Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])(=[O:5])[CH3:4]>C(OCC)C>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=[O:5]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: BrBr
Solvent: CCOCC
Product: N#Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (5.50 g, 34.4 mmol) was slowly added dropwise to a solution of 3-acetylbenzonitrile (5.00 g, 34.4 mmol) in diethyl ether (100 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure to give the desired product as an oil.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].BrCC(C1C=CC=CC=1)=[O:14].O.CCO>CN(C=O)C>[OH:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 70 %

Procedure:
A mixture of 2-chloroacetophenone derivatives (or 2-bromoacetophenone derivatives, 0.19 mol), NaOOCH (0.59 mol) in DMF (140 mL), H2O (100 mL) and EtOH (400 mL) was heated under refluxing. After 5-8 hrs, the reaction mixture was cooled to room temperature, then about half of the solvent was removed under vacuum. The residue was diluted with water, and extracted with CH2Cl2. The combined organic layer was washed by H2O, followed by brine;. After drying over Na2SO4, solvents were evaporated under vacuum. The crude product was washed with hexanes, filtration gave the desired 2-hydroxyacetophenone derivatives as a solid in 70˜85% yield, which were used directly for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:25]([O:27]C)=[O:26])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH3:24])[CH:16]=1)=[O:11].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:25]([OH:27])=[O:26])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH3:24])[CH:16]=1)=[O:11]
Reactant: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)O)c2ccccc21
Yield: 83.7 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 22 (3.1 g), 1 mol/L of an aqueous sodium hydroxide solution (12 mL), and methanol (120 mL), to give the captioned compound (2.5 g, 85%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1C.C1(CN2[C:35](=[O:36])C(CO)=CC(C3C=CC(OC)=C(F)C=3)=N2)CC1>>[CH:16]1([CH2:15][N:13]2[C:12](=[O:19])[C:11]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][C:7]([O:36][CH3:35])=[C:2]([F:1])[CH:3]=3)=[N:14]2)[CH2:17][CH2:18]1
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Reactant: COc1ccc(-c2cc(CO)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F

Procedure:
Following the procedure of Example 1 (9), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl) -4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as slightly yellow needles (yield: 80.4%).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:6]([Cl:20])[N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)(=[O:3])[NH2:2].Cl[Si](C)(C)C>ClCCl.CO>[ClH:20].[Cl:20][C:6]1[N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[C:4]([C:1]([NH2:2])=[O:3])[C:5]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Cl)c(-c3ccccc3)c(C(N)=O)c2C1
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: ClCCl
Product: Cl
Product: NC(=O)c1c(-c2ccccc2)c(Cl)n2c1CNCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 196.6 %

Procedure:
To a solution cooled to about 0° C. of 5.99 g (15.9 mmol) of tert-butyl 8-carbamoyl-6-chloro-7-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 50 ml of dichloromethane and 200 ml of methanol are added portionwise 12.6 g (116 mmol) of chlorotrimethylsilane. The mixture is stirred for 16 hours at room temperature and the reaction medium is then concentrated under reduced pressure and co-evaporated twice with ethyl acetate. The residue is crystallized from ethyl acetate to give 4.88 g of 6-chloro-7-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide hydrochloride in the form of a white solid after drying at 60° C. under reduced pressure.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[N:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:11]([C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)[N:16]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:14]=2)=[O:12])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: N#Cc1ccc(Oc2cc(C(=O)O)cc(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)nc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 89.6 %

Procedure:
2,6-bis(4-Cyano phenoxy)-isonicotinic acid (0.220 g, 0.61 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.142 g, 0.71 mmol) were coupled using the procedure of Example 5(c) to afford 0.295 g of the required product. Percentage purity (LCMS): 59.4%, (M+1)=439.2+1 (with BOC). 1H NMR (DMSO-d6): δ 1.40 (9H, s), 1.81 (4H, m), 2.86 (4H, m), 3.82 (1H, m), 7.26 (2H, s), 7.34 (4H, d), 7.85 (4H, d), 8.64 (1H, d).
Reaction SMILES: [Br:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6]C)=[O:4].[Br:17]Br.C[O-].[Na+].Cl>CO>[Br:1][C:2]([Br:17])([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCOC(=O)C(Br)c1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Br)(Br)c1ccc([N+](=O)[O-])cc1
Yield: 50 %

