Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cc2cc(N3CCCCC3)ccc2o1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=Cc1ccc(-c2cc3cc(N4CCCCC4)ccc3o2)cc1
Yield: 30.8 %

Procedure:
A mixture of 5-(piperidin-1-yl)benzofuran-2-ylboronic acid (90 mg, 0.367 mmol), 4-bromobenzaldehyde (62 mg, 0.330 mmol), triethylamine (1.0 mL, 7.3 mmol) and bis(triphenylphosphine)palladium(II)chloride (12.8 mg, 0.02 mmol) in ethanol (9 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (31 mg, 28% yield). ESI-MS: 306.4 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 7.95 (dd, 4H), 7.42 (d, 1H), 7.11 (m, 2H), 7.07 (dd, 1H), 3.13 (t, 4H), 1.78-1.74 (m, 4H), 1.62-1.56 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCO.O>[Fe].CC(O)=O>[NH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:2]([CH3:1])[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(Cc1cccc([N+](=O)[O-])c1)C(=O)OCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CN(Cc1cccc(N)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a refluxing solution of 60A (1.7 g, 5.8 mmol), EtOH (60 mL), water (15 mL) and AcOH (4 mL) was added portion-wise Fe powder (1.63 g, 29.0 mmol) over 30 min. The mixture was heated for 45 min. before cooling to ambient temperature and filtered through celite. Filtrate concentrated in vacuo to afford 60B (1.5 g, 95%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.25-1.41 (m, J=4.39 Hz, 3 H) 2.27 (s, 3 H) 2.61 (s, 2 H) 2.92 (s, 2 H) 4.22 (s, 2 H) 4.64 (s, 1 H) 6.84-7.56 (m, 12 H)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methane sulphonyl chloride (0.39 ml, 5.0 mmol) was added dropwise to a solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (0.51 g, 2.5 mmol) and 4-(dimethylamino)pyridine (0.61 g, 5.0 mmol) in dichloromethane (15 ml). The mixture was stirred at room temperature for 30 minutes and then concentrated to approximately half volume and purified by silica gel chromatography. Elution with a mixture of 3:1 to 1:1 iso-hexane:ethyl acetate yielded tert-butyl 3-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cccc(C(F)(F)F)c2)C1=O
Yield: 69.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 1-bromo-3-trifluoromethyl-benzene (0.14 mL, 1.016 mmol), 1,4-dioxane (10 mL), copper iodide (16.13 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium phosphate (539 mg, 2.54 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.2% MeOH in CHCl3) afforded 190 mg of the product (70.11% yield).
Reaction SMILES: [CH:1]1[C:2]2[C:9](=O)[NH:8][CH:7]=[N:6][C:3]=2[NH:4][N:5]=1.P(Cl)(Cl)([Cl:13])=O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Cl:13][C:9]1[N:8]=[CH:7][N:6]=[C:3]2[NH:4][N:5]=[CH:1][C:2]=12
Reactant: O=c1[nH]cnc2[nH]ncc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2[nH]ncc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of allopurinol (20 g; 146.94 mmoles) in toluene (205.71 mL), add phosphoryl chloride (68.27 mL; 734.68 mmoles) and diisopropylethylamine (56.38 mL; 323.26 mmoles) and heat the mixture at 80° C. for 2 hours. Remove the solvent in vacuo to half and pour the mixture into 2 M potassium phosphate, dibasic (734.68 mL; 1.47 moles) in water at 4° C. Stir the mixture overnight at room temperature (RT). Filter off the precipitate through a pad of Celite® and wash it subsequently with EtOAc. Separate the filtrate, wash the aqueous layer with more EtOAc, join the organic layers, dry it over MgSO4, filter and concentrate in vacuo to afford the title compound (16 g; 70.45% yield) as a yellow solid. MS (APCI): m/z=155.1 [M+H].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C@@H:19]([NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:20]([CH3:22])[CH3:21])=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C@@H:19]([NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:20]([CH3:21])[CH3:22])=[CH:11][C:10]=1[O:30][CH3:31]
Reactant: [H][H]
Reactant: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCc2ccccc2)c(OC)c1)C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)c(OC)c1)C(C)C

