Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC.[CH:3]1([C@H:6]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[O:22][C:23](=[S:26])[NH:24][N:25]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH3:7])[CH2:5][CH2:4]1.[CH2:27](N(CC)CC)C>CCO>[CH:3]1([C@H:6]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[O:22][C:23]([S:26][CH3:27])=[N:24][N:25]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH3:7])[CH2:5][CH2:4]1
Reactant: CCN(CC)CC
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3n[nH]c(=S)o3)cc12)C1CC1
Solvent: CCO
Solvent: CI
Product: CSc1nnc(-c2cc3c(N[C@H](C)C4CC4)c(C(N)=O)cnn3c2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
Iodomethane (0.069 ml, 1.111 mmol) was added in one portion to a stirred solution of (R)-4-(1-cyclopropylethylamino)-6-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 126, 306 mg, 0.889 mmol) and triethylamine (0.310 ml, 2.221 mmol) in absolute EtOH (3.55 ml). The reaction mixture was allowed to stir at rt for 2 hrs before evaporating in vacuo. The residue was then partitioned between 1N HCl and ethyl acetate. The organic layer was dried (MgSO4) and evaporated in vacuo. The residue was treated with MeOH and the solid filtered to give the title compound (135 mg, 0.377 mmol, 42.4% yield) as a white solid. The filtrate (which contained the remainder of the product) was evaporated and retained. HPLC (condition B): retention time=3.98 min. LCMS (condition B): MH+ m/z 358.9. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.88 (1 H, d, J=8.32 Hz), 8.31 (1 H, s), 8.27 (1 H, d, J=1.66 Hz), 7.32 (1 H, d, J=1.94 Hz), 3.89-4.04 (1 H, m), 3.30 (3 H, s), 1.34 (3 H, d, J=6.38 Hz), 1.01-1.20 (1 H, m), 0.44-0.58 (2 H, m), 0.35-0.44 (1 H, m), 0.20-0.35 (1 H, m).
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].NC1C=C2C(=CC=1)C(=O)OC2.[I:38]C1C=CC(C(C)(C)CC(=O)C(O)=O)=CC=1>>[I:38][C:21]1[CH:22]=[CH:23][C:18]([C:16]([CH3:24])([CH3:17])[CH2:15][C:14](=[O:25])[C:13]([NH:12][C:11]2[CH:2]=[C:3]3[C:8](=[CH:9][CH:10]=2)[C:6](=[O:7])[O:5][CH2:4]3)=[O:26])=[CH:19][CH:20]=1
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Reactant: CC(C)(CC(=O)C(=O)O)c1ccc(I)cc1
Agent: Nc1ccc2c(c1)COC2=O
Product: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1)COC2=O)c1ccc(I)cc1

Procedure:
was obtained analogously to the process that is described for 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroylamino)-phthalide from 5-aminophthalide and 4-(4-iodophenyl)-4-methyl-2-oxo-valeric acid as an oil.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C(OOCC1C=CC=CC=1)C1C=CC=CC=1.[CH3:25][C:26]1[C:30]2[CH:31]=[CH:32][C:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[CH:34][C:29]=2[O:28][N:27]=1>C(Cl)(Cl)(Cl)Cl>[Br:8][CH2:25][C:26]1[C:30]2[CH:31]=[CH:32][C:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[CH:34][C:29]=2[O:28][N:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1noc2cc(O[Si](C)(C)C(C)(C)C)ccc12
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(CBr)noc2c1

