Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][C:32]1[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=1)=[O:6])[CH:2]=[CH2:3].[CH3:38][I:39]>CC(C)=O>[I-:39].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2+:32]1[N:36]([CH3:38])[CH:35]=[CH:34][N:33]1[CH3:37])=[O:6])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3nccn3C)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CC(C)=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C[CH2+]3N(C)C=CN3C)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Reaction time: 35 h

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-(1-methylimidazol-2-ylmethyl)-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl ]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.25 g) in acetone (12 ml) was added methyl iodide (1.47 ml ) at room temperature. The mixture was stirred for 35 hours at the same temperature. The reaction mixture was evaporated in vacuo to give allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-(1, 3-dimethyl-2-imidazoliomethyl)-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (1.49 g) as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:33])[CH:23]([NH2:32])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:18]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:17]1=[O:38])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[C:40]([O:44][C:45]([NH:47][C:48]([CH3:53])([CH3:52])[C:49](O)=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:39])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:33])[CH:23]([NH:32][C:49](=[O:50])[C:48]([NH:47][C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])([CH3:53])[CH3:52])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH:18]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:17]1=[O:38])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(N)Cc2ccc(F)cc2)C(CC2CC2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(CC2CC2)C1=O
Reaction time: 3 h

Procedure:
To a solution of 2-{4-[2-amino-3-(4-fluorophenyl)propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methylester, 25, (37 mg, 0.068 mmol) in DMF (1 mL) are added 2-tert-butoxycarbonylamino-2-methyl-propionic acid (202 mg, 0.079 mmol), 1-hydroxybenzotriazole (20 mg, 0.148 mmol), N-methylmorpholine (41 mg, 0.41 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (16 mg, 0.083 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue which is purified over silica gel (CH2Cl2/CH3OH, 13:1) to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](=O)[CH3:13].Cl[C:16](=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl.C[CH2:26][N:27]([CH:31](C)C)[CH:28](C)C.[Cl-].C[NH2+]C>CCOC(C)=O.O.CC#N>[CH2:21]([O:20][C:18]([C:17]1[C:16]([CH2:26][N:27]([CH3:31])[CH3:28])=[N:1][C:2]2[C:3]([C:12]=1[CH3:13])=[CH:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: CCN(C(C)C)C(C)C
Agent: C[NH2+]C
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CN(C)C)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 100 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
A mixture of 1.0 g (5.0 mmol) 1-(2-amino-4-(trifluoromethyl)phenyl)ethanone, 3.4 ml (25.0 mmol) ethyl 3-chloro-3-oxopropanoate and 435 μl (5.0 mmol) conc. hydrochloric acid was heated in a sealed vessel in the MW to 100° C. for 30 min. The mixture was subsequently diluted with EtOAc and water. The organic phase was separated, washed with a 1M aq. NaHCO3 sol., dried over MgSO4 and concentrated in a vacuum. The raw product (1.14 g) obtained after CC (EtOAc/hexane 3:17) of the residue was dissolved in MeCN (6 ml) and 2.7 ml (15.5 mmol) DIPEA and 838 mg (10.3 mmol) dimethylammoniumchlorid were added. The mixture was subsequently stirred at RT for 16 h. After cooling to RT, the mixture was diluted with water and extracted with EtOAc. The organic layer was extracted twice a 2N aq. HCl and water. The combined aqueous layers were basified with Na2CO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum. As residue 776 mg (2.3 mmol, 46%) 2-((dimethylamino)methyl)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:12][C:13]([CH:16]=O)([CH3:15])[CH3:14].[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:18]1([CH:16]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=2)[C:13]([CH3:14])([CH3:15])[CH3:12])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: NC(=O)c1cc(F)cc(F)c1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1cc(F)cc(F)c1)n1nnc2ccccc21

Procedure:
3,5-Difluorobenzamide, pivaldehyde, benzotriazole and p-toluenesulfonic acid were processed as described in Example 53A to provide the desired product.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>CO>[C:2]1([CH2:1][NH:8][CH:14]([C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=2)[C:13]([O:17][CH3:18])=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)C=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(NCc1ccccc1)c1c[nH]c2ccccc12
Reaction time: 69 h
Yield: 86.3 %

