Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].O=O.[C:7]([OH:10])(=[O:9])[CH3:8]>>[C:7]([O:10][CH:2]([CH:3]([O:10][C:7](=[O:9])[CH3:8])[CH3:4])[CH3:1])(=[O:9])[CH3:8]
Reactant: CC(=O)O
Reactant: C=CC=C
Agent: O=O
Product: CC(=O)OC(C)C(C)OC(C)=O

Procedure:
The conventional butadiene process starts with reaction of butadiene with acetic acid and oxygen-containing gas, followed by hydrogenation to obtain diacetoxybutane (see FIG. 1). As shown in FIG. 2, the resulting diacetoxybutane is hydrolyzed, and acetic acid and water are distilled off from the liquid reaction mixture containing crude 1,4-butanediol (hydrolyzate) in a first distillation tower. Diacetoxybutane and hydroxyacetoxybutane are separated from the hydrolyzate in a second distillation tower. The resulting crude 1,4-butanediol is hydrogenated with hydrogen gas in the presence of a catalyst for hydrogenation. After tetrahydrofuran (hereinafter abbreviated as THF) is concentrated in a third distillation tower, high purity 1,4-butanediol is recovered from a fourth distillation tower as a side stream or a bottom.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:9])[C:5]([F:8])([F:7])[F:6].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[N+:18]([O-:20])=[O:19].OS(O)(=O)=O>>[N+:18]([C:12]1[C:11]([Cl:10])=[C:16]([CH:15]=[CH:14][C:13]=1[Cl:17])[CH2:2][NH:3][C:4](=[O:9])[C:5]([F:8])([F:7])[F:6])([O-:20])=[O:19]
Reactant: O=C(NCO)C(F)(F)F
Reactant: O=[N+]([O-])c1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Product: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1Cl)C(F)(F)F
Temperature: 75 °C
Reaction time: 8 h

Procedure:
N-(Hydroxymethyl)trifluoroacetamide (6.6 mmol; 0.946 g) is added to a mixture of 2,6-dichloro-nitrobenzene (0.899 mL; 6.6 mmol) and conc. H2SO4 (15 mL) at 75° C. The mixture is stirred at 75° C. overnight, poured into ice water and stirred for 1 h. The precipitate is collected by filtration and dried. Yield 0.32 g (15%). MS [M−H]−=315, HPLC-method B: Rt=1.43 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[BH4-].[Na+]>C1(C)C=CC=CC=1.O.CO>[I:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(I)c1
Reactant: O=C1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: Ic1cccc(NC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
13bd) A mixture of 2 g of 3-iodoaniline and 1.26 ml of tetrahydro-4H-pyran-4-one is boiled in 50 ml of toluene on a water separator for 4 hrs. The solution of the imine which remains behind is treated with 20 ml of methanol and 520 mg of sodium borohydride are added in portions. The mixture is stirred at room temperature for 16 hrs., then poured into water and extracted with ethyl acetate. Chromatography on silica gel with ethyl acetate/hexane 3:7 gives 559 mg of (3-iodo-phenyl)-(tetrahydropyran-4-yl)-amine as a colourless oil. Yield: 20%. Mass spectrum: peaks inter alia at m/e: 303 (M+, 100%), 245 (40%), 219 (40%), 130 (90%), 117 (62%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][CH:16]([CH2:21][O:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:18][CH2:19][OH:20])(=[O:14])[CH3:13].O>N1C=CC=CC=1.CCOCC>[S:7]([O:20][CH2:19][CH2:18][CH2:17][CH:16]([O:15][C:12](=[O:14])[CH3:13])[CH2:21][O:22][CH2:23][CH2:24][CH3:25])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CCCOCC(CCCO)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCOCC(CCCOS(=O)(=O)c1ccc(C)cc1)OC(C)=O
Temperature: 20 °C
Reaction time: 0.67 h

Procedure:
A solution of p-toluenesulfonyl chloride (42.0 g., 0.22 mole) in pyridine (100 ml.) is cooled in an ice bath while 4-acetoxy-5-propoxy-1-pentanol (36.8 g., 0.193 mole) is added dropwise with stirring during 40 minutes. The ice bath is replaced by a cool (20° C.) water bath and stirring is continued for 2 hours. The mixture is then poured into 500 ml. of water. The oily product is taken up in ether, washed with 2 N hydrochloric acid and water, and dried over sodium sulfate. The solvent is distilled in vacuo to leave the crude title compound as a yellow oil.
