Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].N1CCCCC1.[CH3:34][C:35]1([CH3:80])[C:47](/[CH:48]=[CH:49]/[CH:50]=[CH:51]/[CH:52]=[CH:53]/[CH:54]=[C:55]2\[C:56]([CH3:74])([CH3:73])[C:57]3[C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][C:63]=4[CH:64]=[CH:65][C:66]=3[N:67]\2[CH2:68][CH2:69][C:70]([OH:72])=[O:71])=[N+:46]([CH2:75][CH2:76][C:77]([OH:79])=[O:78])[C:45]2[CH:44]=[CH:43][C:42]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:36]1=2.[Br-:81].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C>[CH3:34][C:35]1([CH3:80])[C:47](/[CH:48]=[CH:49]/[CH:50]=[CH:51]/[CH:52]=[CH:53]/[CH:54]=[C:55]2\[C:56]([CH3:73])([CH3:74])[C:57]3[C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][C:63]=4[CH:64]=[CH:65][C:66]=3[N:67]\2[CH2:68][CH2:69][C:70]([OH:72])=[O:71])=[N+:46]([CH2:75][CH2:76][C:77]([OH:79])=[O:78])[C:45]2[CH:44]=[CH:43][C:42]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:36]1=2.[Br-:81].[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CC1(C)C(/C=C/C=C/C=C/C=C2/N(CCC(=O)O)c3ccc4ccccc4c3C2(C)C)=[N+](CCC(=O)O)c2ccc3ccccc3c21
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 8 h

Procedure:
Fmoc-Lys was attached to Rink amide resin (60 mg, 0.0366 mmol) and the Fmoc was deprotected by piperidine in DMF (20%). A solution of Cypate (129 mg, 5 equiv), HOBT(24.7 mg), and DIC (11.5 mg, 2.5 equiv) in DMF (3 mL) was added into the resin and swirled overnight. After filtered, the resin was washed with DMF and DCM, cleaved with TFA/H2O (95:5) for 3 h, filtered, concentrated, and dried. The crude product was dissolved in 20 mL DCM and added dropwise into a stirred solution of PyBOP (38 mg), HOBT (9.9 mg), and DIEA (18.9 mg) in DCM/DMF(195:5, 200 mL) and the resulting mixture was stirred overnight, concentrated, and purified by HPLC to afforded 1.5 mg of the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([Cl:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:16])=[C:7]([Cl:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Cl)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h

Procedure:
4-tert-Butyl-2-chloro-6-nitro-phenol (0.214 g, 0.934 mmol) was dissolved in 3 mL acetone and K2CO3 (0.65 g, 4.7 mmol) and MeI (0.58 mL, 9.3 mmol) were added. The reaction was stirred at 65° C. overnight, after which the solvent was removed under reduced pressure. The residue was taken up in DCM, the organic layer was washed with water, dried over MgSO4 and concentrated to yield 0.15 g of target product.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13](C([Sn])=C(CCCC)CCCC)[CH2:14]CC>COCCOC.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:13]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([O:11][CH3:12])[CH:3]=1)=[CH2:14]
Reactant: COc1cc(Br)cc2[nH]ccc12
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Product: C=Cc1cc(OC)c2cc[nH]c2c1
Temperature: 90 °C
Yield: 113.3 %

Procedure:
To a solution of 6-bromo-4-(methyloxy)-1H-indole (900 mg, 3.98 mmol) in 1,2-dimethoxyethane (20 mL) was added tributylvinyltin (1.74 mL, 5.96 mmol). The reaction mixture was degassed with argon and then treated with dichlorobis(tri-o-tolylphosphine)palladium (153 mg, 0.19 mmol). The mixture was heated at 90° C. for 65 hours. The mixture was filtered through a pad of celite, washed with ethyl acetate and then the filtrate concentrated in vacuo. The product was purified by silica gel chromatography eluting with 2-50% ethyl acetate in hexane to yield the title compound (D8), (781 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[CH:15][C:16]([C:17](=[O:40])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][C:27]4[C:36]5[C:31](=[C:32]([C:37](=[O:39])[NH2:38])[CH:33]=[CH:34][CH:35]=5)[N:30]=[CH:29][N:28]=4)[CH:20]=3)=[C:10]2[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[N:14]1[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2=[C:16]([C:17]([NH:18][C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH2:25][NH:26][C:27]2[C:36]3[C:31](=[C:32]([C:37]([NH2:38])=[O:39])[CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][N:28]=2)=[O:40])[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCn2ncc(C(=O)Nc3cccc(CNc4ncnc5c(C(N)=O)cccc45)c3)c2C1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4cnn5c4CNCC5)c3)ncnc12
Reaction time: 8 h

