Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13](=N)OC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]2[O:30][C:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:32][N:31]=2)=[CH:33][CH:34]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=N)CNC(=O)OCc1ccccc1
Reactant: NNC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CO
Product: O=C(NCc1nnc(-c2ccc(OCc3ccccc3)cc2)o1)OCc1ccccc1

Procedure:
A solution of methyl 2-(((benzyloxy)carbonyl)amino)acetimidate (600 mg, 2.7 mmol) and 4-(benzyloxy)benzohydrazide (654 mg, 2.7 mmol) in methanol (45 mL) was heated at 80° C. in a sealed tube for 3 h. The solvent was removed under reduced pressure and the resulting residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield benzyl ((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)carbamate. A solution of benzyl ((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)carbamate (480 mg, 1.12 mmol) in 33% HBr in acetic acid (5 mL) was stirred for 1 h. Diethyl ether was added, and the supernatant was decanted. The process was repeated, and the resulting solid was collected by filtration to yield (5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methanamine. A solution of (5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methanamine (155 mg, 0.43 mmol), 7-(3-fluorophenoxy)-2-hydroxyheptanoic acid (110 mg, 0.43 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (99 mg, 0.52 mmol), DIPEA (0.224 mL, 1.3 mmol) and HOBt (70 mg, 0.52 mmol) in DMF (20 mL) was stirred overnight. The resulting mixture was diluted with NaHCO3 (saturated, aqueous) and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to yield N-((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)-7-(3-fluorophenoxy)-2-hydroxyheptanamide, which was in the next step used without further purification. To a solution of N-((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)-7-(3-fluorophenoxy)-2-hydroxyheptanamide (190 mg, 0.37 mmol) in methylene chloride (5 mL) was added 1,1,1-tris(acetyloxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one (233 mg, 0.55 mmol) and the resulting mixture was stirred overnight, then quenched with excess sodium thiosulfate in saturated aqueous sodium bicarbonate. The mixture was then extracted twice with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 6.60-8.10 (overlapping m, 14H), 5.15 (s, 2H), 4.75-4.85 (m, 2H), 3.85-4.00 (m, 2H), 2.90-3.10 (m, 2H), 1.50-1.90 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:18]Br.CO>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([Br:18])=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Solvent: CO
Product: Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O

Procedure:
halogenating said compound (B) by diluting the reaction mixture with a protic solvent and introducing a bromine/methanol mixture at -20° to +70° C. to give 1-amino-4-bromo-anthraquinone (C),
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19](Cl)=[O:20]>>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19]([O:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:20]
Reactant: OCCn1ccnc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: O=C(OCCn1ccnc1)c1ccc2ccccc2c1
Yield: 81 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 2-(1H-imidazol-1-yl)ethanol was used instead of the triethanolamine, and 2-naphthoyl chloride was used instead of the benzoyl chloride, to give 2-(1H-imidazol-1-yl)ethyl 2-naphthalenecarboxylate in a yield of 81%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([S:20](Cl)(=[O:22])=[O:21])=[CH:5]2.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.O>ClCCl>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([S:20]([C:6]2[N:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)(=[O:22])=[O:21])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (4.41 g) in dichloromethane (75 ml), tert-butyl-1-piperazine carboxylate (2.21 g) and triethylamine (1.65 ml) were added under ice cooling. The resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, water and dichloromethane were added to the reaction mixture. The organic layer so separated was dried over anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (ethyl acetate:n-hexane=1:20), whereby the title compound (3.63 g, 60%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19][N:20]([CH2:22][C:23](Cl)=O)[CH3:21].CN(C=[O:30])C>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH2:23][C:22]([N:20]([CH3:21])[CH3:19])=[O:30])=[CH:4][CH:3]=1
Reactant: CN(C)CC(=O)Cl
Reactant: CN(C)C=O
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CN(C)C(=O)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred solution of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (0.75 g) in 20 ml of DMF at 0° C., were added 128 mg (1.1 eq.) of NaH (60% in oil). The mixture was stirred for 30 min. and then 0.32 ml (1.1 eq.) of dimethylamino-acetyl chloride were added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 598 mg (61%) of 2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamide as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([CH3:9])[N:3]=1.[CH3:10][N:11]([CH2:13][CH2:14][NH2:15])[CH3:12].[OH-].[Na+]>O>[CH3:10][N:11]([CH3:12])[CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ncc(Cl)nc1C
Reactant: CN(C)CCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ncc(NCCN(C)C)nc1C

