Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[C:2]=[O:3].[Cl-:4].[Al+3].[Cl-].[Cl-].C(S(CCC(NNC(N1C[C:26]2[CH:28]=[C:29](Cl)[CH:30]=[CH:31][C:25]=2[O:24][C:23]2[CH:33]=[CH:34][C:35](Cl)=[CH:36][C:22]1=2)=O)=O)(=O)=O)C>BrC1C=CC=CC=1>[Cl:4][C:22]1[C:23]2[O:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[NH:1][C:2](=[O:3])[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: [N-]=C=O
Reactant: [Cl-]
Reactant: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2cc(Cl)ccc2Oc2ccc(Cl)cc21
Agent: [Al+3]
Solvent: Brc1ccccc1
Product: O=C1Nc2ccccc2Oc2c(Cl)cccc21
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of phosgene (1.93 M in toluene, 42 mL) under nitrogen at approximately 5° C. was added dropwise a solution of the title compound of Example 18(b) (3.50 g) in toluene (11 mL). The mixture was stirred at 0°-5° C. for 30 minutes, and then heated on a steam bath for 30 minutes under nitrogen. Evaporation under vacuum yielded the isocyanate compound as a clear oil. IR: 2250 cm (strong). The isocyanate compound was taken up in bromobenzene (2; mL) and added dropwise to a stirred mixture of aluminum chloride (2.14 g) in bromobenzene (21 mL) at 100° C. under nitrogen. The reaction temperature was raised to 150° C., and the reaction was stirred for two hours. The reaction was evaporated under vacuum, and the residue was vigorously shaken with ethyl acetate/1 N NaOH. The resulting emulsion was filtered through a sintered glass funnel, and the resulting layers were separated. The semi-solid which had collected on the filter was washed with ethyl acetate, and this wash was combined with the ethyl acetate from the filtrate. The ethyl acetate layers were combined, washed with 1 N NaOH, 1 N HCl, and brine, dried over magnesium sulfate, and evaporated under vacuum to an oily, solid, yellow residue. This was triturated with ethyl ether, and the solid was collected by filtration. This solid was added to the semi-solid collected earlier, and the combined solids were washed with ether and air dried. The crude product was refluxed with ethanol (3A, 200 mL) for one hour, evaporated to dryness, triturated with ethyl ether, and the solid was collected. Drying under vacuum at 56° C. yielded the title compound as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6]1)[C:3]#N.[OH-:17].[Na+].[OH2:19]>Cl>[OH:1][CH:2]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6]1)[C:3]([OH:19])=[O:17]
Reactant: O
Reactant: N#CC(O)C1CCN(Cc2ccccc2)C1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)C(O)C1CCN(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
A solution of 12.05 g of 2-hydroxy-2-(1-benzylpyrrolidin-3-yl)acetonitrile in 23 ml of concentrated hydrochloric acid is heated on a bath for 1 hour and allowed to stand overnight. After cooling, precipitated ammonium chloride is filtered off and washed with acetone. The combined filtrate and washings are evaporated under reduced pressure to yield the residue, which is dissolved in water, mixed with 20 ml of 23 (w/w) % aqueous sodium hydroxide solution and washed with methylene chloride. The aqueous layer is slowly adsorbed on a column of 300 ml of Amberlite IR-120B(H+) and after washing of the column with water, eluted with 1 N ammonium hydroxide. The eluate is evaporated to dryness under reduced pressure, and the residue is mixed with acetone. The precipitate, which appears, is collected by filtration and recrystallized from a mixture of ethanol and acetone to yield 1.422 g of 2-hydroxy-2-(1-benzylpyrrolidin-3-yl)acetic acid. mp. 174° to 176° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:4]=1)#[N:2].Cl.[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH:17]([C:36]([CH:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[O:37])[C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:4]=1)#[N:2]