Procedure:
Nitrobenzene was treated with ethyl dibromoacetate in dimethylformamide containing potassium tertiarybutoxide at -20° C. to give ethyl 2-bromo-2-(4-nitrophenyl)acetate (1.37 parts) which was dissolved in methanol (50 parts). To this methanol solution was added dropwise separately a solution of bromine (1.72 parts) in methanol (40 parts) and a solution of sodium methoxide (0.56 parts) in methanol (40 parts). The reaction mixture was poured into dilute aqueous hydrochloric acid solution and extracted with dichloromethane. The dichloromethane solution was evaporated to give methyl 2,2-dibromo-2-(4-nitrophenyl)acetate (1.44 parts, 50%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:26][C:27]3[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=3)[C:19]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:37][CH:38]=3)[C:19]([C:21]3[CH:25]=[N:24][NH:23][CH:22]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)c3cn[nH]c3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)C(=O)c3cn[nH]c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl (4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(1H-pyrazol-4-ylcarbonyl)amino]methyl}phenoxy)acetate and NaOH 1N in the presence of MeOH/THF as a white powder (30%). 1H NMR (MeOD, 300 MHz) δ 7.76 (m, 2H), 7.45 (m, 4H), 7.17 (m, 6H), 6.88 (m, 2H), 4.64 (s, 2H), 3.94 (s, 4H), 2.59 (t J=7.7 Hz, 2H), 1.57 (m, 2H), 1.33 (m, 2H), 0.90 (t, J=7.3 Hz, 3H). HPLC, Rt: 4.62 min (Purity: 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.O[N:18]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.N[CH2:40][C:41]1([OH:48])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>CN(C=O)C>[Cl:1][C:2]1[C:10]([CH2:40][C:41]2([OH:48])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)=[CH:7][C:3]=1[C:4]([NH2:18])=[O:6]
Reactant: On1nnc2ccccc21
Reactant: NCC1(O)CCCCCC1
Reactant: Cc1cc(-c2ccc(Cl)c(C(=O)O)c2)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(CC3(O)CCCCCC3)c(Cl)c(C(N)=O)c2)n[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.2 %