Reaction SMILES: CS(C)=O.[H-].[Na+].[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34]Cl)=[CH:25][CH:24]=3)[CH2:18]2)=[O:14])=[CH:10][CH:9]=1>C(Cl)Cl>[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]4=[O:36])=[CH:25][CH:24]=3)[CH2:18]2)=[O:14])=[CH:10][CH:9]=1
Reactant: O=C(CCCCCl)Nc1ccc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCCCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Under inert conditions, 5 ml of DMSO are admixed with 30 mg of NaH (60% in paraffin oil), and the mixture is heated at 75° C. for 30 min, until the evolution of gas has ceased. A solution of 290 mg (0.617 mmol) of 5-chloro-N-[((5S)-3-{4-[(5-chloropentanoyl)amino]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-2-thiophenecarboxamide (from Example 161) in 5 ml of methylene chloride is then added dropwise, and the mixture is stirred at room temperature overnight. The reaction is terminated and the mixture is poured into 100 ml of water and extracted with ethyl acetate. The evaporated organic phase is chromatographed on an RP-8 column and the product is elated with acetonitrile/water. This gives 20 mg (7.5% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:10]O.P(Br)(Br)[Br:13]>ClCCl>[Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:10][Br:13]
Reactant: BrP(Br)Br
Reactant: CC(C)n1ncc(CO)c1Br
Solvent: ClCCl
Product: CC(C)n1ncc(CBr)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
To a stirred solution of (5-bromo-1-isopropyl-1H-pyrazol-4-yl)methanol (10.0 g, 45.7 mmol) in dichloromethane (200 mL) was added PBr3 (6.5 mL, 68.5 mmol) at 0° C. After the addition was complete the mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was poured into ice-cold water (300 mL), shaken, separated, and then washed twice with ice-cold water (2×100 mL) and then brine (100 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo to give 5-bromo-4-(bromomethyl)-1-isopropyl-1H-pyrazole (12.2 g, 95%). 1H NMR (300 MHz, CDCl3, δ): 7.58 (s, 1H), 4.64 (m, 1H), 4.35 (s, 2H), 1.43 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N+:19]([O-])=O>[Ni].CCOC(C)=O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:15])([F:16])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH2:19]
Reactant: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C1(C(F)(F)F)CC1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1Cl
Temperature: 25 °C

Procedure:
A mixture of N-(4-chloro-3-nitro-benzyl)-1-trifluoromethyl-cyclopropanecarboxamide (340 mg, 1.1 mmol), EtOAc (10 mL) and Ra—Ni (30 mg) was stirred at rt under a hydrogen atmosphere (3 bar). The catalyst was removed by filtration and the filtrate was concentrated to give the sub-title compound.
