Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:25]1([CH3:34])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>C1(C)C=CC=CC=1.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>[CH3:11][NH:10][C:8](=[O:9])[C:7]1[C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH3:34])=[CH:3][C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:5][CH:6]=1
Reactant: CNC(=O)c1cnc(N2CCN(C)CC2)cc1I
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
A suspension of 4.00 g (11.1 mmol) 4-iodo-N-methyl-6-(4-methyl-piperzin-1-yl)-nicotinamide and 642 mg (0.555 mmol) tetrakis(triphenylphosphine)palladium(0) in 60 ml toluene was dioxygenated with a stream of argon for 30 min. After addition of 11 ml of a 2 N aqueous solution of sodium carbonate and 1.66 g (12.2 mmol) o-tolylboronic acid, the mixture was heated at reflux overnight. Cooling to room temperature was followed by dilution with water and extraction with three 50 ml portions of ethyl acetate. The aqueous layer was saturated with sodium chloride and extracted with three 50 ml portions of dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated. Column chromatography afforded 2.26 g (63%) of the tide compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=O.[CH:12]([NH2:14])=O>O>[CH3:7][C:6]1[C:2]2[N:1]=[CH:12][NH:14][C:8](=[O:10])[C:3]=2[S:4][CH:5]=1
Reactant: NC=O
Reactant: COC(=O)c1scc(C)c1N
Solvent: O
Product: Cc1csc2c(=O)[nH]cnc12
Temperature: 200 °C
Reaction time: 3 h

Procedure:
Methyl 3-amino-4-methylthiophene-2-carboxylate (3.0 g) was added to formamide (5 mL), and the mixture was stirred at 200° C. for 3 hours. After cooling to room temperature water (50 mL) was added thereto and then stirred for 15 hours at room temperature to obtain a solid. The solid was filtered, washed with water and dried with N2 gas to obtain the title compound as a white solid without further purification.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([NH2:13])=[C:11]([F:17])[CH:10]=1.O.Cl>N1C=CC=CC=1>[Br:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([NH:13][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[C:11]([F:17])[CH:10]=1
Reactant: Cc1cc(Br)cc(F)c1N
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(F)c1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
Pivaloyl chloride (4 mL, 38.4 mmol) was added slowly (caution—exothermic reaction) to an ice cold solution of the crude 4-bromo-2-fluoro-6-methylaniline from step 4 (about 32 mmol) in pyridine (20 mL). After the addition, the ice bath was removed and the warm reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a water solution of 1 N HCl and extracted with EtOAc. The organic layer was washed with 1N HCl three times, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on a Biotage 40M KP-Sil column, eluting with 9:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to provide N-(4-bromo-2-fluoro-6-methylphenyl)-2,2-dimethylpropanamide (4.3 g, 49% for 3 steps) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) in N,N-dimethylformamide (1.3 mL) was added cesium carbonate (615 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added ethyl bromoacetate (326 mg), and the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (210 mg) as white powder crystals.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[CH2:11]([O:13][CH2:14][CH2:15]Br)[CH3:12]>C(O)C>[CH2:11]([O:13][CH2:14][CH2:15][N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:1][CH3:2])[CH3:12]
Reactant: CCOCCBr
Reactant: CCNCc1ccccc1
Solvent: CCO
Product: CCOCCN(CC)Cc1ccccc1
Yield: 61 %

