Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:38])[CH:10]([CH2:13][C:14]1[N:15]=[CH:16][N:17]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[CH2:11][CH3:12])C1C=CC=CC=1.OO.[OH2:41].[OH-:42].[Li+]>C1COCC1.O>[C:26]1([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:17]2[CH:18]=[C:14]([CH2:13][C@H:10]([CH2:11][C:12]([OH:42])=[O:41])[C:9]([OH:8])=[O:38])[N:15]=[CH:16]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O
Reactant: CCC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)OCc1ccccc1
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O
Reaction time: 2 h

Procedure:
4-{[1(S)-(Cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxo-3(R)-{[(1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}butanoic acid benzyl ester: A 30% aqueous solution of H2O2 (4.70 mL, 41.6 mmol) and lithium hydroxide monohydrate (436 mg, 10.4 mmol) were added serially to cooled solution (0°) of the product of section (c) of this example (6.67 g, 10.4 mmol) in THF-H2O (156 mL: 52 mL). The reaction mixture was stirred at 0° for 2 h and then at room temperature for 2 h. Excess peroxide was quenched at 0° with 1.5N aqueous Na2SO3 solution. THF was removed by distillation under reduced pressure. The concentrate was poured into H2O (500 mL). The mixture was rendered acid by the addition of a 10% (w/v) aqueous solution of citric acid, and then extracted with EtOAc. The extract was washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure to yield the desired monoprotected dicarboxylic acid, i.e. the 4-(phenylmethyl) ester of 2(R)-{[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}butanedioic acid. The monoprotected dicarboxylic acid was used for the following coupling step without further purification.
Reaction SMILES: [C:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CCCCCCCCC(O)=O)(=[O:17])CCCCCCCCCCCCCCC.C(Cl)(=O)[C:38]([Cl:40])=[O:39].[O:43]1CCCC1>>[Cl:40][C:38]([O:17][CH2:1][O:18][C:19](=[O:43])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:39]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: O=C(Cl)OCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
16-Hexadecanoyloxyhexadecanoic acid (7.73 g, 15.13 mmol) prepared as in (ah) above was dissolved in tetrahydrofuran (140 ml) and oxalyl chloride (4.80 g, 37.83 mmol) was added dropwise. The mixture was stirred at room temperature for 3 days and then the solvent and unreacted oxalyl chloride were evaporated under reduced pressure to give 8.0 g (100%) of the title compound.
Reaction SMILES: [BH4-].[Na+].[ClH:3].Cl.Cl.[NH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([C:21]3[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=3)=O)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1.Cl.C[OH:34]>>[ClH:3].[ClH:3].[NH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([OH:34])[CH2:19][C:21]3[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1
Reactant: CO
Reactant: O=C(O)COc1ccc(C(=O)CN2CCN(C3CCNCC3)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: O=C(O)COc1ccc(CC(O)N2CCN(C3CCNCC3)CC2)cc1
Reaction time: 8 h

