Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=CC([N+]([O-])=O)=CC=1)=[O:3].[C:14](OCC)(=[O:17])[NH:15][NH2:16].CCN(CC)CC.[N:28]([CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH2:42])=[N+:29]=[N-:30]>C1COCC1.O>[N:28]([CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:14](=[O:17])[NH:15][NH:16][C:2]([O:4][CH2:5][CH3:10])=[O:3])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NNC(=O)NCCOCCOCCOCCN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To 4-nitrophenyl chloroformate (1008 mg, 5.00 mmol) in THF (17 mL) at 0° C. was added ethyl carbazate (0.521 g, 5 mmol) and Et3N (2.08 mL, 15.00 mmol). The mixture was stirred at 0° C. for 30 min. Then a solution of 11-azido-3,6,9-trioxaundecan-1-amine (1.09 ml, 5.50 mmol) in 2 mL THF, and the mixture was stirred at room temperature for 16 h. Water was added, extracted twice with AcOEt, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (40-100% AcOEt/heptane, then 5% MeOH/AcOEt), giving ethyl 16-azido-4-oxo-8,11,14-trioxa-2,3,5-triazahexadecan-1-oate (I-18a: 1.23 g, 71%) as a colorless oil. LC-MS (M+1) 349.4, t=1.63 minute.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH:13]=2)[NH:8][C:7]([CH3:24])([CH3:23])[CH:6]=1)=[N+]=[N-].C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>CCOCC>[NH2:1][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[CH:13]=2)[NH:8][C:7]([CH3:24])([CH3:23])[CH:6]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CN=[N+]=[N-])=CC(C)(C)N2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1-c1ccc2c(c1)C(CN)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A round bottom flask equipped with a stir bar was charged with 4-azidomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline (0.565 mmol) and THF (4.2 mL). The system was placed under argon, after which PPh3 (0.621 mmol, 1.1 equiv) and water (0.621 mmol, 1.1 equiv) were added. The reaction was stirred overnight at room temperature. The crude reaction mixture was diluted with ether and filtered through diatomaceous earth until no more precipitate formed. The diatomaceous earth was washed well with ether. The organic layer was acidified with concentrated HCl affording a white fluffy precipitate which then oiled out. This layer was diluted with water and separated from the aqueous layer. The aqueous layer was then neutralized with Na2CO3 and extracted with methylene chloride. The organic extracts were combined and concentrated in vacuo to afford 122 mg of 4-aminomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][C:2]1=[C:7]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[CH2:8][CH2:9][C:10]([O:12]C)=[O:11].O>O1CCCC1.C(O)C.[OH-].[Na+]>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][C:2]1=[C:7]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)CCC(=C1SCCCS1)c1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC(=C1SCCCS1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Methyl 4-(1,3-dithian-2-ylidene)-4-(4-phenoxyphenyl)-butyrate, 1.29 g, was dissolved in a solvent mixture of 30 ml of tetrahydrofuran and 30 ml of ethanol and, 10 ml of 1 N sodium hydroxide aqueous solution was added to the solution followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture. After washing with ethyl acetate, the aqueous phase was rendered acidic with conc. hydrochloric acid and extracted with ethyl acetate. After drying the ethyl acetate phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was crystallized from ether to give 1.21 g of white crystals.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5]([CH3:17])(C)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)(=O)[CH3:21].[CH2:29]1COCC1>>[CH2:9]([O:8][C:6](=[O:7])/[CH:5]=[C:17](/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)\[CH3:29])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1.[CH2:9]([O:8][C:6](=[O:7])/[CH:21]=[C:20](\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)/[CH3:29])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1ccccn1
Reactant: C1CCOC1
Reactant: CC(C)(O[PH](=O)[O-])C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: C/C(=C/C(=O)OCc1ccccc1)c1ccccn1
Product: C/C(=C\C(=O)OCc1ccccc1)c1ccccn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of sodium hydride 60% dispersion in mineral oil (480 mg, 12 mmol, 1.2 eq.) in THF (20 mL) at 0° C., dimethyl(benzyloxycarbonyl)methyl phosphonate (2.14 ml, 10 mmol, 1.0 eq.) was added dropwise. The mixture was stirred at 0° C. for 15 min. 2-Acetyl pyridine (1.14 mL, 10 mmol, 1.0 eq.) was added dropwise. The mixture was slowly warmed up to r.t. and stirred at r.t. for 18 hours (the ice bath was let expire). The reaction mixture was quenched with sat. aq. NaHCO3 soln. (50 mL). The mixture was extracted with DCM (3×50 mL). The comb. org. phases were washed with sat. aq. NaCl soln., dried over MgSO4, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 40 fractions of 45 mL, Heptane 100% to Heptane+40% AcOEt) to yield (E)-3-pyridin-2-yl-but-2-enoic acid benzyl ester as a white solid (LC-MS 3: tR=0.84 min; 254.3) and (Z)-3-pyridin-2-yl-but-2-enoic acid benzyl ester (LC-MS 3: tR=0.63 min; 254.3) as a colorless oil (E/Z ratio ca. 55:13).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)C=O)=[CH:4][C:3]=1[CH3:26].C1(P(=[CH:46][CH:47]=[O:48])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:49]1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([CH3:25])[CH:19]=2)=[C:9]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)[CH:49]=[CH:46][CH:47]=[O:48])=[CH:4][C:3]=1[CH3:26]
Reactant: Cc1cc(C(=C(C=O)c2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Reactant: c1ccccc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1cc(C(=C(C=CC=O)c2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Yield: 93.3 %

