Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([C:20](=[O:22])[CH3:21])=[C:6]([CH3:19])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[C:11]=2[CH3:18])[C:8]=1[CH3:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH3:31]>>[C:1]([C:4]1[C:5]([C:20](=[O:22])[CH3:21])=[C:6]([CH3:19])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:30][CH3:31])=[C:12]([CH3:17])[C:11]=2[CH3:18])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(C)c2C)c1C
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(C)c1C

Procedure:
Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (100 mg, 0.3 mmol) reacted with bromoethane (300 μL, excess), in the presence of K2CO3 (50 mg), to afford 1-[4-acetyl-1-(4-ethoxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 328 (M+H)+. Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (108 mg, 0.3) and hydrazine (50 μL) reacted to give 6-(4-Ethoxy-2,3-dimethyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as off-white solid: 1H NMR (CDCl3, 500 MHz) δ 6.92 (d, 1H), 6.86 (d, 1H), 4.14 (q, 2H), 2.83 (s, 6H), 2.36 (s, 6H), 2.28 (s, 3H), 1.72 (s, 3H), 1.52 (t, 3H); MS (ESI) 324 (M+H)+.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:5][C:4]=1[F:20].[CH3:23][C:24]([O:27][C:28]([N:30]1[CH2:35][CH:34]=[C:33](OS(C(F)(F)F)(=O)=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])[CH3:25].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1CCCC1=O>[CH3:26][C:24]([O:27][C:28]([N:30]1[CH2:31][CH:32]=[C:33]([C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]3=[O:19])=[CH:5][C:4]=2[F:20])[CH2:34][CH2:35]1)=[O:29])([CH3:23])[CH3:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)c(F)c2)C(=O)O1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 108 h

Procedure:
A mixture of (S)-(-)-N-[[3-[4-trimethylstannyl-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (690 mg), 3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (step 2 of EXAMPLE 20, 500 mg), tris(dibenzylidenacetone)dipalladium(0) (14 mg) and triphenylarsine (37 mg) in N-methyl-2-pyrrolidinone (7.5 mL) is degassed, stirred under N2 at ambient temperature for 4.5 days, diluted with ethyl acetate, washed with water (3×40 mL) and saline (20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (230-400 mesh, 120 g), eluting with a gradient of methanol/methylene chloride (1/99-2/98), and those fraction having an Rf =0.27 by TLC (methanol/chloroform, 2×5/95) are pooled and concentrated to give the title compound, 1H NMR (CDCl3, 400 MHz) 7.39, 7.22, 7.13, 7.01, 5.92, 4.82, 4.06, 3.80, 3.67, 3.61, 2.47, 2.03, 1.49 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[CH:23][N:24]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1.[CH3:47][O:48][C:49]1[CH:50]=[C:51]([CH:55]=[CH:56][C:57]=1[O:58][CH3:59])[C:52](O)=[O:53]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:47][O:48][C:49]1[CH:50]=[C:51]([CH:55]=[CH:56][C:57]=1[O:58][CH3:59])[C:52]([O:18][CH2:17][C@@H:10]1[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@@H:13]([OH:14])[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:19][C:20]3[S:21][C:22]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[CH:23][N:24]=3)[CH:4]=2)[O:9]1)=[O:53]
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccsc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccsc5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1OC
Reaction time: 16 h
Yield: 27 %

Procedure:
To a solution of 48 (150 mg, 0.33 mmol), EDCI (130 mg, 0.66 mmol) and DMAP (20 mg, 0.16 mmol) and pyridine (0.13 ml, 1.65 mmol) in CH2Cl2 (4 ml) was added 3,4-dimethoxybenzoic acid (120 mg, 0.66 mmol) at room temperature and stirred for 16 hours. The reaction mixture was diluted with CH2Cl2 (8 ml), and washed with brine (8 ml). The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC (C18) to provide the titled compound (55 mg, 27%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:13][CH2:14][CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]2)[CH2:18][CH2:17]1>CN(C=O)C.O.CN(C=O)C.C1(C)C=CC=CC=1>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:30][CH2:29][CH2:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([C@H:19]2[CH2:18][CH2:17][C@H:16]([CH2:15][CH2:14][CH3:13])[CH2:21][CH2:20]2)[CH2:23][CH2:24]1
Reactant: Oc1cccc(F)c1F
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCBr)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCOc3cccc(F)c3F)CC2)CC1
Reaction time: 1 h