Procedure:
2-chloro-5,6-dimethylpyrazine (12.8 g., 0.09 mole) is added to unsym-dimethylethylenediamine (26 g., 0.295 mole) containing cuprous chloride (0.25 g.) and the mixture is heated for 48 hours in an oil bath maintained at 135°-140° C. On cooling, 50 ml of water and a single molar excess of 10N sodium hydroxide are added. The mixture is extracted with methylene chloride. The organic extracts are backwashed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under vacuum. The residual oil is dissolved in hexane, filtered and reconcentrated to obtain the product oil (15.8 g., 0.081 mole).
Reaction SMILES: [CH2:1]([S:6][CH2:7][CH2:8][CH2:9]Cl)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:11][C:12]1[N:16]=[C:15]([SH:17])[NH:14][N:13]=1.N1C=CC=CC=1.NC1N=C(SCCSCCSCCCCCC)NN=1>C(#N)C.O>[NH2:11][C:12]1[N:16]=[C:15]([S:17][CH2:9][CH2:8][CH2:7][S:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[NH:14][N:13]=1
Reactant: CCCCCSCCCCl
Reactant: Nc1n[nH]c(S)n1
Agent: CCCCCCSCCSCCSc1nc(N)n[nH]1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: CCCCCSCCCSc1nc(N)n[nH]1

Procedure:
Compound 9 was prepared from a mixture of 3-chloropropyl pentyl sulfide, 3-amino-5-mercapto-1,2,4-triazole and pyridine in acetonitrile, as described previously for Compound 12. The reaction mixture was poured into water and extracted with CH2Cl2. The extracts were washed with water and brine, dried over MgSO4, and concentrated under vacuum to provide Compound 9 in 71% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C1COCC1.O.ClCCl>[OH:15][N:14]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-formylbenzoate, 37-c, (5.0 g, 30.5 mmol) and hydroxylamine hydrochloride (2.5 g, 36.6 mmol) in THF/H2O (VTHF:VH2O=4:1, 50 mL) was added sodium acetate (3.5 g, 42.7 mmol). The reaction mixture was stirred at room temperature overnight and diluted with dichloromethane (400 mL), washed with water, dried with anhydrous Na2SO4, filtrated and concentrated in vacuo to provide compound, 37-d, (4.9 g, 90%).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]1[N:9]([CH3:10])[C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:7][N:6]=1.Cl[CH:18]([C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[O:22][N:21]=1)[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[Cl:31][C:27]1[CH:26]=[C:25]([C:23]2[O:22][N:21]=[C:20]([CH:18]([N:4]([CH3:3])[C:5]3[N:9]([CH3:10])[C:8]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)=[N:7][N:6]=3)[CH3:19])[N:24]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CNc1nnc(-c2cccnc2)n1C
Reactant: CC(Cl)c1noc(-c2cccc(Cl)c2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1noc(-c2cccc(Cl)c2)n1)N(C)c1nnc(-c2cccnc2)n1C
Temperature: 60 °C
Yield: 43.5 %

Procedure:
NaH (14 mg, 0.35 mmol) was added to N,4-dimethyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-amine (33 mg, 0.18 mmol) in DMF (3 mL). After 30 min 3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (80 mg, 0.18 mmol) in DMF (1 mL) was added to the mixture and the reaction was stirred at 60° C. o.n. Brine was added and the mixture was extracted with EA. The organic phase was dried and concentrated. The product was purified by column chromatography (DCM to DCM-MeOH 30:1) to give 31 mg (43%) of the title compound. 1H NMR: 1.71 (d, 3H) 2.97 (s, 3H) 3.67 (s, 3H) 4.88 (q, 1H) 7.46 (m, 2H) 7.56 (d, 1H) 8.00 (d, 1H) 8.10 (d, 2H) 8.71 (bs, 1H) 8.92 (bs, 1H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][NH:11][CH2:12][C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:44]([O:46][CH2:47][CH:48]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][N:11]([CH2:12][C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:44]([O:46][CH2:47][CH:48]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:54]=2[C:55]2[C:60]1=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:45])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](CNC[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)CN(C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
The product from Example 26B (1.28 g, 2.6 mmol) in tetrahydrofuran (11 mL) was treated with triethylamine (0.39 mL, 2.8 mmol) and 9-fluorenylmethyl chloroformate (0.72 g, 2.8 mmol) at ambient temperature. After stirring for 1 hour, the mixture was concentrated and the residue was dissolved in ethyl acetate (10 mL), wash with 10% NaHCO3 (2×10 mL), 10% citric acid (2×10 mL), brine (10 mL), dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with chloroform (1.68 g, 90%). 1H NMR (CDCl3) δ 7.82-6.94 (m, 18H), 4.93 (br s, 1H), 4.66-4.43 (m, 2H), 4.20 (t, 1H), 3.87-3.35 (m, 4H), 3.00-2.20 (m, 7H), 1.38-1.23 (m, 18H); MS (ESI+) m/z 706 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:28])[C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[C:18]([NH:24][CH3:25])=[C:17]([O:26][CH3:27])[CH:16]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]([F:45])([F:44])[CH2:32][N:33]1[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[CH:35]=[C:34]1[CH:42]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:15]2[CH:16]=[C:17]([O:26][CH3:27])[C:18]3[N:24]([CH3:25])[C:42]([C:34]4[N:33]([CH2:32][C:31]([F:45])([F:44])[F:30])[C:37]5=[N:38][CH:39]=[CH:40][CH:41]=[C:36]5[CH:35]=4)=[N:21][C:19]=3[CH:20]=2)=[O:28])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cc2cccnc2n1CC(F)(F)F
Reactant: CNc1c(OC)cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc2nc(-c3cc4cccnc4n3CC(F)(F)F)n(C)c12
Temperature: 100 °C
Yield: 83.9 %

