Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[NH:11][CH:12]=2)[CH2:3][CH2:2]1.C(=O)=O.B(Br)(Br)Br.CO>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[NH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nc(CN3CCOCC3)c[nH]2)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(-c2nc(CN3CCOCC3)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
Under N2, a solution of 52 (2.25 g, .0082 mol) in CH2Cl2 (25 ml) was added dropwise to a dry-ice cooled solution of BBr3 (2.5 ml, d=2.65, 0.0265 mol) in CH2C12 (75 ml). After the addition, the solution was stirred at room temperature overnight and then treated dropwise with CH3OH (50 ml). After stirring overnight at room temperature, the solution was concentrated to dryness, the residue treated with 10% NaOH, the aqueous layer extracted with Et2O, the pH of the solution adjusted to 8.7 and concentrated to dryness. The residue was triturated with hot CH3OH, filtered, the filtrate concentrated to dryness and the residue chromatographed on silica gel. The product was eluted with 10% CH3OH-CHCl3 to yield 1.75 g (82%) of 53.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32]([SH:37])[CH:33]=[CH:34][C:35]=1[CH3:36].C(N(C(C)C)CC)(C)C.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:29][C:30]1[CH:31]=[C:32]([S:37][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]4([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]4)=[CH:10][CH:9]=3)=[C:4]([F:28])[CH:3]=2)[CH:33]=[CH:34][C:35]=1[CH3:36]
Reactant: Cc1ccc(S)cc1C
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC1(CCc2ccc(-c3ccc(Sc4ccc(C)c(C)c4)cc3F)cc2)COC(C)(C)OC1
Yield: 120.4 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (170 mg) of Reference Example 10, 3,4-dimethylbenzenethiol (52 mg), diisopropylethylamine (98 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (9.8 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (11.2 mg) in 1,4-dioxane (1.5 mL) was heated under reflux for 9 hr under a nitrogen atmosphere. 3,4-Dimethylbenzenethiol (10 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (3.9 mg) and Xantphos (4.4 mg) were added to the reaction mixture, and the mixture was further heated under reflux for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.23 g) as pale-yellow crystals.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]>>[CH2:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:1](=[O:7])[CH2:2][C:3](=[O:4])[CH3:5])[CH2:11][CH3:12]
Reactant: CCCNCCC
Reactant: CCOC(=O)CC(C)=O
Product: CCCN(CCC)C(=O)CC(C)=O
Yield: 0.6 %

Procedure:
43.4 g (43.3 mol) of ethyl acetoacetate and 33.7 g (43.3 mol) of dipropylamine were treated as described in preparation 1. The crude oil was distilled at 86°-89° C./ 0.8 mmHg, to give 44.3 g of the title compound.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:25][N:26]([CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Solvent: CCO
Product: CCOC(=O)C1(c2ccc(Cl)cc2)CCN(CC(O)COc2cccc3ccccc23)CC1

Procedure:
To a solution of 5.0 parts of 1,2-epoxy-3-(1-naphthoxy)propane in 79 parts of ethanol is added 5.0 parts of 4-(p-chlorophenyl)-4-ethoxycarbonylpiperidine. The resulting mixture is then refluxed for 24 hours. The solvent is stripped from the reaction mixture under reduced pressure to afford 3-[4-(p-chlorophenyl)-4-ethoxycarbonylpiperidino]-1-(1-naphthoxy)-2-propanol. This material is dissolved in isopropanol and treated with a solution of hydrochloric acid in isopropanol. The resulting salt is separated by filtration and recrystallized from a mixture of isopropanol and ethyl ether to give 3-[4-(p-chlorophenyl)-4-ethoxycarbonylpiperidino]-1-(1-naphthoxy)-2-propanol hydrochloride. This compound exhibits a melting point of 196°-198° C. and is represented by the following structural formula ##STR8##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[CH:10]1([NH:16][CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][N:16]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:17])[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: CNC1CCCCC1
Solvent: CCO
Product: CCOC(=O)CCCN(C)C1CCCCC1
Yield: 90.1 %