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: CCOC(=O)CCc1ccc(C#N)cc1OC[C@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(C#N)cc1OC(C(=O)C1CCN(c2ccncc2)CC1)[C@H]1CCCN1
Reaction time: 8 h

Procedure:
570 mg (1.89 mmol) of ethyl 3-[4-cyano-(2R)-2-(pyrrolidine-2-ylmethoxy)phenyl]propionate was dissolved in 10 ml of DMF. 504 mg (2.1 mmol) of 1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 479 mg (2.8 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.78 ml (5.7 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][CH2:11][C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1.CCOCC>CN(C=O)C>[Br:1][C:16]1[C:12]([CH2:11][O:10][CH3:9])=[N:13][O:14][C:15]=1[CH3:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCc1cc(C)on1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCc1noc(C)c1Br
Temperature: 60 °C
Yield: 92.5 %

Procedure:
N-bromosuccinimide (590 mg, 3.31 mmol) was added to 3-methoxymethyl-5-methyisoxazole (351 mg, 2.76 mmol) in DMF (3.5 mL) at room temperature under nitrogen. The reaction was heated at 60° C. for 15 h then allowed to cool to room temperature. Ether (50 mL) was added to the reaction mixture, then washed with water (3×10 mL), saturated aqueous sodium hydrogen carbonate (10 mL), and brine (10 mL). The organic layer was dried over magnesium sulfate, filtered, and evaporated to provide 526 mg (92% yield) of 4-bromo-3-methoxymethyl-5-methylisoxazole as a clear liquid which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ ppm 4.50 (s, 2H), 3.41 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH2:21][CH2:22][CH3:23])[CH:4]=1.N1C=CN=C1.[C:29]([Si:33]([CH3:36])([CH3:35])Cl)([CH3:32])([CH3:31])[CH3:30].C(OCC)(=O)C>CN(C=O)C>[Si:33]([O:1][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH2:21][CH2:22][CH3:23])[CH:4]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCc1cc(CO)ccc1OC(C(=O)OC)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc(CO[Si](C)(C)C(C)(C)C)ccc1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.4 %

Procedure:
To a solution of 2.34 g (7.45 mmol) of the product of Step J in DMF (30 mL) were added imidazole (609 mg, 8.94 mmol) and tertbutyldimethyl-chlorosilane (1.35 g, 8.94 mmol) at 0° C. The solution was stirred at room temperature for 18 hours, and was then poured into 100 mL of ethyl acetate and washed with H2O (2×). The water layer was extracted with ethyl acetate (2×). The combined organic layer was washed with H2O (3×) and brine, and was dried over anhydrous MgSO4. After concentration the mixture was purified by flash chromatography (hexane: EtOAc=10:1) to give 1.96 g of the title compound as a clear oil.
Reaction SMILES: [NH2:1][CH:2]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24].[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]=O)[CH:45]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+].CCOC(C)=O>[Si:27]([O:26][CH2:25][CH:2]([NH:1][CH2:50][C:46]1[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=1)[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24])([C:40]([CH3:43])([CH3:42])[CH3:41])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=Cc1cccnc1
Reactant: COc1ccc2c(=O)n(CC(N)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(C#N)c(-c3ccccc3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COc1ccc2c(=O)n(CC(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)NCc3cccnc3)c(C#N)c(-c3ccccc3)c2c1
Reaction time: 8 h

Procedure:
To a solution of amine 94 (51 mg, 0.075 mmol) in dichloroethane (2 mL) was added pyridine 3-carboxaldehyde (0.017 mL, 180 mmol). After stirring at RT for 15 min NaBH(OAc)3 (48 mg, 0.23 mmol) was added. After stirring overnight, added 1.2 equiv aldehyde and 1.5 equiv NaBH(OAc)3. After stirring for 5 h, the reaction mixture was diluted with NaHCO3/EtOAc and stirred for 10 min. It was then partitioned between EtOAc and NaHCO3. The organic phase was washed once with brine then dried (Na2SO4) and concentrated. The product was purified by automated flash chromatography (70-100% EtOAc/hexane).
