Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:37])[O:6][C@:7]1([C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@:28]([F:34])([C@@H:29]([OH:33])[CH2:30]2)[C@:26]2([CH3:27])[C:21](=[CH:22][C:23](=[O:35])[CH:24]=[CH:25]2)[CH2:20][CH2:19]3)[CH2:16][C@@H:15]1[CH3:36])[C:8](=[O:14])[CH2:9][O:10]C(=O)C)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO.CO.O>[CH2:1]([NH:4][C:5](=[O:37])[O:6][C@:7]1([C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@:28]([F:34])([C@@H:29]([OH:33])[CH2:30]2)[C@:26]2([CH3:27])[C:21](=[CH:22][C:23](=[O:35])[CH:24]=[CH:25]2)[CH2:20][CH2:19]3)[CH2:16][C@@H:15]1[CH3:36])[C:8](=[O:14])[CH2:9][OH:10])[CH2:2][CH3:3]
Reactant: CCCNC(=O)O[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCNC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
To a solution of (11β,16β)-21-(acetyloxy)-9-fluoro-11-hydroxy-16-methyl-3,20-dioxopregna-1,4-dien-17-yl propylcarbamate (8.5 mg, 0.016 mmol) in 0.3 mL of tetrahydrofuran and 0.1 mL of methanol was added 0.030 mL of a 0.1M solution of potassium carbonate in methanol/water (9:1). After 10 minutes at room temperature, the solution was partitioned between ethyl acetate and water and the organic layer was washed with water (twice) and brine and dried over Na2SO4. The solution was filtered and evaporated in vacuo to give an oil which was purified by preparative thin layer chromatography on silica gel, eluting with ethyl acetate/hexane/dichloromethane/methanol (3:3:3:1), to yield 4.6 mg of the title compound as a semi-solid.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.[CH2:87]([O:89][NH2:90])[CH3:88]>>[CH2:87]([O:89][NH:90][C:40]([C:35]1[CH:34]=[CH:33][C:32]2[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)[CH:3]([CH3:5])[CH3:4])[CH:31]=2)[CH:36]=1)=[O:41])[CH3:88]
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: CCON
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Product: CCONC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Yield: 77.4 %

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (1.77 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with O-ethylhydroxylamine hydrochloride (367 mg) in a similar manner as described in Example 24-(i) to give the titled compound (1.44 g) as a colorless powder.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:9]2[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=2[OH:23])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S([O-])(O)(=O)=O.[C:29]1([C:35]2[CH:40]=[CH:39][C:38]([N+:41]#[N:42])=[C:37]([N+:43]([O-:45])=[O:44])[CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C)C(C)=CC=CC=1>CO>[OH:23][C:10]1[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:14][C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:16])[CH3:17])=[CH:12][C:11]=1[N:42]=[N:41][C:38]1[CH:39]=[CH:40][C:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:36][C:37]=1[N+:43]([O-:45])=[O:44]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(-c2ccccc2)c1
Reactant: N#[N+]c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1C
Product: CC(C)(C)CC(C)(C)c1cc(N=Nc2ccc(-c3ccccc3)cc2[N+](=O)[O-])c(O)c(-c2ccccc2)c1
Reaction time: 2 h
Yield: 25.8 %

