Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]4[C:21]([N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]([C:39]5[CH:40]=[N:41][NH:42][CH:43]=5)=[N:18][C:17]=34)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:46]([O:49][CH2:50][CH2:51]Br)(=[O:48])[CH3:47]>CN(C=O)C>[C:46]([O:49][CH2:50][CH2:51][N:41]1[CH:40]=[C:39]([C:19]2[CH:20]=[C:21]([N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[N:16]3[N:15]=[CH:14][C:13]([C:10]4[CH:11]=[N:12][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)=[C:17]3[N:18]=2)[CH:43]=[N:42]1)(=[O:48])[CH3:47]
Reactant: CC(=O)OCCBr
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(-c2cn[nH]c2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCn1cc(-c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 2-5 mL pressure vial was charged 3-(6-phenylpyridin-3-yl)-5-(1H-pyrazol-4-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.38 mmol, 230 mg), DMF (4 mL), and sodium hydride (40% w/w in mineral oil, 0.56 mmol, 23 mg). This suspension was sonicaided and allowed to stir at room temperature for 15 minutes. At 15 minutes, 2-bromoethyl acetate (0.56 mmol, 62 μL). The vial was then sealed and the reaction was stirred at 80° C. for 18 hours. After 18 hours, the solvent was removed in vacuo, and the resulting residue was purified by flash chromatography to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:28]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:21]2[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.FC(F)(F)S(O[CH2:46][C:47]([C:50]#[N:51])([CH3:49])[CH3:48])(=O)=O>O.CCOC(C)=O>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:28]=1)[C:6]1[CH:7]=[C:8]([C:21]3[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([O:19][CH2:46][C:47]([CH3:49])([CH3:48])[C:50]#[N:51])=[CH:15][C:14]=1[F:20]
Reactant: CC(C)(C#N)COS(=O)(=O)C(F)(F)F
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C#N)COc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Reaction time: 0.25 h

Procedure:
A vial was charged with (S)-2-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (45.0 mg, 0.118 mmol), cesium carbonate (57.7 mg, 0.177 mmol), and DMF (787 μL). The mixture was stirred vigorously for 15 min, then 2-cyano-2-methylpropyl trifluoromethanesulfonate (22.56 μL, 0.130 mmol) was added via syringe. The resulting mixture was stirred at room temperature for 19 hours before being diluted with water (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 12 g Redi-Sep column, eluting with 5-60% MeOH/DCM to give (S)-3-(2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)-2,2-dimethylpropanenitrile as an off-white solid. (MS: MH+=463).
Reaction SMILES: [CH3:1][CH:2]([CH3:40])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:23][C:24](=[O:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:15][C:16]([O:18]C(C)(C)C)=[O:17].FC(F)(F)C(O)=O>>[CH3:1][CH:2]([CH3:40])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([O:23][C:24](=[O:39])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:15][C:16]([OH:18])=[O:17]
Reactant: CC(C)CCCCCCCCCCCC(=O)OC(CCCCCCCCCCCC(C)C)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCCCCCCCCCCC(=O)OC(CCCCCCCCCCCC(C)C)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To tert-butyl 15-methyl-3-(13-methyltetradecanoyloxy)hexadecanoate (500 mg) was added trifluoroacetic acid (5 ml) and the mixture was stirred at ambient temperature for 2 hours. Excess trifluoroacetic acid was distilled off under reduced pressure. Dry benzene was added to the residue and the solvent was evaporated off. This operation was repeated three times. The residue was dried up by using high vacuum pump to afford an oil of 15-methyl-3-(13-methyltetradecanoyloxy)hexadecanoic acid (400 mg).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:26])[NH:23][CH2:24][CH3:25])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=C(C=CC=2)C(NCC)=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:26])[NH:23][CH2:24][CH3:25])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCNC(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)OCC)s2)c1
Agent: CCNC(=O)c1cccc(NCC2CCCC2)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CCNC(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-ethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N-ethyl-benzamide and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21]([OH:23])=O)=[CH:17][CH:16]=1.CCOCC>C(Cl)Cl>[ClH:14].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]([N:2]([CH3:1])[C@@H:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]2[N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:23])=[CH:24][CH:25]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C(=O)COc1ccc(Cl)cc1)[C@@H]1CCCC[C@H]1N1CCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Trans-N-Methyl-2-(1-pyrrolidinyl]cyclohexanamine (0.182 g) was dissolved in methylene chloride (10 ml) and stirred at room temperature. The acid chloride of 4-chlorophenoxyacetic acid (0.205 g) dissolved in methylene chloride (10 ml) was added and let stand for 12 hours. Ether was added to rapidly stirred solution until no more precipitate appeared. After further rapid stirring for one hour, the precipitate was filtered and dried in a vacuum oven at 90° C. for one hour, and stored in a predried bottle. The product was in the form of white needles (360 mg) mp 184°-186° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCCOC)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(CCCOC)CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
4-(3-Methoxy-propyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (6 g) was dissolved in methylene chloride (200 ml) under an argon atmosphere, TFA (35.6 ml) was added and the reaction mixture was stirred for 3 hours at RT. The solvent together with most of the TFA was evaporated off, the residue dissolved in methylene chloride (800 ml) and treated with 2M KHCO3 under ice cooling. The layers were separated, the organic layer was washed with water and brine, dried over sodium sulphate and concentrated in vacuo to give 3.63 g of 4-(3-methoxy-propyl)-piperidine-4-carboxylic acid ethyl ester as a light brown oil which was used in next reaction step without further purification.
