Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH3:12][Al](C)C.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.C1(P([Pd](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][C:4]1[C:3]([CH3:11])=[C:2]([CH3:12])[C:7]([CH3:8])=[CH:6][N+:5]=1[O-:9]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Br
Reactant: C[Al](C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1c[n+]([O-])c(C)c(C)c1C

Procedure:
4-Bromo-2,3,5-trimethyl-pyridine 1-oxide (2 g, 9.2 mmole) and catalytic tetrakis(triphenylphosphino)-palladium (80 mg, 4% by wt) in 20 mL of dry THF before treating with trimethylaluminum (2M in toluene, 15.2 mmole) under nitrogen. The solution was heated to reflux for 3 h, diluted with toluene (20 mL) before quenching the reaction with 4 mL of methanol followed by ammonium chloride (15 mmole). The mixture was refluxed for 2 h and filtered, while hot, on Celite. See J. Med. Chem. 1999, 42(12), 2064–2086. HPLC Rt: 4.183 min. 1H-NMR (CDCl3): δ 8.05 (s, 1H), 2.55 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4][C@H:3]1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH2:35][C:36]#N)=[N:15][C:16]=2[NH:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-:38].[Na+].C[OH:41]>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4][C@H:3]1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH2:35][C:36]([OH:41])=[O:38])=[N:15][C:16]=2[NH:20][CH2:21][CH:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CO
Reactant: [OH-]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CC#N)nc32)[C@H](O)[C@@H]1O
Agent: [Na+]
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CC(=O)O)nc32)[C@H](O)[C@@H]1O

Procedure:
A stirred solution of 2-{9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}acetonitrile (preparation 30) (1.5 g, 3 mmol) in methanol (30 ml) and an aqueous 1 molar solution of sodium hydroxide (10 ml) was heated at reflux for 24 hr. The methanol was then removed under reduced pressure and the residual liquid diluted with more water and washed twice with ethyl acetate. The aqueous phase was acidified to pH<7 with a 1 molar aqueous citrc acid solution and then extracted twice with ethyl acetate. The extracts were combined, washed with brine and dried with anhydrous magnesium sulfate. The residue, after removal of the solvent under reduced pressure, was dissolved into diethyl ether and the solvent removed again twice under reduced pressure to give the title compound (1.25 g) as a foam. MS: 518 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH:9]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:21][C:16]([CH2:17][CH:18]([CH3:20])[CH3:19])=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)CC(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1CC(C)C
Yield: 63.4 %

Procedure:
2.5 g of ethyl 3-(4-chlorobenzoylamino)-3-isovalerylpropionate, 10 ml of dimethylformamide and 2.3 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 1.5 g of ethyl 2-[2-(4-chlorophenyl)-5-isobutyl-4-oxazolyl]acetate are thereby obtained. Yield: 63.3%.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([NH:18][CH:19]=[N:20]2)=[C:16]([Cl:23])[N:15]=1.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:29]=CC=C[CH:25]=1.C(O)(C)C>C1COCC1>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:24]([CH3:29])[CH3:25])=[C:16]([Cl:23])[N:15]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
Add DEAD (4.7 g, 27.09 mmol) slowly to a solution of 2,6-dichloropurine (1, 5 g, 26.5 mmol), triphenylphosphine (11.75 g, 44.5 mmol) and isopropyl alcohol (2b, 10 ml) in THF (100 ml), and stir at room temperature for 24 hours. Concentrate the reaction mixture, dissolve the residue in DCM (20 ml) and filter to remove the unwanted solids. Load the filtrate onto a 90 gram silica gel column (Biotage), and elute with DCM/acetone (95:5). Concentrate the desired fractions to give 3.0 grams of 2,6-dichloro-9-isopropyl-9H-purine (3b).
