Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:15].[C:16]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:16][O:15][C:3]1[CH:4]=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1cc(Oc2ccccc2)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 2-bromo-5-phenoxyphenol (0.38 g, 1.4 mmol) in 6 ml acetone was added K2CO3 (0.58 g, 4.2 mmol) and iodomethane (0.26 ml, 4.2 mmol). The-reaction mixture was heated to reflux for 8 h, cooled to ambient temperature and filtered. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with 1N NaOH, water and brine. Drying over Na2SO4 afforded 0.36 g (92%) of 2-methoxy-4-phenoxybromobenzene.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[CH:21]=[CH2:22].[C:23](=O)([O-])[O-].[K+].[K+].CO.COP(C(=[N+]=[N-])C(=O)C)(=O)OC>CCOCC>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[CH:23])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[CH:21]=[CH2:22]
Reactant: C=Cc1c(C(=O)OC)nc(-c2ccc(C=O)cc2)c(F)c1N
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(C=C)c(N)c2F)cc1
Reaction time: 4 h
Yield: 61.8 %

Procedure:
To a 20 mL reaction vial was added methyl 4-amino-5-fluoro-6-(4-formylphenyl)-3-vinylpicolinate (0.41 g, 1.365 mmol), potassium carbonate (0.377 g, 2.73 mmol) and MeOH (10 mL). Dimethyl(1-diazo-2-oxopropyl)phosphonate (0.315 g, 1.638 mmol) was added in one portion. After stirring for 4 h, the reaction mixture was diluted with Et2O (50 mL) and washed with a 5% solution of NaHCO3 (25 mL) The organic layer was dried over MgSO4 (5 g), filtered, and concentrated on a rotary evaporator. The resulting reside was purified using a Teledyne ISCO purification system with a gradient eluent system of CH2Cl2 and EtOAc to yield the title compound as a white solid (250 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:4](=[O:16])[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]2)=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:5]2[CH:6]=[N:7][C:2]([O:29][CH:26]3[CH2:27][CH2:28][N:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[CH2:25]3)=[N:3][C:4]2=[O:16])=[CH:10][CH:11]=1
Reactant: OC1CCN(c2ccc(F)cc2)C1
Reactant: O=c1nc(Cl)ncn1Cc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: O=c1nc(OC2CCN(c3ccc(F)cc3)C2)ncn1Cc1ccc(Cl)cc1
Yield: 3.8 %

Procedure:
The synthesis was performed using a chloroform solution (2 mL) of 4-chloro-1-(4-chlorobenzyl)-1,3,5-triazin-2(1H)-one (67 mg, 0.26 mmol) synthesized in Reference Synthesis Example 11 and 1-(4-fluorophenyl)pyrrolidin-3-ol (71 mg, 0.39 mmol) synthesized in Reference Synthesis Example 46 in a similar manner to Synthesis Example 79 to obtain the title compound (4.0 mg, yield: 4%).
Reaction SMILES: [H][H].[N+]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH2:16][C:17]#[N:18])([O-])=O>C(O)C.C(O)(=O)C.[Pd]>[CH:16]1[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=[CH:15][C:6]=2[NH:18][CH:17]=1
Reactant: [H][H]
Reactant: N#CCc1c([N+](=O)[O-])ccc2ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc2c(c1)ccc1[nH]ccc12

Procedure:
At ambient temperature and under 4 bars of hydrogen, hydrogenate 33 g of (2-nitro-1-naphthyl)acetonitrile (0.155 mol) dissolved in 630 ml of ethanol containing 10% water and 6.3 ml of pure acetic acid, using 19 g of 10% palladium-on-carbon. After absorption has ceased, filter off the catalyst, concentrate the solvent in vacuo and then take up the residue in 250 ml of dichloromethane; wash the organic phase with 100 ml of 0.1N potassium hydroxide solution and then dry the organic phase over magnesium sulphate, filter and concentrate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:5]=1
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)cc(Cl)n1
Reactant: C1CCNC1
Product: CC1(C)CCCC(C)(C)N1c1nc(Cl)cc(N2CCCC2)n1
Yield: 75.08 %

