Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:32]=[C:33]1[C:44]2[C:45]3[C:37](=[C:38]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[NH:39][C:40]=3[CH:41]=[C:42]([NH:46][C:47](=[O:53])[CH2:48][CH2:49][C:50](O)=[O:51])[CH:43]=2)[CH:36]=[N:35][NH:34]1>CN(C)C=O>[O:32]=[C:33]1[C:44]2[C:45]3[C:37](=[C:38]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[NH:39][C:40]=3[CH:41]=[C:42]([N:46]3[C:50](=[O:51])[CH2:49][CH2:48][C:47]3=[O:53])[CH:43]=2)[CH:36]=[N:35][NH:34]1
Reactant: O=C(O)CCC(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(N4C(=O)CCC4=O)cc1c23
Temperature: 22 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
Triethylamine (0.18 mmol, 0.025 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.04 mmol, 0.013 g) were added to a solution of the title compound of Example 8 (0.013 g, 0.036 mmol) in N,N-dimethylformamide (0.05 M, 0.75 mL). The reaction mixture was stirred at 22° C. for 12 hours and concentrated under reduced pressure. The yellow solid was triturated with methanol (3.0 mL), collected by filtration, and washed with methanol (4.0 mL) and diethyl ether (5.0 mL) to afford the title compound (5.8 mg) in 47% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[C:13]([N:20]1[CH2:25][CH2:24][N:23]2[CH2:26][C@H:27]([CH2:30]OS(C)(=O)=O)[CH2:28][CH2:29][C@H:22]2[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Cl>CN(C=O)C.O>[C:13]([N:20]1[CH2:25][CH2:24][N:23]2[CH2:26][C@H:27]([CH2:30][N:7]3[C:8]4[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[CH2:28][CH2:29][C@H:22]2[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](COS(C)(=O)=O)CC[C@H]2C1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C[C@H](Cn3ccc4cc(F)ccc43)CC[C@H]2C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 35.9 %

Procedure:
A solution of 8.41 g (62 mmol) of 5-fluoroindole in 250 mL of DMF was treated with 2.46 g (62 mmol) of sodium hydride (60% oil dispersion) and the mixture stirred at 50° C. for 1.5 h. Heating was stopped temporarily, 7.73 g (22.2 mmol) of (7R,9aS)-2-BOC-7-(methanesulfonyloxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 250 mL of DMF was added, and the mixture stirred at 100° C. for 2 h. The mixture was cooled to room temperature, diluted with water, acidified to pH 2 with 6M hydrochloric acid, and washed with ethyl acetate. The aqueous phase was basified to pH 12 with conc. ammonium hydroxide and extracted with ethyl acetate (3×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate gave 3.09 g (36%) of (7R,9aS)-2-BOC-7-(5-fluoroindol-1-yl)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH2:17]O)(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][CH2:17][CH2:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(S(=O)(=O)CCO)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCc1ccc(S(=O)(=O)CCCl)cc1
Yield: 109.5 %

Procedure:
A solution of 1.0 ml (14.0 mmol) of thionyl chloride in toluene (15 ml) was added dropwise, while cooling with ice, to a solution of 1.0 g (4.67 mmol) of 2-(4-ethylphenylsulfonyl)-ethanol and 56 μl (0.70 mmol) of pyridine in toluene (20 ml). The mixture was then heated for 3 h under reflux. Quenching with ice and water was then carried out. The phases were separated and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. There were obtained as crude product 1.19 g of slightly impure 1-(2-chloroethylsulfonyl)-4-ethylbenzene, which was reacted further without additional purification.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:14]([S:15][CH3:16])=[N:13][NH:12][C:11]=2[NH2:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:19][CH2:20][C:21](=O)[CH2:22][C:23]([O:25][CH2:26]C)=O>C(O)(=O)C>[C:1]1([S:7]([C:10]2[C:14]([S:15][CH3:16])=[N:13][N:12]3[C:20]([OH:19])=[CH:21][C:22]([CH2:23][O:25][CH3:26])=[N:17][C:11]=23)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1n[nH]c(N)c1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)COC
Solvent: CC(=O)O
Product: COCc1cc(O)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Yield: 84.8 %

Procedure:
A solution of 2.69 g (10 mmol) 4-benzenesulphonyl-5-methylsulphanyl-2H-pyrazol-3-ylamine and 1.46 g (10 mmol) of ethyl 4-methoxy-acetoacetate in 10 ml of acetic acid was heated at reflux for 3 hrs. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was extracted three times with 80 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 25:1) yielded 3.1 g (85%) of 3-benzenesulphonyl-5-methoxymethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol as a beige powder, m.p. 175-155°.
