Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH:4]([NH:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]2)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:6]=1[O:13][CH3:14].[CH2:32]([SH:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:12][C:7]1[C:6]([O:13][CH3:14])=[C:5]([CH:4]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]3)[C:3]([CH2:2][S:34][CH2:32][CH3:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: CCS
Reactant: COc1c(F)cc(F)cc1C(Nc1cccc2nc(C)ccc12)C(O)(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCSCC(O)(C(Nc1cccc2nc(C)ccc12)c1cc(F)cc(F)c1OC)C(F)(F)F

Procedure:
Analogously to example 45 100 mg (0.24 mmol) {[3,5-difluoro-2-methoxyphenyl][2-(trifluoromethyl)oxiranyl]methyl}-2-methylquinolin-5-amine (example 14) are reacted with 0.25 ml of the 1 M ethanthiol solution under the presence of 148 mg Caesium carbonate in DMF. The typical work up after 2 hours yields 49 mg of the title compound after preparative thin layer chromatography on silica gel (aceton in hexane 50%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([S:8][CH3:9])=[N:4]1.[CH:10](N(C(C)C)CC)(C)C.Cl[CH2:20][O:21]C>ClCCl>[CH3:20][O:21][C@:3]1([CH2:2][O:1][CH3:10])[CH2:7][S:6][C:5]([S:8][CH3:9])=[N:4]1
Reactant: COCCl
Reactant: CCN(C(C)C)C(C)C
Reactant: CSC1=N[C@H](CO)CS1
Solvent: ClCCl
Product: COC[C@@]1(OC)CSC(SC)=N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 36 %

Procedure:
3.14 g of Compound (6) obtained in the step (a) and 6.7 ml of diisopropylethylamine were dissolved in 40 ml of dry dichloromethane solution. 2.33 g of chloromethylmethyl ether was added to the above mixture under ice-cooling and the reaction mixture was stirred for 1 hour under the same condition and for 15 hours at room temperature. After the reaction, the reaction mixture was washed with water, saturated sodium bicarbonate solution and saturated saline solution, and dried over magnesium sulfate. After removal of the solvent, the resulting residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to give 1.42 g (36%) of 4(R)-methoxy-methyloxymethyl-2-methylthio-1,3-thiazoline [Compound (7)].
Reaction SMILES: [S:1]1[CH:5]=[C:4](B(O)O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[C:13]1([CH2:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.O=[CH:23][C:24]([OH:26])=[O:25]>C(#N)C>[S:1]1[CH:5]=[C:4]([CH:23]([NH:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:24]([OH:26])=[O:25])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=CC(=O)O
Reactant: OB(O)c1csc2ccccc12
Reactant: NCc1ccccc1
Solvent: CC#N
Solvent: O
Product: O=C(O)C(NCc1ccccc1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
A mixture of benzo[b]thiophen-3-ylboronic acid (300 mg, 1.68 mmol), phenylmethanamine (184 μl, 1.68 mmol) and 2-oxoacetic acid hydrate (155 mg, 1.68 mmol) in acetonitrile (20 ml) was stirred at room temperature for 2 hours. The solvent was removed and crude was triturated with Et2O/CH3CN (9/1) to obtain 2-(benzo[b]thiophen-3-yl)-2-(benzylamino)acetic acid (303 mg, 60.5% yield).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=4[S:14][C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][I:20]>CCOC(C)=O>[I-:20].[CH3:19][N+:9]1[C:10]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]=2[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1
Reactant: c1ccc(-n2cnc3sc4ccccc4c32)cc1
Reactant: CI
Solvent: CCOC(C)=O
Product: C[n+]1cn(-c2ccccc2)c2c3ccccc3sc21
Product: [I-]
Yield: 88 %

Procedure:
A solution of 1-phenyl-1H-benzo[4,5]thieno[2,3-d]imidazole (4 g, 16 mmol) and methyl iodide (11.36 g, 80 mmol) in EtOAc (100 ml) was stirred for 48 h at room temperature. The precipitate was isolated by filtration and washed thoroughly with EtOAc to yield 3-methyl-1-phenyl-1H-benzo[4,5]thieno[2,3-d]imidazol-3-ium iodide (5.52 g, 88%) as a white solid.
Reaction SMILES: ClCCl.FC(F)(F)C(O)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:23][CH:24]2[CH:29]([CH2:30][C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH2:28][O:27][C:25]2=[O:26])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]>C(OCC)(=O)C>[CH3:42][O:41][C:33]1[C:34]([O:39][CH3:40])=[C:35]([O:37][CH3:38])[C:36]2[C:14]3[C:13]([O:12][CH3:11])=[C:18]([O:19][CH3:20])[C:17]([O:21][CH3:22])=[CH:16][C:15]=3[CH2:23][CH:24]3[C:25](=[O:26])[O:27][CH2:28][CH:29]3[CH2:30][C:31]=2[CH:32]=1
Reactant: COc1cc(CC2COC(=O)C2Cc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1c(cc(OC)c(OC)c1OC)CC1C(=O)OCC1C2
Temperature: 25 °C
Reaction time: 19 h
Yield: 57.3 %