Reaction SMILES: [BH4-].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13][CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][N:7]=1)=[O:5].[BH4-].[Na+].Cl>CO.CN(C)C=O.C(O)(=O)C>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH:14]=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:8][N:7]=1)=[O:5]
Reactant: COC(=O)c1ccc(N=CC=Cc2ccccc2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(NCC=Cc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the stirred solution of 8 g of sodim borohydride in 300 ml of methanol the solution of 15 g of 5-cinnamylideneaminopyridine-2-carboxylic acid methyl ester in 60 ml of warm dimethylformamide is added during 1/2 hour while cooling with ice. Simultaneously a 5 g portion and a 3 g portion of sodium borohydride is added and the mixture stirred for 1 hour at 0°. It is warmed to about 20° until dissolution occurs and combined with 18 ml of 12 N hydrochloric acid, 5 ml of acetic acid and 600 ml of ice water. The mixture is cooled to -10°, filtered, the residue washed with water, dried and recrystallized from aqueous methanol, to yield the 5-cinnamylamino-pyridine-2-carboxylic acid methyl ester melting at 131°-133°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=3)[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[N:28]([Si](C)(C)C)=[N+:29]=[N-:30].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]4[N:28]=[N:29][NH:30][N:27]=4)=[CH:21][CH:20]=3)[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:1]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cl
Product: Clc1cccc(-c2nc3c(c(Nc4ccc(Cc5nn[nH]n5)cc4)n2)SCCC3)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A 8-mL vial was charged with 2-[4-[[2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]acetonitrile (32 mg, 0.081 mmol, 1 eq.), azido(trimethyl)silane (0.2 ml, excess) and tetrabutylammonium fluoride hydrate (50 mg, 0.19 mmol, 2.3 eq.). The mixture was stirred at 110° C. overnight. After cooling to room temperature, the mixture was partitioned between dichloromethane (4 ml) and 2N HCl (4 ml). The solid was collected by filtration and washed with water (10 ml) followed dichloromethane (10 ml). After drying, the title compound was obtained as HCl salt (25 mg, 65% yield).). MW/HCl=472.39. 1H NMR (400 MHz, DMSO-D6) δ 8.6 (brs, 1H), 8.16 (s, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.53 (m, 2H), 7.29 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 3.21 (d, J=5.6 Hz, 2H), 2.94 (d, J=6.4 Hz, 2H), 2.19 (m, 2H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]1[CH2:15][CH2:14][O:13][C:12]21[CH2:21][C@@H:20]1[C@H:16]2[CH2:17][C@H:18]([OH:22])[CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]1[CH2:15][CH2:14][O:13][C:12]21[CH2:21][C@@H:20]1[C@H:16]2[CH2:17][C:18](=[O:22])[CH2:19]1
Reactant: O[C@@H]1C[C@@H]2CC3(OCCO3)[C@@H]2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1C[C@@H]2CC3(OCCO3)[C@@H]2C1
Temperature: -78 °C

Procedure:
A tetrahydrofuran solution (120 mL) of (±)-(1′R,2′R,4′S,6′R)-spiro[1,3-dioxolan-2,7′-[3]oxatricyclo[4.2.0.02,4]octane] (J. Chem. Soc. Perkin Trans. 1, 1980, 852) (20.0 g, 119 mmol) was gradually added dropwise to a tetrahydrofuran suspension (480 mL) of lithium aluminum hydride (6.77 g, 178 mmol) with stirring at 0° C. The mixture was stirred overnight at room temperature, and tetrahydrofuran (200 mL), water (6.8 mL), a 15% aqueous sodium hydroxide solution (6.8 mL), and water (20.4 mL) were then added thereto while the reaction solution was cooled on ice. The mixture was stirred at room temperature for 3 hours. The mixture was filtered through Celite and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography (separation from positional isomers in regard to hydroxyl groups) to obtain (±)-(1R,3R,5R)-spiro[bicyclo[3.2.0]heptane-6,2′-[1,3]dioxolan]-3-ol as an oil substance (7.78 g, 38%). Dimethyl sulfoxide (9.11 mL, 128 mmol) was added to a methylene chloride solution (110 mL) of oxalyl chloride (5.50 mL, 64.2 mmol) with stirring at −78° C., and the mixture was stirred at this temperature for 5 minutes. Then, a methylene chloride solution (30 mL) of the above-obtained alcohol (7.28 g, 42.8 mmol) was added thereto. The mixture was stirred at this temperature for 15 minutes. Then, triethylamine (23.7 mL, 171 mmol) was added thereto, and the mixture was heated to room temperature and stirred. The mixture was separated into aqueous and organic layers by the addition of 0.1 M hydrochloric acid. The organic layer was washed with 0.1 M hydrochloric acid, water, and saturated saline and then dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (6.61 g, 92%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.O>CN(C=O)C>[Si:18]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: COC(=O)Cc1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of methyl p-hydroxymethylphenylacetate (3.30 g, 18.3 mmol, prepared according to the method of G. Biagi et al., E. Ed. Farmaco., 43, 597 (1988)) in 6.6 ml DMF was added TBDMS-Cl (3.31 g, 22.0 mmol) and imidazole (3.12 g, 45.8 mmol), and the resulting solution was stirred at ambient temperature for 18 hours. The mixture was poured into 100 ml H2O and extracted (EtOAc, 4×50 ml). The combined extracts were dried (MgSO4), filtered and concentrated. The crude material was chromatographed (EtOAc:hexane, 5:95) to afford the title compound (5.0 g, 92% yield) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2].[F:16][C:17]([F:46])([C:42]([F:45])([F:44])[F:43])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:41]=[CH:40][C:25]([C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37](O)=[O:38])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCCCCC>CN(C)C1C=CN=CC=1.ClCCl>[F:16][C:17]([F:46])([C:42]([F:43])([F:44])[F:45])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:41]=[CH:40][C:25]([C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37]([O:15][CH2:14][CH2:13][C:5]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])=[O:38])=[CH:31][CH:30]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Reactant: O=C(O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)C(F)(F)F)cc2)cc1)OCCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
2.50 g (11.8 mmol) of 2-(2,4-dinitrophenyl)ethanol, 5.24 g (11.8 mmol) of (2E)-3-(4-{[4-(4,4,5,5,5-pentafluoropentoxy)benzoyl]oxy}phenyl)acrylic acid, 144 mg (1.2 mmol) of 4-Dimethylaminopyridine are dissolved in 30 ml of dichloromethane. 2.48 g (13.0 mmol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 200 g silica gel using toluene:ethyl acetate 95:5 as eluant and crystallization form ethylacetate:hexane mixture to yield 5.35 g (71%) 2-(2,4-Dinitrophenyl)ethyl (2E)3-{4-[(4-(4,4,5,5,5-pentafluoropentoxy)benzoyl)oxy]phenyl}acrylate as colorless crystals.
