Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](O)=[O:36]>>[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:36]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1cccs1
Agent: Cl
Product: CN(C(=O)c1cccs1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 2-thiophenecarboxylic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(2-thiophenecarbonyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 474 (M-H)-.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:37])[C@@H:16]([N:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[C:32]([F:35])([F:34])[F:33])[C:24]2=[O:36])[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:18]1([CH2:17][C@H:16]([N:23]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[C:32]([F:34])([F:35])[F:33])[C:24]2=[O:36])[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][C:6]([OH:38])=[O:5])[N:10]=2)=[O:37])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
A mixture of 3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic acid tert-butyl ester (prepared as in Example 19, 130 mg, 0.24 mmol) in methylene chloride (3 mL) at room temperature was treated with trifluoroacetic acid (1 mL) and stirred for 3 h at room temperature. The reaction mixture was then diluted with chloroform (3 mL) and washed with an aqueous semi-saturated sodium bicarbonate solution. The organic layer was then dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate concentrated in vacuo to afford 3-{3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-propionic acid (66 mg, 58%) as a white semi-solid: HR-ES(+) m/e calcd for C23H25N4O4F3 [M+H]+ 479.1901, observed 479.1901; 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.01 (dd, J=7.67, 15.13 Hz, 2H), 7.75 (t, J=7.56 Hz, 1H), 7.53 (d, J=2.13 Hz, 1H), 6.33 (d, J=2.13 Hz, 1H), 4.97-5.11 (m, 2H), 4.70 (d, J=18.11 Hz, 1H), 4.06 (t, J=7.46 Hz, 2H), 2.25 (t, J=7.35 Hz, 2H), 1.05-2.09 (m, 11H).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH2:42][C:43]([O:45]CC)=[O:44])[CH:39]=[CH:40][CH:41]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(CC(=O)O)c3)oc2C)c(OC)c1)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a mixture of ethyl {3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (1.87 g), tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (5 mL) and water, and the precipitated crystals were collected by filtration to give {3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (1.67 g, yield 93%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 174-175° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[C:13](=[O:21])O[C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:29][CH2:30][CH2:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OC(=O)C)(=O)C>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH:12]2[CH2:19][CH2:18][CH2:17][CH:16]1[C:15](=[O:20])[N:32]([CH2:31][CH2:30][O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]2=[O:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCOCc1ccccc1
Reactant: O=C1OC(=O)C2CCCC1N2C(=O)OCc1ccccc1
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: O=C1C2CCCC(C(=O)N1CCOCc1ccccc1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
2,4-Dioxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 2, 1.02 g, 3.52 mmol) was dissolved in dioxane (5 mL), and 2-benzyloxyethylamine (0.50 g, 3.32 mmol) was added from the top. The mixture was stirred at room temperature for 1 hour (hr). Then, acetic anhydride (0.62 mL, 6.64 mmol) was added, and the reaction was refluxed for 5 hours. Dioxane was evaporated, and flash chromatographic purification of the residue (20% EtOAc/hexanes) gave Compound 3 (1.26 g, 90%) as a pale yellow oil: Rf (50% EtOAc/hexanes): 0.80.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([CH3:22])=[CH2:21])=[CH:17][CH:18]=2)[N:13]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:11]=1.B1C2CCCC1CCC2.Br[C:37]1[CH:38]=[N:39][C:40]([CH3:43])=[N:41][CH:42]=1.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:19]2[C:14](=[CH:15][C:16]([CH:20]([CH3:22])[CH2:21][C:37]3[CH:38]=[N:39][C:40]([CH3:43])=[N:41][CH:42]=3)=[CH:17][CH:18]=2)[N:13]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:11]=1
Reactant: C=C(C)c1ccc2c(-c3ccc(OC)cc3F)cc(C(=O)OC)nc2c1
Reactant: Cc1ncc(Br)cn1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(OC)cc2F)c2ccc(C(C)Cc3cnc(C)nc3)cc2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
Methyl 4-(2-fluoro-4-methoxyphenyl)-7-(prop-1-en-2-yl)quinoline-2-carboxylate (1.5 g, 4.27 mmol) was dissolved in THF (7.8 ml), heated to 60° C. and then added 9-BBN (0.5M THF, 10.7 ml, 5.35 mmol) dropwise over 5 minutes. After 1 hour, allowed to cool to ambient. Added 5-bromo-2-methylpyrimidine (0.886 g, 5.12 mmol), Pd2(dba)3 (0.195 g, 0.213 mmol), butyldi-1-adamantylphosphine (0.153 g, 0.427 mmol), potassium carbonate (2.360 g, 17.08 mmol) and water (0.776 ml), degassed 5 minutes with nitrogen and then heated to 90° C. in a sealed tube for 30 minutes. The reaction was allowed to cool to ambient temperature. To the mixture was added brine and then EtOAc. The organic portion was collected, dried (MgSO4) and then concentrated. The residue was purified by column chromatography on silica gel, eluting with CHCl3 to 70:25:5 CHCl3/EtOAc/MeOH to afford methyl 4-(2-fluoro-4-methoxyphenyl)-7-[1-(2-methylpyrimidin-5-yl)propan-2-yl]quinoline-2-carboxylate (335 mg, 0.752 mmol, 17.62% yield) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[C:14]([OH:20])[CH:15]=[C:16]([F:19])[C:17]=1[F:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:20][C:14]1[CH:13]=[C:12]([F:11])[C:17]([F:18])=[C:16]([F:19])[CH:15]=1)[CH:5]=[O:6]
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2cc(F)c(F)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3,4,5-trifluorophenol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=2)[CH:7]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=3)[CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1cccnc1
Reactant: OB(O)c1cccc(F)c1
Product: O=C(Nc1nc2ccc(-c3cccc(F)c3)cn2n1)c1cccnc1
Yield: 52.5 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B6), 75 mg; 0.24 mmol; 1.0 eq.) and 3-fluorophenylboronic acid (66 mg; 0.47 mmol; 2.0 eq.). Purification by flash chromatography on silica (MeOH/EtOAc, 5:95) gave the title compound as a beige powder (42 mg, 53%). HPLC, Rt: 2.40 min. (purity 99.7%). LC/MS, M+(ESI): 334.3, M−(ESI): 332.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]OC(OC)N(C)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([N:17]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:25]=[N:16][C:14]2=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)C1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Product: O=C1N=CN(c2ccc(F)cc2)C12CCN(Cc1ccccc1)CC2

