Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[C:9]([O:18][C:19](=[O:29])[CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:10]3[C:15](=[C:16]([OH:17])[C:6]=2[CH:5]=1)[CH:14]=[CH:13][CH:12]=[CH:11]3)(=[O:3])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31].C(OCC)(=O)C>CN(C=O)C>[C:1]([C:4]1[O:8][C:7]2[C:9]([O:18][C:19](=[O:29])[CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:10]3[C:15](=[C:16]([O:17][C:30](=[O:32])[CH3:31])[C:6]=2[CH:5]=1)[CH:14]=[CH:13][CH:12]=[CH:11]3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1cc2c(O)c3ccccc3c(OC(=O)CNC(=O)OC(C)(C)C)c2o1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c2ccccc2c(OC(=O)CNC(=O)OC(C)(C)C)c2oc(C(C)=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
In an 100 ml round-bottom flask, 0.8 gram (2.0 mmoles) of 2-acetyl-4-hydroxy-9-[(tert-butoxycarbonyl)amino]acetoxy-naphtho[2,3-b]furan (prepared in example 12) was dissolved in 30 ml of DMF with mild heating. To the solution, added 0.9 ml of TEA and 0.5 ml of acetic anhydride. The mixture was sealed or isolated from air, and then had been stirred vigorously at room temperature overnight. After addition of 100 ml of ethyl acetate, the reaction mixture was extracted with 80 ml of ice-cooled aqueous 3% citric acid solution twice, and dried with anhydrous sodium sulfate. The organic phase was evaporated to dryness. Product was purified by silica gel chromatograph using dichloromethane as elution solvent. 0.6 gram (1.36 mmole) of product was obtained with yield of 68.0% and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 1.44 (s, 9H), 2.62 (s, 3H), 2.63 (s, 3H), 4.34 (d, J=6, 2H), 7.67-7.71 (m, 3H), 8.15-8.17 (m, 2H), 8.25 (s, 1H). Mass (M+H) is 442, Mass [M-(tert-butyl)+2H] is 386.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.[O:13]1[CH2:17][CH2:16][C:15](=O)[CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[O:13]1[CH2:17][CH2:16][CH:15]([N:1]2[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]2)[CH2:14]1
Reactant: O=C1CCOC1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C2CCOC2)C1
Reaction time: 8 h

Procedure:
Tert-butyl azetidin-3-ylcarbamate (0.550 g), dihydrofuran-3(2H)-one (0.412 g) and sodium triacetoxyborohydride (1.015 g) were stirred together in dichloromethane (5 mL). After stirring overnight, the reaction was poured into saturated aqueous NaHCO3 solution (25 mL) and extracted with dichloromethane (50 mL). The organic layer was washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (GraceResolv 12 g) eluting with a gradient of 0.5% to 7.5% methanol/dichloromethane over 30 minutes gave tert-butyl 1-(tetrahydrofuran-3-yl)azetidin-3-ylcarbamate. The resulting material was treated with HCl/dioxane for 1 hour, and then concentrated to give the title compound.
Reaction SMILES: [P:1]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([O:3][CH2:4][CH2:5]Br)=[O:2].[O:17]=[C:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:19]1.[OH-].[K+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:8]([O:7][P:1]([O:3][CH2:4][CH2:5][N:23]1[CH2:22][CH2:21][N:20]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH2:19][C:18]1=[O:17])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:2])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CC(C)(C)OP(=O)(OCCBr)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OP(=O)(OCCN1CCN(C(=O)OCc2ccccc2)CC1=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
2-Bromoethyl di-tert-butyl phosphate (298 mg, 0.94 mmol) in tetrahydrofuran (1.0 ml) was added at room temperature to a stirred suspension of benzyl 3-oxopiperazine-1-carboxylate (200 mg, 0.85 mmol), powdered potassium hydroxide (57 mg, 1.0 mmol) and tetra-n-butylammonium bromide (55 mg, 0.17 mmol) in THF (2.0 ml). The reaction mixture was stirred for 90 minutes and then filtered through Celite and the filtrate evaporated to leave a colourless oil. The crude product was purified by silica gel chromatography eluting with a 2-5% mixture of methanol in dichloromethane to give benzyl 4-{2-[(di-tert-butoxyphosphoryl)oxy]ethyl}-3-oxopiperazine-1-carboxylate (220 mg, 55% yield) as a colourless oil:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:12][O:13]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[C:5]2[CH:12]=[O:13])=[CH:10][CH:11]=1
Reactant: COC(Cl)Cl
Reactant: Fc1ccc2ccccc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cccc2ccc(F)cc12
Yield: 21108.4 %

