Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C=[CH:18][CH:19]=1)[C:5]([CH:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9](=[O:16])[O:8]1)=O.[OH-:20].[Na+].Cl.O>CO.O1CCCC1>[OH:20][CH2:18][C:19]1[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:7]=1[C:11]1[C:10]([C:9]([OH:8])=[O:16])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: [OH-]
Reactant: O=C1OC(C(=O)c2cccc(Cl)c2)c2ncccc21
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cccnc1-c1cccc(Cl)c1CO
Temperature: 75 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
7-(3-Chlorobenzoyl)-furo[3,4-b]pyridin-5-one (4.77 g, 19.4 mmoles) and 0.2N sodium hydroxide (21.4 mmoles) was dissolved in methanol and tetrahydrofuran (100 ml, 1:1). The mixture was heated to 75° C. and stirred for 3 hours and cooled. 1N Hydrochloric acid (20 ml) and water (200 ml) was added to the mixture. The resulting solution was extracted with ethyl acetate and dried over Na2SO4. The solution was filtered and the solvent removed yielding 4.94 g (96.8%) of 2-(hydroxymethyl-3-chlorophenyl)-3-carboxypyridine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:15](=O)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)([O:3][CH3:4])=[O:2].C(N(CC)CC)C.Cl[SiH](Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:8]=[C:7]([P:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:5]([C:1]([O:3][CH3:4])=[O:2])[CH:10]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(C(=O)OC)cc(P(=O)(c2ccccc2)c2ccccc2)c1
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)OC)cc(P(c2ccccc2)c2ccccc2)c1

Procedure:
To a mixture of 17.0 g (4.31×10-2 mol) of 3,5-dicarbomethoxyphenyldiphenylphosphine oxide (from Preparation 3), 4.71 g (4.65×10-2 mol) of triethylamine and 196 ml of dry toluene under nitrogen was added 6.76 g (4.74×10-2 mol) of trichlorosilane. The mixture was then heated at reflux for 15.25 hr and cooled. A solution of 20% sodium hydroxide (49 ml) was added and the mixture was stirred. The organic layer was separated, washed with two 250 ml portions of water, dried over MgSO4 and concentrated to an oil which crystallized. The solid was recrystallized twice from methanol and dried. The yield of 3,5-dicarbomethoxyphenyldiphenylphosphine was 14.0 g (85.8% of theory); mp=103°-4.5° C.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])O[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[O:17]=[S:18]1(=[O:34])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:20]([CH2:28]C(OCC)=O)=[N:19]1.[H-].[Na+].C(O)(=O)C>C1COCC1.Cl>[CH2:1]([N:5]1[C:10]2[C:9](=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]([OH:15])=[C:28]([C:20]2[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:18](=[O:34])(=[O:17])[N:19]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)oc(=O)c2cccnc21
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2ccccc2N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2cccnc21
Temperature: 0 °C
Yield: 32.6 %

Procedure:
To a solution of the product of Example 1B (0.220 g, 1.0 mmol) and the product of EXAMPLE 1C (0.268 g, 1.0 mmol) in anhydrous THF (10 mL) under nitrogen at 0° C. was added sodium hydride (95%, 0.10 g, 4.0 mmol). The reaction was heated to reflux for 3 hours, cooled to 0° C., and to it was added dropwise glacial acetic acid (2 mL). The resulting mixture was heated to reflux for 2 hours, cooled to ambient temperature, and diluted with aqueous hydrochloric acid (0.1 M, 10 mL). The resulting precipitate was collected by filtration, washed with water and diethyl ether and dried to give the title compound (0.130 g, 33%). MS (ESI−) m/z 397 (M−H)−.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:18]=[C:17]([C:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])([O-:8])=[O:7].[CH2:22]=[C:23]([CH3:25])[CH3:24]>O1CCOCC1.CCOC(C)=O>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:17]([C:19]([O:21][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:20])=[CH:18][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: C=C(C)C
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 120 h
Yield: 73 %