Reaction SMILES: [F:1][C:2]([F:37])([C:12]([F:36])([F:35])[C:13]([F:34])([F:33])[C:14]([F:32])([F:31])[C:15]([F:30])([F:29])[C:16]([F:28])([F:27])[C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:4][SiH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].C([Br:41])C=C>C1C=CC=CC=1.Cl[Pd]Cl>[F:37][C:2]([F:1])([C:12]([F:35])([F:36])[C:13]([F:33])([F:34])[C:14]([F:31])([F:32])[C:15]([F:29])([F:30])[C:16]([F:28])([F:27])[C:17]([F:26])([C:22]([F:23])([F:24])[F:25])[C:18]([F:20])([F:19])[F:21])[CH2:3][CH2:4][Si:5]([Br:41])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)[SiH](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F)C(C)C
Reactant: C=CCBr
Agent: Cl[Pd]Cl
Solvent: c1ccccc1
Product: CC(C)[Si](Br)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(C(F)(F)F)C(F)(F)F)C(C)C
Temperature: 60 °C
Yield: 205.9 %

Procedure:
In an oven-dried round-bottom flask equipped with a stir bar and cooled under N2, (3,3,4,4,5,5,6,6,7,7,8,8,9,10,10,10-hexadecafluoro-9-trifluoromethyldecyl)diisopropylsilane (4.86 g, 7.94 mmol) was dissolved in 10 mL anhydrous benzene (benzene dried by boiling off 10% by volume prior to use). To this mixture was added allyl bromide (1.44 g, 11.9 mmol, 1.5 eq.) and PdCl2 (30 mg). The solution was heated to 60° C. for 15 hr, then cooled, and concentrated via rotary evaporation. The resulting suspension was dissolved in pentane, filtered to remove residual catalyst, and then solvent was removed to yield ((3,3,4,4,5,5,6,6,7,7,8,8,9,10,10,10-hexadecafluoro-9-trifluoromethyldecyl)diisopropylsilyl)-bromide (11.3 g) as a pale brown liquid. The bromide was treated under anhydrous conditions with 1.2 eq. (based on initial silane) of ethynylmagnesium bromide and heated to 40° C. for 6 hr. The reaction was quenched with water and dilute sulfuric acid, pentane was added, and the organic layer was separated. The organic layer was washed with water (6×50 mL), dried over MgSO4, filtered, and concentrated via rotary evaporation. Further purification via flash chromatography using hexane yielded pure ((3,3,4,4,5,5,6,6,7,7,8,8,9,10,10,10-hexadecafluoro-9-trifluoromethyldecyl)diisopropylsilyl)-acetylene (4.1 g, 6.5 mmol, 82%) as a colorless liquid. Analysis of the product provided the following data: 1H-NMR (200 MHz, CDCl3) δ=2.4 (s, 1H), 2.2 (m, 2H), 1.0 (m, 14H), 0.8 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[N:28]=[CH:27][S:26][C:12]=3[N:13]=[C:14]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21]C)=[O:20])[N:15]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[N:28]=[CH:27][S:26][C:12]=3[N:13]=[C:14]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([OH:21])=[O:20])[N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc(-c2nc(Nc3cccc(C(F)(F)F)c3)c3ncsc3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(-c2nc(Nc3cccc(C(F)(F)F)c3)c3ncsc3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a stirred solution of methyl 3-(7-(3-(trifluoromethyl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (100 mg, 0.23 mmol) in 3 mL of THF and 3 mL of methanol was added a solution of sodium hydroxide (46.5 mg, 1.16 mmol) in 1 mL of water at room temperature. Then the reaction mixture was stirred at room temperature for 16 hours. HCl was added until pH=4. The solvent was evaporated at 40° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:1)) to give 3-(7-(3-(trifluoromethyl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (65 mg, 67.2%) as a pale yellow solid. 