), and pyridine (10 mmol, 0.81 ml) was added, followed by 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine [Patent WO-9901127] (2.44 g, 10 mmol) and a catalytic amount of 4-dimethylaminopyridine [Aldrich]. The mixture was heated for 16 h at 85° C. The mixture was evaporated in vacuo and applied to a Biotage Flash40M cartridge, (eluting with dichloromethane-methanol-aqueous ammonia) to give the 5-bromo-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-isoindole-1,3-dione 3.05 g, 68%, as the trifluoroacetate salt;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].I[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:12]([CH3:14])[CH3:13])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(C)I
Reactant: N#Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1ccc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-bromo-2-hydroxybenzonitrile (25 g) in acetonitrile (150 mL) was added 2-iodopropane (15.14 mL) and potassium carbonate (34.9 g). The reaction mixture was stirred at room temperature for two days. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate (150 mL), washed with water (2*30 mL), the organic phase was dried over sodium sulphate and concentrated to afford 5-bromo-2-[(1-methylethyl)oxy]benzonitrile (D38) (29.8 g) as a white solid without further purification. δH (CDCl3, 400 MHz): 1.39 (6H, d), 4.61 (1H, m), 6.85 (1H, d), 7.58 (1H, dd), 7.64 (1H, d). MS (ES): C10H10BrNO requires 239. found 240.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:17][C:18]([C:21](=[NH:24])[NH:22][OH:23])=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].N12CCCN=C1CCCCC2>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:17][C:18]([C:21]2[NH:24][C:34](=[O:35])[O:23][N:22]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Oc2nc(C(=N)NO)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(Oc2nc(-c3noc(=O)[nH]3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of Compound 6b (0.038 g; 0.0828 mmol) and 1,1′-carbonyldiimidazole (0.015 g; 0.091 mmol) in CH3CN (1 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL, 0.33 mmol) and the resulting mixture was stirred at rt for 20 h. The reaction mixture was washed with water, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield Compound 6c. MS: m/z 485.3 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1>C1C=CC=CC=1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1)=[O:9]
Reactant: O=C(Cl)c1ccccc1O
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: c1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)c2ccccc2O)cc1

Procedure:
1.2 Grams (7.7 m-mol) of salicyloyl chloride and 1.0 g (4.9 m-mol) of 6-(p-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone in 10 ml of benzene were stirred for 6 hours at 50° C. After cooling, the resultant crystals were washed with benzene and recrystallized from methanol-water whereby 750 mg of the title compound was obtained. M.P. 218°-220° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(O)(=O)C.[N+:14]([O-])([OH:16])=[O:15]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Temperature: 2.5 °C
Yield: 13.7 %

Procedure:
A mixture of 10.0 g (53.5 mmol) of 4-bromo-3-methylphenol, 50 ml of acetic acid and 10 ml of water was stirred under cooling at 0 to 5° C. To the resulting mixture was dropwise added 3.71 g (58.8 mmol) of 70% nitric acid. After completion of the dropwise addition, the mixture was stirred at room temperature for about an hour. The reaction solution was then poured onto ice water. The mixture was extracted three times with diethyl ether. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.70 g (13.7%) of 4-bromo-3-methyl-2-nitrophenol.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([CH2:23][C:24]([OH:26])=[O:25])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=3)[S:12][C:13]=2[CH2:23][C:24]([OH:26])=[O:25])=[CH:21][CH:20]=1
Reactant: CC(=O)Oc1ccc(-c2nc(-c3ccc(Cl)cc3)c(CC(=O)O)s2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1sc(-c2ccc(O)cc2)nc1-c1ccc(Cl)cc1