Procedure:
Under nitrogen gas stream, 29.8 g (683 mmol) of 55% sodium hydride was added to 100 ml of DMF and cooled with water, a solution of 74.0 g (569 mmol) of 2,3-difluorophenol in 700 ml of DMF was added by drops thereto, and they were stirred for 1 hour. To the reaction mixture was added by drops a solution of 156 g (474 mmol) of the crude 1-bromo-3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propane in 400 ml of mixed solvent of DMF/toluene (3/1), and then they were stirred at 80° C. for 3 hours. The reaction mixture was added to 500 ml of water to terminate the reaction, and the organic layer was separated, washed with 500 ml of water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: heptane) and recrystallized from heptane to obtain 101 g of 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propyl 2,3-difluorophenyl ether.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[N:10]1([C:15]([CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCOCC1>[CH3:1][CH:2]([CH2:3][C:4](=[O:5])[N:21]1[CH2:20][CH2:19][N:18]([CH2:17][C:15](=[O:16])[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:23][CH2:22]1)[CH2:8][C:7]([OH:6])=[O:9]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Solvent: C1COCCO1
Product: CC(CC(=O)O)CC(=O)N1CCN(CC(=O)N2CCCC2)CC1
Reaction time: 8 h
Yield: 110.7 %

Procedure:
1.6 g of 3-methylglutaric anhydride and then 2.62 g of pyrrolidinocarbonylmethyl-piperazine are added to 10 cm3 of dioxane. After stirring for 8 hours, an additional 320 mg of 3-methylglutaric anhydride are added and then the stirring is continued at 20° C. for 18 hours. The solvent is then evaporated under reduced pressure and then the resulting oil is dried at 45° C. (90 Pa) to give 4.5 g of (3RS)-3-methyl-5-oxo-5-[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]pentanoic acid in the form of an orange-colored oil which is used as it is.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16]C(O)=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC[N:30](CC)CC.[Cl:35]C(OCC)=O.[N-]=[N+]=[N-].[Na+]>O>[ClH:35].[NH2:30][CH2:16][CH:15]([C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1)[C:20]#[C:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)O)cc1OC1CCCC1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(C#Cc2ccccc2)CN)cc1OC1CCCC1
Product: Cl
Reaction time: 0.25 h

Procedure:
A solution of (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)-3-phenylethynylpropionic acid (1.2 g, 3.3 mmol) in Me2CO (40 ml) was cooled to -15° and treated with Et3N (0.505 ml, 3.63 mmol) and then ethyl chloroformate (0.35 ml, 3.63 mmol), at such a rate so the temperature did not exceed -10°. The mixture was stirred at 0° for 15 minutes. A solution of NaN3 (470 mg, 7.25 mmol) in H2O (2 ml) was added dropwise to the cold solution, and stirring continued in the cold for 15 minutes. The reaction was diluted with H2O, and extracted with Et2O. The extracts were washed with H2O, and dried. The ether extract was slowly added to C6H5Me (100 ml) at 110°, and the solution was heated at 110° for 30 minutes, and the solvent was evaporated. The residue was dissolved in a mixture of dioxane (5 ml), H2O (3 ml), and conc. HCl (3 ml), refluxed for 10 minutes, cooled and the solid filtered. Recrystallization from a mixture of i-propanol and Et2O gave the titled compound as the HCl salt, 1.03 g (84%). mp 212-215°. NMR.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1.CCOCC>CN1CCCC1=O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: C1CSCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(N3CCSCC3)c(F)c21
Reaction time: 2 h

Procedure:
A 289 mg portion of 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was dissolved in 3 ml of 1-methyl-2-pyrrolidone. A 350 mg portion of thiomorpholine was added and the mixture was stirred for 2 hours. Ether was added, the solid collected and recrystallized from acetone, giving 250 mg of the desired product as a white solid, mp 308°-310° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[C:24]([C:25]4[CH:26]=[C:27]([C:33]5[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][C:34]=5[CH3:46])[CH:28]=[N:29][C:30]=4[O:31][CH3:32])=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)[C@H:13]2[CH3:51])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[F:53][C:54]1([F:58])[CH2:57][NH:56][CH2:55]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[F:53][C:54]1([F:58])[CH2:57][N:56]([C:21]2[N:20]=[C:19]([CH2:18][N:14]3[C@@H:13]([CH3:51])[C@@H:12]([C:4]4[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([F:1])[CH:3]=4)[O:16][C:15]3=[O:17])[C:24]([C:25]3[CH:26]=[C:27]([C:33]4[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[CH:35][C:34]=4[CH3:46])[CH:28]=[N:29][C:30]=3[O:31][CH3:32])=[CH:23][N:22]=2)[CH2:55]1
Reactant: FC1(F)CNC1
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(N2CC(F)(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-{5-[4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (INTERMEDIATE 48, 96 mg, 0.131 mmol) in THF (1.5 mL) was added 3,3-difluoroazetidine hydrochloride (51.1 mg, 0.394 mmol) and triethylamine (0.082 mL, 0.591 mmol). The resulting mixture was subjected to microwave irradiation at 135° C. for 40 minutes. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (sodium sulfate), filtered and concentrated to give crude tert-butyl 4-{5-[2-(3,3-difluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (98 mg, 0.131 mmol). LCMS (M+H)+: 744.2.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:12]([F:15])([F:14])[F:13])[C:6]=1[C:7]([O:9]CC)=[O:8].C(O)C.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:12]([F:14])([F:13])[F:15])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(C(F)(F)F)coc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1occ(C(F)(F)F)c1C(=O)O
Yield: 90.6 %

