Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[OH:27]/[N:28]=[C:29](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].[H-].[Na+].Cl>CN(C)C=O.O>[CH3:26][O:25][C:5]1[CH:4]=[C:3]([CH:22]=[C:21]([O:23][CH3:24])[C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])[CH2:2][O:27]/[N:28]=[C:29](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: COc1cc(CCl)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC/C(=N\OCc1cc(OC)c(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)c1ccccc1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a stirred solution of 4-(4-chloromethyl-2,6-dimethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) and methyl E-4hydroxyimino-4-phenylbutyrate (585 mg) in N,N-dimethylformamide (40 ml) was added sodium hydride (60% in oil, 115 mg) at 0° C. After stirring for 2 hours, the reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:3, v/v) gave methyl E-4-[3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (970 mg, yield 65%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[I:30]I>O1CCCC1>[I:30][C:18]1[S:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[C:14]=1[O:13][C:12]1[CH:23]=[CH:24][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1
Reactant: II
Reactant: c1ccc(COc2ccc(Oc3csc4ccccc34)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Ic1sc2ccccc2c1Oc1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
To a solution of 3-(4-benzyloxyphenoxy) benzo[b]thiophene (6.00 g, 18.1 mmol) in anhydrous tetrahydrofuran (100 mL) under N2 at -78° C. was added n-butyllithium (12.4 mL, 19.9 mmol, 1.6 M in hexanes) dropwise via syringe. The solution turned from colorless to deep orange. After stirring for 20 minutes at -78° C., the lithio species was treated with I2 (5.03, 19.9 mmol), added dropwise via canula as a solution in 50 mL of anhydrous tetrahydrofuran. Upon completion of the addition, the reaction turned light yellow in color, and was allowed to slowly warm to room temperature. The reaction was quenched by the addition of 0.1 N sodium sulfite solution (200 mL). The layers were separated and the aqueous extracted with ethyl acetate (2×150 mL). The organic layers were combined, dried (sodium sulfate), and concentrated in vacuo to give an oil that crystallized on standing. Recrystallization from hexanes/ethyl ether yielded 7.10 g (86%) of 2-iodo-3-(4-benzyloxyphenoxy)benzo[b]thiophene as a white crystalline powder. mp 87-92° C. 1H NMR (CDCl3) d 7.72 (d, J=8.1 Hz, 1H), 7.47-7.20 (m, 8H), 6.89 (s, 4H), 5.01 (s, 2H). Anal. Calcd. for C21H15O2SI: C, 55.03; H, 3.30. Found: C, 55.29; H, 3.31.
Reaction SMILES: [CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][N:17]([C@@H](C4C=CC=CC=4)C)[CH2:16]3)=[CH:11][CH:10]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].C(O)C>[CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[O:20][CH2:19][CH2:18][NH:17][CH2:16]3)=[CH:11][CH:10]=2)[CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N(C)C3CCCCC3)cc2)C1
Agent: [Pd]
Solvent: CCO
Product: CN(c1ccc([C@H]2CNCCO2)cc1)C1CCCCC1
Temperature: 50 °C
Reaction time: 10 h
Yield: 94.6 %

Procedure:
A 300-ml flask containing a solution of (S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)-4-((R)-1-phenylethyl)morpholine (7.27 g, 19.07 mmol) and 10% palladium on carbon (3.0 g) in ethanol (30 ml) was charged with hydrogen. The reaction mixture was stirred vigorously at 50° C. for 10 hours. The catalyst was filtered off with a Celite pad, and the filtrate was concentrated under reduced pressure to yield (2S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)morpholine (4.95 g, 95%) as a clear oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12]1([N:18]2[C:30]3[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[C:9]([C:27]2[CH:28]=[CH:29][C:30]3[N:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:19]4[C:24]([C:25]=3[CH:26]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Cl)ncn1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(-c2ccc3c(c2)c2ccccc2n3-c2ccccc2)ncn1
Yield: 95 %

