Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)#[CH:40]>O1CCCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:40]#[C:39][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(C#Cc3ccccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (Z)-[4-[3-(4-fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.75 mmol; example 10) was dissolved in anhydrous tetrahydrofuran (10 mL). Anhydrous triethylamine (20 mL) and a solution of 2-ethynylpyridine (155 mg, 1.50 mmol) in anhydrous tetrahydrofuran (2 mL) were added. The solution was degassed and copper(I) iodide (23 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were added. A mixture was stirred at ambient temperature under nitrogen atmosphere overnight; the resulting suspension was filtered through a paddle of silica gel and silica gel was thoroughly washed with ethyl acetate. The obtained filtrate was evaporated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with water (2×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified using column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 90:10) yielding methyl (E)-[4-[3-(4-fluorophenyl)-3-[4-[(pyridin-2-yl)ethynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12](#[N:15])[CH:13]=[CH2:14].N12CCN(CC1)CC2>[OH-].[Na+]>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:13]([C:12]#[N:15])[CH2:14][O:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)OCC(C#N)=C2

Procedure:
2-Hydroxy-4-methoxybenzaldehyde (Aldrich, 5.0 g, 32.9 mmol), acrylonitrile (11 mL, 164 mmol), and 1,4-diazabicyclo[2.2.2]octane (0.92 g, 8.2 mmol) were heated in a microwave Personal Chemistry at 95° C. for 5 hours. Sodium hydroxide (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel eluting with 0-to-50% ethyl acetate in hexane afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.77 (s, 3H), 4.84 (d, J=1.36 Hz, 2H), 6.50 (d, J=2.71 Hz, 1H), 6.61 (dd, J=8.48, 2.71 Hz, 1H), 7.21 (d, J=8.48 Hz, 1H), 7.52 (s, 1H). MS (DCI) m/z 205.07 (M+NH4)+.
Reaction SMILES: Br[C:2]1[C:6]([N:7]([CH3:9])[CH3:8])=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[S:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(O)C.[S:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])(=[O:27])[NH2:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[S:4][C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:30][CH:31]=3)[C:6]=2[N:7]([CH3:9])[CH3:8])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1Br
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a solution of Ethyl 3-bromo-5-(4-chlorophenyl)-4-(dimethylamino)thiophene-2-carboxylate (compound 34d, 2.20 g, 5.65 mmol) in a mixture of toluene:ethanol (10 ml:30 ml) was added (4-sulfamoylphenyl)boronic acid (1.25 g, 6.22 mmol) and potassium carbonate (1.56 g, 11.30 mmol) at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.32 g, 0.28 mmol) under nitrogen and the reaction mixture was heated at about 95 to about 100° C. for 16 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was then washed with ethanol (2×25 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 55% ethyl acetate in hexanes as an eluent to obtain the title compound (2.0 g, 76.05%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][NH:13][C:14](=S)[OH:15].[Na]>C1C=CC=CC=1>[CH3:12][NH:13][C:14](=[O:15])[O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: CNC(O)=S
Agent: [Na]
Solvent: c1ccccc1
Product: CNC(=O)Oc1cccc2ccccc12

Procedure:
To a solution of 1-naphthol (1.44 g, 0.01 mole) and S-methyl ester of N-methylcarbamothioic acid (1.575 g, 0.015 mole) in benzene (6 ml) there was added sodium (0.15 g) and the mixture was refluxed for 20 hrs. The reaction mixture was cooled and washed with water and a cold 5% NaOH solution followed by water and brine and then dried. The removal of solvent afforded the solid which was further purified by crystallization to furnish 1-naphthyl N-methylcarbamate of the formula VII, m.p. 140°-141° C., IR: 3305 (N--H), 1715 (--COO--), 1600, 1540, 770 (aromatic): PMR (CdCl3, 90 MHz), 2.86 (3H, d, J=1Hz, NH--CH3, 5.14 (1H, hr. s, N--H) and 7.17 to 8 (7H, m, aromatic).
Reaction SMILES: FC(F)(F)C1C=C[C:6]([C:7](O)=[O:8])=[CH:5]C=1.[O:14]([C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:20]=2[CH2:5][CH2:6][C:7]3=[O:8])=[N:26][CH:25]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Oc2ccccc2)nc1
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 4-(trifluoromethyl)benzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 6-phenoxy-3-pyridinylamine obtained in Reference Example 32 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain. the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:24]=[CH:23][C:9]2[C:10](=[O:22])[CH2:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]I)([CH3:14])[O:13][C:8]=2[C:7]=1[CH2:25][CH2:26][CH3:27].[CH3:29][CH2:30][CH2:31][C:32]1[C:37]([OH:38])=[C:36]([C:39]([CH3:41])=[O:40])[CH:35]=[CH:34][C:33]=1[OH:42].C(=O)(O)[O-].[K+].Cl>CN(C)C=O.CC(C)=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:24]=[CH:23][C:9]2[C:10](=[O:22])[CH2:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:42][C:33]3[CH:34]=[CH:35][C:36]([C:39](=[O:40])[CH3:41])=[C:37]([OH:38])[C:32]=3[CH2:31][CH2:30][CH3:29])([CH3:14])[O:13][C:8]=2[C:7]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCC(=O)OC)ccc2c1OC(C)(CCCCCCI)CC2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCC2(C)CC(=O)c3ccc(OCC(=O)OC)c(CCC)c3O2)ccc(C(C)=O)c1O
Reaction time: 6 h
Yield: 83.4 %