Procedure:
Sulfuric acid conc (5 ml) was added to a solution of 1-methyl 2-nitroterephthalate (25.2 g, 0.112 mmol) in dioxane (120 ml) in a Parr shaker bottle and cooled to 0° C. Isobutene (100 ml) was added, the vessel was sealed, and vigorously shaken for 5 days. The crude product was dissolved in EtOAc after evaporation of the excess isobutene and washed with sat NaHCO3. The organic layer was dried over MgSO4, filtered, and evaporated leaving 23.0 g (73%) of 2-nitroterephthalic acid 4-tert-butyl ester 1-methyl ester as a yellow liquid.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[CH:15](Br)([CH3:17])[CH3:16]>>[CH:15]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)([CH3:17])[CH3:16]
Reactant: CC(C)Br
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Product: CC(C)n1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano-[3,2-b]indol-4(5H)-one is alkylated with isopropyl bromide to give 2.4 g of product, mp 154°-6° C., after recrystallization from methylene chloride-hexane.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].BrC[C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2.O>CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:21][C:36]2[CH:37]=[CH:38][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)[C:4]2[CH:10]=[C:9]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[N:6]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Reactant: BrCc1cccc2ncccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc2cccnc12
Temperature: 80 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
A mixture of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (500 mg, 1.82 mmol), K2CO3 (502 mg, 3.64 mmol) and 5-(bromomethyl)quinoline (424 mg, 1.91 mmol) in DMF (25 mL) was stirred at 80° C. for 18 h. The reaction mixture was cooled, poured into water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried by Na2SO4 and concentrated. The resulting residue was purified by silica gel chromatography eluted with EtOAc:MeOH=100:1 to give the crude product (350 mg, 46%), finally it was purified by Prep-HPLC to give the product (180 mg, 24%) as a red solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.52 (s, 3H), 3.03 (t, 4H, J=4.8 Hz), 3.70 (t, 4H, J=4.8 Hz), 3.88 (s, 3H), 6.08 (s, 2H), 6.87 (d, 1H, J=7.5 Hz), 7.31 (d, 1H, J=2.1 Hz), 7.36 (d, 1H, J=2.1 Hz), 7.48 (t, 1H, J=7.5 Hz), 7.66 (dd, 1H, J=4.2, 8.4 Hz), 7.93 (d, 1H, J=7.5 Hz), 8.44 (dd, 1H, J=1.8, 8.4 Hz), 9.05 (dd, 1H, J=1.8, 4.2 Hz); LC-MS: m/e=417 [M+1]+
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:15]([N:19]([CH3:21])C)[N:16](C)C)(C)(C)C.Cl.[NH2:23]C(N)=N.[Na]>>[N:23]1[C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]=2[CH:21]=[N:19][C:15]=1[NH2:16]
Reactant: N=C(N)N
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=C1CCCCCCC1
Agent: Cl
Agent: [Na]
Product: Nc1ncc2c(n1)CCCCCC2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Cyclooctanone (5.0 g, 39.7 mmol) and t-butoxy bis(dimethylamino)methane (6.9 g, 39.7 mmol) were heated at 100° C. for 18 h. The solvent was removed under vacuum. The crude residue was taken up in anhydrous ethanol (80 mL). Guanidine hydrochloride (7.6 g, 0.08 Mol, 2 eq.) and sodium metal (1.84 g, 0.08 Mol) were added. After the sodium dissolved, the mixture was heated to reflux for 41 h. After cooling to ambient temperature, sodium metal (0.47 g) and guanidine hydrochloride (1.5 g) were added and heating was resumed for another 23 h. The reaction mixture was concentrated under vacuum and then partitioned between chloroform and water. The aqueous layer was extracted once with chloroform. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under vacuum to give 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-amine as a pale yellow solid, 5.51 g; 1H NMR (CDCl3, 300 MHz) 7.92 (s, 1H), 5.19 (br s, 2H), 2.67 (m, 2H), 2.57 (m, 2H), 1.74 (m, 2H), 1.59 (m, 2H), 1.25-1.50 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz) 170.41, 162.09, 157.55, 123.62, 34.19, 32.60, 30.14, 28.64, 26.30, 26.05; MS(ES) 178 (M+H). The aniline, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-amine, can be used to make the corresponding hydrazine as outlined below, or alternatively, can be used as an aniline (B) as outlined in Reaction Scheme 1 above.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=2[C@:13]([C@@H:21]2[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]2)([OH:20])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=2[C@:13]([C@@H:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)([OH:20])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH2:3][CH2:2]1
Reactant: COCCCC[C@@](O)(c1cccc(F)c1OCC1CC1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCC[C@@](O)(c1cccc(F)c1OCC1CC1)[C@@H]1CCCNC1
Yield: 42.5 %