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19].O>C(Cl)Cl>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18](=[O:20])(=[O:19])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:6]
Reactant: O=S(=O)(Cl)CCCCCCCCCCBr
Reactant: CCCCNC
Solvent: ClCCl
Solvent: O
Product: CCCCN(C)S(=O)(=O)CCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
9.63 mmol of n-butylmethylamine is dissolved in 6 ml of absolute CH2Cl2. In a moisture-free environment, 1.85 mmol of 1-bromo-10-decanesulfonyl chloride is now slowly added in drops to 2.5 ml of CH2Cl2 while being cooled with ice. Then, it is stirred for another five hours at room temperature. The mixture is mixed with 10 ml of water, stirred thoroughly for a short time and the organic phase is separated. The aqueous phase is extracted with ether, and the combined organic phases are then washed with saturated NaCl solution and water. After drying on MgSO4, the solvent is removed in a rotary evaporator.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[F:10][C:11]([F:27])([F:26])[C:12]([N:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:24]([NH2:25])[C:17]=2[CH2:16][CH2:15]1)=[O:13]>C(O)(=O)C>[N+:25]([C:24]1[C:17]2[CH2:16][CH2:15][N:14]([C:12](=[O:13])[C:11]([F:10])([F:26])[F:27])[CH2:20][CH2:19][C:18]=2[CH:21]=[CH:22][CH:23]=1)([O-:6])=[O:5]
Reactant: Nc1cccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: O=C(N1CCc2cccc([N+](=O)[O-])c2CC1)C(F)(F)F
Temperature: 55 °C
Yield: 103.6 %

Procedure:
Under N2, a flame-dried, 100-mL, three-necked flask is charged with sodium perborate tetrahydrate (5.75 g, 37.4 mmol) and acetic acid (20 mL) and heated to 50–60° C. using an oil bath. A solution of 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-6-amine (1.93 g, 7.5 mmol) in acetic acid (20 mL) was slowly added drop-wise over 30 min. The mixture is heated at 55° C. for 1 hour. The mixture was filtered and partitioned between CH2Cl2 and water. The organic layer is washed with water and concentrated to give 2.24 g of an amber oil. Column chromatography (elution with 10–25% EtOAc/heptane) gives 1.52 g (70%) of the title compound as a yellow oil. An analytical sample was crystallized from EtOAc/hexane to give off-white crystals: mp 64–67° C.; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=8 Hz, 1 H), 7.41–7.29 (m, 2 H), 3.89–3.74 (m, 4 H), 3.15–3.10 (m, 4 H); IR (diffuse reflectance) 1687, 1523, 1466, 1451, 1376, 1368, 1295, 1197, 1186, 1179, 1168, 1147, 950, 818, 752 cm−1; MS (EI) m/z 288 (M+); Anal. Calcd for C12H11F3N2O3: C, 50.01; H, 3.85; N, 9.72; F, 19.77. Found: C, 49.95; H, 3.88; N, 9.68.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[O:35])N(C(OCC)=O)[C:24]2=[O:29])([O-:19])=[O:18]>O>[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[O:35])[N:1]([CH:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:24]2=[O:29])([O-:19])=[O:18]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reaction time: 3 h

Procedure:
To a stirred solution of glutamic acid (10 mmol) and sodium carbonate (10.5 mmol) in water (50 mL) is added ethyl 4-nitro-1,3-dioxoisoindoline-2-carboxylate (10 mmol). The resulting mixture is stirred for 3 hours. The mixture is filtered. The filtrate is then acidified to pH 1 with 4 N hydrochloric acid to afford the 1-(4-nitro-1,3-dioxoisoindolin-2-yl)propane-1,3-dicarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:4]=1.[NH3:18]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:18])=[S:11])=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:4]=1
Reactant: COc1ccc(N=C=S)c(N2CCOCC2)c1
Reactant: N
Solvent: CCO
Product: COc1ccc(NC(N)=S)c(N2CCOCC2)c1

Procedure:
Reaction of 4-methoxy-2-morpholinophenyl isothiocyanate (4.1 g) with a saturated solution of ammonia in ethanol (30 ml) for 24 hours at room temperature gave 1-(4-methoxy-2-morpholinophenyl thiourea (m.p. 175° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:14]2[CH2:28][CH2:27][C:17]3([O:22][CH2:21][C:20](=[O:23])[N:19]([CH:24]4[CH2:26][CH2:25]4)[CH2:18]3)[CH2:16][CH2:15]2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[CH:42][CH:43]=[N:44]3)=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH:24]1([N:19]2[CH2:18][C:17]3([CH2:27][CH2:28][N:14]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:37]5[CH:46]=[C:45]6[C:40]([CH:41]=[CH:42][CH:43]=[N:44]6)=[CH:39][CH:38]=5)=[CH:3][CH:4]=4)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:15][CH2:16]3)[O:22][CH2:21][C:20]2=[O:23])[CH2:26][CH2:25]1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: COC(=O)CC(c1ccc(Br)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2

Procedure:
A solution of methyl 3-(4-bromophenyl)-3-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)propanoate (0.399 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.439 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.020 mmol) and 2M aq potassium carbonate (1.196 mmol). The reaction vessel was purged with nitrogen and the reaction irradiated in a Biotage Initiator microwave at 120° C. for 15 minutes. The black reaction mixture was then diluted with water (50 mL) and extracted with dichloromethane three times. The combined organic layer was treated with Silicycle Si-thiol (30 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (15-60% acetonitrile/water with 0.1% NH4OH) afforded the title compound as a yellow oil, which was subsequently lyophilized from 1 mL of water and then triturated with hexanes and dried under a nitrogen stream to afford the title compound as a white solid (61%). MS(ES)+ m/e 500.3 [M+H]+.
