Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21])([O-])=O.Cl.[NH2:24]O.[OH-].[Na+].Cl>O.CO>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[C:7]([NH2:24])=[CH:6][C:5]=1[C:20]([OH:22])=[O:21]
Reactant: NO
Reactant: O=C1c2ccccc2C(=O)c2c1ccc(C(=O)O)c2[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cc(C(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
10 parts of 1-nitroanthraquinone-2-carboxylic acid and 10 parts of hydroxylamine hydrochloride are suspended at room temperature in 60 parts of methanol and 100 parts of 4 N sodium hydroxide. The mixture is refluxed for 3 hours, then cooled to room temperature, diluted with water and acidified with hydrochloric acid. The mixture is filtered and the filter cake is washed neutral with water and dried, affording 7.6 parts of 1,4-diaminoanthraquinone-2-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[CH2:11][N:10]=[C:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])[C:8]2[CH:7]=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=[CH:4][C:3]1=2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[O:29][CH2:30][C:31]([OH:33])=[O:32]>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[O:29][C@@H:30]([C@:9]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])[NH:10][CH2:11][C:12](=[O:13])[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N+:21]([O-:23])=[O:22])=[CH:7][C:8]1=2)[C:31]([OH:33])=[O:32]
Reactant: COc1cc(OC)cc(OCC(=O)O)c1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Product: COc1cc(OC)cc(O[C@H](C(=O)O)[C@]2(c3ccccc3F)NCC(=O)N(C)c3ccc([N+](=O)[O-])cc32)c1

Procedure:
(±)-(S*)-(3,5-Dimethoxy-phenoxy)-[(5S*)-5-(2-fluoro-phenyl)-1-methyl-7-nitro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-5-yl]-acetic acid is prepared starting from flunitrazepam (5-(2-fluoro-phenyl)-1-methyl-7-nitro-1,3-dihydro-benzo[e][1,4]diazepin-2-one) and (3,5-dimethoxy-phenoxy)-acetic acid (Example 1) in analogy to Example 18. LC-MS1: tR=0.82 min, [M+1]+=526.02.
Reaction SMILES: C[O:2][C:3](=[O:17])[C@:4]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH-].[Na+]>C1COCC1.O>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@:4]1([CH3:16])[C:3]([OH:17])=[O:2])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reaction time: 24 h
Yield: 56.9 %

Procedure:
To a stirred solution of N-tert-butoxycarbonyl-2-methylproline methyl ester (3.20 g, 0.0131 mol) in THF (20mL) was added 1N NaOH (15.7 mL) at room temp. After the resulting mixture was stirred for 24 hr, the mixture was diluted with water and washed with EtOAc. The separated aqueous layer was acidified by the addition of 1N HCl, and extracted with EtOAc. The extract was dried over Na2SO4 and evaporated in vacuo to afford 1.71 g(57%) N-tert-butoxycarbonyl-2-methylproline as a yellow syrup. 1H-NMR (CDCl3) δ1.42 (s, 9H), 1.48 (s, 3H), 1.88-2.31 (m, 4H), 3.34-3.57 (m, 2H), 9.35 (br s, 1H)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[OH-].[Na+].Cl[C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.O>CCO>[NH2:23][C:20]1[S:21][CH:22]=[C:18]([S:12][C:9]2[CH:10]=[CH:11][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:13])[F:14])=[CH:7][CH:8]=2)[N:19]=1
Reactant: Nc1nc(Cl)cs1
Reactant: CC(O)(c1ccc(S)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(O)(c1ccc(Sc2csc(N)n2)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To 1,1,1-trifluoro-2-(4-mercaptophenyl)propan-2-ol (5.7 g, 25 mmol) was added NaOH (1.7 g, 42 mmol), a solution of 4-chlorothiazol-2-amine (2.5 g, 18 mmol) in EtOH (18 mL), and water (36 mL). The mixture was brought to reflux and stirred for 2 h. The solution was poured onto water (100 mL) and extracted with Et2O (3×50 mL). The combined organics were washed with brine (100 mL) and dried over MgSO4 and concentrated in vacuo to provide 3.65 g of 2-(4-(2-aminothiazol-4-ylthio)phenyl)-1,1,1-trifluoropropan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=2)=[N:10]1.C1C(=O)N([Br:37])C(=O)C1>>[Br:37][CH2:20][C:13]1[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nc(C(F)(F)F)cs2)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nc(C(F)(F)F)cs2)=NC1c1ccc(Cl)cc1Cl
Yield: 70.5 %

