Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:3]([O:5][C@H:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:7][C:8]([O:10]C)=O)=[O:4].C([Mg]Cl)(C)(C)C>O1CCCC1>[CH2:23]([C:2]1[C:3](=[O:4])[O:5][C@H:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:7][C:8]=1[OH:10])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Yield: 97 %

Procedure:
While the α-halo ester III and the reactive species generating reagent can be combined or added in any sequence, it has been found that when the reactive species generating reagent is a Grignard reagent a simultaneous addition of the α-halo ester III and the Grignard reagent is particularly preferred. For example, simultaneous addition of 13.6 mL solution of 30.7 mmol of methyl (3R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoate in tetrahydro-furan (THF) and 3 equivalents of tert-butyl magnesium chloride in 86 mL of THF over a one hour period to a 60° C. reaction vessel containing about 10 mL of THF solvent resulted in 97% yield (A.N., i.e., area normalized) of (6R)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one when the crude product was analyzed by a gas chromatography 1 hr after the complete addition of reagents.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.C([O:11][C:12](=O)[CH2:13][C:14]([CH2:16][Cl:17])=O)C>>[Cl:8][C:5]1[S:4][C:3]2=[N:2][C:14]([CH2:16][Cl:17])=[CH:13][C:12](=[O:11])[N:7]2[CH:6]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Product: O=c1cc(CCl)nc2sc(Cl)cn12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
2-amino-5-chloro-thiazole hydrochloride (8 g) was reacted with ethyl-4-chloroacetoacetate (15.8 g) in polyphosphoric acid (40 g) under stirring at 110° C. for 1 hour. After cooling, dilution with water and neutralization with 35% NaOH, the precipitate was filtered and washed with water. Crystallization from isopropyl ether gave 2-chloro-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 123°-125° C. (7.45 g), which was reacted with triphenylphosphine (9.42 g) in acetonitrile (100 ml) under stirring at reflux temperature for 10 hours. After cooling the precipitate was filtered and washed with acetonitrile to give (2-chloro-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl)-methyl-triphenylphosphonium chloride, m.p. 300°-310° C. dec. (10 g) which was suspended in dimethylsulfoxide (40 ml) and treated with potassium tert-butoxide (2.48 g) dissolved in dimethylsulfoxide (40 ml) at room temperature under stirring for 10 minutes. To the solution of the ylide so obtained 5 -formyl-2-methyl-thiazole (3.1 g) dissolved in dimethylsulfoxide (20 ml) was added and the reaction mixture was kept under stirring at room temperature for 15 minutes: after dilution with ice water and neutralization with NaH2PO4 the precipitate was filtered and crystallized from CH2Cl2 -methanol to give 3.4 g of 2-chloro-7-trans-[2-(2-methyl-5-thiazolyl)-ethenyl]-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 224°-226° C., NMR (CDCl3) δ ppm: 2.97 (s) (3H, --CH3), 6.61 (s) (1H, C-6 proton), 6.78 (d) (1H, β-ethenyl proton), 7.82 (d) (1H, α-ethenyl proton), 7.88 (s) (1H, C-3 proton), 8.02 (s) (1H, C-4 thiazolyl proton); JHαHβ =16 Hz.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[CH3:17].[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O.CS(C)=O>[CH3:17][C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Reactant: O=Cc1cccc(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
2-Bromo-1,3-dimethyl-5-[3-(methylsulfonyl)propoxy]benzene (1.0 g), 3-formylphenylboronic acid (0.49 g, 1.05 eq), tripotassium phosphate (1.32 g, 2.0 eq), 10% Pd—C(PE) (0.1 g, 1.38 mol %), rac-BINAP (26.8 mg, 1.38 mol %), dimethyl sulfoxide (10 mL) and water (5 mL) were added. After nitrogen substitution, the mixture was stirred at 80° C. for 3 hr. The obtained reaction mixture was analyzed by high performance liquid chromatography to find the title compound (91.2% peak area).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[CH3:17].[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].O[Li].O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[Pd](Cl)Cl.O.CN(C)C(=O)C>[CH3:17][C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Li]O
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
2-Bromo-1,3-dimethyl-5-[3-(methylsulfonyl)propoxy]benzene (1.0 g), 3-formylphenylboronic acid (0.49 g, 1.05 eq), LiOH.H2O (0.26 g, 2.0 eq), palladium chloride (11 mg, 2 mol %) and 2-(dicyclohexylphosphino)biphenyl (44 mg, 4 mol %) were charged in a reaction container, and N,N-dimethylacetamide (10 mL) and water (5 mL) were added thereto. After nitrogen substitution, the mixture was stirred at 60° C. for 3 hr. The obtained reaction mixture was analyzed by high performance liquid chromatography to find the title compound (94.0% peak area).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)=[CH:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Brc1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Temperature: 155 °C
Yield: 42.2 %