1H NMR (300 MHz, DMSO): δ 13.15 (brs, 1H), 10.65 (s, 1H), 9.46 (s, 1H), 9.00 (s, 1H), 8.67 (s, 1H), 8.60 (d, 1H, J=7.8 Hz), 8.26 (d, 1H, J=7.8 Hz), 8.10 (d, 1H, J=7.5 Hz), 7.68-7.63 (m, 2H), 7.49 (d, 1H, J=7.8 Hz). LC-MS: 417 [M+H]+, 415 [M−H]−, tR=1.65 min. HPLC: 95.14% at 214 nm, 95.28% at 254 nm, tR=7.71 min.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[ClH:22].Cl.[NH2:24][CH2:25][C:26]([NH2:28])=[NH:27]>>[ClH:22].[ClH:22].[NH2:28][C:26]1[CH:25]=[N:24][C:9]2[CH2:10][CH2:11][N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:6][CH2:7][C:8]=2[N:27]=1
Reactant: N=C(N)CN
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CCN(C2CCC2)CC1
Agent: Cl
Product: Nc1cnc2c(n1)CCN(C1CCC1)CC2

Procedure:
This compound was prepared analogous to Example 22 from 1-cyclobutyl-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)-azepine and α-amino-acetamidine dihydrochloride.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:22][C:23](O)=[O:24])[C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH:33][CH2:34][CH2:35][OH:36]>>[OH:36][CH2:35][CH2:34][N:33]([CH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=1)[C:23](=[O:24])[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=1)(=[O:12])=[O:11])[C:14]1[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: OCCNCc1ccccn1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)cn1
Product: COc1ccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ccc(C(C)C)cn2)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(6-methoxy-pyridin-3-yl)-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[N:13]1([C:18]2[CH:34]=[CH:33][C:21]([O:22][CH2:23][CH2:24][NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:20][CH:19]=2)[CH:17]=[CH:16][N:15]=[CH:14]1>CO>[N:13]1([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:11][CH:10]([OH:12])[CH2:9][O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:33][CH:34]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1ccc(CNCCOc2ccc(-n3ccnc3)cc2)cc1
Reactant: Cc1cccc(OCC2CO2)c1
Solvent: CO
Product: Cc1cccc(OCC(O)CN(CCOc2ccc(-n3ccnc3)cc2)Cc2ccccc2)c1
Temperature: 50 °C

Procedure:
To a solution of 2.75 g (17 mmol) 2,3-epoxypropyl 3-methylphenyl ether in 50 mL methanol add 4.4 g (15 mmol) 2-[4-(1H-imidazol-1-yl)phenoxy]-N-(phenylmethyl)ethanamine and heat to 50° C. for 24 h. Follow the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride:methanol, 9:1). At the completion of the reaction, evaporate the solvents. The resulting oil is chromatographed on a silica gel column using 2% methanol in methylene chloride to provide the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@H:12]3[O:17][CH2:16][C@@H:15]4[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][N:14]4[CH2:13]3)[CH:9]=2)[C:4](=[O:29])[O:3]1.[CH3:30][C@@H:31]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C@@H:41]3[O:46][CH2:45][C@@H:44]4[CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50][N:43]4[CH2:42]3)[CH:38]=2)[C:33](=[O:58])[O:32]1.BrC1C=C2C(=CC=1)C(=O)O[C@@H](C)C2.OC[C@@H]1NCCN(C(OC(C)(C)C)=O)C1>>[CH3:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@@H:12]3[O:17][CH2:16][C@H:15]4[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][N:14]4[CH2:13]3)[CH:9]=2)[C:4](=[O:29])[O:3]1.[CH3:30][C@H:31]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C@H:41]3[O:46][CH2:45][C@H:44]4[CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50][N:43]4[CH2:42]3)[CH:38]=2)[C:33](=[O:58])[O:32]1
