Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][S:5](=[O:8])[CH2:4][CH2:3]1.[CH3:9][C:10]1[CH:11]=[C:12]([O:28][C:29]2[CH:30]=[N:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25](O)=[O:26])[CH2:22][N:23]=1)=[CH:15]2.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[CH3:9][C:10]1[CH:11]=[C:12]([O:28][C:29]2[CH:30]=[N:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([N:2]3[CH2:7][CH2:6][S:5](=[O:8])[CH2:4][CH2:3]3)=[O:26])[CH2:22][N:23]=1)=[CH:15]2
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: O=S1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)N4CCS(=O)CC4)S3)[nH]c12
Reaction time: 15 h
Yield: 42.4 %

Procedure:
To a solution of thiomorpholine 1-oxide hydrochloride (140 mg) and triethylamine (0.125 mL) in N,N-dimethylformamide (15 mL) were added [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), 1-hydroxybenzotriazole (121 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (172 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 75:25, volume ratio), and the obtained pale-yellow crystals were recrystallized from ethyl acetate-hexane to give the title compound (104 mg, yield 42%) as colorless crystals.
Reaction SMILES: [CH2:1]([OH:7])[C@@H:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC)(OC)OC.C(C(O)=O)(F)(F)F>C(Cl)Cl>[C:9]1([C@@H:8]2[O:6][C@@H:2]([CH2:1][OH:7])[CH2:3][CH2:4][O:5]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: OCC[C@H](O)CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COC(OC)OC
Product: OC[C@H]1CCO[C@H](c2ccccc2)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
A sample of 2.60 g (20.6 mmol) of commercially available (Aldrich) (S)-(−)-1,2,4-butanetriol 5, benzaldehyde (3.47 mL, 29 mmol), and trimethyl orthoformate (3.74 mL, 29 mmol) was dissolved in 80 mL of CH2Cl2, and 1 mL of CF3CO2H was added. After the reaction mixture was stirred for 24 hours at room temperature, the reaction was quenched by the addition of NaOMe (20 mg), diluted with 100 mL of ether, and filtered. After the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel, eluting with petroleum ether (PE)-EtOAc (5:1 to ˜1:1) to afford 3.6 g (90%) of the product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ7.52-7.33 (m, 5H), 5.51 (s, 1H), 4.29 (dd, J=4.1, 10.7 Hz, 1H), 3.95 (m, 2H), 3.60 (m, 2H), 2.85 (s, 1H, OH), 1.85 (m, 2H). 13C-NMR (CDCl3, 75 MHz): δ139.10, 129.58, 128.90, 126.85, 101.96, 78.35, 67.36, 66.29, 27.69.
Reaction SMILES: I[C:2]1[CH:21]=[N:20][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]3[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:31][N:30]=2)[CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:24][CH2:25][N:26]([C:29]2[CH:34]=[C:33]([C:2]3[CH:21]=[N:20][C:5]4[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]5[O:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=5)[C:4]=4[CH:3]=3)[CH:32]=[CH:31][N:30]=2)[CH2:27][CH2:28]1
Reactant: FC(F)(F)c1ccc(CN2CCNc3ncc(I)cc32)o1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Product: CN1CCN(c2cc(-c3cnc4c(c3)N(Cc3ccc(C(F)(F)F)o3)CCN4)ccn2)CC1
Yield: 30 %