Reaction SMILES: O[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH2:3][CH2:4][CH:5]=[CH2:6].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1.O>C1(C)C=CC=CC=1>[N:29]([CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH2:3][CH2:4][CH:5]=[CH2:6])=[N+:30]=[N-:31]
Reactant: C=CCCC(O)c1ccccc1OC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: C=CCCC(N=[N+]=[N-])c1ccccc1OC
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a solution of crude 5-hydroxyl-5-(2-methoxyphenyl)-1-pentene, prepared as described above, in toluene (150 mL) at 0° to 40° C. was added diphenylphosphoryl azide (25.86 mL, 120 mmol) followed by DBU (17.95 mL, 120 mmol) and the resulting reaction mixture was stirred at room temperature (20° C. to 25° C.) for 28 hours. H2O was added, the aqueous layer was extracted with ether (×4), and the combined organic layers were washed with H2O (×2), 0.5N HCl (×2) and brine (×2), dried over MgSO4 and evaporated in vacuo. The crude product was purified by silica gel flash chromatography (5% EtOAc-95% hexanes) to provide the title compound as a colorless liquid (14 g). 1H NMR (CDCl3, 400 MHz) δ: 6.8-7.4 (4H), 5.8 (1H), 5.0 (2H), 3.83 (3H, OMe), 1.8-2.2 (4H).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:5]2)[CH2:3][CH2:2]1.[CH:18]([NH:21][NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](/[CH:13]=[CH:14]/[C:15]([N:21]([CH:18]([CH3:20])[CH3:19])[NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:17])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)/C=C/c1cn(C2CC2)c2ccccc12
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1cn(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To solution containing (E)-3-(1-cyclopropyl-1H-indol-3-yl)acrylic acid (160 mg, 0.70 mmol, 1.0 equivalent), N′-isopropylbenzohydrazide (188.8 mg, 1.05 mmol, 1.5 equivalent) and HATU (401.5 mg, 1.05 mmol, 1.5 equivalent) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.18 ml, 1.05 mmol, 1.5 equivalent) was slowly drop-wise added and stirred at room temperature for 24 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=1:1) and dried so that solid form of (E)-N′-(3-(1-cyclopropyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained. (87.9 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][N:20]([CH2:24][CH3:25])[CH2:21][CH2:22][OH:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:26][C:27](O)=[O:28]>CO.[Pd]>[C:27]([O:23][CH2:22][CH2:21][N:20]([CH2:19]/[CH:18]=[CH:17]\[C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][S:10][C:11]=2[CH:16]=1)[CH2:24][CH3:25])(=[O:28])[CH3:26]
Reactant: CCN(CC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)CCO
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CO
Product: CCN(C/C=C\c1ccc2c(-c3ccc(Cl)cc3)nsc2c1)CCOC(C)=O
Yield: 69.9 %

Procedure:
75 mg (0.2 mmol) 2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-ethyl-amino)-ethanol in 2 ml MeOH with 0.012 ml (0.2 mmol) AcOH were hydrogenated in the presence of 7 mg Pd/C10% (16 h), filtration over decalite and evaporation yielded 58 mg (66%) Z-2-({3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-allyl}-ethyl-amino)-ethanol acetate as light brown oil, MS: 373 (MH+, 1Cl).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])C(C)C.[C:10]([O:14]CC=C)(=[O:13])[CH2:11][CH3:12]>>[C:1]1(=[O:5])[O:6][CH2:7][CH2:8][CH2:9]1.[CH:12]([CH2:11][C:10]([OH:14])=[O:13])=[CH2:1]
Reactant: C=CCOC(=O)CC
Reactant: C=CCOC(=O)C(C)C
Product: C=CCC(=O)O
Product: O=C1CCCO1

Procedure:
The reaction was carried out as described in Example 11, with the exception that 128 grams of allyl isobutyrate were used instead of allyl propionate. 19.1 grams of γ-butyrolactone and 10.6 grams of vinyl acetic acid were obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:13].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[F:1][C:2]1[C:10]([CH:11]2[CH2:12][O:22]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:13]