Procedure:
To a stirred solution of 6.43 g (0.06 mole) of benzylamine and 5 mL (5.25 g, 0.09 mole) of acetic acid in 50 mL of MeOH was added a solution of 5.28 g (0.06 mole) of methyl glyoxylate in 50 mL of MeOH followed by 5.86 g (0.05 mole) of indole. The resulting solution was allowed to stand for 69 hours. The solvent was evaporated. The residue was treated with 200 mL of H2O. Sodium bicarbonate was added until CO2 evolution ceased. The mixture was extracted with CH2Cl2 (3×100 mL). The combined extracts were washed with 50 mL brine and dried over MgSO4. Evaporation of the solvent left 16.2 g of orange-brown oil which solidified upon standing. The solid was chromatographed on a 700 g column of silica gel. The column was eluted with 7.5% MeOH-CH2Cl2 and 200 mL fractions were collected. The fractions were assayed by silica gel (TLC (1×4") (5% MeOH-CH2Cl2). Fractions 10-14 were combined giving 12.7 g of red oil. The oil was chromatographed on a 700 g column of silica gel. The column was eluted with 40% acetone-Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel TLC (1×4") (40% acetone-Skellysolve B). Fractions 11-14 were combined and crystallized from ether-THF-hexane giving 8.07 g (55%) of the title compound as a pale pink solid, m.p. 91.5°-93° C.
Reaction SMILES: OC[C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[N:4]=1.[CH2:32]([N:34]([CH2:37][CH3:38])[CH2:35]C)[CH3:33].CS(Cl)(=O)=[O:41].N1CCOCC1>C(Cl)Cl>[CH3:15][C@H:10]1[CH2:11][O:12][CH2:13][CH2:14][N:9]1[C:7]1[CH:8]=[C:3]([CH2:35][N:34]2[CH2:37][CH2:38][O:41][CH2:33][CH2:32]2)[N:4]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])=[CH:18][CH:17]=2)[N:6]=1
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: C1COCCN1
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CN2CCOCC2)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-phenyl-urea (90 mg) was dissolved in DCM (5 mL) and triethylamine (0.045 mL) and the solution cooled to 0° C. Methane sulfonyl chloride (0.026 mL) was added and the reaction stirred for 1 h at RT. Morpholine (0.2 mL) was added and the reaction was left at RT for 72 hours before being concentrated in vacuo and purified by prep-HPLC (basic) to give the desired compound (64 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22].O>CN(C)C=O>[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: Sc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)(CCl)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CSc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Sodium hydride powder (0.86 g, 35.8 mmol) was added to a mixture of 4-(4-chlorophenoxy)thiophenol (3.55 g, 15 mmol) in N,N-dimethylformamide (12 mL) at 0° C. The mixture was warmed to room temperature over 5 minutes, stirred for an additional 20 minutes, and solid chloropivalic acid (1.64 g, 12.0 mmol) was added in one portion. This mixture was heated to 80° C. for 18 hours, cooled to room temperature, and water (1 mL) added. The residue was partitioned between methylene chloride (50 mL) and 2N hydrochloric acid (25 mL). The aqueous layer was separated and washed with additional methylene chloride (2×25 mL). The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo. Chromatography over silica gel, and eluting with 5% methanol/methylene chloride, gave slightly impure 3-[4-(4-chlorophenoxy)phenylthio]-2,2-dimethyl propionic acid (4 g, 99%). This material was recrystallized from the minimum amount of diethyl ether/hexanes to afford analytically pure acid as a white solid (3.20 g, 80%). mp 84.4-84.9° C.; IR (KBr) 3433 (br), 1732 cm-1 ; 1HNMR (DMSO-d6) δ 1.19 (s, 6H), 3.14 (s, 2H), 6.97 (d, J=8.7 Hz, 2H), 7.01 (d, J=8.9, 2H), 7.40 (d, J=8.8 Hz, 2H), 12.36 (br s, 1H). EIMS(M+): 378. Anal. Calcd. for C17H17SO3Cl: C, 60.62; H, 5.09. Found: C, 60.31; H, 4.96.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)=[O:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1C=CC=CC=1>[N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:8](=[O:9])[C:2]=12
Reactant: O=C(C1=NCCCCN1)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C1C2=NCCCCN2c2ccccc21

