Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[F:27][C:26]([F:29])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([C:2]2[NH:3][C:4](=[O:11])[C:5]3[CH:10]=[CH:9][NH:8][C:6]=3[N:7]=2)=[CH:21][CH:22]=1
Reactant: O=c1[nH]c(Cl)nc2[nH]ccc12
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)nc2[nH]ccc12
Temperature: 150 °C
Yield: 5.6 %

Procedure:
A microwave reaction vial was charged with 2-chloro-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate F) (80 mg, 0.32 mmol), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (154 mg, 0.56 mmol), tetrakis(triphenylphosphine)palladium(0) (27.3 mg, 0.024 mmol) and a 2M aqueous sodium carbonate solution (0.75 mL) in ethanol (3 mL). The vial was sealed and the reaction was heated in the microwave at 150° C. for 10 min. At this time, the resulting mixture was filtered through a pad of Celite® and concentrated in vacuo. Flash chromatography (30/1 methylene chloride/methanol) afforded 2-(4-trifluoromethyl-phenyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (5.0 mg, 3.8%) as a white solid. 1HNMR (400 MHz, DMSO-d6) δ ppm 6.50-6.59 (m, 1H) 7.9 (d, 2H) 7.11-7.19 (m, 1H) 8.3 (d, 2H) 12.1 (s, 1H) 12.3 (s, 1H). LC-MS calcd. for C13H9F3N3O [(M+H)+] 280, obsd. 279.9.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)=[C:4]([CH3:29])[CH:3]=1.[CH3:30][C:31]1[N:36]=[C:35]([CH2:37]O)[CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH-].[Na+].[ClH:74].C(OCC)(=O)C.Cl>O1CCCC1.C(OCC)(=O)C.CO>[ClH:74].[CH3:8][C:6]1[CH:7]=[C:2]([O:1][CH2:37][C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:30])[N:36]=2)[CH:3]=[C:4]([CH3:29])[C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)[CH:10]=1
Reactant: Cc1cccc(CO)n1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(COc2cc(C)c(-c3cccc(COc4ccc(CCC(=O)O)cc4)c3)c(C)c2)n1
Yield: 44 %

Procedure:
To a solution of methyl 3-{4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (0.40 g, 1.03 mmol), (6-methylpyridin-2-yl)methanol (0.14 g, 1.13 mmol) and triphenylphosphine (0.34 g, 1.31 mmol) in tetrahydrofuran (8.0 mL) was added diisopropyl azodicarboxylate (40% toluene solution, 0.59 mL, 1.13 mmol) at room temperature with stirring. The reaction mixture was stirred at room temperature for 12 hrs., and an equivalent amount of the aforementioned reagents ((6-methylpyridin-2-yl)methanol, triphenylphosphine and diisopropyl azodicarboxylate) were added and the mixture was further stirred at the same temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) to give a colorless oil. Then, to a mixture of the oil, methanol (4 mL) and tetrahydrofuran (8 mL) was added 1 N aqueous sodium hydroxide solution (2.1 mL) at room temperature with stirring and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was neutralized with 1 N hydrochloric acid, diluted with ethyl acetate, washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/4) to give a colorless oil. The oil was dissolved in ethyl acetate and 4 N hydrogen chloride-ethyl acetate solution was added. The mixture was concentrated under reduced pressure. The obtained crystals were collected by filtration, washed and dried to give the title compound (0.24 g, yield 44%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[NH2:44][C:45]1[CH:46]=[CH:47][C:48]([F:67])=[C:49]([C:51]23[CH2:58][CH:57]2[CH2:56][CH2:55][S:54][C:53]([NH:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[N:52]3)[CH:50]=1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([F:67])=[C:49]([C:51]34[CH2:58][CH:57]3[CH2:56][CH2:55][S:54][C:53]([NH:59][C:60](=[O:66])[O:61][C:62]([CH3:63])([CH3:65])[CH3:64])=[N:52]4)[CH:50]=2)=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(N)ccc3F)CC2CCS1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=NC2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)CC2CCS1
Temperature: 23 °C
Reaction time: 20 h
Yield: 39.4 %

Procedure:
Commercially available 5-chloro-2-pyridinecarboxylic acid (30 mg, 0.19 mmol) was dissolved in dichloromethane (3 ml) and DMF (1 ml), then diisopropylethylamine (85 μl, 0.50 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (87 mg, 0.23 mmol) were added at 23° C. After 15 min of stiffing tert-butyl (1SR,7SR)-1-(5-amino-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (intermediate rac-A8a) (53 mg, 0.15 mmol) was added. The brown solution was stirred for 20 hours at 23° C. The grey reaction mixture was poured on ice cold sat. NaHCO3 solution and extracted twice with dichloromethane. The organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give a brown oil which was chromatographed on 5 g silica gel with cyclohexane/ethyl acetate 1:1 to give the tert-butyl (1SR,7SR)-1-(5-(5-chloropicolinamido)-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (29 mg; 31%) as a light yellow oil. MS (ISP): m/z=491.1 [(M+H)+] and 493.2 [(M+2+H)+].