Procedure:
2-(4-Acetoxyphenyl)-4-(4-chlorophenyl)-thiazole-5-acetic acid is hydrolysed using 2 N sodium hydroxide to give the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14](O)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:22][C:23]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([NH:26][CH2:25][C:24]3[CH:27]=[CH:28][C:29]([OH:31])=[CH:30][C:23]=3[OH:22])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: NCc1ccc(O)cc1O
Product: COc1ccc(C(=O)NCc2ccc(O)cc2O)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.03 g of the target compound is obtained as white solid in substantially the same manner as in Example 11, except for using 3-adamantan-1-yl-4-methoxybenzoic acid instead of 3-adamantan-1-yl-4-hydroxybenzoic acid and using 2,4-dihydroxybenzylamine instead of 3,4-dihydroxybenzylamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl[C:11]1[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=1[CH:18]=[O:19]>CN(C)C=O>[CH3:16][N:15]1[C:11]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[C:12]([CH:18]=[O:19])[C:13]([CH3:17])=[N:14]1
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: Oc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nn(C)c(Oc2ccccn2)c1C=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 7.9 %

Procedure:
Under a nitrogen gas atmosphere, 3.0 g (0.032 mole) of 2-hydroxypyridine was added at 25° C. to 30 ml of a N,N-dimethylformamide solution containing 1.92 g (0.048 mole) of sodium hydroxide. Then, 5.1 g (0.032 mole) of 5-chloro-1,3-dimethyl-4-formylpyrazole in 20 ml of N,N-dimethylformamide was added to the mixture solution at 25° C. The reaction mixture was heated to 100° C. and stirred at 100° C. for 4 hours. The reaction mixture was then poured into 300 ml of ice water and extracted with two 100-ml portion of ethyl acetate. The organic layers were combined, washed once with 100 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel to obtain 0.55 g of 1,3-dimethyl-5-(2-pyridyloxy)-4-formylpyrazole.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=1)=[O:10].Cl.O1CCOCC1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:24]=[CH:23][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(CCCCCCCBr)Nc1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 99.3 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(8-bromooctanoyl)amino]benzoate (0.61 g, 1.5 mmol, as prepared in Intermediate 35) in dichloromethane (2 ml) was added a 4M solution of HCl in 1,4-dioxane (4 ml, about 10 equivalents), and the mixture was left to stand at ambient temperature for 18 hours. The mixture was evaporated to dryness and the residue was co-evaporated with dichloromethane (20 ml) to give the title compound as a white solid (0.51 g). LCMS showed MH+=342/344 (Br isotope pattern); TRET=3.34 min. NMR (d6-DMSO) suggested that the material was again about 75% pure and that the impurity from the previous reaction (Intermediate 35) was still present. The mixture was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([F:11])[CH:4]=1)#[N:2].[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[C:5]([F:11])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CCC(N)C(=O)OC(C)(C)C
Product: CCC(NCc1ccc(C#N)cc1F)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared following the general procedure 10 starting from 4-cyano-2-fluoro-benzylbromide (Fluorochem, 8.2 g, 38 mmol) and tert-butyl 2-aminobutanoate (6.2 g, 38 mmol), obtained in step 1. It was isolated as a colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.79-7.76 (d, J=10.2 Hz, 1H), 7.68-7.67 (t, J=2.1 Hz, 2H), 3.84-3.79 (m, 1H) 3.71-3.66 (m, 1H), 2.95-2.91 (m, 1H), 2.52-2.48 (m, 1H), 1.58-1.53 (m, 2H), 1.49 (s, 9H), 0.87-0.83 (m, 3H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[CH:4][C:5]([CH:8]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>C1COCC1>[Si:14]([O:13][CH:8]([C:5]1[N:6]=[CH:7][C:2]([B:22]([OH:27])[OH:23])=[C:3]([CH3:21])[CH:4]=1)[C:9]([F:12])([F:11])[F:10])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)ncc1Br
Solvent: C1CCOC1
Product: Cc1cc(C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)ncc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
Isopropylmagnesium chloride lithium chloride complex (1.3 mol/L) in THF (0.72 mL, 0.94 mmol) was added to a solution of 5-bromo-2-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)-4-methylpyridine (120 mg, 0.312 mmol) in THF (1 mL) cooled at −78° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was then cooled at −78° C. and triisopropyl borate (0.26 ml, 1.09 mmol) was added. After 5 minutes, the reaction mixture was warmed to room temperature. After 1 hour at room temperature, the reaction was quenched with a few drops of saturated aqueous ammonium chloride solution. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (5 ml). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, silica, 0-10% methanol in dichloromethane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (40 mg, 37%), which was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].CS(C)=O.Cl.[CH:26]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][CH2:27]2>CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:32]2[CH:26]3[CH2:31][CH2:30][CH:29]2[CH2:28][CH2:27]3)=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: C1CC2CCC1N2
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Temperature: 55 °C
Reaction time: 3 h

