Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9](=O)[O:10][C:11]([CH3:15])=[CH:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC=CN=1.Cl.[NH2:25][OH:26]>>[OH:26][N:25]1[C:11]([CH3:15])=[CH:12][C:13]([CH3:14])=[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:10]
Reactant: Cc1cc(C)c(Cc2ccccc2)c(=O)o1
Reactant: NO
Agent: Cl
Agent: Nc1ccccn1
Product: Cc1cc(C)n(O)c(=O)c1Cc1ccccc1
Yield: 30.4 %

Procedure:
2 g of 3-benzyl-4,6-dimethyl-2-pyrone, 6 g of 2-aminopyridine and 1 g of hydroxylamine-hydrochloride were heated for 8 hours to 70° C. After working up as described in Example 1, 0.65 g (30%) of 1-hydroxy-3-benzyl-4,6-dimethyl-2-pyridone were obtained; melting point 148° C (Calc.: 6.1 % N, found 6.1 % N).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH2:6][C:7]1[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1>CN(C=O)C.CO.[Pd]>[NH2:1][CH2:6][C:7]1[N:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1
Reactant: N#Cc1cccc(CBr)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Pd]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1cccc(CN)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
Sodium azide (0.280 g, 4.32 mmol) was added to a solution of 6-bromomethyl-pyridine-2-carbonitrile (0.610 g, 2.88 mmol) in DMF (12 ml) and the resulting pale yellow solution was stirred at rt for 16 h. Standard basic workup gave the crude product as a tan solid in quantitative yield (0.501 g). The crude solid was dissolved in MeOH (15 ml), treated with 10% Pd/C (0.050 g) and placed under 40 psi H2 on a Parr shaker for 30 minutes (Note: it is imperative that this reduction is stopped at 30 minutes or reduction of the nitrile also occurs). The mixture was filtered through Celite®, the cake was washed with MeOH and the combined filtrate was concentrated under reduced pressure to give a yellow oil. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 83:15:2, v/v/v) afforded 6-aminomethyl-pyridine-2-carbonitrile (0.178 g, 46%) as a white crystalline solid. 1H NMR (CDCl3) δ 1.96 (br s, 2H), 4.02 (s, 2H), 7.53 (d, 1H, J=9.0 Hz), 7.59 (d, 1H, J=9.0 Hz), 7.80 (t, 1H, J=9.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[N:12][NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.C(=O)([O-])O.[Na+].ClCCl>C(#N)C>[Cl:21][C:10]1[N:11]=[N:12][C:13]([C:14]([F:17])([F:16])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]=1
Reactant: O=c1cc(-c2ccc(F)cc2)c(C(F)(F)F)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Fc1ccc(-c2cc(Cl)nnc2C(F)(F)F)cc1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a stirred solution of 5-(4-fluorophenyl)-6-trifluoromethyl-2H-pyridazine-3-one (D6) (0.96 g, 3.7 mmol) in acetonitrile (10 ml) was added phosphorous oxychloride (0.866 ml, 9.3 mmol) and the reaction was stirred at 180° C. for 30 min., under microwave irradiation. After this period, the reaction mixture was poured into a saturated solution of sodium hydrogen carbonate, ice and dichloromethane. Further solid sodium hydrogen carbonate was then added until gas evolution had ceased. The organic layer was then separated, dried (Na2SO4) and the solvents evaporated in vacuo to yield D7 (0.81 g, 79%). Only traces of the undesired isomer were detected after work-up. C11H5ClF4N2 requires 276; Found 277 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][CH2:4][NH:3]1.[H-].[Na+].FC(F)(F)S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O>CN(C=O)C>[O:1]=[C:2]1[C@@H:6]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:4][N:3]1[CH2:23][C:24]([F:27])([F:26])[F:25]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