Procedure:
To a solution of 2-chloro-5-(5-methyl-1H-pyrazol-3-yl)-benzoic acid (100 mg, 0.422 mmol) in DMF (10 mL) was added 1-hydroxybenzotriazole (85 mg, 0.63 mmol), polystyrene supported 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.24 g, 1.27 mmol) and 1-aminomethyl-cycloheptanol hydrochloride (113.4 mg, 0.633 mmol). The mixture was stirred at room temperature for 15 minutes, then polystyrene supported N,N-dimethylaminopyridine (0.64 g, 0.93 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was filtered through a glass frit, and the residue was washed thoroughly with methanol. The filtrate was concentrated to dryness in vacuo. The residue was purified by reverse phase chormatography to afford the title compound as a white solid (40 mg). LC/MS (M/z): 362.5 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:11])[CH2:9][CH2:8][C:7](=[O:10])[NH:6][C:4]1=[O:5].[N+:12]([C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([O:20][C:21](=O)[C:16]=12)=[O:19])([O-:14])=[O:13].C([O-])(=O)C.[Na+]>C(O)(=O)C>[N+:12]([C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([N:2]([C:3]3([CH3:11])[CH2:9][CH2:8][C:7](=[O:10])[NH:6][C:4]3=[O:5])[C:21](=[O:20])[C:16]=12)=[O:19])([O-:14])=[O:13]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CC1(N)CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)CCC(=O)NC1=O
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
A stirred mixture of α-amino-α-methylglutarimide hydrochloride (1.2 g, 6.7 mmol), 3-nitrophthalic anhydride (1.3 g, 6.7 mmol), and sodium acetate (0.6 g, 7.4 mmol) in acetic acid (30 mL) was heated to reflux under nitrogen for 6 hours. The mixture then was cooled and concentrated in vacuo. The resulting solid was slurried in water (30 mL) and methylene chloride (30 mL) for 30 min. The suspension was filtered, the solid was washed with methylene chloride, and dried in vacuo (60° C., <1 mm) to afford 1.44 g (68%) of 3-(3-nitrophthalimido)-3-methylpiperidine-2,6-dione as a off-white solid: mp 265-266.5° C.; 1H NMR (DMSO-d6) δ11.05 (s, 1H), 8.31 (dd, J=1.1 and 7.9 Hz, 1H), 8.16-8.03 (m, 2H), 2.67-2.49 (m, 3H), 2.08-2.02 (m, 1H), 1.88 (s, 3H); 13C NMR (DMSO-d6) δ172.20 171.71, 165.89, 163.30, 144.19, 136.43, 133.04, 128.49, 126.77, 122.25, 59.22, 28.87, 28.49, 21.04; HPLC, Water Nova-Pak/C18 column, 4 micron, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4(aq), 7.38 min(98%). Anal. Calcd For C14H11N3O6: C, 53.00; H, 3.49; N, 13.24. Found: C, 52.77; H, 3.29; N, 13.00.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)[C:5]([C:27]#[N:28])=[C:4]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37](=[O:40])[NH:38][CH3:39])[CH:32]=2)[N:3]=1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[NH2:1][C:2]1[N:3]=[C:4]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([NH:38][CH3:39])=[O:40])[CH:32]=2)[C:5]([C:27]#[N:28])=[C:6]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH2:15][CH2:16][NH2:17])=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccc(OCCNC(=O)OC(C)(C)C)cc3)c2C#N)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccc(OCCN)cc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
413 mg (0.74 mmol) of tert-butyl (2-{4-[2-amino-3,5-dicyano-6-({[2-(methylcarbamoyl)pyridin-4-yl]methyl}sulfanyl)pyridin-4-yl]phenoxy}ethyl)carbamate (Example 45A) were dissolved in 4.3 ml of dichloromethane. After addition of 4.2 g (6.88 mmol) of trifluoroacetic acid, the mixture was stirred at RT for 2.5 h. The reaction mixture was evaporated. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>ClCCl>[N:35]1([C:16]([C:15]2[CH:19]=[CH:20][C:12]([N:5]3[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:3]([C:2]([F:21])([F:22])[F:1])=[N:4]3)=[CH:13][CH:14]=2)=[O:18])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
A solution of 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid (87 mg, 0.28 mmol) in dichloromethane (3 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (46 mg, 0.28 mmol). This mixture was allowed to stir at room temperature for 15 minutes. Pyrrolidine (23 mg, 0.32 mmol) was then added and the stirring continued for 1 hour at room temperature. The reaction mixture was then added to a 5 g pre-packed silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (51 mg, 50%).
Reaction SMILES: Cl.[C:2](O)(=O)C.[CH:6]1([CH2:12][C:13]2[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=2[OH:20])[CH2:11][CH2:10][CH2:9][CH2:8]C1>CO>[CH:12]1([C:13]2[CH:19]=[CH:18][C:16]([OH:17])=[C:15]([CH3:2])[C:14]=2[OH:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:6]1
Reactant: Oc1ccc(CC2CCCCC2)c(O)c1
Reactant: CC(=O)O
Agent: Cl
Solvent: CO
Product: Cc1c(O)ccc(C2CCCCC2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
3 M HCl (13 ml) was added to a solution of crude 4-cyclohexylmethyl resorcinol monoacetate (2.71 g) in methanol (70 ml) and the solution stirred at room temperature for 16 h. At this time, TLC showed the clean formation of product (Rf 0.14) and traces of starting material (Rf 0.48) (Note 11). The solvent was reduced to ⅓ volume under reduced pressure and partitioned between ethyl ether (300 ml) and 1 M HCl (100 ml), washed with saturated NaCl (100 ml), the aqueous layer back extracted with ethyl ether (200 ml), the organic layers dried (Na2SO4), filtered and the solvent removed to give 4-cyclohexyl methyl resorcinol as a light amber-colored oil which crystallized upon standing at room temperature (1.1 g, 75% yield). The crude product was purified by flash chromatography to give 4-cyclohexyl methyl resorcinol B2 as a white solid (617 mg, 51% yield) (Note 12): m.p. 112-113° C.; 1H NMR (60 MHz, acetone-d6) delta 1.08-1.76 (m, 11H), 2.44 (d, JJ=6.2 Hz, 2H), 6.26 (dd, JJ=7.9, 2.3 Hz, 1H), 6.39 (m, 1H), 6.86 (d, JJ=7.9 Hz, 1H), 7.90 (s, 1H); 13C NMR (60 MHz, acetone-d6) delta 27.3, 33.3, 38.2, 39.5, 102.9, 106.7, 119.0, 132.5, 157.0, 157.4; m/z (EI; TMS derivatized; M+) 350.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].[Cl-].[Na+]>CCOCC>[C:1]1([C:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)([OH:14])[CH2:12][CH2:11][CH2:10][Cl:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Mg]C1CCCCC1
Reactant: O=C(CCCCl)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: OC(CCCCl)(c1ccccc1)C1CCCCC1
Yield: 62.2 %