Procedure:
8.5 mg (0.22 mmol) of sodium borohydride are added to a solution of 100 mg (0.22 mmol) of 4-[[4-(4-piperidinyl)-piperazin-1yl]acetyl]phenoxyacetic acid trihydrochloride in 10 ml of methanol and the mixture is stirred overnight. 2 ml of a 0.1N hydrochloric acid are then added and the solution is concentrated to dryness under reduced pressure. The residue is partitioned between saturated sodium chloride solution and ethyl acetate and, after drying over sodium sulphate, the organic phase is concentrated to dryness. Mass spectrum: (M+H)+ =364;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.Cl[C:14]1[C:19]2[N:20]=[N:21][N:22]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=2[CH:17]=[C:16]([CH3:28])[N:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]2[C:10]=1[N:9]([C:14]1[C:19]3[N:20]=[N:21][N:22]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[CH:17]=[C:16]([CH3:28])[N:15]=1)[CH2:8][CH2:7]2
Reactant: COc1cc(Br)c2c(c1)CCN2
Reactant: CCC(CC)n1nnc2c(Cl)nc(C)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)n1nnc2c(N3CCc4cc(OC)cc(Br)c43)nc(C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
Part E: To 7-bromo-5-methoxyindoline (382 mg) and 4-chloro-1-[1-ethylpropyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine (400 mg) in THF (2.0 mL) was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 15 mL) at 0° C. The reaction was warmed to ambient temperature and stirred for 1 hour. Ethyl acetate (150 mL) was added and washed with water and brine. The organics were dried over MgSO4 and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to give 4-(7-bromo-5-methoxy-2,3-dihydro-1H-indol-1-yl)-1-[1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine (538 mg).
Reaction SMILES: O[CH:2]([C:14]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([O:24]COCC[Si](C)(C)C)=[C:16]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:15]=1)[C:3]#[C:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.ClCCl.FC(F)(F)C(O)=O>O>[C:33]([C:16]1[C:17](=[O:24])[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:19][C:14](=[CH:2][C:3]#[C:4][C:5]2[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][CH:13]=2)[CH:15]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1cc(C(O)C#Cc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1OCOCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C1=CC(=CC#Cc2ccc(C(=O)O)cc2)C=C(C(C)(C)C)C1=O

Procedure:
2.2 g (4.7 mmol) of 4-{3-Hydroxy-3-[3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy)phenyl]-1-propynyl}benzoic acid and 75 ml of dichloromethane are introduced into a three-necked flask. 360 μl (4.7 mmol) of trifluoroacetic acid are added at -78° C. and the mixture is allowed to return to room temperature. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is triturated from heptane, filtered and then dried. 1.6 g (90%) of 4-[3-(3,5-di-tert-butyl-4-oxo-2,5cyclohexadien-1-ylidene)-1-propynyl]benzoic acid are collected, with a melting point of 216-8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].O.O.Cl[Sn]Cl.C(O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1c(Cl)cc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)cc(Cl)c1N
Temperature: 25 °C

Procedure:
3,5-Dichloro-1,2-diaminobenzene was prepared using an adaptation of the method of Bellamy, et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25: 839 (1984)). A mixture of 2,4-dichloro-6-nitroaniline (1.00 g, 4.8 mmol) and SnCl2.2H2O (5.41 g, 24.1 mmol) dissolved in 10 mL ethyl acetate and 5 mL absolute ethanol under N2 was heated at 70° C. for 1 h. All the starting material had reacted as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 40 mL crushed ice. Sufficient sat'd NaHCO3 solution was added (foaming!) to bring the pH to 5. The orange oil/thick white emulsion was extracted with 3×25 mL ethyl acetate and the combined organic extracts washed with sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a pale orange oil which crystallized on standing to yield 789 mg (93%). 1H NMR (CDCl3) δ 3.69 (br s, 4H, 2(NH2)); 6.61 (s, 1H, H-6); 6.82 (s, 1H, H-4).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:25][CH2:24][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:26]([CH2:28][C:29](O)=[O:30])#[N:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:25][CH2:24][C:19]3([CH2:23][N:22]([C:29](=[O:30])[CH2:28][C:26]#[N:27])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CCNC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)CC#N)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a solution of 5-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(2-azaspiro[4.5]decan-8-yl)pyrimidine-2,4-diamine (186 mg, 0.545 mmol), 2-cyanoacetic acid (48.4 mg, 0.569 mmol) in a mixture of DCM (32 mL) and DMF (8 mL) were added HATU (423.4 mg, 1.087 mmol) and Et3N (0.21 g, 2.075 mmol). After addition, the reaction mixture was stirred at rt for 2 h, quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the title compound as a beige solid (170 mg, 76.4%).
Reaction SMILES: [N:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CN)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:20]([N:22](CC)CC)C.C1C(=O)N([O:34][C:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH:41]2[S:45][CH2:44][CH:43]3[NH:46][C:47]([NH:49][CH:42]23)=[O:48])=[O:36])C(=O)C1>CN(C=O)C>[OH:36][C:35]([CH2:37][CH2:38][CH2:39][CH2:40][C@H:41]1[C@@H:42]2[C@@H:43]([NH:46][C:47]([NH:49]2)=[O:48])[CH2:44][S:45]1)=[O:34].[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:20][NH-:22])=[O:9])=[CH:18][CH:19]=1)=[N+:2]=[N-:3]
Reactant: O=C1NC2CSC(CCCCC(=O)ON3C(=O)CCC3=O)C2N1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCCCCCCN)cc1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC(C[NH-])NC(=O)c1ccc(N=[N+]=[N-])cc1
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 20 °C
Reaction time: 3 h