Procedure:
To a solution of (R)-tert-butyl(1-(3-methoxy-4-(methylamino)-5-nitrobenzoyl)piperidin-3-yl)carbamate (3.58 g, 8.76 mmol) and 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (2.61 g, 11.44 mmol) in ethanol (140 ml) was added portionwise a solution of sodium hydrosulfite (3.18 g, 15.53 mmol) in water (70 ml). The mixture was flushed with nitrogen then heated at 100° C. overnight (16 hours). The reaction mixture was concentrated under vacuum then diluted with DCM (150 ml) and water (150 ml). The organic layer was collected and the aqueous layer washed with DCM (3×100 ml). Organic layers were collected, dried with Na2SO4, filtered through a hydrophobic frit and concentrated under vacuum to yield 5.5 g of crude product as white solid. This was dissolved in a minimum volume of DCM and purified using Biotage SP4 on a 100 g SNAP silica cartridge. The column was eluted with a gradient of 70-100% ethyl acetate in DCM for 10CV. Appropriate fractions were collected and concentrated under vacuum to yield the title compound as a white solid (4.31 g).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Product: CCOP(=O)(Cc1ccc(F)c(Oc2ccccc2)c1)OCC
Temperature: 140 °C
Reaction time: 7 h

Procedure:
To 6.4 g of 3-phenoxy-4-fluorobenzyl bromide was added 7 ml of triethylphosphite, and the mixture was stirred at 140° C. for seven hours. After cooling, 13.1 g of the reaction mixture was purified by column chromatography on silica gel (eluent: benzene) to give 6.3 g of diethyl 3-phenoxy-4-fluorobenzylphosphonate.
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[F:44][C:45]1[C:53]([N:54]2[CH2:58][CH2:57][CH2:56][C:55]2=[O:59])=[CH:52][C:51]([C:60]([F:63])([F:62])[F:61])=[CH:50][C:46]=1[C:47]([OH:49])=O.[CH:64]12[CH2:70][CH:67]([CH2:68][CH2:69]1)[CH2:66][CH:65]2[NH:71][C:72](=[O:87])[C@H:73]([CH3:86])[CH2:74][C@H:75]([OH:85])[C@@H:76]([NH2:84])[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[CH2:77]([C@H:76]([NH:84][C:47](=[O:49])[C:46]1[CH:50]=[C:51]([C:60]([F:63])([F:62])[F:61])[CH:52]=[C:53]([N:54]2[CH2:58][CH2:57][CH2:56][C:55]2=[O:59])[C:45]=1[F:44])[C@@H:75]([OH:85])[CH2:74][C@H:73]([C:72](=[O:87])[NH:71][CH:65]1[CH2:66][CH:67]2[CH2:70][CH:64]1[CH2:69][CH2:68]2)[CH3:86])[C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: O=C(O)c1cc(C(F)(F)F)cc(N2CCCC2=O)c1F
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(C(F)(F)F)cc(N2CCCC2=O)c1F)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 2-fluoro-3-(2-oxopyrrolidin-1-yl)-5-trifluoromethyl benzoic acid (D25) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [CH:1]([Cl:4])(Cl)[Cl:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH2:14])=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].O>CC1CCCCC1>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:12][CH:11]=3)[CH2:14][C:1]2([Cl:4])[Cl:2])=[CH:20][CH:19]=1
Reactant: C=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: ClC(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC1CCCCC1
Product: COc1ccc(C2(c3ccc(OC)cc3)CC2(Cl)Cl)cc1
Temperature: 20 °C