Procedure:
A mixture of 1.25 g of the iodohexyl chromanone product from Example 4, 0.49 g of 2,4-dihydroxy-3-propylacetophenone, 0.841 g of anhydrous potassium bicarbonate, 25 ml of acetone, and 12 ml of N,N-dimethylformamide was refluxed and stirred for 6 hours. The resulting mixtures was cooled, poured into cold 1N hydrochloric acid, and extracted 3 times with ether. The combined ether extracts were washed with saturated aqueous sodium bicarbonate, water, and brine, then dried (magnesium sulfate), filtered and concentrated in vacuo giving 1.5 of an oil. This material was chromatographed on 45 g of silica gel. Elution with 2:1 hexane-ethyl acetate afforded 1.18 g (83.4%) of rac-[[2-[6-(4-acetyl-3-hydroxy-2-propylphenoxy)-hexyl]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-7-yl]oxy]acetic acid methyl ester as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[NH:20][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=1)([OH:3])=O.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].C(P(=O)(OCC)OCC)#N>CN(C=O)C>[C:21]([NH:25][C:1]([C:4]1[NH:20][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=1)=[O:3])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reaction time: 4 h

Procedure:
To a solution of 144 mg (0.50 mmol) of 6-carboxy-4-(3-chloro-anilino)-7H-pyrrolo[2,3-d]pyrimidine (cf. Example 42) and 116 μl (1.1 mmol) of tert.-butylamine in 5 ml of DMF are added 114 μl (0.75 mmol) of diethyl cyanophosphonate (Aldrich; Milwaukee/USA). After 4 h, the reaction mixture is poured onto ice water, stirred for 30 min and finally filtered. The residue is redissolved in isopropanol, treated with charcoal and filtered. Concentration in vacuo and washing with dichloromethane/diethyl ether yields the title compound; HPLC: tRet (Grad20)=11.4; FAB-MS: (M+H)+ =344.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:13][C:11](=[O:12])[CH:10]([CH3:16])[CH2:15][N:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]1=[O:8]
Reactant: O=c1cc(Br)cc[nH]1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Cn1ccc(Br)cc1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 4-bromo-1H-pyridin-2-one (0.50 g), methyl 2-bromoisobutyrate (0.45 mL), and potassium carbonate (0.68 g) in dimethylformamide (5 mL) was stirred at 60° C. for 3 h. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 70:30->50:50) to afford the title compound. Yield: 0.53 g (67% of theory); Mass spectrum (ESI+): m/z=274/276 (Br) [M+H]+. Additionally 2-(4-bromo-pyridin-2-yloxy)-2-methyl-propionic acid methyl ester was obtained (Yield: 0.15 g; Mass spectrum (ESI+): m/z=274/276 (Br) [M+H]+)
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:38][CH2:39][CH2:40][CH3:41])[N:17]([CH2:18][CH2:19][CH2:20][N:21]([CH2:26][C:27]3[CH:28]=[C:29]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:23][CH2:24]Cl)[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1.[I-].[Na+]>C1COCC1.CN(C=O)C>[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:38][CH2:39][CH2:40][CH3:41])[N:17]([CH2:18][CH2:19][CH2:20][N:21]([CH2:26][C:27]3[CH:28]=[C:29]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:23][CH2:24][N:2]([CH3:3])[CH3:1])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1
Reactant: CNC
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCCl)Cc1cccc(CC(=O)OC)c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(CCCN(C)C)Cc1cccc(CC(=O)OC)c1
Temperature: 55 °C