Procedure:
A solution of o-bromophenyl 4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl ketone (0.7 g.) in dry dimethylformamide (5 ml.) was stirred with potassium carbonate (0.35 g.) and cupric oxide (0.030 g.) at 90°C for 2 hr. under nitrogen. The mixture was diluted with benzene (100 ml.), filtered, washed with water (3 × 50 ml.) and dried over magnesium sulphate. After removal of the solvent under reduced pressure the residue was extracted with hot cyclohexane (ca.150 ml). The extracts slowly crystallised to give the 2,3,4,5-tetrahydro-1,3-diazepino[1,2-a]-indol-11-one as reddish-brown needles (0.179 g.) m.p. 137° - 139°C(dec.). An analytical sample was recrystallised from toluene, m.p. 140° - 141°C(dec.)
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([SH:44])=[CH:40][CH:39]=1>CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([S:44][C:41]2[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Sc2cc(F)c(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3nncs3)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 2, 0.200 g, 0.433 mmol) and potassium carbonate (0.180 g, 1.30 mmol) were stirred in N,N-dimethylacetamide (1 mL). A solution of 4-methoxythiophenol (0.0576 g, 0.411 mmol) in N,N-dimethylacetamide (2 mL) was added dropwise to the reaction mixture and stirred at ambient temperature for 1 hour. The reaction was quenched with a 1M aqueous solution of sodium hydroxide whereupon a precipitate formed. The precipitate was collect by filtration to afford the title compound (0.224 g, 89%) and this was used in the next step without purification.
Reaction SMILES: [CH:1]([S:4]([CH2:7][C:8](=[O:13])[C:9]([O:11]C)=O)(=[O:6])=[O:5])([CH3:3])[CH3:2].[S:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)=[CH:15]1.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O.C(O)(=O)C>CCOCC.C1(C)C=CC=CC=1>[CH:1]([S:4]([C:7]1[CH:30]([C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[O:27][CH3:26])[N:23]([C:22]2[CH:24]=[CH:25][C:19]([C:16]3[CH:17]=[CH:18][S:14][CH:15]=3)=[CH:20][CH:21]=2)[C:9](=[O:11])[C:8]=1[OH:13])(=[O:5])=[O:6])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)CS(=O)(=O)C(C)C
Reactant: COc1ccccc1C=O
Reactant: Nc1ccc(-c2ccsc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccccc1C1C(S(=O)(=O)C(C)C)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A mixture of methyl 3-(i-propylsulfonyl)-2-oxopropanoate (0.23 g, 1 mmol), 4-thiophene-3-ylaniline (0.18 g, 1 mmol), 2-methoxybenzaldehyde (0.14, 1 mmol), acetic acid (0.023 mL, 0.4 mmol) and toluene (3 mL) was heated at reflux overnight. After the reaction was completed, the reaction mixture was allowed to cool to room temperature. To the mixture was added ether and precipitated compound was collected by filtration. The resulting aimed compound was washed with ether/n-hexane solution to give 4-(i-propylsulfonyl)-3-hydroxy-1-(4-thiophene-3-ylphenyl)-5-(2-methoxyphenyl)-1,5-dihydropyrrole-2-one (0.37 g, yield: 79%) as pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10](Cl)[O:11][C:7]=2[CH:6]=1)=[O:4].[CH2:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C@H:22]([NH2:26])[C:23]([OH:25])=O)[CH2:17][CH2:16]1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH2:35][CH2:36][NH2:37])=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([NH:26][C@H:22]([C:23](=[O:25])[NH:37][CH2:36][CH2:35][NH:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[CH2:21][CH:18]3[CH2:17][CH2:16][CH2:15][CH2:20][CH2:19]3)[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: NCCNc1ccc(F)cc1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: COC(=O)c1ccc2nc(Cl)oc2c1
Product: COC(=O)c1ccc2nc(N[C@@H](CC3CCCCC3)C(=O)NCCNc3ccc(F)cc3)oc2c1

Procedure:
The title compound was prepared from 2-Chloro-benzooxazole-6-carboxylic acid methyl ester, L-cyclohexylalanine and N1-(4-fluoro-phenyl)-ethane-1,2-diamine.2HCl using the procedure analogous to that described in example 2. HPLC-MS calcd. for C26H31FN4O4 (M+H+)483.23. found 483.5.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.[CH3:47][O:48][CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>O1CCCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:50](=[O:51])[CH2:49][O:48][CH3:47])=[CH:42][CH:41]=2)=[N:17]1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 9 %