Procedure:
Dissolved in a mixture consisting of 0.5 ml of dichloromethane and 0.05 ml of trifluoroacetic acid were 50 mg (0.112 mmol) of 2,3-bis[1-(3,4,5-trimethoxyphenyl)methyl]butanolide. The solution was added with 150 mg (0.32 mmol) of ferric perchlorate, followed by stirring at room temperature for 19 hours. The reaction mixture was dissolved in 10 ml of ethyl acetate. The resulting solution was washed successively with 2N-HCl, water and saturated NaHCO3. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby colorless oil was obtained. The oil was purified by thinlayer chromatography (TLC) (silica gel: "MERCK #5744", eluent: 1:3 mixed solvent of acetone and hexane), whereby 28.5 mg of the title compound were obtained as a colorless solid (yield: 57%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][C:16]1[C:21]([CH2:22]Br)=[C:20]([F:24])[CH:19]=[CH:18][C:17]=1[F:25]>CN(C)C=O>[F:24][C:20]1[CH:19]=[CH:18][C:17]([F:25])=[C:16]2[C:21]=1[CH2:22][N:10]([S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:11])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH2:15]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Fc1ccc(F)c(CBr)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3c(F)ccc(F)c3C2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A solution of 4-toluenesulphonamide (2.44 g, 14.28 mmol) in N,N-dimethylformamide (10 ml) was added dropwise to a vigourously stirred suspension of sodium hydride (1.2 g, 60 wt % in mineral oil, 30.0 mmol) in anhydrous N,N-dimethylformamide (60 ml). The mixture was stirred at room temperature for 1 hour, at 110° C. for 1 hour and was then cooled to 60° C. and a solution of 2,3-bis-bromomethyl-1,4-difluorobenzene (4.28 g, 14.28 mmol) in N,N-dimethylformamide (30 ml) was added dropwise. The mixture was stirred at 60° C. for 1 hour and then at room temperature for 16 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane and 1M hydrochloric acid. The organic layer was separated, washed with 5% aqueous potassium carbonate solution, the organics were separated and the solvent removed in vacuo. The residue was rinsed with diethyl ether, filtered and the solids sucked dry under reduced pressure to afford 4,7-difluoro-2-(toluene-4-sulphonyl)isoindoline (2.46 g, 56%) as a pale tan solid. 1H NMR (DMSO-d6) 7.82 (2H, d), 7.43 (2H, d), 7.15 (2H, dd), 4.66 (4H, s), 2.36 (3H, s). MS: [M+H]+ 310.
Reaction SMILES: FC(F)(F)C(O)=O.O.COC1C=C(OC)C=CC=1C[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][N:21]([C@H:24]3[C@H:31]4[C@H:27]([O:28]C(C)(C)[O:30]4)[C@@H:26]([CH2:34][N:35]([CH:56]([CH3:58])[CH3:57])[CH:36]4[CH2:39][CH:38]([CH2:40][CH2:41][C:42]5[NH:46][C:45]6[CH:47]=[CH:48][C:49]([O:51][C:52]([F:55])([F:54])[F:53])=[CH:50][C:44]=6[N:43]=5)[CH2:37]4)[CH2:25]3)[C:17]=2[N:18]=[CH:19][N:20]=1.C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:14][C:15]1[C:16]2[CH:23]=[CH:22][N:21]([C@@H:24]3[CH2:25][C@H:26]([CH2:34][N:35]([CH:56]([CH3:57])[CH3:58])[CH:36]4[CH2:37][CH:38]([CH2:40][CH2:41][C:42]5[NH:46][C:45]6[CH:47]=[CH:48][C:49]([O:51][C:52]([F:53])([F:55])[F:54])=[CH:50][C:44]=6[N:43]=5)[CH2:39]4)[C@@H:27]([OH:28])[C@H:31]3[OH:30])[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(OC(F)(F)F)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)N(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(OC(F)(F)F)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Trifluoroacetic Acid (10 mL, 100 mmol) added to a mixture of Water (1 mL, 60 mmol) and N-(2,4-dimethoxybenzyl)-7-((3aS,4R,6R,6aR)-6-((isopropyl(3-(2-(5-(trifluoromethoxy)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.91 g, 1.2 mmol) at RT. The reaction was stirred overnight at RT then quenched by the addition of Triethylsilane (0.37 mL, 2.3 mmol). The volatiles were removed in vacuo and resulting residue was taken up in MeOH (15 mls). 500 mgs of K2CO3 and 8 drops H2O were added and reaction stirred at RT for 1 hour. Mixture was filtered and filter cake washed with 10 mls MeOH. The filtrate was concentrated and the resulting residue purified by flash chromatography (DCM/7N NH3 in MeOH 90:10) to yield the desired product (0.232 g) as an off white foam. MS (ESI+) for C29H36F3N7O3 m/z 588.2 [M+H]+; MS (ESI−) for C29H36F3N7O3 m/z 586.2 [M−H]−; HPLC purity >90% (ret. time, 2.570 min.) 1H NMR (400 MHz, d4-MeOH) δH 8.082 & 8.079 (s, 1H, overlapping peaks due to cis and trans isomers), 7.554-7.524 (m, 1H), 7.414 (s, 1H), 7.225-7.209 (m, 1H), 7.155-7.127 (m, 1H), 6.618-6.609 (m, 1H), 4.363-4.323 (m, 1H), 3.976-3.932 (m, 1H), 3.606-3.524 (m, 0.5H (methine from trans isomer)), 3.156-3.110 (m, 0.5H (methine from cis isomer), 3.089-3.006 (m, 1H), 2.731-2.679 (m, 1H), 2.544-2.360 (m, 2H), 2.256-2.239 (m, 3H), 2.093-2.061 (m, 2H), 1.987-1.861 (m, 3H), 1.648-1.568 (m, 2H), 1.072-1.006 (m, 6H).
Reaction SMILES: N(C(C)C)[CH:2](C)C.[Li]CCCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([O:27][CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16].CI.[NH4+].[Cl-]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][O:14][C:15]([C:17]1([CH3:2])[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([O:27][CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCc2cccc(OC)c2C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCc2cccc(OC)c2C1
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To iPr2NH (202 mg, 2.0 mmol) in THF (1.0 mL) was added BuLi (2.5 M, 0.8 mL, 2.0 mmol) at −78° C. After 10 minutes, 8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester in THF (1.0 mL) was added and the reaction mixture turned yellow. Methyl iodide (568 mg, 4.0 mmol) and HMPA (1.0 mL) were added after 30 minutes. The reaction mixture was allowed to stir at −78° C. for 3 hours at ambient temperature before aqueous NH4Cl was added. The mixture was extracted with ethyl acetate (3×20 mL) and the combined extracts were dried over MgSO4 and purified by column chromatography to give 8-methoxy-2-methyl-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester (170 mg, 84%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13]C(O)(O)CC.[CH2:19]1[O:21][CH:20]1[CH2:22][OH:23]>>[OH:21][CH:20]([CH2:22][OH:23])[CH2:19][NH:13][CH2:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: OCC1CO1
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: CCC(N)(O)O
Product: OCC(O)CNC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
Each diastereoisomer can also be obtained by coupling D-galactose with the pure enantiomer of the aminopropanediol or by the reaction of the enantiomers of glycidol on N-(2,3,4,5,6-pentahydroxyhexyl)benzylamide as follows:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[S:22][C:15]=12.[CH3:28][C:29]([CH3:31])=[O:30]>O1CCCC1.O>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]3[S:24][C:25]([C:29]([OH:30])([CH3:31])[CH3:28])=[CH:26][N:27]=3)[S:22][C:15]=12
Reactant: CC(C)=O
Reactant: Clc1ccnc2cc(-c3nccs3)sc12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(O)c1cnc(-c2cc3nccc(Cl)c3s2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
In a 25 mL round-bottomed flask 2 mL of tetrahydrofuran and diisopropyl amine (0.14 mL, 1.0 mmol) were cooled to −78° C. and n-butyllithium (0.38 mL, 0.95 mmol) was added. The solution was warmed to 0° C. for 10 minutes then recooled to −78° C. A solution of 7-chloro-2-thiazol-2-yl-thieno[3,2-b]pyridine (200 mg, 0.79 mmol) in 2 mL of tetrahydrofuran was added dropwise and the resulting solution was stirred 30 minutes. Acetone (0.88 mL, 1.19 mmol) was added to the anion and the reaction mixture was allowed to warm to room temperature overnight. The mixture was diluted with water and extracted with chloroform (3×50 mL). The combined extracts were dried over NaSO4, filtered, and concentrated. Chromatography on 50 g of silica gel with 30% ethyl acetate:methylene chloride afforded 129 mg (52%) 2-[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-5-yl]-propan-2-ol. 1H NMR (400 MHz, CD3OD) δ8.56 (d, 1H), 7.95 (s, 1H), 7.71 (s, 1H), 7.50 (d, 1H), 1.66 (s, 6H). LC-MS: 308.1, 311 (MH+); HPLC RT: 5.32 min.
Reaction SMILES: [CH:1]1([C:7]([F:14])([F:13])[C:8](OCC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:15]>CCO>[CH:1]1([C:7]([F:14])([F:13])[C:8]([NH2:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: CCOC(=O)C(F)(F)C1CCCCC1
Solvent: CCO
Product: NC(=O)C(F)(F)C1CCCCC1
Reaction time: 8 h

