Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@@H:17]3[O:26][C@@H:20]4[O:21]C(C)(C)[O:23][C@@H:19]4[C@@H:18]3[CH2:27][CH2:28][N:29]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:39])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].Cl(O)(=O)(=O)=O>C(#N)C.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]3[C@@H:18]([CH2:27][CH2:28][N:29]4[C:30](=[O:39])[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:37]4=[O:38])[C@@H:19]([OH:23])[C@@H:20]([OH:21])[O:26]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2ccc(CC[C@@H]3O[C@@H]4OC(C)(C)O[C@@H]4[C@@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cc1F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(-c2ccc(CC[C@@H]3O[C@H](O)[C@H](O)[C@@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cc1F
Temperature: 55 °C

Procedure:
To a solution of the compound obtained from step m above (0.28 g) in acetonitrile (20 mL) and water (2 mL), 30% perchloric acid (0.4 mL) was added at room temperature. The reaction mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched using a sodium bicarbonate solution. The solvents were evaporated at reduced pressure. The residue thus obtained was taken in ethyl acetate and water. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (0.418 g) as crude mass which was used further without any purification and characterization.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:14]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:32]>>[ClH:32].[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:14]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCN(C)C
Agent: Cl
Product: CN(C)CCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O

Procedure:
Prepared by proceeding in a similar manner to Example 3, starting from methyl 6-(benzenesulphonylmethyl)-2-(2-dimethylaminoethoxy)-3-(furan-3-yl)benzoate (Intermediate 17). The product after chromatography was treated with hydrochloric acid (1M) and then evaporated to dryness. The residue was triturated with ether and the solid was collected by filtration.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:42]([C:41]5[CH:45]=[CH:46][C:38]([C:37]([O:36][CH3:35])=[O:47])=[CH:39][CH:40]=5)=[O:43])[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (50.5 mg, 0.1 mmol) in dichloromethane (5 mL) was added terephthalic acid monomethyl ester (18 mg, 0.1 mmol) and triethyl amine (30 μL, 0.2 mmol). The resulting mixture was then cooled down on an ice-water bath before the addition of 1-[3-(dimethylamino)propyl]-3-ethylcarbo-diimide hydrochloride (19 mg, 0.1 mmol) and 4-dimethylaminopyridine (catalytic amount). After being stirred overnight at ambient temperature, the reaction mixture was diluted with dichloromethane (40 mL) and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford methyl 4-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoate as amorphous solid (65 mg, quant.). 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=8.2 Hz, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.41 (d, J=7.3 Hz, 2H), 7.34-7.24 (m, 4H), 7.21-7.15 (m, 2H), 4.66 (br, 1H), 4.26-4.21 (m, 1H), 3.97 (s, 3H), 3.52-3.30 (m, 5H), 2.60 (s, 3H), 2.40 (br, 3H), 2.21-2.17 (br, 1H), 1.99-1.79 (m, 10H), 1.68-1.66 (m, 2H). HRMS m/z (M+H)+ calcd: 591.3335, obsd: 591.3320.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[N:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)[CH3:29].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>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36]2[N:41]=[CH:40][C:39]([NH:42][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)[CH3:29]
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Reactant: CS(=O)(=O)Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCN1CCN(c2ccc(Nc3ncc4scc(-c5cccc(NS(C)(=O)=O)c5)c4n3)cn2)CC1
Temperature: 120 °C
Reaction time: 6 h
Yield: 53.2 %