Procedure:
1.30 g (5 mmol) of product 2b are suspended in 40 ml of distilled DMF and 1.4 ml triethylamine are added under stirring at 20° C. Subsequently, 1.71 g (5 mmol) of biotin-N-hydroxysuccinimide ester 3 are added and stirring is continued for another 3 h at 20° C. Subsequently, the solvent is removed on a rotation evaporator (oil pump vacuum, water bath 50° C.) and the concentrated residue is digested overnight with saturated NaHCO3 solution. Product 4b is drawn off, washed with water and dried in the exsiccator.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]CC3C=CC=CC=3)[N:10]=2)(=[O:8])=[O:7])[CH:5]=[CH:4][CH:3]=[CH:2]1.ClCCl.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[N:1]1([S:6]([C:9]2[NH:10][C:11](=[O:15])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: O=S(=O)(c1cccc(OCc2ccccc2)n1)n1cccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=c1cccc(S(=O)(=O)n2cccc2)[nH]1

Procedure:
The organic washings were combined, dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure to give a crude product identified as 2-(pyrrole-1-sulphonyl)-6-benzyloxypyridine. The crude product was treated with dichloromethane (5 cm3) and trifluoroacetic acid (5 cm3) for 24 hours at the ambient temperature. Toluene (10 cm3) was added and the reaction mixture evaporated to dryness under reduced pressure. The crude product was purified by silica chromatography eluting with 30% ethyl acetate in hexane.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:32][C:33]([O:35][CH2:36]I)=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:36][O:35][C:33]([O:32][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:34])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(C)CCOC(=O)OCI
Agent: [Na+]
Product: CC(C)CCOC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 78.3 %

Procedure:
In the same manner as in Example 81, 153 mg of the title compound was prepared from 150 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 120 mg of isopentyloxycarbonyloxymethyl iodide.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>CN(C)C=O>[CH3:8][C:1]1[CH:6]=[CH:5][C:4]([S:7][C:10]2[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C(O)c1coc(Br)c1
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2cc(C(=O)O)co2)cc1