Procedure:
A mixture of carbazole (300 mg, 1.81 mmol), 4,4′-dibromobiphenyl (846 mg, 2.71 mmol), copper (344 mg, 5.43 mmol), 18-crown-6 (187 mg, 0.71 mmol), potassium carbonate (750 mg, 5.43 mmol), and anhydrous N,N-dimethylformamide (10 mL) was degassed for 30 minutes. The resulting mixture was then heated to about 155° C. for 66 hours under argon. After cooling, the resulting mixture was poured into methylene chloride (400 mL) and the subsequent mixture was filtered. The filtrate was loaded on silica gel. A flash column (silica, 10% methylene chloride in hexane) and reprecipitation in methylene chloride/hexanes yielded 304 mg (42% yield) of pure product; confirmed by HNMR.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:14][CH2:13]1
Reactant: ClCc1nc2cccnc2s1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc(N2CCN(Cc3nc4cccnc4s3)CC2)nc1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 2-(1-piperazinyl)pyrimidine (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.65 (m, 4H) 3.80 (m, 4H) 4.04 (s, 2H) 6.63 (t, J=4.92 Hz, 1H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.34 (m, 2H) 8.43 (d, J=4.75 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 313 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[CH:15]3)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1

Procedure:
To a cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride in DCM (60 mL), obtained as described above for Intermediate 7, step 1 (798 mg; 4.51 mmol) was added dropwise, during a period of 30 minutes, a solution of 5-aminoindazole (Aldrich, 500 mg; 3.76 mmol) and DIEA (1.29 ml; 7.51 mmol) in dry DMF (5 mL). At the end of addition the reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. A white precipitate separated from the organic phase. It was filtered and dried in vacuo to afford the title compound as a beige solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].O.N>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:16]2[NH:10][C:11](=[O:12])[NH:13][C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccc(O)cc1
Agent: N
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccc(O)cc2)N1
Temperature: 90 °C
Yield: 82.9 %

Procedure:
In a 200 mL egg-plant shaped flask, 14.7 g (120 mmol) of 4-hydroxybenzaldehyde was mixed with 15.6 g (156 mmol) of hydantoin, 80 mL of water, and 14.4 g of 28% ammonia water, and the mixture was heated at 90° C. for 12 hours with stirring. After the liquid reaction mixture was cooled to room temperature, the precipitated crystals were collected by filtration. The crystals were then washed twice with water and twice with ethanol. The crystals were dried to give 20.3 g of 5-(4-hydroxybenzylidene)hydantoin. Subsequently, 18.8 g (92.2 mmol) of the product was added to a 500 mL egg-plant shaped flask and then dissolved in 180 mL of N,N-dimethylformamide. To the solution were added to 27.1 g (221 mmol) of ethyl chloroacetate and 30.5 g (221 mmol) of potassium carbonate. The mixture was heated at 120° C. for 2 hours with stirring. After the liquid reaction mixture was cooled to room temperature, the solvent was removed by distillation under reduced pressure. Water was added to the residue, and then the mixture was extracted three times with ethyl acetate. The organic layers were collected, washed twice with water and once with saturated brine, and then dried with sodium sulfate. The sodium sulfate was then removed by filtration. After the solvent was removed by distillation under reduced pressure, the resulting brown crystals were recrystallized with a mixed solvent of ethyl acetate and hexane. The crystals were then dried to give 9.96 g of 5-[4-(2-ethoxy-2-oxoethoxy)benzylidene]-3-(2-ethoxy-2-oxoethyl)hydantoin. In a 50 mL egg-plant shaped flask, 4.50 g (12.0 mmol) of the product was mixed with 7.57 g (72.0 mmol) of diethanolamine, and the mixture was heated at 120° C. for 1 hour with stirring. After the liquid reaction mixture was cooled to room temperature, the precipitated yellow crystals were recrystallized with a mixed solvent of ethanol and water. The crystals were then dried to give 4.46 g of compound 3 (yield: 18%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:15])[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)COc2cc(C(=O)O)ccc21
Yield: 94.1 %