Reactant: C[C@@H]1Cc2cc([C@H]3CN4CCN(C(=O)OC(C)(C)C)C[C@H]4CO3)ccc2C(=O)O1
Reactant: C[C@@H]1Cc2cc([C@@H]3CN4CCN(C(=O)OC(C)(C)C)C[C@H]4CO3)ccc2C(=O)O1
Agent: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Agent: C[C@H]1Cc2cc(Br)ccc2C(=O)O1
Product: C[C@H]1Cc2cc([C@@H]3CN4CCN(C(=O)OC(C)(C)C)C[C@@H]4CO3)ccc2C(=O)O1
Product: C[C@H]1Cc2cc([C@H]3CN4CCN(C(=O)OC(C)(C)C)C[C@@H]4CO3)ccc2C(=O)O1

Procedure:
Intermediates 8E and 8F were prepared in a similar manner as Intermediates 8A and 8B except (3S)-6-Bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one and tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate were used as the starting materials. The cis/trans mixture was purified via MPLC (20-65% EtOAc/Hex). The faster eluting diastereomer was the trans isomer: 8E: 1H NMR (500 MHz; CDCl3): 8.07 (d, J=8.2 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.27 (s, 1H), 4.71 (dd, J=2.0, 10.7 Hz, 1H), 4.68 (m, 1H), 4.0 (bs, 2H), 3.97 (dd, J=3.1, 11.1 Hz, 2H), 3.48 (t, J=10.8 Hz, 1H), 2.99 (m, 4H), 2.74 (d, J=10.5 Hz, 1H), 2.2 (m, 3H), 1.53 (d, J=6.4 Hz, 3H), 1.49 (s, 9H). (M+1)+403.8F: 1H NMR (500 MHz; CDCl3): 8.09 (d, J=8.9 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.39 (s, 1H), 4.81 (t, J=3.6 Hz, 1H), 4.69 (m, 1H), 3.62 (dd, J=3.0, 11.5 Hz, 1H), 3.42 (m, 1H), 3.24 (dd, J=3.6, 12.1 Hz, 1H), 2.97 (m, 4H), 2.76 (m, 3H), 2.50 (m, 2H), 2.28 (m, 1H), 1.54 (d, J=6.2 Hz, 3H), 1.47 (s, 9H). (M+1)+403.
Reaction SMILES: C([O-])(=O)C.[K+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[N+:18]([CH:21]1[C:34]2[C:33](=[O:35])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:36])[C:25]=2[CH:24]=[CH:23][CH2:22]1)([O-:20])=[O:19]>O>[N+:18]([C:21]1[C:34]2[C:33](=[O:35])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:36])[C:25]=2[CH:24]=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=C1C2=C(C(=O)c3ccccc31)C([N+](=O)[O-])CC=C2
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Yield: 86 %

Procedure:
With stirring, 0.38 part (3.89 mmol) of potassium acetate is dissolved in 5 parts of glacial acid at 90° C. Then 2.1 parts (7.77 mmol; 4 equivalents) of potassium persulfate are added, whereupon a white suspension forms. Then 1.0 g (3.84 mmol) of nitrodihydroanthraquinone is added. After stirring for 3 hours at 90° C., the mixture is cooled and poured into 50 ml of water. The precipitate is isolated by filtration, washed with water, and dried. The residue is extracted by boiling 3 times in toluene. Partial concentration of the mother liquors and subsequent cooling and filtration give 0.84 part (86% of theory) of 1-nitroanthraquinone with a melting point of 228°-230° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([CH:7]=[C:8]([S:19]([CH3:22])(=[O:21])=[O:20])[C:9]3[O:10][C:11](=[O:18])[C:12]([CH3:17])([CH3:16])[C:13]=32)=[CH:5][C:4]=1[S:23]([CH3:26])(=[O:25])=[O:24].[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>C(#N)C.O>[S:19]([C:8]1[C:9]2[O:10][C:11](=[O:18])[C:12]([CH3:16])([CH3:17])[C:13]=2[C:14]2[C:6](=[CH:5][C:4]([S:23]([CH3:26])(=[O:24])=[O:25])=[C:3]([CH2:2][N:27]3[CH:31]=[N:30][CH:29]=[N:28]3)[CH:15]=2)[CH:7]=1)([CH3:22])(=[O:20])=[O:21]
Reactant: c1nc[nH]n1
Reactant: CC1(C)C(=O)Oc2c(S(C)(=O)=O)cc3cc(S(C)(=O)=O)c(CBr)cc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C(=O)Oc2c(S(C)(=O)=O)cc3cc(S(C)(=O)=O)c(Cn4cncn4)cc3c21

Procedure:
A solution of 8-bromomethyl-4,7-dimesyl-1,1-dimethyl-2(1H)-naphtho[2,1-b]furanone in acetonitrile (5 ml) was treated with 1,2,4-triazole (0.2 g) and potassium carbonate (0.14 g), and the mixture was stirred under reflux for 18 h. The mixture was diluted with water, neutralised with glacial acetic acid and extracted with ethyl acetate, and the ethyl acetate extract was dried and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography, using methanol:ethyl acetate, 1:99 v/v as eluant, to give 4,7-dimesyl-1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone, m.p. 263°-264° after recrystallisation from ethyl acetate.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]([CH2:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14]C)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>C(O)C.O>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:7]([CH2:10][CH:11]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CC(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1ncc(CC(Cc2ccccc2)C(=O)O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A mixture of methyl 3-[2-n-butyl-1-benzyl-1H-imidazol- 5yl]-2-benzylpropanoate (0.12 g, 0.31 mmol) in 50% aqueous ethanol (4 mL) containing potassium hydroxide (0.072 g, 1.28 mmol) was stirred at 25° C. for 18 hours. The basic solution was diluted with water (8 mL), and extracted with diethyl ether. The water solution was acidified with aqueous hydrochloric acid solution to pH 4, and the product was extracted into methylene chloride, dried, and concentrated. This crude material was dissolved in acetone and acidified with ethereal hydrochloric acid to give a precipitate. Crystallization from acetone/ether provided 0.07 g of 3-[2-n-butyl-1- benzyl-1H-imidazol-5-yl]-2-benzylpropanoic acid; mp 148°-150° C. (hydrochloride salt).
Reaction SMILES: CO[C:3](=[O:8])[CH2:4][C:5]([OH:7])=[O:6].Cl.NCC(OC)=O.[N:16]1([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]3[CH:41]=[CH:40][CH:39]=[C:38]4[C:33]=3[CH2:34][CH2:35][CH2:36][N:37]4[C:42](=[O:55])[CH2:43][CH2:44][CH2:45][O:46][C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[C:48]=3[CH3:54])[CH:27]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:54][C:48]1[C:49]([CH3:53])=[CH:50][CH:51]=[CH:52][C:47]=1[O:46][CH2:45][CH2:44][CH2:43][C:42]([N:37]1[C:38]2[C:33](=[C:32]([C:28]3[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=3)[CH2:25][O:24][C:22]([N:16]3[CH2:21][CH2:20][N:19]([C:3](=[O:8])[CH2:4][C:5]([OH:7])=[O:6])[CH2:18][CH2:17]3)=[O:23])[CH:41]=[CH:40][CH:39]=2)[CH2:34][CH2:35][CH2:36]1)=[O:55]
Reactant: COC(=O)CC(=O)O
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(COC(=O)N5CCNCC5)c4)cccc32)c1C
Agent: COC(=O)CN
Agent: Cl
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(COC(=O)N5CCN(C(=O)CC(=O)O)CC5)c4)cccc32)c1C

Procedure:
Example 128 was prepared using a procedure analogous to Example 126 except that Example 1 was replaced with 3-methoxy-3-oxopropanoic acid and methyl 2-aminoacetate hydrochloride was replaced with 3-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzyl piperazine-1-carboxylate. LCMS, [M+H]+=628.3. 1H NMR (400 MHz, MeOD) δ 7.54-7.42 (m, 2H), 7.41-7.31 (m, 2H), 7.30-7.14 (m, 3H), 7.06 (t, J=7.9 Hz, 1H), 6.79 (d, J=7.5 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 5.25 (s, 2H), 3.97 (br, s, 2H), 3.83 (t, J=7.0 Hz, 2H), 3.74-3.55 (m, 8H), 2.90 (t, J=6.9 Hz, 2H), 2.46 (br. s, 2H), 2.31-2.16 (m, 5H), 1.91 (s, 3H), 1.85 (dt, J=13.3, 6.8 Hz, 2H), 1.37 (s, 2H). HPLC-1: Rt=10.8 min, purity=95.0%; HPLC-2: Rt=10.9 min, purity=93.1%.