Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:21]([C:24]1[CH:33]=[C:32]([C:34]([NH:36][NH2:37])=[O:35])[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])([O-:23])=[O:22]>C(O)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:37][NH:36][C:34]([C:32]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([N+:21]([O-:23])=[O:22])[CH:33]=3)=[O:35])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]
Solvent: CC(C)O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 82.9 %

Procedure:
1-[5-(4-tert-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (1.149 mmol, 312.9 mg) synthesized in Synthetic Example 3, methyl 2-nitro-4-hydrazinocarbonylbenzoate (1.149 mmol, 274.8 mg) synthesized in Reference Synthetic Example 40 and p-tosylic acid monohydride (30 mol %, 59.4 mg) were dissolved in isopropyl alcohol (30 mL) and stirred under heating with reflux for 6 hours, and the reactor was cooled to 0° C. The reaction solution was filtered and dried by means of a vacuum pump to give the desired product as a yellow solid (470 mg, yield 83%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]([NH:14][N:15]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]1[C:21](=[O:29])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.C(N(CC)CC)C.C[S-].[Na+]>>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21](=[O:29])[C:16]2=[C:17]([Br:20])[CH:18]=[CH:19][N:15]2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1ccccc1
Agent: BrBr
Agent: C[S-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nn2ccc(Br)c2c(=O)n1-c1ccccc1
Yield: 90.3 %

Procedure:
(S)-tert-Butyl (4-(benzyloxy)-1-((3-bromo-2-(phenylcarbamoyl)-1H-pyrrol-1-yl)amino)-1-oxobutan-2-yl)carbamate (0.7 g, 1.22 mmol) was treated with triphenylphosphine (0.45 g, 1.72 mmol), bromine (88 μl, 1.72 mmol), triethylamine (683 μl, 4.90 mmol) and sodium methanethiolate (0.17 g, 2.45 mmol) according to the method of Preparation 23. The residue was purified using Isolera® Purification System (0% to 20%, hexane-ethyl acetate) to give 0.61 g (90% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Solvent: CC(C)O
Product: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1

Procedure:
A solution of (S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (4 g, 17.60 mmol) in 2-propanol (10 mL) was added to a nitrogen purged suspension of 10% palladium on carbon (936 mg) in 2-propanol (240 mL) and the flask was charged with hydrogen gas (1 atm). After being stirred 18, the catalyst was removed by filtration over CELITE® and the filtrate concentrated. LC analysis showed the sample contained ˜14% of the trans isomer, and recrystallization from toluene enriched the cis isomer to 96% (16:1). LC-MS retention time 3.26 min; Calcd. for CHH20N6O4: 230.14 m/z Found 252.14 [M+Na]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® 2×5 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 90% methanol/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 4.21-4.17 (m, 1H), 3.76-3.67 (m, 1H), 2.96-2.92 (m, 1H), 2.49-2.46 (m, 1H), 2.30-2.29 (m, 1H), 1.59-1.51 (m, 1H), 1.47/1.43 (m, 9H), 1.10-1.06 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:30])[CH3:29])[C:23]=1[N:31]=[C:32]=[O:33])([CH3:21])[CH3:20]>C(#N)C>[CH3:21][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]([CH3:29])[CH3:30])[C:23]=1[NH:31][C:32]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=1)=[O:33])[CH3:20]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCCCCc1cc(N)on1
Solvent: CC#N
Product: CCCCCCCCCCCCc1cc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)on1
Temperature: -20 °C
Yield: 20.4 %

Procedure:
A slurry of 5-amino-3-dodecylisoxazole (1.44 g, 5.71 mmol) in acetonitrile (50 mL) was warmed until homogeneous. 2,6-Diisopropylphenylisocyanate (1.22 mL, 5.71 mmol) was then added in one portion and the resulting solution was heated under reflux for 24 hours. The resulting solution was cooled to -20° C. The resulting precipitate was collected by filtration, dissolved in a minimal amount of warm chloroform, and chromatographed on silica (70:30 hexane:ethyl acetate). The product containing fractions were concentrated and the resulting solid was recrystallized from acetonitrile to yield 0.53 g (20.4%) of the title compound as white needles, m.p. 112.5°-114° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[O:3]1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl>[Br:22][C:5]1[C:6](=[O:7])[C:2]([CH3:14])([CH3:1])[O:3][C:4]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(c2ccncc2)=CC1=O
Solvent: ClCCl
Product: CC1(C)OC(c2ccncc2)=C(Br)C1=O
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.81 g, 4.28 mmol) CHCl3 (20 mL), NBS (1.3 g, 7.28 mmol) was added portionwise at RT. The reaction mixture was then stirred for 2 h and diluted with DCM (100 mL). The organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.25 g, 21%) as a solid
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:18]([CH:19]=[CH2:20])=[CH:17][C:16]([C:21]#[N:22])=[CH:15][C:14]=1[NH:23][C:24]1[N:29]=[C:28]([NH:30][CH:31]2[CH2:33][CH2:32]2)[C:27]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:26]2[N:25]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:18]([CH:19]2[CH2:20][O:9]2)=[CH:17][C:16]([C:21]#[N:22])=[CH:15][C:14]=1[NH:23][C:24]1[N:29]=[C:28]([NH:30][CH:31]2[CH2:32][CH2:33]2)[C:27]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:26]2[N:25]=1
Reactant: C=Cc1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CO2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.9 %