Procedure:
NBS (12.7 g, 71.5 mmoles) and benzyl peroxide (1.6 g, 6.5 mmoles) were added to a mixture of 3-methyl-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazole (17.1 g, 65 mmoles) and CCl4 (200 ml). The mixture was refluxed overnight and the precipitate was filtered, washed with CCl4 and purified by flash chromatography (AcOEt/Toluene 1/9 with 0.1% TEA) to give
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][NH:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]([NH2:27])=[N:21][C:22]([NH2:26])=[N:23][C:24]=3[CH3:25])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[NH2:26][C:22]1[N:21]=[C:20]([NH2:27])[C:19]([N:16]2[CH2:15][CH2:14][N:13]([C:10]3[CH:9]=[CH:8][C:7]([C:6]([NH:5][CH2:4][C:3]([OH:29])=[O:2])=[O:28])=[CH:12][CH:11]=3)[CH2:18][CH2:17]2)=[C:24]([CH3:25])[N:23]=1
Reactant: COC(=O)CNC(=O)c1ccc(N2CCN(c3c(C)nc(N)nc3N)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)NCC(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1.5 g (3.76 mmole) of N-[4-[4-(2,4-diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl]benzoylglycine methyl ester and 3.8 ml (3.8 mmole of a 1N aqueous sodium hydroxide solution in 500 ml of methanol was stirred at room temperature for 16 hours. The reaction mixture remained cloudy. A solution of 0.4 ml of 1N sodium hydroxide in 200 ml of methanol was added and the reaction mixture was stirred for another two hours and became clear solution. Methanol was removed in vacuo. The solid residue was dissolved in 200 ml of water and filtered. The filtrate was acidified with citric acid to pH 6. The precipitate was collected, washed with water, and triturated with 200 ml of boiling methanol. After drying in vacuo at 78° C. for 16 hours, 1.30 g of the product was obtained as white powder, mp>310° C.
Reaction SMILES: [SH:1][CH2:2][C:3]1([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.S(=O)(=O)(O)O.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(OCC)C>C(O)(=O)C>[C:24]([S:1][CH2:2][C:3]1([C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)(=[O:26])[CH3:25]
Reactant: O=C(O)CNC(=O)C1(CS)Cc2ccccc2C1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(=O)SCC1(C(=O)NCC(=O)O)Cc2ccccc2C1

Procedure:
Mix N-[[2-(mercaptomethyl)-2,3-dihydro-1H-indene-2-yl]carbonyl]-glycine (17.8 g, 67.2 mmol) and sulfuric acid (0.3 mL of a 10% solution in acetic acid). Add acetic anhydride (6.34 mL, 67.2 mmol) over 10 minutes. Allow to cool, pour into ethyl ether and wash with water three times. Separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][OH:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31]>>[CH3:26][C:23]1[C:22]([CH2:27][O:28][CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CC(Br)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CO)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COC(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 45, Step 2, using 1-[4′-(4-hydroxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (1-bromo-ethyl)-benzene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[C:4]([Cl:17])[N:3]=1.C(N(C(C)C)CC)(C)C.[C:27]1([C:33]2[CH:37]=[C:36]([CH2:38][NH2:39])[O:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)CCC>[Cl:17][C:4]1[N:3]=[C:2]([NH:39][CH2:38][C:36]2[O:35][N:34]=[C:33]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:37]=2)[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=1
Reactant: NCc1cc(-c2ccccc2)no1
Reactant: Clc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2cc(-c3ccccc3)no2)n1
Temperature: 90 °C
Reaction time: 30 h
Yield: 60.9 %

Procedure:
To a solution of 2,6-dichloropyrimidin-4-yl-(5-cyclopropyl-1H-pyrazol-3-yl)-amine (19.3 g, 71.7 mmol) in 1-butanol (200 mL) was added diisopropylethylamine (23.7 mL, 143 mmol) and 3-phenylisoxazol-5-ylmethylamine (15.0 g, 86.1 mmol). The mixture was stirred at 90° C. for 30 h, then concentrated on a rotary evaporator. The residue was taken up in 100 mL of methanol and boiled until the volume reached around 50 mL. The solution was allowed to cool to room temperature and then placed in the refrigerator overnight. The solid that formed was collected by filtration, while the filtrate was dissolved in dichloromethane and sonicated. The solid that formed was collected and combined with the first recrystallized crop to give the desired product (17.8 g, 61%) as a white solid.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B.Cl>C1COCC1>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:29]=[CH:28][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COCCOCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COCCOCOc1cc2ccc(-c3ccc(CO)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 40 °C

Procedure:
3 g (6.1 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid and 40 ml of THF were introduced into a three-necked flask under a stream of nitrogen. 20 ml of a solution of borane (1M in THF) were added dropwise and the reaction mixture was heated at 40° C. for one hour. The reaction mixture was poured into a 1N hydrochloric acid solution and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:20]([O:22]CC)=[O:21])[CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:20]([OH:22])=[O:21])[CH:16]=[N:17]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.8 %