Reaction SMILES: CO[O:3][P:4]([O:9][CH2:10][CH:11]([OH:34])[CH2:12][O:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)/[C:18](=[CH:25]/[C:26]2[NH:27][C:28]([CH3:32])=[CH:29][C:30]=2[CH3:31])/[C:17]1=[O:33])=[O:15])([O:6]OC)=[O:5].C[Si](Br)(C)C>C(#N)C.ClCCl>[OH:34][CH:11]([CH2:10][O:9][P:4]([OH:5])([OH:6])=[O:3])[CH2:12][O:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)/[C:18](=[CH:25]/[C:26]2[NH:27][C:28]([CH3:32])=[CH:29][C:30]=2[CH3:31])/[C:17]1=[O:33])=[O:15]
Reactant: COOP(=O)(OCC(O)COC(=O)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21)OOC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)COP(=O)(O)O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.8 %

Procedure:
To a solution of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 3-(dimethoxy-phosphonooxy)-2-hydroxy-propyl ester (60 mg, 0.4 mmol) in 1.5 mL of acetonitrile and 1.5 mL of dichloromethane was added 52 μl (0.40 mmol) of TMSBr dropwise. The reaction mixture was stirred for 6 h at room temperature and concentrated. The residue was quenched with 0.05 mL of water followed by 1.5 mL of EtOAc. The resultant mixture was centrifuged and the solvent was decanted. The precipitate was washed twice with ethyl acetate and dried to afford 120 mg (62%) of 3-[1-(3,5-dim ethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-phosphonooxy-propyl ester as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H, NH-1′), 7.84 (dd, J=2.4, 8.0 Hz, 1H, H-4), 7.79 (dd, J=2.2, 6.8 Hz, 1H, H-7), 7.64 (s, 1H, H-vinyl), 7.16-7.21 (m, 2H, H-5, 6), 6.11 (s, br, 1H, H-4′), 4.40 (dd, J=4.0, 10.8 Hz, 1H), 4.32 (dd, J=5.8, 11.2 Hz, 1H), 4.00-4.05 (m, 1H), 3.90-3.93 (m, 2H), 2.37 (s, 3H, CH3), 2.33 (s, 3H, CH3). 31P NMR(162 MHz, d6-DMSO) δ 0.16.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:15][CH2:16][CH:11]([OH:10])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: OC1CCN(Cc2ccc(Br)cc2)CC1
Yield: 62.5 %

Procedure:
4-Bromobenzylbromide (3 g) was stirred with 4-hydroxypiperidine (1.21 g) and potassium carbonate (1.99 g) in dimethylacetamide (15 ml) at 50° C. for 3 h The reaction mixture was then allowed to cool, poured into water (80 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography, eluting with a gradient of 0-3% methanol in dichloromethane, to afford the product as a viscous, colourless oil (2.02 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([O:15]CC)=[O:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Br:12])[CH:6]=2.O.[OH-].[Li+].C1COCC1.CC(O)=O>O>[NH2:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Br:12])[CH:6]=2
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc2ccc(Br)cc2nc1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a mixture of ethyl 3-amino-7-bromoquinoline-2-carboxylate (Ark Pharm, 113.9 mg, 0.3859 mmol) and lithium hydroxide monohydrate (82.8 mg, 1.97 mmol), THF (2.50 mL) was added, followed by water (0.50 mL). The resulting mixture was stirred at 50° C. for 2 h. The reaction mixture was then cooled to room temperature and water (25 mL) was then added, followed by AcOH (245.9 mg, 4.095 mmol) to adjust the pH to 5. The mixture was extracted with EtOAc (3×25 mL). The combined organic extract was washed with brine (50 mL), then dried over Na2SO4, and concentrated to yield a yellow solid (83.3 mg). The crude product was used directly in the next step without further purification. LCMS calc. for C10H8BrN2O2(M+H)+: m/z=267.0. found 267.0.