Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][NH:12][CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41]>CC(O)C>[Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])[CH2:11][C@H:10]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of tert-butyl (3R,4R,5S)-4-(tert-butyldimethylsilyloxy)-5-methylpiperidin-3-ylcarbamate (1.0 equiv.) in i-PrOH (0.09 M) was added DIEA (2.5 equiv.) and 4-chloro-3-nitropyridine (1.5 equiv.). The reaction mixture was stirred at 60° C. for 2 hours. The volatiles were removed under vacuo, the residue was diluted with ethyl acetate and washed with sat. NaCl. The organic phase was dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexanes (1:2) to give tert-butyl (3R,4R,5S)-4-(tert-butyldimethylsilyloxy)-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in 76% yield. LC/MS=467.3 (M+H), Rt=1.09 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])=[O:11].CI.[C:21](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:21][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])=[O:11]
Reactant: Nc1ccccc1S(=O)c1nc2ccccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(S(=O)c2ccccc2N)nc2ccccc21
Yield: 86.8 %

Procedure:
2-(1H-Benzimidazol-2-yl sulphinyl)benzenamine (850 mg, 3.31 mmole) in dimethylformamide (16 ml) and methyl iodide (515 mg, 3.63 mmole) were stirred at room temperature for 6 hours in a stoppered flask in the presence of potassium carbonate (1.66 g, 12 mmole). The mixture was poured into water and extracted with ethyl acetate (3×). The combined extracts were washed with water (3×), dried (anhydrous sodium sulphate) and evaporated to give a pale grey solid which was triturated with ether to give the title compound as an off-white solid (0.78 g; 87%), mp 146°-8°(dec).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])C.[CH3:7][S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH3:7][S:8]([N:11]=[C:1]([O:4][C:5]1[CH:6]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:3][C:14]1[CH:13]=[CH:12][CH:17]=[CH:16][CH:15]=1)(=[O:10])=[O:9]
Reactant: CCOC(C)=O
Reactant: CCCCCC
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Yield: 49 %

Procedure:
267 g of diphenyl carbonate and 298 g of phosphorus pentachloride were reacted at 160° C. for 15 hours with distilling off the phosphorus oxychloride generated by the reaction. After the completion of the reaction, phosphorus oxychloride and residual phosphorus pentachloride were removed by distillation under reduced pressure to obtain dichloro-diphenoxymethane. Thereto were added 600 ml of anhydrous ethyl acetate and 148 g of methanesulfonamide, and the mixture was refluxed for 8 hours. After cooling, 1 liter of n-hexane was added to the mixture and the crystals deposited were collected by filtration. The crystals were washed with water and dried to obtain 179 g (yield: 49%) of diphenyl methanesulfonylimidocarbonate having a melting point of 124°-125.5° C.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:12])[C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C[N:16]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1.C(N)(=O)C(N)=O>C(Cl)Cl.C(OCC)(=O)C>[C:1]1([NH:7][C:8](=[O:12])[C:9]([NH2:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)C(=O)Nc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=O)C(N)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: NC(=O)C(=O)Nc1ccccc1
Reaction time: 0.08 h