Procedure:
To a solution of ethyl 7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate (Example 3, 150 mg, 0.44 mmol) in MeOH (0.7 mL) and THF (1.7 mL) was added LiOH (13 mg, 0.54 mmol) in H2O (1.7 mL). The reaction was stirred for 14 h at ambient temperature. The crude reaction mixture was concentrated to dryness under reduced pressure. 10% HCl (aq.) (6.0 mL) was added, and the precipitate was collected and dried under high pressure to afford the title compound as a white solid (106 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J=2.3 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H), 8.25 (s, 1H), 8.03 (d, J=9.4 Hz, 1H), 7.63 (s, 1H), 7.58-7.41 (m, 4H), 5.37 (s, 2H). [M+H]=314.2.
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:29])([CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.O1CCOCC1.[NH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(Cl)Cl>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH3:2][Si:3]([CH3:29])([CH3:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](=[O:24])[NH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:21][CH:20]=1
Reactant: CCOC(=O)CN
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 20 g. 4-[14-(trimethylsilyl)tetradecylamino]benzoyl chloride hydrochloride in 100 ml. dioxane is added to 4.9 g. freshly prepared ethyl glycinate in 300 ml. of methylene chloride containing 1 g. of 4-(dimethylamino)pyridine and 10 ml. of triethylamine. After 16 hours at room temperature the reaction is refluxed for 2 hours, cooled and filtered. The mother liquor is extracted with water and 10% hydrochloric acid. The solution is dried and concentrated in vacuo to an amber liquid. A sample is chromatographed on silica, appropriate fractions are pooled and evaporated to yield a solid which is recrystallized to a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH:17]([CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].Cl>[OH-].[Na+]>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1)[O:13][CH:17]([CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(Br)CCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(CCCCCCCCCC(=O)O)Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 255.2 %

Procedure:
3,5-Bis(trifluoromethyl) phenol (20.6 g) was dissolved in 1N sodium hydroxide (270 mL). The solution was refluxed under heating for 10 hours. Further, the solution was added with 11-bromododecanoic acid (4.7 g). After the reflux under heating was continued, the reaction solution was left to be cooled. The reaction solution was added with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed. The resulting crystals was washed with hexane and purified by silica gel column chromatography to obtain 11-(3,5-Bis(trifluoromethyl) phenoxy)dodecanoic acid (18.4 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)=[CH:4][CH:3]=1.[C:17]1([C:23]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:25][N:24]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:27]=3)[CH2:29][CH2:30]2)=[O:16])=[CH:4][CH:3]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1
Yield: 32.3 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (6-aminopyridin-3-yl)carbamate (210 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 90.8 mg (32.3%) of the desired product as a solid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[C:21]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]4[C:37]([F:38])=[CH:36][C:35]([C:39]([OH:42])([CH3:41])[CH3:40])=[CH:34][C:33]=4[F:43])[N:26]=3)=[O:24])=[CH:20][N:19]=[C:18]3[O:44][CH2:45][CH2:46][C:17]=23)[CH2:11][C@H:10]1[NH:47]C(=O)OC(C)(C)C)(C(C)(C)C)(C)C.Cl.O1CCOCC1>>[NH2:47][C@H:10]1[C@H:9]([OH:8])[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[C:21]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]4[C:33]([F:43])=[CH:34][C:35]([C:39]([OH:42])([CH3:40])[CH3:41])=[CH:36][C:37]=4[F:38])[N:26]=3)=[O:24])=[CH:20][N:19]=[C:18]3[O:44][CH2:45][CH2:46][C:17]=23)[CH2:11]1
Reactant: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(C(C)(C)O)cc4F)n3)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(C(C)(C)O)cc4F)n3)cnc3c2CCO3)C[C@@H](N)[C@@H]1O