Procedure:
Chloroform (0.2 moles) was added dropwise with stirring to a solution of 1,1-di-(p-methoxyphenyl)ethylene (0.1 mole) in methyl cyclohexane containing potassium tert-butoxide (0.4 moles) at 0°C. The mixture was allowed to warm to 20°C. overnight and then poured into water. The oil phase was separated and the solvent recovered. The residual solid was recrystallized from petroleum ether to give 1-(p-methoxyphenyl)-1-(p-methoxyphenyl)-2,2-dichlorocyclopropane, m.p. 141°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].CCCCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:18]([O:17][C:15]([C:14]1[CH:20]=[N:1][C:2]2[C:3]([C:13]=1[OH:12])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)=[O:16])[CH3:19]
Reactant: COc1ccc(N)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(OC)nc2c1O

Procedure:
3-Amino-6-methoxypyridine (12.41 g) and diethyl ethoxymethylene malonate (20.2 ml) in Dowtherm A (400 ml) were heated at reflux, under argon for 1 hour. The cooled reaction mixture was poured into pentane (1 liter). The precipitated solid was collected by filtration, washed with pentane and dried to afforded a solid (24.78 g, crude).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([O:36][CH3:37])[CH2:11][CH2:12][CH:13]([C:24]1[NH:25][C:26](=[O:35])[C:27]([OH:34])=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:29]=1)[N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH3:16])C1C=CC=CC=1.C(O)(=O)C>CCOC(C)=O.CO.[Pd]>[C:20]([O:19][C:17]([N:14]([CH2:15][CH3:16])[CH:13]([C:24]1[NH:25][C:26](=[O:35])[C:27]([OH:34])=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:29]=1)[CH2:12][CH2:11][C@H:10]([O:36][CH3:37])[CH2:9][OH:8])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](COCc1ccccc1)OC)c1nc(C(=O)OC)c(O)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](CO)OC)c1nc(C(=O)OC)c(O)c(=O)[nH]1
Reaction time: 96 h

Procedure:
To a solution of methyl 2-{(4S)-5-(benzyloxy)-1-[(tert-butoxycarbonyl)(ethyl)amino]-4-methoxypentyl}-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (13 g, 25.02 mmol) in EtOAc (30 mL) and MeOH (30 mL) was added acetic acid (20 mL) and palladium on carbon (Degussa, 10% by mass, 13 g, 122 mmol). The reaction mixture was shaken on a Parr apparatus under hydrogen gas (50 psi) for 4 days and then filtrated through a pad of celite. The filter cake was washed with MeOH. The filtrate was concentrated in vacuo. The crude residue was used in the next reaction without further purification. LC-MS: 429.89 (M+1).
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([C:12]2[O:13][C:14]3[CH:20]=[C:19]([C:21]([N:23]4[CH2:26][CH:25](O)[CH2:24]4)=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C(Cl)Cl.CN(C=O)C>[CH:6]1([C:12]2[O:13][C:14]3[CH:20]=[C:19]([C:21]([N:23]4[CH2:26][CH:25]([N:46]5[CH2:47][CH2:48][N:43]([C:38]6[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=6)[CH2:44][CH2:45]5)[CH2:24]4)=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(c1ccc2nc(C3CCCCC3)oc2c1)N1CC(O)C1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc2nc(C3CCCCC3)oc2c1)N1CC(N2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C

Procedure:
Methanesulfonyl chloride (0.152 mL, 1.9 mmol) was added dropwise to a solution of (2-cyclohexyl-benzooxazol-6-yl)-(3-hydroxy-azetidin-1-yl)-methanone (0.48 g, 1.6 mmol) and DIPEA (0.558 mL, 3.2 mmol) in DCM (20 mL) at −40° C. under nitrogen. Immediately following the addition, the cooling bath was removed and the mixture slowly warmed to room temperature. The resulting mixture was then washed with water, dried using magnesium sulfate, filtered, and the solvent removed under reduced pressure. The resulting residue was dissolved in acetonitrile (1 mL). DIPEA (0.41 mL, 2.4 mmol) and N-(2-pyridyl)piperazine (1.6 mmol) were added. The resulting mixture was then microwaved at 160° C. for 4 hours. DMF (3 mL) was added to the resulting mixture, which was then purified by reverse phase liquid chromatography. The fractions containing product were diluted with 1N HCl (5 mL) and then lyophilized to yield 2-cyclohexyl-6-{[3-(4-pyridin-2-ylpiperazin-1-yl)azetidin-1-yl]carbonyl}-1,3-benzoxazole as its corresponding hydrochloride salt.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH2:39]([O:38][C:36]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33][CH2:34]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37])[CH3:40]
Reactant: CCOC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A174) and ethyl chloroformate the title compound is obtained as colorless solid.