Procedure:
By the method of Preparation 1, 2-fluoronaphthalene (10 g., 0.068 mmole) in 200 ml. of methylene chloride was reacted with titanium tetrachloride (25.5 g., 14.7 ml. 0.136 mole) and 1,1-dichloromethyl methyl ether (10.1 g., 0.088 mole). The resulting crude product (11 g.) was first recrystallized from hexane to yield 7-fluoro-1-naphthaldehyde [2.5 g., m.p. 95°-96° C., Rf 0.25 (1:1 chloroform:hexane)]. The mother liquor was evaporated to dryness and the residue chromatographed on 400 g. of silica gel, eluting initially with 3:1 hexane:chloroform and then with 3:2 hexane:chloroform. The column was monitored by tlc. Fractions contain clean 2-fluoro-1-naphthaldehyde [Rf 0.31 (3:2 hexane:chloroform)] were combined and evaporated to dryness, yielding purified 2-fluoro-1-naphthaldehyde (2.8 g., m.p. 60°-62° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[C:22]([F:25])[CH:21]=[CH:20][CH:19]=3)=[N:11][C:12](Cl)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]3[CH:45]=[C:44]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[C:43](B4OC(C)(C)C(C)(C)O4)=[CH:42][C:36]=3[C:37]=2[C:38]([NH:40][CH3:41])=[O:39])=[CH:29][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:43]2[C:44]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])=[CH:45][C:35]3[O:34][C:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[C:37]([C:38]([NH:40][CH3:41])=[O:39])[C:36]=3[CH:42]=2)=[N:11][C:10]=1[C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[C:22]([F:25])[CH:21]=[CH:20][CH:19]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2[nH]c(-c3nc(Cl)ccc3OCc3ccccc3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
A mixture of 2-(3-(benzyloxy)-6-chloropyridin-2-yl)-4-fluoro-1H-indole (160 mg, 0.454 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (228 mg, 0.454 mmol), K3PO4.H2O (362 mg, 1.362 mmol), Pd2(dba)3 (21 mg, 0.023 mmol) and X-Phos (22 mg, 0.046 mmol) in dioxane/H2O (2 mL/0.4 mL) was stirred at 80° C. for 2 hours under N2 atmosphere. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine (20 mL×3), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using Prep-TLC (petroleum ether:EA=1:1) to provide 5-(5-(benzyloxy)-6-(4-fluoro-1H-indol-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (120 mg, yield: 38.2%). 1H-NMR (CDCl3, 400 MHz) δ 9.97 (s, 1H), 7.93 (s, 1H), 7.88˜7.91 (m, 2H), 7.55 (s, 1H), 7.33˜7.48 (m, 7H), 6.69˜7.19 (m, 5H), 6.65˜6.69 (m, 1H), 5.83 (d, J=4.4 Hz, 1H), 5.31 (s, 2H), 3.08 (s, 3H), 2.91 (d, J=4.8 Hz, 3H), 2.75 (s, 3H). MS (M+H)+: 693.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][CH:10]([Cl:15])[CH:11]([CH3:14])[CH2:12][CH3:13])=[O:7])=[CH:4][CH:3]=1.N1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][CH:10]([Cl:15])[CH:11]([CH3:14])[CH2:12][CH3:13])=[O:7])=[CH:4][CH:3]=2)=[O:7])=[CH:16][CH:17]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: c1ccncc1
Reactant: CCC(C)C(Cl)COC(=O)c1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=CCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OCC(Cl)C(C)CC)cc2)cc1
Reaction time: 15 h
Yield: 149.5 %

