Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([CH3:24])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])C.[Cl:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[C:30]([CH2:32][C:4]([C:6]2[N:7]=[C:8]([CH3:24])[N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]([F:21])([F:23])[F:22])[CH:13]=3)[C:10]=2[CH3:11])=[O:5])[CH:29]=[CH:28][N:27]=1
Reactant: CCOC(=O)c1nc(C)n(-c2ccc(OC)c(C(F)(F)F)c2)c1C
Reactant: Cc1ccnc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(-n2c(C)nc(C(=O)Cc3ccnc(Cl)c3)c2C)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1-(4-Methoxy-3-trifluoromethyl-phenyl)-2,5-dimethyl-1H-imidazole-4-carboxylic acid ethyl ester (0.8 g, 2.3 mmol) and 2-chloro-4-methylpyridine (0.36 g, 2.8 mmol) were dissolved in 10 mL toluene. This solution was dropped to a cold (0° C.) mixture of potassium bis(trimethylsilyl)amide (1.17 g, 5.84 mmol) in 15 mL toluene. The reaction mixture was stirred for 90 min. at 0° C. 0.4 mL acetic acid were added, and the mixture extracted with water, saturated NaHCO3-Solution and brine. The aqueous layer was washed with toluene (100 mL). The combined organic extracts were dried with sodium sulfate and filtered. The solvent was evaporated, and the crude product [(0.8 g, 81%), [MS: m/e=424.5 (M+H+)] was used without any further purification for the next step.
Reaction SMILES: Br[C:2]1[S:3][C:4](Cl)=[C:5](Cl)[C:6]=1[C:7](=[O:10])[CH2:8]Cl.C(C1C=CSC=1)(=O)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>>[C:7]([C:6]1[CH:5]=[C:4]([C:23](=[O:24])[CH2:22][Cl:21])[S:3][CH:2]=1)(=[O:10])[CH3:8]
Reactant: O=C(CCl)c1c(Br)sc(Cl)c1Cl
Reactant: O=C(Cl)CCl
Agent: CC(=O)c1ccsc1
Product: CC(=O)c1csc(C(=O)CCl)c1
Yield: 41 %

Procedure:
General procedure described for compounds 1 and 2 starting from 3-acetylthiophene and chloroacetyl chloride. Purified by column chromatography column (hexane:ethyl acetate 2:1), yield 41% m.p.: 118-119° C., 1H-NMR (CDCl3): δ8.3 (s, 1H, Ar), 8.1 (s, 1H, Ar), 4.60 (s, 2H, CH2), 2.56 (s, 3H, CH3); 13C-NMR (CDCl3): δ191.6 (CO), 184.5 (CO), 143.3 (C—CO), 141.7 (C—CO), 139.7 (CH), 132.0 (CH), 45.4 (CH2), 27.4 (CH3); M/z (EI): 204, 202 (M+, 6, 17%), 153 (M-CH2Cl, 100%); HPLC: Delta Pak Column C18, 5 μm, 300 A, (150×3.9 mm), Purity 94%, r.t.=2.70 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH:9]([NH:12][C:13](=[O:38])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:22](=[O:31])[C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:15]=1)([CH3:11])[CH3:10]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:24](=[C:23]2/[C:22](=[O:31])[N:21]([CH2:20][C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[C:13]([NH:12][CH:9]([CH3:11])[CH3:10])=[O:38])[C:32]3[C:33]/2=[CH:34][CH:35]=[CH:36][CH:37]=3)/[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: Clc1ccc(I)cc1
Product: CC(C)NC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and N-isopropyl-3-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-benzamide. 1H NMR (CDCl3, 300 MHz) δppm 7.74 (s, 1H), 7.60 (d, 1H), 7.26-7.43 (m, 10H), 7.07 (dt, 2H), 6.70 (t, 1H), 6.68 (d, 1H), 6.53 (d, 1H), 5.99 (d, 1H), 4.94 (s, 2H), 4.26 (m, 1H), 1.26 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=1)=[CH:7]2.C([O-])(O)=O.[Na+].[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33].C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:22][NH:21][C:19]([C:15]1[CH:14]=[C:13]([O:12][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[NH:1][C:32]([C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([Cl:28])[CH:30]=3)=[O:33])[CH:7]=2)[CH:18]=[CH:17][N:16]=1)=[O:20]