Procedure:
The synthesis of FEA was carried out in a manner similar to that of BnEO (process 2) using N-ethylbenzylamine (15 mL, 0.101 mol), bromoethyl ethyl ether (17 mL, 0.101×1.5 mol), and ethanol (100 mL) as a solvent. BnEE (12.79 g, 61.69 mmol, yield 61%) was obtained as a pale yellow clear liquid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:15]([O:13][C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
In a round-bottomed flask were placed N-BocSerine (20.0 g, 89.605 mmol, 1 eq.), benzyl bromide (10.76 ml, 90.50 mmol, 1.01 eq.) and cesium carbonate (56.64 g, 173.84 mmol, 1.94 eq.) in DMF (180 mL). The suspension was stirred under nitrogen at room temperature for 2 hrs to overnight. The mixture was partitioned between water and ethyl acetate (1:1, 1000 ml) and aqueous layer was re-extracted with ethyl acetate(2×200 mL). The combined organic layers were washed with water (2×500 mL), saturated sodium chloride, and dried over sodium sulfate. The solvents were removed in vacuo and the crude material purified on silica gel to get N-Boc-serine benzyl ester.
Reaction SMILES: C(Cl)Cl.[S:4]([NH:14][C@H:15]([C:22]([OH:24])=O)[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([C:7]1[CH:13]=[CH:12][C:10]([CH3:11])=[CH:9][CH:8]=1)(=[O:6])=[O:5].Cl.[CH2:26]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(N(CC)CC)C>[CH2:26]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:22](=[O:24])[C@H:15]([CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)[NH:14][S:4]([C:7]1[CH:8]=[CH:9][C:10]([CH3:11])=[CH:12][CH:13]=1)(=[O:5])=[O:6])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 ml of desiccated methylene chloride were added 10 g of Nα -t-butyloxycarbonyl-Nim -tosyl-L-histidine (47) and 6.50 g of L-proline benzyl ester hydrochloride and the mixture was cooled in an ice bath. After adding thereto 2.72 g of triethylamine, 6.05 g of DCC was further added to the mixture and the resultant mixture was stirred for 30 minutes in an ice-bath and stirred overnight at room temperature. Insoluble matters were filtered off and the filtrate was concentrated. The residue thus formed was purified by silica gel column chromatography. By eluting the product with ethyl acetate-benzene (1:1), 13.5 g of Nα -t-butyloxycarbonyl-Nim -tosyl-L-histidyl-L-proline benzyl ester (49) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:19]C1C=CC2C(=O)C=C(C3C=CC=CC=3)OC=2C=1>>[NH2:19][C:11]1[CH:10]=[CH:9][C:6]2[C:7](=[O:8])[C:2]([Br:1])=[C:3]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:4][C:5]=2[CH:12]=1
Reactant: O=c1c(Br)c(-c2ccccc2)oc2ccccc12
Reactant: Nc1ccc2c(=O)cc(-c3ccccc3)oc2c1
Product: Nc1ccc2c(=O)c(Br)c(-c3ccccc3)oc2c1
Yield: 80 %

Procedure:
Following the procedure for 3-bromo-2-phenyl-1-benzopyran-4-one, 7-amino-2-phenyl-1-benzopyran-4-one (1.08 g, 4.55 mmol) was reacted to give the title compound as a yellow solid (1.15 g, 80%). 1H-NMR (400 MHz, CDCl3) δ 7.97-8.02 (m, 3H), 7.53-7.56 (m, 3H), 6.79-6.82 (m, 2H), 4.77 (bs, 2H).
Reaction SMILES: OS(O)(=O)=O.[C:6]([C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:8])[CH3:7].[N+:17]([O-])([O-:19])=[O:18].[K+].BrC1N=CC=CC=1C(N)=O>O>[C:6]([C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)c1ccccc1N
Agent: NC(=O)c1cccnc1Br
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Temperature: -10 °C

Procedure:
To H2SO4 (98%, 389 mL) in a 500 mL 3-neck flask was added 2-tert-butyl aniline (40.6 mL). The reaction was cooled to −10° C. and KNO3 in 3.89 g aliquots was added every 6 min for a total of 10 aliquots. Tried to maintain temperature at −5° C. to −10° C. After final addition of KNO3, stirred the reaction for five min then it was poured onto ice (50 g). The black mix was diluted with H2O and extracted with EtOAc. The aqueous layer was basified with solid NaOH slowly then extracted with EtOAc (2×). The combined organic layers were washed with 6N NaOH and then with a mix of 6N NaOH and brine, dried over Na2SO4, filtered and concentrated in vacuo to obtain crude 2-tert-butyl-5-nitro-aniline as a dark red-black oil which solidified when standing at RT. The crude material was triturated with about 130 mL hexanes. After decanting the hexanes, the material was dried to obtain a dark-red black solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][C:26](=[O:31])[C:27]([O:29]C)=O)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.[NH3:32].CO>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][C:26]([C:27]([NH2:32])=[O:29])=[O:31])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N
Reactant: COC(=O)C(=O)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: CO
Product: NC(=O)C(=O)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 17 h
Yield: 93 %