Procedure:
Added MCPBA (70% wet, 3330 mg, 13.5 mmol) in portions to an ice-cooled suspension of 2-((2-chloro-5-cyano-3-vinylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 399)(339 mg, 0.900 mmol) in CHCl3 (90 mL). The bath was removed and the reaction was left stirring at room temperature for 2 days. This was diluted with CHCl3 and washed with 5% aq. NaHSO3 solution and then 3 times 1 N Na2CO3 solution. After drying with sodium sulfate, the solvent was removed and radial silica gel chromatography eluting with DCM containing 0 to 10% EtOAc afforded 2-((2-chloro-5-cyano-3-(oxiran-2-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (293 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2nc3ncccc3o2)c1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc(-c2nc3ncccc3o2)c1

Procedure:
A solution of 0.63 g. of 2-(3-aminophenyl)oxazolo[4,5-b]pyridine in 10 ml. of pyridine was treated with 0.35 ml. of acetic anhydride with stirring. After stirring over the weekend the mixture was diluted to 50 ml. with water. After stirring a short time and cooling, the precipitate was collected, washed with water and dried. Recrystallization from ethyl acetate gave 2-(3-acetamidophenyl)oxazolo[4,5-b]pyridine, m.p. 201.5°-202.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C:6](=[O:10])[CH2:7][C:8]#[N:9].[CH3:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[C:16]([CH3:15])=[CH:17][C:18]([CH3:19])=[C:7]([C:8]#[N:9])[C:6]1=[O:10]
Reactant: N#CCC(=O)NCc1ccccc1Cl
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)n(Cc2ccccc2Cl)c(=O)c1C#N
Yield: 87 %

Procedure:
A solution of N-(2'-chlorobenzyl)-2-cyanoacetamide 179 g. (0.86 mole) and 2,4-pentanedione 86 g. (0.86 mole) in 500 ml. of 95% ethanol containing 10 ml. of piperidine is refluxed for 24 hours, after cooling the white crystalline product is isolated by vacuum filtration washed with ether and dried in vacuo to give 237.3 g. (87% yield) mp>250° C.;ν2210 (CN) and 1650 cm.-1 (C=O).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][NH2:20])[CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C.O>C1COCC1.C(OCC)(=O)C>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:20][CH2:19][CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=2)[N:7]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1cnc(NCCc2cccc(Cl)c2)nc1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
A mixture of 2,4-dichloropyrimidine-5-carbonitrile (5.0 g, 28.90 mmol), 2-(3-chlorophenyl)ethanamine (4.78 g, 28.9 mmol) and DIEA (7.45 g, 57.8 mmol) in THF (50 mL) was stirred at 50° C. for 3 h. After cooling to room temperature, water (80 mL) was added and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated aqueous ammonium chloride, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuum to give the crude product, which was treated with ethyl acetate (30 mL) and stirred for 30 min. The mixture was filtered and dried to afford the title compound (3.20 g, 10.92 mmol, 38% yield). MS (ESI) m/z 293.1, 294.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]#[N:5])[C:2]#[N:3].C(OC(=O)C)(=O)C.[CH2:13]([C:15]1[O:16][C:17]([CH2:28][CH3:29])=[C:18]([CH2:25]CC)[C:19](=O)[C:20]=1[CH2:21]CC)[CH3:14]>O>[CH2:28]([C:17]1[O:16][C:15]([CH2:13][CH3:14])=[C:20]([CH3:21])[C:19](=[C:1]([C:4]#[N:5])[C:2]#[N:3])[C:18]=1[CH3:25])[CH3:29]
Reactant: CCCc1c(CC)oc(CC)c(CCC)c1=O
Reactant: N#CCC#N
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCC1=C(C)C(=C(C#N)C#N)C(C)=C(CC)O1
Yield: 47 %