Procedure:
N-(3-(2-chlorothieno[3,2-d]pyrimidin-7-yl)phenyl)methanesulfonamide (20 mg, 0.059 mmol) was dissolved in dioxane (1 mL) and then cesium carbonate (58 mg, 0.18 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (18 mg, 0.088 mmol) were added. After flowing nitrogen gas to the reaction mixture for 10 minutes, Pd(OAc)2 (1 mg, 0.1 mmol) and Xantphos (4 mg, 0.12 mmol) were added. The reaction mixture was stirred at 120° C. for 6 hours and filtered with celite. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried with magnesium sulfate and concentrated by filtering with celite. Purification by chromatography (5% methanol/dichloromethane) yielded the target compound (16 mg, 53% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([NH2:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]([O:18][C:19](=[O:24])[NH:20][CH2:21][CH:22]=O)([CH3:17])([CH3:16])[CH3:15].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C@H:4]([NH:12][CH2:22][CH2:21][NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H](Cc1ccccc1)NCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
(2R)-2-Amino-3-phenylpropionic acid methyl ester (3.2 g; 15.0 mmol) and (2-oxoethyl)carbamic acid tert-butyl ester (3.2 g; 20.0 mmol) (prepared as in Dueholm et al, Org. Prep. Proced. Int. 25(4), 457-61 (1993)) were dissolved in a mixture of methanol (100 ml) and acetic acid (5 ml). Molecular sieves (3 Å; 100 g) were added and the reaction mixture was cooled to 0° C. Sodium cyanoborohydride (1.38 g; 22.0 mmol) was added portionwise and the reaction mixture was left without stirring for 12 h. The reaction mixture was filtered and water (100 ml), aqueous sodium hydrogencarbonate/sodium carbonate (10%; 100 ml; pH 9) and methylene chloride (50 ml) were added to the filtrate. The aqueous phase was extracted with methylene chloride (2×50 ml) and the combined organic phases were dried over magnesium sulfate. The organic phase was evaporated in vacuo and the residue was chromatographed on silica (4×40 cm) using ethyl acetate/heptane (3:2) as eluent to afford 2.07 g of (2R)-2-(2-(tert-butoxycarbonylamino)ethylamino)-3-phenylpropionic acid methyl ester.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[CH:4][CH:3]=1.[CH3:16][N:17](C=O)C>C(OCC)(=O)C.N.[C-]#N.[Zn+2].[C-]#N.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>[CH3:9][O:8][C:6]1[N:7]=[C:2]([C:16]#[N:17])[CH:3]=[CH:4][C:5]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: CN(C)C=O
Reactant: COc1nc(Br)ccc1-n1cnc(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: COc1nc(C#N)ccc1-n1cnc(C)c1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, to a mixture of 6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (25 g) and zinc cyanide (16.4 g) in DMF (250 mL) was added tetrakis(triphenylphosphine)palladium(0) (2.16 g) at room temperature, and the mixture was stirred at 120° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate and 10% aqueous ammonia solution. The precipitate was collected by filtration, washed with ethyl acetate and dried to give the title compound (17.5 g)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:18][C:17]=1[C:26]([O:28][CH3:29])=[O:27].O>CN(C)C=O>[CH2:7]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:18][C:17]=1[C:26]([O:28][CH3:29])=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: CCC(=O)c1ccc(O)c(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Temperature: 60 °C