Procedure:
14.5 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxyphenyl)-ethyl]-amide (Ex. P-1. 1) are dissolved in 420 ml of tetrahydrofuran and shaken together with 3 g of palladium-on-carbon (5%) in a duck-shaped hydrogenation vessel for 5 hours in a hydrogen atmosphere at normal pressure. The catalyst is then removed by filtration. The filtrate is concentrated. The residue is purified by flash-chromatography on silica gel using ethyl acetate/n-hexane 3:1, yielding (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-amide in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH2:4][CH2:5][C:6](=[O:9])[NH:7][N:8]=1.BrBr>C(O)(=O)C>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][N:8]=1
Reactant: O=C1CCC(C(F)(F)F)=NN1
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1ccc(C(F)(F)F)n[nH]1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2.6 g (15.65 mmol) of 6-(trifluoromethyl)-4,5-dihydropyridazin-3(2H)-one were dissolved in 20 ml of glacial acetic acid, and the mixture was heated to 100° C. 0.81 ml (15.65 mmol) of bromine was then slowly added dropwise to the solution, and the mixture was stirred at 100° C. for 4 hours. After cooling of the reaction solution, the solvent was removed under reduced pressure and the residue obtained was purified chromatographically on silica gel (mobile phase dichloromethane/methanol 50:1→20:1). This gave 1.34 g (8.15 mmol, 52% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl.[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40]Cl>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCN1CN(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=591.1 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 3-dimethylaminopropylchloride hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][CH3:21])=[S:19])=[CH:13][CH:12]=1.BrBr>>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]2[N:17]=[C:18]([NH:20][CH3:21])[S:19][C:13]=2[CH:12]=1
Reactant: CNC(=S)Nc1ccc(-c2nc3ccccn3c2C)cc1
Agent: BrBr
Product: CNc1nc2ccc(-c3nc4ccccn4c3C)cc2s1
Yield: 22.2 %

Procedure:
6-(3-Methylimidazo[1,2-a]pyridin-2-yl)-2-methylaminobenzothiazole (0.55 g) was prepared in substantially the same manner as that of Example 36 from 3-methyl-2-[4-(3-methylthioureido)phenyl]imidazo[1,2-a]pyridine (2.49 g) and bromine (1.34 g). mp. 251°-254° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][CH:33]3OC(C)(C)[O:36][CH:35]([CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[CH2:34]3)[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+].O>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@@H:33]3[CH2:34][C@@H:35]([OH:36])[CH2:41][C:42](=[O:43])[O:44]3)[C:10]([CH:28]([CH3:29])[CH3:30])=[C:11]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:20])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC1CC(CC(=O)OC(C)(C)C)OC(C)(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@@H](O)CC(=O)O1
Reaction time: 15 h

Procedure:
(4R-cis))1,1-dimethylethyl 6-[2[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate, 4.37 g (6.68 mol), is dissolved in 200 mL of tetrahydrofuran and 15 mL of 10% hydrochloric acid solution is added, and the solution is stirred for 15 hours. To this solution is added sodium hydroxide (3.6 g) and the mixture is stirred for 30 hours. The reaction is stopped by adding 150 mL of water, 90 mL of hexane, and separating the layers. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 150 mL of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution and the solution is allowed to stand 18 hours. The solution is concentrated in vacuo and the concentrate is redissolved in 50 mL of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred two hours, concentrated in vacuo, and dissolved in 3.0 mL of toluene. (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide (3.01 g) is isolated in two crops.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=2)[CH2:17][CH2:16]1.Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=2)[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCc4ccc([N+](=O)[O-])cc43)c2cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc2ncnc(N3CCc4ccc(N)cc43)c2cc1OC
Yield: 92.4 %

Procedure:
6,7-Dimethoxy-4-(6-nitro-2,3-dihydro-indol-1-yl)-quinazoline (0.50 g, 1.42 mmol; from Example 26) in MeOH (10 mL) with conc. HCl (1 mL) was hydrogenated for 18 hours under 45 psi of H2(g) in the presence of 10% Pd-C (105 mg). Following filtration through a pad of Celite and concentration of the filtrate in vacuo, the residue was taken up in 10% i-PrOH/CHCl3 and the organic phase washed successively with saturated NaHCO3, 0.1M disodium EDTA, and brine. The organic solution was added over Na2SO4(s), filtered and concentrated in vacuo to afford the product as a yellow solid (423 mg; M.P. 215°-217.5° C.; LC-MS: 323 (MH+); anal. RP-HPLC RT: 3.10 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(N2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a stirred solution of 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B, 200 mg, 0.58 mmol) in DMSO (2 ml) in sealed tube, was added pyrrolidine (0.073 ml, 0.89 mmol), K2CO3 (153 mg, 1.11 mmol) and the mixture was stirred at 90° C. for 3 h. After cooling, the crude mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined and washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (100-200 mesh silica, eluting with 10% ethyl acetate in hexane) to obtain 6-chloro-4-phenyl-2-pyrrolidin-1-yl-quinoline-3-carboxylic acid ethyl ester (150 mg, 68%) as pale yellow solid. LC-MS: 381 (M+H)+.
Reaction SMILES: Cl.C(OC([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](OC3CCNC3)[CH:19]=2)[NH:14][C:13]=1C)=O)C1C=CC=CC=1.C(=O)C.C([BH3-])#[N:32].[Na+]>CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[C:13]1[NH2:32]
Reactant: Cc1[nH]c2ccc(OC3CCNC3)cc2c1C(=O)OCc1ccccc1
Reactant: [BH3-]C#N
Agent: CC=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.2 %

