Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([N:11]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]([CH2:23][CH3:24])[C:14](=[O:25])[CH2:13][O:12]1)=O)C1C=CC=CC=1.[C:26](OC(=O)C)(=O)C>[Pd]>[C:9]([N:11]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]([CH2:23][CH3:24])[C:14](=[O:25])[CH2:13][O:12]1)(=[O:8])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1C(=O)CON(C(=O)OCc2ccccc2)C1c1ccccc1
Agent: [Pd]
Product: CCN1C(=O)CON(C(C)=O)C1c1ccccc1
Yield: 82 %

Procedure:
0.69 g. (2 mmoles) of 2-benzyloxycarbonyl-3-phenyl-4-ethyl-tetrahydro-1,2,4-oxadiazin-5-one are dissolved in 7 ml. of acetic anhydride, 0.1 g. of a 5%, palladium-on-activated carbon catalyst are added and hydrogen gas is bubbled through the mixture at room temperature under vigorous stirring. The progress of hydrogenation is monitored by thin layer chromatography. As soon as the reaction is complete, the catalyst is filtered off, the filtrate is evaporated to dryness under reduced pressure and the residue is recrystallized from 1 ml. of ethanol. 0.41 g. (82%) of 2-acetyl-3-phenyl-4-ethyl-tetrahydro-1,2,4-oxadiazin-5-one are obtained, melting at 130° C. to 132° C. RfA =0.6.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:11].[C:12](=O)([O-])[O-:13].[K+].[K+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[O:13]=[C:12]1[NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[S:11]1
Reactant: Nc1ccc(C(=O)O)cc1S
Reactant: O=C([O-])[O-]
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]c(=O)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
4-Amino-3-mercaptobenzoic acid (680 mg) was dissolved in tetrahydrofuran (20 ml), and potassium carbonate (550 mg) was added thereto and stirred for 30 minutes at room temperature. The mixture was cooled to −78° C., and triphosgene (400 mg) was added thereto and stirred for 1 hour. The mixture was warmed to room temperature and concentrated under reduced pressure until the volume of the solvent became ⅓. Water (20 ml) and formic acid were added to the concentrate until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (740 mg, Y.:95%) as white crystals.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]([C@@H:10]([OH:16])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CCCCC.CN(C=O)C>[CH2:18]([O:16][C@H:10]([C@@H:4]([O:3][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCI
Reactant: CN(C)C(=O)[C@H](O)[C@@H](O)C(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CCCCCCCCCCCCO[C@@H](C(=O)N(C)C)[C@@H](OCCCCCCCCCCCC)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.4 %

Procedure:
Sodium hydride (3.60 g, 60%, 90.0 mmol) was washed with pentane (3×) before DMF (150 ml) and (+)-(2R,3R)-2,3-dihydroxy-N,N,N′,N′-tetramethylsuccinamide (9.2 g, 45.0 mmol, origin: Aldrich) were added. The reaction mixture was left stirring at room temperature for 90 min, then a solution of 1-iodododecane (28.0 g, 94.5 mmol) in DMF (50 ml) was added. The reaction was left stirring for another 2 h at room temperature and then heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was extracted with ether (4×), washed with water (2×), dried (Na2SO4), and concentrated. Column chromatography (SiO2, dichloromethane/acetone 3:1) gave 5.93 g (28%) of a pale-yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=O)[C:3]1=[O:13].[CH2:14]([NH2:17])[CH2:15][NH2:16]>>[NH2:16][CH2:15][CH2:14][NH:17][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13]
Reactant: NCCN
Reactant: CCOC(=O)CN1CCC(O)C1=O
Product: NCCNC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3.5 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate and 11.2 g of 1,2-ethylenediamine is left to stand at room temperature for 20 hours. The excess 1,2-ethylenediamine is evaporated in vacuo. The residue is dissolved in 40 ml of hot acetonitrile and stirred at room temperature for 2 hours and then in an ice-bath for 1 hour. By filtration there is isolated N-[2-(amino)ethyl]-2-(3-hydroxy-2oxo-1-pyrrolidinyl)acetamide of melting point 110°-112°.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:23][C@@H:24]([C:26]([OH:28])=[O:27])[CH3:25].C[O-].[Na+]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2[C:8]3[C:9](=[CH:10][N:11]=[C:6]([C:4]([NH:23][C@H:24]([CH3:25])[C:26]([OH:28])=[O:27])=[O:5])[C:7]=3[OH:22])[S:12][N:13]=2)=[CH:20][CH:19]=1
Reactant: C[C@@H](N)C(=O)O
Reactant: CCOC(=O)c1ncc2snc(-c3ccc(Cl)cc3)c2c1O
Agent: C[O-]
Agent: [Na+]
Product: C[C@@H](NC(=O)c1ncc2snc(-c3ccc(Cl)cc3)c2c1O)C(=O)O
Yield: 69.6 %