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16]C)=[O:15])[CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:15]=[C:14]1[CH:4]2[CH2:3][CH:2]([CH2:6][N:5]2[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[O:16]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC1C(=O)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (170.0 g, 0.736 mol) and PPh3 (237.0 g, 0.88 mol) in dry THF (1.5 L) was added dropwise DIAD (178.35 g, 0.88 mol) at 0° C. under N2 gas. After addition, the resulting reaction mixture was stirred at room temperature overnight. TLC (petroleum ether/EtOAc 3:1) indicated the complete consumption of compound 1A. The solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 6:1) which gave the title compound IVa as a white solid (110.0 g, yield: 72.0%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][N:22]=3)[CH:17]=[C:16]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:39]I>C1COCC1>[CH3:39][N:7]([CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][N:22]=3)[CH:17]=[C:16]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:15]=2)[CH2:10]1)[C:6](=[O:36])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C[C@@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under N2, to a solution of (S)-tert-butyl(1-(7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)methylcarbamate (150 mg, 0.31 mmol) in anhydrous THF (10 mL) was slowly added sodium hydride (49 mg, 1.22 mmol) at 0° C. The mixture was warmed up and stirred at room temperature for 0.5 h. The reaction mixture was then cooled to 0° C., and CH3I (174 mg, 1.22 mmol) was added slowly. After the completion of the addition, the reaction mixture was stirred at reflux for 4 hours, cooled to ambient temperature, quenched with H2O, and extracted with EtOAc. The combined extracts were dried and concentrated to give the title compound. MS (m/z): 505 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Fc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1F

Procedure:
The starting compound 2-fluoro-4-(4-fluorobenzyloxy)nitrobenzene (m.p.: 99° C.) was prepared by alkylation of 3-fluoro-4-nitrophenol with 4-fluorobenzyl chloride in DMF in the presence of potassium carbonate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH:16]1[CH:21]=[C:20]2[C:22]([N-:24][S:25](=[O:27])(=[O:26])[C:19]2=[CH:18][CH:17]=1)=[O:23].[Na+]>CN(C)C=O>[C:9]([C:8]1[CH:14]=[CH:15][C:5]([C:3]([CH2:2][N:24]2[C:22](=[O:23])[C:20]3[C:19](=[CH:18][CH:17]=[CH:16][CH:21]=3)[S:25]2(=[O:27])=[O:26])=[O:4])=[CH:6][CH:7]=1)([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C1[N-]S(=O)(=O)c2ccccc21
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(=O)CN2C(=O)c3ccccc3S2(=O)=O)cc1

Procedure:
45 mmol of ethyl 4-bromoacetylbenzoate in 120 ml of dimethylformamide and 48 mmol of sodium saccharinate are maintained at 100° C. for 180 minutes. After evaporation of the solvent, taking up in 200 ml of water, extraction with dichloromethane, drying and evaporation, the residue is taken up in isopropyl ether, then filtered and taken to the expected product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]2=O>C(O)(=O)C.[Pd]>[CH2:15]([O:14][C:12]([CH:7]1[CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:9]=2[O:8]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1cc(=O)c2cc(O)ccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2cc(O)ccc2O1
Reaction time: 17 h
Yield: 59 %

Procedure:
A solution of 8.75 g of ethyl 6-hydroxychromone-2-carboxylate in 200 ml of acetic acid was hydrogenated in the presence of 2 g of 10% palladium on charcoal at 50 psi and room temperature by shaking the suspension over a period of 17 hours. The catalyst was filtered and the filtrate was evaporated under reduced pressure to give 7.85 g of crude material. Purification of this compound by high-performance liquid chromatography (solvent system, hexane-ethyl acetate 3:1) yielded 4.9 g (59%) of pure crystalline racemic-3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester. Recrystallization from ethyl-acetate-hexane gave colorless solid, mp 72°-74° C.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[C:26]([C:31]([O:33]C)=[O:32])[CH:25]=[CH:24]5)=[CH:17][CH:16]=3)=[C:11]([CH:35]([CH3:37])[CH3:36])[O:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+]>C1COCC1>[CH:1]1([O:6][CH2:7][C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[C:26]([C:31]([OH:33])=[O:32])[CH:25]=[CH:24]5)=[CH:19][CH:20]=3)=[C:11]([CH:35]([CH3:37])[CH3:36])[O:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(COC5CCCC5)noc4C(C)C)cc3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(COC2CCCC2)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 100 °C
Yield: 102.8 %

Procedure:
A solution of methyl 6-[4-({[3-[(cyclopentyloxy)methyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (11 mg, 0.02 mmol) in THF (0.22 mL) was placed in a microwave reaction tube. Methanol (0.11 mL) was added followed by 1 N sodium hydroxide (0.05 mL, 0.05 mmol). The tube was sealed and heated to 100° C. for 800 seconds. The solution was concentrated then neutralized with 1 N HCl. Water was added and the mixture was filtered to yield a bright yellow solid. The sample was dried in a vacuum oven under reduced pressure at 45° C. with P2O5. The sample was removed from the oven to yield 6-[4-({[3-[(cyclopentyloxy)methyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (10 mg, 95%). 1H NMR (400 MHz, DMSO-d6): δ 8.37 (d, J=9 Hz, 1H), 8.20-8.17 (m, 2H), 8.08-8.03 (m, 2H), 7.80 (d, J=9 Hz, 2H), 7.14 (d, J=9 Hz, 2H), 5.01 (s, 2H), 4.49 (s, 2H), 3.95-3.93 (m, 1H), 3.40-3.20 (br s, 1H overlapped by water), 1.60-1.37 (m, 8H), 1.24 (d, J=7 Hz, 6H). HRMS C29H30N2O5 m/z 487.2228, (M+H)+Cal; 487.2227 (M+H)+Obs.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:15][NH:10][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:9]
Reactant: COc1ccc(C=O)cc1Br
Reactant: C[C@@H](N)c1cccc(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CN[C@H](C)c2cccc(F)c2)cc1Br
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
(R)-1-(3-Fluorophenyl)ethanamine 115 (1.24 g, 8.92 mmol) and 3-bromo-4-methoxybenzaldehyde 114 (1.92 g, 8.92 mmol) were mixed in 100 mL anhydrous methanol in a round bottom flask. After the mixture was stirred at 20° C. for 10 min, the flask was cooled in an ice-water bath. To this flask was added sodium cyanoborohydride (0.56 g, 8.92 mmol) followed by acetic acid (0.54 g, 8.92 mmol). The resulting mixture was stirred for 12 h and allowed to warm to 20° C. After removing most of the methanol, the remaining residue was dissolved in 200 mL ethyl ether and washed with saturated sodium bicarbonate, 3 times. The organic phase was dried over sodium sulfate. After removing the solvent under reduced pressure, the remaining residue was subjected to a silica gel column using 50% ethylacetate in hexane as the eluant to yield a colorless oil as the pure product (R)—N-(3-bromo-4-methoxybenzyl)-1-(3-fluorophenyl)ethanamine 116 (2.3 g, yield=93%). LCMS (M+1) 338, calc. for C16H17BrFNO 338; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (d, J=6.26 Hz, 3H) 3.46-3.60 (m, 2H) 3.78 (q, J=6.39 Hz, 1H) 6.84 (d, J=8.22 Hz, 1H) 6.90-6.98 (m, 1H) 7.09 (t, J=9.00 Hz, 2H) 7.16 (dd, J=8.41, 2.15 Hz, 1H) 7.27-7.34 (m, 1H) 7.48 (d, J=1.96 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.