Procedure:
To a solution of methyl 3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxylate (0.116 g, 0.562 mmol) in MeOH (6 mL) at rt was added sodium hydroxide (1.969 mL, 1.969 mmol). The mixture was stirred at reflux for 1 h, and then concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2×40 mL). The combine extract was washed with brine (20 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product, 3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid (0.105 g, 0.529 mmol, 94% yield), as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Br[C:13]1[CH:14]=[CH:15][C:16]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[NH:18][C:17]=2[CH:37]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC([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)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([N:21]4[CH2:22][CH2:23][N:24]([C:27]5[C:32]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:30]=[CH:29][N:28]=5)[CH2:25][CH2:26]4)[NH:18][C:17]=3[CH:37]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: FC(F)(F)c1cccnc1N1CCN(c2nc3ccc(Br)cc3[nH]2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ccc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c3c2)cc1F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of 3,4-difluorophenylboronic acid (111 mg, 0.7 mmol, Aldrich) and 6-bromo-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1H-benzoimidazole (213 mg, 0.5 mmol, Example 23c) in ethylene glycol dimethyl ether (2 mL) were added lithium chloride (63 mg, 1.5 mmol, Aldrich) and 2M aqueous sodium carbonate (0.75 mL, 1.5 mmol). Nitrogen gas was bubbled through the mixture for 10 min and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol, Aldrich) was added. The reaction mixture was stirred at 80° C. under nitrogen atmosphere for 16 h, cooled to room temperature, diluted with EtOAc (50 mL) and filtered through Celite® pad. The filtrate was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (55% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 460.2 (M+1).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3(O)[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30]CC)=[O:29])=[CH:4][C:3]=2[O:2]1.[Mg].BrC1C=CC2OCOC=2C=1.C1OC2C=CC([Mg]Br)=CC=2O1.C1OC2C=CC(C3C4C(=CC=CC=4)C(=O)C=3C(OCC)=O)=CC=2O1.Cl>C1COCC1.CCOCC.C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([OH:30])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: Br[Mg]c1ccc2c(c1)OCO2
Agent: Brc1ccc2c(c1)OCO2
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
Ethyl(1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate. To dry magnesium turnings (0.25 g, 10 mmol) under an argon atmosphere was added a solution of 4-bromo- 1,2-methylenedioxybenzene (2.1 g, 10 mmol) in 1: 10 THF Et2O (22 ml). The resulting solution was allowed to stir at room temperature for 2 h. During this time, additional THF (4 ml) was added. The resulting 3,4-methylenedioxyphenylmagnesium bromide was added to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.50 g, 2 mmol) in 1:4 THF/ Et2O (25 ml) under an argon atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 15 min, at which time 1M HCl (50 ml) was added. The phases were separated and the aqueous phase was extracted with Et2O. The combined organic extracts were washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow solid (0.29 g, 42%).
Reaction SMILES: O[CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH2:8][CH2:9][N:10]=2)[CH2:3]1.[C:11]([OH:14])(=[S:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:11]([S:13][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH2:8][CH2:9][N:10]=2)[CH2:3]1)(=[O:14])[CH3:12]
Reactant: CC(O)=S
Reactant: OC1CN(C2=NCCS2)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CN(C2=NCCS2)C1
Reaction time: 1 h
Yield: 65 %

Procedure:
There were added 119 mg of 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) and two molar equivalents of thioacetic acid, while cooled with ice, to 10 ml of tetrahydrofuran solution containing two molar equivalents of triphenylphosphine and two molar equivalents of diethylazodicarboxylate, and the resultant solution was stirred for one hour at the same temperature, and for further one hour at a room temperature. The solvent of the reaction liquid was evaporated in a vacuum, and the obtained residue was subjected to silica gel column chromatography (eluent: chloroform-ethanol), and, thus, there was obtained 107 mg (yield: 65%) of 3-acetylthio-1-(1,3-thiazolin-2-yl)azetidine (7).
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:11])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>>[C:2]1([S:8]([OH:11])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Product: O=S(=O)(O)c1ccccc1
Yield: 80.8 %