Procedure:
To a mixture of 3,3-bis(4-fluoro-3-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal (2.12 g, 5.98 mmoles) and triphenylphosphoranylidene acetaldehyde (1.89 g, 6.22 mmoles) under an argon atmosphere was added dry benzene (26 mL). The suspension was quickly warmed to reflux under argon in an oil bath. The solids dissolved very rapidly at the reflux temperature and the color became dark brownish. The reaction was allowed to proceed at reflux temperature for a total of 60 minutes. Analytical TLC eluted ten times with 20% (v/v) ethyl acetate in hexanes showed the desired product at Rf =0.35. The crude reaction mixture was poured over a short bed of silica gel and eluted with 2 liters of 20% (v/v) ethyl acetate in hexanes to give 2.12 g (93.3%) of the title compound (TLC homogeneous). MS (CI): m/e=381 for (M+H)+.
Reaction SMILES: C([C@@H]1C[C@H](C2C=CC=C(Cl)C=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])C1=O)C=C.[C:35](#N)[CH3:36].I([O-])(=O)(=O)=O.[Na+].[C:44]([OH:56])(=[O:55])[CH2:45][C:46]([CH2:51][C:52](O)=O)([C:48]([OH:50])=O)O>O.CCOC(C)=O.O.[Ru](Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:28]([O:27][C:25](=[O:26])[C@@H:24]([N:6]1[C@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C@@H:52]([C:36]2[CH:35]=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH2:51][C@H:46]([CH2:45][C:44]([OH:56])=[O:55])[C:48]1=[O:50])[CH2:32][CH3:33])([CH3:29])([CH3:30])[CH3:31]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC#N
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC(C)(C)C)C1=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a rapidly stirring solution of 842 mg (1.67 mmol) of tert-butyl (2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl) butanoate (Example 1, Step G) in a mixture of 7 mL of water, 5 mL of acetonitrile and 5 mL of CCl4 was added sodium periodate (1.43 g, 6.70 mmol), followed by ruthenium(III) chloride hydrate (37.8 mg, 0.168 mmol). After being stirred vigorously for 18 h, the reaction was acidified (10% citric acid) and diluted with EtOAc. The reaction mixture was filtered through celite and the filtrate was extracted with EtOAc. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 60 to 80% acetonitrile +0.1% TFA in water +0.1% TFA, gradient elution) to give the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][CH:22]=[CH:23][C:16]=23)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[H-].[K+].I[CH3:27].Cl>CN(C)C=O.C(OCC)C.CCCCCC>[CH3:27][N:21]1[C:17]2=[N:18][CH:19]=[CH:20][C:15]([C:8]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:11][N:10]4[CH2:12][CH2:13][CH2:14][C:9]=34)=[C:16]2[CH:23]=[CH:22]1
Reactant: c1ccc(-c2nn3c(c2-c2ccnc4[nH]ccc24)CCC3)nc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cn1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc21
Yield: 79.3 %