Procedure:
To 0.82 g of p-(decenyloxy)benzoic acid prepared by the procedure of Example 4.(1) was added toluene and the mixture was cooled with ice. To the mixture was dropped 1.1 g of thionyl chloride, and reaction was carried out for 7 hours at 80° C. After the reaction, the resulting reaction solution was concentrated to obtain an acid chloride compound. 0.76 g of 2-chloro-3-methylpentyl p-hydroxybenzoate and 0.5 g of pyridine were dissolved in toluene, and the resulting solution was cooled with ice. To the solution was dropped a toluene solution of the above-obtained acid chloride compound. Reaction was carried out for 15 hours at rool temperature. After the reaction, the resulting reaction solution was washed with water and dried over magnesium sulfate, and the solvent was then distilled out under reduced pressure. The residue was purified by column chromatography to obtain 1.14 g of the objective ester compound. (Yield: 74%).
Reaction SMILES: B(Cl)(Cl)Cl.[CH:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].CS[C:15]#[N:16].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[OH:11][C:10]1[CH:5]=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=1[C:15]#[N:16]
Reactant: CSC#N
Reactant: Cc1cccc(O)c1
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C#N)c(O)c1
Temperature: 80 °C
Yield: 91.1 %

Procedure:
2-Hydroxy-4-methylbenzonitrile was prepared following a modification of the procedure reported by Makoto Adachi and Tsutomu Sugasawa (Synthetic Communications 1990, 20, 71-84.). To a cold (0° C.) solution of BCl3 (1.0 M in heptane, 12.0 mL, 12.0 mmol) in 1,2-dichloroethane was added neat m-cresol (1.00 mL, 9.56 mmol) followed by CH3SCN (0.83 mL, 12.1 mmol) and AlCl3 (1.38 g, 10.4 mmol). The cooling bath was removed and the resultant mixture was heated to 80° C. for 3 hours then cooled to room temperature. The mixture was poured into 4 N NaOH (35 mL) and the mixture was heated at 80° C. for 45 minutes then cooled to room temperature. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The aqueous phase was acidified with 6 N HCl (30 mL) and extracted with diethyl ether (3×50 mL). The combined ether extracts were dried (MgSO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2-EtOAc) provided 1.16 g (91%) of 2-Hydroxy-4-methylbenzonitrile as a white solid. 1H NMR (CDCl3) δ 2.36 (s, 3H), 6.20 (br s, 1H), 6.79-6.81 (m, 2H), 7.38 (d, 1H, J=9 Hz).
Reaction SMILES: [CH2:1]([NH:4][C@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[Cl:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[CH2:1]([N:4]([C@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)[C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH2:15][Cl:14])[CH:2]=[CH2:3]
Reactant: C=CCN[C@@H]1CCc2ccccc21
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: ClCCl
Product: C=CCN(C(=O)C(C)(C)CCl)[C@@H]1CCc2ccccc21
Reaction time: 14 h