Procedure:
7-Iodo-1-[5-(trifluoromethyl)furan-2-ylmethyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (60 mg) was reacted with 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a beige foam (30% yield). M.p. (foam), 1H-NMR (CDCl3, 400 MHz) δ 2.31-3.36 (m, 4H), 2.38-2.53 (m, 4H), 3.42-3.48 (m, 2H), 3.48-3.58 (m, 1H), 3.61-3.66 (m, 2H), 3.74-3.84 (m, 2H), 5.02 (bs, 1H), 6.31 (s, 1H), 6.74 (s, 1H), 6.93 (s, 1H), 7.41-7.50 (m, 3H), 7.73 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:22])[N:8]2[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl.[N:26]1[CH:31]=[CH:30][C:29]([CH2:32]Cl)=[CH:28][CH:27]=1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:32][C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)([CH2:32][C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)[C:7](=[O:22])[N:8]2[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Br)cc2N1Cc1cccc2ccccc12
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1N(Cc2cccc3ccccc23)c2cc(Br)ccc2C1(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
6-Bromo-1-naphthalen-1-ylmethyl-1,3-dihydro-indol-2-one (195 mg, 0.554 mmol) was dissolved in 1 ml of THF and was then added to a previously degassed solution of 3 ml of THF and 5 ml of aqueous 1 N KOH under an atmosphere of dry N2. To this solution was added 4-picolyl chloride hydrochloride (275 mg, 1.67 mmol). The reaction mixture was then stirred at ambient temperature for 2 hours after which time the reaction mixture was concentrated under vacuum to give a green oil. The oil was partitioned between DCM and saturated aqueous NaHCO3. The DCM layer was then washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give a dark oil which was chromatographed on flash silica gel eluting with a gradient from EtOAc/hexanes (50:50) to EtOAc to EtOAc/MeOH (95:5) to give 140 mg of the titled compound as a colorless oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][N:31]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f24) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.Cl>O1CCOCC1>[Cl:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=1
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](O)c1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a solution of (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 250 mg, 1.1 mmol) in dioxane (0.9 mL) was added concentrated hydrochloric acid (0.9 mL). This mixture was allowed to stir at room temperature for 5 h, quenched with saturated aqueous sodium bicarbonate followed by solid sodium bicarbonate until no more gas evolution was evident. Dichloromethane was added and the layers were separated. The aqueous phase was extracted with dichloromethane (3×) and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give 125 mg (71%) of the title compound as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.59 (d, 1H), 7.25 (d, 1H), 4.92 (q, 1H), 3.81 (br s, 1H), 1.56 (d, 3H); MS (APCI) 159, 161 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[O:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[Na+].C(OCCCl)CCl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:14][CH2:15][O:11][CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: N#CCc1cccc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCOCCCl
Product: N#CC1(c2cccc(Br)c2)CCOCC1
Temperature: 22.5 °C

Procedure:
3-Bromophenylacetonitrile (20.0 g, 102 mmole, 1 eq.), tetrahydrofuran (120 ml), 40% aqueous sodium hydroxide solution (180 ml, mmole, eq.), tetrabutylammonium hydrogensulfate (3.46 g, mmole, 0.1 eq.) were stirred in a reaction flask set for boiling at reflux. Thereafter, 2,2′-dichlorodiethylether (13.75 ml, 117.3 mmole, 0.1 eq.) was added with stirring at room temperature, 20-25° C. The resultant reaction mixture was boiled at reflux for 5-8 h at approximately 64° C. The reaction mixture was cooled to ambient temperature and ethyl acetate (154 ml) was added. The lower aqueous layer was separated and the organic layer evaporated down into a red oil. Iso-propanol (100 ml) and water (10 ml) were added to the oil and stirred at 0° C. overnight to yield a crystal slurry. The crystal slurry was vacuum filtered, washed with isopropanol (2×20 ml). The white crystalline solid was dried under vacuum at 40-45° C. Yield 18.57 g (68.4%): mp 82-85° C.; m/z 267 (m+1); 1H NMR (300 MHz, DMSO) δ7.75 (s, 1H), 7.6 (m, 2H), 7.44 (t, 1H), 4.02 (m, 2H), 3.66 (m, 2H), 2.14 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1.Br[C:19]1[C:20](=[O:27])[N:21]([CH3:26])[CH:22]=[C:23]([Br:25])[CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[Br:25][C:23]1[CH:24]=[C:19]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[N:3]=2)[C:20](=[O:27])[N:21]([CH3:26])[CH:22]=1
Reactant: CN(CCn1ccc(N)n1)C(=O)OC(C)(C)C
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(CCn1ccc(Nc2cc(Br)cn(C)c2=O)n1)C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 76.3 %

Procedure:
A mixture of (206e (2 g, 8.3 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (2.2 g, 8.3 mmol), XantPhos (482 mg, 0.83 mmol), Pd2(dba)3 (762 mg, 0.83 mmol) and Cs2CO3 (6.8 g, 21 mmol) in dioxane (80 mL) was heated at 100° C. for 15 h under nitrogen. It was then filtered, evaporated in vacuo, and purified by silical-gel column eluting with 1:2 petroleum ether/ethyl acetate to give 206f as a yellow solid (2.7 g, 77%). MS: (M+H)+ 426.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[O:9][CH:10]=1)=[O:5])[CH3:2].[C:12]([CH:14]1[CH2:16][CH2:15]1)#[CH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:14]1([C:12]#[C:13][C:8]2[O:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:16][CH2:15]1
Reactant: C#CC1CC1
Reactant: CCOC(=O)c1coc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1coc(C#CC2CC2)n1
Reaction time: 2.5 h
Yield: 50.1 %