Procedure:
A solution of ethyl cyclohexyl(difluoro)acetate (2.63 g, 12.75 mmol) in EtOH (6 mL) was sparged with anhyd ammonia for 15 minutes at ambient temperature. The mixture was sealed in a pressure tube and allowed to stand overnight. Volatiles were removed in vacuo and the solid residue was recrystallized from dichloromethane-hexanes affording the title compound as a waxy solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.13-1.37 (m, 5H) 1.48-1.85 (m, 8H) 1.98-2.08 (m, 1H) 4.30 (q, J=7.08 Hz, 2H)
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][CH:7]1[CH:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([NH:25][C:26]4[N:31]=[C:30]([CH:32]([F:34])[F:33])[CH:29]=[CH:28][N:27]=4)[CH:19]=3)[CH:15]=[N:14]2)[O:10][C:9](=[O:35])[NH:8]1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:34][CH:32]([F:33])[C:30]1[CH:29]=[CH:28][N:27]=[C:26]([NH:25][C:20]2[CH:19]=[C:18]([C:16]3[CH:15]=[N:14][N:13]([CH2:12][CH:11]4[O:10][C:9](=[O:35])[NH:8][CH:7]4[CH2:6][OH:5])[CH:17]=3)[CH:23]=[C:22]([CH3:24])[CH:21]=2)[N:31]=1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3OC(=O)NC3COC(=O)C(F)(F)F)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3OC(=O)NC3CO)c2)c1