Procedure:
To the DCM solution of (1R) —N-allylindan-1-amine (prepared in Step A), cooled to −20° C., was added 3-chloro-2,2-dimethylpropanoyl chloride (872 mg, 5.63 mmol). After allowing the reaction to sit at −20° C. for 14 hours LCMS analysis indicated a complete consumption of secondary amine. The reaction mixture was then concentrated in vacuo to a reasonable volume of DCM. This DCM solution was then applied to a silica gel column for purification, eluting with a gradient of 10-50% EtOAc in hexanes to give the title compound. MS: m/z=314 (M+23).
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=O.C([O-])(=O)C.[NH4+:35]>C(O)(=O)C>[F:28][C:27]([F:30])([F:29])[O:26][C:22]1[CH:21]=[C:20]([C:2]2[N:35]=[C:5]([CH:7]3[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]3)[NH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2cccc(OC(F)(F)F)c2)CC1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: FC(F)(F)Oc1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
Add tert-butyl 4-(2-oxo-2-(3-(trifluoromethoxy)phenyl)ethylcarbamoyl)-piperidine-1-carboxylate (1.50 g, 3.48 mmol) to a mixture of ammonium acetate (1.40 g, 18.1 mmol), and glacial acetic acid (10 mL) and heat at reflux for 15 h. Cool the mixture to room temperature and concentrated in vacuo. Dissolve the residue in ethyl acetate (50 mL) and adjust to pH 8 with saturated NaHCO3. Extract the aqueous layer with ethyl acetate (2×50 mL). Combine the organic layers, dry (Na2SO4), filter, and concentrate in vacuo. Purify the residue by silica gel chromatography (80 g, eluting with a gradient of 10% to 20% methanol/ethyl acetate, 1.5 L) to provide 4-(4-(3-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidine (491 mg, 45%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:12][CH:11]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(CC)CC)C.C(OCC)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:7]([CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([S:16][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:15]=1)[CH3:33]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(CCNCc2ccco2)cc1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN(CCc1ccc(SC(C)(C)C(=O)OC(C)(C)C)cc1)Cc1ccco1
Yield: 46.8 %

Procedure:
2.4 g of 1,1-dimethylethyl 2-[[4-[2-[(2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoate, 1.5 g of ethyl bromoacetate, 0.97 g of triethylamine and 7.08 g of tetra-n-butylammonium iodide are dissolved in 100 ml of tetrahydrofuran and heated at reflux overnight. Ethyl acetate and water are added, and the mixture is extracted with water and sat. NaCl solution. Concentration and chromatography (petroleum ether/ethyl acetate 10+1) gives 1.38 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.Cl.[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]2[CH:43]=[C:42]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[NH:41][N:40]=2)[CH2:35][CH2:34]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:16]2[CH:23]=[CH:22][C:19]([CH2:20][N:33]3[CH2:34][CH2:35][CH:36]([C:39]4[NH:40][N:41]=[C:42]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=5)[CH:43]=4)[CH2:37][CH2:38]3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nc3ccccn3c2-c2ccccc2)cc1
Reactant: c1ccc(-c2cc(C3CCNCC3)n[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(-c2c(-c3ccc(CN4CCC(c5cc(-c6ccccn6)n[nH]5)CC4)cc3)nc3ccccn23)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 0.250 g (0.838 mM) of 4-(3-phenylimidazo[1,2-a]pyridin-2-yl)benzaldehyde in 6 mL of THF is added triethylamine (2 eq). The reaction mixture is stirred for 5 minutes. To this solution is added 2-[3-(piperidin-4-yl)-1H-pyrazol-5-yl]pyridine dihydrochloride (Intermediate K) (1.5 eq) followed by acetic acid (2.5 eq). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH(OAc)3 (6 eq) over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained is taken up in chloroform and washed with water, dried and concentrated. The crude is purified on a flash column chromatography to obtain the desired compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@:6]1([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:27]=1)OC)(=[O:3])[CH3:2].C([SiH](CC)CC)C.O.B(F)(F)F.CCOCC>C(#N)C.C(OCC)(=O)C>[C:16]([O:15][C@H:9]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([CH2:33][O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:27]=2)[O:7][C@@H:8]1[CH2:19][O:20][C:21](=[O:23])[CH3:22])(=[O:18])[CH3:17]
Reactant: CO[C@@]1(c2ccc(Cl)c(COc3ccccc3)c2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a solution of (2S,3R,4S,5R,6R)-6-(acetoxymethyl)-2-(4-chloro-3-(phenoxymethyl)phenyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (12.00 g, 20.73 mmol), triethylsilane (10.46 mL, 65.51 mmol) and water (373 mg, 20.73 mmol) in ACN (62.18 mL) was added BF3.Et2O (5.21 mL, 41.46 mmol) at 0° C. The reaction was stirred at r.t. for 18 h. After the completion of reaction as confirmed by TLC, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 3:7 Ethyl acetate:Pet. Ether) to afford the title compound (10.58 g, 93%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH:10][CH2:11][CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1>>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: Clc1ncc(Br)c(Cl)n1
Product: CC(C)(C)OC(=O)N1CC(COc2nc(Cl)ncc2Br)C1
Yield: 67 %