Procedure:
18 g of the product of Stage B were refluxed for 2 and a half hours in 42 ml of water and 126 ml of ethanol in the presence of 3.55 g of sodium hydroxide. The mixture was allowed to return to room temperature and 2N hydrochloric acid was added to neutrality. The mixture was partially concentrated and 2N sodium hydroxide solution was added. The mixture was extracted with isopropyl ether and the solvent was evaporated to obtain 14.25 g of the expected product melting at 140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Br:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[O:32])=[CH:29][CH:28]=1
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4ccc(Br)cc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 4-bromobenzoyl chloride (66 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a free base.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:37])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:26][C:27]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)=[N:28][N:29]=4)[CH:22]=[CH:21][C:20]=3[CH3:37])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nnc(-c5ccc(Cl)cc5)o4)ccc3C)csc12
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(-c5ccc(Cl)cc5)o4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-{5-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.30 g, 0.56 mmol) (from Example 46 supra) in 2-propanol (30 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 5.5 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-{5-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.22 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].[C:15]12([C:25]([OH:27])=O)[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>>[CH3:1][C:2]1[N:3]([CH2:14][CH2:13][CH2:12][CH:11]=[CH2:10])/[C:4](=[N:8]/[C:25]([C:15]23[CH2:16][CH:17]4[CH2:18][CH:19]([CH2:20][CH:21]([CH2:23]4)[CH2:22]2)[CH2:24]3)=[O:27])/[S:5][C:6]=1[CH3:7]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: C=CCCCBr
Reactant: Cc1nc(N)sc1C
Product: C=CCCCn1c(C)c(C)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2

Procedure:
4,5-Dimethylthiazol-2-ylamine, 5-bromo-pent-1-ene and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.68 (q, 6H) 1.74-1.81 (m, 2H) 1.84 (d, J=2.50 Hz, 6H) 1.94-2.02 (m, 3H) 2.10 (q, 2H) 2.15 (s, 3H) 2.20 (s, 3H) 4.11 (t, 2H) 4.95-5.13 (m, 2H) 5.80-5.95 (m, 1H); MS (ESI) m/z 359 (M+H)+.
Reaction SMILES: [Al].[CH2:2](Br)[C:3]#[CH:4].[O:6]1[CH2:11][CH2:10][CH2:9][O:8][CH:7]1[C:12]1[CH:13]=[C:14]([C:18]([CH3:27])([CH3:26])[CH2:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:15]=[CH:16][CH:17]=1>C1COCC1.C(OCC)C>[O:6]1[CH2:11][CH2:10][CH2:9][O:8][CH:7]1[C:12]1[CH:13]=[C:14]([C:18]([CH3:27])([CH3:26])[CH2:19][C:20]([C:21]([F:23])([F:24])[F:22])([OH:25])[CH2:4][C:3]#[CH:2])[CH:15]=[CH:16][CH:17]=1
Reactant: C#CCBr
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc(C2OCCCO2)c1
Agent: [Al]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCC(O)(CC(C)(C)c1cccc(C2OCCCO2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
Aluminum amalgam was prepared from aluminum foil (1.16 g, 14.4 mmol) and mercuric chloride (12 mg, catalytic amount) in 20 mL of anhydrous THF by vigorously stirring the mixture at room temperature for 1 hour under an argon atmosphere. A solution of propargyl bromide (4.80 mL, 80 wt. % in toluene, 43.1 mmol) in 25 mL of anhydrous THF was slowly added to a stirred suspension maintaining a temperature of 30° C.-40° C., and after addition, stirring at 40° C. was continued until a dark gray solution was obtained (ca. 1 hour). The propargyl aluminum sesquibromide solution was added to a solution of 4-(3-[1,3]dioxan-2-ylphenyl)-1,1,1-trifluoro-4-methylpentan-2-one (5.6 g, 14.2 mmol) in 100 mL of anhydrous diethyl ether at −78° C. The reaction mixture was stirred at this temperature for 3 hours, and then was allowed to warm to room temperature, at which time it was stirred for 12 hours. The reaction mixture was then poured into 20 mL of ice-water and extracted with four 30 mL portions of diethyl ether. The combined extracts were washed with 20 mL of brine, dried over magnesium sulfate, and concentrated in vacuo. Chromatography on silica gel (100% hexanes to 40% ethyl acetate in hexanes, gradient) afforded 2.5 g of the title compound as an oil (50% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])=[CH:15][CH:14]=2)[N:10]=1.[C-:26]#[N:27].[Na+].[C:29]([O:32]C(=O)C)(=O)[CH3:30]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl>[C:29]([O:24][CH:23]([CH2:22][CH2:21][CH2:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:9]2[N:10]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:7][C:8]=2[CH3:25])=[CH:18][CH:17]=1)[C:26]#[N:27])(=[O:32])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: [C-]#N
Reactant: Cc1oc(-c2ccco2)nc1CCc1ccc(CCCCC=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC(C#N)CCCCc1ccc(CCc2nc(-c3ccco3)oc2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
After a mixture of 5-[4-[2-[2-(2-furyl)-5-methyl-4-oxazolyl]ethyl]phenyl]pentan-1-al (2.2 g), sodium cyanide (0.383 g), acetic anhydride (0.796 g), benzyltributylammonium chloride (0.608 g) and dichloromethane (40 ml)water (10 ml) was stirred at room temperature for 2 hours, the organic layer was separated, washed with water, dried (MgSO4), and then concentrated under reduced pressure, to yield 2-acetoxy-6-[4-[2-[2-(2-furyl)-5-methyl-4-oxazolyl]ethyl]phenyl]hexanenitrile as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:47]2[CH2:46][CH2:45][CH:44]([NH:43][C:35]3[NH:34][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:49][CH2:48]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Reactant: COc1ccc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)c(OC)c1OC
Agent: I
Product: COc1ccc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)c(OC)c1OC