Procedure:
Ethyl 4-(2,4-dichlorophenyl)-6-methyl-2-(4-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.44 g, 0.94 mmol) was reacted with NBS (0.21 g, 0.94 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.36 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[C:16]([C:17]3[CH:18]=[N:19][N:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH:23]4[O:28][CH3:29])[CH:21]=3)=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C@H:11]([CH3:34])[N:12]3[C:30]([O:32][CH3:33])=[O:31])=[CH:4][CH:3]=1.[CH2:37]=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:16]([C:17]3[CH:18]=[N:19][N:20]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:37])[CH2:24][CH:23]4[O:28][CH3:29])[CH:21]=3)=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C@H:11]([CH3:34])[N:12]3[C:30]([O:32][CH3:33])=[O:31])=[CH:35][CH:36]=1
Reactant: C=O
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CCNCC4OC)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C)CC4OC)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C

Procedure:
(2S)-Methyl 5-(4-fluorophenoxy)-6-(1-(3-methoxy-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized from (2S)-methyl 5-(4-fluorophenoxy)-6-(1-(3-methoxypiperidin-4-yl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate and formaldehyde according to the procedure outlined above for Example 40. 1H NMR (400 MHz, CD3OD) δ ppm 1.16 (d, J=6.80 Hz, 3H), 1.50-1.65 (m, 1H), 1.98-2.11 (m, 1H), 2.15-2.22 (m, 1H), 2.40-2.70 (m, 3H), 2.78-3.01 (m, 5H), 3.02-3.18 (m, 1H), 3.42-3.85 (m, 8H), 4.15-4.25 (m, 1H), 4.55-4.72 (m, 1H), 6.72-6.80 (m, 2H), 6.90-7.01 (m, 2H), 7.50-7.62 (m, 2H), 7.80-8.10 (m, 2H). MS (ESI, pos. ion) m/z 509 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:51]=[CH:50][C:26]([C:27]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([NH:39][CH:40]5[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]5)=[C:35]([N+:47]([O-:49])=[O:48])[CH:34]=4)(=[O:32])=[O:31])=[O:28])=[C:25]([O:52][C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([O:59]COC)[CH:54]=4)[CH:24]=3)[CH2:19][CH2:18]2)=[CH:4][CH:3]=1>O1CCCC1.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:9]=2[CH2:16][N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:51]=[CH:50][C:26]([C:27]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([NH:39][CH:40]5[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]5)=[C:35]([N+:47]([O-:49])=[O:48])[CH:34]=4)(=[O:32])=[O:31])=[O:28])=[C:25]([O:52][C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([OH:59])[CH:54]=4)[CH:24]=3)[CH2:21][CH2:22]2)=[CH:4][CH:3]=1
Reactant: COCOc1cccc(Oc2cc(N3CCN(CC4=C(c5ccc(Cl)cc5)CC(C)(C)CC4)CC3)ccc2C(=O)NS(=O)(=O)c2ccc(NC3CCN(C)CC3)c([N+](=O)[O-])c2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCC(Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCN(CC5=C(c6ccc(Cl)cc6)CC(C)(C)CC5)CC4)cc3Oc3cccc(O)c3)cc2[N+](=O)[O-])CC1