Procedure:
A mixture of 2-bromo-oxazol-4-carboxylic ethyl ester (0.967 g, 4.40 mmol, Combi-Blocks), trans-dichlorobis(triphenylphosphine)palladium (II) (0.201 g, 0.286 mmol, Strem) and copper (I) iodide (0.165 g, 0.866 mmol, Aldrich) in toluene (15 ml) was purged with argon for 10 min. Ethynylcyclopropane (1.00 ml, 11.80 mmol) and triethylamine (1.70 ml, 12.22 mmol) were added. After 2.5 h, the reaction mixture was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine. The solvent was removed under reduced pressure and the residue and was purified by silica gel flash chromatography, eluting with (EtOAc):hexanes (0:1→2:3) to give 452 mg (50%) of a light-orange oil. MS m/z=206 [M+H]+. Calculated for C11H11NO3: 205.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([C@@H:24]([OH:26])[CH3:25])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:29](O)(=[O:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[C:29]([O:26][C@@H:24]([C:22]1[O:23][C:19]([C:16]2[CH:17]=[CH:18][C:13]3[O:12][CH:11]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:27])([F:1])[F:28])[CH:5]=4)[C:14]=3[CH:15]=2)=[N:20][N:21]=1)[CH3:25])(=[O:31])[CH3:30]
Reactant: C[C@H](O)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Reactant: CC(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](C)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of (1S)-1-[5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazol-2-yl]ethanol (390 mg, 1.00 mmol), acetic acid (0.114 mL, 2.00 mmol) and triphenylphosphine (394 mg, 1.50 mmol) in tetrahydrofuran (5 mL) was added dropwise 40% diethyl azodicarboxylate-toluene solution (0.653 mL, 1.50 mmol) at 0° C., and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/1-0/1) to give the title compound (406 mg, yield 94%) as a colorless oil.
Reaction SMILES: Cl.[C:2](=[NH:10])([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[Cl-].[C:19]([O:30][CH3:31])(=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-])=[O:25])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH3:31][O:30][C:19](=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:10]=[C:2]([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:25])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: CCCCC(=N)OCC
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC(=NC(=O)c1ccc(C(=O)OC)cc1)OCC
Temperature: 25 °C
Reaction time: 19 h
Yield: 12.1 %

Procedure:
To a solution of ethyl pentanimidate hydrochloride (9 g, 54 mmol) and triethyl amine (17 mL, 120 mmol) in toluene (110 mL) at 0° C. was added, over 20 minutes, a solution of terephthalic acid, monomethyl ester chloride (10.8 g, 54 mmol) in toluene (21 mL). After stirring at ambient temperature for 19 hours, the reaction was filtered and the solids were rinsed with toluene (200 mL). The combined filtrates were concentrated in vacuo. Flash chromatography (silica gel, CH2Cl2) of a portion of this material afforded the title compound (1.9 g, 47%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=2)[CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([OH:31])[CH:27]=[CH:28][C:29]=1[F:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][C:29]=1[F:30])[O:31][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: Oc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(Nc2cc(Oc3ccc(F)c(Cl)c3)ncn2)c1
Yield: 45.4 %

Procedure:
A solution of tert-butyl 3-(6-chloropyrimidin-4-ylamino)phenylcarbamate (1.6 g, 5 mmol), 3-chloro-4-fluorophenol (1.4 g, 10 mmol) and potassium carbonate (1.4 g, 10 mmol) in 15 mL of DMF was heated to 120° C. for 16 h. The reaction mixture was mixed in 15 mL of water, the crude product was precipitated, filtered, purified by flash chromatography on silica gel with MeOH/DCM solvent system to afford 750 mg (45% yield) of N1-(6-(3-chloro-4-fluorophenoxy)pyrimidin-4-yl)benzene-1,3-diamine as an off-white solid. MS (m/z): MH+=331.
Reaction SMILES: O[C:2]1([C:22]([F:25])([F:24])[F:23])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:22]([F:24])([F:25])[F:23])[N:3]=[C:4]2[C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccsc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccsc2)cc1
Yield: 63.6 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (1.5 g, 3.8 mmol) and p-toluenesulfonic acid monohydrate (0.30 g, 1.5 mmol) in toluene (250 ml) was heated to reflux for 40 hours. An additional p-toluenesulfonic acid monohydrate (0.15.g, 0.78 mmol) was added. The reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (3.5 g) was purified by chromatography on silica gel using ethyl acetate/toluene (55/45) to give pure 3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene (0.90 g, 64%) as a white solid: mp 194–197° C. Anal. Calc'd. for C15H11N2S2O2F3: C, 48.38, H, 2.98, N, 7.52, S, 17.22. Found: C, 48.74, H, 2.98, N, 7.56, S. 17.45
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:5][N:4]=1.IC1C=CC=C(C)C=1>>[OH:9][C:8]1[C:3](=[O:2])[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:7]=1
Reactant: COc1cc(C#Cc2ccccc2C)cnc1OC
Agent: Cc1cccc(I)c1
Product: Cc1ccccc1CCc1c[nH]c(=O)c(O)c1