Procedure:
Prepare by the method of Example 4.1 using 1-(2,3,4-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (1.1 g, 2.3 mmol) and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (1.21 g, 2.6 mmol). Purify by chromatography on silica gel eluting 28% methanol/ethyl acetate containing 20 mL concentrated aqueous ammonia solution/3L to give the title compound: mp; 112-119° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16](C)[C:17](=O)OC(C)(C)C)=[N:13][C:12]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][CH3:17])=[N:13][C:12]=1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N(C)C(=O)OC(C)(C)C)sc1C(=O)NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1nc(C)c(C(=O)NCc2ccccc2)s1

Procedure:
To a solution of tert-butyl 5-(benzylcarbamoyl)-4-methylthiazol-2-yl(methyl)carbamate (0.030 g, 0.083 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) and the resultant mixture was stirred at ambient temperature for 4 h. Toluene (0.5 mL) was added and the reaction mixture was concentrated in vacuo. The residue was triturated with diethyl ether and concentrated in vacuo and dried in vacuum. The crude N-benzyl-4-methyl-2-(methylamino)thiazole-5-carboxamide was obtained and used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[Cl:16][C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22]([SH:24])=[N:23][C:19]=2[CH:18]=1>>[Cl:16][C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22]([S:24][C@@H:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[C@@H:3]3[OH:14])=[N:23][C:19]=2[CH:18]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Reactant: Sc1nc2cc(Cl)ccc2[nH]1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Sc2nc3cc(Cl)ccc3[nH]2)[C@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-chloro-1H-benzoimidazole-2-thiol as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH2:14]O)[CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH3:2].O=S(Cl)[Cl:18]>C(Cl)Cl>[ClH:18].[Cl:18][CH2:14][C:9]1[CH:10]=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=2
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc2cc(CO)cnc2c1
Solvent: ClCCl
Product: CCOc1ccc2cc(CCl)cnc2c1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of (7-ethoxyquinolin-3-yl)methanol MDE 32072 (88 mg, 433 μmol) in dry CH2Cl2 (10 mL) at 0° C. under N2 in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (0.64 mL, 8.82 mmol) and the mixture was stirred for 30 min at 0° C. then for 2 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)-7-ethoxyquinoline hydrochloride CCH 29190 as a brown solid (113 mg, >100% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>>[NH:18]1[C:17]([NH:16][C:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=2)=[O:11])=[N:21][N:20]=[N:19]1
Reactant: CSc1ccc(C(=O)O)nc1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: CSc1ccc(C(=O)Nc2nnn[nH]2)nc1
Yield: 34 %

Procedure:
0.36 g of 5-methylthio-2-pyridinecarboxylic acid, 6 ml of thionyl chloride and 0.18 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.17 g of N-(5-tetrazolyl)-5-methylthio-2-pyridinecarboxamide is obtained.