Reactant: CNC(=O)c1cc(Oc2ccc3c(N)cccc3c2)ccn1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cc(Oc2ccc3c(NC(=O)c4cccc(Cl)c4)cccc3c2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 4-(5-aminonaphthalen-2-yloxy)-N-methylpicolinamide (40 mg, 0.14 mmol) and NaHCO3 (33 mg, 0.44 mmol)in CH2Cl2, 3-chlorobenzoyl chloride (17 □L, 0.14 mmol) was added. The reaction was stirred at RT for 12 h then taken up into CHCl3 and washed with water and brine, dried over Na2SO4, and filtered. The title compound was isolated after purification by column chromatography. MS (ESI pos. ion) m/z: 432.4 (M+H). Calc'd for C24H18ClN3O3−431.87.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([C@@H:15]([NH:17][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)[CH3:16])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[C:3]=1[C:35](O)=[O:36].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([C@@H:15]([NH:17][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[CH3:16])[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:4]=2[C:3]=1[C:35]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:36]
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C(=O)O)c2n1-c1ccccc1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of 5-fluoro-3-phenyl-2-{(S)-1-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid (200 mg, 0.39 mmol) and morpholine (42 μL, 0.48 mmol) in DCM (10 mL) was added HATU (197 mg, 0.52 mmol) and the reaction stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) LCMS (Method C): RT=2.60 min, [M+H]+=571. The product was dissolved HCl in methanol (5 mL, 2.5M) and the reaction stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue loaded onto an SCX 2 cartridge, washed with methanol then eluted with ammonia in methanol (2M). The eluent was concentrated in vacuo and the residue subjected to HPLC purification (C18, 10-90% MeCN in H2O, 0.1% formic acid, 20 min gradient) to give 273 as a white solid (107 mg, 55%) 1H NMR (DMSO-d6+TFA-D, 400 MHz, 80° C.): δ 8.52 (1H, br s), 8.46 (1H, d, J=6.25 Hz), 7.83-7.75 (1H, m), 7.57-7.43 (5H, m), 7.32-7.15 (2H, m), 5.66 (1H, br s), 3.50-3.24 (5H, m), 3.15-3.05 (1H, m), 3.04-2.95 (1H, m), 2.70-2.58 (1H, m), 1.74-1.65 (3H, m). LCMS (Method K): RT=2.63 min, [M+H]+=487, RT=2.66 min, [M+H]+=487
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Cl[CH:23]([C:29](=O)[CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(O)C.CN(C)C(=O)C>O>[CH3:30][C:29]1[N:20]=[C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])[S:21][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1sc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)nc1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.50 g), ethyl 2-chloro-3-oxobutyrate (0.40 mL), ethanol (4 mL) and N,N-dimethylacetamide (4 mL) was stirred at 90° C. overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.47 g, yield 73%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 226-228° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][C:6]2[N:12]=[C:13]([N:24]3[CH2:30][CH:29]4[O:31][CH:26]([CH2:27][CH2:28]4)[CH2:25]3)[N:14]=[C:15](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4]1=[O:32])[CH3:2].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[CH:43][C:44]([NH2:47])=[N:45][CH:46]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C(OCC)(=O)C.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>[NH2:47][C:44]1[N:45]=[CH:46][C:41]([C:15]2[C:5]3[C:4](=[O:32])[N:3]([CH2:1][CH3:2])[CH2:9][C:8]([CH3:10])([CH3:11])[O:7][C:6]=3[N:12]=[C:13]([N:24]3[CH2:25][CH:26]4[O:31][CH:29]([CH2:28][CH2:27]4)[CH2:30]3)[N:14]=2)=[CH:42][CH:43]=1
Reactant: CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(OS(=O)(=O)C(F)(F)F)c2C1=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(-c3ccc(N)nc3)c2C1=O
Temperature: 100 °C
Yield: 79.9 %

Procedure:
170 mg (353.83 μmol) of trifluoromethanesulfonic acid 6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl ester and 90.16 mg (389.21 μmol) of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-ylamine are dissolved in 3 ml of dioxane in a microwave tube. 150.21 mg (707.66 μmol) of tripotassium phosphate and 1 ml of water are added The solution is purged with argon. Finally, 24.84 mg (35.38 μmol) of bis(triphenylphosphine)palladium(II) chloride are added and the mixture is heated in a Biotage microwave machine for 15 minutes at 100° C. The reaction mixture is diluted in ethyl acetate and washed with water and then with saturated NaCl solution. The precipitate present in the organic phase is filtered off to give 120 mg of 4-(6-aminopyridin-3-yl)-6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-6H-9-oxa-1,3,6-triazabenzocyclohepten-5-one.