Procedure:
Using reagent quantities identical to that of Example 9, p-toluenethiol and cuprous oxide were combined in 45 ml. of dimethylformamide heated at 135° C. for about 1.5 hours, cooled somewhat, 5-bromofuran-3-carboxylic acid in 40 ml. of dimethylformamide added, and the mixture refluxed for 24 hours. Crude product (185 mg.) was recovered according to the procedure of Example 10. Recrystallization from methanol/water afforded purified 5-(4-methylphenylthio)furan-3-carboxylic acid (135 mg., m.p. 116°-119° C.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C:5]([NH2:8])([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.[C:19]([O:23][C:24]([NH:26][C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:2][O:3][C:4](=[O:9])[C:5]([CH3:7])([CH3:6])[NH:8][C:28](=[O:29])[C:27]([CH3:32])([CH3:31])[NH:26][C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: COC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
Aminoisobutyric acid methyl ester hydrochloride 2 (11.44 g, 74.47 mmol) and N,N-diisopropylethylamine (9.63 g, 74.5 mmol) were dissolved in DMF (400 mL) and the solution added to solid N-tert-butoxycarbonyl α,α-dimethylglycine (15.14 g, 74.49 mmol). The solution/suspension was cooled to 0° C. (icebath) and HOBt hydrate (11.41 g, 74.51 mmol) and then EDC hydrochloride (15.71 g, 81.95 mmol) added together with more DMF (100 mL). The reaction mixture was stirred for 30 min at 0° C., after which the icebath was removed and stirring continued for 66 h at room temperature. The solvent was evaporated and the residue taken up in EtOAc (500 mL). The solution was washed with 2 M HCl (3×175 mL), 7.5% (w/w) K2CO3 solution (3×175 mL) and saturated brine (175 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a slightly yellowish solid (17.04 g). The solid (16.72 g) was washed with hexane (4×70 mL) affording an off-white solid (14.72 g, 67%), with spectral characteristics in accordance with literature data2,3; 1H NMR (200 MHz; DMSO-d6) δ 7.57 (s, 1H, NH(Aib2)), 6.63 (br s, 1H, NH(Aib1)), 3.55 (s, 3H, OCH3), 1.37 (s, 9H, (CH3)3), 1.34 (s, 6H, CH3), 1.28 (s, 6H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 174.5, 174.0, 154.1, 78.0, 55.5, 55.1, 51.7, 28.1, 24.8, 24.7; HRMS (m/z): [M+Na]+ calcd. for C14H26N2O5Na, 325.1739. found, 325.1746; Anal. Calcd. for C14H26N2O5: C, 55.61; H, 8.67; N, 9.26. Found: C, 55.9; H, 8.7; N, 9.2.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.C(O)(=O)C.O.CN(C)/[CH:17]=[CH:18]/[C:19]([C:21]1[CH:22]=[CH:23][C:24]([O:31][CH3:32])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27])=O>CS(C)=O>[O:8]=[C:6]1[NH:7][C:2]2[N:1]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:31][CH3:32])=[C:25]([CH:30]=3)[C:26]([O:28][CH3:29])=[O:27])[CH:18]=[CH:17][C:3]=2[C:4](=[O:9])[NH:5]1
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Reactant: COC(=O)c1cc(C(=O)/C=C/N(C)C)ccc1OC
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(-c2ccc3c(=O)[nH]c(=O)[nH]c3n2)ccc1OC
Temperature: 99 °C
Reaction time: 1.5 h
Yield: 106.4 %