Procedure:
To a solution of sodium hydroxide (12 g, 0.3 mol) and 2-phenyl-4-tert-octylphenol (14.1 g, 0.05 mol) in 150 mL of methanol maintained at 0–5° C. is added portionwise over 1.25 hours 4-phenyl-2-nitrobenzenediazonium hydrogen sulfate (30.6 g, 0.065 mol), prepared in (C) above. The reaction mixture is stirred for two hours at 0–5° C. Xylene (200 mL) is added to the reaction mixture. The organic phase is separated and extracted with water (4×200 mL). The organic phase is filtered and the solvent removed by distillation under an atmosphere of nitrogen. The residue is purified by flash chromatography (90:10 heptane:ethyl acetate eluent) to give 6.56 g of the title compound as a viscous dark red liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:54]=[CH:53][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH2:23][N:24]([CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[C:25](=[O:44])[C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:43])[CH2:34][C:35]5[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=5)=[CH:28][CH:27]=4)=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:54]=[CH:53][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH2:23][N:24]([CH2:45][C:46]([OH:48])=[O:47])[C:25](=[O:44])[C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:43])[CH2:34][C:35]5[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=5)=[CH:28][CH:27]=4)=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(Cc2nc3cc(CN(CC(=O)OC(C)(C)C)C(=O)c4ccc(NC(=O)Cc5ccc(OC)cc5)cc4)ccc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(Cc2nc3cc(CN(CC(=O)O)C(=O)c4ccc(NC(=O)Cc5ccc(OC)cc5)cc4)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a stirring solution of tert-butyl 2-(N-((2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-49 (40 mg, 0.055 mmol) in DCM (2 mL) was added TFA (1 mL). After stirring at room temperature for 2 h, the solvents were concentrated and the residue purified by preparative HPLC to afford 15 mg (40%) of 2-(N-((2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetic acid 366 as a white powder. LCMS-ESI (m/z) calculated for C40H44N4O6: 676; found 677 [M+H]+, tR=6.77 min (Method 4). 1H NMR (400 MHz, DMSO) 12.82 (br s, 1H), 12.21 (br s, 1H), 10.29 (s, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.30-7.57 (m, 4H), 7.27-7.15 (m, 4H), 7.15-6.92 (m, 1H), 6.89-6.75 (m, 4H), 4.71 (s, 1H), 4.62 (s, 1H), 4.08 (s, 2H), 3.91 (m, 3H), 3.81-3.69 (m, 4H), 3.57 (s, 2H), 1.73-1.61 (m, 2H), 1.43-1.20 (m, 8H), 0.90-0.80 (m, 3H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]2[C:15]([CH3:20])=[C:16]([CH2:18]O)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[CH2:21]([SH:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]2[C:15]([CH3:20])=[C:16]([CH2:18][S:29][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:2])[CH3:3]
Reactant: Cc1c(CO)oc2cccc(OCCCNC(C)C)c12
Reactant: SCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(CSCCc2ccccc2)oc2cccc(OCCCNC(C)C)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
To a solution of [4-(3-isopropylamino-propoxy)-3-methyl-benzofuran-2-yl]-methanol (14 mg, 0.05 mmol) and phenethyl mercaptan (10.3 mg, 0.075 mmol) in anhydrous CH2Cl2 (0.9 ml) was added TFA (0.2 ml). The Mixture was stirred at room temperature for 2.5 hours. The solvent was removed in vacuo. The residue was purified over preparative TLC (CH2Cl2/MeOH=100/1) to give desired compound (15 mg, 74%). FAB-MS: m/z 398 (MH+); 1H-NMR (CDCl3): δ 1.11 (6H, d, J=6.2 Hz), 2.05 (2H, m), 2.34 (3H, s), 2.61-2.96 (7H, m), 3.80 (2H, s), 4.11 (2H, m), 6.56 (1H, m), 6.95-7.28 (7H, m).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[C:17]([O:16][C:14](=[O:15])[NH:13][C@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([Br:12])=[CH:10][CH:11]=1)[CH:3]=[O:2])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Next, to a solution of (R)-3-(4-bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (1.0 g, 2.79 mmol) in DCM (20 mL) is added DIBAL-H (4.85 mL, 1.0M in DCM) slowly by using syringe pump at −78° C. After the addition is complete the reaction is quenched by adding EtOAc and the mixture is warmed to room temperature. Then a saturated sodium potassium tartaric acid is added and the mixture is and stirred at room temperature for 1 hour. The organic phase is separated and the aqueous layer is extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give [(R)-1-(4-bromo-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester which is used directly in the next reaction.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH:10]=[CH:9]1>O1CCCC1>[SH:1][C:2]1[S:3][C:4]([S:7][CH:10]2[CH2:9][C:8](=[O:14])[O:13][C:11]2=[O:12])=[N:5][N:6]=1
Reactant: Sc1nnc(S)s1
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: O=C1CC(Sc2nnc(S)s2)C(=O)O1