Reaction SMILES: [CH2:1]([C@@H:7]1[CH2:9][O:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O1CCCC1.[CH2:15]([Mg]Cl)[CH3:16].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].S(=O)(=O)(O)O>O1CCCC1.[Cl-].[Na+].C(OCC)(=O)C>[CH3:26][C:25]1[CH:27]=[CH:28][C:22]([S:19]([O:8][C@@H:7]([CH2:9][CH2:15][CH3:16])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: CC[Mg]Cl
Reactant: CCCCCC[C@@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCC[C@H](CCC)OS(=O)(=O)c1ccc(C)cc1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 103.8 %

Procedure:
Under an argon atmosphere, cuprous chloride (4.6 g) was added to a solution of (2R)-2-hexyloxirane (300 g) in tetrahydrofuran (642 mL), and then ethylmagnesium chloride tetrahydrofuran solution (2.1 mol/L, 1309 g) was added dropwise at −40 to −20° C. (inner temperature). The reaction mixture was stirred at −30 to −20° C. (inner temperature) for about 30 minutes, and then tosyl chloride (491 g) was added, and the mixture was stirred at 0-20° C. (inner temperature) for about 4 hours. To the reaction mixture was then added 10 v/v % sulfuric acid (conc. sulfuric acid:water=65 mL:650 mL), aqueous sodium chloride (13.6 g) solution (272 mL) and ethyl acetate (1.5 L) for extraction. The resulting organic layer was washed with (1) a solution of sodium chloride (32 g) in water (636 mL), (2) a mixture of a solution of potassium carbonate (73 g) in water (730 mg) and a saturated brine (200 mL), and (3) a saturated brine (600 mL) in order, and then concentrated to give the title compound (758.7 g; yield 89%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>C(Cl)(Cl)Cl.CN(C)C=O>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1I
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-iodobenzoic acid (5.00 g, 20.1 mmol) in chloroform (50 ml) were added oxalyl chloride (1.9 ml, 21.7 mmol) and N,N-dimethylformamide (5 drops with Pasteur pipette) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure and ethyl acetate (5 ml) was added to the residue to give a solution of 2-iodobenzoyl chloride in ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:10]([O:13][CH3:14])[O:11][CH3:12])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH:10]([O:13][CH3:14])[O:11][CH3:12])=[C:4]([O:9][CH:16]([F:21])[F:20])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(OC)c1c(O)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1c(OC(F)F)ccc(F)c1Cl
Temperature: 90 °C
Yield: 62.8 %

Procedure:
In a single neck flask, 3-chloro-2-dimethoxymethyl-4-fluorophenol (22 g, 100 mmol), sodium chlorodifluoroactate (30.3 g, 200 mmol) and potassium carbonate (27.5 g, 200 mmol) were taken up in DMF (145 mL) under nitrogen atmosphere and heated at 90° C. for 16 h. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate (2×200 mL, 100 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated to give crude product, which was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as an eluent to give 17 g (63% yield) of the title compound. 1H NMR (CDCl3, 300 MHz): δ=7.11-7.13 (m, 2H), 6.45 (t, J=75 Hz, 1H), 5.70 (s, 1H), 3.46 (s, 6H).