To a solution of (S)-tert-butyl (2-oxopyrrolidin-3-yl)carbamate (250 mg, 1.25 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (52.9 mg, 1.32 mmol). After stirring at rt for 1 h, 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.18 mL, 1.25 mmol) was added then the reaction mixture was allowed to warm to rt and stirred for 3.5 h. The reaction mixture was concentrated under reduced pressure and the residue purified on silica gel eluting with 0 to 75% EtOAc/DCM to give Compound 91a (95 mg, 27% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.11 (br. s., 1H), 4.24 (br. s., 1H), 4.07 (dq, J=15.0, 9.2 Hz, 1H), 3.91-3.67 (m, 1H), 3.63-3.37 (m, 2H), 2.84-2.47 (m, 1H), 2.12-1.84 (m, 1H), 1.53-1.42 (m, 9H). COSY NMR shows coupling of NH at 5.11 ppm to methine at 4.24 ppm, confirming regioselectivity of alkylation on the pyrrolidinone nitrogen. US 2009/760005 A1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH2:28].CN(C)C=O.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C>[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:28][C:20](=[O:22])[C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6.65 g. of Nα -benzyloxycarbonyl-D-phenylalanine (0.022 mol) and 4.38 g. (0.022 mol) of L-leucine methyl ester hydrochloride in 60 ml. of spectrograde dimethylformamide is chilled in ice and treated with 3.0 ml. of triethylamine (2.24 g.). 1-Hydroxybentriazole, 3.3 g., and dicyclohexylcarbodiimide, 5 g., are added and the reaction stirred at room temperature overnight and for 24 hours longer at room temperature. The mixture is filtered and the solvent evaporated under reduced pressure. The residue is dissolved in 200 ml. of ethyl acetate and washed with 0.1N hydrochloric acid, saturated salt solution, 5% sodium bicarbonate solution, saturated salt solution and water. The ethyl acetate solution is dried over magnesium sulfate, filtered and evaporated to a crystalline residue. The product is recrystallized twice from ethyl acetate and petroleum ether; 7.3 g.; m.p. 125°-126° C.; [α]D23 -20.3° (c 1.02, methanol).
Reaction SMILES: [CH3:1][N:2]1[CH:20]=[N:19][C:18]2[N:7]([C@@H:8]3[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:9]3[O:10][CH3:11])[CH:6]=[N:5][C:4]=2[C:3]1=N.CN1C=NC2N([C@@H]3O[C@H](CO)[C@@H](OC)[C@H]3O)C=NC=2C1=N.[S-2:43].[Na+].[Na+]>CN(C)C=O>[CH3:1][N:2]1[CH:20]=[N:19][C:18]2[N:7]([C@@H:8]3[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:9]3[O:10][CH3:11])[CH:6]=[N:5][C:4]=2[C:3]1=[S:43]
Reactant: [S-2]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=N)n(C)cnc21
Agent: CO[C@H]1[C@@H](O)[C@H](n2cnc3c(=N)n(C)cnc32)O[C@@H]1CO
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=S)n(C)cnc21

Procedure:
Reaction Scheme 2 discloses the presently preferred method for preparing 1-N-,2'-O-dimethyl-6-thioinosine (Compound 25). In accordance with this method, adenosine (Compound 20) is reacted with methylchloride in a polar aprotic solvent, such as dimethylformamide (DMF) or dimethylacetamide (DMA) in the presence of strong base, such as sodium hydride. The resulting 2'-O-methyl adenosine is reacted, without isolation, with iodomethane to introduce the methyl group to the 1-N-position. After the treatment with iodomethane a crude product is obtained which contains approximately 60% of the desired 1-N-,2'-O-dimethyladenosine intermediate, and also contains some 1-N-,3'-O-dimethyladenosine as well as monomethylated derivatives. The crude product is reacted at a moderately elevated temperature (approximately 45° C.) with anhydrous sodium sulfide in anhydrous dimethylformamide, and the resulting crude product is purified by chromatography to yield the desired 1-N-,2'-O-dimethyl-6-thioinosine (Compound 25). ##STR7##