Procedure:
To a solution of 0.33 g (5 mmol) of malonodinitrile in 2.4 ml (25 mmol) acetic anhydride 1.20 g (5 mmol) of 2,6-diethyl-3,5-dipropyl-pyran-4-one (prepared according to J. Chem. Soc (C), 1967, 828-830) was added. After addition of 150 ml of water the resulting solution was extracted twice with ether (50 ml). The combined organic phases were washed with water (2×50 ml) and with saturated NaCl-solution (1×30 ml). After drying (Na2SO4), the solvent was evaporated (HV) and the crude product was purified via FC (n-hexane/EtOAC 7:3) yielding 0.54 g (47%) of 2-(2,6-diethyl-3,5-dimethylpyran-4-ylidene)malononitrile as a brown solid.
Reaction SMILES: [NH:1]1[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>[OH-].[Na+]>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:1]2[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])=[O:19])=[CH:13][CH:12]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1ccc(Cl)cc1
Temperature: -1 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
9.4 g (71.685 mmol) of L-hydroxyproline are dissolved in 71.68 ml of NaOH solution (c=1 mol/l) at from −2 to 0° C., a solution of 11.008 g (71.685 mmol) of 4-chlorophenyl isocyanate in 70 ml of IBMK is subsequently added, and the mixture is stirred at −1° C. for 1 hour. Conventional work-up gives 18.52 g of (2S,4R)-1-(4-chlorophenyl-carbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid;
Reaction SMILES: CSC[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[N:6]=1.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>>[CH3:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[N:6]=1
Reactant: CSCCc1nc(C(=O)O)cc2ccccc12
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: Cc1nc(C(=O)O)cc2ccccc12
Yield: 11 %

Procedure:
0.25 g (11% overall yield) of 1-methyl-isoquinoline-3-carboxylic acid was synthesized according to the procedure described for the synthesis of 1-(2-methylsulfanyl-ethyl)-isoquinoline-3-carboxylic acid (in Example 298) starting from 2.20 g (10 mmol) of phenylalanine methyl ester hydrochloride. LCMS: 188 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9](\[CH2:20][O:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)/[CH2:10][NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O.[OH-].[Li+]>O1CCCC1.O>[O:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH:11][CH2:10]/[C:9](/[CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:8]/[CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])[CH2:15][CH2:16]1
Reactant: COC(=O)CCCC/C=C(/CNCCN1CCOCC1)COc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCC/C=C(/CNCCN1CCOCC1)COc1cccc2ccccc12
Yield: 99.7 %

Procedure:
(Z)-Methyl-8-(2-morpholinoethylamino)-7-((naphthalen-1-yloxy)-methyl)oct-6-enoate (278 mg, 0.63 mmol) obtained in Example (3-1-1) was dissolved in tetrahydrofuran (2.52 ml) in a 25 ml vessel and stirred. To the resulting mixture, a solution of lithium hydroxide monohydrate (LiOH.H2O) (79 mg, 1.89 mmol, 3 eq.) dissolved in water (0.63 ml) was added and stirred at room temperature for 12 hrs. After the completion of reaction, the aqueous layer was washed with ethyl ester and acidified (pH 4) with 6N hydrochloric acid. The resultant was distilled under reduced pressure and extracted with ethyl acetate twice. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure. The residue thus obtained was purified with a silica gel column chromatography to obtain 268 mg of the title compound as pale yellow foam (100%).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1>CO.O>[C:1]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:10]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(C=O)c1
Reactant: c1ccc(C2=NCCN=C2c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: COc1cccc(Cc2cnc(-c3ccccc3)c(-c3ccccc3)n2)c1