Procedure:
The title compound was prepared as described in Example 376, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.302 g, 0.50 mmol) in tetrahydrofuran (4.5 mL) was added methoxyacetyl chloride (0.07 mL, 0.75 mmol) and triethylamine (0.35 mL, 2.52 mmol). The final crude product was purified by preparative HPLC (5–100% acetonitrile to H2O, 30 min.) (0.015 g, 9% yield): 1H NMR (CD3OD) δ 8.75 (d, 1H), 8.40 (s, 1H), 8.10 (dd, 1H), 8.02 (d, 2H), 7.83 (d, 2H), 7.68 (dd, 1H), 4.09 (s, 2H), 3.52 (s, 3H); ES-MS (m/z) 349 [M+1]+.
Reaction SMILES: CS(C)=O.CCN(C(C)C)C(C)C.[CH2:14]([O:21][C:22]([N:24]([CH2:26][CH2:27][OH:28])[CH3:25])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[CH2:14]([O:21][C:22]([N:24]([CH2:26][CH:27]=[O:28])[CH3:25])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCO)C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(CC=O)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
DMSO (71 mL, 1 mol) and DIPEA (87.1 mL, 0.5 mol) were added to a stirred solution of the product of step (a) (20.9 g, 0.1 mol) in dichloromethane (200 mL) at −10° C. The reaction mixture was stirred at −10° C. for 15 min and then sulfur trioxide pyridine complex (79.6 g, 0.5 mol) was added and the resulting mixture was stirred for 1 hour. The reaction mixture was quenched with addition of 1M hydrochloric acid (200 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried (potassium carbonate) and solvent removed under reduced pressure to give the title compound (20.7 g, 100% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[CH2:7][C@H:8]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH2:28]1)=[O:26])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6](=[O:50])[CH2:7][C@H:8]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH2:28]1)=[O:26])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(C#Cc2ccc(O)cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(CCc2ccc(O)cc2)c1
Yield: 45.9 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[(4-hydroxyphenyl)ethynyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (190 mg, 0.28 mmol) in ethyl acetate (8.1 mL) and methanol (1.34 mL) was stirred for 4.45 hours at room temperature under a hydrogen atmosphere in the presence of palladium on charcoal (10%, 19 mg). The suspension was filtrated through celite, which were washed thoroughly with methanol. The solution was concentrated under reduced pressure and purified by preparative HPLC to yield 89 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[2-(4-hydroxyphenyl)ethyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([CH:21]=O)[N:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].C(N(CC)CC)C.N1CCCCC1>C(O)C>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19](/[CH:21]=[C:28]3/[C:27](=[O:29])[NH:26][C:25](=[O:30])[S:24]/3)[N:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cc(C=O)ncn2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCN(c2cc(/C=C3\SC(=O)NC3=O)ncn2)CC1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
An 8 mL round-bottomed vial was charged with tert-butyl((1-(6-formylpyrimidin-4-yl)piperidin-4-yl)methyl)carbamate (77.9 mg, 0.24 mmol, 1 equiv.), ethanol (1 mL), thiazolidine-2,4-dione (28.5 mg, 0.24 mmol, 1 equiv.) and triethylamine (68 μL, 0.48 mmol, 2 equiv.). Piperidine (1.04 mg, 23 μL of a solution of 52 μL in 0.95 mL ethanol, 0.012 mmol, 5% eq.) was added and Argon was bubbled through the solution. The reaction mixture was shaken at 85° C. for 18 h. LC-MS of the crude reaction mixture showed mostly the desired product. The solvent was evaporated. The residue was partitioned between EtOAc (10 mL) and 10% NH4Cl (5 mL). The organic layer was dried over Na2SO4. Evaporation of solvent gave the crude (Z)-tert-butyl((1-(6-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-4-yl)piperidin-4-yl)methyl)carbamate (79.8 mg, 78%). LC-MS: M+1=420.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:21])[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9]2)=[O:4].[CH3:22][CH2:23][O:24]CC.[CH3:27]N(C)C=O>>[OH:24][CH2:23][CH2:22][CH2:1][N:2]([CH3:27])[C:3]([C:5]1[N:6]([CH3:21])[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9]2)=[O:4]
Reactant: CN(C)C=O
Reactant: CCOCC
Reactant: CNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Product: CN(CCCO)C(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Temperature: 100 °C

Procedure:
A suspension of 30.0 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid methylamide in 380 ml. of dimethylformamide is treated under an atmosphere of argon with 16.8 g. of potassium tert. butylate and the mixture is stirred in ice-bath for 15 minutes. At 10°-15° C. there is then added a solution of 44.5 g. of (3-bromopropyl) [tetrahydropyranyl-(2)] ether in 30 ml. of dimethylformamide, the mixture is then stirred at 20°-25° C. for 30 minutes and subsequently heated to 100° C. for 30 minutes. After cooling, the solvent is removed by evaporation under reduced pressure and the residue partitioned between water and methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness. The residual oily tetrahydropyranyl derivative is dissolved in a mixture of 120 ml. of ethanol, 80 ml. of water and 20 ml. of concentrated hydrochloric acid and the solution is boiled at reflux for 3 hours. The mixture is then evaporated to dryness under reduced pressure and the residue dissolved in methylene chloride. The organic solution is washed with a saturated aqueous sodium chloride solution and dried over sodium sulfate. After concentration, the residue is purified by chromatography on 500 g. of silica gel using methylene chloride/ethyl acetate (2:1) for the elution, and there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid(3-hydroxypropyl)methylamide having a melting point of 85°-88° C. which can be used in the next step without further purification. An analytical sample is obtained by recrystallization from methylene chloride/pentane and has a melting point of 92°-94° C.