Procedure:
The reaction of 4,6-dichloro-2-(2,2,6,6-tetramethyl-1-piperidinyl) pyrimidine with pyrrolidine as described in Example 7 gives the title compound in a yield of 75.08%, m.p.:130°-135° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=[NH:9])=[O:8])[CH3:2].[H-].[Na+].I[CH2:24][CH3:25]>CN(C)C=O.O>[CH2:24]([N:9]=[S:7]([CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:8])[CH3:25]
Reactant: CCI
Reactant: CCN(CC)CCCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN=S(=O)(CCCN(CC)CC)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of S-(3-diethylaminopropyl)-S-(4-nitrophenyl)sulfoximine (10 mmol) in dimethylformamide is added to a stirred suspension of 60% sodium hydride-oil dispersion (10 mmol) at ambient temperature. After stirring for 30 min the mixture is warmed to 50° C. for 30 min and then cooled to ambient temperature. Iodoethane (10 mmol) is added dropwise to the reaction mixture and stirred at ambient temperature for 30 min and then warmed to 50° C. for 1 hr. The reaction mixture is diluted with water and extracted with methylene chloride. The methylene chloride extract is concentrated in vacuo and the residue partitioned between methylene chloride-1N hydrochloric acid. The acid layer is separated and basified with 50% sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extract is washed with water, dried, and concentrated to obtain the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:14])=[N+:2]=[N-:3].[Se](=O)=[O:16]>>[N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:16])[C:9]2=[O:14])=[N+:2]=[N-:3]
Reactant: O=[Se]=O
Reactant: [N-]=[N+]=Nc1cccc2c1CCCC2=O
Product: [N-]=[N+]=Nc1cccc2c1C=CC(=O)C2=O

Procedure:
Treatment of 5-azido-1-tetralone with selenium dioxide as described in Reference Example 1A yielded 5-azido-[1,2]naphthoquinone which was coupled with 2,3-diamino-benzoic acid, diacetate salt, as described in Reference Example 1A to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[CH:14]1[C:23]2[C:18](=[C:19]([C:24]([CH3:29])([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1.FC1C(F)=C(C(F)(F)F)C=CC=1CN>>[CH:14]1[C:23]2[C:18](=[C:19]([C:24]([CH3:29])([CH3:28])[C:25]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([S:3][C:2]([F:12])([F:1])[F:13])=[CH:5][CH:6]=3)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: NCc1ccc(SC(F)(F)F)cc1
Reactant: CC(C)(C(=O)O)c1cccc2cnccc12
Agent: NCc1ccc(C(F)(F)F)c(F)c1F
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C)(C(=O)NCc1ccc(SC(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-[(trifluoromethyl)thio]benzylamine and 2-(5-isoquinolinyl)-2-methylpropanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 405 (M+H)+; MS (ESI−) m/z 403 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.57 (s, 3H), 1.64 (s, 3H), 4.33 (d, J 6.1, 2H), 6.57 (s, 1H), 7.18 (m, 1H), 7.33(m, 1H), 7.52 (m, 2H), 7.82 (m, 1H), 8.11 (m, 1H), 8.36 (d, J 7.8, 1H), 8.57 (m, 1H), 9.42 (s, 1H), 10.08 (s, 1H); Anal. Calcd for C21H19F3N2OS+2 HCl: C, 52.84; H, 4.43. Found: C, 52.66; H, 4.39.
Reaction SMILES: O1CCCC1.[CH:6]1([C:12]2[C:20]3[C:19](=[O:21])[NH:18][C:17]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33]O)[CH3:31])=[CH:24][C:23]=4[O:36][CH3:37])=[N:16][C:15]=3[N:14]([CH3:38])[N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.N(C(N(C)C)=O)=NC(N(C)C)=O>O>[CH:6]1([C:12]2[C:20]3[C:19](=[O:21])[NH:18][C:17]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:30]([CH3:31])[C:29]5=[O:35])=[CH:24][C:23]=4[O:36][CH3:37])=[N:16][C:15]=3[N:14]([CH3:38])[N:13]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1cc(NC(=O)N(C)CCO)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C)C2=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.6 %

