Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])=[O:7].CN1CCOCC1.[NH2:31][C:32]1[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][N:33]=1>C(Cl)Cl>[NH2:31][C:32]1[N:37]=[CH:36][C:35]([NH:38][C:14](=[O:15])[C:13]2[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:22])([F:23])[F:1])[CH:4]=3)[CH:10]=[CH:11][C:12]=2[Cl:18])=[CH:34][N:33]=1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Reactant: Nc1cnc(N)nc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Nc1ncc(NC(=O)c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2Cl)cn1
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of intermediate 1 (Example 2) (380 mg, 1.11 mmol) in DCM was charged with CDMT (233 mg, 1.33 mmol), and NMM (0.3 mL, 2.73 mmol). After 1 hr of stirring, 2,5-diaminopyrimidine (121 mg, 1.10 mmol) was added and the solution was allowed to stir for 48 h. The mixture was concentrated and purified by HPLC to afford the title compound as a white solid (350 mg, 73%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[CH:12][C:13](F)=[C:14]([CH3:16])[CH:15]=1)([O-:9])=[O:8].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:16][C:14]1[CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=[CH:12][C:13]=1[N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCSCC1

Procedure:
In the same manner as in Production Example 5-1, but using thiomorpholine in place of N-ethylpiperazine used in Production Example 5-1, using 5-nitro-2-fluorotoluene in place of 2-fluoro-5-nitrobenzyl alcohol, using N,N-diisopropylethylamine in place of potassium carbonate, and using dimethylsulfoxide in place of N-methylpyrrolidone, crude 4-(2-methyl-4-nitrophenyl)thiomorpholine was obtained.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[C:7]([O:15][CH2:16][CH2:17][O:18][C:19](ON1C(=O)CCC1=O)=[O:20])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:2][N:1]([C:19]([O:18][CH2:17][CH2:16][O:15][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])=[O:20])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CNCC(=O)O
Reactant: O=C(OCCOC(=O)c1ccccc1)ON1C(=O)CCC1=O
Product: CN(CC(=O)O)C(=O)OCCOC(=O)c1ccccc1
Yield: 44.4 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.104 g, 1.17 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl benzoate (0.3 g, 0.976 mmol) were reacted to provide 122 mg (44% yield) of the title compound (40) as a colorless semi-solid after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=8.01 (d, 2H), 7.61 (t, 1H), 7.44 (t, 2H), 7.01 (q, 1H), 4.12 (m, 2H), 3.01 (2s, 3H), 1.62-1.58 (dd, 3H). MS (ESI) m/z 304.05 (M+Na)+; 280.11 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[S:19][C:18]([CH3:20])=[C:17]3[C:13]=2[CH2:14][C@H:15]2[C:21]([CH3:23])([CH3:22])[C@H:16]23)=[O:11])=[CH:4][C:3]=1[CH3:24].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].C(O)(=O)C>[CH3:24][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][C:10]([C:12]2[S:19][C:18]([CH3:20])=[C:17]3[C:13]=2[CH2:14][C@H:15]2[C:21]([CH3:22])([CH3:23])[C@H:16]23)=[O:11])[CH:6]=[CH:7][C:2]=1[O:1][CH2:25][CH:27]1[CH2:28][O:29]1
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)ccc1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)ccc1OCC1CO1
Reaction time: 1.5 h
Yield: 32.7 %

Procedure:
A solution of 3-(4-hydroxy-3-methyl-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (179 mg, 0.525 mmol, Intermediate 4) in isopropanol (10 mL) and 3 N aq. NaOH (4 mL) is treated with epichlorohydrine (197 mg, 1.58 mmol). The reaction mixture is stirred at 70 for 1.5 h. The mixture is diluted with acetic acid (0.3 mL) and the solvent is removed under reduced pressure. The residue is purified by prep. HPLC (Waters Xterra MS18, 75×30 mm ID, 10 μm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 3-(3-methyl-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (68 mg) as a pale brown oil; LC-MS: tR=1.15 min, [M+1]+=397.27.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].Cl[C:13]([F:18])([F:17])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(OCC)(=O)C>[F:17][CH:13]([F:18])[O:11][C:4]1[CH:3]=[C:2]([F:1])[C:7]([CH2:8][OH:9])=[C:6]([F:10])[CH:5]=1
Reactant: OCc1c(F)cc(O)cc1F
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCc1c(F)cc(OC(F)F)cc1F
Temperature: 100 °C
Yield: 56 %