Reaction SMILES: [CH2:1]([C@@:4]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br.CO>C(Cl)Cl.[Cl-].[Na+].O>[CH2:1]([C@@:4]1([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(OC)cc2)C(=O)O1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(O)cc2)C(=O)O1
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one (0.1094 g, 0.30 mmol, 1.0 equiv) in 6 mL of dry CH2Cl2 was cooled to −78° C. At this temperature, BBr3 (1.0 M solution in CH2Cl2, 0.6 mL, 0.60 mmol, 2.0 equiv) was added under N2 atmosphere. After 1 h, the reaction mixture was stirred at an ice bath for further 3 h. After the reaction mixture was cooled with a dry ice—acetone bath, surplus of BBr3 was hydrolyzed with methanol (3 mL). The mixture was then treated with brine, diluted with CH2Cl2, and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 ml/min) to afford 0.0669 g (64%) of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-hydroxyphenyl)ethyl)-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.57 min, m/z 356 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.23-7.18 (m, 2H), 7.00-6.96 (m, 2H), 6.63 (d, J=8.8 Hz, 2H), 6.43 (d, J=8.2 Hz, 2H), 5.64-5.54 (m, 1H), 5.34 (q, J=7.0 Hz, 1H), 4.96-4.89 (m, 2H), 2.93-2.88 (m, 1H), 2.50 (d, J=7.0 Hz, 2H), 2.34-2.29 (m, 1H), 2.18-2.03 (m, 2H), 1.36 (d, J=7.0 Hz, 3H); 19F NMR (376 MHz, CD3OD) δ −117.48 (m).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:17][C:18]1([CH3:49])[O:23][C:22](=[O:24])[CH:21]([CH2:25][CH2:26][CH2:27][S:28][C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20](=[O:48])[O:19]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[C:13]([C:11]1[CH:12]=[C:3]([CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=1)[CH2:2][C:21]1([CH2:25][CH2:26][CH2:27][S:28][C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:22](=[O:24])[O:23][C:18]([CH3:49])([CH3:17])[O:19][C:20]1=[O:48])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC1(C)OC(=O)C(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O1
Reactant: COC(=O)c1cc(CBr)cc(C(C)(C)C)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: COC(=O)c1cc(CC2(CCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)OC(C)(C)OC2=O)cc(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of methyl 3-bromomethyl-5-tert-butylbenzoate (10.3 g, 36.1 mmol), 2,2-dimethyl-5-[3-[(triphenylmethyl)-thio]propyl]-[1,3]dioxane-4,6-dione IX (13.8 g, 30.0 mmol), and benzyltriethylammonium chloride (6.38 g, 30 mmol) in acetonitrile (90 mL) was added potassium carbonate (4.35 g, 30 mmol) at 25° C., and the reaction mixture was stirred at 60° C. overnight (the synthesis of compound IX was previously described in International Publication No. WO 00/01668). The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and a 10% aqueous KHSO4 solution. The organic layer was dried over MgSO4, concentrated. The crude material was recrystallized from ethyl acetate/hexane mixture to afford 5-(3-tert-butyl-5-methoxycarbonyl-benzyl)-2,2-dimethyl-5-[3-[(triphenyl-methyl)thio]propyl]-[1,3]dioxane-4,6-dione X (14.0 g, 79%) as a white solid: 1H NMR (CDCl3) δ 0.7 (s, 3H), 1.3 (s, 9H), 1.2–1.3 (m, 2H), 1.5 (s, 3H), 2.0 (m, 2H), 2.2 (m, 2H), 3.3 (s, 2H), 3.8 (s, 3H), 7.2–7.4 (m, 16H), 7.6 (s, 1H), 7.8 (s, 1H); 13C NMR (CDCl3) δ 24.8, 29.1, 29.4, 31.2, 31.4, 34.9, 40.3, 43.7, 52.3, 57.3, 66.8, 105.8, 126.0, 126.8, 128.0, 128.5, 129.6, 130.5, 132.3, 135.3, 144.8, 152.4, 167.1, 168.5.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[OH:6][CH:7]([CH3:11])[C:8](=O)[CH3:9].C(NCC)C>CO>[NH2:4][C:3]1[O:6][C:7]([CH3:11])=[C:8]([CH3:9])[C:2]=1[C:1]#[N:5]
Reactant: CC(=O)C(C)O
Reactant: N#CCC#N
Solvent: CCNCC
Solvent: CO