Procedure:
To a 3 ml tetrahydrofuran suspension of 114 mg (0.25 mmol) of the compound obtained in Example 151, 52 mg (0.30 mmol) of 1,1′-azobis(N,N-dimethylformamide) and 75 μl (0.30 mmol) of n-tributylphosphine were added, and the mixture was stirred at room temperature for 20 hours. Then, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 71.6 mg (66%) of the captioned compound.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].F[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].O>C1(C)C=CC=CC=1>[CH3:5][C:3]1[O:4][C:12]2[C:13]([C:14](=[O:15])[C:2]=1[C:1]([O:7][CH3:8])=[O:6])=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: O=C(Cl)c1ccccc1F
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(C)oc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a dried flask, a solution of methyl acetoacetate (2.16 mL, 20.0 mmol) in toluene (100 mL) was treated with sodium hydride (60% mineral oil dispersion, 880 mg, 22.0 mmol). The resulting mixture was stirred at rt for 10 min, and then a solution of 2-fluorobenzoyl chloride (2.23 mL, 20.0 mmol) in toluene (50 mL) was added over about a 1 min. period. The resulting mixture was heated at reflux for 24.5 h, and then poured into water (200 mL). The mixture was extracted twice with ether (50 mL each). The combined organic phases were dried over sodium sulfate and concentrated under vacuum to provide a viscous yellow oil, which crystallized. The solid was recrystallized from a ethyl acetate/hexane solution to provide methyl 2-methyl-4-oxo-4H-chromene-3-carboxylate as off-white crystals in two crops (2.10 g, 48%). 1H NMR (400 MHz, CDCl3) δ ppm 2.53 (s, 3 H) 3.94 (s, 3 H) 7.42 (m, 2 H) 7.67 (ddd, J=8.5, 7.0, 1.8 Hz, 1 H) 8.21 (dd, J=7.9, 1.8 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](Cl)=[N:5][OH:6].[CH3:12][O:13][C:14](=[O:18])[CH2:15][C:16]#[N:17].C[O-].[Na+]>CO>[CH3:12][O:13][C:14]([C:15]1[C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])=[N:5][O:6][C:16]=1[NH2:17])=[O:18]
Reactant: COC(=O)CC#N
Reactant: ON=C(Cl)c1ccccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2Cl)noc1N
Yield: 88.4 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), 2-chloro-N-hydroxybenzimidoylchloride (8.00 g, 42.10 mmol), methylcyanoacetate (5.22 g, 52.63 mmol) and sodium methoxide (4.55 g, 84.20 mmol), a white solid required compound (9.40 g, 37.21 mmol, 88%) was obtained.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].COC(=O)CC.[H][H]>CO>[CH:3]([OH:2])=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC=CC(=O)OC
Reactant: [H][H]
Solvent: CO
Solvent: CCC(=O)OC
Product: CCCCCCCCCC=CO
Reaction time: 5 h