Procedure:
A suspension of methyl N-[2-(3,4-dibenzyloxyphenyl)ethyl]oxamate (5.0 g, 11.9 mmol) in methanol (100 mL) contained in a Fischer-Porter pressure vessel under argon was cooled to -78° C. Ammonia (ca. 60 mL) was condensed into the vessel, the vessel was sealed and allowed to come to room temperature. The suspension was allowed to stir at room temperature under a pressure of approximately 60 psi for 17 h. The mixture was cooled to -78° C., the vessel was opened and the vigorously stirred suspension was allowed to come to room temperature under a stream of argon. After 1.5 h, the solvent was removed in vacuo and the solid was triturated with 20% methylene chloride/ether to provide a white solid (4.5 g, 93%): m.p. 187° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:24][C:25]([NH:27][C@@H:28]([CH3:32])[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH:11][C:29](=[O:30])[C@@H:28]([NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH3:32])[C:5]=1[NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1c(F)ccc(N)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1c(F)ccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-6-fluoro-2-phenylaminobenzoic acid methyl ester (2.0 g, 7.7 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.6 g, 8.45 mmol), HOAt (760 mg, 8.45 mmol), 4-methylmorpholine (1.86 mL, 16.9 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.07 g, 8.45 mmol) in DCM (20 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford 3-((S)-2-tertbutoxycarbonylaminopropionylamino)-6-fluoro-2-phenylaminobenzoic acid methyl ester. LCMS (Method B): RT 3.65 min [M+H]+ 432.3.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29]>O>[Br:1][C:2]1[N:10]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: CC(C)=CCBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reaction time: 3 h

Procedure:
50 g of 8-bromo-3-methyl-3,7-dihydropurine-2,6-dione are introduced into 900 ml of DMF, and 14.1 g of potassium carbonate are added. The suspension is heated to an internal temperature of 60° C., and 31.7 g of 1-bromo-3-methyl-2-butene are slowly added. The mixture is stirred at this temperature for 3 hours and then 1.2 l of water are added. The solid is filtered off with suction, thoroughly washed with water and dried in vacuo at 45° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1>NC(C)(C)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=1
Reactant: CC(C)(C)Nc1nc(Cl)cc(Cl)n1
Solvent: CC(C)(C)N
Product: CC(C)(C)Nc1cc(Cl)nc(NC(C)(C)C)n1
Temperature: 130 °C

Procedure:
A solution containing 5.0 g of 4,6-dichloro-2-(1,1-dimethylethylamino)pyrimidine in 25 ml of 1-amino-1,1-dimethylethane is heated in a closed tube at 130° C. for 15 hours. Thereafter, the reaction mixture is evaporated and the evaporation residue is distributed between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. The evaporation residue is recrystallized from hexane to give the title compound in a yield of 5.45 g (93.4%), m.p.: 128°-130° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[CH:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:45]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:46])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)C1CCCCC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure D using cyclohexanecarbonyl chloride. The final product was obtained in 56% yield.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][CH:13]1[CH2:15][O:14]1)[CH:7]=[CH:6][C:5]=2[CH3:16].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[N:27]1[CH2:34][C@H:33]2[NH:35][CH2:36][C@@H:28]1[CH2:29][CH:30]=[CH:31][CH2:32]2.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][CH:13]([OH:14])[CH2:15][N:35]1[CH2:36][CH:28]3[N:27]([C:18]4[CH:19]=[CH:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:17]=4)[CH2:34][CH:33]1[CH2:32][CH:31]=[CH:30][CH2:29]3)[CH:7]=[CH:6][C:5]=2[CH3:16]
Reactant: Cc1cc2c(OCC3CO3)ccc(C)c2[nH]1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(OCC(O)CN3CC4CC=CCC3CN4c3ccc4ccccc4c3)ccc(C)c2[nH]1