Procedure:
Next, in a recovery flask equipped with a reflux pipe were put 1.00 g of 4-tert-butyl-6-chloropyrimidine obtained in Step 2, 3.44 g of 9-phenyl-9H-carbazol-3-ylboronic acid, 1.32 g of sodium carbonate, 0.050 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: PdCl2(PPh3)2), 20 mL of water, and 20 mL of DMIF, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Then, water was added to this solution and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride, and was dried with magnesium sulfate. The solution obtained by the drying was filtered. The solvent of this solution was distilled off, and then the given residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 2:1 to give HtBupczpm (white powder, yield of 95%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). Synthesis Scheme (a-3) of Step 3 is shown below.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][NH:24]C(OCC2C=CC=CC=2)=O)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].[BrH:35].CCOCC>C(O)(=O)C>[BrH:35].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][NH2:24])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCNC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN
Reaction time: 2 h

Procedure:
4.8 G. of 2-{2-[(benzyloxycarbonyl)amino]-ethyl}-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester are dissolved in 10 ml. of glacial acetic acid; 15 ml. of a solution of 33% hydrobromic acid in glacial acetic acid are added. The mixture is left to stand for 2 hours at room temperature with occasional shaking and then poured into 150 ml. of ether. The precipitated crystals are removed by filtration under suction and washed with ether. Recrystallization from ethanol yields 2-(2-aminoethyl)-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester hydrobromide; melting point 230°-234° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:49]([O:56][C:57]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][C@H:64]([NH2:75])[C:65]1[NH:69][C:68]2[CH:70]=[CH:71][C:72]([Cl:74])=[CH:73][C:67]=2[N:66]=1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.ClCl>O1CCCC1.ClCCl.CO>[CH2:49]([O:56][C:57]([NH:59][CH2:60][CH2:61][CH2:62][CH2:63][C@H:64]([NH:75][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:65]1[NH:69][C:68]2[CH:70]=[CH:71][C:72]([Cl:74])=[CH:73][C:67]=2[N:66]=1)=[O:58])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 71 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and N-[(1S)-5-(benzyloxycarbonylamino)-1-(5-chloro-1H-benzimidazol-2-yl)pentylamine in tetrahydrofuran. Yield: 71%; Rf value: 0.53 (silica gel; dichloromethane/methanol=9:1); C33H36ClN5O4 (602.13); mass spectrum: (M+H)+=602/604 (chlorine isotope) and (M−H)−=600/602 (chlorine isotope).
Reaction SMILES: [N:1]1([CH:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:30])C(=O)C1.O>CN(C=O)C>[Br:30][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]([CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1)[CH2:2][CH2:3][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)C1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3cc(Br)ccc32)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
A solution of tert-butyl 3-(3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylate (1.86 g, 6.15 mmol) in 15 mL of DMF was cooled to 0° C. then treated dropwise with NBS (1.09 g, 6.15 mmol) in 15 mL DMF. The reaction was stirred at 0° C. for 1.5 hours then treated with 100 mL H2O. The suspension was extracted with 2×150 mL EtOAc. The combined organic layer was rinsed with brine (3×20 mL), dried over Na2SO4, filtered and concentrated to give a viscous oil. This residue was subjected to flash chromatography on silica gel using 15% EtOAc/Hexanes to give a viscous oil (1.50 g, 63.8%). 1H-NMR (CDCl3) δ 7.13 (d, J=9.0 Hz, 1H), 7.07 (brs, 1H), 6.55 (d, J=9.0 Hz, 1H), 4.35-4.33 (m, 1H), 3.58-3.18 (m, 6H), 2.71 (t, J=6.3 Hz, 2H), 2.11-2.04 (m, 2H), 1.91-1.87 (m, 2H), 1.47 (s, 9H). MS (ESI): 325.1 and 327.1 (M+1, 100%).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][O:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=2)[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: COc1cccc(O)c1
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COc1cccc(OCCCOc2cccc(CC(OC)C(=O)O)c2)c1