Procedure:
500 mg 3,5-difluoro-4-(hydroxymethyl)phenol (3.12 mmol, 1.0 eq.) were dissolved in DMF. 523 mg sodium chloro(difluoro)acetate (3.44 mmol, 1.1 eq.), 1.22 g cesium carbonate (3.75 mmo, 1.2 eq) and 0.20 mL water (10.9 mmol, 3.5 eq.) were added. The reaction mixture was stirred at 100° C. over night. The reaction mixture was divided between water and ethyl acetate. The aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo. The crude product was purified by flash chromatography to provide 161 mg (0.69 mmol, 22%) of the 56% pure target compound.
Reaction SMILES: [H-].[Na+].[C:3](Cl)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+:13]>CN(C)C=O>[C:3]([N:13]1[C:7]2[CH2:8][CH2:9][CH:4]([C:3]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:10])[CH2:5][C:6]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Reaction time: 1 h

Procedure:
A solution of 291 mg of benzyl 1,2,3,4-tetrahydrocarbazole-3-carboxylate, as obtained in Example 50, in 2 ml of N,N-dimethylformamide was added, with ice-cooling, to a suspension of 87 mg of sodium hydride (55% w/w dispersion in mineral oil) in 4 ml of N,N-dimethylformamide. 0.12 ml of benzoyl chloride was added to the reaction mixture which was then stirred for 1 hour. After this time, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic extract was washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 10 g of silica gel with a 5:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 384 mg of the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[CH:2].I[C:10]1[CH:11]=[C:12]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:13]([NH:15][C:16]1[CH:35]=[CH:34][C:19]([CH2:20][N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[C:18]([C:36]([F:39])([F:38])[F:37])[CH:17]=1)=[O:14]>>[CH3:43][C:42]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[CH:35]=[CH:34][C:19]([CH2:20][N:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[C:18]([C:36]([F:39])([F:37])[F:38])[CH:17]=2)=[O:14])=[CH:40][C:41]=1[C:2]#[C:1][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: C#Cc1cnccn1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCNCC3)c(C(F)(F)F)c2)cc1C#Cc1cnccn1

Procedure:
The title compound can be synthesized from 2-ethynylpyrazine and tert-butyl 4-(4-(3-iodo-4-methylbenzamido)-2-(trifluoromethyl)benzyl)piperazine-1-carboxylate in a manner similar to that described for Example 1. Following deprotection using saturated MeOH/HCl (g), the product can be obtained as an HCl salt. 2-ethynylpyrazine is prepared from 2-bromopyrazine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:12][C:13]([CH3:15])=[O:14].[OH-].[Na+].O>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:13](=[O:14])[CH:15]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=2)=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(C=CC(=O)C=Cc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
4-Dimethylaminobenzaldehyde (1g, 1.00 g, 6.7 mmol) and acetone (19, 0.24 ml, 3.2 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethanol to give 0.53 g (51%) of an orange solid: mp 179-181° C. [expected mp 174-176° C.]; 1H NMR: δ 3.01 (s, 12H), 6.69 (d, 4H, J=8.7 Hz), 6.87 (d, 2H, J=15.7 Hz), 7.50 (d, 4H, J=8.7 Hz), 7.67 (d, 2H, J=15.7 Hz); 13C NMR: δ 40.2, 98.9, 111.8, 121.2, 122.9, 129.9, 142.8, 151.6.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>CC#N.CN(C=O)C.CCOC(C)=O>[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH:37][C:8](=[O:10])[CH2:7][C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:35][CH:34]=1
Reactant: Cc1ccc(CC(=O)O)o1
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccc(CC(=O)Nc2ccc(F)cc2)o1
Reaction time: 3 h
Yield: 94.9 %