Procedure:
Using the procedure of Example 1 Step 1, 5-bromo-2,4-dichloropyrimidine was reacted with tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate to provide the title compound at 67% yield. 1H NMR (CDCl3, 400 MHz) 8.46 (s, 1H), 4.61 (d, 2H), 4.10 (m, 2H), 3.82 (m, 2H), 3.03 (m, 1H), 1.45 (9H); MS (ESI) m/z: Calc: 377.0 (M+). Found. 322.9 (M+-(CH3)3C+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](O)=[O:13])=[CH:6][CH:5]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[BH4-].[Na+].Cl>C1COCC1.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCC(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCCO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(2-Carboxy-ethyl)-benzoic acid methyl ester (5 g, 24 mmol) is dissolved in THF (50 ml), N,N-carbonyldiimidazole (4.25 g, 26.2 mmol) is added and stirred for 1 h at room temperature. Then sodium borohydride (1.9 g, 50 mmol) and water (10 ml) are added to the reaction mixture and stirred for additional 1 h. 1M HCl is added dropwise to the reaction mixture, extracted with ethyl acetate, the organic phase is dried and concentrated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol) to afford the title compound. LC (method F): tR=1.83 min; Mass spectrum (ESI+): m/z=195 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCCc4ccc(Cl)cc4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NCCCc1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
Ethyl 6-chloro-7-(4-(3-(4-chlorophenyl) propylcarbamoyl)phenoxy)chroman-4-carboxylate (80 mg, 0.15 mmol) was diluted with THF (1 mL) followed by the addition of NaOH (757 μl, 0.76 mmol) and ethanol (500 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylic acid (76 mg, 0.15 mmol, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[SH:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:16]=2[N:17]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:16]=2[N:17]=1
Reactant: FC(F)(F)c1ccc2sc(S)nc2c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Product: O=[N+]([O-])c1ccc(Sc2nc3cc(C(F)(F)F)ccc3s2)c(Cl)c1

Procedure:
2-(2-Chloro-4-nitro-phenylsulfanyl)-5-trifluoromethyl-benzothiazole (252) was prepared (92%) from 2-chloro-1-fluoro-4-nitrobenzene, obtained from Aldrich, and 5-trifluoromethyl-benzothiazol-2-thiol (239) in a similar manner as described in example 251.
Reaction SMILES: [CH3:1][C:2]([S:24]([CH3:27])(=[O:26])=[O:25])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].BrC1C=CC(CCC(C)(S(C)(=O)=O)C(O)=O)=CC=1>>[CH3:1][C:2]([S:24]([CH3:27])(=[O:25])=[O:26])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCc1ccc(COc2ccccc2)cc1)S(C)(=O)=O
Agent: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Product: CC(CCc1ccc(COc2ccccc2)cc1)(C(=O)O)S(C)(=O)=O
Yield: 24.3 %

Procedure:
The title compound (247 mg, 24%) was prepared from ethyl 2-methyl-2-(methylsulfonyl)-4-[4-(phenoxymethyl)phenyl]butanoate (1.1 g, 2.8 mmol) following the general procedure of step 3, from Preparation 2, for the formation of compound (II). MS (LC/MS) m/z 361.2 (M−1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.62-1.69 (m, 3H) 2.06-2.18 (m, 1H) 2.42-2.65 (m, 2H) 2.74-2.86 (m, 1H) 3.10 (s, 3H) 5.04 (s, 2H) 6.91 (t, J=7.42 Hz, 1H) 6.97 (d, J=7.81 Hz, 2H) 7.22-7.29 (m, 4H) 7.37 (d, J=8.20 Hz, 2H).