Procedure:
4-fluoro-1-nitro-2-(trifluoromethyl)benzene (7) (901 g, 4.309 mol) was introduced into a 30 L jacketed vessel along with Na2CO3 (959.1 g, 9.049 mol) and DMSO (5 L, 5.5 vol) under nitrogen atmosphere and stirring. 7-azabicyclo[2.2.1]heptane hydrochloride (8-HCl) (633.4 g, 4.740 mol) was then added to the vessel in portions. The temperature was gradually raised to 55° C. When the reaction was substantially complete, the mixture was diluted with 10 vol EtOAc and washed with water (5.5 vol) three times or until DMSO in the aqueous layer disappeared (HPLC). The organic layer was concentrated to 4 vol and then the solvent was swapped with cyclohexane until all the EtOAc was removed, and the total volume in the flask was about 4 vol containing cyclohexane. The reaction mixture was heated to 60° C. on a rotary evaporator for 30 min. Then the solution was cooled to room temperature with stirring or rotation for 3 h. When all the solid crystallized, the solution was concentrated to dryness to provide 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (9).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:24]3[CH:25]=[CH:26][NH:27][C:23]=3[CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1.C([Li])(C)(C)C.CN(C)[CH:35]=[O:36].[NH4+].[Cl-]>O1CCCC1>[NH:27]1[C:23]2[CH:22]=[CH:21][N:20]=[C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([CH:35]=[O:36])[CH:3]=5)[NH:7][CH:6]=4)[CH2:14][CH2:15]3)[C:24]=2[CH:25]=[CH:26]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Reaction time: 1 h

Procedure:
A solution at −78° C. of 1.5 mmol of the compound obtained in Step 3 in tetrahydrofuran is treated with 9 mmol of tert-butyllithium (1.8M in hexane). After stirring the mixture for 1 hour, 12 mmol of dimethylformamide are added and the mixture is brought to ambient temperature. After reaction for 4 hours, the solution is hydrolysed by a saturated solution of NH4Cl and then extracted with dichloromethane. After treating the organic phase in conventional manner, chromatography of the residue on silica gel enables the expected product to be isolated.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(Cl)(Cl)Cl>O>[O:25]=[C:13]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCC(=O)N1CCOCC1

Procedure:
Example 1(A) was repeated using morpholine, potassium carbonate and dodecanoyl chloride in a biphasic mixture of chloroform and water followed by the usual workup to obtain the above product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[I:19]N1C(=O)CCC1=O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([I:19])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1
Reactant: Oc1ccc(-c2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Oc1cc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
2-Chloro-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 50, 310 mg, 1.14 mmol) was dissolved in acetic acid (2 mL), and cooled to 0° C. N-iodosuccinimide (256 mg, 1.14 mmol) was added followed by concentrated sulphuric acid (0.067 μL). The reaction was stirred at room temperature for 18 hours. A second portion of N-iodosuccinimide (25 mg, 0.11 mmol) was added and the reaction stirred at room temperature for a further 1 hour. The reaction mixture was partitioned between ethyl acetate (70 mL) and water (50 mL). The ethyl acetate was separated, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica eluting with a gradient of heptane:ethyl acetate 100:0 to 80:20 to give the title compound (230 mg, 0.58 mmol, 51%) as a white solid.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)(O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)([F:11])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.4 %