Procedure:
37 mg (0.56 mmol) 3-{3-[(8-Carbamoyl-quinazolin-4-ylamino)-methyl]-phenylcarbamoyl}-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester were dissolved in 1.5 ml dioxane and 280 μl 4 N HCl in dioxane were added. The mixture was stirred overnight and evaporated to dryness. 30 mg, off-white solid. Product is the hydrochloride salt.
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]([F:18])[F:17])[NH:12][C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]([F:17])[F:18])[N:12]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:25]=3[CH3:34])[C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: O=[N+]([O-])c1cc(Br)c2nc(C(F)F)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cn2c(C(F)F)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a 100 mL round bottomed flask containing DMF (30 mL) was added 4-bromo-2-(difluoromethyl)-6-nitro-1H-benzo[d]imidazole (3.2 g, 10.96 mmol), 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (1.60 mL, 9.48 mmol) and potassium carbonate (2.3 g, 16.64 mmol). The resultant suspension was heated to 65° C. and after stirring for 2 hrs the mixture was allowed to cool to rt and diluted with 35 mL H2O. The resulting slurry was extracted several times with EtOAc, the organic dried over Na2SO4 and concentrated to give a thick oil which was adsorbed onto a silical gel column and was eluted with EtOAc/Hex 10% to 20% gradient over 15 column volumes on a 25 g silica column. The fractions containing desired product were combined and concentrated desired product (1.54 g, 3.32 mmol, 30.3% yield) as a light orange powder. LC/MS: MS (ES+) m/e 464.2 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.52 (d, J=1.77 Hz, 1H), 8.07 (d, J=2.02 Hz, 1H), 7.66 (d, J=7.83 Hz, 1H), 7.20 (d, J=3.79 Hz, 1H), 7.07 (s, 1H), 6.94 (s, 1H), 6.52 (d, J=8.08 Hz, 1H), 5.73 (s, 2H), 2.58 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1)#[N:2].Cl>C(O)C.CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1
Reactant: N#Cc1cncc(-c2ccccn2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: NCc1cncc(-c2ccccn2)c1
Reaction time: 4 h
Yield: 79.4 %