Procedure:
Mix 1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carboxylic acid amide (20 mmol) and hot toluene (240 mL). Add dimethoxy-N,N-dimethylmethanamine (20 mL) and heat at reflux for 48 h. Concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:52]1[CH:57]=[C:56]([O:58][CH3:59])[N:55]=[C:54]([S:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:63]=2[F:69])[N:53]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:69][C:63]1[C:64]([F:68])=[CH:65][CH:66]=[CH:67][C:62]=1[CH2:61][S:60][C:54]1[N:53]=[C:52]([NH:10][S:7]([CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)(=[O:9])=[O:8])[CH:57]=[C:56]([O:58][CH3:59])[N:55]=1
Reactant: NS(=O)(=O)C1CCNCC1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)C2CCNCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of piperidine-4-sulfonamide (0.33 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.43 g) and, 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product from example 35 step i), 0.4 g) in dioxane (20 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 2 h. The reaction mixture was then reduced in vacuo and the residue partitioned between DCM (100 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×100 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting yellow residue was purified prep HPLC to give the title compound as a white solid. Yield 13 mg
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-benzylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:7][CH2:6][C@@H:5]([O:8][C:9]2[C:10]([CH3:18])=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)[CH2:4][C@@H:3]1[N:19]1C(=O)C2C(=CC=CC=2)C1=O>CN.C(O)C>[CH3:1][C:2]1([CH3:30])[CH2:7][CH2:6][C@@H:5]([O:8][C:9]2[C:10]([CH3:18])=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)[CH2:4][C@@H:3]1[NH2:19]
Reactant: Cc1c(O[C@@H]2CCC(C)(C)[C@@H](N3C(=O)c4ccccc4C3=O)C2)ccc2[nH]ncc12
Agent: CN
Solvent: CCO
Product: Cc1c(O[C@@H]2CCC(C)(C)[C@@H](N)C2)ccc2[nH]ncc12

Procedure:
To trans-2-{2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione was added 30%-methylamine/ethanol (10 ml) at room temperature, and the resulting mixture was refluxed for 8 hours. The reaction solution was concentrated under reduced pressure at room temperature and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform→chloroform/methanol/(1%-aqueous ammonia)=20/1) to obtain trans-2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (143 mg, 60%, containing about 10% of cis isomer).
Reaction SMILES: BrC1C=CC(O)=C(C2(O)C3C(=CC=CC=3)N(CCCCC)C2=O)C=1.[CH2:25]([O:27][C:28](=[O:52])[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](O)([C:39]2[C:48]([OH:49])=[CH:47][C:46]3[CH2:45][CH2:44][CH2:43][CH2:42][C:41]=3[CH:40]=2)[C:31]1=[O:51])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:52])[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]([C:39]2[C:48]([OH:49])=[CH:47][C:46]3[CH2:45][CH2:44][CH2:43][CH2:42][C:41]=3[CH:40]=2)[C:31]1=[O:51])[CH3:26]
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)CCCC3)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Product: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)CCCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 15B, and making non-critical variations to replace 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl[3-hydroxy-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained: 1H NMR (300 MHz, CDCl3) δ 7.42-7.32 (m, 2H), 7.20 (t, 1H), 6.84 (d, 1H), 6.78 (s, 1H), 6.61 (s, 1H), 5.12 (s, 1H), 4.47 (ABq, 2H), 4.21 (q, 2H), 2.76-2.44 (m, 4H), 1.78-1.64 (m, 4H), 1.24 (t, 3H); MS (ES+) m/z 366 (M+1).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][C:31]1[N:35]([CH:36]2[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]2)[C:34]2[CH:47]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH:49]=[CH:50][C:33]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:48]3[CH:49]=[CH:50][C:33]4[N:32]=[C:31]([CH3:30])[N:35]([CH:36]5[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH2:39]5)[C:34]=4[CH:47]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2n1C1CN(C(=O)OC(C)(C)C)C1
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: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc(C)n(C5CN(C(=O)OC(C)(C)C)C5)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (54 mg, 0.11 mmol), tert-butyl 3-(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)azetidine-1-carboxylate (181 mg, 0.44 mmol), then Pd(PPh3)4 (23 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (2 mL) and to this was added 2M aqueous K2CO3 (0.2 mL, 0.4 mmol). The vial was sealed, heated to 100° C. for 16 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-10% MeOH/CH2Cl2 gradient) to afford the desired product. LCMS-ESI+: calc'd for C38H44ClN4O5S C31H33ClN3O4S: 703.3 (M+H+); Found: 703.5 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>Cl>[ClH:15].[CH2:1]([N:8]([CH2:9][CH2:10][Cl:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CN(CCCl)Cc1ccccc1
Reaction time: 2 h
Yield: 133.2 %