Procedure:
To a stirred and ice-cooled solution of cyclohexyl magnesium chloride (60 mmol) in dry ether (23.2 ml), 4-chlorobutyrophenone (5.5 g) in ether (17 ml) was added dropwise. The mixture was stirred at 0° C. for 2 hours, then an aqueous solution of sodium chloride was cautiously added. The organic phase was separated and dried. The solvent was removed and the residue was purified by column chromatography (hexane, ether 98:2), affording 5 g of 1-phenyl-1-cyclohexyl-4-chloro-1-butanol as an oil.
Reaction SMILES: C(O[N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][F:23])=[C:15]([Br:24])[CH:14]=1)[C:7]([N:9]=C=O)=[NH:8])(C)(C)C.[ClH:25]>O1CCOCC1.O.C(#N)C>[ClH:25].[Br:24][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH2:20][CH2:21][CH2:22][F:23])[CH2:12][NH:6][C:7]([NH2:9])=[NH:8]
Reactant: CC(C)(C)ON(Cc1ccc(OCCCF)c(Br)c1)C(=N)N=C=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: N=C(N)NCc1ccc(OCCCF)c(Br)c1
Yield: 99 %

Procedure:
A solution of 1,3-bis(tert-butoxy-carbonyl-[3-bromo-4-(3-fluoro-propoxy)-benzyl]-guanidine (250.6 mg, 50 mmol) in 4N HCl in dioxane (6 mL) was heated to 50° C. for 2 h. The reaction mixture was diluted with water (4 mL) and ACN (1 mL) and lyophilized to afford N-[3-bromo-4-(3-fluoro-propoxy)-benzyl]-guanidine hydrochloride as a white solid (169.1 mg, 99% yield). 1H NMR (DMSO-d6, 600 MHz): δ 8.03 (br t, 1H), 7.55 (m, 1H), 7.31-7.27 (m, 2H), 7.15 (d, J=9 Hz, 1H), 4.72 (t, J=6 Hz, 1H), 4.56 (t, J=6 Hz, 1H), 4.30 (m, 2H), 4.15 (t, J=6 Hz, 2H), 2.19-2.06 (m, 2h).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:18][CH:17]2[C:16](=[O:19])[NH:15][C:14]3=[O:20])=[CH:9][CH:8]=1.CN(C1C=CC=CN=1)C.Cl>C(Cl)Cl.O.N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]23[CH2:18][CH:17]2[C:16](=[O:19])[NH:15][C:14]3=[O:20])=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: Nc1ccc(C23CC2C(=O)NC3=O)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C23CC2C(=O)NC3=O)cc1
Reaction time: 16 h

Procedure:
A solution of 1.2 ml of methanesulfonyl chloride in 10 ml of methylene chloride is stirred dropwise at room temperature into a mixture of 3 g of 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione, 90 mg of dimethylaminopyridine and 37 ml of pyridine. After it has been stirred for 16 hours, the reaction mixture is freed from solvent in vacuo. The residue is dissolved in 100 ml of water and the solution is adjusted to pH 1 with hydrochloric acid. After further stirring, the crystals are isolated by filtration and recrystallised from methanol. The title compound is obtained in the form of whitish orange crystals with a melting point of 208°-209° C. and with Rf=0.32 on thin-layer silica gel plates in the system methylene chloride/methanol (10:1).
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][C:6]([OH:14])([CH2:7]3)[CH2:5]1)[CH2:11]2)(=[O:3])[CH3:2].[C:15]([C:18]12CC3CC(CC(C3)C1)C2)(=O)[CH3:16]>>[OH:14][C:6]12[CH2:12][CH:10]3[CH2:9][CH:8]([CH2:13][C:4]([C:1]([CH:15]([CH3:18])[CH3:16])([CH3:2])[OH:3])([CH2:11]3)[CH2:5]1)[CH2:7]2
Reactant: CC(=O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Product: CC(C)C(C)(O)C12CC3CC(CC(O)(C3)C1)C2
Yield: 48 %