Procedure:
In about the same way as described under Example 2, an experiment was carried out with difference being that 10 ml methyl-undecenoate was included in the autoclave instead of 10 ml methylpropionate, while after 5 min hydrogen was added until a pressure increase of 30 bar was reached. The autoclave was kept at 80° C. for 5 hours giving a yield of 2.4 g methanol and about 1 g 1-undecenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C(N(CC)CC)C.[Cl-].C([O:27][C:28](=O)[C:29](O)=[O:30])C>O1CCCC1>[N+:8]([C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][CH:5]=1)[N:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:28](=[O:27])[C:29](=[O:30])[NH:1]2)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1NCCC(=O)O
Reactant: CCOC(=O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
At a bath temperature of +40° C., under argon and with exclusion of moisture, 211 mg (0.9 mmol) of 3-(2-amino-4-nitrophenylamino)propionic acid is combined with 200 mg (2 mmol) of triethylamine in 20 ml of dry tetrahydrofuran. A solution of 270 mg (2 mmol) of oxalic acid ethyl ester chloride and 5 ml of dry tetrahydrofuran is added dropwise to the batch, and the latter is stirred for 2 hours at room temperature. Furthermore, 0.05 ml of triethylamine and 0.05 ml of oxalic acid ethyl ester chloride are added to the mixture and the latter stirred for one hour at room temperature. The batch is filtered and the filtrate concentrated and distributed in water and ethyl acetate. The organic phase is concentrated. The residue is taken up in 15 ml of ethanol and 15 ml of 1N hydrochloric acid and refluxed for 2 hours at a bath temperature of 110° C. The batch is concentrated, taken up in a small amount of water, and suctioned off, yielding 120 mg of 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)propionic acid, mp: 148-156° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH:6]=[CH:7][CH:8]=1.Br[CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:39]([CH2:38][CH2:37][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:10]([NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[C:11]1=[O:19])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)[nH]c3ncccc23)c1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCOc3ccccc3)c3ncccc23)c1
Reaction time: 10 h
Yield: 72.6 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (500 mg, 1.06 mmol) in DMF (10 ml) were added β-bromophenetole (256 mg, 1.28 mmol) and potassium carbonate (441 mg, 3.19 mmol), and the mixture was stirred at 40°-50° C. for 10 hours. The mixture was allowed to stand for cooling, and then poured into water. The mixture was extracted with ethyl acetate, and the extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1-3% methanol in chloroform), and crystallized from ether to give the title compound (446 mg, 0.77 mmol) as a colorless crystal.
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16]>C(Cl)Cl>[CH3:14][Si:15]([CH3:17])([CH3:16])[O:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)O
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)C(C)(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.2 %

Procedure:
To a solution of 1.2 mL (10.4 mmol) of methyl 2-hydroxy-isobutyrate in 50 mL of CH2Cl2 were added 1.2 g (17.6 mmol) of imidazole and 2.1 mL (16.6 mmol) of TMSCl. The mixture was stirred at r.t. for 1.5 h and quenched with 20 mL of H2O. The organic layer was dried over MgSO4, concentrated and passed through a short plug of silica gel eluted with 9:1 hexane/EtOAc. Evaporation of solvent afforded 1.27 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[NH2:26][CH2:27][C:28]1[C:29]([OH:36])=[N:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34]>ClCCl>[OH:36][C:29]1[C:28]([CH2:27][NH:26][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:2]=2[CH3:1])=[C:33]([CH3:34])[CH:32]=[C:31]([CH3:35])[N:30]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc(COc2ccccc2)ccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(COc3ccccc3)cc2C)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.1 %

Procedure:
2-Methyl-4-(phenoxymethyl)benzoic acid (42 mg, 0.17 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyfluoroniumhexafluorophosphate (99 mg, 0.26 mmol), triethylamine (0.1 mL) and dichloromethane (15 mL) were stirred at 25° C. for half hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (27 mg, 0.17 mmol) was added to the mixture. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was washed with water (20 mL), dried over sodium, filtered, and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-4-(phenoxymethyl)benzamide as a white solid (50 mg, 78%). LRMS (M+H+) m/z: calcd 376.18. found 376. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.11 (t, J=4.8 Hz, 1H), 7.28-7.20 (m, 5H), 7.00-6.84 (m, 3H), 5.86 (s, 1H), 5.07 (s, 2H), 4.27 (d, J=4.8 Hz, 2H), 2.31 (s, 3H), 2.19 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5(CCCCC)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:20][C:19]=4[F:35])(O)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:36]1(C)[CH:41]=[CH:40]C(S(O)(=O)=O)=[CH:38][CH:37]=1.C1(C)C=CC=CC=1>O>[F:35][C:19]1[CH:20]=[C:21]([CH:24]2[CH2:25][CH2:26][CH:27]([CH2:38][CH2:37][CH2:36][CH2:41][CH3:40])[CH2:28][CH2:29]2)[CH:22]=[CH:23][C:18]=1[C:14]1[CH2:13][CH2:12][CH:11]([CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH2:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCC1(c2ccc(C3(O)CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2ccc(C3=CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Temperature: 30 °C
Yield: 537.4 %