Procedure:
10 g of 4-bromobutyric acid ethyl ester and 15 g of N-cyclohexyl-N-methylamine were added to 40 mL of ethanol, and the mixture was heated to reflux for 2 hours. After air-cooling, the mixture was concentrated under reduced pressure and extracted with 200 mL of ethyl acetate. The extracted material was washed with purified water, dried with magnesium sulfate, and then concentrated. The obtained residue was distilled under reduced pressure to give 10.5 g of N-cyclohexyl-N-methyl-gamma-aminobutyric acid ethyl ester. The obtained N-cyclohexyl-N-methyl-gamma-aminobutyric acid ethyl ester was added to a sodium hydroxide solution (2.4 g of sodium hydroxide/100 mL of purified water), and THF was added thereto until the mixture became homogeneous. After stirring at room temperature for 3 hours, the mixture was neutralized with DOWEX50W [H+ form] and concentrated under reduced pressure. The obtained residue was recrystallized to give 5.2 g of the desired product.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([NH:9][C@@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[N:5]=[C:4]([C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH3:8][C:7]1[C:2]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:3][C:4]([C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)=[N:5][C:6]=1[NH:9][C@@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1
Reactant: Cc1c(Cl)nc(-c2cccc(O)c2)nc1N[C@@H]1CCOC1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(N[C@@H]2CCOC2)nc(-c2cccc(O)c2)nc1N1CCOCC1
Yield: 12.9 %

Procedure:
A mixture of (R)-3-(4-chloro-5-methyl-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl)phenol (800 mg, 2.6 mmol); neat morpholine (274 mg, 3.1 mmol) and Na2CO3 (556 mg, 5.2 mmol) in EtOH (12 mL) was stirred at 80° C. in a sealed vial for 14 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by chromatographic column on silica gel (EtOAc/petroleum ether, gradient elution, from 1/2 to 2/1) to give the (R)-3-(5-methyl-4-morpholino-6-(tetrahydrofuran-3-ylamino)pyrimidin-2-yl)phenol (120 mg, 13% yield) as a light yellow solid. ESI-LCMS (m/z): 357.1 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][NH:13][CH3:14])=[CH:10][C:5]=2[S:4](=[O:15])[CH2:3]1.[Cl:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]([CH3:14])[CH2:18][CH2:17][Cl:16])=[CH:10][C:5]=2[S:4](=[O:15])[CH2:3]1
Reactant: CNCCc1ccc2c(c1)S(=O)CN2C
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(CCCl)CCc1ccc2c(c1)S(=O)CN2C
Temperature: 60 °C
Reaction time: 48 h

Procedure:
In a ground-necked flask, 6 mmol of 3-methyl-6-[2-(N-methylamino)ethyl]benzothiazolinone are dissolved in 50 ml of dioxane, 20 mmol of 1-chloro-2-bromoethane and 20 mmol of potassium carbonate. The mixture is stirred for 48 hours at a temperature of 60° C. After cooling, the mixture is evaporated and the reaction medium is extracted with chloroform after adding water. After washing, drying and evaporation of the organic phase, 3-methyl-6-{2-[N-methyl-N-(2-chloroethyl)amino]ethyl}benzothiazolinone is obtained, which product is transferred to a ground-necked flask. A catalytic amount of potassium iodide, 25 cm3 of methanol and 10 cm3 of chloroform are added. A stream of gaseous ammonia is bubbled into the solution to the point of saturation and a reflux condenser is then fitted. The temperature is stabilized at 50° C. with an oil bath and the mixture is then left stirring magnetically for 72 hours. After cooling, the reaction mixture is evaporated on a water bath under vacuum. The residue is ground with distilled water acidified with 5% HCl solution, and then drained. The filtrate is recovered, washed with ethyl acetate and then alkalinized with 10% sodium hydroxide solution. It is extracted with chloroform, leaving the 2 phases agitating for 1/2 hour, and the organic phase is washed with distilled water and then dried over calcium chloride. The organic phase is evaporated on a water bath under vacuum, the residue is then taken up in absolute ethanol, a stream of gaseous HCl is bubbled through and the mixture is then evaporated to dryness on a water bath under vacuum. The product is dried and then recrystallized.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([CH2:9][S:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])(=[O:12])=[O:11])=[O:8])=[CH:3][CH:2]=1.[NH2:26][OH:27].Cl>C(N(CC)CC)C>[OH:27][NH:26][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][S:10]([CH2:9][C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:2][CH:3]=1)=[O:8])(=[O:12])=[O:11]
Reactant: O=C(O)CCCCS(=O)(=O)CC(=O)c1ccc(-c2ccccc2)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCS(=O)(=O)CC(=O)c1ccc(-c2ccccc2)cc1)NO
Yield: 52 %