Procedure:
The procedure of Example 1 was repeated, except that 1.0 mol of 1-acetyl-3-adamantanol obtained according to the process of Reference Example 2 was employed instead of 1-acetyladamantane, to give 3-hydroxy-α-isopropyl-α-methyl-1-adamantanemethanol in yield of 48%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15].CC(=CC)C.P([O-])([O-])(O)=[O:22].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([CH3:12])([CH3:10])[CH3:11])[N:5]=[C:4]([C:13]([OH:22])=[O:14])[C:3]=1[Cl:15]
Reactant: O=P([O-])([O-])O
Reactant: CC(C)(C)c1nc(C=O)c(Cl)c(N)c1F
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)c1nc(C(=O)O)c(Cl)c(N)c1F
Temperature: 70 °C

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-6-(tert-butyl)-3-chloro-5-fluoropicolinaldehyde (316 mg, 1.370 mmol) and t-butanol (6.85 mL). The mixture was treated with H2O (2.283 mL), 2-methylbut-2-ene (1.1 mL, 1.370 mmol), sodium hydrogenphosphate (389 mg, 2.74 mmol). Finally, sodium chlorite (372 mg, 4.11 mmol) was added in one portion. The mixture was heated to 70° C. in the microwave for 2 h. An aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was diluted with EtOAc (15 mL) and washed with 1 M HCl (1×5 mL), H2O (1×5 mL) and saturated NaCl (1×5 mL). HPLC analysis of the combined aqueous washes showed only trace amounts of the desired product. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give 414 mg of a cream colored solid. The crude material was stirred with Et2O (˜5 mL). After stiffing for ˜3 h the solid was removed by vacuum filtration washing with Et2O. The solid was air-dried for several hours and then dried under vacuum. The title compound (348 mg, >99%) was isolated as a white solid: mp 149-151° C.; 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 4.97 (s, 2H), 1.41 (d, J=1.5 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −132.92; 13C NMR (101 MHz, CDCl3) δ 161.62, 151.12, 149.21, 146.63, 141.58, 117.18, 36.69, 28.37.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([C:33]([O:35]CC2C=CC=CC=2)=[O:34])[CH:22]=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.O1CCOCC1.[Li+].[OH-]>O>[CH2:1]([O:8][C:9]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([C:33]([OH:35])=[O:34])[CH:22]=[CH:21][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)c(OCc2ccccc2)c1OCc1ccccc1
Temperature: 60 °C

Procedure:
2 (56.970 g, 0.102 mol) was dissolved in 200 mL 1:1:EtOH:dioxane in a 1-L round-bottom flask, resulting in a dark orange, clear solution, to which a suspension of LiOH (7.315 g, 0.305 mol) in 75 mL water was added. The flask was fitted with a reflux condenser and magnetically stirred. The emulsion (containing undissolved LiOH) was heated to 60° C. for 12 h, and became a translucent, orange solution. The reaction mixture was filtered through a M glass frit, dissolved in 500 mL basic water, and washed with DCM (3×250 mL). The aqueous layer was acidifed with ˜80 mL conc. HCl, and the resulting white precipitate was filtered and washed with water. The solid was dried using house vacuum overnight, ground into a white powder, and dried on the vacuum line for 12 h (100%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[S:39][C:38]([CH2:40][C:41]([O:43]CC)=[O:42])=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>>[C:12]([O:11][C:9]([C:8]1[C:7]([OH:16])=[C:6]([C:24]([F:27])([F:25])[F:26])[CH:5]=[CH:4][C:3]=1[CH2:2][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[S:39][C:38]([CH2:40][C:41]([OH:43])=[O:42])=[CH:37][CH:36]=2)=[CH:33][CH:34]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1ccc(-c2ccc(O)cc2)s1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)s3)cc2)ccc(C(F)(F)F)c1O
Yield: 14 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (366 mg, 0.8 mmol) obtained in Example (28-5) and ethyl [5-(4-hydroxyphenyl)-2-thienyl]acetate (211 mg, 0.8 mmol) obtained in Example (28-6), the title compound was obtained as a colorless powder (56 mg, three-step total yield: 14%).