Procedure:
2-(3-Cyanopyridin-5-yl)pyridine (Method 101; 0.98 g, 5.4 mmol) was dissolved in a mixture of ethanol (45 ml) and methanol (30 ml). Concentrated hydrochloric acid (1.2 ml) and 10% palladium on carbon catalyst (575 mg) were added and the mixture stirred under an atmosphere of hydrogen for 4 hours. The mixture was filtered through diatomaceous earth, the filter pad washed with ethanol and the volatiles removed from the filtrate by evaporation. The crude solid was suspended in a small volume of methanol and filtered to give the title compound (794 mg, 66%) as an orange solid. NMR (DMSO): 4.31 (m, 2H) 7.58 (t, 1H), 8.09 (t, 1H), 8.24 (d, 1H), 8.78 (d, 1H), 8.89 (bs, 2H), 9.03 (s, 1H), 9.26 (s, 1H), 9.43 (s, 1H); m/z 186 (MH)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH:12]1[C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.Cl>ClC(Cl)C>[C:1]([C:20]1[CH:21]=[CH:22][C:23]2[S:24][C:25]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:17][C:18]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)Sc1ccccc1S2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc2c(c1)Sc1ccccc1S2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (22.4 g) in dichloroethane (75 ml) was added to a suspension of aluminium chloride (58.4 g) in dichloroethane (100 ml) at 0° C. This was then added to a solution of thianthrene (43.2 g) in dichloroethane (600 ml) at 0° C. The reaction mixture was stirred for 1 hour at 0° C, then allowed to warm to room temperature and poured onto ice and concentrated hydrochloric acid. The organic layer was separated and the aqueous extracted with dichloroethane. The combined extracts were washed, dried and evaporated to give a brown oily product of crude 2-acetylthianthrene. This was heated to 90° C. for 2.5 hours with sodium hypochlorite solution (containing 14% available chlorine) (270 ml), normal sodium hydroxide solution (600 ml) and 1,4 dioxan (600 ml). After standing for 16 hours fine needles were filtered from the reaction mixture. These were washed and dried to give thianthrene, m.pt. 155° C. The reaction liquors were poured onto ice and concentrated hydrochloric acid. The precipitated solid was filtered off, washed with water, and dissolved in 0.5 Normal sodium hydroxide solution. The mixture was filtered from some insoluble material, and the alkaline filtrates re-acidified with concentrated hydrochloric acid. The precipitated solid was washed with water, and dried in vacuo to yield thianthrene-2-carboxylic acid, m.pt. ca. 220° C. Recrystallisation from glacial acetic acid and acetonitrile raised the melting point to 227°-8° C.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[C:26](OC)=[O:27]>O1CCCC1.CCCCCC.C(O)(=O)C>[O:27]=[C:26]([CH:18]1[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17]1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)C1Cc2ccccc2C1
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COP(=O)(CC(=O)C1Cc2ccccc2C1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
A solution of 20.4 g (164 mmoles) dimethyl methylphosphonate (Aldrich) in 200 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 82.6 ml of 2.25M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 20 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 14.0 g (73.5 mmole) methyl indane-2-carboxylate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 20 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 50 ml water, the aqueous phase extracted with 75 ml portions of methylene chloride (4x), the combined organic extracts were backwashed (75 ml H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 150°-160° (0.1 mm) to give 17.0 g (86.4%) dimethyl 2-oxo-2-(2-indany)ethylphsphonate (2i).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([CH3:11])=[N:4][C:3]=1[CH3:12].[F:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][C:15]=1[OH:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)C>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[F:13][C:14]1[CH:19]=[C:18]([C:2]2[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([CH3:11])=[N:4][C:3]=2[CH3:12])[CH:17]=[CH:16][C:15]=1[OH:29]
Reactant: Cc1nc(C)c(C(N)=O)nc1Cl
Reactant: CC1(C)OB(c2ccc(O)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Cc1nc(C)c(-c2ccc(O)c(F)c2)nc1C(N)=O
Temperature: 80 °C
Yield: 69.5 %

Procedure:
A solution of 6-chloro-3,5-dimethylpyrazine-2-carboxamide (Intermediate A) (492 mg, 2.65 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Intermediate 6-6; 630 mg, 2.65 mmol) and potassium phosphate, tri-basic (674 mg, 3.18 mmol) in DME (10 mL), ethanol (5 mL) and water (2.5 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (108 mg, 0.13 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 80° C. for 4 hours. The reaction mixture was allowed to cool to room temperature and then evaporated. The crude product was partitioned between EtOAc (75 mL), and 1N citric acid (25 mL) and the precipitate was collected by filtration, washed with water (10 mL) and air dried to afford 6-(3-fluoro-4-hydroxyphenyl)-3,5-dimethylpyrazine-2-carboxamide (481 mg, 69.6%) as a beige solid, which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:31])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:19]=3)[N:14]=2)=[CH:8][C:7]=1[CH2:29][CH3:30].[C:32](O)(=[O:35])[CH2:33][OH:34].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:29]([C:7]1[CH:8]=[C:9]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][CH:26]([CH3:27])[CH3:28])[N:19]=3)[N:14]=2)[CH:10]=[C:11]([CH3:12])[C:6]=1[O:5][CH2:4][C@@H:3]([OH:31])[CH2:2][NH:1][C:33](=[O:34])[CH2:32][OH:35])[CH3:30]
Reactant: O=C(O)CO
Reactant: CCc1cc(-c2nc(-c3cc(C)nc(NC(C)C)n3)no2)cc(C)c1OCC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCc1cc(-c2nc(-c3cc(C)nc(NC(C)C)n3)no2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.7 %