Procedure:
A mixture of 95 grams (0.5 moles) of 2,5-dimercapto-1,3,4-thiadiazole and 49.0 grams (0.5 moles) of maleic anhydride in 500 ml. tetrahydrofuran was refluxed for six hours. After distilling off the solvent, a light tan solid (123 g.) was obtained (m.p. 194°-196° C.). Its infrared spectrum and elemental analysis appeared to be consistent with the proposed structure.
Reaction SMILES: [OH:1][C@H:2]([CH2:35][OH:36])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].[CH:37]([Si:40](Cl)([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])([CH3:39])[CH3:38].C(N(CC)CC)C.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:1][C@H:2]([CH2:35][O:36][Si:40]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:37]([CH3:39])[CH3:38])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][Si:19]([CH:23]([CH3:24])[CH3:25])([CH:26]([CH3:27])[CH3:28])[CH:20]([CH3:21])[CH3:22])[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)NC[C@H](O)CO[Si](C(C)C)(C(C)C)C(C)C)[nH]2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.1 %

Procedure:
N-[(2S)-2,3-Dihydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxamide (9.30 g, 17.9 mmol) synthesized in Example (125d) was dissolved in methylene chloride (180 mL), and triisopropylsilyl chloride (4.25 mL, 19.9 mmol), triethylamine (7.45 mL, 53.5 mmol) and 4-dimethylaminopyridine (2.20 g, 18.0 mmol) were added, followed by stirring at room temperature for 2.5 hours under nitrogen atmosphere. Water (300 mL) was added to separate the solution, and the organic layer was washed with saturated brine and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-35%) to afford the desired compound (10.56 g, yield 87%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Reactant: CS(=O)(=O)NCc1cccc(Nc2cc(Cl)ncn2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CS(=O)(=O)NCc1cccc(Nc2cc(-c3ccccc3OCc3ccccc3)ncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
219 mg N-[3-(6-Chloro-pyrimidin-4-ylamino)-benzyl]-methanesulfonamide (prepared in Example 1) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 228 mg 2-benzyloxyphenyl-boronic acid (1 mmol), 318 mg anhydrous Na2CO3 (3 mmol) and 6 ml water was added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (127 mg, 40% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: C1(O)C=CC=CC=1.[CH2:8]([O:15][CH2:16][CH2:17]Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:19][CH2:20][CH2:21]/[C:22](/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[C:23](\[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:8]([O:15][CH2:16][CH2:17][O:36][C:33]1[CH:32]=[CH:31][C:30](/[C:23](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:22](/[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)\[CH2:21][CH2:20][OH:19])=[CH:35][CH:34]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCOCc1ccccc1
Reactant: OCC/C(=C(/c1ccccc1)c1ccc(O)cc1)c1ccccc1
Solvent: Oc1ccccc1
Product: OCC/C(=C(/c1ccccc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1