Procedure:
5-Methyl-2-furanacetic acid (1.00 g, 7.14 mmol, synthesized as described WO 9507893, Example 19) was dissolved in CH3CN/DMF (4:1, 25 mL), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (1.37 g, 7.14 mmol) and 1-hydroxy-7-azabenzotriazole (0.972 g, 7.14 mmol) were then added followed by 4-fluoroaniline (0.676 mL, 7.14 mmol). After 3 h, the reaction was diluted with EtOAc (150 mL) and washed with 1 N HCl (1×30 mL), sat. aq. NaHCO3 (1×30 mL), brine (1×40 mL) and dried over sodium sulfate. Compound 216A (1.58 g, 95%)) was isolated as a yellow foam after concentration in vacuo. No further purification was necessary. HPLC: 78% at 2.647 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: C([N:8]1[C:20]2[C:19]([Cl:21])=[CH:18][CH:17]=[C:16]([O:22]C)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:24](=[O:26])[NH2:25])C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[C:24]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:15]1[C:16]([OH:22])=[CH:17][CH:18]=[C:19]([Cl:21])[C:20]=1[NH:8]2)(=[O:26])[NH2:25]
Reactant: COc1ccc(Cl)c2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)c1cccc2[nH]c3c(Cl)ccc(O)c3c12
Temperature: 25 °C
Yield: 60.9 %

Procedure:
A solution of 0.66 g of 9-benzyl-5-carbamoyl-4-methoxy-1-chlorocarbazole in 40 ml of dichloromethane was cooled in an ice bath treated dropwise with 14 ml of 1.0 M boron tribromide solution in dichloromethane. The reaction was allowed to warm to room temperature slowly over 2 hours and then quenched by pouring into ice and then adding 50 ml of 1 N HCl. The mixture was extracted with dichloromethane (3×200 ml) and the extracts were washed with brine, dried with magnesium sulfate and concentrated. The aqueous layers exhibited a precipitate and was then extracted twice with ethyl acetate, washed with brine, dried with magnesium sulfate and concentrated to afford 0.287 g of the subtitle compound. The first residue was chromatographed on silica gel using 0.5% methanol in dichloromethane to afford another 93 mg of the subtitle compound. (total yield 80%) ESIMS m/e 259 (M+−1) NMR (300 MHz, d6-DMSO): δ 11.79 (s, 1H); 10.76 (s, 1H); 8.87 (br s, 1H); 8.41 (br s, 1H); 7.77 (t, J=4.6, 1H); 7.48 (d, J=4.2, 2H); 7.34 (d, J=8.5, 1H); 6.54 (d, J=8.5, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:17]=[CH:16][S:15][CH:14]=1>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Brc1ccsc1
Solvent: ClCCl
Product: CSc1ccc(-c2ccsc2)cc1

Procedure:
Prepared according to the procedure Coupling-1 using [4-(methylthio)phenyl]boronic acid and 3-bromothiophene as starting material. Flash chromatography (CH2Cl2) afforded the title compound.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH3:32])[CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[CH:15]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[Na+]>C(O)C>[CH3:32][N:12]([CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1)[CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=2)[CH:15]=1
Reactant: CCOC(=O)N1CCC(N(C)Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-c2cc(CN(C)C3CCNCC3)ccn2)cc(OC)c1OC