Procedure:
The same procedures as in Example 3 were repeated using 2,3-diphenyl-5,6-dihydropyrazine and m-anisaldehyde. 2,3-Diphenyl-5-(m-methoxybenzyl)pyrazine was obtained as colorless prisms, m.p. 65°-66° C. (recrystallized from methanol-water). Physical properties of the product support a chemical structure of the below formula (IX).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1([C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1.CN(C)P(N(C)C)(N(C)C)=O.C([N-]C(C)C)(C)C.[Li+].[Cl-].[NH4+]>C1COCC1>[C:4]12([C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:8][C:7]([C:10]([O:12][CH3:13])=[O:11])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: COC(=O)C1CCC(CCCl)(C(=O)OC)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C12CCC(C(=O)OC)(CC1)CC2
Temperature: -78 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To a mixture of dimethyl 1-(2-chloroethyl)cyclohexane-1,4-dicarboxylate (116 g, 0.44 mol) and hexamethylphosphoramide (317 mL, 1.7 mol) in anhydrous THF (800 mL) was added freshly prepared lithium diisopropylamide (preparation described above) over 30 min at −40° C. The mixture was stirred for 2 h at −78° C. and then stirred overnight allowing warming to room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution (200 mL) and the mixture was stirred for 10 min. The volatile solvents were removed by evaporation under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×200 mL) and the combined extracts were washed with brine (300 mL×2) and dried over sodium sulfate. Concentration under reduced pressure gave crude product, which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to afford the title compound (58.0 g, 0.25 mol, yield 50% over two steps). 1H NMR (400 MHz, CDCl3): δ ppm 3.65 (s, 6H), 1.81 (s. 12H).
Reaction SMILES: CS(O[C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[CH2:7]1)(=O)=O.[C:42]([SH:45])(=[O:44])[CH3:43].[H-].[Na+].O>CN(C)C=O>[C:42]([S:45][C@@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][O:25][CH2:26][CH2:27][NH:28][C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[CH2:7]1)(=[O:44])[CH3:43]
Reactant: CC(=O)S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCCNC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)S[C@H]1C[C@@H](COCCNC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
A solution of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.90 g) in dimethylformamide (2 ml) was added to a reaction mixture of thioacetic S-acid (0.16 ml) and sodium hydride (62.8% in oil suspension) (0.07 g) in dimethylformamide (9 ml) in a nitrogen stream and the mixture was heated at 70°-75° C. for 6 hours. The mixture was poured into water (100 ml), extracted with ethyl acetate (50 ml×2), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with chloroform to give (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.60 g).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:22]1([CH:14]2[C:15]3([CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[O:21][C:6](=[O:7])[NH:13]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(c1ccccc1)C1(O)CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1NC(c2ccccc2)C2(CCOCC2)O1
Reaction time: 5 h

Procedure:
To a mixture of CDI (388 mg, 2.394 mmol) in THF (1.5 mL) was added slowly a solution of 4-(amino(phenyl)methyl)tetrahydro-2H-pyran-4-ol (451 mg, 2.176 mmol) in THF (3 mL). The mixture was stirred under argon for ˜5 hours. The mixture was diluted with saturated aqueous NaHCO3 solution and DCM. The separated aqueous layer was extracted with DCM (2×) and the combined organic layers were washed with 0.5N aqueous HCl solution and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 12 g, 0-100% heptane/ethyl acetate] providing 4-phenyl-1,8-dioxa-3-azaspiro[4.5]decan-2-one as a white solid. Yield: 330 mg. LCMS m/z 234.1 (M+H)+; Rt 0.52 min.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH2:29]([N:31]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[C:32]1=[O:49])[CH3:30].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:36]3[CH:37]=[C:38]4[C:33](=[CH:34][CH:35]=3)[C:32](=[O:49])[N:31]([CH2:29][CH3:30])[CH2:39]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCN1Cc2cc(-c3n[nH]c4cc(-c5c(F)c(OC)cc(OC)c5F)ncc34)ccc2C1=O
Temperature: 110 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
A mixture of 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (9 mg, 0.02 mmol), 2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (7.7 mg, 0.027 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (1 mg, 0.001 mmol), and sodium carbonate (5.7 mg, 0.054 mmol) in 1,4-dioxane (0.2 mL) and water (0.03 mL) was degassed and recharged with nitrogen three times. The mixture was stirred at 110° C. for 3 h. After cooling the solid was filtered off. The filtrate was concentrated. The residue was dissolved in methanol (0.5 mL). At r.t. to the solution was added HCl solution prepared previously from acetyl chloride (0.30 mL) and methanol (0.30 mL). The mixture was stirred at r.t. for 2 h, and purified by RP-HPLC (pH=10) to afford the desired product (5.6 mg). LCMS (M+H)+=451.1.
Reaction SMILES: [CH2:1]([O:8][C:9](/[N:11]=[C:12](/[C:18]([F:21])([F:20])[F:19])\[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(OCC)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([F:19])([F:20])[F:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(=N\C(=O)OCc1ccccc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)[C@@H](NC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl (2E)-2-{[(benzyloxy)carbonyl]imino}-3,3,3-trifluoropropanoate (2500 g, 8.25 mol) in diethyl ether (15 L) under a nitrogen atmosphere was added sodium borohydride (627 g, 16.5 mol) in several batches at 0° C. The reaction mixture was allowed to warm to ambient temperature. After 16 hours, the reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (3×2000 mL). The organic layers were combined, washed with brine (2×500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified via chromatography on silica gel (10% ethyl acetate/petroleum ether) to afford ethyl N-[(benzyloxy)carbonyl]-3,3,3-trifluoroalaninate.