Procedure:
Acid 84 (20 mg, 1.4 eq) in CH2Cl2 (1 mL) was treated with PyBOP (53 mg, 1.2 eq) and NMM (0.028 mL, 3.0 eq) and stirred for 5 minutes. To this was added a solution of oxalamide (50 mg, 1.0 eq) and NMM (0.028 mL, 3.0 eq) in CH2Cl2 (1 mL) and the mixture stirred at room temperature overnight. The mixture was diluted with ethyl acetate, the organic phase washed with 0.5N HCl, brine, saturated bicarbonate solution, and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparative HPLC yielded 24 mg (38%) of N-[cyclohexyl-(1-{2-[1-cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-octahydro-indole-1-carbonyl}-2,2-dimethyl-propylcarbamoyl)methyl]-N′-phenyl-oxalamide 96 as a white solid with consistent analytical data. LCMS ret time=4.07, M+H=737.26, M−H=735.22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][C:58]=1[O:59][CH3:60])CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][C:56]2[CH:53]=[CH:52][C:51]([O:50][CH3:49])=[C:58]([O:59][CH3:60])[CH:57]=2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccc(CO)cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1OC
Temperature: 25 °C
Yield: 65.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (65 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (100 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3,4-dimethoxybenzyl alcohol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (70 mg, yield 60%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([O:10][C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:19][NH2:20].C1COCC1.[BH4-].[Na+].[ClH:28]>CC#N.CCOC(C)=O>[ClH:28].[ClH:28].[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([O:10][C:11]3[CH:18]=[CH:17][C:14]([CH2:15][CH2:19][NH2:20])=[CH:13][CH:12]=3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: CN
Reactant: O=Cc1ccc(Oc2cnc(C3CC3)nc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NCCc1ccc(Oc2cnc(C3CC3)nc2)cc1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 4-[(2-cyclopropylpyrimidin-5-yl)oxy]benzaldehyde (0.240 g, 1.0 mmol) in MeCN (0.50 mL) was added 2M methylamine in THF (2.0 mL, 4.0 mmol) followed by sodium borohydride (0.120 g, 3.2 mmol) and MeCN (0.50 mL). The slurry was stirred for 30 minutes. The solvents were removed by evaporation, water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine and evaporated onto silica gel. This gel was applied onto a 20 g silica gel column. Column chromatography using a gradient of 10% to 60% EtOAc in heptanes eluted impurities. Elution with 10% MeOH in EtOAc (100 mL) followed by 5% concentrated NH3 in MeOH (100 mL) gave the product in the basic fractions. These fractions were combined, concentrated and re-dissolved in water. The pH was adjusted to 13 to 14 using sodium hydroxide solution and the mixture was extracted several times with EtOAc. The organic extracts were washed with brine, dried over potassium carbonate, filtered and concentrated to give an oily residue. This oil was dissolved in EtOAc and an excess of a 1.5M solution of hydrogen chloride in EtOAc was added. The solvent was removed by evaporation to give 0.186 g (56% yield) of the crude subtitle compound. The salt obtained was 93.9% pure and was used without further purification.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>O>[N:32]1([C:23]2[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=2[NH:21][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21)c1ccncc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.1 %

Procedure:
Isonicotinoyl chloride hydrochloride (669 mg, 3.76 mmol, commercially available product) and triethylamine (773 μl, 5.58 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 1-[2-amino-4-(trifluoromethyl)phenyl]indoline (518 mg, 1.86 mmol), obtained as described in Referential Example 19-2. The resulting mixture was warmed to room temperature and stirred for 2.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=1/1). Thus, N-[2-(1-indolinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0619) (643 mg, 90.1%) was yielded as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]#[CH:11])[C:3]1[S:4][C:5]([CH3:8])=[CH:6][N:7]=1.CCCCCC.C([Li])CCC.[I:23]I>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH2:9][C:10]#[C:11][I:23])[C:3]1[S:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: II
Reactant: C#CCN(C)c1ncc(C)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1cnc(N(C)CC#CI)s1
Yield: 82.7 %

Procedure:
Compound (b) (950 mg) was dissolved in anhydrous tetrahydrofuran (30 ml) and a hexane solution (4.5 ml) of butyllithium was added thereto at -78° C. After 30 minutes iodine (1.6 g) was added to the above mixture, which was then allowed to react for 10 minutes at room temperature and evaporated to remove the tetrahydrofuran. Water is added to the residue, which was then extracted with ether. The extract was washed with water and evaporated to remove the solvent. The residue was applied to chromatography on silica gel (25 g) to give 2-(N-methyl-3-iodo-2-propynylamino)-5-methylthiazole (No.1) (1.38 g, yield 83%) from chloroform eluate. mp. 97°-98° C. (hydrochloride: mp. 205°-213° C. (decomp.))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][S:23][C:21]1[O:22][C:18]([C:15]2[CH:16]=[CH:17][C:12]3[O:11][CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:13]=3[CH:14]=2)=[N:19][N:20]=1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Reactant: COc1cccc(CCl)c1
Product: COc1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(OC)c5)o4)cc23)cc1
Yield: 87 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-methoxybenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 87%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([CH3:18])[CH:5](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:6]>C1CCN2C(=NCCC2)CC1.CCOCC>[CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([CH3:18])[CH:5]=[CH2:6]
Reactant: COC(=O)C(C)(C)C(C)OS(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: C=CC(C)(C)C(=O)OC
Temperature: 25 °C
Yield: 130 %

