Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:5]=[C:4]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.FC1C=CC(C2C3N([CH:61]=[N:62][N:63]=3)C(NC(C3C=CC=CC=3)(C)C)=NC=2C2C=CN=CC=2)=CC=1>>[C:26]1([CH2:25][CH2:24][C:4]2[N:3]3[CH:61]=[N:62][N:63]=[C:2]3[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=3)=[C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:5]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(Nc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c2nncn12)c1ccccc1
Reactant: FC(F)(F)c1cccc(-c2c(Cl)nc(CCc3ccccc3)nc2-c2ccncc2)c1
Product: FC(F)(F)c1cccc(-c2c(-c3ccncc3)nc(CCc3ccccc3)n3cnnc23)c1

Procedure:
The title compound was synthesized from 4-chloro-2-(2-phenylethyl)-6-(4-pyridyl)-5-(3-(trifluoromethyl)phenyl)pyrimidine in the same manner as 2-(8-(4-fluorophenyl)-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidin-5-yl)amino-2-phenylpropane; MS m/z (M+H)+ 446; C25H18F3N5 requir. 445.4.
Reaction SMILES: ClC(OC)=O.[C:6]([NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])(=[O:8])[CH3:7].[BH4-].[Na+].Cl>O1CCCC1.O.C(OCC)(=O)C.C(N(CC)CC)C>[OH:15][CH2:14][C:13]1[CH:17]=[CH:18][C:10]([NH:9][C:6](=[O:8])[CH3:7])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CO)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
8.3 ml (108 mmol) methyl chloroformate dissolved in 25 ml tetrahydrofuran (THF) is added dropwise over 15 minutes to a solution of 23.9 g (107 mmol) 4-(acetylamino)-3-nitrobenzoic acid and 14.8 ml (107 mmol) triethylamine in 150 ml dry THF under nitrogen and chilled in an acetone/ice bath. The temperature is kept below -5°. After stirring at -5° for 30 minutes, the triethylamine.HCl is filtered off and washed with 30 ml cold THF. The combined filtrates are added dropwise to a stirred solution of 10.3 g (108 mmol) sodium borohydride in 100 ml water chilled in an acetone/ice bath. The temperature is not allowed to exceed 15°. The resulting mixture is stirred at room temperature for 4 hours. After acidification with concentrated hydrochloric acid, the reaction mixture is taken up in ethyl acetate which is washed with water, 10% NaOH (X 2), water (X 2), dried (Na2SO 4), and evaporated: 17 g. This material is crystallized from 20 ml methanol to give 9.1 g of the title compound, m.p. 114°-115°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C1([O:18][C:19]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=O)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][NH:11][C:19]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: NCCOc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)NCCOc1ccc(Cl)cc1

Procedure:
A solution of 0.6 g (3.5 mmol) of [(4-chloro-phenyl)oxy]ethylamine (Chim. Ther. 1973, 8, 259-270) and 1.3 g (5.8 mmol) of ethyl [(phenyloxy-carbonyl)oxy]acetate, prepared in Step 1.1., in 30 ml of toluene is heated at 60° C. overnight. It is evaporated to dryness and the product is purified by chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane. This gives 0.7 g of oily product, containing ˜10% of cyclized oxazolidine dione product, used as it is in the following step.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)#[N:7]>C1C=CC=CC=1>[C:1]([NH:5][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([C:6]#[N:7])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Product: CC(C)(C)NC(=O)c1ccc(C#N)cc1
Yield: 92 %