Procedure:
Prepared as described for 2,3-dimethoxy-5-[(2-methylphenyl)ethynyl]pyridine (Intermediate 33) but using 1-iodo-3-methylbenzene instead of 1-iodo-2-methylbenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1Cl)([O-:3])=[O:2].C1(CC2C=CC=CC=2)C=CC=CC=1.[CH2:31]([O:33][P:34]([CH2:39][NH2:40])(=[O:38])[O:35][CH2:36][CH3:37])[CH3:32]>C(Cl)Cl>[CH2:31]([O:33][P:34]([CH2:39][NH:40][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:38])[O:35][CH2:36][CH3:37])[CH3:32]
Reactant: CCOP(=O)(CN)OCC
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1Cl
Solvent: ClCCl
Solvent: c1ccc(Cc2ccccc2)cc1
Product: CCOP(=O)(CNc1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12)OCC
Yield: 68 %

Procedure:
4 g of 2,4 dinitro-1-chloronaphthalene (15.84 mmol) is dissolved in 6.5 g of aminomethanephosphonic acid diethyl ester and 4 g of diphenylmethane and stirred for 72 hours at room temperature. The batch is diluted with methylene chloride, washed with 1N NaOH and washed twice with brine, dried and spun in. The crude product is chromatographed on silica gel with 3.5 liters of cyclohexane and ethyl acetate 1:1 as mobile solvent. 68% of product is obtained in several fractions as viscous oil. NMR (DMSO, delta in ppm): 1.15(6H,tr), 4(4H dq)4.25 (2H m), 7.8, 7.98, 8.9, 9.05 each 1H, 8.6 (2H,d)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2].[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[N:8]([Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])[C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C

Procedure:
Such a preferred procedure comprises treating the (3S,4S)-4-acetoxy-3-phenylacetamido-azetidin-2-one (II) with tert-butyldimethyl chlorosilane in the presence of 4-dimethylaminopyridine and, optionally, of pyridine in an organic solvent, isolating the (3S,4S)-4-acetoxy-3-phenylacetamido-1-tert-butyldimethylsilyl-azetidin-2-one (III) thus obtained and treating with an inorganic sulfide to obtain (3S,4S)-4-acetoxy-3-phenylethanethioylamino-1-tert-butyldime thylsilyl-azetidin-2-one (IV) and treating this compound with a base in an organic solvent at a temperature of 70°÷130° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl.CN(C)C.[CH3:24][C:25]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:26][CH2:27][CH2:28][OH:29].CN(C)CCCN>C(Cl)Cl.O>[CH3:24][C:25]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:26][CH2:27][CH2:28][O:29][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=CCCO)CCCC(C)CCCC(C)CCCC(C)C
Agent: CN(C)C
Agent: CN(C)CCCN
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.49 mL (3.5 mmol) of triethylamin, 0.68 g (3.54 mmol) of p-toluenesulfonyl chloride, 15 mg (0.16 mmol) of trimethylamine hydrochloride were added to a solution of 1.0 g (3.2 mmol) of 4,8,12,16-tetramethylheptadec-3-en-1-ol in dry methylene chloride (3.2 mL) at 0° C., sequentially. After being stirred for 2 hours at room temperature, 0.080 mL (0.64 mmol) of N,N-dimethyl-1,3-propanediamine was added to the reaction mixture at 0° C. After being stirred for 15 min, water was added, and the mixture was extracted with methylene chloride. The extract was washed with 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain (4,8,12,16-tetramethylheptadec-3-enyl)tosylate as a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:8]([CH3:9])[C:4]=2[C:3]=1[C:21]([NH2:23])=[O:22].[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1.CC(C)=O.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][C:7]1[N:8]([CH3:9])[C:4]2=[C:3]3[C:2](=[CH:20][CH:19]=[C:5]2[N:6]=1)[NH:1][C:24]([CH3:29])([CH3:25])[NH:23][C:21]3=[O:22]
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc3c(c21)C(=O)NC(C)(C)N3
Temperature: 25 °C
Reaction time: 1 h
Yield: 333.1 %

Procedure:
A mixture of 38 mg (0.11 mmol) of 5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzimidazole-4-carboxylic acid amide (Example 7), 3 mg (0.02 mmol) p-toluenesulfonic acid, and 2 mL (27 mmol) of acetone was stirred at room temperature for 1 h, then heated to reflux for 1.5 h. The reaction was cooled and poured into a mixture of saturated aqueous sodium bicarbonate and EtOAc. The aqueous phase was extracted with EtOAc, the combined organics were extracted with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), treated with activated carbon, filtered, and concentrated in vacuo to afford 26 mg of an orange solid. The crude product was chromatographed over silica gel to afford 20 mg (47%) of title compound 17, mp 238-239° C.