Procedure:
To a solution of crude 1-amino-3-{2-ethyl-4-[3-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-5-yl]-6-methyl-phenoxy}-propan-2-ol (43 mg, 97 μmol) in DMF, glycolic acid (11 mg, 146 μmol), HOBt (20 mg, 146 μmol), and EDC hydrochloride (28 mg, 146 μmol) are added. The mixture is stirred at rt for 18 h before it is diluted with sat. aq. NaHCO3 and extracted twice with EtOAc. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. TLC plates with DCM containing 10% of 7M NH3 in MeOH to give (S)—N-(3-{2-ethyl-4-[3-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-5-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (21 mg) as a white solid; LC-MS: tR=0.85 min; [M+H]+=485.14; 1H NMR (CDCl3): δ 1.29 (m, 9H), 2.35 (m, 3H), 2.46 (s, 3H), 2.72 (q, J=7.5 Hz, 2H), 3.52 (m, 1H), 3.76 (m, 1H), 3.87 (m, 3H), 4.20 (m, 3H), 4.31 (m, 1H), 5.31 (m, 1H), 7.22 (s, 1H), 7.25 (t, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.91 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[C:12](I)[N:11]=[CH:10]1.C([Mg]Cl)(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].[NH4+].[Cl-]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[C:12]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])[N:11]=[CH:10]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1ccc(F)c(-n2cnc(I)c2)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(F)ccc2F)cn1
Reaction time: 1.5 h
Yield: 111.1 %

Procedure:
A solution of 1-(2,5-difluorophenyl)-4-iodo-1H-imidazole (0.115 g, 0.38 mmol) in 2 mL of tetrahydrofuran was chilled in an ice/water bath 5 min. Isopropylmagnesium chloride solution (2.0 M in tetrahydrofuran, 0.190 mL, 0.38 mmol) was added all at once. The bath was removed, and the pale yellow solution stirred 1.5 h. Tributyltin chloride (0.105 mL, 0.39 mmol) was added all at once, and the pale yellow solution was stirred 1.5 h. A sat. aq. NH4Cl solution (10 mL) was added, and the mixture was extracted with two 10 mL portions of ethyl acetate. The combined organic layers were washed with 20 mL of a sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated to provide 0.198 g of 1-(2,5-difluoro-phenyl)-4-tributylstannanyl-1H-imidazole as a yellow oil which was used without further purification. MS: (M+H)+=471.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.C1CCC=CC=1>C1(C)C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH2:6][CH2:5]2
Reactant: COc1ccc(OC)c2c1CCC2=O
Solvent: Cc1ccccc1
Solvent: C1=CCCC=C1
Product: COc1ccc(OC)c2c1CCC2

Procedure:
A mixture of intermediate A (1 g, 6 mmole), 1,3-cyclohexadiene (0.6 ml, 6 mmole), and toluene (15 ml) was refluxed about 15 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure to yield 1.5 g of crude Diels-Alder adduct (intermediate B), which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6](=[O:18])(=[O:17])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.S1(CCCC1)(=O)=O.[BH4-].[Na+]>CCOCC>[CH:9]1[C:8]2[CH2:2][NH:3][C:4]3[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=3[S:6](=[O:18])(=[O:17])[C:7]=2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=1
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1NC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Suspend 6.7 gm. (20 mmole) of methyl 11-chlorodibenzo[b,f][1,4]thiazepin-3-carboxylate 5,5-dioxide in 60 ml. of sulfolane and stir under nitrogen at room temperature while adding 1.52 g. (40 mmole) of sodium borohydride in small portions. Control foaming, if desired, by adding small portions of dry ether. After 2 hours, pour the reaction mixture into 300 ml. of ice-water and 75 ml. of ether. Separate the precipitate by filtration, wash with water and dry in vacuo. Dissolve the precipitate in 175 ml. of boiling acetonitrile, filter and concentrate to 100 ml. Separate the precipitate to obtain the title product. (m.p. 236° C.)
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[Br:13][C:14]1[CH:15]=[C:16]([C:20]2([CH3:27])[NH:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([CH2:2][N:22]2[C:21](=[O:26])[C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([Br:13])[CH:15]=3)([CH3:27])[NH:24][C:23]2=[O:25])[CH:4]=1
Reactant: CC1(c2cccc(Br)c2)NC(=O)NC1=O
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2C(=O)NC(C)(c3cccc(Br)c3)C2=O)c1
Reaction time: 18 h
Yield: 107.2 %