Procedure:
The preparation of Example 1 was repeated with the changes that the starting reactants were tert-butyl amine (4.38 g, 0.060 mole) and 4-cyanobenzoyl chloride (5.08 g, 0.030 mole) and the reaction was carried out in benzene to produce 5.58 g of crystals of the desired product (92% yield), mp 146°-148° C. Proton nuclear magnetic resonance (89.55 MHz) showed absorptions at 7.829 ppm (d, 8.4 Hz, 2H; 3,5-aryl H); 7.690 ppm (d, 8.4 Hz, 2H; 2,6-aryl H); 5.996 ppm (bs, 1H; N-H); 1.477 ppm (s, 9H; tert-butyl H) .
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[C:9]([C:11]3[N:15]([CH3:16])[C:14]([C:17]([C:19]4[CH:23]=[C:22]([CH3:24])[O:21][N:20]=4)=[O:18])=[N:13][C:12]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[BH4-].[Na+].O>CO>[NH2:1][C:2]1[C:3]2[N:10]=[C:9]([C:11]3[N:15]([CH3:16])[C:14]([CH:17]([C:19]4[CH:23]=[C:22]([CH3:24])[O:21][N:20]=4)[OH:18])=[N:13][C:12]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc(C(=O)c2nc(-c3ccccc3)c(-c3nc4c(N)ncnc4s3)n2C)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(C(O)c2nc(-c3ccccc3)c(-c3nc4c(N)ncnc4s3)n2C)no1
Reaction time: 1 h
Yield: 59.7 %

Procedure:
[5-(7-Amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazol-2-yl](5-methylisoxazol-3-yl)methanone (Example 39) (6 mg) was dissolved in MeOH (2 mL), sodium borohydride (3 mg) added then stirred for 1 hour. Water (1 mL) was added, stirring continued for 20 minutes then concentrated in vacuo. The residue was diluted with water (5 mL), extracted with DCM (2×6 mL), organic extracts dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a pale yellow solid (3.6 mg, 60%); MS m/e MH+ 420.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][O:12][C:11](=[O:14])[C:10]=2[CH3:15])[CH:5]=[CH:6][C:7]=1[F:8]>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][C:11](=[O:14])[C@H:10]2[CH3:15])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1=C(c2ccc(F)c(F)c2)COC1=O
Solvent: CO
Product: C[C@@H]1C(=O)OC[C@@H]1c1ccc(F)c(F)c1
Reaction time: 72 h
Yield: 98.5 %

Procedure:
4-(3,4-Difluorophenyl)-3-methyl-2(5H)-furanone (235 mg, 1.1 mmol.) was dissolved in methanol (20 ml) in a thick-walled flask and degassed by nitrogen bubbling. Palladium on charcoal (10%, 300 mg) was added and the flask shaken under an atmosphere of hydrogen at 40 psi on a Parr hydrogenator for 72 hours. The reaction was placed under nitrogen and filtered through a pad of Celite® washing well with methanol and the combined washings evaporated to afford the desired cis-dihydro-4-(3,4-difluorophenyl)-3-methyl-2(3H)-furanone as an oil (230 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][CH2:19]Cl)C>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:16][O:18][CH3:19]
Reactant: CCOCCl
Reactant: Oc1ccc(Br)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(Br)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A flask was charged with 2,4-dibromophenol (50.4 g, 200 mmol), potassium carbonate (69.1 g, 500 mmol) and acetone (500 mL). The suspension was stirred at RT for 30 minutes and then treated dropwise with chloromethyl ethyl ether (19 mL, 213 mmol). After 3 h at RT the mixture was filtered and the filtrate was partitioned between EtOAc and water. The organic phase was separated, washed with water, aqueous saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford 54.2 g 2,4-dibromo-1-(methoxymethoxy)benzene, which was used in the next step without further purification.
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][I:22])[C:16](=[O:23])[C@@H:15]([CH2:24][C:25](OCC)=O)[O:14][C@H:13]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[C:12]=2[CH:40]=1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][I:22])[C:16](=[O:23])[C@@H:15]([CH2:24][C:25]#[N:6])[O:14][C@H:13]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[C:12]=2[CH:40]=1
Reactant: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CCCCI)C1=O
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#CC[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CCCCI)C1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
Trimethylaluminium (2M in toluene, 15.0 ml, 30.1 mmol) was added dropwise to a suspension of ammonium chloride (1.6 g, 30.1 mmol) in toluene (25 ml) at ice bath temperature under a nitrogen atmosphere. The resulting solution was stirred for 1 hour. Ethyl trans-7-chloro-5-(1-naphthyl)-1-(4-iodobutyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (5.1 g, 8.6 mmol) was added as a solid and the solution heated at 85° C. for 18 hours. The solution was cooled and acidified with 2 N hydrochloric acid cautiously. Ethyl acetate (100 ml) was added and the layers were separated. The organic layer was washed with 2 N hydrochloric acid. The combined acidic layers were re-extracted once with ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide solution (2×), dried (MgSO4), concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/hexane 1:4→2:3) to give a solid which was recrystallized from ethyl acetate/hexane to afford the title compound (1.58 g, 34%) as a pink solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([CH3:17])[CH:9]=2)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([CH3:17])[CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(OC)c(C)cc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2cc(OC)c(C)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 0.20 g (0.60 mmol) 5-methoxy-6-methyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 4 mL dichloromethane was cooled to 0° C. and 2 mL (3.0 g, 26.1 mmol) trifluoroacetic acid were added. The ice bath was removed and after stirring 1 h at room temperature the solution was evaporated to dryness. The residue was dissolved in dichloromethane, washed with aqueous 1M sodium hydroxide solution and brine, dried over magnesium sulfate, filtered and evaporated to afford the title compound as a white solid (97%) which was pure enough to be used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6](C)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].CS([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 97.8 %