Procedure:
A mixture of 3-(4-Chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (50 mg, 0.149 mmol), D-alanine (400 mg, 4.49 mmol) and NaOMe (7.45 mL, 3.72 mmol, 0.5 M solution in MeOH) was refluxed for 48 h before it was concentrated in vacuo. The residue was dissolved in water (50 mL) and washed with CH2Cl2 (2×20 mL). The aqueous solution was then acidified by addition of 1N HCl solution. The resulting precipitate was sucked off, washed with water, and dried in vacuo to give the title compound as a white solid (39.2 mg): MS (m/z) 376.0 (M−1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5([C:31]#[N:32])[CH2:30][CH2:29]5)[CH:23]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH3:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[CH2:35][C:36](Cl)=[O:37].O.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>CN(C)C=O>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:36](=[O:37])[CH2:35][N:44]5[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]5)[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)CN3CCN(C)CC3)sc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
A solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (91 mg, 0.20 mmol)) produced in Example A18(iv) and chloroacetyl chloride (113 mg, 1.00 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1) to give a colorless oil. This was dissolved in N,N-dimethylformamide (2 mL), 1-methylpiperazine (100 mg, 1.00 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel chromatography (eluent:ethyl acetate/methanol=10:1), and triturated with diethyl ether to give the title compound (47 mg, 39%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11]O)[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1[SH:49]>ClCCl.O>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][S:49][C:40]3[CH:41]=[CH:42][C:43]4[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:39]=3)[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1
Reactant: OCc1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: Sc1ccc2ccccc2n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Brc1cnc(N2CCOCC2)c2nc(CSc3ccc4ccccc4n3)cn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of compound 1e (10 g, 30.45 mmol) and DIPEA (10.23 g, 79.30 mmol) in dichloromethane (200 mL) was cooled in an ice bath and MsCl (7.3 g, 63.48 mmol) was added dropwise. Upon complete addition, the reaction mixture was stirred for 3 h at room temperature and concentrated under reduced pressure. To the residue was added CH3CN (150 mL), followed by potassium carbonate (6.57 g, 47.6 mmol) and quinoline-2-thiol (5.62 g, 34.9 mmol). The resulting mixture was stirred overnight at 60° C. and allowed to cool to rt. Water (300 mL) was then added. The solids were collected by filtration. The crude product was recrystallized from DCM/ethyl ether (1:2 v/v) to obtain compound 78a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C20H18BrN5OS: 457.1 (M+H). found: 457.0
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[NH:3][CH:2]=1.CO[C:21]([CH3:23])=[CH2:22].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[N:1]1[CH:5]=[C:4]([CH2:6][N:7]([CH:21]([CH3:23])[CH3:22])[C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=2)[NH:3][CH:2]=1
Reactant: FC(F)(F)Oc1ccc(NCc2cnc[nH]2)cc1
Reactant: C=C(C)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(Cc1cnc[nH]1)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a solution of (3H-imidazol-4-ylmethyl)-(4-trifluoromethoxy-phenyl)-amine (0.39 g, 1.5 mmol) in 1,2-dichloroethane (5 ml) were added successively 2-methoxypropene (0.16 g, 2.25 mmol), trifluoroacetic acid (0.26 g, 2.25 mmol) and sodium triacetoxyborohydride (0.48 g, 2.25 mmol). After stirring the mixture overnight at 60° C. 1 M sodium hydroxide solution (5 ml) was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (heptane/ethyl acetate=1:1) to yield a white solid (0.24 g, 53%); MS (ISP): 300.1 ((M+H)+.).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].N1CCC[CH2:17]1>>[CH2:11]([N:13]([CH2:14][CH3:15])[CH2:17][C:9]#[C:8][CH2:7][N:4]1[CH:5]=[CH:6][N:2]([CH3:1])[C:3]1=[O:10])[CH3:12]
Reactant: CCNCC
Reactant: C#CCN1CCN(C)C1=O
Reactant: C1CCNC1
Product: CCN(CC)CC#CCn1ccn(C)c1=O