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH2:30]([O:37][C:38]([N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[C:43](B3OC(C)(C)C(C)(C)O3)[CH:44]=[CH:45][C:46]=2[F:50])[CH2:41]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([O:72][C:73](=[O:86])[CH2:74][C:75]1[CH:80]=[CH:79][C:78]([O:81][CH:82]2[CH2:84][CH2:83]2)=[C:77](Cl)[CH:76]=1)(C)(C)C>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:30]([O:37][C:38]([N:40]1[CH2:49][CH2:48][C:47]2[C:42](=[C:43]([C:77]3[CH:76]=[C:75]([CH2:74][C:73]([OH:86])=[O:72])[CH:80]=[CH:79][C:78]=3[O:81][CH:82]3[CH2:84][CH2:83]3)[CH:44]=[CH:45][C:46]=2[F:50])[CH2:41]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(OC2CC2)c(Cl)c1
Reactant: CC1(C)OB(c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)Cc1ccc(OC2CC2)c(-c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture under N2 of palladium (II) acetate (0.4 mg, 2 μmol, 0.01 eq.), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.7 mg, 4 μmol, 0.02 eq.), 5-fluoro-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (82.3 mg, 0.2 mmol, 1.00 eq.) and potassium phosphate (84.9 mg, 0.4 mmol, 2.00 eq.) in toluene (0.6 mL) and water (35 μL) was stirred at r.t. during 2 min. A solution of (3-chloro-4-cyclopropoxy-phenyl)-acetic acid tert-butyl ester (57 mg, 0.2 mmol, 1.00 eq.) in toluene (0.6 mL) was added and the mixture was stirred at 100° C. for 18 hours. The mixture was allowed to cool to r.t., filtered through celite, and concentrated in vacuo. The residue, redissolved in MeCN (1.8 mL) and formic acid (0.2 mL), was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated. Trifluoroacetic acid (0.23 mL) was slowly added to an ice-cooled solution of the previous tert-butyl ester in DCM (0.23 mL). The reaction mixture was stirred at r.t. for 1.5 hours. The mixture was concentrated in vacuo without heating and the residue was redissolved in DMF (1.3 mL). Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the title compound as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[C:4]([CH3:21])[CH:3]=1.[OH-].[Li+]>CO>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[C:4]([CH3:21])[CH:3]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(F)ccc1CC1CCc2[nH]c(C(=O)O)cc21

Procedure:
The title compound was synthesized from methyl 4-(4-fluoro-2-methylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate and lithium hydroxide (0.92 mL, 44.2 mg, 1.85 mmol, 5.6 equiv) according to General Procedure 7. Methanol (5 mL) was used to solubilize the starting material. The resulting product was purified by silica-gel chromatography, eluting with a gradient of 0-40% EtOAc/heptane to afford to title compound. 44.9 mg. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 2.02-2.13 (m, J=12.81, 8.71, 5.64, 5.64 Hz, 1H) 2.26 (s, 3H) 2.46-2.58 (m, 1H) 2.59-2.70 (m, 1H) 2.70-2.81 (m, 3H) 3.23 (dd, J=7.47, 5.42 Hz, 1H) 6.21 (d, J=1.85 Hz, 1H) 6.87 (td, J=8.61, 2.78 Hz, 2H) 7.16 (dd, J=8.35, 6.20 Hz, 1H) 9.62 (br. s, 1H); 19F NMR (400 MHz, ACETONITRILE-d3) δ ppm −120.19 (s, 1F); LCMS-MS (ESI−) 272.31 (M−1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([O:13][CH2:14][C:15]([NH2:17])=[O:16])[CH:6]=[CH:5][C:4]1=2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>O1CCCC1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][CH2:2][CH:3]2[CH2:12][CH2:11][CH2:10][C:9]3[CH:8]=[C:7]([O:13][CH2:14][C:15]([NH2:17])=[O:16])[CH:6]=[CH:5][C:4]2=3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCC1CCCc2cc(OCC(N)=O)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)COc1ccc2c(c1)CCCC2CNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