Procedure:
In analogy to the literature (Moloney et al., J. Med. Chem. 1997, 40, 2347-2362), methyl 3-bromomethylbenzoate (4.75 g, 20.7 mmol) was added to a suspension of hydantoin 1 (5.0 g, 18.6 mmol) and potassium carbonate (3.1 g, 22.5 mmol) in DMF (75 mL) at 23° C. After 18 h, the reaction mixture was partitioned between water and EtOAc, and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water (1×), NaHCO3 (1×), water (1×), brine (1×), then dried over MgSO4. After filtration, concentration in vacuo gave an oil, which was subjected to silica gel chromatography (20→50% EtOAc/hexanes) to yield the desired material as a white sticky foam (8.32 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.58 (m, 1H), 7.34-7.46 (m, 4H), 7.20 (m, 2H), 4.66 (s, 2H), 3.84 (s, 3H), 1.76 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:29]4[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(Br)ccc32)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(-c4ccc(OC)cc4)ccc32)cc1
Yield: 91.3 %

Procedure:
A mixture of 4-(5-bromo-3cyanoindol-1yl)benzoic acid ethyl ester (0.1 g), 4-methoxyphenylboronic acid (0.066 g), potassium carbonate (0.09 g) in a mixed solvent of 1,2-dimethoxyethane (3 mL), ethanol (0.5 mL) and water (0.5 mL) was stirred in the presence of tetrakis(triphenylphosphine) palladium catalyst at 90° C. for 18 hours. This reaction mixture was poured into water, and the precipitated solid was collected by filtration. This solid was washed with water, dried under reduced pressure at 50° C. to give the title compound (0.098 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[CH2:11][O:10][NH:9]2>C(O)(=O)C.[Zn]>[NH2:9][C@@:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[CH2:11][OH:10]
Reactant: CO[C@@H]1C[C@H]2CON[C@@]2(c2ccccc2F)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: CO[C@@H]1C[C@@H](CO)[C@](N)(c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
Zinc (533 mg) was added to a solution of (3aR*,5R*,6aS*)-6a-(2-fluorophenyl)-5-methoxy-hexahydrocyclopenta[c]isoxazole (275 mg) in acetic acid (5.57 mL), and the mixture was stirred at room temperature for 12 hours. More zinc (500 mg) was added to the reaction solution, followed by stirring at room temperature for three hours. Zinc was removed by filtration and the filtrate was poured into a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (270 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:6]([C:8]2[O:9]CC(C)(C)N=2)[CH:7]=1.Cl.[O:23]1CCOCC1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:4][CH:3]=1)[C:8]([OH:9])=[O:23]
Reactant: Cc1ccccc1-c1ccc(Cl)cc1C1=NC(C)(C)CO1
Reactant: C1COCCO1
Agent: Cl
Product: Cc1ccccc1-c1ccc(Cl)cc1C(=O)O

Procedure:
The starting material is prepared as follows: The mixture of 17 g of 2-(5-chloro-2-o-tolylphenyl)-4,4-dimethyl-2-oxazoline (prepared as shown in Example 2), 150 ml of p-dioxane, and 160 ml of 5 N aqueous hydrochloric acid is refluxed for 3 days while stirring. It is evaporated, the residue taken up in diethyl ether, the organic phase separated, dried, evaporated and the residue crystallized from hexane to yield the 3-chloro-6-o-tolylbenzoic acid melting at 135°-137°.