Procedure:
The alkylation of the starting phenol with benzyl-(2-bromoethyl)ether was carried out as described in Example 1 of the International Patent Application WO 96/07402 with the exception that now the starting compound was the other geometric isomer, E-4-(4-hydroxy-1,2-diphenyl-but-1-enyl)-phenol which was prepared by the method described in U.S. Pat. No. 4,996,225. The product was extracted to toluene. The toluene phases were combined, washed with water, dried and evaporated to dryness. The residue was recrystallized from a minor quantity of toluene and the precipitated product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[O:13])[C:9]([OH:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2>N1CCCCC1>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([Cl:22])[CH:19]=1)[CH2:15][NH:14][C:12]([C:10]1[C:9]([OH:24])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([N:7]2[CH2:8][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:11]=1)=[O:13]
Reactant: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Cl)c2cccnc2c1O
Solvent: C1CCNCC1
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(N2CCCCC2)c2cccnc2c1O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of the chloride from Example 44 Step 5 (40 mg, 0.105 mmol) in piperidine (0.5 ml) was heated at 100 C. for 36 hrs under argon. The resulting solution was cooled to room temperature and the solvent evaporated in vacuo. The residue was dissolved in hot DMF (0.7 ml) and purified by preparative HPLC. (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: O.C([O-])([O-])=O.[K+].[K+].[CH2:8]([C@@:15]12[CH2:28][CH2:27][C:26]([O:29]CC)=[CH:25][C:24]1=[CH:23][CH2:22][C:21]1[CH:20]=[C:19]([C:32]#[N:33])[CH:18]=[CH:17][C:16]2=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H][H]>C1COCC1.CCOC(C)=O>[CH2:8]([C@@:15]12[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][C@H:24]1[CH2:23][CH2:22][C:21]1[CH:20]=[C:19]([C:32]#[N:33])[CH:18]=[CH:17][C:16]2=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC1=CC2=CCc3cc(C#N)ccc3[C@]2(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)CC[C@@H]1CC(=O)CC[C@@]21Cc1ccccc1
Reaction time: 5 h
Yield: 56 %

Procedure:
To a solution of water wet 5% palladium on carbon (7.0 grams) and K2CO3 (7.0 g) in THF (100 mL) was added 4b(S)-Benzyl-7-ethoxy-4b,5,6,10-tetrahydro-phenanthrene-2-carbonitrile (35.0 g, 103 mmol) in tetrahydrofuran (600 mL). The resulting slurry was transferred to a 1 L hydrogenator with overhead stirring under 50 psi of hydrogen. After 5 hours no starting material could be detected by HPLC and the reaction mixture was filtered through a pad of Celite. The filtrate was diluted with 1N hydrochloric acid (70 mL) and after standing for 1 hour no vinyl ether could be detected by HPLC. The solution was diluted with EtOAc (700 mL), water (700 mL) and brine (100 mL) and phases were separated. The organic was washed with water (700 mL) and brine (700 mL). The organic was concentrated under reduced pressure to approximately 500 mL and EtOAc (500 mL) was added and the solution concentrated again to approximately 300 mL. To the vigorously stirring solution were added hexanes (1 L) in one portion. The resulting solids were allowed to granulate for 1 hour and then filtered. HPLC showed some impurities so the solids were allowed to granulate in hexanes (75 mL) and EtOAc (25 mL) for 24 hours. The solids were filtered and allowed to air dry. The mother liquor was concentrated to give orange solids, which were granulated in EtOAc (15 mL) and hexanes (85 mL) for 24 hours. The solids were filtered and combined with the first crop. After air drying overnight a white solid was collected: 18 grams (57.1 mmol), 56% yield; mp 128-129° C.; IR (film) ν 2226, 1713 cm−1; [α]25D−252.50; 1H NMR (CDCl3) δ 7.43 (s, 1H), 7.21-7.08 (m, 4H), 6.58 (d, 2H, J=7.1 Hz), 6.40 (d, 1H, J=7.9 Hz), 3.21 (d, 1H, J=13.3 Hz), 3.13-2.97 (m, 2H), 2.85 (ddd, 1H, J=14.9, 14.9, 6.2 Hz), 2.80 (d, 1H, J=14.1 Hz), 2.66-2.51 (m,2H), 2.60 (d, 1H, J=14.1 Hz), 2.45-2.40 (m, 1H), 2.24-2.16 (m, 1H), 2.09-1.98 (m, 1H), 1.83-1.76 (m, 1H), 1.61 (dd, 1H, J=14.1, 14.1, 5.4 Hz); 13C NMR (CDCl3) δ 210.1, 147.6, 137.3, 136.5, 133.1, 130.9, 128.4, 128.1, 128.0, 127.0, 119.3, 110.4, 44.5, 42.7, 40.7, 38.2, 36.2, 33.0, 28.0, 24.7. Anal. Calcd for C22H2, NO: C, 83.77; H, 6.71; N, 4.44. Found: C, 83.76; H, 6.90; N, 4.40. The structure and absolute configuration were confirmed by single crystal X-ray analysis.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[CH3:11][C:12]1([CH3:24])[CH2:17][O:16][C:15]2([CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[O:14][CH2:13]1>>[CH3:11][C:12]1([CH3:24])[CH2:13][O:14][C:15]2([CH2:18][CH2:19][CH:20]([O:23][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=3[O:9][CH3:10])[CH2:21][CH2:22]2)[O:16][CH2:17]1
Reactant: COc1c(Cl)ccnc1C
Reactant: CC1(C)COC2(CCC(O)CC2)OC1
Product: COc1c(OC2CCC3(CC2)OCC(C)(C)CO3)ccnc1C
Yield: 75 %