Procedure:
To a solution of 1-(ethoxycarbonyl)-4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (100 mg) in ethanol (2 mL) was added 4 M sodium hydroxide (8 mL). The mixture was refluxed overnight and extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to a column of silica gel and liquid chromatography was performed using chloroform-methanol (20:1) to give the title compound as yellow syrup.
Reaction SMILES: O[CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=2)[C:5](=[O:14])[CH2:4][C:3]1([CH3:16])[CH3:15].FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[I:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[CH2:2][C:3]([CH3:15])([CH3:16])[CH2:4][C:5]2=[O:14])=[N:8][CH:9]=1
Reactant: CC1(C)CC(=O)N(c2ccc(I)cn2)C1O
Agent: CC[SiH](CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(=O)N(c2ccc(I)cn2)C1
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
(275 mg, 828 μmol) (5RS)-5-Hydroxy-1-(5-iodopyridin-2-yl)-4,4-dimethylpyrrolidin-2-one (Example 13, step 2) was dissolved in CH2Cl2 (2 ml) and trifluoroacetic anhydride (140 μl, 994 μmol, 1.2 equiv.) was added at room temperature. The mixture was stirred for 1 hr at 20-25° C. The solution was evaporated to dryness and the residue was dissolved in trifluoroacetic acid (957 μl, 12.4 mmol, 15 equiv.) and triethylsilane (159 μl, 994 μmol, 1.2 equiv.) was added at room temperature. The mixture was stirred 1 h at room temperature. The reaction mixture was evaporated and extracted with sat. NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(5-iodopyridin-2-yl)-4,4-dimethylpyrrolidin-2-one (209 mg, 80% yield) was obtained as a white solid, MS: m/e=317.0 (M+H+).
Reaction SMILES: CCCCCC.C([Al](CC(C)C)CC(C)C)C(C)C.C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.C(O)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:56]([Cl:65])[C:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:58]>C1(C)C=CC=CC=1>[Cl:65][CH2:56][C@H:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[OH:58]
Reactant: O=C(CCl)c1ccccc1
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Agent: OC(c1ccccc1)c1ccccc1
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O[C@H](CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.5 ml (0.5 mmol) of hexane solution of triisobutylaluminum (1.0 M) was added a slurry solution of 143 mg (0.5 mmol) of (R)-1,1′-bi-2-naphthol in 10 ml of toluene at room temperature, and the mixture was stirred at room temperature for 30 minutes. Thereto 1.84 g (20 mmol) of benzhydrol was added and the mixture was stirred further at room temperature for 30 minutes. Thereto 1.55 g (10 mmol) of phenacyl chloride was added and the mixture was stirred further at room temperature for 2 hours. The after-treatment and the analysis of the product were then carried out in the same manner as described in Example 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:10]([CH:16]=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:8]=2)[CH:7]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nc1ccc(Br)cn1
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(Br)cn12
Temperature: 75 °C
Reaction time: 48 h
Yield: 29.5 %

Procedure:
A mixture of 5-bromopyridin-2-amine (5.22 g, 30.2 mmol) and ethyl 2-chloro-3-oxopropanoate (5.00 g, 33.2 mmol) (Toronto Research Chemicals; 5% solution on benzene) was stirred in ethanol (151 mL, 30.2 mmol) under nitrogen. The mixture was heated to 75° C. for 4 hours and then at ambient temperature for 2 days. The solvent was removed under vacuum to give a solid residue which was purified by silica gel chromatography, eluting with hexane/ethyl acetate (6:4 to 4:6) to give the desired product as a solid (2.40 g; 30%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=1)[Si:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:7]([Si:8]([CH3:11])([CH3:9])[CH3:10])[C:6](=[O:23])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13][C:14]=1[Si:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)[Si](C)(C)C)cc1[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(c1ccc(CBr)c([Si](C)(C)C)c1)[Si](C)(C)C