0.1 mol of 5-aminomethyl-5,6,7,8-tetrahydro-naphth-2-yl-oxyacetamide (Example 7), 0.11 mol of 4-chlorobenzenesulphonyl chloride and 0.11 mol of triethylamine are stirred in 200 ml of tetrahydrofuran at room temperature for 3 hours. The mixture is filtered, the filtrate is evaporated, the residue is taken up in CH2Cl2 and the mixture is washed with 1N HCl, saturated NaHCO3, 1N HCl and saturated NaCl solution, dried over Na2SO4 and evaporated. The residue is purified by flash chromatography over silica gel using CH2Cl2MeOH 5:1.
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][C:23](=O)[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].[CH3:27][NH2:28].O>ClCCCl.C(O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[CH3:27][NH:28][CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1
Reactant: CN
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCCl
Product: CNC1CCN(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.00 g) in 1,2-dichloroethane (60 mL) was added 30% solution of methylamine in ethanol (750 mg) and sodium triacetoxyborohydride (1.66 g). The mixture was stirred at room temperature for 3 hours, then small amount of water was added and evaporated. Water was added to the residue and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to silica gel column chromatography using chloroform-methanol (40:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=2)[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[C:21]([O:28][CH3:29])[CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:34]1C=C(S(Cl)(=O)=O)C=C(Cl)[CH:39]=1>>[CH2:34]([O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:30]=[CH:31][CH:32]=[C:13]([NH:12][S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH:14]=2)=[CH:20][C:21]=1[O:28][CH3:29])[CH3:39]
Reactant: COc1cc(NC(=O)c2cccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c2)ccc1C(=O)O
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c2)cc1OC

Procedure:
4-[3-(3,5-Dichloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid, MS (ISP): m/e=493.2 (M−H), was prepared in analogy to example 17, steps A to D. Step C was performed using 3,5-dichloro-benzenesulfonyl chloride and yielded 4-[3-(3,5-dichloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[CH2:15]([N:18]1[C:26]2[C:21](=[N:22][C:23]([N:28]3[CH:32]=[C:31]4[CH2:33][NH:34][CH2:35][C:30]4=[N:29]3)=[C:24]([Cl:27])[CH:25]=2)[N:20]=[C:19]1[O:36][C@@H:37]1[CH2:41][O:40][C@@H:39]2[C@H:42]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:43][O:44][C@H:38]12)[CH:16]=[CH2:17].[CH3:53][S:54](Cl)(=[O:56])=[O:55]>C(Cl)Cl.CCOC(C)=O.O.Cl>[CH2:15]([N:18]1[C:26]2[C:21](=[N:22][C:23]([N:28]3[CH:32]=[C:31]4[CH2:33][N:34]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:35][C:30]4=[N:29]3)=[C:24]([Cl:27])[CH:25]=2)[N:20]=[C:19]1[O:36][C@@H:37]1[CH2:41][O:40][C@@H:39]2[C@H:42]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH2:43][O:44][C@H:38]12)[CH:16]=[CH2:17]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(-n3cc4c(n3)CNC4)c(Cl)cc21