Procedure:
A solution of (5-{[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]methyl}-2-oxo-1,3-oxazolidin-4-yl)methyl trifluoroacetate (80 mg, 0.15 mmol) and potassium carbonate (80 mg, 0.58 mmol) in methanol (3 mL) was stirred at 25° C. for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by prep-TLC (ethyl acetate) to give racemic 5-{[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]methyl}-4-(hydroxymethyl)-1,3-oxazolidin-2-one. MS ESI calc'd. for C20H21F2N6O3 [M+H]+ 431. found 431.
Reaction SMILES: O[CH2:2][C@@H:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH2:5][N:4]1[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>C(Cl)(Cl)Cl>[Cl:38][CH2:2][C@@H:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH2:5][N:4]1[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13]
Reactant: C=CCOC(=O)N1CC=C(C(=O)OC)[C@H]1CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)N1CC=C(C(=O)OC)[C@H]1CCl
Yield: 24 %

Procedure:
To a solution of 1-allyl 3-methyl(2S)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (1.29 g, 4.28 mmol) in carbontetrachloride (16 ml) was added at room temperature triphenylphosphine (1.35 g) and the mixture was refluxed under heating for 6 hours. The insoluble materials were dissolved in chloroform and the solvent was removed in vacuo. The residue was purified with silica gel (150 g) column chromatography (hexane/ethyl acetate 4/1→2/1) to give 1-allyl 3-methyl (2S)-2-(chloromethyl)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (268 mg, 24%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][S:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1CSCCN1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 47 %

Procedure:
As described for example 147, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg, 0.3 mmol) was converted, using thiomorpholine instead of cyclopropylmethylamine, to the title compound (56 mg, 47%) which was obtained as an off white solid. MS: m/e=397.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@@:5]12[CH2:17][CH2:16][CH2:15][N:6]1[C@@H](C(Cl)(Cl)Cl)[O:8][C:9]2=O)[CH3:3].[NH3:18]>CO>[CH3:1][N:2]([CH2:4][C@@:5]1([C:9]([NH2:18])=[O:8])[CH2:17][CH2:16][CH2:15][NH:6]1)[CH3:3]
Reactant: CN(C)C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Reactant: N
Solvent: CO
Product: CN(C)C[C@@]1(C(N)=O)CCCN1
Temperature: 50 °C