Procedure:
Combine hydrogen chloride (50 mL; 4M in dioxane), N-benzyl-N-methylethanolamine (61.12 mmol; 10 g), thionyl chloride (73.30 mmol; 5.34 mL) and heat to 90° C. Stir for 2 h, evaporate and crush the solids under ether, sonicate 15 min, filter, wash with ether, dry under vacuum to provide the title compound (10.75 g; 80%). MS (ES): m/z=184 (M+H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])=[O:10])=[CH:7][N:8]=1)[CH3:2].[OH:18]O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[S:5][C:6]([C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])=[O:10])=[CH:7][N:8]=1)=[O:18])[CH3:2]
Reactant: OO
Reactant: C=CCCCCNC(=O)c1cnc(SCC)s1
Solvent: CC(=O)O
Product: C=CCCCCNC(=O)c1cnc(S(=O)CC)s1

Procedure:
In this preparation a mixture of 0.064 mole of 2-ethylthio-5-(hex-5-enylaminocarbonyl)thiazole; 40 ml. of 30% aqueous hydrogen peroxide and 200 ml. of acetic acid is stirred at a temperature of from 40° to 50° C for four hours. The mixture is concentrated by evaporation of a large portion of the acetic acid, under vacuum, at room temperature (about 20° C) and the resulting residue poured into 500 ml. of ethyl acetate and then washed with aqueous sodium bicarbonate solution until no acetic acid is present in the organic layer. The ethyl acetate layer is then separated, dried with anhydrous magnesium sulfate, filtered, and the resulting filtrate evaporated to dryness, under vacuum, affording 2-ethylsulfinyl-5-(hex-5-enylaminocarbonyl)thiazole.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19](CC2C=CC=CC=2)[CH2:18][CH2:17]1)[CH3:2].CO>O.[Pd].C(N(CC)CC)C.CO>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1)[CH3:2]
Reactant: CCOCCn1c(NC2CCN(Cc3ccccc3)CC2)nc2ccccc21
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reaction time: 24 h

Procedure:
Combine (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(1-benzylpiperidin-4-yl)amine (0.51 g, 1.35 mmol), 20% palladium hydroxide-on-carbon, and methanol (40 mL). Hydrogenate in a Parr apparatus at an initial pressure of 40 psi. After 24 hours, filter through celite, rinse with methanol, and evaporate invacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 4% triethylamine/methanol to give the title compound: Rf =0.28 (2% triethylamine/methanol).
Reaction SMILES: N[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([Br:13])=[CH:4][C:3]=1[Cl:14].C1(C)C=CC=CC=1.S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C>[Br:13][C:5]1[C:6]2[CH2:7][C:8]([CH3:11])([CH3:12])[O:9][C:10]=2[CH:2]=[C:3]([Cl:14])[CH:4]=1
Reactant: CC1(C)Cc2c(Br)cc(Cl)c(N)c2O1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)Cc2c(Br)cc(Cl)cc2O1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A stirred solution of 5.1 grams (0.018 mole) of 7-amino-4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran and 25 mL of toluene in 100 mL of ethanol was cooled in an ice bath, and 2 mL (0.036 mole) of concentrated sulfuric acid was added slowly. Upon completion of addition, 2.0 grams (0.029 mole) of sodium nitrite was then added. The ice bath was then removed, and the reaction mixture was warmed to 75° C., where it stirred for 30 minutes. After this time the reaction mixture was warmed to 95° C., where it stirred for one hour. The reaction mixture was then cooled and poured into 200 mL of water. The mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.6 grams of 4-bromo-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:3]1.[C:16]1([CH2:22][CH2:23][CH:24]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:22][CH2:23][CH2:24][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3)[CH2:3]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CCCc1ccccc1
Reactant: Oc1ccc(SC2CCCNC2)cc1
Agent: Br
Product: Oc1ccc(SC2CCCN(CCCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=328.3 (M+H+) was prepared from (RS)-4-(piperidin-3-yl-sulfanyl)-phenol hydrobromide and 3-phenylpropionaldehyde.