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 3-methoxyphenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C20H24O6 [M+Na]+: 383.3.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)[N:5]=[C:4]([S:22][CH3:23])[N:3]=1.C(=O)([O-])[O-:25].[K+].[K+].OO.Cl>O.CS(C)=O>[CH3:23][S:22][C:4]1[NH:3][C:2](=[O:25])[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)[N:5]=1
Reactant: O=C([O-])[O-]
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)n1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc(Nc2cccc(S(C)(=O)=O)c2)c(C(N)=O)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
To a mixture of 4-chloro-2-(methylsulfanyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide (Preparation Example 298) (1.95 g) and DMSO (30 mL), potassium carbonate (1.81 g) and 30% hydrogen peroxide solution (2.65 mL) were added and stirred at 50° C. for 1.5 hours. The reaction liquid was ice-cooled, and 1M hydrochloric acid (25 mL) and thereafter water (150 mL) were added and stirred for 30 minutes. The precipitated solid was collected by filtration and washed with water to give 2-(methylsulfanyl)-4-{[3-(methylsulfonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (1.40 g) as a light yellow solid.
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30].N([O-])=O.[Na+].CC#N.O.[ClH:41]>O.Cl[Cu]>[Cl:41][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30]
Reactant: Cl
Reactant: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 70 °C
Reaction time: 0.67 h

Procedure:
Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.280 g, 0.64 mmol) was dissolved in a mixture of MeCN/H2O/HCl 10 mL/10 mL/4 mL at 0° C. A solution of NaNO2 (0.066 g, 0.96 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (0.32 g, 3.2 mmol) in water (2 mL) was added drop wise at 0° C. The reaction mixture was heated to 70° C. for 1 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated to give oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate as a yellow oil (0.110 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.[F:35][CH2:36][CH2:37][NH2:38].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[NH:38][CH2:37][CH2:36][F:35])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Reactant: NCCF
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NCCF
Yield: 79.3 %

Procedure:
The same operation as in Example (247a) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (250 mg, 0.50 mmol), 2-fluoroethylamine hydrochloride (100 mg, 1.00 mmol), WSC hydrochloride (288 mg, 1.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol), to obtain 216 mg of the title compound as a white solid (79%).
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]1=[O:15].C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24].ClCCl>CN(C)C=O>[C:23]([N:12]1[CH2:13][CH2:14][C:6]2([C:5](=[O:15])[N:4]([O:3][CH3:2])[C:8](=[O:9])[CH2:7]2)[CH2:10][CH2:11]1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CON1C(=O)CC2(CCNCC2)C1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON1C(=O)CC2(CCN(C(C)=O)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (2.35 g) in dimethylformamide (200 ml) was added triethylamine (2.8 ml), followed by acetyl chloride (0.8 ml), and this was followed by 30 minutes of stirring at room temperature. To the resulting residual oily substance dichloromethane (50 ml) was added, after which it was washed with 1N hydrochloric acid and then with water. After drying the organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure; the resulting residual solid was recrystallized from ethanol-ethyl ether to obtain 1.2 g of a colorless crystal having a melting point of from 153° to 157° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Fc1ccc(CCl)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OCc1ccc(F)cc1
Temperature: 140 °C
Yield: 58.2 %

Procedure:
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (5 g, 25 mmol), KI (2 g) and K2CO3 (7 g, 50 mmol) in DMF (100 mL) was added 1-chloromethyl-4-fluoro-benzene (3.96 g, 28 mmol). The mixture was heated at 140° C. for 2 h, then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water for 3 times, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (4.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:23]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccc(Cl)c4)cc3c2C1
Yield: 24.8 %