Procedure:
To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (Example 113, step B) (0.5 g, 2.7 mmol) in 25 mL of DMSO was added, 1-(methylsulfonyl)piperazine (0.53 g, 3.24 mmol), and K2CO3 (1.12 g, 8.1 mmol). The mixture was heated to 130° C. for 24 h. The mixture was poured into 500 mL of H2O, filter, washed with H2O, air dried for 15 min, dissolved in DCM, dried (MgSO4), filtered, and rotovaped down to give the title compound of step A (0.87 g, 2.64 mmol, 98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (s, 1H), 6.76 (s, 1H), 3.89 (s, 3H), 3.23-3.28 (m, 4H), 3.06-3.11 (m, 4H), 2.93 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=[O:6].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(OCc2ccccc2)c1
Reaction time: 0.33 h

Procedure:
A solution of methyl 3-hydroxybenzoate (1.00 g, 6.56 mmol)in THF was treated with sodium hydride (60% by wt in oil, 276 mg, 6.90 mmol). After 20 minutes, the mixture was treated with benzyl bromide (0.78 mL, 6.56 mmol) and then heated at reflux. The mixture was cooled, treated with saturated ammonium chloride and EtOAc. The layers were separated and the aqueous layer was washed with EtOAc (3×). The combined organic extracts were washed with saturated NaCl, dried over MgSO4 and concentrated. A solution of the crude material in dioxane (20 mL) was treated with 2.5 N NaOH (13 mL) and stirred vigorously. The mixture was acidified by addition of 5 N HCl and partitioned with EtOAc. The aqueous layer was washed with EtOAc (3×) and the combined extracts were dried (MgSO4) and concentrated yielding the title compound.
Reaction SMILES: C(O[CH:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]([O:8][CH3:9])=[O:7])(=O)C.[CH2:18](Br)[C:19]#[CH:20].[Br-]>CN(C=O)C.CCOC(C)=O.[Zn]>[CH3:17][C:14]([CH3:15])([O:13][C:11]([NH:10][CH:5]([CH2:20][C:19]#[CH:18])[C:6]([O:8][CH3:9])=[O:7])=[O:12])[CH3:16]
Reactant: C#CCBr
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Agent: [Br-]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCC(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cooled suspension of the product of Example 2 (4.00 g, 16.2 mmol) and zinc dust (2.63 g, 40.5 mmol) in DMF (30 mL) under nitrogen was added slowly via syringe propargyl bromide (80% w/w in toluene) (6.02 g, 40.5 mmol). The bromide was added at such a rate as to maintain the internal temperature between 20°-25° C., then stirred at that temperature for an additional 1 hour. The reaction mixture was diluted with 100 mL of EtOAc, washed successively with 0.5N HCl (200 mL), sat'd NaHCO3 (200 mL) and sat'd NaCl and then dried (MgSO4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.Cl.[CH3:13][NH:14][O:15][CH2:16][C:17]([OH:19])=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([N:14]([CH3:13])[O:15][CH2:16][C:17]([OH:19])=[O:18])=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CNOCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cl)cc1NC(=S)N(C)OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A mixture of 5-chloro-2-methylphenyl-isothiocyanate (36.7 g), N-methyl aminooxy acetic acid hydrochloride (28.3 g), triethylamine (50 g) and chloroform (300 mL) was heated at reflux for one hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (700 mL) and washed with 2N HCl (3×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness affording (48 g) of [[[[(5-Chloro-2-methylphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as a semi solid. 1H-NMR (DMSO-d6; 300 Mhz) δ12.8 (br s, 1H), 10.15 (s, 1H), 7.35-7.20 (m, 3H), 4.62 (s, 2H), 3.56 (s, 3H), and 2.18 ppm (s, 3H). The acid (48 g) was dissolved in benzene (300 mL). Phosphorus pentachloride (42 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (10% ethyl acetate in hexane). Crystallization from ethyl acetate/hexane afforded the title compound (18 g) as a solid, m.p. 100-102° C. Mass spectrum (El, M.+) m/z 270/272. 1H-NMR (CDCl3; 400 MHz) δ7.32 (d, 1H), 7.24 (d, 1H), 7.14 (s, 1H), 4.84 (ABq, 2H), 3.74 (s, 3H), and 2.13 ppm (s, 3H).