[CH3:20][S-:21].[Na+]>CO>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[O:10][C:11]3[C:3]([CH2:2][S:21][CH3:20])=[CH:4][C:5]([OH:19])=[CH:6][C:7]=3[CH:8]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution of benzyl bromide 4 (0.052 g, 0.161 mmole) in 5 mL methanol was added sodium thiomethoxide (0.013 g, 0.177 mmole). After stirring at R.T. for 1 hour, the solvent was evaporated and the residue was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 4:1) to afford 0.025 g (54%) of thioether 10 as a white solid: Mp=188-190° C.; 1H NMR (DMSO-d6) δ 9.82 (s, 1 H), 9.14 (s, 1 H), 7.69 (d, 2 H, J=8.5 Hz), 7.01 (s, 1 H), 6.86 (d, 2 H, J=8.5 Hz), 6.77 (d, 1H, J=2.1 Hz), 6.63 (d, 1 H, J=2.1 Hz), 3.91 (s, 2 H), 2.05 (s, 3 H); MS 285 (M−H)−
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[S:16])[N:6]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7]=1[NH2:8].[CH:18](OCC)(OCC)OCC>CCCCCCC>[CH:10]1([CH2:9][N:6]2[C:7]3[N:8]=[CH:18][NH:1][C:2]=3[C:3](=[O:17])[NH:4][C:5]2=[S:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(N)n(CC2CCCCC2)c(=S)[nH]c1=O
Solvent: CCCCCCC
Product: O=c1[nH]c(=S)n(CC2CCCCC2)c2nc[nH]c12
Temperature: 25 °C
Yield: 63 %

Procedure:
5,6-Diamino-1-cyclohexylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one, (1.44 g, 5.67 mmol) together with triethyl orthoformate (15 mL) was heated at 146° C. for 2 h and 10 minutes. The mixture was allowed to cool to ambient temperature and then further cooled on an ice-bath, followed by addition of heptane (5 mL). After filtration of the suspension and washing with heptane (20 mL), the obtained solid was dried in vacuo. Suspending the solid (1.2 g) in a hot mixture of 2-propanol (125 mL), water (5 mL) and tert-butyl methyl ether (25 mL) gave, after cooling and filtration, a white precipitate which was washed with further tert-butyl methyl ether (5 mL). The solid was dried in vacuo to give the title compound (0.95 g, 63%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:39])=[C:30]([S:32]([NH:35][CH:36]2[CH2:38][CH2:37]2)(=[O:34])=[O:33])[CH:31]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:39][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:21]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=2)=[O:22])=[CH:31][C:30]=1[S:32](=[O:34])(=[O:33])[NH:35][CH:36]1[CH2:37][CH2:38]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Reactant: NCc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(Cl)c(S(=O)(=O)NC4CC4)c3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (60 mg, 0.19 mmol) in N,N-dimethylformamide (1.0 mL) were added 5-(aminomethyl)-2-chloro-N-cyclopropylbenzenesulfonamide (80 mg, 0.31 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150 mg, 0.39 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol). The reaction mixture was stirred for 16 hours at 50° C. The reaction mixture was purified by preparative HPLC to afford a light colour solid.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[C:41]([O:45][C:46]([N:48]([C:61]1[CH:66]=[C:65]([N:67]([CH3:90])[C:68]([N:70]([C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[C:71]2[C:76]([Cl:77])=[C:75]([O:78][CH3:79])[CH:74]=[C:73]([O:80][CH3:81])[C:72]=2[Cl:82])=[O:69])[N:64]=[CH:63][N:62]=1)[C:49]1[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][C:50]=1[N+:58]([O-:60])=[O:59])=[O:47])([CH3:44])([CH3:43])[CH3:42]>CN(C=O)C.O.CO.C(Cl)Cl>[N+:58]([C:50]1[CH:51]=[C:52]([C:53]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[O:54])[CH:56]=[CH:57][C:49]=1[N:48]([C:61]1[CH:66]=[C:65]([N:67]([CH3:90])[C:68]([N:70]([C:71]2[C:76]([Cl:77])=[C:75]([O:78][CH3:79])[CH:74]=[C:73]([O:80][CH3:81])[C:72]=2[Cl:82])[C:83]([O:85][C:86]([CH3:87])([CH3:88])[CH3:89])=[O:84])=[O:69])[N:64]=[CH:63][N:62]=1)[C:46](=[O:47])[O:45][C:41]([CH3:44])([CH3:42])[CH3:43])([O-:60])=[O:59]