Procedure:
A suspension of EXAMPLE 176E (35.5 mg) in tetrahydrofuran (3 mL) and HCl (1.25M in methanol, 2 mL) was stirred for 1 hour at 60° C. The product was concentrated. The crude product was purified by RP HPLC(C8, 30%-100% CH3CN/water/0.1% TFA) to yield the product. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 9.31 (s, 1H), 8.10 (s, 1H), 7.66-7.73 (m, 2H), 7.56 (d, 1H), 7.34-7.38 (m, 2H), 7.02-7.09 (m, 2H), 6.95-7.02 (m, 1H), 6.65 (dd, 1H), 6.34 (s, 1H), 6.29 (d, 1H), 6.20 (d, 1H), 6.14 (d, 1H), 4.14 (dd, 1H), 3.75 (s, 1H), 3.05 (d, 4H), 2.68-2.80 (m, 3H), 2.20 (d, 6H), 2.08 (d, 2H), 1.97 (s, 2H), 1.69-1.79 (m, 2H), 1.63 (s, 1H), 1.39 (d, 2H), 1.21-1.36 (m, 9H), 0.94 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15](Cl)([N:17]=[C:18]=[O:19])=[O:16]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[O:14][C:18](=[O:19])[NH:17][C:15](=[O:16])[C:11]=3[CH2:12][CH2:13]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCCC1c1cc(F)cc(F)c1
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1cc(F)cc(F)c1)CC2
Temperature: 130 °C
Yield: 10.9 %

Procedure:
A mixture of 2-(3,5-difluorophenyl)cyclopentanone (4.765 g, 24.29 mmol) and carbonisocyanatidic chloride (4.61 g, 43.7 mmol) was heated at 58° C. for 1 h and at 130° C. for 2 h. Upon cooling to room temperature, the reaction mixture was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 7-(3,5-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (700 mg, 2.64 mmol, 10.87% yield). LC-MS (M+H)+=266.1. 1H NMR (500 MHz, CDCl3) δ ppm 8.79 (1H, br s), 6.68-6.86 (3H, m), 4.22 (1H, br s), 2.87 (1H, dt, J=7.0, 4.4 Hz), 2.63-2.82 (2H, m), 2.15 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[C:7]([Br:14])[CH:6]=1
Reactant: COC(=O)Cc1ccc(SC)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc(SC)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
A solution of (4-methylsulfanyl-phenyl)-acetic acid methyl ester (5.11 g, 26.03 mmol) in carbon tetrachloride (130 mL) was slowly treated with bromine (1.74 mL, 33.84 mmol). The reaction mixture was stirred at 25° C. for 4 h, at which time, thin layer chromatography still indicated the presence of a substantial amount of starting material. The reaction mixture was treated with more bromine (1.74 mL, 33.84 mmol). The reaction mixture was stirred an additional 4 h at 25° C. and then quenched with a 10% aqueous sodium bisulfite solution (150 mL). The reaction mixture was concentrated in vacuo to remove carbon tetrachloride. The resulting aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl acetate) afforded (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (6.10 g, 85%) as a light yellow oil: EI-HRMS m/e calcd for C10H11BrO2S (M+) 273.9663, found 273.9661.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:19](=[O:38])[CH:18]([CH2:39][C:40]([O:42]CC)=[O:41])[S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[C:12]([C:9]1[CH:8]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][N:24]([CH3:37])[CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)[C:19](=[O:38])[CH:18]([CH2:39][C:40]([OH:42])=[O:41])[S:17]2)[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCOC(=O)CC1SC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N(CCCN(C)CCOc2ccc3c(c2)OCO3)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(CCCN1C(=O)C(CC(=O)O)SC1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
In ethanol (5 ml) was dissolved 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-5-ethoxycarbonylmethyl-1,3thiazolidin-4-one (100 mg) prepared in Example 46, and a solution of sodium hydroxide (200 mg) in 20% water-containing ethanol was added, then the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. To the residue was added a mixture of water (50 ml) and chloroform (50 ml), and the mixture was stirred. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with n-hexane to afford 80 mg (84%) of the title compound as a pale yellow solid. NMR (CDCl3) (200 MHz) δ: 1.41 (18/2H, s), 1.42 (18/2H, s), 1.4-2.4 (2H, m), 2.85 (3/2H, s), 2.90 (3/2H, s), 2.7-3.8 (8H, m), 4.1-4.7 (3H, m), 5.2-5.4 (1H, m), 5.66 (1/2H, brs), 5.81 (1/2H, brs), 5.89 (2H, s), 6.2-6.7 (3H, m), 7.13 (2/2H, s), 7.14 (2/2H, s)
Reaction SMILES: [Br-].[CH2:2]([PH3+])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(C)([O-])C.[K+].[Si:16]([O:23][C@@H:24]1[CH2:32][C@@H:27]2[O:28][C:29](=[O:31])[CH2:30][C@@H:26]2[C@H:25]1[CH:33]=O)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1>[Si:16]([O:23][C@@H:24]1[CH2:32][C@@H:27]2[O:28][C:29](=[O:31])[CH2:30][C@@H:26]2[C@H:25]1[CH:33]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:17])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H]2OC(=O)C[C@@H]2[C@H]1C=O
Reactant: CCCCCCC[PH3+]
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCC=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.2 %