Procedure:
Dissolve 4-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (Example 1; 0.150 g, 0.50 mmol) in N,N-dimethylformamide (10 ml). Add n-hexane (2 mL) and cool to 0° C. Add potassium hydride (35% suspension in mineral oil, 0.12 g, 1.0 mmol) and stir under nitrogen at 0° C. for 5 min. Add iodomethane (0.18 g, 1.3 mmol) and stir at 0° C. for 15 min. Dilute the reaction mixture by adding 1.0M aqueous hydrochloric acid (10 mL) and with excess diethyl ether. Extract the mixture with 0.2M aqueous hydrochloric acid. Combine the acidic aqueous extracts, add 5M aqueous sodium hydroxide until basic, and extract with dichloromethane. Concentrate the organic extracts under reduced pressure and purify via chromatography (silica gel, 95% ethyl acetate/5% methanol containing 0.1M ammonia) to obtain 0.125 g (79%) of the title compound as a cream colored solid. TOF MS (ES) exact mass calculated for C19H18N5 (p+H): m/z=316.1562, Found: 316.1536.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>>[S:18]1[CH:22]=[CH:21][C:20]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)=[CH:19]1
Reactant: OB(O)c1ccsc1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Oc1ccc2ncn(-c3ccsc3)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and thiophen-3-ylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=218.1 [M+H]+.
Reaction SMILES: C([N:3]1[C:7]([CH2:8]CN)=[N:6][N:5]=[N:4]1)C.[CH3:11][C:12]1[N:13]=NNN=1.C(I)C.C(OC(=O)NCCBr)(C)(C)C>>[CH3:8][C:7]1[N:6]=[N:5][N:4]([CH2:11][CH2:12][NH2:13])[N:3]=1
Reactant: CCn1nnnc1CCN
Reactant: Cc1nn[nH]n1
Agent: CC(C)(C)OC(=O)NCCBr
Solvent: CCI
Product: Cc1nnn(CCN)n1

Procedure:
This compound is prepared by an analogous procedure to intermediate CI2 by replacing [2-(1H-Tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester in step 1 with 5-Methyl-2H-tetrazole and by replacing ethyliodide with (2-Bromo-ethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11]Br)=[O:4].[F:26][C:27]1([F:35])[CH2:33][CH:32]2[NH:34][CH:28]1[CH2:29][O:30][CH2:31]2>>[Cl:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C@H:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH2:11][N:34]2[CH:28]3[C:27]([F:35])([F:26])[CH2:33][CH:32]2[CH2:31][O:30][CH2:29]3)[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7]1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: FC1(F)CC2COCC1N2
Product: COC(=O)C1=C(CN2C3COCC2C(F)(F)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Yield: 5.2 %

Procedure:
The title compound was prepared in analogy to Example 1a in Scheme 3 by using methyl (4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (compound C, 100 mg) and 6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octane 108a (200 mg). 6 mg of the title compound was isolated as yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15](=[O:16])[CH2:14][O:12][N:11]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: NO
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Product: CC(C)(C)OC(=O)CON=Cc1ccc(F)cc1
Yield: 84 %

Procedure:
Condensation of 4-fluorobenzaldehyde with hydroxylamine hydrochloride using the same procedure as Compound 44-A followed by reaction with tert-butyl bromoacetate gave the title oxime ether as a clear oil (84% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.52 (9H, s, t-Bu), 4.61 (2H, s, OCH2), 7.08 (2H, m, aromatics), 7.59 (2H, m, aromatics), 8.19 (1H, s, CH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:5][CH:6]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:8]([CH2:9][CH2:10]2)[CH2:7]1.[CH2:24](N(CC)CC)C.IC.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:5][CH:6]1[CH2:7][CH:8]2[N:13]([CH2:14][C:15]3[N:19]([CH3:24])[N:18]=[N:17][N:16]=3)[CH:11]([CH2:10][CH2:9]2)[CH2:12]1
Reactant: Clc1ccc(OC2CC3CCC(C2)N3Cc2nnn[nH]2)cc1Cl
Reactant: CCN(CC)CC
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnnc1CN1C2CCC1CC(Oc1ccc(Cl)c(Cl)c1)C2