Procedure:
The compound (3) (108.6 g), p-toluenesulfonic acid (4.02 g) and toluene (500 ml) were mixed, and the mixture was heated under reflux for 1.5 hours while the water being distilled was removed. The reaction mixture was cooled to 30° C., and then water (1,000 ml) and toluene (1,800 ml) were added and mixed with it. The mixture was then allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent of the solution was distilled off under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=7:3 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from heptane and dried, giving 58.8 g of 8-{4-[2-fluoro-4-(4-pentyl-cyclohexyl)-phenyl]-cyclohex-3-enyl}-1,4-dioxa-spiro[4,5] decane (4). The yield based on the compound (1) was 53.4%.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=O)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[O:8][C:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=3[N:24]=2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: O=C1CCCCC1Cl
Product: c1ccc(CN2CCC(c3nc4c(o3)CCCC4)CC2)cc1
Temperature: 160 °C
Yield: 70.9 %

Procedure:
A mixture of 2.43 g 2-chlorocyclohexanone and 1 g 1-benzylpiperidine-4-carboxylic acid amide (see WO2005/61483) is heated to 160° C. in the microwave until there is no further reaction. The product is purified by chromatography. 963 mg of the product are obtained. Analytical HPLC-MS (method B): RT=1.28 min.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[NH2:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)([OH:12])[CH3:11].O>C(Cl)Cl>[OH:12][C:10]([C:13]1[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=1)([CH3:11])[CH2:9][NH:8][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5]
Reactant: CC(O)(CN)c1ccc(I)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(I)cc1
Temperature: 0 °C
Yield: 19.4 %

Procedure:
Into a 250 mL 3 necked flask fitted with a stirrer and thermometer, was added dropwise 2-propanesulfonyl chloride (1.60 g, 0.011 mol) to 1-amino-2-(4-iodophenyl)propan-2-ol (2.77 gm, 0.01 mol) in 125 mL CH2Cl2 while stirring at 0° C. under nitrogen. The reaction was then allowed to warm to room temperature and stirred overnight at this temperature. In the morning, the mixture was poured into H2O and the layers were separated. The organic layer was washed once with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was purified via silica gel chromatography employing the Prep. LC-2000 and eluting with a solvent of Hexane/EtOAc 3:1 to provide the intermediate title compound (744 mg, 19%) as a solid material. FDMS 382 (M*).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][NH2:14])[N:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH:23]([C:27](=O)[CH3:28])[C:24](=O)[CH3:25])=[CH:18][CH:17]=1>C(O)CC>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([S:22][C:23]2[C:24]([CH3:25])=[N:14][N:13]([C:9]3[N:8]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[N:12]=[CH:11][N:10]=3)[C:27]=2[CH3:28])=[CH:20][CH:21]=1
Reactant: CC(=O)C(Sc1ccc(Cl)cc1)C(C)=O
Reactant: NNc1ncnc(-c2ccccn2)n1
Solvent: CCCO
Product: Cc1nn(-c2ncnc(-c3ccccn3)n2)c(C)c1Sc1ccc(Cl)cc1
Temperature: 95 °C
Yield: 8 %

Procedure:
A stirred suspension of the product of step 3 (0.333 g, 1.77 mmol) and 3-(4-chloro-phenylsulfanyl)-pentane-2,4-dione (0.473 g, 1.95 mmol) in n-propanol was heated at 95° C. overnight. The reaction solution was concentrated directly onto silica and flash chromatographed (methylene chloride/methanol) to afford a dirty yellow solid. This material was further purified by trituration with diethyl ether to afford 0.056 g (8%) of product as a white solid: 1H NMR (DMSO-d6) δ 9.44 (s, 1H), 8.94–8.77 (m, 1H), 8.68–8.43 (m, 1H), 8.18–7.96 (m, 1H), 7.77–7.57 (m, 1H), 7.45–7.24 (m, 2H), 7.20–6.98 (m, 2H), 2.83 (s, 3H), 2.20 (s, 3H) ppm.