Procedure:
A mixture of (3R,7aR)-7a-dimethylaminomethyl-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (0.26 g) and 7M ammonia in methanol (4 ml) is heated at 50° C. for 3 days in a sealed vessel. The cooled reaction mixture is then evaporated to give the title compound as a brown oil which is used without further purification.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=2[Cl:13])[CH2:3][CH2:2]1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C(N(CC)CC)C.BrC1C=CC(C2C3C(=C(Cl)C=C(Cl)C=3)CN(C)C2)=CC=1>O1CCOCC1>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=2[Cl:13])[CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:2][CH2:3]1
Reactant: Clc1ccc(CNC2CC2)c(Cl)c1
Reactant: O=C(CBr)c1ccccc1
Agent: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(Br)cc2)C1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(CN(Cc1ccc(Cl)cc1Cl)C1CC1)c1ccccc1

Procedure:
Intermediate 1 was reacted with alpha-bromoacetophenone in the presence of triethylamine in dioxane by the method described in example 1, intermediate 3. For workup, the solvent was distilled off, and the residue was taken up in ethyl acetate. It was washed twice with H2O and twice with 2 N HCl, dried with MgSO4 and concentrated. The crude product obtained in this way was reacted further without further purification.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.Br[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[CH2:1]1)[CH2:22][CH2:23][CH3:24]
Reactant: N#Cc1ccc2c(c1)CNCC2
Reactant: CCCCBr
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN1CCc2ccc(C#N)cc2C1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To an ice-cold, stirred solution of 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile (J. Med. Chem. 1997, 40, 3997) (485 mg, 3.1 mmol) and triethylamine (0.47 mL, 3.4 mmol) in methylene chloride (5 mL) is added DMAP (37 mg, 0.3 mmol) and bromobutane (0.5 mL, 4.6 mmol). The reaction mixture is stirred for 20 h, diluted with methylene chloride, washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 50% ethyl acetate/hexanes) affords the title compound. ESI MS m/z 215 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(N2CCOCC2)cc1
Yield: 80.1 %

Procedure:
According to the general procedure B, 4-tert-butylbromobenzene (94 mg, 0.44 mmol) reacted with morpholine (36 mg, 0.41 mmol) using 1 mol % of catalyst and sodium tert-butoxide (42 mg, 0.44 mmol) at 100° C. for 21 h to give the title compound (72 mg, 82%) as a white solid: 1H-NMR (300 MHz, CDCl3): δ 7.35 (d, 2H, J=8.7 Hz), 6.91 (d, 2H, J=8.7 Hz), 3.89 (t, 4H, J=4.5 and 4.8 Hz), 3.17 (t, 4H, J=4.5 and 4.8 Hz), 1.34 (s, 9H). 13C{1H}-NMR (100 MHz, CDCl3): δ 148.89, 142.76, 125.95, 115.38, 66.99, 49.54, 33.94, 31.42. GC/MS(EI): m/z 219 (M+), 204 (M+−CH3), 146 (M+−morpholine).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9](=[O:12])[CH2:10][Cl:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl-:11].[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9](=[O:12])[CH2:10][N+:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)CCl)cc1
Reactant: c1ccncc1
Product: CC(C)(C)c1ccc(C(=O)C[n+]2ccccc2)cc1
Product: [Cl-]
Yield: 94 %

Procedure:
The title compound was prepared similarly to Example 1 from 4-tert-butylphenacyl chloride and pyridine in a yield of 94%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(Cl)cc2Cl)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Methyl 2-(2,4-dichlorophenyl)piperidine-4-carboxylate hydrochloride (2.8 g, 8.63 mmol) was diluted with DCM (24.18 mL). DIPEA (3.76 mL, 21.56 mmol) and methyl carbonochloridate (0.815 mL, 10.35 mmol) were added. The reaction mixture was stirred at room temperature for 30 min, then washed with 3×0.1 M HCl and brine. Filtered through a phase separator. Evaporated to yield dimethyl 2-(2,4-dichlorophenyl)piperidine-1,4-dicarboxylate (2.78 g, 93%) as an oil. MS m/z 346 (M+H)+
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:17]([O:16][C:14]([CH2:13][O:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])=[O:15])[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(C=O)cccc1OC

Procedure:
A solution of 2-hydroxy-3-methoxybenzaldehyde (6.08 g), ethyl bromoacetate (4.9 ml) and potassium carbonate (12.14 g) in N,N-dimethylformamide (30 ml) was stirred for 2 hours at ambient temperature. Water was added to the reaction mixture, and the resulting precipitates were collected by filtration and recrystallized with ethanol to give 2-ethoxycarbonylmethoxy-3-methoxybenzaldehyde (5.04 g).