Procedure:
A solution of dimethylamine in THF (2M, 6 mL) was added to a mixture of the product from step (ix) (1.17 mmol) and sodium iodide (250 mg) in DMF (5 mL) at rt. The mixture was heated at 55° C. in a sealed vessel for 24 h, cooled, filtered and the filtrate purifed by RPHPLC. The fractions containing the desired compound were evaporated to dryness and the residue triturated with ether/isohexane, 270 mg.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:14]=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[O:12][N:11]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:14]1[C:10]([CH3:9])=[N:11][O:12][C:13]=1[NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)cc2)cc1
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
N-bromosuccinimide (NBS) (0.178 g, 1 mmol), in one lot, was added to a stirred suspension of N-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (0.327 g, 1 mmol, Example 206B) in chloroform (12 ml). The reaction mixture was stirred for 10 min then diluted with dichloromethane (50 ml). This was washed with water (2×50 ml). The organic layer was dried over MgSO4 and concentrated. The crude product was recrystallized using hexane/ethyl acetate giving N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (350 mg, 86% yield, m.p. 153-156° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7](=[O:9])[CH3:8].[C:10]([Mg]Br)#[CH:11]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]([OH:9])([C:10]#[CH:11])[CH3:8]
Reactant: CC(=O)c1ncccn1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)c1ncccn1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A solution of 1-(pyrimidin-2-yl)ethan-1-one (2.5 g, 20.47 mmol) in tetrahydrofuran (60 mL) was added dropwise into a ethynylmagnesium bromide (0.5 M in tetrahydrofuran, 60 mL, 30 mmol) solution with stirring at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hr and then quenched by the addition of saturated aqueous ammonium chloride (200 mL). The resulting solution was extracted with ethyl acetate (2×300 mL) and the combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified on a silica gel column, elution with ethyl acetate/petroleum ether (0:1-1:1) afforded 2-(pyrimidin-2-yl)but-3-yn-2-ol (1.5 g, 50%) as yellow oil. 1H NMR (400 MHz, CDCl3) delta 8.82 (d, J=4.4 Hz, 2H), 7.33-7.29 (m, 1H), 5.1 (s, 1H), 2.56 (s, 1H), 1.93 (s, 3H); LC-MS: m/z=149 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:22]>CS(C)=O>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:8][CH2:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1
Reactant: OCCC1CCCO1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OCCC1CCCO1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of 2-(tetrahydrofuran-2-yl)ethanol (1.0 g, 8.61 mmol), prepared following the procedure as described in Synthesis 1996, 594, in 15 mL of DMSO was added NaH (344 mg, 8.61 mmol, 60% in mineral oil) in portions. After the resulting suspension was stirred for 15 min., a solution of 1-chloro-2-methoxy-4-nitrobenzene in 5 mL of DMSO was added dropwise. The reaction mixture was stirred overnight, quenched with 15 mL of H2O, and extracted with EtOAc (3×30 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to yield a brown oil. The oil was purified by column chromatography (silica gel, 0%-35% gradient elution with EtOAc/hexanes) to yield 1.68 g (73%) of 2-(2-(2-methoxy-4-nitrophenoxy)ethyl)tetrahydrofuran as a yellow solid. MS (ESI) 268 (M+H)+. Subsequent conversion of the aryl nitro substituent to the title aryl amine was accomplished in 98% yield, following the procedure described in Example 6 step C. MS (ESI) 238 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.Cl.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH:28]1[C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][C:25]4[CH:37]=[C:38]([O:42][CH3:43])[C:39]([O:40][CH3:41])=[C:23]([O:22][CH3:21])[CH:24]=4)[CH:28]([C:33]([O:35][CH3:36])=[O:34])[CH2:29]3)=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Reactant: COC(=O)C1CNCCN1Cc1cc(OC)c(OC)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(C(=O)C2=Cc3cc(OC)c(OC)cc3CCC2)CCN1Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In dichloromethane (18 ml) is dissolved 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (1.44 g). The solution is added dropwise taking 5 minutes, while stirring at 0° C., to a mixture of methyl 1-(3,4,5-trimethoxybenzyl)piperazine-2carboxylate dihydrochloride (2.16 g), triethylamine (2.5 g) and dichloromethane (25 ml). The reaction mixture is stirred for one hour at room temperature, and then poured into ice-water, followed by extraction with dichloromethane. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:ethyl acetate:acetone =3:3:1) to afford methyl 4-(2 3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -1-(3,4,5-trimethoxybenzyl)piperazine -2- carboxylate, which is identical with the product obtained in Working Example 25, as a colorless oily product (2.2 g).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([CH:27]([OH:31])[C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH:17][C:28](=[O:29])[CH:27]([C:22]2[CH:23]=[C:24]([F:26])[CH:25]=[C:20]([F:19])[CH:21]=2)[OH:31])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCCC(N)C(=O)Nc1cn(C(CC)CC)cn1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Product: CCCC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cn(C(CC)CC)cn1