Procedure:
6-Aminouracil (14.32 g, 112.7 mmol) was added to glacial acetic acid (112.5 mL) and water (75 mL) and the mixture heated to 99° C. A solution of methyl 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-methoxybenzoate (15 g, 56.3 mmol) in DMSO (75 mL) was then added over 180 minutes. The reaction was stirred at 99° C. for a further 90 minutes and cooled to 60° C. Water (75 mL) was then added and the reaction maintained at 60° C. for a further 60 minutes and then filtered off to afford a beige solid. The solid was washed with fresh water (75 mL) and dried visibly dry thus affording 19.6 g of water wet solid (9).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]([C:17]([O-:19])=[O:18])[C:5]=1[C:20]([O:22]CC)=[O:21])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:15]([O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:20]([OH:22])=[O:21])[C:6]=1[C:17]([OH:19])=[O:18])[CH3:16]
Reactant: CCOC(=O)c1c(C(=O)[O-])c(OCC)c2ccccc2c1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2ccccc12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
Ethyl 1,4-diethoxy-2,3-naphthalenedicarboxylate (32 g, 89 mmol) was added to a solution of sodium hydroxide (20 g) in ethanol (200 ml) and water (40 ml) and stirred for 1.5 h at 60° C. The reaction was cooled and the thick white suspension was filtered. The solid was dissolved in a mixture of ethyl acetate (200 ml) and water (800 ml). The layers were separated and the aqueous was acidified with hydrochloric acid (2M, 120 ml). The aqueous was extracted with ethyl acetate (2×) and the combined organics were dried (MgSO4). Evaporation of the solvent under vacuum gave 1,4-diethoxy-2,3-naphthalenedicarboxylic acid as a white solid (25 g, 92%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[I:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=2)[CH3:2].CN(C=O)C.[CH2:21](I)[CH3:22]>C(OCC)(=O)C>[CH2:21]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=2)[C:11]([I:12])=[C:3]1[CH2:1][CH3:2])[CH3:22]
Reactant: CCI
Reactant: CCc1[nH]c2cc([N+](=O)[O-])ccc2c1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1c(I)c2ccc([N+](=O)[O-])cc2n1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
Add to a solution of 2-ethyl-3-iodo-6-nitro-1H-indole (0.30 g, 00.95 mmol) in anhydrous DMF (5 mL) sodium hexamethyldisilylamide (1.0M in THF, 1.0 mL, 1.00 mmol) dropwise followed by ethyl iodide (0.23 mL, 2.85 mmol) and stir 3 hours at ambient temperature. Quench the reaction with 1N HCl and add ethyl acetate. Wash the organic layer 2×1N HCl, 1× brine. Dry the organic layer over sodium sulfate, concentrate in vacuo, and flash chromatograph with 20% ethyl acetate hexane to afford 0.28 g (86%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([CH2:25][NH2:26])[CH:23]=C.[CH3:27]C(N(C)C)=O>>[C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][N:26]([CH2:25][CH:22]=[CH2:23])[CH3:27])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCN
Reactant: CC(=O)N(C)C
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OCCCCBr)CC1
Product: C=CCN(C)CCCCO[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To 1.7 g (4.7 mmol) trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 22 ml DMA, 1.34 ml (14 mmol, 3 eq) N-allylmethylamine were added over a period of 10 min. The reaction was stirred at RT over night, concentrated and the residue was dissolved in CH2Cl2/5% aqueous NaHCO3. The phases were separated and the inorganic phase was extracted with CH2Cl2, the combined organic phases were washed with brine, dried over Na2SO4 and concentrated to yield 1.5 g (92%) trans-(4-[4-(Allyl-methyl-amino)-butoxy]-cyclohexyl)-methyl-carbamic acid tert-butyl ester as colorless oil, MS: 355 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH:18]1([N:13]2[C:12]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Fc1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1
Yield: 85.6 %

Procedure:
The title compound (113 mg) was prepared as in Example 177, Steps C and D, using 200 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 185 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C18H22FN3, 299.18; found, m/z 300.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.45-7.39 (m, 2H), 7.35-7.29 (m, 2H), 4.53 (m, 1H), 3.48-3.42 (m, 2H), 3.36-3.28 (m, 2H), 3.28-3.23 (m, 2H), 2.84-2.78 (m, 2H), 2.08-1.85 (m, 6H), 1.67-1.56 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[F:17][C:18]([F:28])([C:24]([F:27])([F:26])[F:25])[CH2:19][CH2:20][C:21](Cl)=[O:22]>C1COCC1>[F:17][C:18]([F:28])([C:24]([F:25])([F:26])[F:27])[CH2:19][CH2:20][C:21](=[O:22])[CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: O=C(Cl)CCC(F)(F)C(F)(F)F
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To a stirred solution of ethyl acetate enolate, prepared from ethyl acetate (4.4 g, 50 mmol) and sodium hexamethyldisilazide (50 mmol) in THF at −70° C., was added neat 4,4,5,5,5-pentafluoropentanoyl chloride (2.1 g, 10 mmol) at −70° C. Cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The mixture was diluted with diethyl ether and quenched with water. The organic layer was separated, washed with aqueous 2 N hydrochloric acid, saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The crude product was purified by flash chromatography on-silica gel (hexane ethyl acetate 5:1) to give ethyl 6,6,7,7,7-pentafluoro-3-oxoheptanoate as colorless oil yield: 1.46 g (56%).