Procedure:
A solution of (R)-tert-butyl 3-((S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (120 mg) in 20% TFA/CH2Cl2 (20 mL) was stirred at 0° C. for 5 min. The solvent was neutralized by addition of sat'd aq NaHCO3, and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4 and evaporated to give the crude product. LC-MS analysis of the crude product indicated the presence of two isomers (10:1). The crude product was purified by reverse phase prep HPLC to afford the major isomer, (S)-1-(2-(cyclopropylmethoxy)-3-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (40 mg, 42%). 1H NMR (400 MHz, CD4O): 0.36 (m, 2H), 0.63 (m, 2H), 0.86 (m, 1H), 1.55-1.11 (m, 1H), 1.82 (m, 1H), 2.29 (m, 2H), 2.45 (m, 1H), 2.66 (t, 1H), 2.94 (d, 1H), 3.24 (s, 3H), 3.31 (m, 2H), 3.91 (m, 2H), 6.98 (m, 2H), 726 (m, 1H). MS (E/Z): 366 (M+1). In addition, 2-fluoro-6-((S)-1-hydroxy-5-methoxy-1-((R)-piperidin-3-yl)pentyl)phenol was isolated as a byproduct.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(OCC)C>[C:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1CCNCC1
Solvent: CCOCC
Product: CC(=O)N1CCC(C(=O)O)CC1
Reaction time: 8 h

Procedure:
A mixture of 300 g (2.32 mol) of isonipecotic acid and 1,200 ml of acetic anhydride is heated under reflux for 2 hours in a 4 liter reactor equipped with a mechanical stirrer, a condenser and a thermometer, and the mixture is left to stand overnight. 1 liter of diethyl ether is added to the mixture, which is starting to crystallise, the solid is filtered off and the cake is washed with diethyl ether (4×500 ml), drained and recrystallised from a 40/60 mixture of diisopropyl ether/isopropyl alcohol. 153 g are isolated in a first crop and 141 g in a second crop. The N-acetylisonipecotic acid obtained melts at 148° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>O1CCCC1>[C:27]([O:13][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[C:3]([C:1]#[N:2])[CH:12]=2)[NH:7][C:8](=[O:15])[C:9]1=[O:14])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)On1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(C#N)cc21
Yield: 90.6 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.3 ml (2.18 mmol) dry triethylamine and 0.15 ml (2.10 mmol) acetyl chloride. The mixture was refluxed for 3 h, and then evaporated in vacuo. The residue was stirred with water to give 0.42 g (92%) of 1-acetoxy-7-cyano-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione. M.p. 230° C. 1H-NMR (DMSO-d6): 8.16 (1H, s), 7.53 (1H, s), 2.37 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[OH-].[Na+].C(OCCO)C.[CH2:16]([O:20][CH2:21][CH:22]=[CH2:23])[CH:17]1[O:19][CH2:18]1>N(C1C=CC(O)=CC=1)=O.O>[OH:19][CH:17]([CH2:16][O:20][CH2:21][CH:22]=[CH2:23])[CH2:18][NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5]
Reactant: NCCS(=O)(=O)O
Reactant: C=CCOCC1CO1
Agent: O=Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCCO
Product: C=CCOCC(O)CNCCS(=O)(=O)O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 40.2 %

Procedure:
Into a 2 liter volume flask equipped with a stirrer, taurine (125 g), sodium hydroxide (40 g), deionized water (200 g) and ethylene glycol monoethyl ether (600 g) were charged. The contents were maintained at 60° C. while stirring, and a mixture of allyl glycidyl ether (114 g) and p-nitrosophenol (0.1 g) was dropwise added thereto in 20 minutes. Thereafter, stirring was continued for 2 hours. The reaction mixture of pH 9 was treated with an ionic exchange resin (Amberlite IR-120) to eliminate Na+ ion, whereby a solution of pH 4 was obtained. The solution was concentrated in a rotary evaporator to make a 7/10 volume so that needle crystals were precipitated. These crystals were identified to unreacted taurine by NMR and IR. The filtrate was poured into a 3 time volume of acetone to precipitate brown oily materials. The oily materials were collected and dried in vacuo as give N-(2-hydroxy-3-allyloxypropyl)taurine (96 g) of the formula: ##STR7##
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH:7]1([Mg]Cl)[CH:11]=[CH:10][CH:9]=[CH:8]1>>[CH2:2]=[CH:3][CH2:4][CH:5]([C:8]1[CH2:7][CH:11]=[CH:10][CH:9]=1)[CH3:6]
Reactant: Cl[Mg]C1C=CC=C1
Reactant: C=CCCCBr
Product: C=CCC(C)C1=CC=CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-1-pentene (100 g of 95 wt %, 0.637 mol) was added cyclopentadienyl magnesium chloride (700 mL of 1 M solution in THF, 0.7 mol) at 0° C. in an hour. After stirring for an additional 30 minutes at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a yellow-brown liquid (98 g, crude penten-4-ylcyclopentadiene). To the crude penten-4-yl-cyclopentadiene (89 g, ca. 0.579 mol, theoretical number=(89/98)*0.637) dissolved in THF (500 mL) was added n-BuLi (60 mL of 10 M in hexanes, 0.6 mol) at −78° C. The mixture was warmed up to room temperature and stirred overnight. The anion solution was added to benzophenone (110 g, 0.604 mol) dissolved in THF (500 mL) at 0° C. in 25 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 40° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (145 g, 84% yield based on 5-bromo-1-pentene) as a dark red viscous oil.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH2:15][CH2:16][CH:17]1[O:22][CH2:21][CH2:20][CH2:19][O:18]1)[C:10]([O:12]CC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1CO.O>[CH2:1]([NH:8][CH:9]([CH2:15][CH2:16][CH:17]1[O:18][CH2:19][CH2:20][CH2:21][O:22]1)[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCC1OCCCO1)NCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: OCC1CCCO1
Product: O=C(O)C(CCC1OCCCO1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.5 %