Reactant: C=Cc1ccc2c(c1F)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-fluoro-5-vinyl-3H-isobenzofuran-1-one (4.0 g, 17.3 mmol) in 100 mL of DCM was slowly added mCPBA (6.0 g, 85% purity, 34.6 mmol) in 50 mL of DCM at 0° C. After warming to room temperature, the mixture was stirred overnight. The mixture was washed with aqueous Na2SO3 until KI paper didn't change color. The organic layers were washed with brine and then concentrated. The residue was purified by column chromatography to give 4-fluoro-5-oxiranyl-3H-isobenzofuran-1-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.71 (d, J=7.8 Hz, 1H), 7.37-7.40 (m, 1H), 5.37 (s, 2H), 4.21-4.22 (m, 1H), 3.25-3.27 (m, 1H), 2.80-2.82 (m, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[C:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:12])[CH2:10][O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].C(O)C.Cl>O1CCCC1.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:9]2([CH3:12])[C:8]3[CH:21]=[CH:22][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[O:11][CH2:10]2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC1(Cc2ccc(Cl)cc2)COc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-(4-Chloro-benzyl)-3-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (100 mg, 0.32 mmol), sodium hydroxide (100 mg, 2.5 mmol), ethanol (3 ml) and water (0.5 ml) in tetrahydrofuran (4 ml), was stirred for 12 h at room temperature. The reaction medium was acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with water, dried (Na2SO4), and concentrated in a rotary evaporator. The product was obtained as a white solid. (M: 89 mg, 92%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH3:20][C:21]1([CH3:33])[C:30]2[C:25](=[CH:26][C:27]([Br:31])=[CH:28][CH:29]=2)[C:24](=O)[CH2:23][CH2:22]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=3)[C:21]([CH3:33])([CH3:20])[CH2:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cn1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 6-methyl-3-bromopyridine (890 mg, 5.2 mmol) in THF (15 mL) was added n-BuLi in hexane (1.6M solution, 3.5 mL, 5.6 mmol) and stirred for 1 hour. This mixture was added to a flask containing 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound A, 1.35 g, 5.4 mmol), in THF (5 mL) at −78° C. The reaction mixture was gradually warmed to ambient temperature and stirred for 16 hours. Thereafter it was diluted with ethyl acetate (100 mL), washed with water (10 mL), brine (10 mL) and dried with MgSO4. Solvent was removed by distillation, the crude material was dissolved in toluene (25 mL) and pTSA (530 mg, 2.8 mmol) was added. The mixture was heated at 90° C. for 36 hours. Thereafter it was diluted with ethyl acetate (100 mL), washed with 10% NaHCO3 (2×10 mL), brine (10 mL), dried with MgSO4 and the solvent was removed by evaporation. The title compound was obtained by recrystallization from ethyl acetate and hexane mixture (1:9).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[O:7]=[C:8]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]2[CH2:24][CH2:25][C:26](=[O:27])[C:11]=2[CH:10]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[NH:9]1.Br[CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39].O>CN(C)C=O>[C:32]([C:31]1[CH:30]=[CH:29][C:28]([CH:10]2[N:9]([CH:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[C:8](=[O:7])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)[C:12]3[CH2:24][CH2:25][C:26](=[O:27])[C:11]2=3)=[CH:35][CH:34]=1)#[N:33]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
Cesium carbonate (737 mg, 2.26 mmol) is added to a solution of 4-(2,5-dioxo-1-(3-(tri-fluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 300 mg, 0.76 mmol) and methyl 2-bromopropionate (252 mg, 1.51 mmol) in N,N-dimethylformamide (10.0 mL), and the mixture is stirred at 50° C. over night. Water is added, and the mixture is extracted with dichloromethane. The organic layer is washed twice with water, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 160 mg; ESI mass spectrum: [M+H]+=484; Retention time HPLC: 0.85 min (Z018_S04).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3C(C)=NO[N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CC[C@H](OC(=O)C(F)(F)F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:58][N:57]=[C:56]([CH3:59])N=1>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[O:58][N:57]=[C:56]([CH3:59])[N:16]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Reactant: Cc1noc(CCl)n1
Agent: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Product: Cc1noc(Cn2nc3nc(C(C)(C)C)nc(N4CC[C@H](O)C4)c3n2)n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole and isolated as brown gum. MS (m/e): 359.3 (MH+).