Procedure:
Following the procedure described in Example 14, step 3, but substituting carboxylic acid 228b for 37, and using 1.1 equivalent of NH2OH.HCl and triethylamine each, the title compound 228b was obtained in 52% yield. 1H NMR: (300 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.70 (s, 1H), 8.11 (d, J=8.5 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.77 (dd, J=1.4 Hz, J=8.5 Hz, 2H), 7.53-7.43 (m, 3H), 5.08 (s, 2H), 3.38-3.25 (t, 2H), 1.99 (t, J=6.6 Hz, 2H), 1.72-1.61 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([C:14]([CH3:16])=[CH2:15])[C:10]=1[C:17]#[N:18].[H][H]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([CH:14]([CH3:16])[CH3:15])[C:10]=1[C:17]#[N:18]
Reactant: C=C(C)c1nsc(-c2ccc(C)cc2F)c1C#N
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2snc(C(C)C)c2C#N)c(F)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Into a 25-mL 3-necked round-bottom flask, was placed 5-(2-fluoro-4-methylphenyl)-3-(prop-1-en-2-yl)-1,2-thiazole-4-carbonitrile (140 mg, 0.54 mmol, 1.00 equiv), ethyl acetate (10 mL), Pd(no water)/C (140 mg). To the above hydrogen gas was introduced. The resulting solution was stirred for 2 h at 20° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 130 mg (crude) of 5-(2-fluoro-4-methylphenyl)-3-(propan-2-yl)-1,2-thiazole-4-carbonitrile as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH:9][C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[S:18][CH2:19][CH3:20])=O)=[CH:7][C:6]([C:21]([F:24])([F:23])[F:22])=[CH:5][N:4]=1.C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[CH2:19]([S:18][C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:10]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:21]([F:24])([F:23])[F:22])[CH:7]=[C:8]2[N:9]=1)[CH3:20]
Reactant: CCSc1ccncc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCSc1ccncc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 150 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A mixture of 700 mg of 4-ethylsulfanylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide, 704 mg of p-toluenesolufonic acid-hydrate and 3.5 ml of NMP was heated and stirred at 150° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 650 mg of 2-(4-ethylsulfanylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 9).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=1[NH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:19][C:20]([F:26])([F:25])[CH2:21][C:22](O)=[O:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=1[NH:12][C:22](=[O:23])[CH2:21][C:20]([F:26])([F:25])[F:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(N)c(CO[Si](C)(C)C(C)(C)C)c1
Reactant: O=C(O)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(NC(=O)CC(F)(F)F)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 2-((tert-butyldimethylsilyloxy)methyl)-4-methoxyaniline (14.0 g), 3,3,3-trifluoro-propionic acid (7.30 g, 57.0 mmol), EDCI (15.0 g, 76.5 mmol), HOBT (11.0 g, 80.2 mmol) and NMM (22 mL, 157 mmol) in anhydrous CH2Cl2 (200 mL) was stirred at 20° C. for 2 hours. The mixture was diluted with CH2Cl2 (100 mL), the organic layer was washed with 1M HCl (100 mL), H2O (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated to give the product.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4](Cl)=[O:5])[CH3:2].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33]>>[CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33])=[O:5])[CH3:2]
Reactant: CCCCC(CC)C(=O)Cl
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Product: CCCCC(CC)C(=O)Nc1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Yield: 76 %