Procedure:
38 g of potassium carbonate and 12.65 ml, (14 g) of benzyl chloride are added to 20.8 g of 4'-hydroxy-3'-methoxycarbonylpropiophenone in 100 ml of dimethylformamide. The mixture is heated at 60° C. for 4 hours, with stirring. It is then poured into iced water, the mixture is extracted with ethyl acetate and the organic phase is washed with water, dried and evaporated to dryness. The residual oil crystallises on trituration with pentane. The crystals are filtered off and recrystallised from ethanol. 18 g of crystals melting at 76°-78° C. are collected.
Reaction SMILES: C(OP(C[N+]#[C-])(=O)[O:5][CH2:6][CH3:7])C.C([Li])CCC.[CH2:17]1[C:21]2(C[CH2:25][CH2:24][CH2:23][C:22]2=O)[CH2:20][CH2:19][CH2:18]1.Cl>C(OCC)C.CCCCCC.O>[CH2:20]1[C:21]2([CH2:22][CH2:23][CH2:24][CH2:25][CH:7]2[CH:6]=[O:5])[CH2:17][CH2:18][CH2:19]1
Reactant: [C-]#[N+]CP(=O)(OCC)OCC
Reactant: O=C1CCCCC12CCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: O=CC1CCCCC12CCCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of diethyl(isocyanomethyl)phosphonate (410 μL) in diethyl ether (5 mL) was cooled to −78° C. in nitrogen atmosphere. After addition of 1.54M n-butyl lithium solution in hexane (1.7 mL) to the reaction mixture at −78° C., the temperature was raised to 0° C. and stirred for 15 minutes. To the resulting solution spiro[4.5]decane-6-one (300 mg) was added at 0° C., and the temperature was raised to room temperature under stirring. An hour thereafter, conc. hydrochloric acid (5 mL) was added to the reaction mixture at room temperature, followed by further 10 hours' stirring. The resulting solution was diluted with water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and from which the solvent was distilled off to provide the title compound in crude, unpurified form, as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[C:22]([F:27])=[CH:21][C:20]=2[N+:28]([O-:30])=[O:29])[C:12]=1[F:31])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]#[N:26])[C:22]([F:27])=[CH:21][C:20]=2[N+:28]([O-:30])=[O:29])[C:12]=1[F:31])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)c(F)cc2[N+](=O)[O-])c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(5-cyano-4-fluoro-2-nitrophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (78.0 mg, 0.085 mmol) in DCM (7 ml) was added TFA (3.0 mL) and the reaction mixture was stirred at RT for 2 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-({4-chloro-3-[(5-cyano-4-fluoro-2-nitrophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (39 mg, 0.083 mmol, 98% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.14 (d, 1H), 7.75 (s, 1H), 7.27-7.50 (m, 3H), 4.64 (s, 2H). LC-MS (ES+) m/z 468.07, [M+H].
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]([OH:8])([CH3:7])[CH3:6].[C:9]([NH:22][C@H:23]([C:29](O)=[O:30])[CH2:24][CH2:25][C:26](=[O:28])[NH2:27])(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O>[CH:5]([O:8][C:29](=[O:30])[C@H:23]([CH2:24][CH2:25][C:26](=[O:28])[NH2:27])[NH:22][C:9](=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH3:7])[CH3:6]
Reactant: CC(C)O
Reactant: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)OC(C)C
Yield: 52.4 %

Procedure:
108 g of L-glutamine was dissolved in 343 g of water and 102 g of aqueous 27% sodium hydroxide solution, and cooled to 10° C. 138 g of acetone was added to it, and 152 g of lauroyl chloride and 108 g of aqueous 27% sodium hydroxide solution were dropwise added thereto. The acylation liquid was diluted with 300 g of water, then neutralized with 35 g of 75% sulfuric acid and filtered to obtain a white powdery substance, N-lauroyl-L-glutamine. 72.4 g of thionyl chloride was dropwise added to 424 g of isopropyl alcohol, then 100 g of N-lauroyl-L-glutamine was added thereto and reacted at room temperature for 8.5 hours. The reaction liquid was added to 2.0 L of water to precipitate the intended product, and this was taken out by filtration to obtain a crude product. This was recrystallized repeatedly three times with acetone to obtain 59.1 g of N-lauroyl-L-glutamine isopropyl ester.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5][N:4]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.[Na+].[I-]>C(#N)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:4]2[CH:5]=[C:6]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:7]=[CH:8][C:3]2=[O:2])=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COc1ccc(COc2ccc(OC)nc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(COc2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Yield: 28.7 %

