Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Cl-].[NH:9]([C:16]1[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][O:31]CCO)=[CH:26][CH:25]=2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(NCC)C>C(Cl)Cl>[NH:9]([C:16]1[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][O:31][CH2:2][CH2:1][N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])=[CH:28][CH:29]=2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reactant: CCN(CC)CC
Agent: [Cl-]
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)CCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Triethylamine (33 ml, 0.241 mmol) and mthanesulphonyl chloride (19 ml, 0.241 mmol) were added to a solution of 4-anilino-5-bromo-2-[4-(2-hydroxyethoxy)methylanilino]pyrimidine (Example 31; 100 mg, 0.241 mmol) in DCM (5 ml) at 0° C. The solution was warmed to ambient temperature and left to stand for 1 hour. Diethylamine (2 ml) was added, and the mixture was heated at 50° C. for 3 hours. The solvent was removed by evaporation, and the residue was purified by column chromatography, eluting with 0–2% methanol solution in DCM containing 0.5% aqueous ammonia solution, to give the product as a cream solid (38 mg, 34%). NMR (CDCl3): 1.03 (t, 6H), 2.58 (q, 4H), 2.69 (t, 2H), 3.54 (t, 2H), 4.48 (s, 2H), 7.06 (d, 2H), 7.17 (t, 1H), 7.22 (s, 1H), 7.26 (s, 1H), 7.38 (dd, 2H), 7.49 (d, 2H), 7.58 (d, 2H), 8.15 (s, 1H); MS (MH+): 470.4, 472.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1)[OH:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[N:24]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH:23]=1.O>O1CCCC1.C(#N)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:28]2[CH:29]=[C:30]3[C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][CH3:14])=[CH:23][N:24]([S:40]([C:43]4[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=4)(=[O:42])=[O:41])[C:25]3=[N:26][CH:27]=2)[N:7]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)C(O)c1cccc(Br)n1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: COC(=O)C(O)c1cccc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 80 °C
Yield: 32.8 %

Procedure:
In a microwave vial (6-bromo-pyridin-2-yl)-hydroxy-acetic acid methyl ester (430.9 mg, 1.75 mmol), 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 1.75 mmol) in tetrahydrofuran/acetonitrile/1 N aqueous sodium bicarbonate (20 ml) was degassed with nitrogen and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (143.0 mg, 0.18 mmol) was added and the vial sealed. This reaction mixture was heated to 80° C. for 30 minutes in a microwave reactor. 100 ml water was added and this mixture was extracted with ethyl acetate (3×) the combined organic layers were dried over magnesium sulfate and purified by silica gel chromatography to yield hydroxy-{6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-2-yl}-acetic acid methyl ester as a white solid (312 mg, 32% yield). MS: m/z 544.5 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10](O)[C:11]([F:14])([F:13])[F:12].Cl.[CH3:17][NH:18][CH3:19].CCN(CC)CC>C(#N)C>[CH3:17][N:18]([CH3:19])[CH:10]([C:3]1[N:4]([CH3:9])[CH:5]=[CH:6][C:7](=[O:8])[C:2]=1[OH:1])[C:11]([F:14])([F:13])[F:12]
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C)C(c1c(O)c(=O)ccn1C)C(F)(F)F
Reaction time: 2 h
Yield: 32 %

Procedure:
To a suspension of 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (5.00 g, 22.4 mmol) in 40 mL of acetonitrile at ice-water bath was added Vilsmeier's reagent (4.30 g, 33.6 mmol) portionwise. The resulting mixture was stirred for 2 h before being added to a suspension of dimethylamine hydrochloride (6.00 g, 73.6 mmol) and Et3N (15.0 mL, 107.6 mmol) in 30 mL of acetonitrile. The resulting suspension was stirred at RT for overnight. The solid was filtered off and the filtrate was concentrated to dryness. The residue was purified by flash chromatography on silica gel (10% MeOH in EtOAc as eluant) to afford title compound, Apo7041 (1.8 g). Yield=32%; 1H NMR (90 MHz, CD3OD-D4) δ (ppm): 7.63 (d, J=7.3 Hz, 1H), 6.41 (d, J=7.3 Hz, 1H), 4.78 (q, J=8.1 Hz, 1H), 3.99 (s, 3H), 2.41 (s, 6H); MS m/z 273 [M+Na]+, 251 [M+1]+, 206 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].C1CCN2C(=NCCC2)CC1.[F:34][C:35]([F:40])([F:39])[CH2:36][CH:37]=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[CH:37][CH2:36][C:35]([F:40])([F:39])[F:34]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=CCC(F)(F)F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=CCC(F)(F)F)NC(=O)OCc1ccccc1
Temperature: -30 °C