Procedure:
A solution of 2,2-dimethyl-3-(toluene-4-sulfonyloxy)-butyric acid methyl ester (18.06 g, 0.06 mol) in DBU (15 ml) was heated at 140-160° for 3.5 h. The mixture was allowed to cool to room temperature and was then diluted with ether. The mixture was washed with HCl (1 M), sodium bicarbonate, then brine. The ethereal layer was dried and partially evaporated to give a concentrated solution of 2,2-dimethyl-but-3-enoic acid methyl ester (10 g). (Savu and Katzenellenbogen, J. Org. Chem, 46:239-250 (1981)). Further evaporation was avoided due to the volatility of the product (bp 102°). (Tsaconas et al., Aust. J. Chem., 53:435-437 (2000)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=1>N1C=CC=CC=1>[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)=[CH:34][CH:33]=1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)cc2)cc1
Reactant: Fc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A mixture of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (172 mg, 0.5 mmol), prepared according to the method of Example 10, Cu powder (32 mg), anhydrous K2CO3 (207 mg, 1.5 mmol) and 4-fluoroiodobenzene (0.12 mL, 1 mmol) was prepared in 20 mL of pyridine. The solution was stirred at reflux for 14 hours. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with 10% citric acid, water, brine and concentrated in vacuo. Separation by column chromatography (silica gel, CH2Cl2-diethyl ether 15:1) provided 190 mg of crude product. Crystallization from CH2Cl2-diethyl ether-hexanes furnished the title compound (yield: 175 mg, 79.9%). mp 168–169° C. 1H NMR (300 MHz, CDCl3) δ 3.07 (s, 3H), 6.98 (t, J=9 Hz, 2H), 7.20 (m, 4H), 7.40 (d, J=9 Hz, 2H), 7.69 (m, 2H), 7.92 (d, J=9 Hz, 2H), 7.98 (s, 1H). MS (DCI/NH3) m/z 439 (M+H)+, 456 (M+NH4)+. Anal. calc. for C23H16F2N2O3S.0.25 H2O: C, 62.36; H, 3.75; N, 6.32. Found: C, 62.23; H, 3.55; N, 6.26.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([O:15][C:16]([NH:18][CH:19]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:20]([O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CCOC(C)=O>[Br-:1].[C:11]([O:15][C:16]([NH:18][CH:19]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:20]([O:22][C@@H:23]1[CH:28]2[CH2:27][CH2:26][N+:25]([CH2:2][C:3](=[O:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)([CH2:30][CH2:29]2)[CH2:24]1)=[O:21])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccc(Cl)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 36 h
Yield: 42.1 %

Procedure:
2-Bromo-1-phenylethanone (55.4 mg, 0.28 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)acetate (C47) (100 mg, 0.25 mmol) in EtOAc (3 ml). The reaction was stirred at RT for 36 hours, and then a second portion of 2-bromo-1-phenylethanone (50.4 mg, 0.25 mmol) was added, and the reaction was stirred at RT for additional 48 hours. The organic phase was washed with aq. Na2CO3, dried over Na2SO4 and evaporated. The crude was dissolved in acetonitrile (3 ml), and 2-bromo-1-phenylethanone (60.0 mg, 0.30 mmol) was added. The reaction was heated under microwave irradiation at 100° C. for 45 minutes. The solvent was evaporated and the crude was purified by flash chromatography (DCM/MeOH=95/5 to 9/1) to obtain (3R)-3-(2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (62.5 mg; 42% yield).
Reaction SMILES: Cl.Cl.[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][C:29]5([CH2:35][CH3:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])CC1.CNC(C1C2C=C(C3C([Cl:56])=CN=C(Cl)N=3)SC=2C=CC=1)=O.C(OC(N1CCC(CCCN)(CC)CC1)=O)(C)(C)C>>[ClH:24].[ClH:56].[CH3:3][NH:6][C:7]([C:9]1[C:17]2[CH:16]=[C:15]([C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][C:29]4([CH2:35][CH3:36])[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]4)[N:19]=3)[S:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCNCC1
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: CCC1(CCCN)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC)cccc4s3)n2)CCNCC1