Procedure:
n-heptylphosphonium bromide (3.185 g, 7.22 mmol) was dried under vacuum for 3 days and was then taken into dry THF (22 mL). Potassium tert-butoxide (7.2 mL, 7.2 mmol, 1 M/THF) was added and the resulting red-orange solution was stirred for 45 min. at room temperature. A solution of (3aR,4R,5R,6aS)-5-(tert-butyldimethylsilyloxy)-2-oxohexahydro-2H-cyclopenta[b]furan-4-carbaldehyde (5-1, 502 mg, 1.78 mmol, Cayman) in 7 mL THF was added by cannula, rinsing with 3 mL THF. After 1.5 h, the reaction was quenched by addition of saturated NH4Cl solution. The resulting mixture was extracted with ethyl acetate (3×) and the combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (Isco Combiflash unit) gave the title compound (595 mg, 91%).
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([NH:58]O)=[O:57])=[O:49])=[CH:43][CH:42]=1>CN(C=O)C>[C:11]1([NH:10][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:18][NH:58][C:56](=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][C:48]([NH:47][C:44]2[CH:45]=[CH:46][CH:41]=[CH:42][CH:43]=2)=[O:49])=[O:17])=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(CCCCCCC(=O)Nc1ccccc1)NO
Reactant: O=C(O)CCCCCCC(=O)Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCCCCC(=O)Nc1ccccc1)NOC(=O)CCCCCCC(=O)Nc1ccccc1
Reaction time: 0.08 h
Yield: 77.3 %

Procedure:
To a stirring solution of suberanilic acid (3.0 g, 12.0 mmol) in DMF (60 mL) was added 1-hydroxybenzotriazole (1.79 g, 13.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (2.54 g, 13.2 mmol). After 5 mins, a solution of SAHA (3.18 g, 12.0 mmol) in DMF (30 mL) was added to the mixture with stirring. After 24 h, the solvent was removed and the residue was triturated with EtOAc (50 mL). The slurry was filtered to yield an off-white solid, which was triturated in CH2Cl2 (50 mL). The slurry was filtered yielding a white solid (4.6 g, 77%). Half of the material was purified further by repeating the washing procedures with an addition of H2O (20 mL) in the EtOAc wash. The white solid was filtered to yield the desired material (2.1 g). MP: 151-153° C. 1H NMR (DMSO-d6) δ 11.51 (s, 1H), 9.82 (s, 2H), 7.54 (d, J=7.9 Hz, 4H), 7.23 (dd, J=7.9, 7.6 Hz, 4H), 6.97 (t, J=7.6 Hz, 2H), 2.39 (t, J=7.2 Hz, 2H), 2.24 (t, J=6.8 Hz, 4H), 1.98 (t, J=6.8 Hz, 2H), 1.66-1.38 (m, 8H), 1.38-1.16 (m, 8H). 13C NMR (DMSO-d6) δ 171.33, 169.94, 139.49, 128.72, 123.02, 119.21, 36.49, 32.02, 31.06, 28.50, 28.37, 28.14, 25.12, 25.05, 24.79, 24.38. MS (EI): cal'd (MH+) 496, exp (MH+) 496.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]#[C:29][C:30](O)=[O:31]>ClCCl.CO>[N:1]1([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH:16][C:30](=[O:31])[C:29]#[C:28][C:19]4[CH:20]=[CH:21][C:22]([C:24]([F:26])([F:25])[F:27])=[CH:23][C:18]=4[Cl:17])=[CH:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc2oc(CN3CCCC3)nc2c1
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(C(F)(F)F)cc1Cl)Nc1ccc2oc(CN3CCCC3)nc2c1