Procedure:
Crude 2-methyl-5-(pyrrolidin-3-yloxy)-1H-indole-3-carboxylic acid benzyl ester, hydrochloride (0.075 g, 0.194 mmol, 1 eq) was suspended in methanol (5 mL). Acetaldehyde (0.028 mL, 0.5 mmol, 2.6 eq) was added followed by the addition of sodium cyanoborohydride (0.032 g, 0.5 mmol, 2.6 eq). The reaction mixture was kept at pH 6 and stirred at room temperature. After 24 hours, the reaction was quenched with aqueous sodium bicarbonate, extracted several times with CH2Cl2. The combined organic layers were dried over sodium sulfate, loaded on silica gel and chromatographed (ethyl acetate/methanol/triethylamine 87/10/3). Impure product was further purified by reverse-phase prep-HPLC 10-100% Acetonitrile/water, 0.1% TFA. 0.008 g (10% yield) of the indole-amine was obtained as a brown semisolid: LC/MS (ESI+) 379 (M+1), Anal. (C23H26N2O3.TFA.1.0H2O) C, H, N.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>CCCCCC.O1CCCC1>[Cl:24][C:16]1[C:15]([F:14])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1cccc(F)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1cccc(F)c1Cl
Temperature: 10 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A solution of 1.6N n-butyl lithium in hexane (294 ml) was added to 71 ml of tetramethyl ethylene diamine (TMEDA) in tetrahydrofuran at -70° C. under an inert atmosphere. 3-Fluorobenzoic acid (30 g) in tetrahydrofuran was added and the mixture was stirred for one hour. Hexachloroethane (111.5 g) was added and the reaction mixture was stirred for two hours at -70° C. The reaction mixture was allowed to warm to 10° C. and acidified (to pH 1) with 3M hydrochloric acid solution, extracted with diethyl ether, dried (anhydrous magnesium sulphate) and concentrated to give a solid that was recrystallised from heptane/ethyl acetate to give 2-chloro-3-fluorobenzoic acid (26 g).
Reaction SMILES: [CH2:1]([N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])[CH2:2][N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6].[CH2:21]([NH:28][NH:29][C:30]([NH:32][NH2:33])=[S:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:34]1(=[O:53])[N:38]([CH2:39][CH2:40][CH2:41][C:42](ON2C(=O)CCC2=O)=[O:43])[C:37](=[O:52])[CH:36]=[CH:35]1>CN(C)C=O>[CH2:2]([N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6])[CH2:1][N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15].[CH2:21]([N:28]([C:42](=[O:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:37](=[O:52])[CH:36]=[CH:35][C:34]1=[O:53])[NH:29][C:30]([NH:32][NH2:33])=[S:31])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CCCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Reactant: NNC(=S)NNCc1ccccc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CN(C)C=O
Product: NNC(=S)NN(Cc1ccccc1)C(=O)CCCN1C(=O)C=CC1=O