Procedure:
A suspension of tert-butyl[4-methyl-3-(trimethylsilyl)phenyl](trimethylsilyl)carbamate (3.00 g, 6.55 mmol), N-bromosuccinimide (NBS, 1.59 g, 8.97 mmol), 2,2′-azobis(2-methylpropionitrile) (AIBN, 42 mg, 0.26 mmol) in CCl4 (40 mL) was refluxed under N2 for 16 h. The reaction mixture was cooled down; hexanes (100 mL) were added and the solid was filtered off and washed with EtOAc. The combined filtrate was washed with aq. NaHCO3, dried over Na2SO4, filtered, concentrated on rotavap and further dried under vacuum. This material was not purified but used directly in the next step (˜80%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=[CH:5]2.C([Li])CCC.[NH:21]1[CH:25]=[C:24]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[N:23]=[CH:22]1.[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:13][O:12][C:8]1[C:7]([O:14][CH3:15])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:26]([C:24]1[N:23]=[CH:22][NH:21][CH:25]=1)([OH:30])[CH:27]([CH3:29])[CH3:28])=[CH:3]2
Reactant: CC(C)C(=O)c1c[nH]cn1
Reactant: COc1ccc2cc(Br)ccc2c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
6-Bromo-1,2-dimethoxynaphthalene (2.10 g) was dissolved in THF (30 ml). The solution was cooled to −78° C. To the reaction mixture was added dropwise a solution of n-butyllithium in hexane (1.6M: 6 ml), and the mixture was stirred for 1 h. To the mixture was added a solution of 1-(1H-imidazol-4-yl)-2-methyl-1-propanone (0.367 g) in THF (10 ml), and the temperature of the mixture was elevated to room temperature. To the reaction mixture were added an aqueous solution of ammonium chloride and ethyl acetate, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give the titled compound (0.459 g) as a colorless solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:21]1[O:28][C@H:27]([CH2:29]O)[C@@H:25]([OH:26])[C@H:23]([OH:24])[CH2:22]1.C(Br)(Br)(Br)[Br:39].CO>N1C=CC=CC=1>[Br:39][CH2:29][C@H:27]1[O:28][C@@H:21]([O:20][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:22][C@@H:23]([OH:24])[C@@H:25]1[OH:26]
Reactant: OC[C@H]1O[C@@H](OCc2ccccc2)C[C@@H](O)[C@@H]1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CO
Product: O[C@H]1[C@H](O)C[C@H](OCc2ccccc2)O[C@@H]1CBr
Temperature: 50 °C
Yield: 72.6 %

Procedure:
A solution of triphenylphosphine (4.5 g, 17.3 mmol, 2.2 eq) in pyridine (30 mL) was added dropwise to a cooled solution of Compound 1 (2.0 g, 7.9 mmol) and CBr4 (3.1 g, 9.4 mmol) in pyridine (30 mL) at zero degrees C. The mixture was then heated at 50° C. for 10 hours. After cooling, methanol (5 mL) was added dropwise, and the mixture was concentrated. The product was purified by flash column chromatography with CHCl3—MeOH (32:1) to give 1.82 g (yield 73 percent) of Compound 2.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[OH-].[Na+].[C:8]([C:12]1([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:14][O:13]1)([CH3:11])([CH3:10])[CH3:9].C(=O)=O>CN1CCCC1=O.O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][C:12]([CH2:14][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)([OH:13])[C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:22][CH:21]=1
Reactant: CC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 120 °C
Yield: 88.7 %

Procedure:
20.7 g (0.3 mole) of 1,2,4-triazole, 4.15 g (0.103 mole) of sodium hydroxide and 1 ml of water were added to a solution of 71.55 g (0.3 mole) of 2-tert.-butyl-2-(4-chloro-phenyl-ethyl)-oxirane in 125 ml of N-methyl-pyrrolidone at room temperature, with stirring. The reaction mixture was heated at 120° C. for 4 hours, with stirring, during which a dry stream of CO2 -free air was slowly passed through. Thereafter, the mixture was worked up by a procedure in which the solvent was distilled off under reduced pressure and the residue which remained was washed with water and then dried and stirred with 150 ml of benzine. The solid product which deposited was filtered off and dried again. 81.9 g (88.8% of theory) of 1-(4-chloro-phenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl-methyl)-pentan-3-ol were obtained in this manner.