Procedure:
Using a similar procedure to that described in Example 1, but starting from 2-ethylhexanoyl chloride and (A), there was obtained the title compound in 76% yield; partial NMR: 0.84(m,6H, 2×CH3), 1.24[m,6H, (CH2)3 ], 2.24(m,1H, CHCON), 10.78(d,1H, NH).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=[O:5])=[O:4].C[O-].[Na+].[CH2:22](Br)[CH:23]=[CH2:24]>CO.C1COCC1.O>[CH2:22]([N:2]([CH3:1])[S:3]([C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:10])([F:12])[F:11])(=[O:5])=[O:4])[CH:23]=[CH2:24]
Reactant: C=CCBr
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 40 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A mixture of 313 g (1 mol) N-methylnonafluorobutanesulfonamide (3M Co., U.S. Pat. No. 6,664,354, Savu), 216 g (1 mol) 25% sodium methoxide in methanol (Aldrich), and 100 mL THF (EMD) was stirred at 50° C. for one hour and stripped. The residue was diluted with 600 mL THF and treated with 100 mL (1.15 mol) allyl bromide (Aldrich). The mixture was stirred at 40° C. for about 8 hr and then diluted with water. Extraction with methylene chloride and distillation yielded 321.7 g colorless liquid, by 75-80° C./1.1 mm Hg.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[CH:25][N:26]=4)=[C:18]([CH2:27][CH3:28])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=C(CC)C(O)=CC=3OCCC)OC(=O)CC(=O)C2)CCCC1.CO[CH:59]([C:61]1[N:69]=[C:64]2[N:65]=[CH:66][CH:67]=[CH:68][N:63]2[N:62]=1)O.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][CH:24]=[CH:25][N:26]=4)=[C:18]([CH2:27][CH3:28])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:59][C:61]3[N:69]=[C:64]4[N:65]=[CH:66][CH:67]=[CH:68][N:63]4[N:62]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1-c1ncco1
Reactant: COC(O)c1nc2ncccn2n1
Agent: CCCOc1cc(O)c(CC)cc1CCC1(C2CCCC2)CC(=O)CC(=O)O1
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncccn4n3)C(=O)O2)ccc1-c1ncco1

Procedure:
The title compound was prepared analogously to Example A(1) where 6-cyclopentyl-6-{2-[3-ethyl-4-(1,3-oxazol-2-yl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione (Example A(135)) was substituted in place of 6-cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-propoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione in that example and methoxy-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl-methanol was substituted in place of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde. Yield (57 mg, 11%). 1H NMR (300 MHz, CDCl3): δ ppm 1.20 (t, J=7.44 Hz, 3H) 1.53-1.67 (m, 8H) 2.00-2.11 (m, 2H) 2.35-2.47 (m, 1H) 2.51-2.63 (m, 1H) 2.65-2.72 (m, 2H) 2.72-2.83 (m, 2H) 3.04 (q, J=7.54 Hz, 2H) 4.14 (d, J=3.77 Hz, 2H) 7.04-7.10 (m, 2H) 7.14-7.20 (m, 1H) 7.25 (s, 1H) 7.71 (s, 1H) 7.82 (d, J=7.91 Hz, 1H) 8.84 (d, J=5.46 Hz, 2H). MS (ESI): 514 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][CH:11]=1)([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[CH:14]1[C:15]2[NH:1][C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:10]=2[CH:11]=[CH:12][C:13]=1[C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(-c2nc3ccccc3o2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: c1ccc2oc(-c3ccc4c(c3)[nH]c3ccccc34)nc2c1
Temperature: 180 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
To a three-necked flask equipped with a magnetic stir bar and a condenser was added 2-(2′-nitrobiphenyl-4-yl)benzo[d]oxazole (1.08 g, 3.41 mmol, 1.0 eq) and PPh3 (4.48 g, 17.07 mmol, 5.0 eq). The flask was evacuated and back-filled with nitrogen. The evacuation and back-fill procedure was repeated twice. Then 1,2-dichlorobenzene (20 mL) was added under the protection of nitrogen. The mixture was stirred in an oil bath at a temperature of 175-185° C. for 24 hours, and cooled. The solvent was removed by distillation under high vacuum. Some ethyl acetate and dichloromethane was added to the residue and stirred at room temperature overnight. The residue was filtered and washed with dichloromethane. The collected solid was dried in air to get the desired product as an off-white solid 809 mg. The filtrate was concentrated and the residue was purified through column chromatography on silica gel using hexane and ethyl acetate (10:1-5:1-3:1) as an eluent to obtain the desired product (117 mg in 96% total yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.25 (t, J=7.6 Hz, 1H), 7.41-7.52 (m, 3H), 7.60 (d, J=8.4 Hz, 1H), 7.82-7.86 (m, 2H), 8.05 (dd, J=8.4, 1.2 Hz, 1H), 8.24 (d, J=7.2 Hz, 1H), 8.34-8.37 (m, 2H), 11.63 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](O)=[O:6])=O.O.[NH2:17][NH2:18]>C(O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([O:14][CH3:15])[CH:8]=[C:4]2[C:3]=1[CH:1]=[N:17][NH:18][C:5]2=[O:6]
Reactant: NN
Reactant: COc1cc(OC)c(C=O)c(C(=O)O)c1
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c2cn[nH]c(=O)c2c1
Yield: 86 %