Procedure:
The amide intermediate prepared as described above was treated with 4.0 M HCl in dioxane (8 mL, 30 mmol) at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to give the title compound as a white powder. LCMS calc. for C28H31F3N5O4 (M+H)+ m/z=558.2. found: 558.0. 1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.69 (s, 1H), 8.32 (m, 1H), 8.16 (m, 1H), 7.32 (d, J=9.0 Hz, 2H), 5.27 (br s, 1H), 4.49 (m, 3H), 3.05 (m, 1H), 2.96 (m, 1H), 2.66-2.42 (m, 5H), 1.47 (s, 6H), 0.68 (d, J=6.6 Hz, 3H) ppm.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[S:6](Cl)(Cl)=[O:7]>O1CCCC1>[S:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:7]
Reactant: c1c[nH]cn1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=S(c1ncc[nH]1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Imidazole (43.2 g, 635 mmol) was dissolved in tetrahydrofuran (100 ml), and under ice cooling, thionyl chloride (23.5 g, 199 mmol) was added thereto. The reaction mixture was stirred for 3 hours at room temperature, and then the salt thus produced was separated by filtration. Thus, a sulfinyldiimidazole solution was obtained.
Reaction SMILES: [OH:1][C@:2]1([C:14]2[S:15][C:16]([C:19]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21]([CH2:28][OH:29])[CH:20]=3)=[CH:17][N:18]=2)[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH3:13])([CH3:12])[CH2:3]1.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)CC)C>ClCCl>[C:30]([O:29][CH2:28][C:21]1[CH:20]=[C:19]([C:16]2[S:15][C:14]([C@@:2]3([OH:1])[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH3:13])([CH3:12])[CH2:3]3)=[N:18][CH:17]=2)[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CO)cc([N+](=O)[O-])c3)s2)CC1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(COC(C)=O)cc([N+](=O)[O-])c3)s2)CC1(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
To a solution of the product of Step 4 (194 mg, 0.46 mmol) dissolved in dichloromethane (1.8 mL) at −20° C. was added acetyl chloride (34 μL, 0.48 mmol) and triethylamine (129 μL, 0.92 mmol). The reaction was warmed to room temperature and stirred for 2.5 h. The reaction was quenched with saturated aqueous sodium bicarbonate, and extracted with dichloromethane (3×). The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and concentrated to afford methyl(1S,4R)-4-(5-{3-[(acetyloxy)methyl]-5-nitrophenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (203 mg, 0.39 mmol, 86% yield) as a yellow foam. MS ESI: [M+H]+ m/z 463.1.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:34])[C:21]([CH3:33])([CH2:30][CH2:31][CH3:32])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:33])([CH2:30][CH2:31][CH3:32])[C:20](=[O:34])[C:19]=1[C:14]1[NH:13][C:12]2[CH:35]=[CH:36][C:9]([OH:8])=[CH:10][C:11]=2[S:16](=[O:17])(=[O:18])[N:15]=1
Reactant: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.8 %

Procedure:
A solution of Example 26G (1.44 g, 2.87 mmol) in tetrahydrofuran (40 mL) was treated with 10% palladium on carbon (0.145 g, 10% weight) and stirred at 25° C. under a hydrogen balloon for 72 hours. The vessel was purged with nitrogen gas and the mixture was filtered through celite. The filtrate was concentrated in vacuo to give the title compound (0.732 g, 62%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.63 (m, 4 H) 0.89 (m, 1 H) 1.57 (m, 3 H) 2.01 (m, 1 H) 2.19 (m, 1 H) 7.17 (m, 2 H) 7.55 (m, 2 H) 7.75 (m, 2 H) 8.15 (m, 1 H) 10.37 (m, 1 H) 13.71 (m, 1 H). MS (ESI−) m/z 411 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:13][C:12]2([C:17]([OH:19])=O)[CH2:14][CH2:15][CH2:16][CH:11]2[C:10]1=[O:20].C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[F:35][C:36]([F:49])([F:48])[C:37]1[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[NH2:40]>C1COCC1>[F:35][C:36]([F:48])([F:49])[C:37]1[CH:38]=[C:39]([NH:40][C:17]([C:12]23[CH2:14][CH2:15][CH2:16][CH:11]2[C:10](=[O:20])[N:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH2:13]3)=[O:19])[CH:41]=[C:42]([C:44]([F:45])([F:47])[F:46])[CH:43]=1
Reactant: Cc1cccc(C)c1N1CC2(C(=O)O)CCCC2C1=O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1N1CC2(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCCC2C1=O
Temperature: 75 °C
Yield: 55 %