Product: Cc1oc(N)c(C#N)c1C
Temperature: 10 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
To a solution of malononitrile (28.2 g) in methanol (30 mL) is added a suspension of acetoin (25 g) in methanol (30 mL) and thereto is added dropwise diethylamine (11 mL) under ice-cooling (internal temp.: 10° C.). The mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice water (300 mL) and the precipitated crystals are collected by filtration to give 2-amino-4,5-dimethyl-3-furonitrile (28.91 g, yield; 75%) as colorless crystals.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:36])[CH2:13][C:14]1[N:15]=[C:16]([N:19]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[S:17][CH:18]=1)[CH3:10].CI>C1COCC1>[CH2:9]([O:11][C:12](=[O:36])[CH:13]([C:14]1[N:15]=[C:16]([N:19]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[S:17][CH:18]=1)[CH3:1])[CH3:10]
Reactant: CCOC(=O)Cc1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of lithium diisopropylamide (prepared in situ) (4.24 g, 39.6 mmol) in dry THF (40 mL) was added the solution of {2-[tert-butoxycarbonyl-(4-methoxy-benzyl)-amino]-thiazol-4-yl}-acetic acid ethyl ester (8.0 g, 19.68 mmol) in 20 mL of dry THF in a dropwise fashion at −78° C. The reaction mixture was continued to stir at −78° C. for 1 hour followed by the addition of methyl iodide (4.19 g, 29.52 mmol) at the same temperature. The reaction mixture was kept on stirring and slowly allowed to come to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo to get the sticky compound (8.2 g). The compound was used for the next reaction without any purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:14]([O:16][C:17]([C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH2:34]Br)=[O:18])[CH3:15].[Br-]>C(#N)C>[CH2:14]([O:16][C:17]([C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=2)=[N:21][C:20]=1[CH2:34][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1COc1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
Phenol (0.518 g, 5.5 mmol) is combined with anhydrous acetonitrile (20 mL) and cesium carbonate (2.3 g, 10 mmol) and allowed to stir at room temperature under nitrogen. To the reaction is added 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.97 g, 5.00 mmol). The reaction is monitored by TLC until all of the bromide is consumed. The reaction is diluted with ethyl ether (100 mL), then 0.1N NaOH (50 mL) is added. The two phases are separated, then the organic layer is washed with water (50 mL) and brine (50 mL). The organic layer is dried over anhydrous sodium sulfate, then concentrated. The material is further purified using flash chromatography to yield 1.75 g or 86% yield of the product.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccc2C(F)(F)F)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(trifluoromethyl)benzyl bromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, (8S)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (82%) as a colorless solid: mp 137-138° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.7 Hz, 1H), 7.52-7.33 (m, 2H), 7.22-7.12 (m, 3H), 7.07-7.00 (m, 1H), 6.61 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.26 (d, J=17.1 Hz, 1H), 5.07 (d, J=17.1 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.23-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.9, 155.4, 144.8, 141.8, 138.4, 133.9, 132.5, 132.1, 129.0, 127.9 (q, 2JC-F=30.8 Hz), 127.6, 126.8, 126.4 (q, 5JC-F=5.8 Hz), 124.4 (q, 1JC-F=273.8 Hz), 124.1, 123.8, 120.8, 111.6, 109.2, 99.6, 80.3, 64.5, 64.0, 58.2, 40.6 (q, J=3.4 Hz); MS (ES+) m/z 454.0 (M+1); Anal. Calcd. for C25H18F3NO4: C, 66.22; H, 4.00; N, 3.09. Found: C, 66.06; H, 3.98; N, 3.12.