Procedure:
A mixture of ethyl 2-benzylamino-4-(1,3-dioxan-2-yl)butyrate (77.5 g, 0.252 mol) and lithium hydroxide monohydrate (15.87 g, 0.378 mol) in tetrahydrofuran-methanol-water (1:3:1; 1 L) was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the aqueous residue was diluted with water (200 mL), washed with diethyl ether (200 mL) and freeze dried. The residue was purified by flash chromatography (silica gel, 20-30% MeOH/CH2Cl2) to give 59.5 g (85%) of the title compound as a white solid. δH (360 MHz, d6 -DMSO/D2O) 1.29 (1H, br d, J=13.4 Hz), 1.54 (2H, m), 1.63 (2H, m), 1.79 (1H, m), 3.05 (1H, t, J=6.0 Hz), 3.64 (2H, m), 3.80 (1H, d, J=13.1 Hz), 3.91-3.94 (3H, m), 4.44 (1H, t, J=5.1 Hz), 7.32-7.39 (5H, m), m/e (ES+) 280 (M+H)+, 204 (M-C6H5 +2H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:2]1.S(Cl)(Cl)=O>COCCOCCOC.N1C=CC=CC=1>[S:1]1[C:2]2[C:9](=[O:11])[CH2:8][CH2:7][CH2:6][C:3]=2[CH:4]=[CH:5]1
Reactant: O=C(O)CCCc1ccsc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: COCCOCCOC
Product: O=C1CCCc2ccsc21
Temperature: 70 °C
Yield: 69.3 %

Procedure:
The product from Step D (1.8 g, 11.0 mmol) was dissolved in 2-methoxyethyl ether (2 mL) and added thionyl chloride (0.89 mL, 12.2 mmol) and pyridine (1 drop) and heated to 70° C. for 24 hours. The mixture was purified by column chromatography (silica gel, 0-15% ethyl acetate/hexanes as an eluent) to provide 5,6-dihydro-4H-benzothiophen-7-one (1.16 g, 72%): 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J=4.9 Hz, 1H), 6.97 (d, J=4.9 Hz, 1H), 2.89-2.87 (m, 2H), 2.63-2.60 (m, 2H), 2.21-2.16 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[CH2:9]([N:11]=[C:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:20])=[CH:13]1)[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]([N:11]([CH2:9][CH3:10])[C:12]1[CH:13]=[C:14]([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH:17]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCN=C1C=C(C)CC(C)(C)C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(C(=O)COC(C)=O)C1=CC(C)(C)CC(C)=C1
Temperature: -5 °C
Reaction time: 1 h
Yield: 1076.8 %