Procedure:
Beginning with 10.6 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.8 μL (0.063 mMol) 3-chlorobenzoyl chloride, 4.2 mg (25%) of the title compound were recovered as a brown solid.
Reaction SMILES: O[CH:2]([CH2:18][N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29]C)[N:27]=2)[CH2:22][CH2:21][C:20]1=[O:31])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[I-].[Na+]>C(Cl)(Cl)Cl>[O:29]=[C:26]1[CH:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20](=[O:31])[N:19]3[CH2:18][CH:2]([CH2:3][N:4]4[CH2:5][CH2:6][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:8][CH2:9]4)[N:27]1[C:28]=23
Reactant: COc1ccc2c(n1)N(CC(O)CN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CC2
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(CC2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Temperature: 80 °C
Yield: 69.5 %

Procedure:
A solution of 1,1-dimethylethyl (1-{2-hydroxy-3-[7-(methyloxy)-2-oxo-3,4-dihydro-1,8-naphthyridin-1(2H)-yl]propyl}-4-piperidinyl)carbamate (301 mg, 0.694 mmol) in chloroform (10 ml) and triethylamine (0.24 ml, 1.735 mmol) at rt under argon was treated with methanesulfonic anhydride (242 mg, 1.388 mmol) and heated at reflux for 2 h. The reaction mixture was then evaporated and dissolved in acetonitrile (10 ml), treated with sodium iodide (520 mg, 3.47 mmol) and heated at 80° C. for 0.25 h. The mixture was then cooled, evaporated was then treated with water (200 ml), extracted with 20% methanol/DCM (3×200 ml). The organic extracts were dried (MgSO4), evaporated and chromatographed (0-10% methanol/DCM) to give the product as an orange oil (194 mg, 70%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:23]=[CH:22][C:13]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:16][C:12]=2[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:9][C:10]1[CH:23]=[CH:22][C:13]2[CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:16][C:12]=2[CH:11]=1)[S:37]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:39])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc2ccc(CNCc3ccccc3)cc2s1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2ccc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-[(benzylamino)methyl]-1-benzothiophene-2-carboxylate (0.147 g, 0.452 mmol) and triethylamine (0.20 mL, 1.43 mmol) in anhydrous CH2Cl2 (1 mL) was slowly added benzene sulphonylchloride (100 μL, 0.784 mmol). The resulting mixture was allowed to stir overnight at room temperature. The solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous layer was washed three times with ethyl acetate. The combined organic layer was dried with sodium sulfate, filtered, and concentrated. The resultant residue was purified by column chromatography yielding the desired product. 1H NMR (CDCl3, 600 MHz) δ 7.97 (d, J=0.6 Hz, 1H), 7.86 (dt, J=8.4, 1.6 Hz, 2H), 7.68 (d, 8.2 Hz, 1H), 7.60 (tt, J=7.2, 1.2 Hz, 1H), 7.51 (t, J=7.2 Hz, 2H), 7.40 (broad s, 1 μl), 7.16-7.19 (m, 3H), 7.09 (dd, J=8.3, 1.5 Hz, 1H), 6.99-7.05 (m, 2H), 4.43 (s, 2H), 4.39 (q, J=7.1 Hz, 2H), 7.35 (s, 2H), 1.40 (t, J=7.1 Hz, 3H). MS: cal'd (MH+), exp 466 (MH+).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:22]1([C:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=3)[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc2c(I)cn(C(=O)OC(C)(C)C)c2c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(-c3ccccc3)cn(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A mixture of 1-tert-butyl 6-methyl 3-iodo-1H-indole-1,6-dicarboxylate 62a (5.02 mmol, 2.016 g), phenylboronic acid 1x (7.53 mmol, 0.92 g), Pd(OAc)2 (0.402 mmol, 90 mg), Sphos 0.904 mmol, (0.37 g), and K3PO4 (10.1 mmol, 2.13 g) in toluene (10 mL) in sealed reaction vial was stirred at room temperature for 2 min and then heated at 90° C. under N2 for 4 h. The reaction mixture was quenched with EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 8% EtOAc/hexanes). The desired product was collected as a light yellow solid that was washed with small amount of hexanes to obtain 62b as a white solid.