Procedure:
N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester and DBU were dissolved in dry methylene chloride (50 mL) and the reaction mixture was chilled to −30° C. 3,3,3-trifluoropropanal (1 eq) was added dropwise to the chilled and stirred solution and the reaction was allowed to stir for an additional hour at −30° C., and then overnight at ambient temperature. Methylene chloride (ca. 100 mL) was added and the organic phase was washed with 1N HCl (ca. 100 mL), then saturated brine (ca. 100 mL). The organic phase was dried over MgSO4, filtered, and concentrated by rotary evaporation. This crude product was purified by silica gel chromatography with a gradient of 10-30% ethyl acetate in hexanes to yield 2-benzyloxycarbonylamino-5,5,5-trifluoro-pent-2-enoic acid methyl ester as a white, crystalline solid.
Reaction SMILES: CCN(CC)CC.I[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:20][O:19][CH2:18][CH2:17][N:16]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:11][CH:10]=1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][O:23][C:21]([C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:20][O:19][CH2:18][CH2:17][N:16]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:11][CH:10]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc([C@@H]2COCCN2C(=O)OC(C)(C)C)cc1
Temperature: 65 °C
Yield: 321.2 %

Procedure:
Carbon monoxide gas was bubbled through a reaction mixture containing Et3N (4.742 g, 6.532 ml, 48.86 mmol), tert-butyl (3R)-3-(4-iodophenyl)morpholine-4-carboxylate 8 (5.21 g, 13.39 mmol) and Pd(dppf)Cl2—CH2Cl2 (1.093 g, 1.339 mmol) in methanol (157 mL) cooled in an ice bath for 10 mins. The reaction vessel was quickly sealed and the reaction mixture heated at 65° C. for 18 h. The reaction mixture cooled to rt and filtered through celite, washing through with methanol. The filtrate was concentrated in vacuo and crude product purified by ISCO companion (330 g SiO2 0 to 20% EtOAc/petroleum ether) and the product fractions combined and concentrated in vacuo to leave the product as a colourless oil (6.91 g, 81% yield); 1H NMR (400.0 MHz, DMSO) d 1.39 (9H, s), 3.01 (1H, m), 3.51 (1H, m), 3.71-3.85 (6H, m), 4.29 (1H, m), 5.04 (1H, s), 7.48 (2H, m) and 7.97 (2H, m) ppm.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:15](OCC)=[O:16].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.C(OCC)C>[OH:16][CH2:15][C:3]1[N:4]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1nc(C=Cc2ccccc2)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1oc(C=Cc2ccccc2)nc1CO

Procedure:
Ethyl 5-methyl-2-styryl-4-oxazolecarboxylate (2.14 g) was dissolved in a mixture of dry tetrahydrofuran (10 ml) and dry ethyl ether (15 ml) and the solution was added dropwise to a suspension of lithiumaluminum hydride (0.34 g) in dry ethyl ether (20 ml) with ice-cooling and stirring. The mixture was further stirred under ice-cooling for an hour and water (2 ml) was added portionwise for decomposition. The precipitate was filtered off and the filtrate was concentrated to give 4-hydroxymethyl-5-methyl-2-styryloxazole as crystals; yield 1.28 g (71.5%). Recrystallization from acetone gave colorless prisms melting at 106°-107° C.
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](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:25]([O:24][C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23])[CH3:26]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N=C(OCC)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and ethyl chloroformate, there is obtained ethyl N-ethoxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as an oil, mass spectrum m/e: M+ 338 (14), 309 (19), 293 (12), 263 (78), 194 (100);
Reaction SMILES: C(O)(=O)C.C([O-])(=O)C.[Na+].Cl.[NH2:11][C@H:12]([C:18]([O:20][CH3:21])=[O:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1>ClCCl.O>[N:11]1([C@@H:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:18]([O:20][CH3:21])=[O:19])[CH:24]=[CH:28][CH:27]=[CH:26]1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C[C@@H](C(=O)OC)n1cccc1
Temperature: 80 °C
Yield: 69 %