Procedure:
This product, a liquid, was prepared according to Example 1, Part B by substituting 1,3-dihydro-1-methyl-3-(2-propynyl)-2H-imidazol-2-one for 1-methyl-3-(2-propynyl)-2-imidazolidinone and diethylamine for pyrrolidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:28][C:29]([F:34])([F:33])[C@H:30]1[CH2:32][O:31]1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C@@:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([NH2:20])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1.[F:28][C:29]([F:34])([F:33])[C@H:30]([OH:31])[CH2:32][NH:20][C@@:12]([C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=1)([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)[C@H]1CO1
Agent: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Solvent: CC#N
Product: O[C@H](CN[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 160 °C
Yield: 92.2 %

Procedure:
(R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine was prepared as described in Procedures 4, 5 and 6. (R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (50 mg, 0.133 mmol) was dissolved in anhydrous acetonitrile (0.26 mL). (R)-2-(trifluoromethyl)oxirane (0.07 mL, 0.625 mmol), (approximate 85:15 ratio of R to S) was added to the solution in a microwave vial followed by Yb(OSO2CF3)3 (0.005 g, 0.008 mmol). The sealed vial was heated to 160° C. for 30 minutes under microwave irradiation. The crude product was purified by preparative HPLC using 30-100% acetonitrile in H2O with 0.1% TFA as mobile phase to give (R)-1,1,1-trifluoro-3-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)propan-2-ol as a colorless oil (30 mg, 46% yield). LC-MS (ESI): 361.15 (M+H), retention time=4.10 min (0-100% MeOH in H2O with 0.1% TFA); Analytical HPLC: 3.49 min (CH3CN in H2O with 0.1% TFA in 4 min run, purity 100%); 1H NMR (400 MHz, CD3OD) δ ppm 2.59-2.73 (m, 1H), 2.72-2.84 (m, 1H), 3.69 (m, 2H), 4.09 (m, 1H), 6.61-6.82 (m, 2H), 7.00-7.19 (m, 5H), 7.20-7.48 (m, 5H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25]C=C)[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32][CH2:33]Cl.[C:37](#N)C>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[C:24]=1[CH3:37])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Si:1]([O:18][CH2:19][C:20]1[N:21]([CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[CH:22]=[N:23][C:24]=1[CH3:37])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCn1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC#N
Product: Cc1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncn1COCC[Si](C)(C)C
Product: Cc1ncn(COCC[Si](C)(C)C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C

Procedure:
The mixture (35.4 g) obtained in (1) was dissolved in acetonitrile (500 mL), followed by addition of TEA (37.8 mL) and then 2-trimethylsilylethoxymethyl chloride (hereinafter, also referred to as SEMCl) (21.4 mL) while stirring under ice cooling, followed by stirring at 70° C. for 12 hours. The reaction mixture was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, subsequently washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by flash chromatography (ethyl acetate/hexane=15%→50%) using silica gel column (product name: cartridge 65i, manufactured by Biotage, Ltd.) to afford 4-(tert-butyldiphenylsilyloxymethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)-1H-imidazole (17.9 g) as a low polar component, and 5-(tert-butyldiphenylsilyloxymethyl)-4-methyl-1-(2-trimethylsilylethoxymethyl)-1H-imidazole (9.42 g) as a high polar component.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:18]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][OH:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:29][CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:26]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OCc1cccc(Oc2ccccc2)c1
Product: N=C(OCc1cccc(Oc2ccccc2)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and m-phenoxybenzyl alcohol, there is obtained m-phenoxybenzyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e:M+ 420 (14), 327 (13), 237 (35), 194 (100);
Reaction SMILES: C1([C@@H]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]3)[CH2:10]2)C)C=CC=CC=1.CC(O)=O.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[C@@H:16]12[NH:9][CH2:10][C@@H:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2
Reactant: C[C@@H](c1ccccc1)N1C[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H]2CN[C@H]2C1
Yield: 75 %