Procedure:
To benzenesulfonic acid sodium salt (10.0 g, 0.061 mol), 25% HCl was added dropwise with stirring until the solid dissolved. The reaction mixture was extracted (100 mL each, 3 times) with EtOAc, dried over Na2SO4 and concentrated to give benzenesulfonic acid (7.8 g, 90%). To a 100 mL round bottom with a magnetic stir bar, benzenesulfonic acid (4.61 g, 0.0324 mol), CaCl2(3.6 g, 0.0324 mol) and dry dichloromethane (30 mL) were added. The reaction mixture was cooled to 0° C. and (2S) (5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy-tetrahydrofuran (4.6 g, 0.0216 mol) in dry CH2Cl2 (20 mL) was added. The reaction mixture was stirred for 3 h and monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.25). The reaction mixture was filtered through celite and washed with CH2Cl2 (3 times). The combined organic layer was washed with saturated aqueous Na2CO3, water brine and dried over Na2SO4. Solvent was removed under reduced pressure to afford the crude (2S) (5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetrahydrofuran 14 which was crystallized from chloroform-hexane to give pure white solid, yield 6.8 g (93%), m.p. 102° C.-104° C. 1H NMR (200 MHz, CDCl3): δ 1.90-3.0 (m, 4 H), 3.85-5.0 (m, 4 H), 6.70-7.05 (m, 4 H), 7.45-7.72 (m, 3 H), 7.77-8.0 (m, 2 H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].Cl.[Cl-].[Na+]>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1
Reactant: CC(C(=O)O)c1ccc(C=C2CCCCC2=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: CC(C(=O)O)c1ccc(C=C2CCCCC2O)cc1

Procedure:
2 g of 2-[4-(2-oxocyclohexylidenemethyl)phenyl]propionic acid (which may be prepared as described in United Kingdom Patent Specification No. 2,002,762) and 0.6 g of sodium cyanoborohydride were dissolved in 40 ml of methanol. The pH of the solution was adjusted to a value of 3 by the addition of 6N hydrochloric acid, whilst ice-cooling. The mixture was then heated under reflux for 1 hour, after which a saturated aqueous solution of sodium chloride was added and the mixture was extracted with diethyl ether. The extract was dried and the solvent was then distilled off. The residue was purified by high speed liquid chromatography, to give the desired compound in a crude form. This was recrystallised from a 1:1 by volume mixture of ethyl acetate and hexane, to give 350 mg of the title compound, melting at 135°-136° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:14][NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4.5 g of 1-N-Benzyl-4-phenyl-4-cyanopiperidine (16.3 mmol, Fisher Scientific) in 50 mL of THF was added 49 mL of lithium aluminum hydride (1 M in THF, 49 mmol) and the reaction mixture was stirred for 12 hr at rt. The reaction was quenched by the addition of 5 mL of water, 5 mL of 15% solution of NaOH followed by 5 mL of water. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated to give the title compound which was used without further purification.
Reaction SMILES: BrBr.Br[C:4]1[CH:5]=[C:6]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[O:7][C:8]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:41][N:42](C=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:21][C:19]1[CH:20]=[C:4]([CH:5]=[C:6]([O:7][C:8]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[CH:18]=1)[C:41]#[N:42]
Reactant: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]ncc23)c1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: BrBr
Agent: CC(=O)[O-]
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]ncc23)c1
Temperature: 85 °C
Reaction time: 4.5 h

Procedure:
Bromine (154 g; 0.964 mole; 0.10 eq.) was added to a slurry of zinc (particle size <10 microns; 192 g; 2.940 moles; 0.30 eq.) in DMF (10 L) at room temperature. The resulting mixture was then stirred fast for 30 minutes while 4-(3-bromo-5-chlorophenoxy)-5-chloro-1H-indazole (3.508 kg; 9.798 moles; 1.00 eq., zinc cyanide (690 g; 5.879 moles; 0.60 eq.), triphenylphosphine (308 g; 1.176 moles; 0.12 eq.), palladium acetate (66 g; 0.294 mole; 0.03 eq.) and DMF (11 L) were added at room temperature. The reaction mixture was then degassed for 15 minutes using a subsurface stream of nitrogen, heated to 85° C., and then aged for 4.5 hours. The reaction mixture was then cooled to room temperature and stirred overnight. The reaction mixture was then diluted with THF (18 L) and heated to 50° C., after which aqueous EDTA.3Na (0.5M, 20 L) was added and the mixture aged at 50° C.-60° C. for 1 hour. The mixture was then filtered through solka floc and washed with THF (20 L), and the filtrate transferred to an extractor (100 L) filled with brine (15 L) and separated. The aqueous layer was extracted with EtOAc (15 L), and the combined organic layers were washed with a second portion of EDTA.3Na (0.5M, 20 L), then water (20 L), and then brine (15 L). The solution was treated with activated carbon (Darko KB), filtered through solka floc, concentrated to a slurry of less than 10 L, switched to toluene (6 L), concentrated to half volume, heated to 40° C., added heptane (6 L), and cooled below 25° C. The resulting slurry was filtered, washed with extra toleuene:heptane (1:3; 4 L), heptane (4 L), and dried to provide the title product as a solid.