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccccc3C2c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(O)cc1)N1c2ccc(Br)cc2-c2ccccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A stirred suspension of 2-bromo-5-[(4-methoxyphenyl)sulfonyl]-6-phenyl-5,6-dihydrophenanthridine (1.01 g, 2.0 mmol) and cyclohexene (3.70 g, 45 mmol) was treated at room temperature under nitrogen with a solution of 1.0 M boron tribromide in dichloromethane (12 mL, 12 mmol). After stirring for approximately two hours at room temperature, the reaction was quenched with methanol (20 mL) and diluted with dichloromethane. The mixture was washed sequentially with an aqueous potassium carbonate solution, a saturated, aqueous, sodium chloride solution, and water. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and eluted with ethyl acetate. The ethyl acetate phase was evaporated in vacuo to a crude orange residue (1.0 g,). The crude residue was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g) with gradient elution of between 10% to 30% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min; and afforded, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from a mixture of ethyl acetate-diethyl ether-hexane yielded the title compound (0.845 g, 1.72 mmol, 86%) as a homogeneous, colorless, crystalline solid, m.p. 262-265° C.;
Reaction SMILES: [I:1]I.[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:11])[C:8]=1[CH2:9][OH:10]>C1C=CC=CC=1>[CH3:3][C:4]1[S:5][C:6]([I:1])=[C:7]([CH3:11])[C:8]=1[CH2:9][OH:10]
Reactant: II
Reactant: Cc1csc(C)c1CO
Solvent: c1ccccc1
Product: Cc1sc(I)c(C)c1CO
Temperature: -50 °C

Procedure:
10.0 G. (46 mmol) of mercuric oxide and 14.7 g. (58 mmol) of iodine were added alternately over a period of 11/4 hrs. to a vigorously stirred solution of 8.2 g. (57.7 mmol) of 2,4-dimethyl-3-hydroxymethylthiophene in 300 ml. of benzene. The reaction mixture was kept at room temperature by cooling with and ice bath and stirring was continued for an additional hour. The mercuric iodide which precipitated was filtered and washed well with warm ethyl ether. The combined organic solutions were washed with 10% sodium thiosulfate and saturated sodium chloride solution, dried and evaporated. The resulting residue was dissolved in a minimum amount of hot ether, an equal amount of hexane was added and the solution cooled to -50° C. The crystals which precipitated were filtered and washed with cold hexane to yield after drying 2,4-dimethyl-3-hydroxymethyl-5-iodothiophene, m.p. 118.5°-120.5° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[OH:1][C:2]1[C:11]([C:12]([Cl:17])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccccc2cc1O
Reaction time: 4 h

Procedure:
To 30 grams (0.16 moles) of 2-hydroxy-3-naphthoic acid in 125 milliliters of methylene chloride was added 24 grams of thionyl chloride. The reaction mixture was maintained at reflux under a nitrogen atmosphere. After 4 hours, a dark brown solution of 2-hydroxy-3-naphthoic acid chloride was obtained. The solution was cooled to room temperature, placed in a 125 milliliter pressure equalizing funnel, and added slowly to a 200 milliliter methylene chloride solution of 24 grams of N,N-diethylaniline and 27 grams of 2,3-dichloroaniline (0.16 moles). The mixture was heated to reflux. The reaction was substantially complete after approximately 3 hours; and allowing the reaction to continue for up to 20 hours was not observed to affect the product. Half of the reacting solvent was distilled off and 50 to 100 milliliters of ethanol was introduced. After cooling the mixture to room temperature, the precipitated product was collected by filtration and washed twice with 50 milliliter portions of methanol. The crude product was then recrystallized from a mixture of duimethylformamide and methanol. Yield of the coupler compound 2-hydroxy-3-naphtho-2',3'-dichloroanilide was 37 grams (70 percent). The coupler compound exhibited the following properties:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][CH3:11])[CH:4]=1.[C-:12]#[N:13].[Na+]>C(O)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:12]#[N:13])=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: [C-]#N