Procedure:
2,7-Dimethyl-4-oxiranylmethoxy-1H-indole (30 mg, 0.138 mmol), Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (40 mg, 0.15 mmol), DIPEA (0.1 mL, 0.55 mmol), ethanol (2 mL) were heated for 900 sec. at 120° C. in a μW reaction tube to yield crude product. The solvent was evaporated under reduced pressure to yield a solid that was purified with flash chromatography gradient [0% Ethyl acetate/heptane to 100% Ethyl acetate] to yield the title compound as a residue.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH2:33][NH:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:52](I)[CH3:53]>CN(C=O)C.CCOC(C)=O>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][C:21]([C:17]2[O:18][C:19]([CH3:20])=[C:15]([CH2:14][CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:41])=[C:7]([CH2:33][N:34]([CH2:52][CH3:53])[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:8]=3)[N:16]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1CNC(=O)OC(C)C
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1CCC(=O)O)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of 3-[4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid methyl ester (200 mg, 0.36 mmol) in DMF (15 mL) was treated with sodium bis(trimethylsilyl)amide (132 mg, 0.719 mmol). Ethyl iodide (112 mg, 0.719 mmol) was added, and the reaction mixture was stirred overnight at room temperature under N2. The mixture was diluted with EtOAc (100 mL) and washed with brine (100 mL), then water (100 mL). The organic layer was dried (MgSO4) and concentrated to the penultimate ester as white solid (179 mg). The material was dissolved in EtOH (20 mL), treated with 5N NaOH (20 mL), and stirred at room temperature overnight. The mixture was acidified with 1N HCl (10 mL) and extracted with EtOAc (50 mL). The organics were dried (MgSO4) and concentrated to give a white solid (201 mg). MS [EI+] m/z 571 (M+H)+. Anal. Calculated for C34H38N2O6: C, 71.6; H, 6.7; N, 4.9. Found: C, 70.8; H, 6.8; N, 5.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33]C1C=C(CCC(O)=O)C=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(CCC(=O)O)c1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1cccc(CCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)c1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(3-methoxy-phenyl)-propionic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.C=O.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:9][CH2:10][CH2:11][N:12]([C:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:22])[CH2:25][C:7]=2[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(SCCNC(=O)OCc2ccccc2)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CCS2
Temperature: 70 °C
Reaction time: 8 h
Yield: 295.6 %

Procedure:
A mixture of compound 2 (7.3 g, 23 mmol), paraformaldehyde (6.9 g 0.23 mol) and p-toluenesulfonic acid (1.45 g, 7.6 mmol) in 250 mL of toluene was stirred at 70° C. overnight. After cooling to r.t., the solid was filtered off. The solution was extracted with sat. sodium carbonate (100 mL), and the organic layer was dried over anhydrous sodium sulfate. The target product (7.4 g) was obtained as a liquid after removal of the solvent in 97% yield.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C@H:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9](=[O:23])[NH:10][C@H:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:33]1[CH2:32][CH2:31][CH:30]([O:29][C:28]2[CH:36]=[CH:37][C:25]([F:24])=[CH:26][CH:27]=2)[CH2:35][CH2:34]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)NC[C@H](CI)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H](CN1CCC(Oc2ccc(F)cc2)CC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of [(R)-1-(tert-butoxycarbonylamino-methyl)-2-iodo-ethyl]-carbamic acid benzyl ester (0.61 g, 1.2 mmol) and 4-(4-fluoro-phenoxy)-piperidine (0.24 g, 1.23 mmol) in dichloromethane (5 ml) is treated with triethylamine (0.335 ml, 2.46 mmol). The reaction mixture is stirred at ambient temperature for 5 days, the solvent evaporated and the residue partitioned between ethylacetate and saturated aqueous NaHCO3. The ethylacetate phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 4:1 hexane/ethylacetate) to afford {(R)-1-(tert-butoxycarbonylamino-methyl)-2-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-ethyl}-carbamic acid benzyl ester [MH]+ 502.2.