Procedure:
[Bis(2-Methoxyethyl)amino]sulfur trifluoride (2.1 mL, 11.4 mmol) was added to a stirred solution of 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (810 mg, 2.28 mmol) in anhydrous DCM (25 mL), at −78° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 72 h. The reaction mixture was quenched by the addition of saturated aqueous potassium carbonate (10 mL) and extracted into DCM (3×10 mL). The combined organic phase was concentrated in vacuo and the residue purified by flash chromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a colourless oil (738 mg, 91%). 1H NMR (CDCl3, 300 MHz): 7.50 (d, J=8.5 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H), 4.19-4.05 (m, 2H), 3.29-3.05 (m, 2H), 2.04-1.84 (m, 4H), 1.49 (s, 9H). LCMS (Method B): RT=4.55 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([OH:10])=[O:9]>S(=O)(=O)(O)O>[F:5][C:6]1[C:7]([C:8]([OH:10])=[O:9])=[C:11]([CH3:15])[C:12]([N+:1]([O-:4])=[O:2])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(F)c1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])ccc(F)c1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of nitric acid (6.96 mL, 156 mmol) in sulfuric acid (44 mL) was added a solution of 2-fluoro-6-methylbenzoic acid (16 g, 104 mmol) in concentrated sulfuric acid (150 mL) at −15° C., and the mixture was stirred at 0° C. for 30 min. The reaction solution was poured into ice water (500 mL), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound as a crudely purified product (20.7 g, yield 100%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.S=[C:15]1[CH2:19][S:18][C:17](=[O:20])[NH:16]1>C(O)C>[O:20]=[C:17]1[N:16]=[C:15]([NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH2:19][S:18]1
Reactant: NCC(N)=O
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of glycinamide hydrochloride (5.00 g) and triethylamine (6.30 mL) in ethanol (60 mL) was added 4-thioxo-1,3-thiazolidin-2-one (5.02 g), and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration and washed with ethanol to give the title compound (6.50 g).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH:10]=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16].II>[Zn].C1C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH:9]1[CH:10]([OH:11])[CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:21])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(O)C1CCCN1C(=O)OC(C)(C)C
Yield: 41 %

Procedure:
Freshly activated zinc powder (0.79 g, 12 mmol, Aldrich) and benzene (50 mL) were placed into a 250-mL two neck round bottom flask under N2. This flask was attached to a Dean-Stark apparatus and 25 mL of benzene was distilled into the trap. Under reflux, a solution of Boc- D-Prolinal (1.90 g, 9.5 mmol) and ethylbromoacetate (2.0 g, 12 mmol, Aldrich) was added dropwise. A crystal of iodine was added to initiate the reaction after half of the dropping solution was added. After complete addition, the mixture was refluxed for 3 hours, cooled, and carefully washed with 0.5 n HCl. The aqueous solution was extracted with ether (25 mL) and the combined organic solution was washed successively with water (30 mL) and saturated NaHCO3 (30 mL), then dried with anhydrous Na2SO4 and concentrated under vacuum. A yellow oil was chromatographed on silica (with hexane/ethyl acetate) to isolate a colourless oil (1.12 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7]O)=[C:5]([Cl:9])[N:4]([CH2:10][CH3:11])[N:3]=1.P(Br)(Br)[Br:13].O>C(OCC)C>[Br:13][CH2:7][C:6]1[C:2]([Cl:1])=[N:3][N:4]([CH2:10][CH3:11])[C:5]=1[Cl:9]
Reactant: BrP(Br)Br
Reactant: CCn1nc(Cl)c(CO)c1Cl
Solvent: CCOCC
Solvent: O
Product: CCn1nc(Cl)c(CBr)c1Cl
Temperature: -30 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A solution of 0.82 g (4.2 mmoles) of (3,5-dichloro-1-ethyl-1H-pyrazol-4-yl)methanol dissolved in 50 ml of diethyl ether was cooled to −30° C. Thereto was added 1.3 g (4.8 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.9 g (yield: 81.8%) of 4-bromomethyl-3,5-dichloro-1-ethyl-1H-pyrazole as a yellow oily substance.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].Cl.[NH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[OH:21].C(N(CC)CC)C>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:15][CH:16]2[CH2:20][CH2:19][CH2:18][C@@H:17]2[OH:21])[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCC[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.040 g, 0.20 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added trans-2-aminocyclopentanol hydrochloride (56 mg, 0.41 mmol) and triethylamine (0.14 ml, 1.02 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 262 (M+H)+; 1H NMR (MeOH) 4.79 (m, 1H), 4.17-4.40 (m, 3H), 3.18 (m, 1H), 2.48 (m, 4H); 2.00-2.30 (m, 4H), 1.80 (m, 2H), 1.66 (2H, m).