Procedure:
Prepared analogously to Example 2.3.f. from 0.2 g (0.92 mmol) of 2-pyrrolidin-1-ylmethylbenzoxazol-5-ylamine and 0.2 g (0.8 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 290 mg (81% of theory); C22H17ClF3N3O2 (M=447.84); melting point: 218° C.-223° C.; calc.: molecular ion peak (M+H)+: 448/450 (Cl); found: molecular ion peak (M+H)+: 448/450 (Cl); Rf value: 0.33 (silica gel, dichloromethane/methanol (19:1)).
Reaction SMILES: C(N(CC)CC)C.[C:8]([Cl:11])(Cl)=[O:9].[S:12]([N:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21])(=[O:15])(=[O:14])[NH2:13]>ClCCl>[Cl:11][C:8]([N:18]1[CH2:19][CH2:20][N:16]([S:12](=[O:15])(=[O:14])[NH2:13])[C:17]1=[O:21])=[O:9]
Reactant: NS(=O)(=O)N1CCNC1=O
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Reaction time: 17 h

Procedure:
A solution of 17.8 parts by vol. of triethylamine in 30 parts by vol. of dichloromethane was added dropwise over the course of 2 hrs. to a mixture of 100 parts by vol. of dichloromethane, 6.15 parts by vol. of (condensed) phosgene and 7.0 parts by wt. of 1-sulphamyl-2-oxo-imidazolidine at 20° C and the mixture was then left to stand for 17 hrs. The precipitate present was removed by filtration, the filtrate was concentrated by evaporation in vacuo and the residue was repeatedly extracted with ethyl acetate at 20° C. The ethyl acetate extracts were combined. On evaporation, they left a hard varnish. The IR spectrum showed a strong acid chloride band at 1,805 cm-1 (Nujol). Furthermore, it could be seen from the IR spectrum that the substance still contained considerable amounts of the starting product.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20]([C:22]1[O:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]([C:22]1[O:26][CH:25]=[C:24]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:23]=1)=[O:21]
Reactant: CC1(C)OB(c2coc(C=O)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2coc(C=O)c2)C1
Temperature: 85 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.18 g, 3.60 mmol), 5-formylfuran-3-boronic acid pinacol ester (800 mg, 3.60 mmol), saturated aqueous sodium carbonate solution (15 ml), and tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.102 mmol) in ethylene glycol dimethyl ether (20 ml) was stirred under a nitrogen atmosphere at 85° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (900 mg, 72.6%) as an oil.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30](O)[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:36]2)=[CH:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30]([O:4][C:3](=[O:5])[C:2]([CH3:1])([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:6])[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[CH2:36]2)=[CH:23]1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(C)(Oc1ccccc1)C(=O)O
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)Oc3ccccc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 87.3 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 654 mg of 2-methyl-2-phenoxypropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.13 g of the title compound as a colorless foam.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5]C)=[O:4].[OH-].[K+:11]>CO.O>[CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O-:5])=[O:4].[K+:11]
Reactant: COC(=O)C(C)(C)CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(CO)C(=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
A solution of methyl 2,2-dimethyl-3-hydroxypropionate (25.0 g, 0.189 mol) in 100 mL of MeOH was treated with a solution of KOH (11.7 g, 0.208 mol) in 50 mL of H2O and the resulting mixture stirred at room temperature for 5 hours. The reaction mixture was heated under reflux for 30 minutes, methanol was distilled and the remaining solution shell frozen and lyophilized to give 26.7 g (90.6%) of potassium 2,2-dimethyl-3-hydroxypropionate as a white solid. The potassium salt (13.0 g, 0.083 mol) was suspended in 100 mL of dry DMF and chloromethylenebenzylether (14.3 g, 0.092 mol) was added. After stirring 48 hours at room temperature the mixture was quenched with 100 mL of H2O and extracted with Et2O (200 mL). The ether layer was separated, washed with H2O (3×100 mL), saturated NaCl (100 mL) and dried over MgSO4. Evaporation and distillation of the residue gave 13.6 g (73%) of benzyloxymethyl 2,2-dimethyl-3-hydroxypropionate as a clear liquid.