Procedure:
2-Acetoxyacetyl chloride (6.42 g, 4.7 mmol) is added slowly to a mixture of 1A (7.62 g, 4.2 mmol) and toluene (50 ml), which is cooled to −5° C. After the addition is complete, the mixture is stirred for a further 1 hour at −5° C., then allowed to warm to room temperature and stirred for a further 1.5 hours. The reaction mixture is then cooled down to −3° C. and a mixture of triethylamine (6.5 ml, 4.7 mmol) and toluene (25 ml) is added slowly to the mixture. The mixture is stirred for a further 16 hours, during which time the temperature is gradually allowed to rise to room temperature. The mixture is filtered, and the filtrate is washed three times with water, dried over sodium sulfate and evaporated in vacuo to give the crude product (12.0 g, 89%) as an oil. A portion of this crude material (4 g) is purified by flash column chromatography, eluting with a mixture of ethyl acetate and petroleum ether (1:4) to give pure product (2.3 g, equivalent to 51% overall), with m.p. 38-40° C. NMR analysis of this indicates that the product has a purity of about 88 mol %, the impurity consisting mainly of two isomeric products.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1.ClCCCl.CN(C=O)C>ClCCCl.CN(C=O)C>[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][N:26]2[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[N:15]5[C:11]([S:12][CH:13]=[CH:14]5)=[N:10][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=4)[CH:22]=[CH:21][N:20]=3)[CH2:25]2)=[CH:40][CH:39]=1
Reactant: Fc1ccc(-c2nc3sccn3c2-c2ccnc(NC3CCCNC3)n2)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1ccc(CN2CCCC(Nc3nccc(-c4c(-c5ccc(F)cc5)nc5sccn45)n3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
The racemic 4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[piperidin-3-yl]pyrimidin-2-amine hydrochloride (70 mg g, 0.15 mmol) was dissolved in a 80/20 mixture of DCE and DMF (1.2 ml) and treated with three equivalent of triethylamine (63 uL). The 4-fluorobenzaldehyde (19 mg, 0.15 mmol) was added, followed by a 0.2 M solution of Me4NBH(OAc)3 in 80/20 DCE/DMF (1.2 ml). The mixture was stirred at room temperature for 18 hours. The mixture was washed with a 1N sodium hydroxide solution (2 ml). Concentration in vacuo followed by purification on reverse phase HPLC provides the title compound as a pale yellow solid (42.4 mg, 56%). M.p.=131-133° C. 400 MHz 1H NMR (DMSO-d6) δ: 8.73 (br. s, 1H), 8.06 (d, J=5.1 Hz, 1H), 7.64-7.58 (m, 2H), 7.44 (d, J=4.7 Hz, 1H), 7.35-7.31 (m, 2H), 7.30-7.23 (m, 2H), 7.07 (t, J=8.8 Hz, 2H), 7.00 (br. s, 1H), 6.29 (d, J=5.1 Hz, 1H), 4.00-3.90 (m, 1H), 3.49 (s, 2H), 2.96-2.90 (m, 1H), 2.69-2.62 (m, 1H), 2.08-1.94 (m, 2H), 1.93-1.85 (m, 1H), 1.76-1.67 (m, 1H), 1.61-1.48 (m, 1H), 1.42-1.30 (m, 1H). LCMS: 503 [M+H].
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([C:22]2([Cl:25])[CH2:24][CH2:23]2)=O)=[CH:14][CH:13]=1.[OH-].[K+].OO>C(O)(C)(C)C>[Cl:25][C:22]1([C:20]2([CH2:19][CH2:18][C:15]3[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=3)[CH2:10][O:9]2)[CH2:23][CH2:24]1
Reactant: COS(=O)(=O)OC
Reactant: O=C(CCc1ccc(Cl)cc1)C1(Cl)CC1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CSC
Product: Clc1ccc(CCC2(C3(Cl)CC3)CO2)cc1
Temperature: 30 °C
Reaction time: 14 h
Yield: 74.4 %

Procedure:
16 ml (0.22 mol) of dimethyl sulphide and 24.2 g (0.19 mol) of dimethyl sulphate are added to 30 ml of tert.-butanol and the mixture is allowed to stand for 14 hours at 20° C. A solution of 17 g (0.07 mol) of 1-chlorocyclopropyl 4-chlorophenylethyl ketone in 70 ml of tert.-butanol is initially added dropwise with stirring to the reaction mixture and 22 g of potassium hydroxide powder are then introduced, the temperature of the reaction mixture being held t 20° to 30° C. The mixture is stirred for a further 3 hours at 30° C., then the dimethyl sulphide is stripped off under reduced pressure and the reaction mixture is then poured into 50 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted using ethyl acetate. The organic phase is washed using water and is concentrated by stripping off the solvent under reduced pressure after drying over sodium sulphate. In this manner, 13.4 g (75% of theory) of 2-(1-chlorocyclopropyl)-2-(4-chlorophenylethyl)-oxirane are obtained in the form of an oily product, which is further reacted without additional purification. ##STR68##