Reactant: CN1CCNCC1
Reactant: COc1cc(OC)c(Cl)c(N(C(=O)OC(C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(C(=O)O)cc3[N+](=O)[O-])ncn2)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(N(C(=O)OC(C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(C(=O)N4CCN(C)CC4)cc3[N+](=O)[O-])ncn2)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
DIPEA (0.3 mL, 1.62 mmol), HATU (0.515 g, 1.355 mmol) and N-methyl piperazine, 6 (0.09 mL, 0.813 mmol) were added to a solution of 4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrobenzoic acid (0.4 g, 0.542 mmol) in DMF (5 mL) at 0° C. under argon atmosphere. The resulting reaction mixture was then allowed to warm to rt and stirred for 18 h. After completion of the reaction by TLC (MeOH:DCM 1:19), water was added to the reaction mixture. The precipitated crude solid was filtered, dried and purified by silica gel column chromatography to obtain the title compound (0.27 g, yield: 61%) as a solid. MS (ESI): 819.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:28][C@H:29]([C:36]([NH:38][C@H:39]([CH2:44][OH:45])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([NH:28][C@H:29]([C:36]([NH:38][C@H:39]([CH2:44][OH:45])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:37])[CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Reactant: CC(C)C[C@@H](CO)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of 121 mg of (±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid and 200 mg of L-histidyl-L-leucinol.2p-toluenesulfonic acid salt in 5 ml of N,N-dimethylformamide were successively added 0.09 ml of diphenylphosphoryl azide and 0.15 ml of triethylamine while ice-cooling, and the mixture was stirred overnight. To the reaction mixture was added a 5% aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 44 mg of N-[2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl-L-leucinol (isomer A) and 75 mg of isomer B as a white powder, respectively.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=[O:2].[Cl:11][C:12]1[CH:13]=[N+:14]([O-:32])[CH:15]=[C:16]([Cl:31])[C:17]=1[CH2:18][C@@H:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)O.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:31][C:16]1[CH:15]=[N+:14]([O-:32])[CH:13]=[C:12]([Cl:11])[C:17]=1[CH2:18][C@H:19]([O:9][C:8]([C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)=[O:10])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: COc1ccc([C@@H](O)Cc2c(Cl)c[n+]([O-])cc2Cl)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
A stirred solution of 5-formyl-2-thiophenecarboxylic acid (400 mg, 2.56 mmol) in dichloromethane (20 mL) was added with (1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethanol I-1/A (881 mg, 2.56 mmol) followed by 4-(dimethylamino)-pyridine (156 mg, 1.28 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (983 mg, 5.12 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, passed through a hydrophobic fit and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography, eluting with 0-100% EtOAc in DCM, to afford the title compound (488 mg, 39%) as yellow oil.