Reactant: COc1cc(CBr)ccc1Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CC#N)ccc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.290 mol) in C2H5OH (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). The mixture was stirred at 60° C. overnight. Ethanol was evaporated and the residue was dissolved in H2O. The mixture was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-methoxyphenyl)acetonitrile (25 g, 48%). 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8 Hz, 1 H), 6.88-6.84 (m, 2 H), 3.92 (s, 3 H), 3.74 (s, 2 H). 13C NMR (100 MHz, CDCl3) δ 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(N(C(C)C)CC)(C)C.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[B-](F)(F)(F)F.CCCC[P+](C1SC(C(OC)=O)=C(C(OC)=O)S1)(CCCC)CCCC.[C:73]([O:77][CH2:78][C@@H:79]([NH2:94])[CH2:80][CH2:81][N:82]1[CH2:85][CH:84]([O:86][C:87]2[CH:92]=[CH:91][C:90]([F:93])=[CH:89][CH:88]=2)[CH2:83]1)([CH3:76])([CH3:75])[CH3:74]>CN(C)C=O>[C:73]([O:77][CH2:78][C@@H:79]([NH:94][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:80][CH2:81][N:82]1[CH2:83][CH:84]([O:86][C:87]2[CH:88]=[CH:89][C:90]([F:93])=[CH:91][CH:92]=2)[CH2:85]1)([CH3:76])([CH3:74])[CH3:75]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CC(C)(C)OC[C@@H](N)CCN1CC(Oc2ccc(F)cc2)C1
Agent: CCCC[P+](CCCC)(CCCC)C1SC(C(=O)OC)=C(C(=O)OC)S1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@@H](CCN2CC(Oc3ccc(F)cc3)C2)COC(C)(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 3,4,5-trimethoxy-benzoic acid (0.246 g, 1.16 mmol) and diisopropylethylamine (0.62 ml, 3.47 mmol) in dry dimethylformamide (10 ml) is treated with [(benzotriazol-1-yloxy)-dimethylamino methylene]-dimethyl-ammonium; tetrafluoro borate (0.32 g, 1.0 mmol). The reaction mixture is stirred at ambient temperature for 5 minutes, then (S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine (0.968 mmol) is added and the reaction mixture stirred for 20 hours. The dimethylformamide is evaporated and the residue partitioned between ethylacetate and saturated aqueous NaHCO3. The ethylacetate phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution 50% ethylacetate/hexane to 100% ethylacetate) to afford N-{(S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-3,4,5-trimethoxy-benzamide [MH]+ 505.3.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[N:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:3]1.[C:41]1([CH:47]2[CH2:49][O:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[C:21]([C:18]1[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:15]([C:13]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@H:6]2[CH2:7][C@@H:2]([NH:1][CH2:49][CH:47]([OH:48])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:3][N:4]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])[CH2:5]2)=[O:14])=[CH:20][N:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: c1ccc(C2CO2)cc1
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N)CN(C(=O)OCc2ccccc2)C1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](NCC(O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzyl (3R,5S)-3-amino-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (100 mg) and 2-phenyloxirane (55 μl) were dissolved in acetonitrile (5 ml), and lithium perchlorate (55 mg) was added. The mixture was stirred at room temperature for 3 days and thereafter stirred at 80° C. for 7 hr. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane-methanol (10:90:0-100:0:0-85:0:15) and concentrated under reduced pressure to give the object compound (53.2 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([Cl:20])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:23]N1C(=O)CCC1=O.CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([Cl:20])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17]([I:23])[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nc3c(I)cnn3c(Cl)c2CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 0.1 g (0.31 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (route 1, step a to d) in 2 mL DMF, under nitrogen, was added 0.104 g (0.46 mmol) N-iodosuccinimide, and the reaction was stirred at room temperature for 16 hours. 