Procedure:
2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 10.7, 13.7, 13.7, 19.0, 19.1, 35.5, 35.7, 52.9, 53.2, 62.9, 73.4, 73.5, 103.4, 103.7, 105.0, 105.2, 109.6, 109.8, 109.9, 110.1, 132.5, 132.6, 137.4, 137.5, 144.1, 161.7, 161.9, 164.3, 169.2, 169.6, 171.8, 172.0; MS 423.21 m/z (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][CH:8]([C:14]([CH3:16])=O)[C:9](OCC)=[O:10]>>[CH3:7][C:8]1[C:9](=[O:10])[N:6]2[CH:5]=[CH:4][S:3][C:2]2=[N:1][C:14]=1[CH3:16]
Reactant: Nc1nccs1
Reactant: CCOC(=O)C(C)C(C)=O
Product: Cc1nc2sccn2c(=O)c1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-amino-thiazole (3.06 g) was reacted with ethyl 2-methylacetoacetate (6.4 g) in polyphosphoric acid (15.3 g: 7.1 g of P2O5 and 8.2 g of 99% H3PO4) under stirring at 100° C. for two hours. After cooling, dilution with ice water and neutralization, the precipitate was filtered, washed with water and crystallized from isopropyl ether to give 6,7-dimethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 112°-113° C. (5.04 g), which was reacted with 3-pyridine-carboxaldehyde (5.99 g) in methanol (130 ml) in the presence of sodium methoxide (4.55 g) under stirring at reflux temperature for 12 hours. After cooling the precipitate was filtered and washed with water until neutral: crystallization from methanol gave 3.2 g of 6-methyl-7-trans-[2-(3-pyridyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 192°-194° C., NMR (CDCl3) δ ppm: 2.36 (s) (3H, CH3), 6.97 (d) (H, C-2 proton), 7.38 (dd) (1H, C-5 pyridyl proton), 7.38 (d) (1H, β-ethenyl proton), 7.91 (d) (1H, α-ethenyl proton), 7.97 (d) (1H, C-3 proton), 8.00 (m) (1H, C-4 pyridyl proton), 8.62 (dd) (1H, C-6 pyridyl proton), 8.88 (d) (1H, C-2 pyridyl proton); JHα Hβ =16 Hz.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1.C(O)C>ClCCl>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)=[O:4]
Reactant: CC(C)(O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(COC(=O)C(C)(C)O)cc1

Procedure:
2-hydroxy isobutyric acid (1.56 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-1, step a). The title compound (2.65 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). Rf (2%MeOH/CHCl3) 0.45.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH:22]([CH3:24])[CH3:23])([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:27][CH:28]([N-]C(C)C)[CH3:29].C(Br)C=C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH:22]([CH3:23])[CH3:24])([CH:13]([C:28]([CH3:29])=[CH2:27])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]1=[O:25])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)C1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCN(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 115.9 %

Procedure:
A solution of tert-butyl N-tert-butyloxycarbonyl-3-(2-methylpropyl)-2-oxo-3-pyrrolidineacetate (3.65 g, 10.3 mmol) in dry THF (45 mL) is cooled to -78° C. and treated drop-wise with LDA (5.70 mL, 11.3 mmol). After 30 minutes at -78° C., allyl bromide (1.10 mL, 12.4 mmol) is added. The solution is maintained at -78° C. for 3 hours, and is then allowed to slowly warm to room temperature under N2. After 12 hours, the solution is quenched with saturated NH4Cl (10 mL) and diluted with H2O (50 mL). The crude lactem is extracted into EtOAc (3×100 mL). The organic extracts are combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4.72 g of gold oil. The oil is purified by silica gel chromatography (300 g SG, 5% EtOAc/hexane) to yield 2.98 g (73%) of the title compound as a clear, pale gold oil as a mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][C:19]([F:35])([C:31]([F:34])([F:33])[F:32])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([F:18])([F:35])[C:31]([F:32])([F:33])[F:34])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ccc(OCC(F)(F)C(F)(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)C(F)(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=495.2 [M+H]+.