Procedure:
3-(3,4-Dichloro-phenoxy)-8-(1H-tetrazol-5-ylmethyl)-8-aza-bicyclo[3.2.1]octane (5 g) in 50 ml of N,N-dimethylformamide was added 3 ml of triethylamine and stirred under a nitrogen atmosphere. Iodomethane (2 ml) was added drop wise. The reaction mixture was stirred at room temperature overnight and poured into 100 ml of water. The mixture was extracted with diethyl ether, which was dried with magnesium sulphate and evaporated to an oil, the oil was triturated in dry diethyl ether. Yield 0.55 g (11%) Mp. 119-120° C.
Reaction SMILES: [CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:20](S)CCCCC>>[CH2:1]([S:6][C:7]1[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:20]
Reactant: CCCCCCS
Reactant: CCCCCSc1c[nH]nc1C1CN2CCC1CC2
Product: CCCCCCSc1c[nH]nc1C1CN2CCC1CC2
Yield: 25 %

Procedure:
Compound 49F was prepared following the procedure as described for the synthesis of compound 49B (see Scheme 10) using hexane-1-thiol as reagent. Subsequent purification by flash chromatography (EtOH) afforded compound 49F.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12]Cl)(=[O:3])[CH3:2].[C-:14]#[N:15].[Na+]>CS(C)=O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:14]#[N:15])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccccc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)OCc1ccccc1CC#N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a glass-made three-necked flask (volume: 100 ml) with a condenser, 50.0 g of [2-(chloromethyl)phenyl]methyl acetate (purity: 89%) and 50.0 g of dimethyl sulfoxide were added, and the mixture was heated to 80° C. Thereto, 50.0 g of a 34 wt % aqueous sodium cyanide solution was added dropwise while stirring over one hour. After completion of the dropwise addition, the mixed solution was continuously stirred for one hour while keeping the temperature at 80° C. The reaction mixture obtained was analyzed by the gas chromatography. As a result, the amount of [2-(cyano-methyl)phenyl]methyl acetate produced was 34.0 g (180 mmol) and the yield was 80 mol % based on [2-(chloromethyl)-phenyl]methyl acetate. Also, it was verified that 3.6 g (24 mmol) of [2-(hydroxymethyl)phenyl]acetonitrile which is a precursor of 3-isochromanone was produced.
Reaction SMILES: [C:1]1([C:7]2[CH:18]=[CH:17][C:10]([O:11][CH2:12][CH2:13][C:14](O)=[O:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=CC([O:29]C(C)CC(O)=O)=CC=2)C=CC=CC=1.[NH3:38]>>[C:1]1([C:7]2[CH:18]=[CH:17][C:10]([O:11][CH2:12][CH2:13][C:14]([NH:38][OH:29])=[O:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(CC(=O)O)Oc1ccc(-c2ccccc2)cc1
Reactant: N
Reactant: O=C(O)CCOc1ccc(-c2ccccc2)cc1
Product: O=C(CCOc1ccc(-c2ccccc2)cc1)NO

Procedure:
The desired compound was prepared according to the method of Example 1, step 3, except substituting 3-(4-phenylphenoxy)propionic acid, prepared as in step 1, for 3-(4-phenylphenoxy)butanoic acid. 1H NMR (DMSO-d6) δ 2.44 (t, 2H, J=7 Hz), 4.22 (t, 2H, J=7 Hz), 7.01 (d, 2H, J=6 Hz), 7.31 (t, 1H, J=5 Hz), 7.42 (t, 2H, J=5 Hz), 7.61 (m, 4H), 8.88 (bds, 1H, 10.53 (s, 1H). MS (DCI/NH3) 275 (M+NH4+, 100). Anal. Calcd for C15H15NO3 ·0.25 H2O: C, 68.82; H, 5.36; N, 5.70. Found: C, 68.78; H, 5.27; N, 5.18.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]2[N:12]([CH:13]=1)[CH2:11][CH2:10][S:9]2(=[O:15])=[O:14])(=O)C.N>>[OH:4][CH2:5][C:6]1[N:7]=[C:8]2[N:12]([CH:13]=1)[CH2:11][CH2:10][S:9]2(=[O:15])=[O:14]
Reactant: CC(=O)OCc1cn2c(n1)S(=O)(=O)CC2
Agent: N
Product: O=S1(=O)CCn2cc(CO)nc21
Reaction time: 2.5 h