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-ethylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and 4-(3-aminopropyl)-4-ethylpiperidine-1-carboxylic acid tert-butyl ester and isolated as a solid. ES+(m/z) 472 (35Cl) and 474 (37Cl) [M(free base)+H].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]#[N:32])[CH:21]=1.N1C=CC=CC=1.CCCP(=O)=O>CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]#[N:32])[CH:21]=1)=[O:6]
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)c1cc(-c2ncccc2F)c(F)cc1Cl
Agent: CCCP(=O)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1cc(NC(=O)c2cc(-c3ncccc3F)c(F)cc2Cl)n(-c2ccccc2)n1
Temperature: 90 °C
Yield: 34.6 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-(3-fluoropyridin-2-yl)benzoic acid (Preparation 21, 160 mg, 0.59 mmol) in 2-Methyl-THF (3 mL) was added 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53, 120 mg, 0.65 mmol) and pyridine (0.14 mL, 1.77 mmol). The reaction was heated to 90° C. before the addition of propylphosphonic anhydride (752 mg, 1.18 mmol) and the reaction was continued heating at 90° C. for 16 hours. Further propylphosphonic anhydride (752 mg, 1.18 mmol) was added and the reaction continued to heat at 90° C. for 3 hours. The reaction was cooled to room temperature, diluted with EtOAc (20 mL) and washed with 2M NaOH(aq) (2×20 mL), saturated aqueous NH4Cl solution (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulphate and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting from 5-60% MeCN (with 0.1% HCO2H) in water (with 0.1% HCO2H) to afford the title compound (89 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ncccc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-hydroxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.3 mmol) in N,N-dimethylformamide (2.0 ml) was added at 22° C. sodium hydride (55% in oil, 64 mg) and stirring was continued until gas evolution ceased. The suspension was cooled to 0° C. and treated with trifluoroethyl trifluormethanesulfonate (728 mg) and stirring was continued at 22° C. for 2 hours. The mixture was partitioned between saturated sodium hydrogen-carbonate solution and ethyl acetate, and the organic layer was dried and evaporated. The residue was purified by chromatography on silica using n-heptane and ethyl acetate (3:1) as the eluent to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester as a pale green oil. MS (ESI): m/z=236.2 [M+H]+. b) A solution of 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg, 0.9 mmol) in methanol (1 ml) was treated with a solution of lithium hydroxide (78 mg, 3.3 mmol) in water (0.1 ml) and stirring was continued at 22° C. for 2 hours. The solution was evaporated and the residue triturated with 1N aqueous hydrochloric acid. The suspension was filtered, the residue washed with water and dried to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid as a colorless solid. MS (ESI): m/z=220.0 [M−H]−. c) The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tent-butyl ester and 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid yielded the title compound as a white powder. MS (ESI): m/z=427.1 [M+H]+.
Reaction SMILES: [F:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.C(N(CC)CC)C.FC(F)(F)C(O)=O.[NH:43]1[CH2:47][CH2:46][C@@H:45]([S:48][C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[CH2:44]1>CN(C=O)C>[F:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([N:43]1[CH2:47][CH2:46][C@@H:45]([S:48][C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[CH2:44]1)=[O:5]
Reactant: Oc1ccc(S[C@@H]2CCNC2)cc1
Reactant: O=C(O)C(F)CCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(C(F)CCc1ccccc1)N1CC[C@@H](Sc2ccc(O)cc2)C1
Temperature: 55 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
(RS)-2-Fluoro-4-phenyl-butyric acid (0.66 g, 3.63 mmol) was dissolved in DMF (5 ml) and carbonyldiimidazole (0.64 g, 3.8 mmol) was added portionwise. After evolution of CO2 has ceased, the reaction mixture was warmed to 55° C. for 20 minutes and then cooled to room temperature. A mixture of triethylamine (0.46 ml, 3.3 mmol) and (3R)-4-(pyrrolidin-3-ylsulfanyl)-phenol trifluoroacetic acid (1.02 g, 3.3 mmol) in DMF (5 ml) was added. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue taken up in H2O (30 ml).The mixture was extracted with ethylacetate (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed over silica gel (CH2Cl2—MeOH, 99:1) to provide (2RS,3R)-2-fluoro-1-[3-(4-hydroxy-phenylsulfanyl)-pyrrolidin-1-yl]-4-phenyl-butan-1-one (1.12 g, 95%) as light yellow oil, MS: m/e=359.1(M+).