Procedure:
The EDTA-benzylthiocarbazide prepared in step 1 (20 mg; 34 μmol) and N-(gamma-maleimidobutyryloxy)succinimide (8 mg, 29 μmol=0.9 equiv.) were stirred in anhydrous dimethylformamide for 1 h. The mixture was then evaporated to dryness, and the residue was dried under high vacuum.
Reaction SMILES: C([O-])(=O)C.[Na+].Br[CH:7](Br)[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[Cl:15][C:16]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][C:17]=1[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>O>[Cl:15][C:16]1[CH:28]=[CH:27][C:26]([NH:29][N:30]=[CH:7][C:8](=[O:9])[C:10]([F:13])([F:12])[F:11])=[CH:25][C:17]=1[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: CCOC(=O)C=Cc1cc(NN)ccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C=Cc1cc(NN=CC(=O)C(F)(F)F)ccc1Cl
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
First, 7.4 g (90.2 mmol) of sodium acetate and 8.0 g (28.2 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone were mixed with 70 ml of water, and the mixture was stirred at 80° C. for 30 minutes and then cooled, to which 7.0 g of ethyl 2-chloro-5-hydrazinocinnamate was added at 10° C. or lower, and the mixture was stirred for 3 hours. The precipitated crystals were collected by filtration and dried, which afforded 9.6 g (27.5 mmol) of ethyl 2-chloro-5-(3,3,3-trifluoro-2-oxopropylidenehydrazino)cinnamate.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]([CH3:19])[CH3:18])=[N:15][CH:16]=3)=[N:8][C:7]=2[CH:20]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>ClCCl>[CH3:18][N:17]([CH3:19])[C:14]1[N:15]=[CH:16][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:20][C:7]=3[N:8]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc2oc(-c3ccc(N(C)C)nc3)nc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)c1ccc(-c2nc3cc(O)ccc3o2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To a solution of 5-(5-methoxy-1,3-benzoxazol-2-yl)-N,N-dimethylpyridin-2-amine (0.368 mmol) in dichloromethane (2.0 mL) was added BBr3 in dichloromethane (1.84 mmol) at 0° C. under an atmosphere of argon and the reaction stirred for 1 h at 0° C. The reaction mixture was neutralized with NaHCO3 (sat. aq.) and dichloromethane was added. The layers were separated and the aqueous phase was extracted with dichloromethane (4×). The combined organic phases were dried (MgSO4), filtered and the solvents removed in vacuo. The crude material was purified by preparative HPLC to give 22.3 mg of the title compound as a white solid. 1H NMR δ ppm 9.44 (s, 1H), 8.83 (d, 1H), 8.13 (dd, 1H), 7.48 (d, 1H), 7.01 (d, 1H), 6.80 (d, 1H), 6.76 (dd, 1H), 3.14 (s, 6H). MS m/z (M+H) 256.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH2:7][CH2:6]1)=[O:4].FC1C=C(F)C=CC=1C1CCNCC1.ClCC(Cl)=O.[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([NH:47][C@H:48]2[CH2:53][CH2:52][C@H:51]([OH:54])[CH2:50][CH2:49]2)=[CH:43][C:42]=1[C:55]([F:58])([F:57])[F:56])([O-:40])=[O:39]>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[CH:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][O:54][C@H:51]2[CH2:52][CH2:53][C@H:48]([NH:47][C:44]3[CH:45]=[CH:46][C:41]([N+:38]([O-:40])=[O:39])=[C:42]([C:55]([F:56])([F:57])[F:58])[CH:43]=3)[CH2:49][CH2:50]2)[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Reactant: O=C(CCl)N1CCC(c2ccc(F)cc2F)CC1
Agent: Fc1ccc(C2CCNCC2)c(F)c1
Agent: O=C(Cl)CCl
Product: O=C(CO[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCC(c2ccc(F)cc2F)CC1

Procedure:
1-[4-(2,4-Difluoro-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(2,4-difluoro-phenyl)-piperidine (also known as 2-chloro-1-[4-(2,4-difluoro-phenyl)-piperidin-1-yl]-ethanone) was prepared from 4-(2,4-difluoro-phenyl)-piperidine and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(2,4-difluoro-phenyl)-piperidin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the 1-chloracetyl-4-(2,4-difluoro-phenyl)-piperidine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (16% yield). The structure was confirmed using Protocol II-A. Calculated mass=542; observed mass=543; HPLC retention time=4.36 min.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[C:3]=1Cl.[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23]>ClCCl>[CH3:5][C:4]1[CH:3]=[CH:2][C:14]2[C:5]3([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:12]4[C:4]3=[CH:3][CH:2]=[CH:14][CH:13]=4)[C:20]3[C:21]([O:22][C:13]=2[CH:12]=1)=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]=3
Reactant: Cc1cccc(O)c1
Reactant: Clc1ccc2c(c1Cl)Cc1ccccc1-2
Solvent: ClCCl
Product: Cc1ccc2c(c1)Oc1cc(C)ccc1C21c2ccccc2-c2ccccc21
Temperature: 40 °C

Procedure:
Dichlorofluorene (DCF) (35.27 g, 0.15 mole) is weighed into a powder addition funnel and dissolved in 20 mL of dry dichloromethane. Liquid m-cresol (64.88 g, 0.6 mole) is weighed into a 250 mL three-necked round-bottomed flask which is equipped with a stirrer, heating mantle, nitrogen inlet, condenser, thermometer, and drying tube. Dry dichloromethane (80 mL) is added and the mixture is heated to 40° C. with stirring. DCF solution is added slowly to the mixture as the temperature is maintained at about 40° C. The reaction is rapid as evidenced by copious production of HCl bubbles after each addition. After addition is complete, the reaction is stirred for an additional half hour and then checked by LC. The reaction is complete, and the chromatograph shows peaks for the desired bisphenol (9,9-bis(2-hydroxy-4-methylphenyl)fluorene) along with isomers. The mixture is dissolved in toluene and refluxed with 0.5 mL of methane sulfonic acid collecting water formed during the cyclization reaction in a Dean-Stark trap. The toluene is then removed by rotary evaporation and the residue is slurried with acetonitrile, chilled and filtered to yield the spiroether [3',6'-dimethylspiro[fluorene-9,9'-xanthene] as an off-white powder. The isomeric bisphenols formed in the alkylation reaction do not cyclize and remain dissolved in the acetonitrile.