Procedure:
Preparation was carried out analogously to Example 43 from 4-chloro-3-methoxy-2-methylpyridine and 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-ol. Yield: 75%; M.p.: 90° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[N:24][CH:23]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[S:26][C:22]([CH3:21])=[CH:23][N:24]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.89 min.; [M+H]+: 423.09 g/mol.
Reaction SMILES: C[O:2][CH:3]([O:23]C)[CH:4]([CH3:22])[N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.S(=O)(=O)(O)O>C(O)(=O)C.O>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[N:6][N:5]([CH:4]([CH3:22])[C:3]([OH:23])=[O:2])[C:9]=2[CH:10]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(OC)C(C)n1nnc2ccc(OCc3ccccc3)cc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)n1nnc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C

Procedure:
A solution of 6-(benzyloxy)-α-methyl-1H-benzotriazole-1-acetaldehyde dimethyl acetal (95 g, 0.272 mole) and concentrated sulfuric acid (20 ml) in acetic acid and water is heated at 72° C. for 20 hours, cooled to room temperature and concentrated in vacuo. The concentrated solution is diluted with acetone and water and treated with KMnO4 (140 g) in portions over a three hour period at 18°-30° C. with stirring.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Cl:15][CH:16]([Cl:20])[C:17](Cl)=[O:18]>>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:17](=[O:18])[CH:16]([Cl:20])[Cl:15])=[CH:10][CH:9]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)C(Cl)Cl
Product: O=C(Nc1ccc(Nc2ccccc2)cc1)C(Cl)Cl

Procedure:
This compound is prepared from 4-aminodiphenylamine (36.8 g) in the same manner as Compound 1, except that dichloroacetyl chloride (29.8 g) is used in place of trichloroacetyl chloride. The product is recrystallized from benzene. The m.p. and chemical analysis are reported in Table I.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C([O-])=O)=O)([CH3:4])([CH3:3])[CH3:2].[NH:12]1[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C1COCC1>[C:1]([O:5][C:6]([N:12]1[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[CH2:13]1)=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C(O)C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A mixture of t-butyldicarbonate (21.15 g) and THF (170 ml) was added under ice cooling to a mixture of azetidine-3-carboxylic acid (9.80 g), potassium carbonate (26.8 g) and water (150 ml). After stirring the reaction mixture at room temperature for 20 hours, the mixture was adjusted to pH 4 using 2 mol/L hydrochloric acid, extracted with chloroform, the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was crystallized with a mixed solution of hexane and ethyl acetate to obtain 19.5 g of 1-(t-butoxycarbonyl)azetidine-3-carboxylic acid.