Procedure:
6-Acetoxymethyl-2,3-dihydroimidazo[2,1 -b]thiazole-1,1-dioxide (305 mg, 1.33 mmol) was treated with methanolic ammonia (prepared by saturating methanol (20 ml) with ammonia gas then diluting with more methanol (20 ml)) at room temperature. After 2.5 h, the volatiles were removed under reduced pressure and the residue triturated with diethyl ether and the resulting solid collected by filtration, washed with diethyl ether and dried in air (207 mg, 83%) (Found: M+ 188.0256. C6H8 N2O3S requires M 188.0256); nmax (nujol) 3354, 1377, 1325 and 1133 cm-1 ; dH [250MHz; (CD3)2SO] 4.14 (2H, t, J 6Hz), 4.40 (2H, d, J 6Hz), 4.54 (2H, t, J 6Hz), 5.20 (1H, t, J 6Hz, exchangeable), 7.36 (1H, s).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:12](=[O:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:10][C:9]3[CH:22]=[CH:23][CH:24]=[N:25][C:8]2=3)[CH:2]=1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.O1CCOCC1.C(OCC)(=O)C>[C:39]([O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[C:12](=[O:13])[N:7]([C:3]3[CH:2]=[C:1]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:6]=[CH:5][CH:4]=3)[C:8]3[N:25]=[CH:24][CH:23]=[CH:22][C:9]=3[N:10]=2)=[CH:20][CH:19]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c(Cc2ccc(O)cc2)nc2cccnc2n1-c1cccc(-c2ccccc2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(Cc2nc3cccnc3n(-c3cccc(-c4ccccc4)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(3-biphenylyl)-2-(4-hydroxybenzyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (76 mg), triethylamine (0.05 ml) and 4-dimethylaminopyridine (3 mg) in 1,4-dioxane (2 ml) was added acetic anhydride (0.035 ml). The mixture was stirred at room temperature for 1 hour, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to give 2-(4-acetoxybenzyl)-4-(3-biphenylyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (58 mg).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]12([C:23](=[O:53])[CH2:24][N:25]3[C:30](=[O:31])[C:29]4[CH:32]=[C:33]([CH2:35][CH3:36])[S:34][C:28]=4[N:27]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([C:44]5[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=5)=[CH:40][CH:39]=4)[C:26]3=[O:52])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>O.C(OCC)(=O)C>[C:13]12([C:23](=[O:53])[CH2:24][N:25]3[C:30](=[O:31])[C:29]4[CH:32]=[C:33]([CH2:35][CH3:36])[S:34][C:28]=4[N:27]([CH2:37][C:38]4[CH:39]=[CH:40][C:41]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=5[C:50]5[NH:3][C:4](=[O:7])[O:5][N:51]=5)=[CH:42][CH:43]=4)[C:26]3=[O:52])[CH2:20][CH:19]3[CH2:21][CH:15]([CH2:16][CH:17]([CH2:18]3)[CH2:22]1)[CH2:14]2
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)C34CC5CC(CC(C5)C3)C4)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)C34CC5CC(CC(C5)C3)C4)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogencarbonate (1.02 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C. for 30 min, 4′-{[3-[2-(1-adamantyl)-2-oxoethyl]-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.68 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (6 mL). N,N′-Carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.46 g, 62%).
Reaction SMILES: [Zn:1].[CH2:2]([Br:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[Br-:9].[CH2:2]([Zn+:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: [Zn]
Product: [Br-]
Product: [Zn+]Cc1ccccc1

Procedure:
Using the procedure of Example 1, 2.9 g of electrolytic zinc and 4.8 ml of benzyl bromide were reacted.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]([NH2:25])[CH3:24])=[CH:22][C:17]=2[NH:16][CH2:15][CH2:14]1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]([NH:25][C:6](=[O:8])[CH:5]=[CH:4][C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=3[F:1])[CH3:24])=[CH:22][C:17]=2[NH:16][CH2:15][CH2:14]1
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CC(N)c1ccc2c(c1)NCCO2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1ccccc1F)c1ccc2c(c1)NCCO2
Reaction time: 72 h

Procedure:
A mixture of 2-fluorocinnamic acid (0.5 mmol), (±)-1-(3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethylamine, Preparation 13 (28.5 mg, 0.16 mmol), EDC hydrochloride (192 mg, 1 mmol), DMAP (61 mg, 0.5 mmol), and triethylamine (202 mg, 2 mmol) in CH2Cl2 was stirred for 3 days. The reaction mixture was directly subjected to purification by flash column chromatography on silica using EtOAc/Hexane (8:1) to provide the desired product (149 mg).