Procedure:
The 2-formyl-3,5-dimethoxybenzoic acid (2.7 g, 13 mmol) is partially dissolved in 300 mL of ethanol, and 6.2 mL of hydrazine hydrate are then added. The mixture is refluxed for 6 hours. After cooling, the precipitate formed is filtered off and then dried. 2.3 g of a white solid are obtained (86% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([NH2:12])=[S:11])=[C:7]([O:13][CH3:14])[N:6]=[CH:5][N:4]=1.[CH3:15]C[O-].[Na+]>>[CH2:1]([O:2][C:3]1[C:8]([NH:9][C:10]([NH2:12])=[S:11])=[C:7]([O:13][CH3:14])[N:6]=[CH:5][N:4]=1)[CH3:15]
Reactant: COc1ncnc(OC)c1NC(N)=S
Reactant: CC[O-]
Agent: [Na+]
Product: CCOc1ncnc(OC)c1NC(N)=S
Yield: 56.4 %

Procedure:
3.0 g N-(4,6-dimethoxy-5-pyrimidyl)-thiourea are mixed with a sodium-ethylate solution (0.317 g sodium in 30 ml absolute ethanol) and heated for 3 hours under reflux. After cooling the mixture is neutralized. The reaction product is vacuum treated and purified chromatographically on silica gel (developer; chloroform/methanol 95:5). 0.6 g N-(4-ethoxy-6-methoxy-5-pyrimidyl)-thiourea having a melting point of 186° to 187° C. are obtained.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][P:9](=[O:16])([O:13]CC)[O:10]CC)(=[O:4])[CH:2]=[CH2:3].[CH3:17][Si:18](Br)([CH3:20])[CH3:19]>C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][P:9](=[O:16])([O:13][Si:18]([CH3:20])([CH3:19])[CH3:17])[O:10][Si:18]([CH3:20])([CH3:19])[CH3:17])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCP(=O)(OCC)OCC
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: C=CC(=O)OCCCP(=O)(O[Si](C)(C)C)O[Si](C)(C)C
Yield: 99 %

Procedure:
To a solution of diethyl 3-acryloyloxypropylphosphonate (31.12 g; 0.124 moles) in CH2Cl2 (85 g) is added a solution of trimethylsilyl bromide (40 g; 0.261 moles) in CH2Cl2 (9.2 g) dropwise at room temperature. The mixture is refluxed for 4 hours. The solvent is evaporated on a rotary evaporator under reduced pressure to afford di(trimethylsilyl) 3-acryloyloxypropylphosphonate as a clear, colorless liquid (42.4 g; purity 95% by GC). 1H NMR (CDCl3, δ ppm) 0.006 (s, 9H, CH3—Si), 1.4-1.54 (m, 2H, CH2—P), 1.59-1.72 (m, 2H, CH2—CH2—), 3.91 (t, 2H, CH2—O), 5.55 (dd, 1H, CH═), 5.83 (dd, 1H, CH═), 6.12 (dd, 1H, CH═). 31P NMR (CDCl3, δ ppm) 13.55.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:22][CH3:23])[C:9]=3[CH:8]2[OH:24])=[CH:4][CH:3]=1.[CH2:27](Cl)Cl.C(O)(C(F)(F)F)=O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:22][CH3:23])[C:9]=3[CH:8]2[O:24][CH3:27])=[CH:25][CH:26]=1
Reactant: ClCCl
Reactant: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2OC

Procedure:
A solution of 21 (6.7 mg, 0.019 mmol) in a 1:1 solution of CH2Cl2:MeOH was stirred with TFA (3 μL, 0.038 mmol) at room temperature for 2 hours when complete conversion was observed by LCMS. The solution was dried in vacuo and the residue was washed with hexanes to yield 7 mg of the product 22. EI MS (m/z) 355.4 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.C([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:28]3[CH2:29][CH2:30][NH:25][CH2:26][CH2:27]3)[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Product: Clc1cc(NC2CCNCC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
7-Amino-5-chloro-2-phenyl-1H-indole prepared in Example 3 and 1-BOC-4-piperidinone were reacted according to the same procedure as Step B of Example 1 to give the title compound.