Reaction SMILES: I[C:2]1[C:3]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][C:8]([C:3]1[C:2]([C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:12])[C:9]#[N:10]
Reactant: CC(C)(C#N)c1ncccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C#N)c1ncccc1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
2-(3-Iodopyridin-2-yl)-2-methylpropanenitrile (1.8 g, 6.6 mmol), cuprous iodide (0.045 mL, 1.3 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.46 g, 0.66 mmol) were dissolved in TEA (20 mL, 143 mmol). Ethynyltrimethylsilane (4.7 mL, 33 mmol) was added to the reaction mixture, and the reaction mixture was placed under an argon atmosphere. The reaction mixture was stirred and heated at 80° C. After 45 minutes, the reaction was >95% complete as determined by LCMS. The reaction was cooled to room temperature and then filtered through Celite to remove a dark solid. The filtrate was concentrated in vacuo and purified by silica flash chromatography (0-50% EtOAc/hexane) to give the title compound as a light-orange oil (1.6 g, 100%). MS (m/z)=243 (M+H)+. Calculated for C14H18N2Si 242.4.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[CH2:5][C:3](=[O:4])[CH2:2]1.[H-].[Na+].[O:10]1[CH:16]2[CH:11]1[C:12]([CH3:24])([CH3:23])[O:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:15]=12>O1CCCC1.[Cu]Br>[OH:10][C@H:11]1[C@H:16]([O:4][C:3]2[CH2:2][CH2:1][C:6](=[O:7])[CH:5]=2)[C:15]2[CH:17]=[C:18]([C:21]#[N:22])[CH:19]=[CH:20][C:14]=2[O:13][C:12]1([CH3:24])[CH3:23]
Reactant: O=C1CCC(=O)C1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)CC2)[C@@H]1O
Reaction time: 67 h

Procedure:
10.1 g of 1,3-cyclopentadione are dissolved in 1000 ml of tetrahydrofuran under a protective gas, and 2.7 g of sodium hydride (80%) are slowly added. After half an hour, 18.5 g copper(I)bromide.dimethylsulphide complex were added to this mixture. To this reaction solution are added in drops 12.1 g of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (J. M. Evans et al., J. Med. Chem. 26, 1582 [1983]) in 100 ml of tetrahydrofuran. After 67 hours, the reaction is quenched with water, and the reaction solution is subsequently partitioned between dichloromethane and water. Drying of the organic phase over sodium sulphate, filtration and concentration on a rotary evaporator yields a yellowish mass, which is purified by flash-chromatography (dichlormethane, 1% methanol). Recrystallisation from dichloromethane/ethanol yields white crystals having a m.p. of 199°-201° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][CH:9]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH2:10][CH:11]([OH:17])[CH:12]([N+:14]([O-:16])=[O:15])[CH3:13].CCOCC>OS(O)(=O)=O.O>[C:1]([O:17][CH:11]([CH2:10][CH:9]([CH3:8])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH:12]([N+:14]([O-:16])=[O:15])[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCCC(C)CC(O)C(C)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: CC(=O)OC(CC(C)CCC=C(C)C)C(C)[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.21 h
Yield: 87 %