20 mL EtOAc was added and the mixture was washed with a 10% solution of Na2S2O3 (2×5 mL). The aqueous layers were combined and extracted with EtOAc (2×10 mL). The organic layers were combined, washed with 10 mL saturated brine, and dried with MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 9:1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[H-].[Na+].CC1C=CC(S(O[CH2:38][CH2:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH3:41])(=O)=O)=CC=1.O>CS(C)=O>[CH3:41][N:40]([CH2:39][CH2:38][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:6]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:16]=1)[C:42](=[O:43])[O:44][C:45]([CH3:46])([CH3:48])[CH3:47]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)C(=O)OC(C)(C)C)cc1
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(CCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 44; 200 mg, 0.62 mmol) in dimethylsulfoxide (8 ml) was added sodium hydride (17.98 mg, 0.75 mmol) at 0° C., and the mixture was stirred at room temperature for 1 h. 2-[{[(1,1-Dimethylethyl)oxy]carbonyl}(methyl)amino]ethyl 4-methylbenzenesulfonate (247 mg, 0.75 mmol) in dimethylsulfoxide (8 ml) was added to the solution dropwise, and the mixture was stirred at 75° C. for 18 h. The mixture was poured into water (100 ml), extracted thoroughly with ethyl acetate. The organic layer was dried, and concentrated to obtain a crude product. The crude product was purified by chromatography on silica gel (dichloromethane/methanol=15:1) to yield the title compound as a yellow oil. 140 mg.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)=[CH2:2].[CH:8]([C:11]([CH3:21])([N:14]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]1=[O:20])[C:12]#[N:13])([CH3:10])[CH3:9].C(Cl)(Cl)Cl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH:8]([C:11]([CH3:21])([N:14]1[C:18](=[O:19])[C:17]2[C:16](=[CH:2][CH:1]=[C:3]3[CH:7]=[CH:6][S:5][C:4]3=2)[C:15]1=[O:20])[C:12]#[N:13])([CH3:10])[CH3:9]
Reactant: C=Cc1ccsc1
Reactant: CC(C)C(C)(C#N)N1C(=O)C=CC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)C(C)(C#N)N1C(=O)c2ccc3ccsc3c2C1=O
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A mixture of 3-vinylthiophene (10.0 g, 0.0908 mol), α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1- acetonitrile (18.3 g, 0.0953 mol) and chloroform is stirred at 50° C. for 20 hours and at room temperature for one week. The mixture is concentrated in vacuo to give a yellow oil residue, which is column chromatographed on silica gel using methylene chloride as an eluent to afford a yellow oil. The oil is taken up in dioxane and treated with dichlorodicyano-p-benzoquinone, (17.2 g, 0.0760 mol), stirred for 21 hours at 100° C., cooled to 25° C. and filtered (the filter cake is washed once with benzene). The filtrate is concentrated in vacuo to give an orange semisolid residue. The residue is washed through neutral alumina with methylene chloride:hexanes (1:1) and flash chromatographed on silica gel using hexane:ethyl acetate (4:1) as an eluent to afford the title product as a pale yellow solid, 4.21 g (15.6%), mp 99°-107° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>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.[Pd].[Pd].C1(C)C(C)=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Yield: 72.8 %

Procedure:
Under a nitrogen atmosphere, a xylene solution (65 mL) of tert-butyl 4-amino-piperidine-1-carboxylate (1.00 g, 5.00 mmol), 4-bromo-1-fluorobenzene (0.500 mL, 4.57 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (360 mg, 1.00 mmol), and tris(dibenzylideneacetone)dipalladium (0) (209 mg, 0.250 mmol) was stirred at 140° C. for 4 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate=100/0→70/30 (v/v)) to obtain the title compound (980 mg, yield 66%).