Procedure:
Acetic acid (2.5 ml) and sodium acetate (32.5 mmol, 2.6 g) were added to a solution of dimethyl L-aspartate hydrochloride (29.5 mmol, 5.830 g) in dichloromethane (60 ml) and water (30 ml). Tetrahydro-2,5-dimethoxyfuran (29.5 mmol, 3.8 ml) was added to the resulting mixture heated at 80° C. After 90 min. the solution was cooled and the acqueous layer was washed with DCM. The combined organic layers were washed with brine and then dried, filtered and evaporated. The crude residue was purified by chromatograpgy on silica gel (eluent:Hex/AcOEt:7/3) to give the wanted compound as a colorless viscous oil (4.3 g, 68% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[CH2:3][O:4]/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8].C(N(CC)CC)C.FC(F)(F)S(O[Si:25]([CH3:28])([CH3:27])[CH3:26])(=O)=O.C(=O)(O)[O-].[Na+]>C(OCC)C.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:11])([CH3:10])[CH2:3][O:4]/[CH:5]=[CH:6]/[C:7](=[CH2:8])[O:9][Si:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)/C=C/OCC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(/C=C/OCC(C)(C)C)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
(E)-4-(2,2-dimethylpropoxy)but-3-en-2-one (14 g, 90 mmol) and triethylamine (10 g, 101 mmol) were combined in ethyl ether (200 mL). Trimethylsilyl trifluoromethanesulfonate (20 g, 90 mmol) (Aldrich) in carbon tetrachloride (30 mL) was added at −5° C. over 0.5 hr. This was stirred for 0.5 hr at 0° C. This was poured into cold 5% sodium bicarbonate (50 mL) and the organics were extracted into hexane. This was washed with saturated aqueous sodium chloride, dried (MgSO4), and evaporated to give 21 g of [(E)-3-(2,2-dimethylpropoxy)-1-methylene-allyloxy]trimethylsilane.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14](S)=[N:13][N:12]=3)[CH:9]=2)[CH:4]=[CH:3]1.[N:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[NH:20][CH2:19][CH2:18]2.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>CO.C(OCC)C.C(O)CC>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([N:20]4[CH:21]5[CH2:24][CH2:25][N:17]([CH2:23][CH2:22]5)[CH2:18][CH2:19]4)=[N:13][N:12]=3)[CH:9]=2)[CH:4]=[CH:3]1
Reactant: C1CN2CCC(CC2)N1
Reactant: Cn1ccc2ccc(-c3nnc(S)o3)cc21
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: CCCO
Product: Cn1ccc2ccc(-c3nnc(N4CCN5CCC4CC5)o3)cc21
Temperature: 130 °C
Reaction time: 15 h
Yield: 29 %

Procedure:
A mixture of 5-(1-methyl-1H-indol-6-yl)[1,3,4]oxadiazole-2-thiol (1.25 g, 5.41 mmol), 1,4-Diazabicyclo[3.2.2]nonane (0.69 g, 5.41 mmol) and 1-propanol (5 ml) was stirred at 130° C. for 15 h. The reaction-mixture was allowed to cool to room-temperature. Aqueous sodium hydroxide (1 M) was added and the mixture was extracted twice with chloroform. The mixture was extracted twice with aqueous hydrochloric acid. The aqueous phase was washed with chloroform and was made alkaline by adding sodium hydroxide (4 M), followed by extraction three times with chloroform. The free base was isolated as a brown oil. Yield 500 mg (29%) The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid. Yield 250 mg (36%). LC-ESI-HRMS of [M+H]+ shows 324.1823 Da. Calc. 324.182435 Da, dev. −0.4 ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:28]=[CH:27][C:15]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.Cl.[CH3:30][NH:31][CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>>[CH3:30][N:31]([CH3:32])[C:24]([CH:21]1[CH2:20][CH2:19][N:18]([C:16](=[O:17])[C:15]2[CH:27]=[CH:28][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22]1)=[O:25]
Reactant: O=C(O)C1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: CN(C)C(=O)C1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1