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([CH2:31][C@H:32]4[CH2:37][CH2:36][C@H:35]([CH3:38])[CH2:34][CH2:33]4)[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][C@H:20]4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:18][C:14]=3[CH:13]=[C:12]([C:39]([O:41]C)=O)[N:11]=2)[CH:7]=[N:8][CH:9]=1>CO.ClCCl>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[N:16]([CH2:31][C@H:32]4[CH2:33][CH2:34][C@H:35]([CH3:38])[CH2:36][CH2:37]4)[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][C@H:20]4[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:18][C:14]=3[CH:13]=[C:12]([C:39]([NH:1][NH2:2])=[O:41])[N:11]=2)[CH:7]=[N:8][CH:9]=1
Reactant: COC(=O)c1cc2nc(N3CCOC[C@H]3c3ccccc3)n(C[C@H]3CC[C@H](C)CC3)c2c(-c2cncc(Cl)c2)n1
Reactant: NN
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C(=O)NN)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydrazine (9.2 mL, 293 mmol) was added to methyl 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylate (4.11 g, 7.33 mmol) dissolved in methanol (36.6 mL), and the solution was stirred at room temperature for 30 minutes. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carbohydrazide. MS ESI calc'd. for C30H34ClN7O2 [M+H]+ 560. found 560.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([C:16]([F:19])([F:18])[F:17])([S-:15])[C:11]([F:14])([F:13])[F:12].CN([S+](N(C)C)N(C)C)C>C(#N)C>[F:12][C:11]([F:13])([F:14])[C:10]([S:15][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([F:9])[C:16]([F:19])([F:18])[F:17]
Reactant: FC(F)(F)C(F)([S-])C(F)(F)F
Reactant: BrCc1ccccc1
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CC#N
Product: FC(F)(F)C(F)(SCc1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Benzyl bromide, 16.76 g (0.098 mol), was added dropwise at 25° to a solution of 0.098 mole of tris(dimethylamino)sulfonium 1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethanethiolate (prepared as in Example 12) in 125 mL of acetonitrile. The reaction mixture was stirred for 18 h and then poured into 500 mL of ice-water. The aqueous mixture was extracted with ether, and the ether extracts were washed with water, dried (MgSO4) and distilled to give 21.31 g (75% yield) of benzyl heptafluoroisopropyl sulfide as a pale yellow liquid: bp 70°-71° (10 mm); 1H NMR (CDCl3) δ4.09 ppm (s, 2H) and 7.27 ppm (s, 5H); 19F NMR (CDCl3) δ-75.2 ppm (d, J=11 Hz, 6F) and -162.6 ppm (septet, J=11 Hz, 1F). Anal. Calcd. for C10H7F7S: C, 41.10; H, 2.41; F, 45.51. Found: C, 40.89; H, 2.45; F, 45.27.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]2)=[N:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1.O>C(#N)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[N:6][C:7]=1[Br:21]
Reactant: Nc1cnc([C@@H]2CC[C@H](O)C2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: Nc1ncc([C@@H]2CC[C@@H](O)C2)nc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,N-Di-tert-butyl (5-((1R,3S)-3-hydroxycyclopentyl)pyrazin-2-yl)carbamate (35 mg, 0.092 mmol) in DCM (461 μl) was added HCl (922 μl, 3.69 mmol), the reaction mixture was stirred at room temperature overnight and concentrated to dryness yielding HCl salt. The crude product was used in next step reaction without purification. LCMS (m/z): 180.1 (MH+), 0.22 min. (+/−)-(1S,3R)-3-(5-aminopyrazin-2-yl)cyclopentanol (15 mg, 0.084 mmol) was dissolved in acetonitrile (2 mL), then NBS (16.39 mg, 0.092 mmol) was added, the reaction mixture was stirred at room temperature for 30 min, water was added, the reaction mixture was then extracted by EtOAc, the organic was dried and concentrated, the crude material was used in next step reaction. LCMS (m/z): 258.1/260.2 (MH+), 0.45 min. Following the above method, using (+/−)-N,N-Di-tert-butyl (5-((1R,3S)-3-hydroxycyclopentyl)pyrazin-2-yl)carbamate, (+/−)-(1R,3R)-3-(5-amino-6-bromopyrazin-2-yl)cyclopentanol was obtained. LCMS (m/z): 258.1/260.1 (MH+), 0.50 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH2:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([O:20][CH3:21])=[O:19]>CCOC(C)=O.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([O:20][CH3:21])=[O:19])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COC(=O)c1sccc1N
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1Nc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
5-Chloro-2-fluoro-nitrobenzene and methyl 3-amino-thiophene-2-carboxylate, m.p. 207°-208° C. (EtOAc/Hexane).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:16])[O:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:8]=1[OH:9].C(O)(=O)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CN(C)C=O>[OH:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:16])[C:3]=1[NH:2][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1c(O)cc(-c2ccccc2)oc1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1oc(-c2ccccc2)cc(O)c1NCc1ccccc1

Procedure:
The title compound was prepared by method D using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.500 g, 2.08 mmol), 1% acetic acid in dimethylformamide (20 mL), benzaldehyde (0.233 mL, 2.29 mmol), sodium cyanoborohydride (0.144 g, 2.29 mmol). m.p. dec. 205° C., 1H NMR (250 MHZ, DMSO-d6) δ 4.37 (s, 2 H), 6.56 (s, 1 H), 7.27 (m, 5 H), 7.45 (m, 3 H), 7.67 (m, 2 H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[N:19]=[CH:18]3)=[C:13]([F:31])[CH:12]=2)[CH2:6]1)=[N+]=[N-].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(OCC)(=O)C.[Pd]>[Si:24]([O:23][CH2:22][C:20]1[N:19]=[CH:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][NH:1][C:39](=[O:41])[CH3:40])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[F:31])[CH:21]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)cn1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CO[Si](C)(C)C(C)(C)C)c3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To (5R)-5-azidomethyl-3-(4-(4-t-butyldimethylsilyloxymethylimidazol-1-yl)-3-fluorophenyl)oxazolidin-2-one(10.0 g) in ethyl acetate (560 ml) was added triethylamine (13.3 ml), acetic anhydride (4.5 ml), and palladium catalyst (10% on charcoal, 1.5 g), and the mixture hydrogenated at ambient temperature for 17 hours. The mixture was filtered through celite, the celite washed well with ethyl acetate, and the organic layer stirred with a saturated solution of sodium bicarbonate (100 ml) at ambient temperature for 1 hour. The organic layer was separated, dried over magnesium sulfate, and evaporated. Crude product (15 g, from two batches) was dissolved in dichloromethane and chromatographed on silica, eluting with a gradient from dichloromethane (100%) to 10% methanol in dichloromethane. Product fractions were combined to give a gum (12.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C1COCC1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:5]=[CH:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Chloro-3-iodobenzene (10.0 g, 41.9 mmol) was dissolved in 100 mL dry THF and 17.5 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (329 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I)iodide (239 mg, 1.25 mmol) and trimethylsilylacetylen (6.28 g, 6.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel (heptane/ethyl acetate 100:0->80:20 gradient). The desired product was obtained as a light yellow oil (7.38 g, purity ˜70%, yield ˜59%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[C:10]=3[CH:11]=2)=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.CCOCC.[NH4+].[Cl-]>O1CCCC1.CCOC(C)=O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:12]2([OH:16])[C:10]3[CH:11]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:8][C:9]=3[CH2:15][CH2:14][CH2:13]2)=[CH:20][CH:19]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C1CCCc2sc(-c3ccncc3)cc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccc(Cl)cc2)CCCc2sc(-c3ccncc3)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a 250 mL round bottomed flask was placed 2-pyridin-4-yl-6,7-dihydro-1-benzothiophen-4(5H)-one (1400 mg, 6.1 mmol) and then dissolved in tetrahydrofuran (50 mL). To the mixture was added 1 M of 4-chlorophenylmagnesium bromide in ether (10 mL, 10 mmol) and the mixture was stirred for 1.5 h at rt. To the mixture were added a 5% aqueous solution of NH4Cl (100 mL) and EtOAc (100 mL). The resulting bi-phasic mixture was vigorously stirred for 15 min and then the aqueous phase was discarded. The organic phase was washed with brine (50 mL), and then dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (40 g) column chromatography eluted with a 20% to 80% EtOAc/hexane to obtain 4-(4-chlorophenyl)-2-pyridin-4-yl-4,5,6,7-tetrahydro-1-benzothiophene-4-ol (2.9 g) as a colorless foam.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[K].Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-])=O>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]2[O:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:9])[NH:19][C:13]=2[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: O=Cc1ccccc1O
Agent: [K]
Product: O=C1Nc2cc(Cl)ccc2Oc2ccccc21

Procedure:
The starting material 8-chloro-10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one was prepared according to the procedures reported in Coyne et al (J. Med. Chem., 1967, 10:541). Briefly, this entailed coupling potassium salicylaldehyde with 2,5-dichloronitrobenzene, followed by oxidation to carboxylic acid, reduction of nitro, and finally ring closure, to yield the desired 8-chloro starting material.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH3:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][C:25]=2[N:26]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:28]2[CH:29]=[CH:30][C:24]3[S:23][C:22]([CH3:21])=[N:26][C:25]=3[CH:27]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1nc2cc(C=O)ccc2s1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc2sc(C)nc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 2-methylbenzo[d]thiazole-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.23 min.; [M+H]+: 411.11 g/mol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][N:23]([CH3:31])C(=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33](C)C=O>C(OCC)(=O)C.[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>[ClH:1].[CH3:31][NH:23][CH2:22][C:13]1[CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([C:32]#[N:33])=[N:7][CH:6]=2)(=[O:9])=[O:10])[CH:12]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(Cl)nc2)c1)C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C#N)nc2)c1
Product: Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, a mixture of tert-butyl {[1-(6-chloro-3-pyridinesulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg), zinc (II) cyanide (51 mg), tetrakis(triphenylphosphine)palladium (50 mg) and N,N-dimethylformamide (4 mL) was stirred at 100° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, and washed successively saturated aqueous sodium hydrogencarbonate solution, water and saturated brine. The mixture was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→7:3) to give N-Boc compound of the title compound. The obtained N-Boc compound was dissolved in ethyl acetate (2 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethanol to give the title compound (yield 57 mg, 68%).