Procedure:
According to Scheme 32 Step 1: 2-Methoxy-5-(4-methoxybenzyloxy)pyridine (1.38 mmol, 339 mg), 4-chlorobenzylchloride (2.76 mmol, 468 mg), NaI (1.38 mmol, 207 mg) in acetonitrile (15 mL) was heated at 150° C. for 50 minutes under microwave conditions. The cooled crude reaction washed with water, extracted with AcOEt. The organic layer was collected, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge CH2Cl2 and CH2Cl2/acetone 90/10) yielding 1-(4-chlorobenzyl)-5-(4-methoxybenzyloxy)pyridine-2(1H)-one (141 mg, 29%).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([CH2:27][NH2:28])[C:23]([CH3:29])=[N:22]1.CCN(C(C)C)C(C)C>>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([CH2:27][NH:28][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[C:23]([CH3:29])=[N:22]1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: Cc1nn(C)c(C)c1CN
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C)c(C)c1CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-amine and DIEA to give 2-[(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-amino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 378 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[Br:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:2][C:3]([NH2:5])=[O:4]
Reactant: Oc1cccc(Br)c1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)COc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 103.8 %

Procedure:
A mixture of 2-chloroacetamide (5.6 g), 3-bromophenol (10 g), potassium carbonate (8.3 g) and potassium iodide (1 g) in acetonitrile was stirred at room temperature for 72 hours. The resulting mixture was filtered, and the solids washed with ethyl acetate, and then water. The dried solids were recrystallised from boiling ethanol: water(8:2) to give the sub-title compound as a solid (13.8 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C:13](/[CH:15]=[CH:16]/[CH3:17])=[CH:12][N:11]1[C:18]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[CH:22][C:21]=1[N+:39]([O-])=O)=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Zn].C(O)=O.C(O)C>[NH2:39][C:21]1[CH:22]=[C:23]([O:28][Si:29]([CH:33]([CH3:34])[CH3:35])([CH:36]([CH3:38])[CH3:37])[CH:30]([CH3:32])[CH3:31])[C:24]([O:26][CH3:27])=[CH:25][C:20]=1[C:18]([N:11]1[CH:12]=[C:13](/[CH:15]=[CH:16]/[CH3:17])[CH2:14][C@H:10]1[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])=[O:19]
Reactant: C/C=C/C1=CN(C(=O)c2cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc2[N+](=O)[O-])[C@H](CO[Si](C)(C)C(C)(C)C)C1
Agent: [Zn]
Solvent: O=CO
Solvent: CCO
Product: C/C=C/C1=CN(C(=O)c2cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc2N)[C@H](CO[Si](C)(C)C(C)(C)C)C1
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
Zinc dust (22.0 g, 0.33 mol, 37 eq) was added, in portions over 20 mins, to a solution of the propenyl intermediate 6 (5.5 g, 9.1 mmol, 1.0 eq) in 5% v/v formic acid/ethanol (55 mL), using an ice bath to maintain the temperature between 25-30° C. After 30 mins, the reaction mixture was filtered through a short bed of Celite®. The Celite® was washed with ethyl acetate (65 mL) and the combined organics were washed successively with water (35 mL), saturated sodium bicarbonate (35 mL) and brine (10 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 90/10 v/v n-hexane/EtOAc) to afford the product as a pale yellow oil (3.6 g, 69.0%). LC/MS (4.439 min (ES+)), m/z: 575.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 6.75 (m, 1H), 6.40 (br s, 1H), 6.28 (m, 1H), 6.11 (d, 1H, J=15.4 Hz), 5.53 (m, 1H), 4.67 (m, 1H), 4.36 (m, 2H), 3.93 (br s, 1H), 3.84 (br s, 1H), 3.73 (s, 3H), 2.86 (dd, 1H, J=15.7, 10.4 Hz), 2.73 (dd, 1H, J=15.9, 4.5 Hz), 1.80 (dd, 3H, J=6.8, 1.3 Hz), 1.35-1.23 (m, 3H), 1.12 (d, 18H, J=7.3 Hz), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: ClC1C=CC(C2SC(CC(OC)=O)=CC=2)=CC=1.[H-].[Na+].CI.[CH3:22][C:23]([CH3:40])([C:28]1[S:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)=[CH:31][CH:32]=1)[C:24]([O:26]C)=[O:25]>O1CCOCC1>[CH3:22][C:23]([CH3:40])([C:28]1[S:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)=[CH:31][CH:32]=1)[C:24]([OH:26])=[O:25]
Reactant: COC(=O)C(C)(C)c1ccc(-c2ccc(Cl)cc2)s1
Agent: COC(=O)Cc1ccc(-c2ccc(Cl)cc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CI
Product: CC(C)(C(=O)O)c1ccc(-c2ccc(Cl)cc2)s1
Reaction time: 0.5 h