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(-n3cc4c(n3)CN(S(C)(=O)=O)C4)c(Cl)cc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (91 uL, 0.653 mmol) was added to a ice cold mixture of [(3R,3aR,6R,6aS)-3-[1-allyl-6-chloro-5-(5,6-dihydro-4H-pyrrolo[3,4-c]pyrazol-2-yl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro-[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane 2,2,2-trifluoroacetic acid (86.4 mg, 0.128 mmol) and methane sulfonyl chloride (16 uL, 0.205 mmol) in DCM (1.0 ml). After 20 minutes, the reaction mixture was diluted with EtOAc (30 ml), water (20 ml) and 2N HCl (2 mL). The EtOAc layer was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under reduced pressure to give an oil. The oil was purified on preparative silica plates (2×1000 u developed with 1:1 EtOAc/hexanes) to give the title compound. LC-MS: calculated for C27H37ClN6O6SSi 636.20 observed m/e: 637.13 (M+H)+ (Rt 1.35/2 min)
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:5]=2[CH2:4][CH2:3][NH:2]1.[C:15]([O:18][CH2:19][C:20]1[C:25]([Br:26])=[CH:24][CH:23]=[CH:22][C:21]=1Br)(=[O:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>[Cu](I)I.O1CCOCC1>[C:15]([O:18][CH2:19][C:20]1[C:21]([N:2]2[CH2:3][CH2:4][C:5]3[C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=4[S:7][C:6]=3[C:1]2=[O:14])=[CH:22][CH:23]=[CH:24][C:25]=1[Br:26])(=[O:17])[CH3:16]
Reactant: CC(=O)OCc1c(Br)cccc1Br
Reactant: O=C1NCCc2c1sc1c2CCCC1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 30.5 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 104e (214 mg, 1.04 mmol), 2,6-dibromobenzyl acetate 104g (519 mg, 2.08 mmol), cesium carbonate (678 mg, 2.08 mmol), N,N′-dimethylethylenediamine (92 mg, 1.04 mmol) and 1,4-dioxane (10 mL). After bubbling nitrogen through the resulting suspension for 30 min, copper iodide (99 mg, 0.520 mmol) was added, and the reaction mixture was heated at 100° C. (oil bath temperature) for 16 h. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 30% yield (138 mg) of 2-Bromo-6-(1-oxo-3,4,5,6,7,8-hexahydrobenzothieno[2,3-c]pyridin-2(1H)-yl)benzyl acetate 104f as a yellow oil: 1H NMR (500 MHz, CDCl3) d 7.59 (dd, 1H, J=7.0, 1.5 Hz), 7.30-7.24 (m, 2H), 5.23 (m, 2H), 4.06 (m, 1H), 3.77 (m, 1H), 2.98 (m, 1H), 2.83-2.77 (m, 3H), 2.50 (m, 2H), 2.04 (s, 3H), 1.85 (m, 4H)
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=2)[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>C1COCC1.CO>[CH2:1]([C:5]1[O:6][C:7]2[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=2)[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCc4ccc(C(=O)OC)cc4)ccc3c2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCc4ccc(C(=O)O)cc4)ccc3c2)o1
Yield: 891.6 %

Procedure:
A mixture of methyl 4-[({6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)methyl]benzoate (51 mg, 0.0096 mmol), prepared in the previous step, and 1 N NaOH (145 μL, 0.145 mmol) in 10 mL of THF plus 10 mL of methanol, plus 5 mL of water was refluxed under nitrogen. The reaction was monitored by LC/MS. An additional three aliquots of 145 μL of 1 N NaOH were added over approximately three days of reflux. After cooling to room temperature 1 mL of 1 N HCl was added. The solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (44.3 mg, 89%) as a white solid, mp 251-254° C. Elemental Analysis for C33H27NO5. 0.10 H2O Calc'd: C, 76.31; H, 5.28; N, 2.70. Found: C, 72.79; H, 5.11; N, 2.47.