Procedure:
To a solution of 2-(2,6-dimethylphenyl)-1-oxooctahydrocyclopenta[c]pyrrole-3a-carboxylic acid (86 mg, 0.3 mmol) and diisopropylethyl amine (104 μL, 0.6 mmol) in THF, methanesulfonyl chloride (32 μL, 0.4 mmol) was added. The mixture was treated with 3,5-bis(trifluoromethyl)aniline (137 mg, 0.6 mmol) and heated at 75° C. for 3 h. After evaporating the solvent, the crude product was applied on C18 preparative HPLC column and eluted with acetonitrile/water solvent system (5-80% acetonitrile gradient with 0.1% TFA). After neutralization and solvent evaporation of the combined product containing fractions, 80 mg of N-(3,5-bis(trifluoromethyl)phenyl)-2-(2,6-dimethylphenyl)-1-oxooctahydrocyclopenta[c]pyrrole-3a-carboxamide was obtained (53% yield). 1H NMR (400 MHz, CDCl3) 1.72-1.84 (m, 1H), 1.94-2.04 (m, 1H), 2.09 (s, 3H), 2.18 (s, 3H), 2.24-2.40 (m, 4H), 3.43 (d, 1H, J=11 Hz), 3.52-3.58 (m, 1H, 4.06 (d, 1H, J=11 Hz), 7.00-7.17 (m, 3H), 7.61 (s, 1H) 8.13 (s, 2H), 8.61 (s, 1H). LC-MS: Rt (retention time)=2.99 min, MS: (ES) m/z 485 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O.CO>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1ccccc1N

Procedure:
The appropriate 2-nitrobenzoic acid was initially reacted in analogy to general methods 2 and 5 with the particular amine to give a 2-nitrobenzamide. Subsequently, 4 mmol of the 2-nitrobenzamide were hydrogenated in 50 ml of THF and 50 ml of methanol in the presence of a spatula tip of 10% palladium on carbon at RT under atmospheric pressure. The catalyst was filtered off with suction, the reaction mixture was concentrated, and the appropriate 2-aminobenzamide was obtained.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH:10]([OH:13])[CH2:11][CH3:12])=[C:8]([OH:14])[CH:7]=[C:6]([CH3:15])[C:3]=1[CH:4]=[O:5].O[C:17]1[C:24]([CH:25](O)[CH2:26][CH2:27][CH2:28][CH3:29])=C(O)C=C(C)[C:18]=1[CH:19]=O.OC1C(C(O)CCCCCC)=C(O)C=C(C)C=1C=O.OC1C(C(O)CCCCCCCC)=C(O)C=C(C)C=1C=O.OC1C(C(O)CCCCCCCCC)=C(O)C=C(C)C=1C=O>>[OH:1][C:2]1[C:9]([CH:10]([OH:13])[CH2:11][CH2:12][CH2:19][CH2:18][CH2:17][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:8]([OH:14])[CH:7]=[C:6]([CH3:15])[C:3]=1[CH:4]=[O:5]
Reactant: CCCCC(O)c1c(O)cc(C)c(C=O)c1O
Reactant: CCC(O)c1c(O)cc(C)c(C=O)c1O
Agent: CCCCCCC(O)c1c(O)cc(C)c(C=O)c1O
Agent: CCCCCCCCC(O)c1c(O)cc(C)c(C=O)c1O
Agent: CCCCCCCCCC(O)c1c(O)cc(C)c(C=O)c1O
Product: CCCCCCCCCCCC(O)c1c(O)cc(C)c(C=O)c1O

Procedure:
In addition to this compound, 2,4-dihydroxy-3-(1-hydroxypropyl)-6-methylbenzaldehyde (195-3), 2,4-dihydroxy-3-(1-hydroxypentyl)-6-methylbenzaldehyde (195-5), 2,4-dihydroxy-3-(1-hydroxyheptyl)-6-methylbenzaldehyde (195-7), 2,4-dihydroxy-3-(1-hydroxynonyl)-6-methylbenzaldehyde (195-9) and 2,4-dihydroxy-3-(1-hydroxydecyl)-6-methylbenzaldehyde (195-10) were synthesized by the same reaction with the use of respective corresponding starting raw materials.