Procedure:
Methyl 5-p-chlorophenylthien-2-ylacetate (1 g.) was dissolved in dry dioxan (10 ml.). Sodium hydride (0.1 g.) was added, the mixture was stirred for 30 minutes, and methyl iodide (0.6 g.) was then added. The mixture was refluxed for 30 minutes, cooled, and further sodium hydride (0.1 g.) and methyl iodide (1.1 ml.) were added. The mixture was refluxed for 2 hours, cooled and evaporated in vacuo to give an oil which was chromatographed on a column of Florisil (column: 9 inches long × 1 inch diameter) which was eluted with a mixture of equal volumes of benzene and petroleum ether (b.p. 60°-80°C.). The first 350 ml. of eluate was evaporated in vacuo to give an oil. This oil, which was mainly methyl α,α-dimethyl-α-(5-p-chlorophenylthien-2-yl)acetate, was hydrolysed by conventional means and gave α,α -dimethyl-α-(5-p-chlorophenylthien-2yl)-acetic acid, m.p. 146°-148°C.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH:15]([CH:17]=[CH2:18])=[O:16]>>[CH3:3][C@H:2]([C@@H:15]([OH:16])[CH:17]=[CH2:18])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: C=CC=O
Product: C=C[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
This compound was prepared according to the procedure of paragraph C, by reaction of N-propionyl-2-benzoxazolone with acrolein. 1H-NMR (CDCl3, 400 MHz) δ 8.06 (m, 1 H), 7.27–7.20 (m, 2 H), 5.91 (ddd, J=17,10, 5 Hz). 5.37 (dt, J=1, 17 Hz, 1 H), 5.24 (dt, J=1, 10 Hz, 1 H), 4.60 (m, 1 H), 4.06 (dq, J=3, 6 Hz, 1 H), 2.62 (d, J=4 Hz, 1 H), 1.30 (d, 6 Hz, 3 H). 13C-NMR (CDCl3, 100 MHz) δ 175.4, 151.1, 142.2, 137.2, 127.7, 125.5, 124.9, 116.6, 116.2, 109.9, 72.7, 44.0, 10.7.
Reaction SMILES: BrC1C(=O)C(C(O)=O)=CN(C(C)C)C=1C.[Br:16][C:17]1[C:18](=[O:31])[C:19]([C:28]([OH:30])=O)=[CH:20][N:21]([CH:24]2[CH2:27][CH2:26][CH2:25]2)[C:22]=1[CH3:23].Cl.CS(C1C=CC(CN)=CC=1)(=O)=O.[CH3:45][S:46]([C:49]1[CH:50]=[CH:51][C:52]([CH2:55][NH2:56])=[N:53][CH:54]=1)(=[O:48])=[O:47].BrBr>>[CH3:45][S:46]([C:49]1[CH:50]=[CH:51][C:52]([CH2:55][NH:56][C:28]([C:19]2[C:18](=[O:31])[C:17]([Br:16])=[C:22]([CH3:23])[N:21]([CH:24]3[CH2:25][CH2:26][CH2:27]3)[CH:20]=2)=[O:30])=[N:53][CH:54]=1)(=[O:48])=[O:47]
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C1CCC1
Reactant: CS(=O)(=O)c1ccc(CN)nc1
Agent: BrBr
Agent: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Product: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cn2)cn1C1CCC1

Procedure:
Preparation 18 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 7b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine. ESI mass spectrum: [M+H]+=454 (bromine isotope pattern); Retention time HPLC: 1.14 min (Z002_006).