Procedure:
In a similar manner to Example 5, Compound 9-2 (27 mg, 5%) was obtained using Compound 50 (500 mg, 1.33 mmol), dimethylamine hydrochloride (230 mg, 1.50 mmol), 1-hydroxybenzotriazole monohydrate (306 mg, 2.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg, 2.00 mmol) and N-methylmorpholine (0.439 mL, 4.00 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH:8]=[CH:9][N:10](C)C)[S:5][CH:6]=1.O.[NH2:15]N>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[CH:9][NH:10][N:15]=2)[S:5][CH:6]=1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1cc(Br)cs1
Solvent: O
Solvent: CCO
Product: Brc1csc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A mixture of 1-(4-bromo-2-thienyl)-3-(dimethylamino)prop-2-en-1-one (43.5 mmol) and hydrazine hydrate (86.9 mmol) in 50 mL ethanol was refluxed for 18 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was successively washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4, filtered and concentrated to afford 9.74 g (94% yield) 3-(4-bromo-2-thienyl)-1H-pyrazole which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15](I)[CH:16]=[CH2:17]>CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH:16]=[CH2:15]
Reactant: C=CCI
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Bromophenol (10.0 g, 57.8 mmoles) in anhydrous DMF (60 mL) was treated with K2CO3 (24.0 g, 173 mmoles) and allyl iodide (5.81 mL, 63.6 mmoles). Reaction stirred overnight at 80° C. Reaction allowed to cool to room temperature and diluted with ethyl acetate. The mixture was washed with H2O (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound with no further purification.
Reaction SMILES: [OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].Cl.[NH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:1][C:2]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:4](=[O:19])[C:3]=1[C:20]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(OC)ccc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C21CCOCC1
Temperature: 95 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of ethyl 4-hydroxy-6-methoxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.6 g, 2 mmol), tert-butyl 2-aminoacetate hydrochloride (0.5 g, 3 mmol) in 5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.7 g, 5 mmol). The mixture was warmed to 95° C. and stirred for 4 hours, M+1=418. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.74 g of the title compound as a white yellow solid. MS (m/z)=418 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:32])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:41]([O:45][C:46](=[O:49])[CH2:47]Br)([CH3:44])([CH3:43])[CH3:42].O>C(#N)C>[C:41]([O:45][C:46](=[O:49])[CH2:47][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[N:9]([C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]2=[O:32])=[CH:33][CH:34]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione (20.0 g) in acetonitrile (200 ml) was added cesium carbonate (21.0 g), followed by the addition of bromoacetic acid t-butyl ester (7.4 ml). The resulting mixture was stirred at 25° C. for 3 hours. To the reaction mixture was added water and the organic layer was separated and concentrated in vacuo. The residue was extracted with toluene and the extract was washed with diluted hydrochloric acid and water and concentrated in vacuo to afford the desired compound (24.9 g).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([C:16]2[N:51]=[C:19]3[N:20]([CH2:43][C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)[C:21](=[O:42])[C:22]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=5)=[CH:30][CH:29]=4)=[C:23]([CH2:24][CH2:25][CH3:26])[N:18]3[N:17]=2)[CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([C:16]2[N:51]=[C:19]3[N:20]([CH2:43][C:44]4[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=4)[C:21](=[O:42])[C:22]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[C:40]5[NH:3][C:4](=[O:7])[O:5][N:41]=5)=[CH:30][CH:29]=4)=[C:23]([CH2:24][CH2:25][CH3:26])[N:18]3[N:17]=2)[CH2:14][CH2:15]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(F)cc2)c2nc(C3CC3)nn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(Cc2ccc(F)cc2)c2nc(C3CC3)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogen carbonate (1.4 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[2-cyclopropyl-4-(4-fluorobenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.44 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 58%).
Reaction SMILES: [C:1]([N:4]1[CH2:35][CH2:34][N:7]2[C@H:8]([CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9][N:10](CC3C=CC=CC=3OC)[CH2:11][C@@H:6]2[CH2:5]1)(=[O:3])[CH3:2].[Cl:36]C(OC(Cl)C)=O>ClC(Cl)C>[ClH:36].[ClH:36].[C:1]([N:4]1[CH2:35][CH2:34][N:7]2[C@H:8]([CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:9][NH:10][CH2:11][C@@H:6]2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccccc1CN1C[C@@H]2CN(C(C)=O)CCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: CC(=O)N1CCN2[C@H](CNC[C@H]2C(c2ccccc2)c2ccccc2)C1
Product: Cl
Temperature: 70 °C

Procedure:
To a solution of (4R,9aR)-8-acetyl-4-benzhydryl-2-(2-methoxybenzyl)octahydro-2H-pyrazino[1,2-a]pyrazine (5.9 g) in dichloroethane (60 ml) was added 1-chloroethyl chloroformate (2.3 ml) at room temperature, and the reaction mixture was heated at 70° C. for 30 minutes with stirring. After removal of solvent by evaporation, to the resulting residue was added methanol (45 ml), and the solution was refluxed for 40 minutes. After being concentrated, the residue was triturated with diisopropyl ether. The resulting precipitate was collected by filtration and dried under, reduced pressure for 5 hours at 40° C. to give (4R,9aR)-8-acetyl-4-benzhydryloctahydro-2H-pyrazino[1,2-a]pyrazine dihydrochloride (3.1 g) as colorless foam.