Reaction SMILES: C(NC(C1OC2(CCN([C:18](=[O:30])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=3)CC2)CN(CC2C=CC=CC=2)C1)=O)C(C)=O>C1COCC1>[CH:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([CH:18]=[O:30])=[CH:20][C:21]=1[CH3:29])([CH3:28])[CH3:27]
Reactant: CC(=O)CNC(=O)C1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1OC(C)C
Temperature: 75 °C
Yield: 164 %

Procedure:
To N-acetonyl-8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxamide (136 mg, 0.26 mmol) in THF (3 mL) was added Burgess' Salt (155 mg, 0.65 mmol) and the reaction mixture was heated at 75° C. in a sealed vial for 2 hours. The solvents were removed under reduced pressure, and the residue was dissolved in DMF (1 mL), filtered and purified by Waters preparative LC/MS (1-99% ACN/H2O (5 mM HCl)). The desired fractions were concentrated in vacuo and the residue partitioned between EtOAc/saturated aqueous NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to yield 8-benzyl-10-(5-methyloxazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (76 mg, 58%) as a foam. ESI-MS m/z calc. 503.6. Found 504.5 (M+1)+; Retention time: 1.74 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=[N:11]2)[S:5][C:6]=1[C:7]([OH:9])=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[N:54]1[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][NH2:61])[CH:55]=1>CN(C)C=O.ClCCl>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=[N:11]2)[S:5][C:6]=1[C:7]([NH:61][CH2:60][C:56]1[CH:55]=[N:54][CH:59]=[CH:58][CH:57]=1)=[O:9]
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2cc(CCCc3ccccc3)nn2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-n2cc(CCCc3ccccc3)nn2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a solution of 4-methyl-2-(4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl)thiazole-5-carboxylic acid (4.62 g, 14.07) in anhydrous N,N-dimethylformamide (50 mL) was added 1-hydroxybenzotriazole (2.28 g, 16.88 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (3.24 g, 16.88 mmol), N,N-diisopropylethylamine (7.35 mL, 42.20 mmol) and pyridin-3-ylmethanamine (1.72 mL, 16.88 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with dichloromethane (150 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a white solid in 51% yield (3.00 g): mp 108-110° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.00 (t, J=6.0 Hz, 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.48 (d, J=6.0 Hz, 1H), 7.77-7.73 (m, 1H), 7.40-7.36 (m, 1H), 7.31-7.18 (m, 5H), 4.47 (d, J=6.0 Hz, 2H), 2.76-2.61 (m, 7H), 2.03-1.95 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 160.4, 155.1, 152.6, 148.8, 148.7, 148.2, 141.5, 135.2, 134.5, 128.3, 128.2, 125.7, 123.9, 123.5, 119.7, 40.6, 34.4, 30.1, 24.3, 17.1; MS (ES+) m/z 419.4 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:19]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:18][C@@:17]2([CH3:26])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:27])[CH2:3]1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]([C:38]([N:40]2[CH2:47][CH2:46][CH2:45][C@H:41]2[C:42](O)=[O:43])=[O:39])[N:29]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:1][C@@H:2]1[C@@H:19]([N:20]2[CH2:21][CH2:22][N:23]([C:42]([C@@H:41]3[CH2:45][CH2:46][CH2:47][N:40]3[C:38]([C:30]3[N:29]=[CH:28][C:37]4[C:32]([CH:31]=3)=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:39])=[O:43])[CH2:24][CH2:25]2)[CH2:18][C@@:17]2([CH3:26])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:27])[CH2:3]1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)c1cc2ccccc2cn1
Reactant: C[C@]12C[C@H](N3CCNCC3)[C@@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@]12C[C@H](N3CCN(C(=O)[C@@H]4CCCN4C(=O)c4cc5ccccc5cn4)CC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 8 h

Procedure:
To a solution of compound 23 (356 mg, 0.95 mmol) in anhydrous DMF (5 mL) at room temperature under an atmosphere of argon were added 1-(isoquinolin-3-ylcarbonyl)-L-proline (335 mg, 1.2 mmol), PyBOP (647 mg, 1.2 mmol), HOBt (168 mg, 1.2 mmol), and DIPEA (662 μL, 3.8 mmol). The solution was subsequently stirred overnight at room temperature. The resulting solution was then poured into water and extracted with EtOAc (2×30 mL), washed with brine, dried with MgSO4 and evaporated to dryness. Purification by two successive flash chromatography procedures using (DCM/MeOH: 95:5) and (Hexanes/Acetone: 1:1) respectively yielded 302 mg (50%) of compound 43. 1H NMR (CDCl3) δ: 0.84 and 0.86 (2s, 18-CH3), 0.89 and 0.90 (2s, 19-CH3), 0.70-2.30 (residual CH and CH2), 2.35-2.85 (broad m, 2×CH2N, 16β-CH and 2α-CH), 3.10-4.27 (broad m, 2×CH2NCO, CH2N of proline, and 3β-CH), 5.10 and 5.88 (2m, NCHCO of proline), 7.58 (m, CH of quinoline), 7.76 (m, CH of quinoline), 7.84 (t, J=8.3 Hz, CH of quinoline), 7.98 (t, J=8.7 Hz, CH of quinoline), 8.02 and 8.12 (2d, J=8.6 Hz, CH of quinoline), 8.21 and 8.24 (2d, J=8.9 Hz, CH of quinoline).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@H:20]([NH:26][C:27]([C:29]1[N:30]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[O:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:70](O)(=[O:79])[CH:71]=[CH:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1.C(N1CCOCC1)C>C(OCC)(=O)C.O.CN(C)C=O>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@H:20]([NH:26][C:27]([C:29]1[N:30]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:70](=[O:79])[CH:71]=[CH:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:19]
Reactant: O=C(O)C=Cc1ccccc1
Reactant: COC(=O)Cn1c(C(=O)N[C@H](CCCCN)C(=O)NCCCCCc2c(OC)cc(C)cc2OC)cc2ccccc21
Agent: CCN1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1c(C(=O)N[C@H](CCCCNC(=O)C=Cc2ccccc2)C(=O)NCCCCCc2c(OC)cc(C)cc2OC)cc2ccccc21
Temperature: -5 °C
Reaction time: 18 h

Procedure:
0.87 g of methyl (R)-{2-[N-{1-[(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl]-5-aminopentyl}carbamoyl]indol-1-yl}acetate, 0.645 g of BOP and 0.23 g of cinnamic acid are successively added to 30 ml of dimethylformamide. After cooling to -5° C., 0.26 g of N-ethylmorpholine is added under an inert atmosphere and the reaction mixture is maintained at 0° C. for 2 hours and is then left at room temperature for 18 hours. The reaction mixture is poured into a large volume of water and extraction is carried out with ethyl acetate. The organic extracts are dried over anhydrous sodium sulphate and evaporated to dryness. The residual oil is purified by flash chromatography on silica gel, eluent: CH2Cl2 /CH3OH 97/3 (v/v) in order to obtain methyl (R)-{2-[N-{1-[(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl]-5-(cinnamoylamino)pentyl}carbamoyl]indol-1-yl}acetate in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.[OH:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17](=[O:23])[C:18](=[O:22])[NH:19]2)=[C:15]([NH:24][C:25](=[O:27])[CH3:26])[CH:14]=1.[CH:28]1[C:33]([NH:34][NH2:35])=[CH:32][CH:31]=[C:30]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:29]=1.Cl>>[OH:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17](=[O:23])[C:18](=[O:22])[NH:19]2)=[C:15]([NH:24][C:25](=[O:27])[CH3:26])[CH:14]=1.[CH3:9][C:7]1[O:8][C:4]2[C:5](=[CH:10][C:11]3[C:14](=[N:35][NH:34][C:33]4[CH:28]=[CH:29][C:30]([S:36]([NH2:39])(=[O:37])=[O:38])=[CH:31][CH:32]=4)[C:13](=[O:12])[NH:1][C:2]=3[CH:3]=2)[N:6]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nc2ccc(N)cc2o1
Agent: CC(=O)Nc1cc(O)cc2c1C(=O)C(=O)N2
Agent: Cl
Product: Cc1nc2cc3c(cc2o1)NC(=O)C3=NNc1ccc(S(N)(=O)=O)cc1

Procedure:
N-(6-Hydroxy-2,3-dioxo-2,3-dihydro-1H-indol-4-yl)acetamide was prepared from 6-amino-2-methylbenzoxazole (Heleyova, et al., Collection of Czechoslovakian Chemical Communications 1996, 61, 371–80) according to Procedure A in 12% overall yield. Condensation of N-(6-hydroxy-2,3-dioxo-2,3-dihydro-1H-indol-4-yl)acetamide and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 6% yield: 1H NMR (DMSO-d6): δ 2.55 (s, 3H), 7.13 (s, 1H), 7.23 (s, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.78 (s, 1H), 11.12 (s, 1H), 12.67 (s, 1H); APCI-MS m/z 370 (M−H)−. Anal. Calcd for C16H15N5O4S: C, 51.75, H, 3.53; N, 18.86; S, 8.86. Found C, 51.50, H, 3.61; N, 18.69; S, 8.49.