Procedure:
To a solution of (1R,6S)-tert-butyl 8-((S)-1-phenylethyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.5 g, 75%) in EtOH (50 mL) was added AcOH (1.5 mL). The resulting mixture was cycled through an H-Cube containing a 20% Pd(OH)2/C catalyst cartridge at 50° C. and 100 bar of hydrogen pressure. After 16 hours the resulting mixture was removed from the H-Cube and poured over a saturated sodium carbonate solution (100 mL). The aqueous layer was extracted with DCM (50 mL) four times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (755 mg, 75%) which was used in the next step without purification. MS (ESI) mass calcd. for C11H20N2O2, 212.2; m/z found, 213.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 4.21-4.02 (m, 1H), 3.84-3.59 (m, 3H), 3.47-3.36 (m, 1H), 3.33 (dd, J=8.3, 4.4 Hz, 1H), 3.28-3.20 (m, 1H), 2.91-2.71 (m, 2H), 1.94-1.81 (m, 1H), 1.81-1.68 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:12])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].[C:23](Cl)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+].C(OCC)(=O)C>N1C=CC=CC=1.CCCCCC>[C:23]([O:1][CH:2]([CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)=[O:12])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: C=CCOC(=O)C(O)CCC(=O)OCc1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: C=CCOC(=O)C(CCC(=O)OCc1ccc(OC)cc1)OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Allyl 2-hydroxy-5-[(4-methoxybenzyl)oxy]-5-oxopentanoate (1.26 g, 4.09 mmol) obtained from Example 2-(2) was dissolved in pyridine (15 ml) at 0° C., and acetyl chloride (481.2 mg, 6.13 mmol) was added thereto. The mixture was warmed to room temperature and stirred for 30 minutes, and then, after cooling to 0° C., a saturated aqueous solution of sodium hydrogen carbonate was added thereto followed by extraction of the product with ethyl acetate. The organic layer was washed with a dilute aqueous solution of hydrochloric acid and with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to give an oily residue. The residue was subjected to chromatography on a silica gel (60 g) column (eluent; ethyl acetate:hexane=1:5) to afford the title compound (1.36 g, 95% yield) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.[CH3:15][NH:16][C:17]([NH2:19])=[S:18].N12CCCN=C1CCCCC2.CS(O)(=O)=O>C(O)C.O>[SH:18][C:17]1[N:16]([CH3:15])[C:9](=[O:11])[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:19]=1
Reactant: CNC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: CS(=O)(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCO
Product: Cn1c(S)nc(-c2ccncc2)cc1=O
Yield: 76.5 %

Procedure:
A mixture containing 70.0 g (0.36 mol) of ethyl 3-(4-pyridinyl)-3-oxopropionate, 98.1 g (1.09 mol) of N-methylthiourea, 55.0 g (0.36 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 551 ml of ethanol is heated under reflux during 2 h. The cooled mixture is treated with 34.9 ml (0.36 mol) of methanesulfonic acid in 143.6 ml of water and the precipitate recovered by filtration to afford 60.4 g of pure product as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>O1CCCC1>[C:21]([O:20][C:18](=[O:19])[CH2:17][O:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (704 mg, 60% in mineral oil, 17.6 mmol) was added to an ice-cooled solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (J. Med. Chem. 1998, 41(25), 4983) (5 g, 26.7 mmol) in tetrahydrofuran (100 ml), and the mixture was allowed to warm to room temperature and stirred for 20 minutes. tert-Butyl bromoacetate (5.2 g, 26.7 mmol) was added and the mixture was heated under reflux for 18 hours, then cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the phases separated. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 20:80) to afford the title compound, 1.95 g.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Br-:1].[C:5]([CH2:4][CH2:3][CH2:2][P+:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([OH:7])=[O:6]
Reactant: O=C(O)CCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solid mixture of 4-bromobutyric acid (100 g, 0.60 mol) and triphenylphosphine (157.1 g, 0.60 mol) was reacted at 140° C. (oil bath temperature) under argon for 3 hours. When heat was first applied, both solid starting materials melted to form a homogeneous solution. After a few minutes of heating, extensive precipitation occurred. After cooling to room temperature, a rock-hard solid was broken up, suspended in 250 mL of refluxing chloroform under argon, and diluted with 800 mL of ether. Stirring at room temperature was carried out for 30 minutes. The suspension was cooled to 0° C. (ice bath temperature), and the product was collected by filtration and washed with ether. Yield: 218.12 g.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:19])=[CH:9][C:10]=3[N+]([O-])=O)[C:5](=[O:20])[C:4]=2[CH:3]=1.[F-:21].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:19])=[CH:9][C:10]=3[F:21])[C:5](=[O:20])[C:4]=2[CH:3]=1
Reactant: [F-]
Reactant: O=c1c2cc(Br)ccc2oc2c([N+](=O)[O-])cc(Cl)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2oc2c(F)cc(Cl)nc12
Reaction time: 0.25 h

Procedure:
To a solution of 8-bromo-2-chloro-4-nitro-10H-chromeno[3,2-b]pyridin-10-one (80 mg, 0.225 mmol) in 0.8 mL of DMF at 0° C. was added tetrabutylammonium fluoride (1M in THF, 0.45 mL, 0.450 mmol) dropwise. After 15 minutes, the reaction was quenched with saturated NH4Cl (20 mL) and extracted with ethyl acetate (2×10 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. Purification of the crude residue by column chromatography (SiO2, CH2Cl2 to CH2Cl2/EA=100:3) gave 8-bromo-2-chloro-4-fluoro-10H-chromeno[3,2-b]pyridin-10-one as an off white solid.