Procedure:
A flask containing 1.3 g of acetic anhydride was cooled to −10° C. with a salt-ice bath, and 2.34 g of 6 was added with magnetic stirring under an N2 atmosphere. After 10-15 min, 2-5 drops of concentrated H2SO4 were added. The reaction mixture was allowed to stir for an additional 10 min, after which it was treated with 40 mL of ether and 10 mL of H2O. The mixture was extracted three times with 15 mL of saturated aqueous sodium bicarbonate and once with 10 mL of saturated aqueous NaCl. The ether layer was dried over anhydrous MgSO4, and the solvent was removed by rotary evaporation to yield 2.41 g (88%) of a mixture of stereoisomers of the nitro acetate 7. 1H NMR δ (ppm) 5.4 (broad m, CH2CH(OAc)), 5.2 (t, C═CH), 4.65 (m, CH3CHNO2), 2.1 (s, CH3CO2), 2.0 (br m, ═CHCH2), 1.60 and 1.65 (both s, CH3C(CH3)═), 1.5 (d, CH3CHNO2), 1.2-1.5 (m, CH2CH(CH3)CH2), 0.95 (d, CH2CH(CH3)CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[NH:14][C:13]=2[C:12](=[O:20])[N:11]([CH3:21])[CH2:10]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:41][O:42][CH2:43][CH:44](O)[CH2:45][CH2:46][CH3:47].CCOC(/N=N/C(OCC)=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]=[C:15]([CH2:18][CH3:19])[N:14]([CH:44]([CH2:43][O:42][CH3:41])[CH2:45][CH2:46][CH3:47])[C:13]=2[C:12](=[O:20])[N:11]([CH3:21])[CH2:10]1
Reactant: CCc1nc2c([nH]1)C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Reactant: CCCC(O)COC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(COC)n1c(CC)nc2c1C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.4 %

Procedure:
A solution of 3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-1,2,3,7-tetrahydro-6H-purin-6-one (80 mg, 0.246 mmol) in anhydrous THF (1.2 mL) was heated to 50° C. PPh3 (100 mg, 0.492 mmol) and 1-methoxy-2-pentanol (87 mg, 0.738 mmol) were added. After stirring 5 min, DEAD (85 μL, 0.541 mmol) was added rapidly via syringe and the reaction mixture was stirred 25 min at 50° C. The mixture was cooled to rt and was poured into a separatory funnel containing saturated aqueous NaHCO3 (15 mL). The aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. Purification of the residue by prep plates (1000 μM silica gel plates, 50% ethyl acetate/50% hexanes) followed by further purification by reverse phase HPLC furnished the title compound (59 mg, 56% yield) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.45 (d, J=2.2 Hz, 1H), 7.18 (dd, J=8.5, 2.2 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 4.84 (ABq, J=11.4, Δυ=46.9 Hz, 2H), 4.24-4.17 (m, 2H), 3.79-3.74 (m, 1H), 3.32 (s, 3H), 2.96 (s, 3H), 2.75 (q, J=7.7 Hz, 2H), 2.21-2.05 (m, 1H), 1.95-1.81 (m, 1H), 1.30-1.20 (m, 5H), 0.92 (t, J=7.0 Hz, 3H); HRMS (ESI) m/e 425.1519 [(M+H)+, calcd for C20H26N15OCl2 425.1511].
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17]([C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([NH:16][C:17]([C:19]1[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=1)=[O:18])([C:4]([OH:5])=[O:3])[CH2:14]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccc(F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccc(F)cc2C1)c1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
The mixture of 5-fluoro-2-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (86) (190 mg, 0.50 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more precipitate formed. The precipitate is filtered to give a pure product (87) as a pale brown solid (178 mg, 100%).